·      THYMUS:


·      SPLEEN:


·       PATHOLOGY:  CLASSIFICATION OF HEMATOLOGIG DISEASES:  CHANT (Yes! You will be CHANT-ing how I’ve made this complex subject easier to deal with) → C-clonal hematopoietic disorders (these are your neoplastic proliferations), H-hemostasis disorders, which consist of H-hemorrhagic diathesis (aka coagulopathy), H-ereditary H-hypercoagulable states (aka hereditary thrombophilia), A-anemia, N-non-neoplastic deficiencies or proliferation of hematopoietic cell, T-transfusion reactions, T-transplant medincine.

·       CLONAL HEMATOPOIETIC DISORDER:  CLASSIFICATION OF CLONAL HEMATOPOIETIC DISORDER:  H-hot LAMP → H-histiocytic disorders, L-lymphomas, A-acute leukemia (chronic leukemia is included in other categories), M-myeloproliferative disorders, M-myelodysplastic syndromes, M-mast cell disorders (mastocytosis), P-plasma cell dyscrasias (e.g. multiple myeloma).




o   CLASSIFICATION OF NON-LANGERHANS CELL HISTIOCYTOSES:  H-high S-school JunioR = HS JR (patient are usually less than this age) → H-hemophagocytic lymphohistiocytosis (HLH, both familial and reactive types), S-sinus histiocytosis with massive lymphadenopathy (SHML aka Rosai-Dorfman disease), J-juvenile xanthogranuloma (JXG), R-reticulohistiocytoma

·       CLASSIFICATION OF LYMPHOMA:  HODGKIN’S LYMPHOMA (lymphomas containing Reed-Sternberg cells and NON-HODGKIN’S LYMPHOMA (all other lymphomas; B-cell, T-cell & NK-cell).

·       CLASSIFICATION OF ACUTE LEUKEMIA:  I) Acute lymphoblastic leukemias (ALL) and II) Acute myelogenous leukemias (AML)






·       MYELODYSPLASTIC SYNDROME (aka preleukemia): 



·       MULTIPLE MYELOMA (MM aka plasma cell myeloma or as Kahler's disease)



·       HEMOSTASIS DISORDERS: Classified into Hemorrhagic diathesis and Hereditary hypercoagulable states (thrombophilia)


        I.     DISORDER OF PLATELETS: TYPES:  HIT G-giant V-volleyB-ball = HIT (quantitative disorder due to ↓ platelet number) GB (qualitative disorder due to defective platelet function) → H-HIT (heparin-induced thrombocytopenia), H-HUS (hemolytic uremic syndrome), H-HELLP (H-hemolytic anemia, E-elevated L-liver enzymes, L-low P-platelets) syndrome, I-ITP (idiopathic thrombocytopenic purpura), T-TTP (thrombotic thrombocytopenic purpura), G-glanzmann’s thrombasthenia (deficiency of GpIIb/IIIa → defective platelet aGGregation), V-von Willebrand disease, B-bernard-soulier syndrome (deficiency of GpIb/IX → defective platelet adhesion).

      II.     DISORDERS OF COAGULATION FACTORS:  Usually manifest as deeper bleeding involving the joints (hemarthrosis) and body cavities (hemoperitoneum).  PT and aPTT are elevated.  TYPES:  Hemophilia A, Hemophilia B, and Hemophilia C (hereditary), and DIC (acquired).

·       HEREDITARY HYPERCOAGULABLE STATES (aka thrombophilia):  Hereditary propensity to develop thrombosis due to an abnormality in the coagulation system.

·       TYPES OF HEREDITARY THROMBOPHILIA:  F-feel M-my A-ass P-please = FMAP → F-FVL (20-60%), M-MTHFR mutation, A-antiphospholipid antibodies syndrome, A-antithrombin III deficiency (1-4%), P-prothrombin G20210A mutation (5-15%), P-protein C or S deficiency (total 4-10%), P-PNH-paroxymal nocturnal hemoglobinuria, P-plasminogen disorder

·       ANEMIA WITH ELEVATED CRCAHH! (imagine a bloody scream from blood loss) → A-acute blood loss, H-hemolytic anemia, H-hemophagocytic syndromes.

                   I.     ACQUIRED CAUSES OF HEMOLYTIC ANEMIA (Often due to defects of the extraerythrocytic environment such as auto-antibodies): SIM → S-splenomegaly (e.g. from cirrhosis, CHF, amyloidosis, sarcoidosis…), I-infection (e.g. malaria, babesiosis), I-immune-mediated (autoimmune or alloimmune factors), M-microangiopathic hemolytic anemia (MAHA).

                 II.     HEREDITARY CAUSES OF HEMOLYTIC ANEMIA (Often due to defects in the RBCs, i.e. intraerythrocytic factors): HEMoglobin = HEM → H-hemoglobin disorders, E-enzyme defect, M-membrane defects

·       ANEMIA WITH REDUCED CRC: HALF, M.D. CHARMS CLITS  HALF, M.D. (macrocytic anemia MCV > 100 fL); CHARMS (normocytic anemia MCV 80-100 fL); CLITS (microcytic anemia MCV < 80 fL).

o   MACROCYTIC ANEMIA (MCV > 100 fL):  HALF, M.D. → H-hypothyroidism, A-alcoholism, L-liver disease, F-folate &/or Vit B12 deficiency, M-myelodysplastic syndrome, D-drugs (e.g. MTX, zidovudine inhibits DNA replication).

o   NORMOCYTIC ANEMIA (MCV 80-100 fL):  CHARMS → C-chronic disease anemia, H-hypothyroidism, A-aplastic anemia, R-renal failure-induced anemia, M-multiple myeloma, M-myelopthisis, S-sideroblastic anemia

o   MICROCYTIC ANEMIA (MCV < 80 fL):  CLITS → C-chronic disease anemia, L-lead poisoning, I-iron deficiency anemia, T-thalassemia, S-sideroblastic anemia 


·       ELEVATION OF HEMATOPOIETIC CELLS:  Leukocytosis, thrombocytosis, and erythrocytosis (see PRV). 


·       TYPES OF TRANSFUSION REACTION:  → T-TRALI (transfusion-associated acute lung injury), H-hemolytic reaction, I-infection, I-iron overload, V-volume overload, F-febrile non-hemolytic transfusion reaction, A-anaphylactic reaction, G-GVHD (graft versus host disease). 



·       PRIMARY LYMPHOID ORGANS:  These sites produce and host the cells of the hematopoietic system.

1.     Bone marrow:  Principle site of hematopoiesis in adults.  All cells are created and matured here except for the T-cell, which heads to the thymus prior to maturation. 

2.     Thymus:  Site of final maturation for T-cells 

·       SECONDARY LYMPHOID ORGANS:  These sites only host the cells of the hematopoietic system under normal condition.  But they have the capability of reverting to being a “producer” under stress.

1.  Lymph nodes:  Filter antigens in lymph.
2.  Spleen: Filter antigens in blood.
3.  Muscosa-associated lymphoid tissues (MALT): Includes bronchus-associated lymphoid tissues (BALTs).

Lymphatic System

By BruceBlaus. When using this image in external sources it can be cited as:Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=28086436

Sites of haematopoesis (human) in pre- and postnatal periods

By M.KomorniczakIllustration by : Michał KomorniczakThis file has been released into the Creative Commons 3.0. Attribution-ShareAlike (CC BY-SA 3.0)If you use on your website or in your publication my images (either original or modified), you are requested to give me details: Michał Komorniczak (Poland) or Michal Komorniczak (Poland).For more information, write to my e-mail address: m.komorniczak.pl@gmail.com - Own work based on:B.F. Rodak, G.A. Fritsma. K. Doig: Hematology: Clinical Principles and Applications. 3rd ed.. Saunder, 2007. ISBN 9781416030065 Figure 7-1R. Hoffman et al.: Hematology: Basic Principles and Practice, 5th ed.. Philadelphia: Churchill Livingstone, An Imprint of Elsevier, 2009. ISBN 978-0-443-06715-0.I. Damjanov: Patofizjologia, Wrocław 2010, Elsevier Urban & Partner. ISBN 9788376092010File:Human skeleton front no-text no-color.svg by: LadyofHats Mariana Ruiz Villarreal, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=16076834


·       EMBRYONIC SITES OF HEMATOPOIESIS:  Initially in developing embryos, blood islands in the visceral endoderm of the yolk sac contain hemocytoblasts and produce all cell types found in the embryonic blood.  Later, hematopoiesis begins to occurs in the liver (5th week), spleen (12th week), and the bone marrow (8th week).  Eventually, the hematopoietic function completely shifts to the bone marrow during the neonatal period.

·       THYMUS:  Development begins when endodermal cells from the 3rd and 4th pharyngeal pouches migrate toward the sternum and interact with the neural crest-derived mysenchyme in front of the ventral aorta.  The endodermal cells differentiate into the thymic epithelial stromal cells, while the neural crest cells form the thymic capsule and septa.  The thymus continues to grow between birth and puberty and then begins to atrophy, a process directed by the high levels of circulating sex hormones.

 ·       SPLEEN: The splanchnic mesoderm forms the stroma and capsule of the spleen, which is subsequently invaded by developing blood vessels.


·       BONE MARROW:  Constitutes 4% of total body weight in adults.  Bone marrow is the site of origin of all hematopoietic cells.  It consists of multipotent stem cells (e.g. hematopoietic, mesenchymal, and endothelial stem cells), hematopoietic cells (e.g. myelocytes, erythrocytes, and thrombocytes), stromal cells (e.g. macrophages, adipocytes, fibroblasts, blood vessels…).  Traversing within the marrow are bony trabeculae lined by osteoblasts and osteoclasts.   With age, the cellularity of marrow is reduced as adipocytes become more abundant.  The estimated percentage of marrow cellularity in a normal person is 100 – age (e.g. for a 50 y/o the cellularity is 100-50 = 50%). 

A femoral head with a cortex of bone and medulla of trabecular bone. Both red bone marrow and a central focus of yellow bone marrow are visible.

By OpenStax College - Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013., CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=30131421

The preferred sites for the procedure

By http://www.scientificanimations.com - http://www.scientificanimations.com/wiki-images/, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=54898121

Hematopoietic precursor cells: promyelocyte in the center, two metamyelocytes next to it and band cells from a bone marrow aspirate.

By Bobjgalindo - Own work, GFDL, https://commons.wikimedia.org/w/index.php?curid=7777568

·       THYMUS:  Lies in the midline of the thorax on the pericardium and trachea just beneath the sternum. 

o   Arterial supply:  From the internal mammary, and the superior thyroid and inferior thyroids.

o   Venous drainage:  Left innominate vein and in the thyroid veins.

o   HISTOLOGY:  Thymus composed of numerous lobules enclosed in an investing capsule.   The lobules vary in size and are made up of a number of small nodules or follicles, each consisting of a cortex and a medulla.  The thymic medulla contains Hassall's corpuscles formed by concentrically-arranged epithelial reticular cells.

o   PHYSIOLOGY:  Thymus is the site for maturation of precursor T-cells (i.e. immature thymocyte) derived from bone marrow.  These cells undergo both positive selection (selection of T cells that are functional) and negative selection (elimination of T cells that are autoreactive) as they traverse the thymus. 

1.     Subcapsular region:  This is the initial receiving center for precursor T-cell freshy arrived from the bone marrow, thus it contains the earliest thymic precursor T-cells characterized by the expression of surface CD2, CD7, TdT but no CD3, CD4, CD8.

2.     Cortex:  Further maturation produces thymocytes with additional expression of surface CD1, CD5, CD3 and both CD4 & CD8.

3.     Medulla: In the final stage, mature thymocytes are forced to express either CD4 (i.e. CD3+CD4+ T-helper cell) or CD8 (i.e. CD3+CD8+ cytotoxic T-cell) but not both.  Mature T-cells then move to the systemic circulation.


Public Domain, https://commons.wikimedia.org/w/index.php?curid=1394154

Normal Process of Intrathymic T Cell Differentiation

By Wilson Savino Thymus Research, Department of Immunology, Oswaldo Cruz Institute, Inserm-Fiocruz Associated Laboratory of Immunology, PLoS Pathog 2(6): e62. doi:10.1371/journal.ppat.https://commons.wikimedia.org/w/index.php?curid=953210

Structure of thymus

By Henry Vandyke Carter - Henry Gray (1918) Anatomy of the Human Body (See "Book" section below)Bartleby.com: Gray's Anatomy, Plate 1179, Public Domain, https://commons.wikimedia.org/w/index.php?curid=567161

Structure of thymus

By Henry Vandyke Carter - Henry Gray (1918) Anatomy of the Human Body (See "Book" section below)Bartleby.com: Gray's Anatomy, Plate 1179, Public Domain, https://commons.wikimedia.org/w/index.php?curid=567161

Micrograph showing a thymic corpuscle (Hassall corpuscle), a characteristic histologic feature of the human thymus.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8751047

·       LYMPH NODES:

o   HISTOLOGY:  A fibrous capsule surrounds each lymph node, and extends inside the lymph node to form trabeculae.  The parenchyma of the lymph node is divided into an outer cortex and an inner medulla.

1.     Cortex:  Further divided into the outer and inner cortex.

a)    Outer cortex (aka nodular cortex):  Consists mainly of B-cells and has lymphoid follicles/nodules.  Lymphoid follicle are divided into 2 types primary and secondary follicles.

Ø  Primary follicle:  Do not contain germinal centers (GCs).  Consists of naïve B-cells that express the pan B-cell marker CD19 and surface IgM and IgD.  These B-cells do not express CD10.

Ø  Secondary follicle:  Form as a result of antigen stimulation of primary follicles and characterized by the presence of GCs.  Consists of activated B-cells that express CD10 and show somatic hypermutation.  Distint zone within a secondary follicles:  Mantle zone (the outer rim made up of non-transformed primary follicles cells and is stained specifically with bcl-2); Germinal center (this is where B-cells are exposed to antigens presented by follicular dendritic cells and CD4+ T-cells, and matured into either plasma cells or memory B-cell; germinal center cells stain specifically with bcl-6 and FDCs stain specifically with CD21).

b)    Inner cortex (aka paracortex): Consists mainly of T-cells and monocyte-derived interdigitating dendritic cells (IDC). 

2.     Medulla: Contains two structures.

a)    Medullary cords:   Lymphatic tissues (mainly plasma cells and B-cells)

b)    Medullary sinuses:  Vessel-like spaces separating the medullary cords.

o   PHYSIOLOGY:  Lymph circulates to the lymph node via afferent lymphatic channels and initially arrives at the subcapsular sinus.  From there, the lymph flow throught the trabecular sinuses into the medullary sinuses, which converge at the hilum and lymph then leaves the lymph node via the efferent lymphatic vessel. The sinus space is criss-crossed by the pseudopods of macrophages which act to trap foreign particles and filter the lymph.

Thymus of a fetus

By Anatomist90 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18360310

Lymphatic system. There are clusters of nodes under the arms, in the groin, neck and abdomen.

Public Domain, https://commons.wikimedia.org/w/index.php?curid=1368384

Afferent and efferent vessels

By SEER - http://training.seer.cancer.gov/module_anatomy/unit8_2_lymph_compo1_nodes.html (archived version)U.S. National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program (http://training.seer.cancer.gov/index.html), Public Domain, https://commons.wikimedia.org/w/index.php?curid=865809

Diagram of a lymph node

By Cancer Research UK - Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34332684

Lymphatics of the axillary region

By Henry Vandyke Carter - Henry Gray (1918) Anatomy of the Human Body (See "Book" section below)Bartleby.com: Gray's Anatomy, Plate 607, Public Domain, https://commons.wikimedia.org/w/index.php?curid=566553

1) Capsule; 2) Subcapsular sinus; 3) Germinal centre; 4) Lymphoid nodule; 5) Trabeculae

By Gleiberg - Own work, selbst fotografiertTransferred from de.wikipedia to Commons., http://de.wikipedia.org/wiki/Bild:Lymphknoten_%28Schwein%29.jpg, CC BY-SA 2.0 de, https://commons.wikimedia.org/w/index.php?curid=4463752

·      SPLEEN:  Located in the left upper abdomen, behind the stomach and just below the diaphragm. Normally, it weighs of 150 grams.

o   HISTOLOGY:  The spleen is encapsulated; the dense connective tissue of the capsule invades and makes trabeculae, dividing the spleen into compartments.  The spleen is composed of white pulp, red pulp, and marginal zone.

1.     White pulp:  Consists of nodules (i.e. Malpighian corpuscles) of lymphoid tissues arranged around a central arteriole.  T-cells are found primarily an area around the central arteriole, which is named the periarteriolar lymphoid sheath (PALS).  B-cells are organized into either primary ‘unstimulated’ follicles, or stimulated secondary follicles with germinals centers.  These follicles lie within the PALS.  The white pulp helps fight infection.

2.     Red pulp: Consists of venous sinuses (i.e. sinusoids) and splenic cords containing macrophages, RBCs, platelets, lymphocytes, and plasma cells.  The red pulp filters and removes unwanted materials from the blood (e.g. senescent RBCs).

3.     Marginal zones (MZ):  Region at the interface between the non-lymphoid red pulp and the lymphoid white-pulp. It contains contains B and T cells, and macrophages, which trap particulate antigen from the circulation and present the antigen to the lymphocytes of the spleen.


By Anatomist90 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19142528

The spleen contains two different tissues, white pulp (A) and red pulp (B). The white pulp functions in producing and growing immune and blood cells. The red pulp functions in filtering blood of antigens, microorganisms, and defective or worn-out red blood cells.

By Senioritisisreal - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49026059

Micrograph of splenic tissue showing the red pulp (red), white pulp (blue) and a thickened inflamed capusule (mostly pink - top of image). H&E stain.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11054496

·      SUMMARY OF HEMATOPOIETIC CELLS:  BEN MET TB (Ben met tuberculosis; try to make sense of this).

o   MYELOID CELLS:  BEN MET = BEN (i.e. granulocytes or PMNs) → B-basophil, E-eosinophil, N-neutrophil; MET → M-monocytes, E-erythrocytes, T-thrombocytes.

o   LYMPHOID CELLS:  TB (i.e. agranulocytes or mononuclear leukocytes) → T-T-cell and B-B-cell.

PATHOLOGYCLASSIFICATION OF HEMATOLOGIG DISEASES:  CHANT (Yes! You will be CHANT-ing how I’ve made this complex subject easier to deal with) → C-clonal hematopoietic disorders (these are your neoplastic proliferations), H-hemostasis disorders, which consist of H-hemorrhagic diathesis (aka coagulopathy), H-ereditary H-hypercoagulable states (aka hereditary thrombophilia), A-anemia, N-non-neoplastic deficiencies or proliferation of hematopoietic cell, T-transfusion reactions, T-transplant medincine.

·       C _______________, _______________, _______________, _______________, _______________

·       H _______________, _______________, _______________, _______________, _______________

·       A _______________, _______________, _______________, _______________, _______________

·       N _______________, _______________, _______________, _______________, _______________

·       T _______________, _______________, _______________, _______________, _______________

·       CLONAL HEMATOPOIETIC DISORDERCLASSIFICATION OF CLONAL HEMATOPOIETIC DISORDERH-hot LAMP → H-histiocytic disorders, L-lymphomas, A-acute leukemia (chronic leukemia is included in other categories), M-myeloproliferative disorders, M-myelodysplastic syndromes, M-mast cell disorders (mastocytosis), P-plasma cell dyscrasias (e.g. multiple myeloma).

H _______________, _______________, _______________, _______________, _______________
L _______________, _______________, _______________, _______________, _______________
A _______________, _______________, _______________, _______________, _______________
M _______________, _______________, _______________, _______________, _______________
P _______________, _______________, _______________, _______________, _______________

o HISTIOCYTIC DISORDER: A group of rare diseases that characteristically an excessive number of histiocytes (i.e. tissue macrophages) in affected tissue.


Ø  LANGERHANS CELL HISTIOCYTOSES (DENDRITIC CELLS RELATED):   Clonal proliferation of langerhans cells.  It is also known as histiocytosis X.

v EPIDEMIOLOGY:  US incidence: 1/200,000/year; peaking between 5-10 y/o and mostly in Caucasians.  M > F 2X. 

v PATHOPHYSIOLOGY:  Usually from sporadic clonal accumulation and proliferation of cells resembling the epidermal dendritic cells (i.e. langerhans cells).   These cells in combination with lymphocytes, eosinophils and normal histiocytes form typical LCH lesion that can be found in almost any organ.  Langerhans Cell Histiocytoses are traditionally divided into three groups:

1.     Unifocal (aka eosinophilic granuloma): Slowly progressing and characterized by an unifocal proliferation of Langerhans cells in bones, skin, lungs or stomach.

2.     Multifocal unisystem (aka Hand-Schuller-Christian disease): Characterized by fever, diffuse skin eruptions (usually on the scalp and in the ear canals), and bone lesions.  In 50% of cases the stalk of the pituitary gland is involved, leading to diabetes insipidus. Hand-Schuller-Christian triad:  Diabetes insipidus, proptosis, and lytic bone lesions. 

3.     Multifocal multisystem (aka Letterer-Siwe disease):  Rapidly progressing and characterized by Langerhans cells proliferation in many tissues.  Mostly seen children < 2 y/o.  Prognosis is poor with a 5-year survival of only 50% even with aggressive chemotherapy.   

A patient with Hand–Schüller–Christian disease which is a subtype of Langerhans Cell Histiocytosis.

By Madhero88 - http://www.dermnet.com/Histiocytosis-X/picture/23373, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9699572

v PRESENTATION:  Non-specific symptoms (from generalized inflammatory response):  Fever, lethargy, and weight loss.  Other symptoms (due to specific organ involvement):  BELLS → B-bone (most frequent manifestation; present as painful osteolytic swelling of, most commonly, the skull, upper extremities long bone and flat bones, which can lead to pathological fractures),  B-bone marrow (pancytopenia from bone marrow infiltration), E-endocrine glands (hypothalamic-pituitary axis is involved and diabetes insipidus is the most common effect), L-lung lesion, L-liver (hepatomegaly occurs in 20%), L-lymphadenopathy (cervical commonest),  S-splenomegaly (in 30%), S-skin (from scaly erythematous lesions to red papules most pronounced in intertriginous areas, up to 80% have extensive scalp eruptions). 

§  B _______________, _______________, _______________, _______________, _______________

§  E _______________, _______________, _______________, _______________, _______________

§  L _______________, _______________, _______________, _______________, _______________

§  L _______________, _______________, _______________, _______________, _______________

§  S _______________, _______________, _______________, _______________, _______________

v DIAGNOSTIC EVALUATION:  CBC. CMP.  CXR: May show micronodular and interstitial infiltrate in the mid and lower zone of lung, with sparing of the costophrenic angle or honeycomb appearance in older lesions.  Bone X-ray:  May show osteolytic bone lesions.  Head CT/MRI: May show sella turcica infiltration.  Tissue biopsy (confirm diagnosis):  Features of Langerhans cell (e.g. distinct cell margin, pink granular cytoplasm).  EM:  Birbeck granules (tennis-racket" or rod shaped cytoplasmic organelles with a central linear density and a striated appearance).  IF:  CD1 positivity.  Molecular: BRAF mutation.

CT scan showing LCH infiltrating peri-orbital tissue (arrowed).

By The original uploader was Countincr at English Wikipedia - Transferred from en.wikipedia to Commons., CC BY 2.5, https://commons.wikimedia.org/w/index.php?curid=6927253

Micrograph showing Langerhans Cell Histiocytosis. H&E stain.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11127345

Micrograph showing a Langerhans cell histiocytosis with the characteristic reniform Langerhans cells accompanied by abundant eosinophils. H&E stain.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11127322


- REACTIVE (secondary) TYPE:  Proliferation of histiocytes in response to viral (e.g. EBV), bacterial, fungal, and parasitic infections, as well as to various cancers.

-FAMILIAL (primary) TYPE (FHLH):  Due to mutation of various genes involving in the release of perforin molecules from NK- and cytotoxic T-cells.  HLH onset usually during the first year of life and almost always appear before 17 y/o.

§  PATHOPHYSIOLOGY:  Five types of familial HLH is recognized and linked to chromosomes 9 and 10.  These genes involve in various step leading to the release of perforin form NK- and T-cells onto cells targeted for cytolysis by the immune system.

FHL2: PRF1 (Perforin)
FHL3: UNC13D (Munc13-4)
FHL4: STX11 (Syntaxin 11)
FHL5: STXBP2 (Syntaxin binding protein 2)/UNC18-2

In both reactive and familial HLH, the underlying problem is dysregulation of immune response activation and termination. Molecular defects in the peforin cytolytic pathway of NK and cytotoxic T-cells in HLH result in highly stimulated, but ineffective immune responses. Hypercytokinemia generated by activated cytotoxic lymphocytes leads to systemic activation of macrophages, multiorgan dysfunction, and potentially death.

§  PRESENTATION: Multiorgan involvement with fever, hepatomegaly (93%), splenomegaly (94%), rash (30%), and CNS disease (30%).

§  DIAGNOSTIC EVALUATION:  CBC:  Thrombocytopenia (98%), anemia (89%), neutropenia (75%).  Serum ferritin:  ↑ in 93%.  Fibrinogen:  ↓ in 76%. CSF analysis: Pleocytosis (52%).  Head CT/MRI: Up to 70% of patients have nonspecific abnormalities including periventricular white matter involvement, with enlarged ventricular system, gray matter disorders, and brainstem and corpus callosum disease.

The current (2008) diagnostic criteria for HLH are 

1. A molecular diagnosis consistent with HLH. These include the identification of pathologic mutations of PRF1, UNC13D, or STX11.


2. Fulfillment of five out of the eight criteria below:

-Fever (>100.4 °F, >38 °C)
-Cytopenias affecting at least two of three lineages in the peripheral blood:Haemoglobin <9 g/100 ml (in infants <4 weeks: haemoglobin <10 g/100 ml)
      Platelets <100×109/L
      Neutrophils <1×109/L
-Hypertriglyceridemia (fasting, greater than or equal to 265 mg/100 ml) and/or hypofibrinogenemia (≤ 150 mg/100 ml)
-Ferritin ≥ 500 ng/ml
-Haemophagocytosis in the bone marrow, spleen or lymph nodes
-Low or absent natural killer cell activity
-Soluble CD25 (soluble IL-2 receptor) >2400 U/ml (or per local reference laboratory)

• TREATMENT:   In secondary cases, treatment of the cause, where possible, is indicated. Additionally, treatment for HLH itself is usually required.  While optimal treatment of HLH is still being debated, current treatment regimes usually involve high dose corticosteroids, etoposide and cyclosporin.

Light microscopic image of bone marrow showing stromal macrophages containing numerous red blood cells in their cytoplasm

By Jon salisbury at English Wikipedia - Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=11557969

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14917669

v SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY (SHML aka Rosai-Dorfman disease):  Persistent, massive enlargement of the nodes with an inflammatory process.

§  EPIDEMIOLOGY:  M > F.  African Americans > Caucasians.

§  PATHOPHYSIOLOGY:  Overproduction of histiocytes, which accumulate in lymph nodes throughout the body, as well as the skin, upper respiratory tract, and bone.

§  PRESENTATION:  History: Constituitional symptoms (e.g. fever, weight loss, malaise, joint pain, and night sweats).  Physical exam:  Lymphadenopathy (cervical lymph nodes are most characteristically involved), rash, and bone lesion. The symptoms of this disease vary with the site of accumulation.

§  DIAGNOSTIC EVALUATION:  CBC:  Leukocytosis, anemia.   Ig levels:  Elevated.  ANA + RhF:  Positive in some.  Biopsy of affected tissue:  Histiocytes accumulation with intracytoplasmic cells (emperipolesis) surrounded by a plasma cell rich infilatrate.

§  TREATMENT:  The disease is benign and has a high rate of spontaneous remission.  Persistent cases with obstructive complications:  Surgery, radiation therapy, and chemotherapy may be used.

Very high magnification micrograph showing emperipolesis in a lymph node affected by Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy. H&E stain. Rosai-Dorfman histiocytes stain with S100 antibodies and do not stain with CD1a antibodies. Emperipolesis is phagocytosis of whole cells.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11102407

v JUVENILE XANTHOGRANULOMA (Dendritic-cell disorders): 

§  EPIDIMIOLOGY:  Usually presents at birth.

§  PRESENTATION:  Multiple yellow-to-pink cutaneous nodules usually 0.5-1 cm in diameter and often appear in the head and neck region. Lesions may occur in deep soft tissues or organs.

§  DIAGNOSTIC EVALUATION:  Biopsy:  Well circumscribed lesion consisting of an accumulation of histiocytic cells with giant cells, including multinucleated Touton cells with horse-shoe arrangement of nuclei, and spindle cells. IHC studies:  Positivity for factor XIIIa, fascin CD68, and peanut agglutinin lectin. 

§  TREATMENT:  Spontaneous resolution of the lesion is usual. Systemic forms of JXG that involve the CNS can be devastating, thus, chemotherapy may be required.

Micrograph of a juvenile xanthogranuloma with the distinctive Touton giant cells.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15316190

v  RETICULOHISTIOCYTOMA:  Occurs in 2 forms solitary reticulohistiocytoma to multicentric reticulohistiocytosis.

§  SOLITARY RETICULOHISTIOCYTOMA:  Usually occur in adults and present as a single yellowish-red skin lump.  Biopsy:  Nodule composed of glycolipid-containing multinucleated large histiocytes.

§  MULTICENTRIC RECULOHISTIOCYTOSIS (aka lipoid dermatoarthritis or lipoid rheumatism):   A very rare and aggressive condition characterised by skin lesions, mucosal lesions and arthritis.

•       EPIDEMIOLOGY:  It usually arises in middle-aged women.

•       PATHOPHYSIOLOGY:  Unknown cause.  However, has been associated with an underlying malignancy (in 20-30% of cases), vasculitis, and autoimmune diseases.

•       PRESENTATION:  Constitutional symptoms: Fever and weight loss.  Arthritis:  Most commonly involves the fingers, hands, knees and shoulders but any joint can be affected. May wax and wane, but in 45% cases it rapidly become severe and lead to joint destruction and deformity.  Skin lesions:  Reddish brown papules and nodules from 1-2 mm to several centimetres in diameter.  Most commonly occur on the upper half of the body, especially the face, ears, hands and forearms.  Multiple tiny lumps around the nails may occur. This has been described as coral-beading. Mucosal lesions:  May occur on the lips, tongue, gums, nostrils, throat, and eyelids. In some cases, it causes destruction of cartilage around the ears and nose resulting in a disfigured appearance.  Lesions are usually symptomless but about one third of patients complain of pruritus (itching).   The disease may progress to polyvisceral involvement (including heart, eyes, lungs, thyroid, liver, kidney, muscle, salivary gland, bone marrow) and death.

•       DIAGNOSTIC EVALUATION:  CBC: Anemia.  CMP.  Biopsy of lesions.  Evaluation for malignancy is indicated because ~ 30% of cases may stem from an underlying malignancy. 

•       TREATMENT:  There is no specific treatment for multicentric reticulohistiocytosis. In many patients, after an average course of 8 years the disease can go into remission, however, by this time considerable joint destruction may have occurred. Patients are left with crippling, deformed joints and disfigured facial appearance. The following treatments may be used: Methotrexate, prednisolone/prednisone,  ciclosporin, azathioprine, and cyclophosphamide.

o   LYMPHOMA:  Clonal (neoplastic) proliferation of hematopoietic cells originating from peripheral lymphoid tissues, frequently lymph nodes, and spreads to the blood and bone marrow.   

Ø  EPIDEMIOLOGY:  Lymphomas account for ~ 5% of all cases of cancer in the US.   Patients with a weakened immune system, such as from HIV infection or from certain drugs or medication, also have a higher incidence of lymphoma.

Ø  CLASSIFICATION:  HODGKIN’S LYMPHOMA (lymphomas containing Reed-Sternberg cells) and NON-HODGKIN’S LYMPHOMA (all other lymphomas; B-cell, T-cell & NK-cell).

Ø  HODGKIN’S LYMPHOMA (aka Hodgkin's disease):  HD is characterized pathologically by the presence of Reed-Sternberg (RS) cells, and clinically by contiguous lymph node spread (i.e. orderly from one lymph node group to another), and by the development of systemic symptoms with advanced disease.

v  EPIDEMIOLOGY:  HD accounts for ~ 1% of all cancers worldwide.  Bimodal incidence curve:  1st peak in young adulthood (age 15–35) and 2nd peak in people > 55 y/o.  US incidence:  1/25,000/yr.    M > F, except for the nodular sclerosis variant, which is more common in women.  Incidence of HD is increased in patients with HIV infection.  In contrast to many other HIV-associated lymphomas, HD occurs most commonly in patients with higher CD4 T cell counts.

v  PRESENTATION:  History: Systemic symptoms (occur in ~1/3):  Low-grade fever, night sweats, > 10% weight loss over 6 months, fatigue, and pruritus (due to eosinophilia).  B-symptoms (marker for more advanced disease): Fever, night sweats, and weight loss.  Physical exam: Lymphadenopathy (LAD is the most common sign): Swollen, painless, rubbery lymph nodes often occurring in the neck (cervical and supraclavicular nodes 80-90% of the time) and mediastinum.  Splenomegaly: Occurs in about 30%. Hepatomegaly: Occur in about 5%. 

Ø  HODGKIN’S LYMPHOMA (aka Hodgkin's disease):  HD is characterized pathologically by the presence of Reed-Sternberg (RS) cells, and clinically by contiguous lymph node spread (i.e. orderly from one lymph node group to another), and by the development of systemic symptoms with advanced disease.

v  EPIDEMIOLOGY:  HD accounts for ~ 1% of all cancers worldwide.  Bimodal incidence curve:  1st peak in young adulthood (age 15–35) and 2nd peak in people > 55 y/o.  US incidence:  1/25,000/yr.    M > F, except for the nodular sclerosis variant, which is more common in women.  Incidence of HD is increased in patients with HIV infection.  In contrast to many other HIV-associated lymphomas, HD occurs most commonly in patients with higher CD4 T cell counts.

v  PRESENTATION:  History: Systemic symptoms (occur in ~1/3):  Low-grade fever, night sweats, > 10% weight loss over 6 months, fatigue, and pruritus (due to eosinophilia).  B-symptoms (marker for more advanced disease): Fever, night sweats, and weight loss.  Physical exam: Lymphadenopathy (LAD is the most common sign): Swollen, painless, rubbery lymph nodes often occurring in the neck (cervical and supraclavicular nodes 80-90% of the time) and mediastinum.  Splenomegaly: Occurs in about 30%. Hepatomegaly: Occur in about 5%. 

Photograph from a 1938 medical textbook labeled of Hodgkin's disease

By Unknown - Scanned from Charles Phillips Emerson, Nellie Gates Brown, Essentials of medicine (J.B. Lippincott company, 1938), Public Domain, https://commons.wikimedia.org/w/index.php?curid=11291052

v  DIAGNOSTIC EVALUATION:  Blood test: CBC and CMP to assess function of major organs and safety for chemotherapy.  CXR: Visualize mediastinal LAD.  CT scan.  PET scan:  Can detect small deposits that do not show on CT.  Flow cytometry:  Analysis of the lymphocytes to confirm clonality and molecular markers expression.  Biopsy (definitive diagnosis):  Effacement of LN architecture by scattered large malignant cells known as RS cells admixed within a reactive cell infiltrate composed of lymphocytes, histiocytes, eosinophils, and plasma cells. The classic RS cells are characteristically large (20–50 micrometres), bi-nucleated cells (i.e. owl eyes) with prominent nucleoli, thick nuclear membrane (from chromatin distribution at the cell periphery), and an unusual CD45-, CD 20- and CD30+, CD15+ immunophenotype. In ~ 50% of cases, the RS cells are infected by the EBV.  Variants of RS cells include:  Hodgkin's cell (mononuclear RS cell), Lacunar RS cell (single hyperlobated nucleus, multiple, small nucleoli and cytoplasmic retraction around the nucleus, creating an empty space-lacunae), Pleomorphic RS cell (multiple irregular nuclei), Popcorn RS cell  (small cell, with a very lobulated nucleus and small nucleoli), Mummy RS cell (compact nucleus, no nucleolus).  These RS cells variants can be CD15-, CD30-, CD45+, CD20+ (e.g. Hodgkin’s cell and lacunar cells).  Hodgkin's lymphoma can be sub-classified by histological type. However, this classification is not as important as it is in NHL as the treatment and prognosis in HD depend on the stage of disease rather than the histotype.

CT image of a 46-year-old patient with Hodgkin's lymphoma, image at neck height. On the left side of the patient's neck enlarged lymph nodes are visible (marked in red).

By JHeuser - JHeuser, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=786572

Hodgkin lymphoma (Field stain)

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9716436

Classic Reed–Sternberg cell

By Unknown - National Cancer Institute, AV Number: CDR576466, Public Domain, https://commons.wikimedia.org/w/index.php?curid=5580965

Micrograph showing a "popcorn cell", the Reed–Sternberg cell variant seen in nodular lymphocyte predominant Hodgkin lymphoma. H&E stain

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11165996

Stage 1 Hodgkin's lymphoma.

By JHeuser - JHeuser, CC BY-SA 3.0, By Cancer Research UK - Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333633

Stage 2 Hodgkin's lymphoma.

By JHeuser - JHeuser, CC BY-SA 3.0, By Cancer Research UK - Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333633

Stage 3 Hodgkin's lymphoma.

By Cancer Research UK - Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333711

Stage 4 Hodgkin's lymphoma.

By Cancer Research UK - Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333755

v  TYPES OF HDNML (just in reverse alphabetical order; please remember this) → N-nodular sclerosis, M-mixed cellularity, L-lymphocyte-rich, and L-lymphocyte-depletion (these are the classical HD with CD45-, CD 20- and CD30+, CD15+ RS cells); L-lymphocytes-predominance (non-classical HD with CD15-, CD30-, CD45+, CD20+ RS cells).

§  N _______________, _______________, _______________, _______________, _______________

§  M _______________, _______________, _______________, _______________, _______________

§  L ______________, ______________, ______________, _____________, _____________

§  NODULAR SCLEROSING (65-75%):  Most common type.  Usually in patient 15-35 y/o.  F > M.  May have mediastinal mass, cervical or supraclavicular LAD, and B-symptoms.  F > M.  Histology:  Often have CD15+, CD30+, CD20-, CD45- lacunar RS cell variants surrounded by fibrotic collagen bands.

§  MIXED-CELLULARITY (25%):  Usually in patient >20 y/o.  M > F.  Associatied with HIV+ status. May affect any lymph nodes and present with B-symptoms.  Histology: CD15+, CD30+, CD20-, CD45- classic RS cell admixed with numerous inflammatory cells including lymphocytes, histiocytes, eosinophils, and plasma cells.

§  LYMPHOCYTE-DEPLETED (10%):  Usuallly in patient >35 y/o. M > F. May affect any node.  Histology:  CD15+, CD30+, CD20-, CD45- RS cell.  Worst prognosis.

Quyen Nguyen MD, CPA


Creighton Universtiy 

Lymph node biopsy showing Hodgkin's lymphoma, lymphocyte-rich type

CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=518562

§  L YMPHOCYTE-RICH (10%):   Histology:  CD15+, CD30+, CD20-, CD45- Reed-Sternberg and Hodgkin-cells admixed with numerous reactive lymphocytes.  

NODULAR LYMPHOCYTE PREDOMINANT HODGKIN'S LYMPHOMA (NLPHL OR NON-CLASSICAL HODGKIN LYMPHOMA):   Usually in patients 20-35 y/o.  M > F.  May have axillary or inguinal, but not not mediastinal LAD.  Histology:  CD15-, CD30-, CD20+, CD45+ popcorn-cells admixed with numerous reactive lymphocytes.  Unlike classic HL, lymphocyte-predominance type may progress to diffuse large B cell lymphoma. Prognosis best of all.  

Micrograph showing a "popcorn cell", the Reed–Sternberg cell variant seen in nodular lymphocyte predominant Hodgkin lymphoma. H&E stain

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11165996

v  STAGING OF HD:  Ann Arbor staging classification

§  Stage I:  Involvement of a single lymph node region (I) or single extralymphatic site (Ie)

§  Stage II:  Involve ≥ 2 lymph node regions on the same side of the diaphragm (II) or one lymph node region and a contiguous extralymphatic site (IIe);

§  Stage III:  Involve of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIs) and/or limited contiguous extralymphatic organ or site (IIIe, IIIes);

§  Stage IV:  Disseminated involvement of one or more extralymphatic organs.

§  The absence of systemic symptoms is signified by adding 'A' to the stage; the presence of systemic symptoms is signified by adding 'B' to the stage.

v  TREATMENT:  Early stage disease (IA or IIA) or any stage with a large mass in the chest:  Radiation therapy or chemotherapy.  Later disease (III, IVA, or IVB):  Combination chemotherapy alone. ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine):  Current chemotherapy regimen of choice.   Other regimen: Stanford V (shown to be inferior to ABVD),  BEACOPP (10-15% higher cure rate than with standard ABVD in advanced stages).  The high cure rates (~93%) and long survival of many patients with Hodgkin's lymphoma has led to a high concern with late adverse effects of treatment, including cardiovascular disease and second malignancies (e.g. acute leukemias, lymphomas, and solid tumors within the radiation therapy field).    

Ø  NON-HODGKIN’S LYMPHOMA (NHL):   Most cases start with infiltration of lymph nodes, but some subtypes may be restricted to other lymphatic organs (e.g. spleen, lymph nodes, or tonsils).  NHL is characterized by non-contiguous lymph node spread and the development of systemic B-symptoms with advanced disease.

v  EPIDEMIOLOGY: M > F.  Incidence depends of subtypes as some types are more likely to occur in children while others in adults. 

v  PATHOPHYSIOLOGY:  Some types of NHL are associated with viruses:  EBV (e.g. Burkitt's lymphoma, extranodal NK/T cell lymphoma, and most AIDS-related lymphoma); HTLV-1 (e.g. adult T-cell lymphoma/leukemia); H. pylori (extranodal marginal zone B-cell lymphoma of the stomach).  Other risk factors associated with NHL:  Weak immune system (e.g. patients with inherited immune deficiencies, autoimmune diseases, or HIV/AIDS, and those taking immunosuppressant drugs following organ transplants) and environmental exposure (e.g. pesticides, solvents, or fertilizers).   

v  PRESENTATION: History (similar to HD):  Systemic symptoms:  Low-grade fever, night sweats, weight loss, anorexia, fatigue,  pruritus (due to eosinophilia), and abdominal pain.  B-symptoms: Fever, drenching night sweats, and > 10% weight loss over 6 months.  Physical exam: Lymphadenopathy (LAD is the most common sign): Swollen, painless, rubbery lymph nodes often occurring in the neck, axilla, mediastinum, and groin.  Splenomegaly: Occurs in about 30%. Hepatomegaly: Occur in about 5%. 

v  DIAGNOSTIC EVALUATION:  SAME AS FOR Hodgkin disease and include Blood test: CBC and CMP.  CXR.  CT scan.  PET scan.  Flow cytometry.   Biopsy (definitive diagnosis): 

v  STAGING OF NHD:  Ann-Harbor system (like Hodgkin disease) or RAI Staging System  

v  CLASSFICATION OF NON-HODGKIN’S LYMPHOMA:  2 types base on cell type I) B-cell tumors II) T-cell & Natural killer cell (NKC) tumors

                        I.     NEOPLASMS OF B-CELL LINEAGE:  S-smart M.D’s F-fight B-bad H-harry P-potter– SMDFBHP → S-small lymphocytic lymphoma/chronic lymphocytic leukemia, M-mantle cell lymphoma, M-marginal zone lymphoma, D-diffuse large B-cell lymphoma, F-follicular lymphoma, B-burkitt lymphoma, H-hairy cell leukemia, P-precursor B-cell acute lymphoblastic leukemia/lymphoma.

§  S _______________, _______________, _______________, _______________, _______________

§  M _______________, _______________, _______________, _______________, _______________

§  D _______________, _______________, _______________, _______________, _______________

§  F _______________, _______________, _______________, _______________, _______________

§  B _______________, _______________, _______________, _______________, _______________

§  H _______________, _______________, _______________, _______________, _______________

§  P _______________, _______________, _______________, _______________, _______________

Smudge cells in peripheral blood

By Dr Graham Beards - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/

Terminal ileum with mantle cell lymphoma (bottom of image - brown colour). Cyclin D1 immunostain.

By Nephron - Own work, CC BY-

Gastric MALT lymphoma in body of stomach in patient who presented with upper GI hemorrhage. 

By Samir at the English language Wikipedia

Diffuse large B-cell lymphoma with immunoblastic morphology

Quyen Nguyen MD,CPA

Follicular lymphoma, note nodular pattern 

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=32752068

Burkitt lymphoma, touch prep, Wright stain

By Ed Uthman, MD. - http://flickr.com/photos/euthman/144136197/in/set-72057594114099781/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1208814

Hairy cell leukemia: abnormal B cells look "hairy" under a microscope because of radial projections from their surface.

By Paulo Henrique Orlandi Mourao - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8045229

II.     NEOPLASMS OF T-CELL and NK-CELL LINEAGE:  TEAM P-player = TEAM P → T-T cell granular lymphocytic leukemia, E-extranodal NK/T cell lymphoma-nasal type, E-enteropathy-type T-cell lymphoma, A-adult T-cell lymphoma/leukemia, A-anaplastic large cell lymphoma,  M-mycosis fungoides/Sezary syndrome, P-precursor T-cell acute lymphobastic lymphoma/leukemia

§  T _______________, _______________, _______________, _______________, _______________

§  E _______________, _______________, _______________, _______________, _______________

§  A _______________, _______________, _______________, _______________, _______________

§  M _______________, _______________, _______________, _______________, _______________

§  P _______________, _______________, _______________, _______________, _______________

Micrograph of enteropathy-associated T cell lymphoma (upper right of image).

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11211441

Micrograph of an anaplastic large cell lymphoma.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17451566

Skin lesions on the knee of a 52-year-old male patient with Mycosis fungoides

By Bobjgalindo - Own work, GFDL, https://commons.wikimedia.org/w/index.php?curid=7139812

Plaque of mycosis fungoides

By kilbad (talk) - I (kilbad (talk)) created this work entirely by myself., CC BY 3.0, https://en.wikipedia.org/w/index.php?curid=36321562

v  TREATMENT:  Depends on the specific type of NHL and the stage of the disease.   Factors that influence specific treatment treatment: Behavior of the lymphoma type (indolent vs. aggressive); stage (limited vs. advanced); first line treatment vs. treatment for refractory or relapsed lymphoma.  Available modalities:

§  Watchful waiting:  For indolent lymphomas. 

§  Chemotherapy:  CHOP (Cyclophosphamide, Hydroxydaunorubicin (Adriamycin), Oncovin (Vincristine), Prednisone/Prednisolone) is the most commonly used combination. 

§  Radiation therapy:  May be given alone or with chemotherapy. 

§  Immunotherapy (biologics):  Such anti-CD20 antibody (rituximab).

§  Hematopoietic stem cell transplantation (aka BMT):   Option, especially for patients with recurrent NHL non-Hodgkin's lymphoma has recurred (come back).

After treatment for NHL, the response is classified as follows:  Complete Response (disappearance of all detectable disease); Partial Response (reduction in the bulk of disease by at least 50%); Stable Disease (less than partial remission, but no progression and no new site); Progressive Disease (growth in bulk of disease by >50%, or new sites of disease); Cure (complete remission for ≥ 3 years).   Standard guidelines:  Monitored for relapse every 3 months in the first year following a complete remission, every 6 months in the second year, and finally once annually in the third and later years.  

o   ACUTE LEUKEMIA: CLASSIFICATION:  Clonal (neoplastic) proliferation of hematopoietic cells originating in the bone marrow, and then spreads to the peripheral blood and the rest of the body.  Acute refers to the presence of blasts (undifferentiated, immature circulating lymphocytes), and to the rapid progression of disease (can be fatal in weeks-months if untreated).  We are only discussing acute leukemia in this section.  Chronic leukemias, which include chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML), occur more often in older adults and run a more indolent course.  CLL and CML are classified under NHL and myeloproliferative disorders, respectively. 

Ø  EPIDEMIOLGY:  US incidence:  30,800/yr.  

Ø  PATHOPHYSIOLOGY:  In leukemias chromosomal translocations occur regularly.  While most translocations occur during fetal development, some are caused by environmental factors such as chemicals (e.g. benzene), drugs (e.g. chemotherapy especially alkylating agents and anthracyclines), radiation (e.g. radiation therapy, Chernobyl nuclear reactor, atom bombs in Hiroshima and Nagasaki), Down syndrome (risk ↑ 20X), chromosomal instability syndrome (e.g. Bloom syndrome, Fanconi anemia), and pre-leukemic blood disorders (e.g. myelodysplastic syndrome and  myeloproliferative disorders can evolve into AML).  These translocations cause differentiation arrest (freeze the cell in its immature state) and trigger oncogenes to ‘turn-on’ or tumor-suppressor gene (TSG) to ‘turn-off’, resulting in unregulated mitosis and leukemia.  These malignant, immature WBCs cause damage and death by crowding out normal cells in the bone marrow, and by metastasizing to other organs.

Ø  PRESENTATION:  Manifestations of acute leukemia are due to tumor cells invasion.  Damage to the bone marrow results in bone pain, bleeding/petechiae/brusing (thrombocytopenia), frequent infection (functional leukopenia), and pallor/fatigue/dyspnea (anemia).  Other possible manifestation:  Fever, chills, night sweats, swollen or bleeding gums, neurological symptoms (tumor cells invasion of CNS), LAD, and hepatosplenomegaly.  Also, rarely patients can develop a chloroma (aka granulocytic sarcoma), a solid tumor of leukemic cells outside the bone marrow, which can cause various symptoms depending on its location (e.g. leukemic cutis, gingival hyperplasia).

Diffusely swollen gums due to infiltration by leukemic cells in a person with acute myelomonocytic leukemia

By Herbert L. Fred, MD and Hendrik A. van Dijk - http://cnx.org/content/m14986/latest/, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11893755

Ø  DIAGNOSTIC EVALUATION:  CBC:  Leukocytosis (worst prognosis if > 50,000), anemia, thrombocytopenia.  Aleukemia:  Leukemic patient with normal to low WBC.  In this this, leukemic cells are staying in the marrow instead of entering the bloodstream; this is more common with hairy cell leukemia.  CMP:  Check renal and liver functions.  Peripheral smear:  Circulating leukemic blasts.  Bone marrow aspiration and biopsy (definitive diagnosis).  Flow cytometry:  Diagnose and to classify the subtype of disease.  Cytogenetics or fluorescent in situ hybridization (FISH):  Test for chromosomal translocations and molecular markers to differentiate AML from ALL (e.g. MPO+, sudan black+ only in AML) and in subclassification of AML.  Spinal tap:  Determine if the CNS has been invaded.  US/CT/MRI:   Rule out invasion of the lung, liver, spleen, lymph nodes, brain kidneys and reproductive organs.

Ø  CLASSIFICATION OF ACUTE LEUKEMIA:  I) Acute lymphoblastic leukemias (ALL) and II) Acute myelogenous leukemias (AML)

I.     ACUTE LYMPHOBLASTIC LEUKEMIA (ALL):  The malignant cell in ALL is the lymphoblast, the immature precursor of B-cell and T-cell.

v  EPIDEMIOLOGY:  ALL is the most common childhood malignancy, and accounts for ~ 80% of all childhood leukemia.  Peak incidence at 4-5 y/o. US incidence:  4000/year, with ~ 3000 occur in children and majority of the rest in people > 50 y/o.  M > F.  Risk factors:  Down Syndrome, Fanconi anemia, Bloom syndrome, Ataxia telangiectasia, X-linked agammaglobulinemia and SCID.

v  CLASSIFICATION OF ALL:   Precursor B-cell ALL (85%) & Precursor T-cell ALL (~15%)

Wright's stained bone marrow aspirate smear of patient with precursor B-cell acute lymphoblastic leukemia.

By The original uploader was VashiDonsk at English Wikipedia - Transferred from en.wikipedia to Commons., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2128622

bone marrow smear (large magnification) from a patient with acute lymphoblastic leukemia

By Furfur - Own work, CC BY-SA 2.5, https://commons.wikimedia.org/w/index.php?curid=1990182

II.     ACUTE MYELOGENOUS LEUKEMIA (AML):  The malignant cell in AML is the myeloblast, the immature precursor of BEN MET → N-neutrophils, E-eosinophil, B-basophils, M-monocytes, E-erythocyte, T-thrombocyte.  Under WHO criteria, the diagnosis of AML is established by demonstrating involvement of > 20% of the blood and/or bone marrow by leukemic myeloblasts.  AML must be carefully differentiated from "pre-leukemic" conditions such as myelodysplastic or myeloproliferative syndromes, which are treated differently.   

v  EPIDEMIOLOGY:  US incidence:  10,500 cases/yr.  Incidence increases with age; the median age at diagnosis is 63 y/o. M > F.  The rate of therapy-related AML (i.e. caused by previous chemotherapy) is rising, and account for ~10–20% of all cases of AML.


Bone marrow aspirate showing acute myeloid leukemia, arrows indicate Auer rods.  Only the presence of Auer rods definitively differentiate 

By VashiDonsk at the English language Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2571505

Bone marrow: myeloblasts with Auer rods seen in acute myeloid leukemia

By <a href="//commons.wikimedia.org/w/index.php?title=User:Paulo_Mourao&amp;action=edit&amp;redlink=1" class="new" title="User:Paulo Mourao (page does not exist)">Paulo Henrique Orlandi Mourao</a> - <span class="int-own-work" lang="en">Own work</span>, <a href="http://creativecommons.org/licenses/by-sa/3.0" title="Creative Commons Attribution-Share Alike 3.0">CC BY-SA 3.0</a>, <a href="https://commons.wikimedia.org/w/index.php?curid=9100126">Link</a>

Acute promyelocytic leukemia with t(15;17) (formerly FAB-M3) with characteristic deeply lobated, butterfly-shaped nuclei.

Acute monoblastic leukemia (AML-M5a):  Monoblasts are large with abundant cytoplasm and nuclei lacking folds but have dinstinct nucleoli

Acute myeloid leukemia with inv16 (former AML-M4eo): Increased blasts and eosinophils at various stages of maturation

Pure erythroid leukemia (AML-M6): Erythroid precursors comprise >80% of marrow cells and are at all stages of maturation


I.     ALL:  Chemotherapy (e.g. hyperfractionated CVAD-cyclophosphamide, vincristine, adriamycin and dexamethasone protocol), steroids, radiation therapy (used on painful bony areas, in high disease burdens, preparations for a bone marrow transplant or CNS prophylaxis), growth factors, and stem cell transplants. The overall cure rate in children is 85%, and about 50% of adults have long-term disease-free survival.

 II.     AML:  Treatment is primarily chemotherapy, and is divided into two phases: induction and consolidation therapy.   Induction therapy (achieve complete remission by reducing leukemic cells to undetectable level):  All FAB subtypes except M3 are usually given cytarabine (ara-C) and an anthracycline (such as daunorubicin or idarubicin).  AML-M3 is treated with ATRA  in addition to induction chemotherapy.  In general, all remissions will fail without consolidation chemotherapy.  Consolidation therapy (eliminate any residual undetectable disease and achieve a cure):  Individualized based on a patient's prognostic factors and general health. For good-prognosis leukemias (e.g. t(8;21), t(15;17)), inv(16), patients will typically undergo an additional 3–5 courses consolidation chemotherapy.  For patients at high risk of relapse (e.g. those with high-risk cytogenetics, underlying MDS, or therapy-related AML), allogeneic stem cell transplantation is usually recommended.  Despite aggressive therapy, however, only 20%–30% of patients enjoy long-term disease-free survival. For patients with relapsed AML, the only proven potentially curative therapy is a stem cell transplant, if one has not already been performed.

o   MYELOPROLIFERATIVE NEOPLASMS (MPN):  Clonal hematopoietic stem cell proliferations which run a chronic course. They are related to, and may evolve into MDS and AML, although the MPDs on the whole have a much better prognosis than these conditions.

Ø  PATHOPHYSIOLOGY: MPDs arise from myeloid precursors in the bone marrow. The lymphoid lineage may produce similar diseases, the lymphoproliferative disorders (e.g. ALL, CLL, lymphomas, and multiple myeloma).  MPDs consist of four main diseases, which can be further categorized by the presence or absence of the Philadelphia chromosome: C-chronic M-myeloid P-precursors E-expansion (this is what is happening; get it) = CMPE (or just think of CoMPuter Engineering) → C-chronic myelogenous leukemia (this is the only one that is Philadelphia chromosome positive), M-myelofibrosis, P-polycythemia vera, E-essential thrombocytosis (these last 3 are Philadelphia chromosome negative; however they may be positive for JAK2 mutation).  MPD is a pre-leukemic condition:  All subtypes may end up in causing marrow fibrosis or transform into acute leukemia.  

v  C _______________, _______________, _______________, _______________, _______________

v  M _______________, _______________, _______________, _______________, _______________

v  P _______________, _______________, _______________, _______________, _______________

v  E _______________, _______________, _______________, _______________, _______________

Ø  CHRONIC MYELOGENOUS LEUKEMIA (CML):  Proliferation of bone marrow element with a predominance of the myeloid lineage (i.e. BEN → B-basophils, E-eosinophils, N-neutrophils and their precursors).

v  EPIDEMIOLOGYConstitute ~15–20% of all cases of adult leukemia.  US incidence:  1–2/100,000/yr.  Most commonly in the middle-aged and elderly (mostly 30-60 y/o). M > F. Risk factor:  Ionizing radiation (e.g. post-atomic bombings of Hiroshima and Nagasaki)

v  PATHOPHYSIOLOGYLinked to the Philadelphia chromosome t(9;22)(q34;q11), which results in the formation of a fusion protein BCR-ABL, a constitutively active tyrosine kinase.  The BCR-ABL protein activates an intracellular cascade that speeds up cell division.  BCR-ABL protein also inhibits DNA repair, making the cell more susceptible to developing further genetic abnormalities.

Diagram showing the translocation found in the Philadelphia chromosome

By A Obeidat in ar.wikipedia - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1569299

v  PRESENTATION:  Often asymptomatic and discovered incidentally with an elevated white blood cell.  Possible symptoms:  Malaise, low-grade fever, gout, frequent infections (functional leukopenia), dypsnea/fatigue (anemia), easy bruising (thrombocytopenia), and LUQ discomfort (massive splenomegaly).  In the absence of intervention, CML often sequentially progress through three phases:  I) Chronic II) Accelerated III) Blast crisis.   The duration of time over which this progression occurs last from <1 to >20 years, with a median 4-5 years.

I.     CHRONIC PHASE:  ~85% of CML cases are diagnosed at this phase.  Patients are usually asymptomatic or have only mild symptoms of fatigue or abdominal fullness.

II.     ACCELERATED PHASE:  Diagnosis is met if any of these WHO criteria is met:  a) 10–19% myeloblasts in the blood or bone marrow b) >20% basophils in the blood or bone marrow c) Platelet count <100,000 (unrelated to therapy) or >1,000,000 (unresponsive to therapy) d) New cytogenetic abnormalities in addition to the Philadelphia chromosome e) Increasing splenomegaly or WBC count (unresponsive to therapy).  The accelerated phase signals that the disease is progressing and transformation to blast crisis is imminent.

III.     BLAST CRISIS:  Diagnosed if any of the following are present a) >20% myeloblasts or lymphoblasts in the blood or bone marrow b) Large clusters of blasts in the bone marrow on biopsy c) Chloroma development (solid focus of leukemia outside the bone marrow).  Blast crisis is the final phase of CML, and behaves like an acute leukemia, with rapid progression and short survival.

v  DIAGNOSTIC EVALUATION:  CBC:  Leukocytosis; especiall basophilia and eosinophilia.  CMP: Check liver and renal function.  LAP (leukocyte alkaline phosphatase):  LOW.  Peripheral smear:  Leukocytosis (median of 150,000 cells/mL) prominent myeloid cells and basophilia.  Bone marrow biopsy.  Cytogenetics/FISH (definitive diagnosis):  Detect the Philadelphia chromosome t(9,22). CML must be distinguished from a LEUKEMOID REACTION, which can have a similar appearance on a blood smear and can be a result of hemorrhage, infection (e.g. TB, pertussis), drugs (e.g. glucocorticoids, G-CSF, ATRA), trisomy 21, and paraneoplastic phenomenon. Leukemoid reaction often have the following features:  WBC >50,000 but <100,000, no basophilia, elevated LAP, and bone marrow examination reveal hypercellularity but is otherwise typically unremarkable.

Chronic myelogenous leukemia.Peripheral blood: peak of myelocytes and bands/neutrophils; basophilia is demonstrated elsewhere

By J3D3 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=47341095

Peripheral blood (MGG stain): marked leukocytosis with granulocyte left shift

By Paulo Henrique Orlandi Mourao - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8793165

A small, hypolobated megakaryocyte (center of field) in a bone marrow aspirate, typically of chronic myelogenous leukemia.

By Difu Wu - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15185317

he Philadelphia chromosome as seen by metaphase FISH.

By No machine-readable author provided. Pmx assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims)., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=254833

v  TREATMENT:  Chronic phase:  ~ 91% response rate when treated with the specific inhibitors of  the BCR/ABL tyrosine kinase (e.g. imatinib mesylate STI-571-Gleevec®), which has replaced antimetabolites (e.g. cytarabine, hydroxyurea), alkylating agents, and biologic agents (e.g. INF-a2b) as the drug of choice.  Dasatinib, a TK inhibitor that blocks several oncogenic proteins, is used for patients who are either resistant to or intolerant of imatinib.  BMT:  Curative in 60%, there is a high rate of transplant-related mortality from GVHD.    Accelerated phase:  Response rate to Gleevec is ~17%.  BMT is often performed.  Blast crisis:   Response rate to Gleevec is ~7%.  It is most effectively treated with BMT after high-dose chemotherapy.  In any case, the relapse rate and mortality are both very high.

v  SUMMARY OF CML: BLAST (as in the associated BLAST crisis) → B-BRC-ABL protein, B-blast crisis, B-basophilia, B-B12 vitamin elevated, B-bone pain, L-leukocytosis, L-LAP lowered, L-lymphadenopathy, A-nemia, S-splenomegaly, T-thrombocytopenia, T-thirty to fifty is the typical age.  

§  B _______________, _______________, _______________, _______________, _______________

§  L _______________, _______________, _______________, _______________, _______________

§  A _______________, _______________, _______________, _______________, _______________

§  S _______________, _______________, _______________, _______________, _______________

§  T _______________, _______________, _______________, _______________, _______________

Ø  MYELOFIBROSIS (aka chronic idiopathic myelofibrosis, Agnogneic Myeloid Metaplasia, Heuck-Assmann disease, or Assmann's Disease):  Proliferation of bone marrow element with a predominance of the fibroblast lineage.   

v  EPIDEMIOLOGYMedian age 60 y/o.

v  PATHOPHYSIOLOGYLinked to the present of JAK2 mutation.  Bone marrow is replaced by collagen fibrosis, which impair hematopoiesis, and resulting in pancytopenia.  Compensatory extramedullary hematopoeisis occurs in the liver and spleen, leading to hepatosplenomegaly.  It can occur secondarily to other MPD, such as polycythemia vera (PCV) or essential thrombocytosis (ET).

v  PRESENTATIONSymptoms are due to pancytopenia and hepatosplenomegaly and include: Infection, bleeding, organ failure, portal hypertension, and early satiety.  Leukemic transformation and bone marrow failure can occur.

v  DIAGNOSTIC EVALUATION:  Diagnosis is based upon:  Peripheral smear:  Normochromic normocytic anaemia and presence of tear-drop RBCs and leukoerythroblastosis (presense of left-shift granulopoiesis and nucleated red blood cells).  Cytogenetics: JAK 2 mutation (occur in 50%); LDH ↑; Neutrophil alkaline phosphatase ↑; Bone marrow biopsy:  Fibrosis

Focal bone remodeling and streaming of cells suggested of marrow fibrosis. Megakaryocytes include small hypolobated forms.

Reticulin stains show patchy increase reticulin deposition with focal intersections (WHO fibrosis grade 1/3).

v  TREATMENT:  Hematopoietic cell transplant (HCT):  The only therapy with a curative potential in myelofibrosis. However, as patients are old, the disease is slowly progressive (may live 10-20 years with supportive treatment), and BMT is associated with high mortality/morbidity, BMT is indicated only for young patients.  Other modalities are usually employed for palliative therapy and include:  Androgens + corticosteroid combination (improves anemia),  Chemotherapy (e.g. Busulfan and melphalan provide symptomatic relief of constitutional symptoms, organomegaly, cytopenias), hydroxyurea (may relieve splenomegaly, thrombocytosis, leukocytosis, and bone marrow fibrosis), thalidomide + prednisone (may improve constitutional symptoms, anemia, thrombocytopenia, and splenomegaly), radiation (provides 3-6 months benefit to symptomatic foci of extramedullary hematopoiesis including the spleen, liver, spinal cord, peritoneal and pleural cavities or focal areas of bone pain due to chloroma), Anagrelide (control thrombocytosis),  Splenectomy (considered for patients who have symptomatic splenomegaly including transfusion-dependent anemia of > 2-3 PRBC units/week, painful splenomegaly, portal hypertension). 

v  PROGNOSIS:  The mean survival is 5 years. 

Ø  POLYCYTHEMIA RUBRA VERA (PRV):  Proliferation of bone marrow element with a predominance of the erythroid lineage.   Often, excess WBCs and platelets are also produced.

v  EPIDEMIOLOGY:  Incidence:  2/100,000/yr.  Median age at diagnosis to be 60 y/o.  M > F.  

v  PATHOPHYSIOLOGY:  Linked to the present of JAK2 mutation. 

v  PRESENTATION:  Often asymptomatic. Classic signs & symptom:  PRV (it’s the name of the disease) à P-polycythemia (Hct >54 ♂ or > 49 ♀), P-platelets & WBCs are often increased also, P-plethoric face, P-pruritus (40%, particularly after exposure to warm water, which may be due to abnormal histamine or P-prostaglandin), P-peptic ulcer disease ↑ (due to ↑ susceptibility to H. pylori), R-red neuralgia (aka erythromelalgia; a sudden, severe burning pain in the hands or feet, usually accompanied by a reddish or bluish skin discoloration caused by the formation of tiny blood clots in the vessels of the extremity secondary to thrombocytosis or increased platelet "stickiness"; it responds rapidly to treatment with aspirin), V-viscosity of blood ↑ → thrombotic complication (e.g. visual change, HA, MI, stroke, DVT, PE, or Budd-Chiari syndrome). Others:  Gouty arthritis (~20% of patients), splenomegaly.  

§  P _______________, _______________, _______________, _______________, _______________

§  R _______________, _______________, _______________, _______________, _______________

§  V _______________, _______________, _______________, _______________, _______________

Erythromelalgia is a rare symptom of PV, here present in a patient with longstanding polycythemia vera. Note reddish limbs and swelling.

By by Herbert L. Fred, MD and Hendrik A. van Dijk - http://cnx.org/content/m14932/latest/, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5038143

v  DIAGNOSTIC EVALUATION:  CBC:  Elevated hemoglobin & hematocrit, modest thrombocytosis and leukocytosis.  EPO: Low.  Cytogenetics:  JAK2 kinase mutation.  Bone marrow biopsy: ↑ erythroblast, and myelofibrosis is seen in advanced disease. Exclude reactive polycythemia:

Blood smear from a patient with polycythemia vera

By The Armed Forces Institute of Pathology (AFIP) - PEIR Digital Library (Pathology image database). Image# 404905. Image and description are from the AFIP Atlas of Tumor Pathology. Declaration of PEIR: «Copyright Information - The Armed Forces Institute of Pathology Electronic Fascicles (CD-ROM Version of the Atlas of Tumor Pathology) contains both U.S. Government work and copyrighted materials used with permission of non-Government contributors. U.S. Government works may be used without restriction, but users of the Electronic Fascicle may not lawfully modify, rent, loan, distribute, create derivative works in whole or in part, or electronically transmit the copyrighted images from one computer to another or over a network without first obtaining permission from the copyright owners. All attempts have been made to remove copyrighted images from the PEIR Digital Library. If a copyright-protected image has inadvertently been included, please notify us and it will be removed immediately.», Public Domain, https://commons.wikimedia.org/w/index.php?curid=4352246

v  TREATMENT:  PRV cannot be cured.  Therapy focuses on treating symptoms and reducing thrombotic complications.  Phlebotomy:  Lower hematocrit below 45.  Hydroxyurea:  Used if concurrent thrombocytosis.  Low dose aspirin: ↓ thrombotic complications.  Previously used to suppress the bone marrow, phosphorus-32 should be avoided due to a high rate of AML transformation.  Bone marrow transplants are rarely undertaken in PRV since this condition is non-fatal if treated and monitored.

Ø  ESSENTIAL THROMBOCYTOSIS (ET):  Proliferation of bone marrow element with a predominance of the megakaryocytic lineage.

v  EPIDEMIOLOGY:  Incidence:  2-3/100,000/year.  Average age at diagnosis 50-60 y/o.   

v  PATHOPHYSIOLOGY:  Linked to the present of JAK2 mutation (50%).  Platelets derived from the abnormal megakaryocytes do not function properly, which contributes to the clinical features of bleeding and thrombosis. 

v  PRESENTATION: History:  ET (name of the disease) → E-epistaxis (and other bleeding such as from gum, GI tract), E-erythromelalgia (throbbing and burning of the hands and feet due to the occlusion of small arterioles by platelets), T-thrombosis. ET also increases spontaeous abortion or miscarriage in the first trimester of pregnancy. Physical:  Splenomegaly may be found.

§  E _______________, _______________, _______________, _______________, _______________

§  T _______________, _______________, _______________, _______________, _______________

DIAGNOSTIC EVALUATION:  Diagnosis criteria:  Requires the presence of both A criteria + B3 to B6, or A1 together + B1 to B6. Criteria B1-B6 is basically rule out reactive thrombocytosis, other MPD, & MDS.

Essential Thrombocythaemia

By Prof. Osaro Erhabor - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=42667879

v  TREATMENT:  Don’t treat young asymptomatic women.  Hydroxyurea, anagrelide, or INF-a:  ↓ platelet to normal range in those with high risk of thrombosis or bleeding (older age, history of bleeding or thrombosis, or very high platelet count).  Low-dose aspirin:  ↓ thrombosis.  Platelet apheresis:  ↓ platelets rapidly in case  of life-threatening complications.  Pregnant patient:  Hydroxyrea and anagrelide are contra-indicated during pregnancy and nursing. Close monitoring for thrombosis (both mother & placenta) and post partum use of LMWH is indicated to prevent blood clot.

v  PROGNOSIS:  ET is a slowly progressive disorder with long asymptomatic periods punctuated by thrombotic or hemorrhagic events.

o   MYELODYSPLASTIC SYNDROME (MDS aka preleukemia):  Dysplasia of one or more cell lineages resulting in ineffective hematopoiesis leading to anemia, leukopenia, thrombocytopenia alone or in combination. It may transform into AML, in which case is notoriously resistant to treatment.

Ø  EPIDEMIOLOGY:  US incidence: 10,000-20,000 new cases/year.   M > F. More common in the elderly (average ~65 y/o at diagnosis).

Ø  PATHOPHYSIOLOGY:  Accumulation of DNA mutations in the multi-potent bone marrow hematopoietic stem cell lead to clonal expansion of the abnormal cells which have lost the ability to differentiate. There is a significant increase in the production of non-functional cells and apoptotic cell death in bone marrow resulting in peripheral cytopenias.  If the overall percentage of bone marrow blasts rises over a particular cutoff (20% for WHO and 30% for FAB) then transformation to AML is said to have occurred.  Cytogenetic abnormalities are found in most cases of MDS, and include -5, -5q, -7, -7q, +8, -Y.  MDS can be primary or idiopathic, but may also be secondary to various insults that lead to bone marrow dysplasia (e.g. chemo or radiationtherapy for other malignancies especially alkylating agents, exposure to hydrocarbons in the petroleum industry, and exposure to benzene/xylene).

Ø  PRESENTATION:  Chronic fatigue, dyspnea (anemia), frequent infection (neutropenia), and bleeding. (thrombocytopenia).   

➢ DIAGNOSTIC EVALUATION: CBC: Cytopenias, MCV > 100 (macrocytosis). Peripheral smear: Monocytosis, Pelger-Huet cells (hypolobated neutrophils). ANA, hepatitis serologies, TSH, LFTs, RFTs, Folate & Vitamin B12 levels, SPEP: Rule out other causes of cytopenias. Bone marrow biopsy (required for diagnosis): Hypercellular, dysplastic erythroid precursors (e.g. binucleated, nuclear budding, nuclear strings or internuclear bridging, PAS+, and ≥ ringed sideroblasts seen on Prussian blue iron stain-≥10 iron granules encircling ≥1/3 of the nucleus), dysplastic myeloid precursors (e.g. hypersegmented neutrophils, hyposegmented neutrophils-Pseudo-Pelger Huet, hypogranular neutrophils or pseudo Chediak Higashi large granules, and dimorphic granules [basophilic and eosinophilic granules] within eosinophils), &/or dysplastic megakaryocytes precursors (e.g. hyposegmented megakaryocytes lacking of lobation, hypersegmented megakaryocytes, ballooning of the platelets). Cytogenetics: May reveal -5, -5q, -7, -7q, +8, -Y or others genetic abnormalities. Flow cytometry: Rule out other hematopoietic disorders.

American Society of Hemalogy 2015

Blood smear from a person with myelodysplastic syndrome. A hypogranular neutrophil with a pseudo-Pelger-Huet nucleus is shown. There are also abnormally shaped red blood cells,

By AFIP - PEIR Digital Library (Pathology image database). Image# 404814. Image and description are from the AFIP Atlas of Tumor Pathology. Declaration of PEIR: https://commons.wikimedia.org/w/index.php?curid=4345884

Ø  Under the WHO classification, MDS is divided into the following 7 categories based on bone marrow findings:    

1.     Refractory anemia (RA):  Erythroid dysplasia only, < 5% blasts, < 15% sideroblasts.

2.     Refractory anemia with ringed sideroblasts (RARS):  Same RA but with ≥ 15% sideroblasts.

3.     Refractory cytopenia with multilineage dysplasia (RCMD): Dysplasia in 10% of cells in ≥ 2 cell lineage, < 5% blasts, < 15% sideroblasts, no Auer rods.

4.     Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS): Same as RCMD but with ≥ 15% ringed sideroblasts.

5.     Refractory anemia with excess blasts I (RAEB-I): Uni or multilineage dysplasia, 5-9% blasts, no Auer rods.

6.     Refractory anemia with excess blasts II (RAEB-II): Same as RAEB-I but with 10-19% blasts.

7.     Myelodysplastic syndrome, unclassifiable (MDS-U):  Dysplasia in granulocytes or megakaryocytes, < 5% blasts, no Auer rods.

8.     MDS associated with isolated deletion of 5q (5q- syndrome):  Megakaryocytes with hypolobated nuclei, < 5% blasts, no Auer rods.

The International Prognostic Scoring System (IPSS), which helps triage patients for more aggressive treatment (i.e. bone marrow transplant) as well as help determine the best timing of this therapy, include these 3 major variables: % blasts, cytogenetic findings, and number of cytopenia (i.e. anemia, neutropenia, thrombocytopenia).   

Ø  TREATMENT:  Goals are to control symptoms and decrease progression to AML.  Supportive care:  Blood product transfusion and hematopoeitic growth factors (e.g. EPO). Currently, 3 agents have been approved by the US FDA for the treatment of MDS.  5-azacytidine and decitabine (hypomethylating agents):  Shown to ↓ blood transfusion dependency and to retard progression to AML. Lenalidomide:  Approved only for the 5q- syndrome.  Stem cell transplant:  Particularly in younger patients (i.e. < 40 y/o) with severe disease as it offers the potential for curative therapy.

o   PLASMA CELLS DYSCRASIAS (aka monoclonal gammopathy):  Clonal proliferation of B-lymphocytes or plasmacytoid lymphocytes and/or plasma cells accompanied by accumulation of monoclonal immunoglobulin in the blood (i.e. M protein). Fragments of these monoclonal Ig (e.g. the k or l light chains) can pass through the renal glomeruli, and be identified in the urine as Bence-Jones protein.  Of note, plasmacytoid lymphocyte is an intermediate stage between B-lymphocyte and plasma cells. 

Ø  CLASSIFICATION:  Just think of W-waldenstrom’s M-macroglobulinemia = WM → W-Waldenstrom’s M-macroglobulinemia (IgM) [~2%], M-monoclonal gammopathy of undetermined significance (MGUS), [~65%], M-multiple myeloma (MM), [~20%].  Other subtypes do exist (i.e. plasmacytoma and heavy-chain disease), but they occur at a much lower rate.  SEE ALSO AMYLOIDOSIS AL SUBTYPE. 

v  W _______________, _______________, _______________, _______________, _______________

v  M _______________, _______________, _______________, _______________, _______________

Ø  WALDENSTROM’S MACROGLOBULINEMIA:  A low-grade lymphoplasmacytic lymphoma characterized by the production of monoclonal IgM.

v  EPIDEMIOLOGY:  US incidence: 1,500/yr. Median age of onset 60 y/o.  M > F.

v  PATHOPHYSIOLOGY:  Plasmacytoid lymphocytes circulate in the blood and infiltrate into the bone marrow (anemia), lymph nodes (LAD), and liver and spleen (hepatosplenomegaly).  The resultant production of monoclonal IgM either circulates in the blood (hyperviscosity, cryglobulinemia, platelet dysfunction) or deposits in tissue (peripheral neuropathy, renal disease, AL amyloidosis).

v  PRESENTATION:  History: Anemia (weakness, fatigue, weight loss), platelet dysfunction (chronic bleeding from the nose and gums), peripheral neuropathy (occur in 10%), hyperviscosity (HA, blurry of vision, stroke), and cryoglobulinemia (vasculitis, purpura, arthralgia, myalgia).  Physical exam: LAD and hepatosplenomegaly (occur in 30-40%).

v  DIAGNOSTIC EVALUATION:  Presence of an IgM monoclonal paraprotein is the distinguishing feature of WM.   There is also a concurrent decrease in levels of uninvolved immunoglobulins (i.e. IgG and IgA).

v  TREATMENT:  Asymptomatic patient:  Monitor.  Symptomatic patients:  Initiate treatment.  Plasmapheresis:  Treat the hyperviscosity syndrome by removing the IgM paraprotein.  Medical therapy:  Rituximab, fludarabine, chlorambucil, cyclophosphamide, or vincristine alone or in combination with corticosteroids.   Autologous BMT.

Ø  DIAGNOSTIC EVALUATION:  CBC: Anemia.  CMP: May show renal dysfunction, hypercalcemia.  ESR: May be elevated.  UA: Proteinuria.  Serum protein:  Elevated due to Ig.  Peripheral smear:  May show RBCs rouleaux formation.  SPEP and UPEP (serum and urine protein electrophoresis):  Presence of M protein band on SPEP and Bence Jones protein on UPEP.  Paraprotein quantitation:  Necessary to establish a diagnosis and to monitor the disease.  Immunohistochemistry: Identify monoclonal cell by surface markers.  Bone marrow biopsy:  Estimate the percentage of bone marrow occupied by plasma cells.  Full body skeletal survery:  Identify "lytic lesions" or "punched-out lesions".  MRI:  Even more sensitive than bone scan in the detection of lytic lesions and may be the better choice when when vertebral disease is suspected.

Schematic representation of a normal protein electrophoresis gel. A small spike would be present in the gamma (γ) band in MGUS

By Jfdwolff at en.wikipedia - Transferred from en.wikipedia; description page is/was here., Public Domain, https://commons.wikimedia.org/w/index.php?curid=3929045

Serum protein electrophoresis showing a paraprotein (peak in the gamma zone) in a patient with multiple myeloma.

By Steven Fruitsmaak - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5661501

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Ø  MGUS (MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE aka benign monoclonal gammopathy):  Monoclonal protein identified in asymptomatic persons; the significance of which cannot be determined at the time of its detection.

v  EPIDEMIOLOGY:  Most common monoclonal gammopathy.  Prevalence: 3% otherwise healthy individual > 50 y/o and up to 5% of those > 70 y/o. 

v  PATHOPHYSIOLOGY:  The pathophysiology of MGUS is similar to multiple myeloma (SEE BELOW).  In both, there is a predominance of clonal plasma cells in the bone marrow with an abnormal immunophenotype (CD38+ CD56+ CD19−) mixed in with cells of a normal phenotype (CD38+ CD56− CD19+).  What causes MGUS to transform into multiple myeloma not yet fully known.

v  DIAGNOSTIC EVALUATION:  Must meet these diagnostic criteria: 

1.     Monoclonal paraprotein spike (usually IgG) < 3 g/dl

2.     Plasma cell < 10% on bone marrow examination

3.     No large atypical plasma cells

4.     No Bence-Jones proteinuria

5.     No clinical consequences of paraproteinemia (i.e. No CRAB → C-calcium elevation [hypercalcemia], R-renal failure, A-anemia, B-bone lytic lesion).   

v  TREATMENT:  No treatment.  Follow up with SPEP q 6 months or 1 year. 

v  PROGNOSIS:  MGUS may be considered a pre-malignant condition as the annual risk of progressing to multiple myeloma is around 1–2%. In addition, MGUS may also progress to Waldenström's macroglobulinemia, primary amyloidosis, B-cell lymphoma, or CLL.

Ø  MULTIPLE MYELOMA (MM aka plasma cell myeloma or as Kahler's disease):  A malignant plasma cell tumor.   

v  EPIDEMIOLOGY:  2nd  most common blood cancer (10%) after NHL. US annual incidence:  14,600/year.   Peak age on onset is between 65-70 y/o.  M > F. African Americans > Causcasians > Asians.

v  PATHOPHYSIOLOGY:  Chromosomal abnormalities, including translocation of the Ig heavy chain locus on chromosome 14 (e.g. t(14;16)), have been documented in MM, and is thought to be an important initiating event.  Much of the problems arising from MM is the result of 1) Malignant plasma cell infiltration into the tissue and bone marrow 2) Malignant plasma cells production of monoclonal protein and 3) Malignant plasma cell production of cytokines.

1.     Malignant plasma cell infiltration into the tissue causes plasmacytoma (i.e. a malignant monoclonal plasma cell tumor growing either in bone or soft tissue) and peripheral neuropaty. Malignant plasma cell infiltration into the bone marrow causes physical crowding, and thus, anemia, and possibly leukopenia and thrombocytopenia.

2.     Malignant plasma cells production of monoclonal protein (IgG 60%, IgA 25%; in 15% of cases only light chains are produced):  Results in an M protein spikes on electrophoresis and Bence Jones proteinuria, impair production of normal Ig causing immunodeficiency, amyloidosis, renal failure, and hyperviscosity syndrome.

3.     Malignant plasma cell production of IL-1b and IL-6:  IL-1b is an osteoclast-activating factor and causes osteoporosis, lytic bone (punched-out) lesions, hypercalcemia, and bone pain.  IL-6 creates a microenvironment in which the malignant plasma cells thrive, and also causes anemia and immunodeficiency.

v  PRESENTATION:  MR CRAB (this dude is from Sponge Bob Squarepant)  M-monoclonal M-malignant plasma cells producing excessive Ig causing M-M protein spikes, R-rouleaux (poker chip) formation of RBCs seen on peripheral smear, C-calcium is elevated (from lytic lesions), R-renal failure (from Bence Jones protein, hypercalcemia, amyloid…), A-anemia (from the replacement of normal bone marrow by infiltrating tumor cells and cytokine inhibition of hematopoiesis), A-amyloidosis (from amyloid light chain), B-bone lesions (most commonly involve the vertebral bones causing spinal cord compression; other sites in descending order ribs, skull, pelvis, fumur, clavicle, scapular). 

§  M _______________, _______________, _______________, _______________, _______________

§  R _______________, _______________, _______________, _______________, _______________

§  C _______________, _______________, _______________, _______________, _______________

§  R _______________, _______________, _______________, _______________, _______________

§  A _______________, _______________, _______________, _______________, _______________

§  B _______________, _______________, _______________, _______________, _______________

Illustration showing the most common site of bone lesions in vertebrae

By Blausen Medical Communications, Inc. - Donated via OTRS, see ticket for details, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=27639943

v  DIAGNOSTIC EVALUATION:  IHC:  Myeloma cells are typically CD56+, CD38+, CD138+ and CD19-, CD45-.  Diagnostic criteria:  Must meet one major and one minor criteria OR ≥ 3 minor criteria.  b2-microglobulin levels:  Use in MM staging.

§  MAJOR CRITERIA:  1) Plasmacytoma on tissue biopsy 2) Marrow plasmacytosis >30% 3) Monoclonal protein (IgG > 3.5 g/dl or IgA > 2.0 g/dl or light-chains only > 1.0 g/dl).

§  MINOR CRITERIA:  1) Marrow plasmacytosis 10-29%  2) Monoclonal proteins that is less than that required in the major criteria 3) Lytic bone lesions 4) Decrease in uninvolved Igs (IgM < 50 mg/dl, IgA < 100 mg/dl &/or IgG < 600 mg/dl)

CT scan of the lower vertebral column in a man with multiple myeloma, showing multiple osteoblastic lesions. These are more radiodense (brighter in this image) than the surrounding cancellous bone, in contrast to osteolytic lesions which are less radiodense.

By Mikael Häggström - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=56847744

Pathological fracture of the lumbar spine due to multiple myeloma

By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49320717

Skull X-ray showing multiple lucencies due to multiple myeloma

By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49320711

A CT of the brain revealed a lytic lesion in the left temporal bone (right side of image), and petrous temporal bones involving the mastoid segment of the facial nerve canal. Red arrows: lesion; green arrow: normal contralateral facial nerve canal. The lesions are consistent with a myeloma deposit.

By dr Laughlin Dawes - radpod.org, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=5661636

Bone marrow aspirate showing the histologic correlate of multiple myeloma under the microscope. H&E stain.

By No machine-readable author provided. KGH assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims)., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=516830

Atypical plasma cell infiltrate with both Russell (cytoplasmic) and Dutcher (nuclear) bodies (H&E, 50x).

By Gabriel Caponetti - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=23284279

Micrograph of a plasmacytoma. H&E stain

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7350554

Micrograph showing myeloma cast nephropathy in a kidney biopsy. Hyaline casts are PAS positive (dark pink/red - right of image). Myelomatous casts are PAS negative (pale pink - left of image).

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17547364

v  TREATMENT:  Focus on disease containment and suppression. Commonly used induction/initial chemotherapy:  Various combination of  dexamethasone, melphalan, thalidomide, cyclophosphamide, and VAD (vincristine, adriamycin, and dexamethasone).  BMT: Offers the possibility of a cure, but has many unwanted side effects.  Plasmapheresis:  Treat hyperviscosity syndrome.  Dialysis:  For renal failure.  EPO: For anemia.  Bisphosphonates:  Prevent bone fractures.  Relapsing disease can be re-treated with the original agent; however, "treatment resistance" can occurs.  For patients with relapsed disease, bortezomib (or Velcade®), a proteosome inhibitor, can be considered.


o   PHYSIOLOGY OF HEMOSTASIS:  When a blood vessel is traumatized, several steps occur to top the bleeding:

1.     Vasoconstriction:  Slow the bleeding.

2.     Primary hemostasis (seconds to minutes):  Platelets bind to collagen in the exposed walls of the blood vessel to form a hemostatic plug.

Diagram of the structure of a platelet showing the granules

By Dr Graham Beards - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=21906052

Diagram of the structure of a platelet showing the granules

By Dietzel65, Steffen Dietzel - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=10205180

3.     Secondary hemostasis (minutes to hours): A complex cascade of coagulation factors generate fibrin to strengthen the primary hemostatic plug into a fine clot.

Coagulation with arrows for negative and positive feedback.

By Joe D - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1983833

-Factor I = Fibrin

-Factor III = Thromboplastin

-Factor IV = Ca++

-Factor VI = Suture

-Factor II, VII, IX, X, and protein C and S require post-translationally modification by a vitamin K-dependent reaction to become activated.

-Fibrin forms a "mesh" over the platelet plug, strengthening it. 

Feedback activation of FV, FVIII and FXI by Factor IIa and extrinsic pathway FVIIa cross-over activation of FIX render FXII non-essential.  Therefore, FXII deficiency leads to prolongation of aPTT, but does not result in clinical bleeding.

3.     Tertiary hemostasis (hours to days):  The clot retracts into a coarse clot.  Anti-thrombotic process is activated to keep the coagulation cascade in check.  Finally, the fibrinolysis cascade begins the repair process which ultimately results in the dissolution of the fibrin clot.




v  PATHOPHYSIOLOGY:  Typically develops 4-14 days after the administration of heparin (occur much more frequently UFH than LMWH).  Despite the thrombocytopenia, it is a thrombotic disorder, with very high rates of thrombosis (arterial > venous).    There are two forms of HIT. Type II HIT is the main adverse effect of heparin use. 

-       Type I:  Usually occur within 4 days.  Asymptomatic transient thrombocytopenia. Platelet counts rarely < 100,000, and it recovers even if heparin administration is continued. It occurs in 10-20% of all patients on heparin and is not due to an auto-immune disorder (as Type II is).

-       Type II:  Usually occur between 5–14 days.  It is an autoimmune reaction where antibodies form against complexes of PF4 (platelet factor 4) and heparin.  These antibodies (most commonly IgG), then binds to platelets through their Fc receptors and cause their activation.  Activated platelets release more PF4 setting up a vicious cycle.  Activated platelets are removed from the circulation by spleen causing thrombocytopenia.  This consumptive process also activates platelets leading to thrombosis via the generation of thrombin.  Type II HIT develops in 3-5% of all patients on UFH, but only in 0.1% of patients LMWH.

A schematic drawing of platelet factor 4, which when bound to heparin leads to an immune response in HIT.

By ProteinBoxBot at en.wikipedia - www.pdb.org, Public Domain, https://commons.wikimedia.org/w/index.php?curid=16256159

v  PRESENTATION:  Systemic bleeding and localized arterial and venous thromboses occur.  Arterial thromboses:  Limb gangrene, stroke, MI.  Venous thromboses:  DVT, pulmonary embolism, cerebral sinus thrombosis.  Patients also develop skin lesions/necrosis at the heparin infusion site.  Clot formation is mainly arterial and rich in platelets ("white clot syndrome"), in contrast with fibrin-rich clots (which are red due to trapped red blood cells).

v  DIAGNOSTIC EVALUATION:  CBC:  Thrombocytopenia.  BT: ↑.  Enzyme Immunoassay-Serotonin Release assay (EIA-SRA): Most commonly used technique to diagnose HIT.  It measures release of serotonin from platelets on exposure to serum of patient in the presence of heparin. 

v  TREATMENT:  Prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. To block the thrombotic state, lepirudin, fondaparinux, bivalirudin, argatroban, danaparoid or other direct thrombin inhibitors are used.

Ø  HUS (HEMOLYTIC UREMIC SYNDROME):  Characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure (ARF). 

v  EPIDEMIOLOGY:  Peak incidence between 6 months and 4 y/o.  Occurs after 2-7% of all E. coli O157:H7 infections. 

v  PATHOPHYSIOLOGY:  The classic childhood case of HUS occurs after bloody diarrhea caused by the Shiga toxin-producing (aka verotoxin) E coli O157:H7.  Intestinal mucosal damage facilitates systemic absorption of the toxin, which then bind to globotriaosylceramide (Gb3), a glycolipid receptor on the surface of endothelial cells in the gut, kidney, and other organs.  Toxin-binding causes endothelial cells swell, microthrombi formation, and intravascular fibrin deposition on the injured vessel walls.  Microangiopathic hemolytic anemia (MAHA) is the result of RBCs destruction as they traverse the fibrin mesh.  Thrombocytopenia results from a combination of platelet destruction, consumption, splenic sequestration, and intrarenal aggregation.  ARF arises from damage to the glomerular capillaries.  Non–diarrhea-associated HUS:  Typically occuring in adult and may be the outcome chemotherapy (e.g. mitomycin, cyclosporine, cisplatin, bleomycin), HIV infection, autoimmune disease (e.g. antiphospholipid syndrome, scleroderma), malignant hypertension, and post partum renal failure.  Familial HUS (~ 5-10% cases):  Due to mutations in the complement proteins factor H, membrane cofactor protein &/or  factor I leading to uncontrolled complement system activation. Usually are not preceded by diarrheal illness, and frequently recurrent with a worse prognosis.

v  PRESENTATION:  3-12 days of bloody diarrhea followed by sudden onset of fatigue, irritability, and pallor (anemia),  petechiae, purpura, &/or oozing from venipuncture sites (thrombocytopenia), and hematuria, oliguria, edema (ARF).  Other potential symptoms: CNS (ataxia, coma, seizures), pancreas (varies from mild involvement to pancreatic necrosis), and cardiovascular (CHF).  Clinically, HUS can be difficult to distinguish from thrombotic thrombocytopenic purpura (TTP). The only distinguishing feature is that neurological symptoms occur more often in TTP.

v  DIAGNOSTIC EVALUATION:  CBC:  Anemia, thrombocytopenia, leukocytosis.  CMP:  Look for signs of renal &/or liver failure, and electrolytes abnormalities.  Peripheral blood smear:  Schistocytes, helmet cells, burr cells.  Coombs test:  Negative.  Serum haptoglobin:  ↓.  PT and aPTT: Normal.  FDPs:  ↑.  Bilirubin: ↑.  LDH: ↑.  UA:  Hematuria, renal casts.  Stool culture:  Detect E coli O157:H7.

Schistocytes as seen in a person with hemolytic-uremic syndrome

By Paulo Henrique Orlandi Mourao - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8823735

v  TREATMENT:  Dialysis: May be required in up to 50% of patients and is indicated in case of AEIOU → severe A-acidosis, E-electrolytes abnormalities, I-ingestion of toxic substances, O-verload of fluid, U-uremic syndrome.  Supportive therapy:   Transfusion (PRBC for symptomatic anemia; platelet transfusion is ontroversial since it may increase thrombus formation), anti-hypertensive agents, and TPN.  Antibiotic treatment of O157:H7 colitis may stimulate further verotoxin release and thereby increase the risk of HUS.

v  PROGNOSIS:  Despite aggressive therapy, ~ 9% may develop ESRD, ~ 8% have other lifelong complications (e.g. HTN, seizures, blindness), and ~ 1/3 develop varying degree of CRD.  The overall mortality rate is 5-15%.  Older children and adults have a worse prognosis.

Ø  HELLP SYNDROMEA life-threatening obstetric complication characterized by HELLP → H-hemolytic anemia, E-elevated L-liver enzymes, and L-low P-platelet count.

v  EPIDEMIOLOGY:  Incidence: 0.2-0.6% of all pregnancies. However, in patients with (pre)eclampsia, 4-12% also develop superimposed HELLP syndrome. HELLP usually begins during the 3rd trimester, and in Caucasian women > 25 y/o.

v  PATHOPHYSIOLOGY: The main underlying problem is the general activation of the coagulation cascade.  As a result, platelets are consumed (causing L-low P-platelets) and fibrin are crosslinked in a mesh-like networks in the small blood vessels (causing MAHA).   The liver appears to be the main site of this process, and downstream hepatocytes suffer ischemia, leading to periportal necrosis.

v  PRESENTATION:  Usually a patient has already been followed up for pregnancy-induced hypertension (new arterial hypertension after 20 weeks gestation), or is suspected to develop pre-eclampsia (HTN > 140/90 [mild] or > 160/110 [severe] on 2 separate readings taken ≥ 6 hours apart; proteinuria > 300 mg/24hr [mild] or > 5 g/24hr [severe]; and dependent edema).  Severe pre-eclampsia is also diagnosed if the patients only meet the above criteria for mild pre-eclampisa, but also develop HELLP syndrome, RUQ abdominal pain (from hepatic capsule rupture), cerebral changes (HA, somnolence), visual changes (blurred vision), and/or hyperactive reflexes.  If the patient gets a seizure or coma, the condition has progressed into full-blown eclampsia.   Finally, 20% of HELLP syndrome is complicated by DIC. 

v  DIAGNOSTIC EVALUATION:  CBC: Thrombocytopenia.  CMP: Check renal functions, electrolytes, and liver enzymes.  UA &/or 24-hour urine protein: Proteinuria.  FDPs/d-dimers (markers of coagulopathy): May be ↑.  Lactate dehydrogenase (marker of hemolysis):  ↑ >600 U/L.  Mississippi classification:  Mild (platelet > 100 x 103/mL); moderate (platelet 50-100 x 103/mL); severe (platelet < 50 x 103/mL).

v  TREATMENT:  IVF.  Delivery of the baby:  The only effective treatment.  Antihypertensives (labetalol, hydralazine, nifedipine).  Magnesium sulfate:  Seizure prophylaxis to prevent progression to eclampsia.  Diazepam:  For recurrent seizures.  Blood products:  FFP is used in DIC to replenish the coagulation factors;  PRBC to combat anemia. Mortality is 7-35%.

Ø  ITP (IDIOPATHIC THROMBOCYTOPENIC PURPURA): AKA Werlhof's disease or immune thrombocytopenic purpura.

EPIDEMIOLOGY: Annual incidence:  50–100/1 million.  50% occurs in children.  In adults, the peak age at diagnosis is 20-50 y/o.  F > M. 

PATHOPHYSIOLOGY:  An autoimmune disorder with antibodies against platelets detected in ~ 60% of cases.  Often the antibodies are IgG directed against GPIIb-IIIa or GP Ib-IX, which coat the platelets and renders them susceptible to opsonization and phagocytosis by splenic macrophages. 

v  PRESENTATION:  Most cases are asymptomatic; however patients with a very low platelet count will suffer from bruising, petechiae, purpura, nosebleeds, bleeding gums, and menorrhagia (in women).  Severe bleeding (e.g. subarachnoid hemorrhage or other internal bleeding) are very serious possible complications if platelets count drops < 20,000.  Patients are usually afebrile and splenomegaly is absent.  In children, ITP is usually postviral and self-limited (> 70% end up in remission within 6 months whether treated or not).  In adults, ITP is usually chronic (> 6 months) and the probability of durable remission is only 20–40%.  In pregnant patient, the anti-platelet IgG antibodies can cross the placental membrane causing thrombocytopenia in the newborns.

Oral petechiae/purpura - lower lip

By Mdscottis - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=24734024

Petechia on the tongue in a person with platelets of 3 due to ITP

By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49061284

Petechiae on the lower extremities

By The original uploader was Seasurfer at Chinese Wikipedia - http://www.cdc.gov/ncidod/dvbid/dengue/slideset/set1/vi/slide07.htm, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2111479

Petechia of the lower leg in a person with platelets of 3 due to ITP

By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49061283

Purpura spots

By User:Hektor - the English Wikipedia: http://en.wikipedia.org/wiki/Image:Purpura.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1222775

v  DIAGNOSTIC EVALUATION:  ITP is a diagnosis of exclusion.  CBC:  Thrombocytopenia.  BT: Prolonged.  PT and aPTT: Normal.  Periphereal smear:  Megathrombocytes without schistocytes. Bone marrow examination: Increase megakaryotes.  In ~1% of cases autoimmune hemolytic anemia and ITP coexist, which is a condition called Evans syndrome.

v  TREATMENT:  In generally, there is no need to treat the patients with above 50,000/mL.  On the other hand, platelet count < 20,000/mL is an indication for treatment.  In cases where platelets count is 20,000–50,000/μL decision is made on a case by case basis.  IV steroids (methylprednisolone or prednisone): Usually given as the first-line therapy.   IVIg:  Expensive and the improvement is temporary (usually < 1 month).  It is often used in pre-splenectomy ITP patients with severe thrombocytopenia (< 10,000) to rapidly raise platelet counts, making the splenectomy operation less dangerous.  Anti-Rho (D):  An effective treatment, but only in Rh+ patients.  Platelet infusions:  Given to raise the count quickly in cases of uncontrollable bleeding. Otherwise, it is not normally recommended and the anti-platelet antibodies will also destroy donor platelets.  Splenectomy:  Effetive in 60% of cases refractory to medical treatment.  Immunosuppresants (e.g. mycophenolate mofetil, azathioprine, and rituximab):  These are increasingly being used because of their effectiveness.  Other treatment:  H. pylori eradication has been shown in some studies to improve platelet count dramatically.

v  SUMMARY OF ITPITP  → I-immune disorder that is usually I-idiopathic in adults but associated with I-infection (i.e. postviral) in children;  I-IgG anti-platelet antibodies causes T-thrombocytopenia because they coat the platelet surface render them susceptible to opsonization and P-phagocytosis by splenic macrophages.

§  I _______________, _______________, ______________, ______________, ______________

§  T _______________, _______________, ______________, _______________, _____________

§  P _______________, _______________, ______________, ______________, ______________


EPIDEMIOLOGY:  Annual incidence:  ~ 4-6/1 million. F > M.  Blacks > whites. 

PATHOPHYSIOLOGY:  TTP is a form of MAHAs, which is characterized by spontaneous aggregation of platelets and activation of coagulation in the small blood vessels.  These processes causes thrombocytopenia from the consumption of platelets and hemolysis from the shearing of RBCs as they traverse the intravascular fibrin mesh.  There are 3 forms of TTP: 1) Idiopathic 2) Secondary 3) Inherited (aka Upshaw-Schulman syndrome).

1)    IDIOPATHIC TTP:  According to the Furlan-Tsai hypothesis,  idiopathic TTP is an autoimmune disorder characterized by the inhibition of the enzyme ADAMTS13 by antibodies.  In fact, in ~ 80% of patient, severely decreased (<5% of normal) ADAMTS13 activity can be detected.  ADAMTS13 is a metalloproteinase that breakdown von Willebrand factor (vWF).  Without proper cleavage of vWF by ADAMTS13, coagulation occurs at a higher rate, especially in the part of the vasculature where vWF is most active due to high shear stress, the microvasculature. 

2)    SECONDARY TTP (~40% of TTP cases):  Diagnosed when the patient has a predisposing factors for TTP, which include:  Cancer, Bone marrow transplantation, Pregnancy, HIV-1 infection, and Medication use (e.g. Platelet aggregation inhibitors such as ticlopidine and clopidogrel and Immunosuppressants such as cyclosporine, mitomycin, tacrolimus/FK506, INF-α).  The mechanism of secondary TTP is not known and ADAMTS13 activity is generally not as depressed as in idiopathic TTP.

3)    HEREDITARY TTP (aka Upshaw-Schulman syndrome; ~ 10% of TTP cases):  Inherited deficiency of ADAMTS13.  Surprisingly, these patients are usually asymptomatic and develop TTP in clinical situations with increased vWF levels (e.g. infection).

PRESENTATION:  Classically, five symptoms are indicative of TTP:  FAT R-registered N-nurse = FAT RN → F-fever (occur in 33%), A-anemia (MAHA type causing jaundice and dark urine), T-thrombocytopenia (causing easy bruising, purpura), R-renal failure (occur in 46%), N-neurological symptoms (HA, altered mental status, seizures, stroke).  In addition, microthrombus formation can results in ischemia in the GI tract  (N/V, abdominal pain), heart (chest pain), muscle (mylagia, arthralgia). 

§  F _______________, _______________, ______________, ______________, ______________

§  A _______________, _______________, ______________, ______________, ______________

§  T _______________, _______________, ______________, ______________, ______________

§  R _______________, _______________, ______________, _______________, _____________

§  N _______________, _______________, ______________, ______________, ______________

DIAGNOSTIC EVALUATION:  CBC:  Anemia, thrombocytopenia, leukocytosis.  CMP:  Look for signs of renal &/or liver failure, and electrolytes abnormalities.  Peripheral blood smear:  Schistocytes.  Coombs test:  Negative.  Serum haptoglobin:  ↓.  PT and aPTT: Normal.  BT: ↑.  Bilirubin: ↑.  LDH: ↑.  UA:  Hematuria, renal casts.  Stool culture:  Detect E coli O157:H7.

v  Lactate dehydrogenase levels are generally used to monitor disease activity.

TREATMENT:  Plasmapheresis (treatment of choice): Removal of the patient's blood plasma and replacement with donor plasma (FFP or cryoprecipitate) to eliminate the inhibitor of ADAMTS13. Plasmapheresis may need to be continued daily for 1-8 weeks before patients with idiopathic TTP cease to consume platelets and begin to normalize their hemoglobin.  Many TTP patients need additional immunosuppressive therapy, with corticosteroids (e.g. prednisolone or prednisone), vincristine, &/or cyclophosphamide.  Splenectomy or rituximab, are used to treat patients with refractory disease.  Children with Upshaw-Schulman syndrome receive plasma every 2-3 weeks prophylactically to maintain adequate levels of functioning ADAMTS13.

PROGNOSIS:  Idiopathic TTP:  Mortality rate ~ 95% for untreated cases and ~ 10-20% for cases diagnosed and treated early with plasmapheresis.  Secondary:  Mortality rates 59% -100% despite treatment.  The ten-year relapse rate after one TTP episode is 33%. 


PATHOPHYSIOLOGY:  Glanzmann's thrombasthenia can be inherited in an autosomal recessive manner or acquired as an autoimmune disorder (e.g. occuring with NHL).  In Glanzmann's thrombasthenia, platelets lack glycoprotein IIb/IIIa, a receptor for fibrinogen. Hence, no platelet-platelets fibrinogen bridging can occur, and platelet aGGregation is inhibited.   

PRESENTATION:  Characteristically, there is increased cutaneous bleeding (petechiae, ecchymoses), mucosal bleeding (epistaxis, menorrhagia), and post-operative bleeding (e.g. dental extraction).

DIAGNOSTIC EVALUATION:  CBC, PT, and aPTT: Normal.  BT: ↑ significantly.  Peripheral smear:  Normal platelet morphology. Platelet aggregation studies:  Aggregation of platelets occurs in response to ristocetin, but not to other agonists such as ADP, thrombin, collagen or epinephrine.

TREATMENT: Platelet transfusion (use in acute bleeding or surgery prophylaxis), OCP (control menorrhagia), recombinant human-activated factor VII (also useful for controlling bleeding). Patients should avoid medications that affect platelet function (e.g. aspirin and other NSAIDs).

Ø  VON WILLEBRAND DISEASE (vWD):  Due to a qualitative or quantitative deficiency of von Willebrand factor (vWF).

2)    ACQUIRED vWD:  Associated a) Patients with autoantibodies resulting from the rapid elimination of  vWF-antibody complex from the circulation b) Heyde’s syndrome: A syndrome of aortic valve stenosis (↑ breakdown of large vWF multimer by ADAMTS13 under conditions of high shear stress around the stenosed valve) and GI bleeding from colonic angiodysplasia (shear stress in these vessel is much higher than in average capillaries) and c) Others:  Wilms' tumour, hypothyroidism and mesenchymal dysplasias.

PRESENTATION:  Varying degrees of bleeding tendency depending on the specific type, including bruising, nosebleeds, heavy menstrual periods and blood loss during childbirth.  Severe internal or joint bleeding is rare and occur only in Type 3 vWD.

DIAGNOSTIC EVALUATION:  CBC.  BT. PT.  aPTT.  TT.  Fibrinogen level.  vWF:Ag (vWF antigen assay):  Measure vWF and indicates a quantitative deficiency but not the functionality of vWF.  It is likely to be decreased in all types of vWD.  vWF:RCoF (ristocetin cofactor activity) or RIPA (ristocetin-induced platelet aggregation):  Ristocetin promotes the binding of vWF to platelet GP Ib-IX-V enabling platelet agglutination.  These tests provide information about the function of vWF. The results will be decrease or absent in all type of vWD except with Type 2B, which characteristically has in increased RIPA.  Factor VIII levels:  Decreased.   Factor IX:  If hemophilia B is suspected.

EPIDEMIOLOGYThe most common hereditary coagulation abnormality.  It can also be acquired as a result of other medical conditions.  Prevalence:  1/100 individuals.  Most forms are mild, so they are detected more often in women, whose bleeding tendency shows during menstruation. It may be more severe or apparent in people with blood type O.

PATHOPHYSIOLOGY:  The vWF gene is located on chromosome 12.  vWF is a multimeric protein that is synthesized in megakaryocytes and endothelial cells and stored in alpha granules and Weibel-Palade body, respectively.  Clinically, vWF release is induced by DDAVP.  In the blood stream, it is bound to and protects factor VIII from degradation and is required for platelet adhesion to the damaged blood vessel wall.  vWF is mainly active in conditions of high blood flow and shear stress (i.e. the small blood vessels).  As such, deficiency of vWF shows primarily in organs with extensive small vessels, such as the skin, the gastrointestinal tract and the uterus. vWF is broken down by a protein named ADAMTS13. 

CLASSIFICATION OF vWD:  1) Hereditary 2) Acquired

1)    HEREDITARY vWD:  4 types type 1, type 2, and type 3. Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive.

Ø  BERNARD-SOULIER SYNDROME:  AKA hemorrhagiparous thrombocytic dystrophy.

EPIDEMIOLOGY:  Prevalence: 1/1 million. 

PATHOPHYSIOLOGY:  An autosomal recessive disorder characterized by unsually large platelets that lack GP Ib-IX-V, a receptor for vWF. Hence, platelet adhesion is inhibited.

PRESENTATION:  Increased cutaneous bleeding (petechiae, ecchymoses), mucosal bleeding (epistaxis, menorrhagia), and post-operative bleeding (e.g. dental extraction).

DIAGNOSTIC EVALUATION:  CBC: Thrombocytopenia. BT: Prolonged.  PT and aPTT: Normal.  Periperipheral smear: Thrombocytopenia with presence of megathrombocytes.

TREATMENT: Similar to Glanzmann thrombasthenia.  Platelet transfusion (use in acute bleeding or surgery prophylaxis), OCP (control menorrhagia), recombinant human-activated factor VII (also useful for controlling bleeding). Patients should avoid medications that affect platelet function (e.g. aspirin and other NSAIDs).

II) DISORDERS OF COAGULATION FACTORS:  Usually manifest as deeper bleeding involving the joints (hemarthrosis) and body cavities (hemoperitoneum).  PT and aPTT are elevated.  TYPES:  Hemophilia A, Hemophilia B, and Hemophilia C (hereditary), and DIC (acquired).


Ø  HEMOPHILIA CA relatively mild form of hemophilia.  Epidemiology:  Prevalence:  1/100,000; predominantly Ashkenazi Jews.  Pathophysiology:  Autosomal recessive deficiency of factor XI, whose gene is on chromosome 4.  Presentation:  Prolonged bleeding from injuries, epistaxis, menorrhagia, &/or hematuria.  It can be distinguished from hemophilia A and B by the fact it does not lead to bleeding into the joints or other deep compartments.  Treatment:   FFP or recombinant factor XI may be used as needed.


PATHOPHYSIOLOGY:   In DIC, the processes of coagulation and fibrinolysis lose control, and the result is widespread clotting with resultant bleeding. One critical mediator of DIC is the release of tissue factor (TF), which is exposed to the circulation after vascular damage. TF binds with coagulation factors that then trigger both the intrinsic and the extrinsic pathways of coagulation, resulting in the production of excess circulating thrombin.  The excess thrombin cleaves fibrinogen, which ultimately leaves behind multiple fibrin clots that then trap platelets to become larger clots, leading to microvascular and macrovascular thrombosis. These thromboses lead to tissue ischemia and end-organ damage seen with DIC.  In the process, platelets, coagulation factors, and coagulation inhibitors are consumed, which contribute to the bleeding seen with DIC.  Simultaneously, the excess thrombin also activate the fibrinolysis system (seen as ↑ FDPs) and  activates the complement and kinin systems (manifested as increased vascular permeability, hypotension, and shock).  Causes of DIC include:  DIC → D-destruction of organ (e.g. severe pancreatitis, acute hepatic necrosis) or tissue (e.g. burns, surgery), I-infection (gram-negative sepsis > gram-positive bacteria > virus/fungi), I-intrauterine fetal demise and other obstetric complications (due to release of chemicals in to maternal blood), C-cirrhosis, C-cancers (e.g. stomach, colorectal or pancreatic cancer, mucin-secreting adenocarcinoma, and treatment of AML-M3).  Others causes:  Blood transfusion reactions, GVHD, viral hemorrhagic fevers, malaria, and snake venom.

§  D _______________, _______________, _______________, ______________, ______________

§  I _______________, _______________, _______________, ______________, ______________

§  C _______________, _______________, _______________, ______________, ______________

PRESENTATION:  Acute DIC presents with petechiae and echymoses on the soft palate and legs, bleeding from venipuncture sites, hematemesis, digital gangrene, venous thromboembolism, hypotension, shock, and death.

DIAGNOSTIC EVALUATION:  CBC:  Thrombocytopenia.  BT, PT, aPTT: All prolonged. FDP &/or D-dimer tests (markers of fibrinolysis):  Elevated.  Fibrinogen:  Reduced.  Peripheral blood smear:  Signs of MAHA including schistocytes and helmet cells.   

Micrograph showing an acute thrombotic microangiopathy, the histologic correlate of DIC, in a kidney biopsy. A thrombus is present in the hilum of the glomerulus (center of image). PAS stain.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18646566

TREATMENT:  The only effective treatment is the reversal of the underlying cause.  Platelets, FFP, &/or cryoprecipitate transfusion:  Attempt to replenish plates (especially when it is < 5,000-10,000/mm3), coagulation factors, anti-thrombotic factors.  Drotrecogin alfa (Xigris®):  Recombinant activated protein C, which inactivates factors V and VIII, is indicated in patients with severe sepsis. Anticoagulants:  Given rarely in cases when thrombus formation is likely to lead to imminent death (e.g. coronary artery thrombosis or cerebrovascular thrombosis).

o   HEREDITARY HYPERCOAGULABLE STATES (aka thrombophilia):  Hereditary propensity to develop thrombosis due to an abnormality in the coagulation system.

Ø  EPIDEMIOLOGY:  Prevalence: 5-8% of the U.S. population has one of these clotting disorders.

Ø  PRESENTATION: Young patients (< 50 y/o), recurrent (≥ 2) unprovoked episodes of thrombosis, recurrent miscarriage, and unusual sites and types of thrombosis (e.g. Budd-Chiari syndrome) are indications for thrombophilia screening.  The presence of acquired hypercoagulable states increases the chance that an individual with hereditary thrombophilia will manifest the disease. These acquired hypercogulable states include OCP (remember OCP is contraindicated in female smokers > 35 y/o due to ↑ risk of DVT) → O-obesity, O-OCP use (estrogen-containing), C-cancers (most commonly with pancreatic and bronchogenic carcinoma), P-pregnancy, P-post-operative.

v  O _______________, _______________, _______________, _______________, _______________

v  C _______________, _______________, _______________, _______________, _______________

v  P _______________, _______________, _______________, _______________, _______________

A right-sided acute deep vein thrombosis (to the left in the image). The leg is swollen and red due to venous outflow obstruction.

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9444797

Ø  DIAGNOSTIC EVALUATION:  Generally, screening for thrombophilia include PT/INR, aPTT, TT, fibrinogen levels.  Disease specific test includes: 1) Functional assays:  Activated protein C (APC) resistance, Protein C levels, Protein S levels, AT-III levels, and Antiphospholipid antibody levels 2) Plasma levels: Homocystein levels, Fibrinogen levels 3) Molecular tests (PCR): Factor V Leiden (FVL) mutation, Prothrombin G20210A mutation.

Ø  TREATMENT:  Diagnosis of hereditary thrombophilia alter the clinical care of the patient and family members.  The information is used to determine the duration or intensity of oral anticoagulation, the intensity of prophylaxis for high-risk situation (e.g. surgery, prolong immobilization, pregnancy), counseling as to the risks of OCP/HRT/pregnancy, and study family members at risk of thrombosis. Medications: Aspirin (inhibit platelet activation), warfarin (anticoagulate with INR 3-4), &/or heparin/LMWH (used during pregnancy to prevent warfarin's teratogenicity). Women with recurrent miscarriage are often advised to take aspirin and to start LMWH after missing a menstrual cycle.

Ø  TYPES OF HEREDITARY THROMBOPHILIA:  F-feel M-my A-ass P-please = FMAP → F-FVL (20-60%), M-MTHFR mutation (testing is no longer recommended), A-antiphospholipid antibodies syndrome, A-antithrombin III deficiency (1-4%), P-prothrombin G20210A mutation (5-15%), P-protein C or S deficiency (total 4-10%), P-PNH-paroxymal nocturnal hemoglobinuria, P-plasminogen disorder

v  F _______________, _______________, _______________, _______________, _______________

v  M _______________, _______________, _______________, _______________, _______________

v  A _______________, _______________, _______________, _______________, _______________

v  P _______________, _______________, _______________, _______________, _______________

Ø  FVL (FACTOR V LEIDEN):  A variant of human factor V that cannot be inactivated by APC.

EPIDEMIOLOGY:  The most common hereditary hypercoagulability disorder.  Prevalence: ~5% of caucasians in North America.  Caucasians > Hispanics > African-Americans > Asians.  Up to 30% of patients who present with DVTor pulmonary embolism have this condition.

PATHOPHYSIOLOGY:  Autosomal dominant Factor V mutation in which Arg is replaced by Glu at the 506th amino acid producing FVL, which cannot be destroyed by APC. When factor V remains active, it facilitates overproduction of thrombin leading to excess fibrin generation and excess clotting.

v PRESENTATION:  In FVL, excessive clotting is almost always restricted to the V-veins (FVL), causing DVT, pulmonary embolism, and cerebral vein thrombosis.  There is no increase the formation of clots in arteries that can lead to stroke or heart attack.  Female patients have increased risk of recurrent miscarriage, preeclampsia, stillbirth (from clotting in the placenta, umbilical cord, or fetus).

DIAGNOSTIC EVALUATION:  Measure aPTT as APC is added:  With FVL, APC will barely affect aPTT.  In normal patients, adding APC prolongs aPTT.  Molecular test (PCR): Identify FVL mutation.


EPIDEMIOLOGY: Prevalence:  ~5% of the North American population.  

PATHOPHYSIOLOGY:  MTHFR is an cytoplasmic enzyme that irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is then used to convert homocysteine (a potentially-toxic amino acid) to methionine by the enzyme methionine synthase.  MTHF C677T mutation results in a thermolabile enzyme with decreased enzymatic activity.  The ultimate outcome of MTHFR mutation is hyperhomocysteinemia.  Of note, low dietary intake of folic acid, Vit B6 & B12 and use of certain drugs (e.g. MTX, TMP, phenytoin) also causes mild hyperhomocysteinemia.

PRESENTATION:  Hyperhomocysteinemia is associated with arterial and venous thrombosis (DVT, PE, CVA, obstetric complications) cardiovascular disease (CAD, MI), neural tube defects in offspring, and schizophrenia.

DIAGNOSTIC EVALUATION:  Fasting serum homocysteine

Ø  ANTI-PHOSPHOLIPID SYNDROME (APLS):   AKA Hughes syndrome.  It is an autoimmune disease, in which antiphospholipid antibodies (aPL) develop against phospholipoproteins on plasma membranes.

EPIDEMIOLOGY: Prevalence: 5% of the general population and up to 40% of those with a rheumatic disease (e.g. SLE) have anti-phospholipid antibodies.  However, only a small portion of these individuals develops the complication stemming form the presence of these antibodies (i.e. APAS). F > M. 

PATHOPHYSIOLOGY There are 2 types of aPL (usually IgG, but can be IgA, IgM):  Anticardiolipin antibodies and Lupus anticoagulants.  The main target of anti-cardiolipin antibodies is apolipoprotein H (aka β2-Glycoprotein 1) and the main target of Lupus anticoagulant is prothrombin.  aPL bind to phospholipid and thereby interfere with the ability of phospholipid to serve its essential cofactor function in the coagulation cascade, thus prolonging both PT and aPTT.  Despite the prolonged clotting times, bleeding is not a typical feature associated with these antibodies.  While it is known that aPL also activate platelets, the vascular endothelium and the complement system, and inhibit protein C & S and other coagulation factors, it is not well-established how the presence of aPL causes thrombosis.  CLASSIFICATION OF APLS:  Primary (no underlying disease state) and secondary (in association with an underlying disease such as SLE or from drugs such as hydralazine and phenytoin).  It also causes FALSE POSITIVE VDRL

PRESENTATION:  APLS causes both arterial (#1 is stroke) and venous (#1 is DVT) thrombosis in any organ system:  DVT, cardiac vegetations, CAD, hemolytic anemia, thrombocytopenia, and APLS → A-adrenal infarction, P-pregnancy-related complications (especially miscarriage in the 2nd or 3rd trimester, P-pulmonary embolism, L-livedo reticularis and other skin lesions, S-strokes. 

§  A _______________, _______________, _______________, ______________, ______________

§  P _______________, _______________, _______________, _______________, ______________

§  L _______________, _______________, _______________, _______________, ______________

§  S _______________, _______________, _______________, _______________, ______________

Micrograph showing an advanced thrombotic microangiopathy, as may be seen in ALPA syndrome. Kidney biopsy. PAS stain.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17293564

DIAGNOSTIC EVALUATION:  Laboratory diagnostic criteria for APLS: Require ≥ 1 of

1.     Anticardiolipin antibodies (ACA) &/or beta2-glycoprotein:  Identified on ≥ 2 occasions ≥ 6 weeks apart by ELISA assays. 

2.     Lupus anticoagulant antibodies (LAC):  Identified on ≥ 2 occasions ≥ 6 weeks apart in the following manner: a) Prolongation of aPTT, PT, kaolin clotting time (kaolin, an activator of coagulation system, is added to blood and the mixture is timed until a clot forms), and dilute Russell's viper venom time (the venom induce thrombosis by directly activates factor X, which turns prothrombin into thrombin in the presence of factor V and phospholipid) b) Failure to corrrect the prolonged coagulation time by mixing studies c) Correction of coagulation time by the addition of excess phospholipid d) Exclusion of other thrombophilia.


EPIDEMIOLOGY: Prevalence: 0.02% of the general population.

PATHOPHYSIOLOGY:  ATIII complexes with endogenous heparan sulfates to inactivates both thrombin and Factor Xa.  ATIII deficiency, therefore, leads to uncontrolled thrombin activation of the coagulation cascade resulting in thrombosis.  Hereditary ATIII deficiency is divided into 3 types (all autosomal dominant inherited): Type 1 (quantitative defect), Type II (qualitative defect-thrombin binding site defects), and Type III (qualitative defect-heparin binding site defects).  Acquired ATIII deficiency results from accelerated consumption ( acute clot, DIC, sepsis), reduced synthesis (liver disease), increased excretion (nephrotic syndrome), and medications (e.g. OCP, estrogens, heparin).

PRESENTATION: Homozygous cases are lethal in utero.  Heterozygous cases manifest as recurrent venous thrombosis (DVT-50% occur 25 y/o, pulmonary embolism, cerebral vein thrombosis, mesenteric vein thrombosis) and arterial thrombosis.  Acquired ATIII deficiency only impose a slight increased risk of thrombosis


TREATMENT:  Short term:  ATIII replacement +/- heparin.  Long term: Warfarin.


EPIDEMIOLOGY: Prevalence: 1-2% of the general population.  Whites > blacks.

PATHOPHYSIOLOGY:  Autosomal dominant inheritied substitution of adenine for guanine at position 20210 of the prothrombin gene.  This leads to an elevated prothrombin plasma level, and consequently, an increase in thrombin formation.

PRESENTATION: Increased risk of both arterial (CVA, MI) and venous (DVT, PE) thrombosis.    

DIAGNOSTIC EVALUATION: Molecular tests (PCR): Prothrombin G20210A mutation.


EPIDEMIOLOGY:  Prevalence:  Protein C deficiency occurs in 0.2-0.5% of the general population; while that of Protein S deficiency is uncertain.

PATHOPHYSIOLOGY:  Protein C is converted to APC by thrombin:thrombomodulin complex on endothelial cell surface.  APC inactivates both Factor Va and Factor VIIIa.  Protein S serves as a co-factor for protein C.  Thus, deficiency of these proteins results in unregulated coagulation from decreased inactivation of Factor Va and VIIIa.  Inheritance: Autosomal recessive for protein C deficiency and autosomal dominant for protein S deficiency.  

PRESENTATION:  Mainly venous thrombosis at a young age (20-40 y/o).  Homozygous cases: Neonatal purpura fulminans (widespread venous thrombosis and skin necrosis) and cerebral vein thrombosis.  Heterozygous: DVT, PE, and warfarin-induced skin necrosis (occur in adults after initiation of warfarin therapy without simultaneous heparinization; the basis for this condition is the fact that warfarin inhibits production of vitamin K-dependent protein C & S and Factors II, VII, IX & X; since protein C has a relatively short half-life compare to the aforementioned factors, shortly after starting warfarin treatment there can be a procoagulation imbalance that occasionally result in widespread microvascular thrombosis).

DIAGNOSTIC EVALUATION: Protein C levels & Protein S activity levels

Ø  PLASMINOGEN DISORDER:  These conditions are rare and they lead to decreased plasmin

v  Tissue plasminogen activator (t-PA) deficiency:  Plasminogen is activated to plasmin by t-PA and u-PA (urokinase).  Plasmin breaks down fibrin clots into soluble FDPs (fibrin degradation products), including D-dimer.   Deficiency in plasmin may lead to thrombosis, as clots are not degraded adequately.

v  Plasminogen activator inhibitor (PA-I) excess:  PA-I is the principal inhibitor of tPA and uPA.

Ø  PNH (PAROXYSMAL NOCTURNAL HEMOGLOBINURIA):  A rare, acquired, potentially life-threatening disease of the blood characterized by hemolytic anemia, red urine, and thrombosis.

PATHOPHYSIOLOGY:  PIGA (phosphatidylinositol glycan A) is needed to make GPI (glycosylphosphatidylinositol) anchor that is required for the fixation of a number of diverse proteins to cellular surfaces. Among these proteins are CD16, CD55 (DAF downregulates the C4b2a complex) and CD59 (MIRL inhibits the formation of polymeric C9), which are required for the protection of RBCs, granulocytes, and platelets from complement-mediated lysis.  In PNH, there is an acquired hematopoietic stem cell mutation of the PIGA gene that leads to a defect in the GPI anchor. Without the proteins that protect them from complement, hematopoietic cells are destroyed resulting in pancytopenia. The GPI anchor defect also lead to increased platelet aggregation and expression of tissue factor, and impaired fibrinolysis, thus causing an increased rate of thrombosis.

PRESENTATION:  Despite the name, PNH usually cause on-going hemolysis.  The classic episodic nocturnal red urine is seen in only 25% of cases.  Thus, anemia is the most common symptom (e.g. fatigue, SOB, palpitations). An inconsistent, but life-threatening, complication of PNH is the development of venous thrombosis.  These may develop in common sites (DVT, PE), but may also form in unusual sites (Budd-Chiari syndrome, portal vein thrombosis, cerebral vein thrombosis, dermal vein thrombosis, and mesenteric ischemia).

DIAGNOSTIC EVALUATION:  UA:  Hemoglobinuria and hemosiderinuria.  LDH ↑, reticulocyte ↑, haptoglobin ↓:  Signs of hemolysis.  Sucrose lysis test (patient's blood are placed in low ionic strength solution and observed for hemolysis):   For screening.  Ham's acid hemolysis:  A specific test performed to confirm a positive sucrose lysis test.  Flow cytometry:  CD16 and CD59.

TREATMENT:  Steroids (prednisolone):  ↓ severity of hemolytic crises at moderate dosage. Blood transfusion:  Correcting the anemia and suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Iron supplement: Should be accompanied by steroid therapy, iron can result in more hemolysis as more PNH cells are produced. Androgens (danazol):  May be effective in steroid refractory disease.  Monoclonal antibody (eculizumab): Protects hematopoietic cells by inhibiting the complement system.  Anti-coagulants (warfarin):  Prophylaxis against thrombosis.  Bone marrow transplants:  Considered in severe aplasia. 

·       ANEMIA:  Decreased in whole body RBC mass defined as a decreased in RBC count (♂ < 4.5 x 1012/L, ♀ < 4.0 x 1012/L), hematocrit (♂ <39%, ♀ < 35%) or hemoglobin (♂ < 14, ♀ < 12 g/dL).

o   PATHOPHYSIOLOGY: RBCs contain hemoglobin (hgb), the molecule that transports O2 from the lungs to peripheral tissue.  Anemia is the the reduction in the amount of O2 carried by the blood secondary to a decrease in the number of normal RBCs &/or a decrease in the amount of normal hemoglobin.  Since all human cells depend on  O2 for survival, they hypoxia arising from anemia can have a wide range of clinical consequences.  There are many different causes of anemia, each with a unique pathophysiology as we will see.

o   PRESENTATION:  Generally, the symptoms can be vague and go unnoticed in many people.  Symptoms:   Fatigue, malaise, poor concentration, dyspnea on exertion, palpitation and perspiration (due to a catechoaminergic compensation by increasing cardiac output), symptoms of heart failure (in severe decompensated cases), and pica (especially with iron deficiency anemia).  In children, chronic anemia may result stunted growth and impaired neurological development resulting in behavioral disturbances and reduced scholastic performance.  Physical exam:  Pallor of skin/mucosal linings/nail beds, cheilosis, koilonychia. 

Main symptoms that may appear in anemia

By Mikael Häggström.When using this image in external works, it may be cited as:Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain.orBy Mikael Häggström, used with permission. - All used images are in public domain.ReferenceseMedicineHealth > anemia article Author: Saimak T. Nabili, MD, MPH. Editor: Melissa Conrad Stöppler, MD. Last Editorial Review: 12/9/2008. Retrieved on 4 April, 2009, Public Domain, https://commons.wikimedia.org/w/index.php?curid=6508894

o   DIAGNOSTIC EVALUATION:  Hemogram:  RBC count (normal ♂ 4.5-5.5 x 1012/L, ♀ < 4-5 x 1012/L) hemogloblin (hgb normal ♂ 13-18, ♀ 12-16 g/dL), hematocrit (hct normal ♂ 42-52%, ♀ 37-48%), mean corpuscular volume (MCV normal 80-100 fL), mean cell hemoglobin (MCH normal 23-28 pg/cell), mean cell hemoglobin concentration (MCHC normal 32-36 g/dL), red cell distribution width (RDW normal 12-15%), WBC, and platelet counts.  Reticulocyte count (normal 1-2%):  New RBCs that have extruded their nuclei but still show rRNA seen as blue/purple dots.  Peripheral blood smear:  Qualitatively gauge the activity of the bone marrow by subtle changes in the numbers and the morphology of young RBCs.   MORE SPECIFIC TEST:  Iron studies (e.g. ferritin/serum iron/transferring for suspected iron deficiency anemia), serum vitamin B12 & folate levels (for suspected megaloblastic anemia), hemoglobin electrophoresis (for suspected thalassemia and hemoglobinopathies), serum LDH/haptoglobin/bilirubin levels (for suspected hemolytic anemias), detection of serum autoantibodies (for suspected autoimmune hemolytic anemia), flow cytometry of red cells and neutrophils (for suspected PNH), and bone marrow biopsy (for suspected aplastic anemia; confirmation of iron deficiency; diagnosis of sideroblastic anemia; myelodysplastic syndrome; myelophthistic process in the marrow such as leukemia, lymphoma, metastatic malignancies, and extensive marrow infections). 


o   ANEMIA WITH ELEVATED CRCAHH! (imagine a bloody scream from blood loss) → A-acute blood loss, H-hemolytic anemia, H-hemophagocytic syndromes.

Ø  A _______________, _______________, _______________, _______________, _______________

Ø  H _______________, _______________, _______________, _______________, _______________

o   HEMOLYTIC ANEMIA:  Anemia from abnormal breakdown of RBCs either in the blood vessels (intravascular) or elsewhere in the body (extravascular). Intravascular hemolysis:  RBCs are destroyed by the complement system.  Hemoglobin is released and quickly binds to serum haptoglobin, and the hemoglobin-haptoglobin complex is then cleared by the reticuloendothelial (RE) system, thus a decrease in haptoglobin is seen.  Once intravascular hemoglobin overloads the haptoglobin capacity, it spills into the kidney and hemoglobinuria is detected.  Extravascular hemolysis: RBCs are destroyed in the reticuloendothelial system (e.g. spleen) by macrophages, and little hemoglobin is released into the serum, thus, haptoglobin levels may be normal and hemoglobinuria is not present.  In both cases, bilirubin, a breakdown product of hemoglobin, can accumulate in the blood causing jaundice, and be excreted in the urine causing the urine to become a dark brown colour.

Ø  PRESENTATION:  History:  Medication use (e.g. pyrazinamide), fava bean consumption; symptoms of anemia (fatigue, SOB, palpitations); symptoms of biliary colic (from pigmented gallstones).  Physical exam: Sign of anemia (e.g. pallor) and hyperbilirubinemia (e.g. jaundice). 

Ø  DIAGNOSTIC EVALUATION:  CBC.  Peripheral blood smear: Schistocytes (MAHA), spherocytes, ↑ reticulocytes, sickled cells (SCA), intracellular parasites (malaria, babesisosi).  LDH: ↑.  Unconjugated bilirubin:  ↑.  Haptoglobin:  ↓.  Coombs test:  Positive if hemolysis is caused by an immune process.  UA: Hemosiderinuria and presence of urobilinogen indicates intravascular hemolysis.

Ø  CLASSIFICATION OF HEMOLYTIC ANEMIA I) Acquired causes (extra-erythrocytic factors) and II) Genetic causes (intra-erythrocytic factors)

  I.     ACQUIRED CAUSES OF HEMOLYTIC ANEMIA (Often due to defects of the extraerythrocytic environment such as auto-antibodies): SIM → S-splenomegaly (e.g. from cirrhosis, CHF, amyloidosis, sarcoidosis…), I-infection (e.g. malaria, babesiosis), I-immune-mediated (autoimmune or alloimmune factors), M-microangiopathic hemolytic anemia (MAHA). 

v  S _______________, _______________, _______________, _______________, _______________

v  I _______________, _______________, _______________, _______________, _______________

v  M _______________, _______________, _______________, _______________, _______________

Ø  SPLENOMEGALY (extravascular hemolysis):

Ø  INFECTIOUS CAUSES OF HEMOLYTIC ANEMIA (both intravascular and extravascular hemolysis):  Malaria and babesiosis.


§  EPIDEMIOLOGY:  Worldwide incidence:  400–900 million cases/year and 1-3 million deaths.  Majority of cases occur in children < 5 y/o.  Pregnant women are especially vulnerable.  Malaria is presently endemic in rural areas of the Americas, many parts of Asia, and much of Africa; however, it is in sub-Saharan Africa where 85– 90% of malaria fatalities occur.  It is a major hindrance to economic development in these countries, where the disease may account for as much as 40% of public health expenditure. 

§  PATHOPHYSIOLOGY:  Malaria is caused by protozoan parasites of the genus Plasmodium, including P. falciparum, P. malariae, P. ovale, and P. vivax., which together responsible for about 80 % of all malaria cases. Of these, P. falciparum is the most important cause of disease, and responsible for about 90% of deaths. The parasite are transmitted to human only by female Anopheles mosquitoes when it feed on human blood (male mosquitoes do not feed on blood).  Malaria in humans develops via two phases: 1) Exoerythrocytic (hepatic) phase:  Infected mosquito pierces a person's skin, releasing sporozoites from its saliva into the bloodstream.  Sporozoites infect hepatocytes, multiplying asexually and asymptomatically for a period of 6–15 days. This phase yield thousands of merozoites 2) Erythrocytic phase: Merozoites rupture their host hepatocyte, escape into the blood and infect RBCs.  Within the RBCs merozoites round up to re-form trophozoite (seen as the characteristic ring-shaped structure in RBC), which again multiply asexually to form new merozoites.  Periodically, RBCs lysis occur with release of merozoites, manifested as anemia, fevers, chills, and sweats.  Hypnozoites:  Dormant form unique to P. vivax and P. ovale that can remain in hepatocytes for 6 months to a few years.  Cerebral malaria:  Unique to P. falciparum, which displays adhesive proteins on the surface of the infected RBC, causing the them to stick to the walls of small blood vessels.  This plug up post-capillary venules in organs such as kidney, lung, and brain, resulting in hemorrhage and blocked blood delivery.  Renal failure, lung edema, and cerebral manifestation (seizure, coma) ensue.   Hematologic disorders that confer resistance to malaria include: Sickle-cell disease (confer protection against P. falciparum as the rapid plasma clearance of  deformed sickled-cell also rid the body of the protozoa), absence of Duffy a + b antigens on RBC membrane (confer resistance to P. vivax as it uses the Duffy antigen to enter RBC), G6PD deficiency (confer protection against severe malaria as the protozoa is destroyed along with the oxidatively stressed RBCs). 

The life cycle of malaria parasites. A mosquito causes an infection by a bite. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells, where they multiply into merozoites, rupture the liver cells, and return to the bloodstream. The merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts that in turn produce further merozoites. Sexual forms are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.

By National Institutes of Health (NIH) - National Institutes of Health (NIH), Public Domain, https://commons.wikimedia.org/w/index.php?curid=29552307

An Anopheles stephensi mosquito shortly after obtaining blood from a human (the droplet of blood is expelled as a surplus). This mosquito is a vector of malaria, and mosquito control is an effective way of reducing its incidence.

By Jim Gathany - This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #5814.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−, Public Domain, https://commons.wikimedia.org/w/index.php?curid=799284

§  PRESENTATION:  Classical symptoms:  Cyclical occurrence of fever, shivering, sweating, arthralgia, N/V, lasting 4-6 hours, occurring every two days in P. vivax and P. ovale infections,  every three days for P. malariae infection, and can be continuous for P. falciparum infection.  The symptomatic period corresponds to the lysis of RBCs with the release of merozoites, which then invade other RBCs to start a new erythrocytic cycle.  Others symptoms: Anemia, hypoglycemia, hemoglobinuria, HA, hepatosplenomegaly, renal failure, cerebral ischemia (convulsion, coma), and death.   

§  DIAGNOSTIC EVALUATION:  Peripheral smear: Both a thin film (allow species identification because the parasite's appearance is best preserved) and a thick film (more sensitive at picking up low levels of infection) are used to identify ring-form trophozoites in the RBCs.  Antigen detection tests (e.g. OptiMAL-IT®) and parasite nucleic acids detection (e.g. the PCR based QT-NASBA test):  These techniques are more accurate than microscopy. However, it is expensive, and requires a specialized laboratory. 

The blood film is the gold standard for malaria diagnosis.

By CDC/ Steven Glenn, Laboratory & Consultation Division - CDC - Public Health Image Library (PHIL), #5901, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4878350

Ring-forms and gametocytes (banana-shaped, extracellular) of Plasmodium falciparum in human blood

By The original uploader was TimVickers at English Wikipedia - Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2932677

Electron micrograph of a Plasmodium falciparum-infected red blood cell (center), illustrating adhesion protein "knobs",  which may stick to the microvasculature of the brain causing ischemia (cerebral malaria seen in severe P. falciparum.

By Rick Fairhurst and Jordan Zuspann, National Institute of Allergy and Infectious Diseases, National Institutes of Health - https://www.flickr.com/photos/nihgov/25534997493/in/photolist-EUrx8t-CvR53a-B3Ad52-ydGygr-wZzPff-C5BN5H, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=49182050

§  TREATMENT:  Active P. falciparum infection is a medical emergency requiring hospitalization, while P. vivax, P. ovale or P. malariae infections can often be treated on an outpatient basis. Treatment of malaria involves supportive measures (e.g. IVF) as well as specific antimalarial drugs.  General guidelines for the use of antimalarial drugs: 

1)    P. ovale and P. vivax: Chloroquine + primaquine

2)    P. malariae and non-chloroquine resistant P. falciparum: Chloroquine.

3)    Chloroquine-resistant P. falciparum: Quinine + sulfadoxine/pyrimethamine.

4)    Prophylaxis (start the drugs 1-2 weeks before arriving and continue 4 weeks after departure from malarial regions):  Chloroquine resistance absent: Low dose chloroquine; Chloroquine resistant area: Mefloquine or doxycycline.    

PREVENTION:  Mosquito eradication (e.g. with DDT or permethrin spraying) and mosquito bite prevention (use of permethrin-treated mosquito nets).

BABESIOSIS:  A malaria-like parasitic disease caused by protozoan parasites of the genus Babesia.

§  EPIDEMIOLOGY:  In North America, the disease exists mostly in northeastern coastal US (e.g. Nantucket Island). 

§  PATHOPHYSIOLOGY:  Babesia microti is transmitted to human by the tick vector Ixodes scapularis (same as Lyme disease).  Babesia sporozoites are released from the tick saliva into the human blood, where they invade RBCs and asexually divide into 4 merozoites that attach together to form an x-shaped structure (Maltese Cross).  Similar to malaria, Babesia merozoites   and cause hemolytic anemia.  Unlike malaria, babesiosis lack an exo-erythrotic phase, so the liver is usually not affected. 

§  PRESENTATION:  Babesiosis usually results in mild hemolysis, and thus asymptomatic.  However, in the very young, very old, or persons with underlying medical conditions (e.g. immunocompromised, asplenia), who are unable to clear the organism, the infection can be severe and very similar to Malaria.  In these individuals, symptoms can include fevers, shaking chills, anemia, hemoglobinuria, and organ failure (e.g. ARDS, DIC, and cerebral babesiosis caused by sludging of erythrocytes in cerebral capilaries).

§  DIAGNOSTIC EVALUATION:  Peripheral smear: Thin and thick smear reveal ring-shaped  trophozoites or x-shaped tetrad of merozoites (Maltese cross).  PCR-based tests are also available to identify the species.   

§  TREATMENT:  Most resolve without treatment.  Ill patients are treated with two-drug regimen:  Quinine + clindamycin or atovaquone + azithromycin (better tolerated).  In life-threatening cases, exchange transfusion is performed.

Babesia lifecycle

By LadyofHats Mariana Ruiz Villarreal - did it myself basically using the information found here and here, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4339875

Other hemoprotozoan parasites such as these Babesia sp. resemble Plasmodium falciparum organisms. Though developmentally the Babesia spp. organisms resemble Plasmodium falciparum, these parasites present several distinguishing features: they vary more in shape and in size; and they do not produce pigment.

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Ø  IMMUNE-MEDIATED HEMOLYTIC ANEMIA:   Autoimmune and Alloimmune

v  AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA):  Auto-antibodies and associated complement are fixed onto the RBC surface causing intravascular or extravascular hemolysis.   TYPES: Warm and Cold AIHA. 

§  WARM AIHA (usually extravascular hemolysis):  More common type.

·      PATHOPHYSIOLOGY:  In most cases, the warm antibody AIHA is IgG (but sometimes IgA), and it attaches to RBC, leaving the FC portion sticking out. The FC region is recognized by splenic macrophages, which pick off portions of the RBC membrane causes the RBCs to become spherocytes. Spherocytes are singled-out for destruction and become trapped in the spleen causing splenomegaly.  About half of the cases are idiopathic, with the other half attributable to a predisposing condition (e.g. lymphoma, SLE) or medications (e.g. penicillins, cephalosporins).  It is thought that these medication bind the red cell membrane and act as haptens, inducing the production of antibodies against the cell-drug complex.

·      DIAGNOSTIC EVALUATION:  Hemogram: CBC (anemia), reticulocytosis.  LDH: ↑. Bilirubin: ↑.  Haptoglobin: ↓.  Direct Cooms tests:  Positive for antibodies attached to the surface of RBC.  Peripheral smear: Spherocytes.

·      TREATMENT:  Corticosteroids:  Initial therapies of choice.  If ineffective: Consider splenectomy, rituximab, danazol, cyclosphosphamide, azathioprine, or cyclosporine.  High dose IVIG is effective in controlling hemolysis, but it is expensive and the benefit is short lived (1-4 weeks). 


v ALLOIMMMUNE (ISOIMMUNE) HEMOLYTIC ANEMIA:  A condition in which the body gains immunity, from another individual, against its own cells.  A good example is hemolytic disease of the newborn (HDN i.e. erythroblastosis fetalis), which occur when the maternal IgG antibodies passed through the placental membrane and attack fetal RBCs.  RBC hemolysis ensue resulting in fetal development of anemia, reticulocytosis, erythroblastosis, and hydrops fetalis (fetal death from heart failure).  Alloimmunity arising from blood transfusion or organ transplantation will be discussed in respective section.

§  PATHOPHYSIOLOGY:  Maternal antibodies against fetal RBC antigens are produced when the mother is exposed to exposed to fetal antigens, which commonly include to following:  ABO system (Anti-A and anti-B antibodies are usually IgM that can not pass through the placenta, but some mothers "naturally" have IgG anti-A or IgG anti-B antibodies, that can cross the placenta and cause ABO HDN, which can occur in a firstborn and does not become more severe during subsequent pregnancies), Rhesus system (following delivery of an Rh+ fetus, an Rh- mother forms anti-Rh IgG → in a subsequent pregnancy with an Rh+ fetus, maternal anti-Rh IgG crosses the placenta causing fetal hemolysis), and other system (Kell, Duffy, Lewis, etc).  Maternal exposure to foreign RBC antigen can be through fetal-maternal hemorrhage (e.g. trauma, abortion, childbirth, abruptio placenta, or medical procedures carried out during pregnancy that breach the uterine wall) and maternal blood transfusion with an incompatible blood type.  

§  PRESENTATION:  Jaundice within 24 hours after birth, anemia (pallor, high-output heart failure in severe cases), hepatosplenomegaly (hyperbilirubin can damage the liver), generalized swelling, respiratory distress, kernicterus, and hydrops fetalis.

Hemolytic disease of the newborn

By OpenStax College - Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013., CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=30148179

§  DIAGNOSTIC EVALUATION:  Fetal tests: Amniocentesis (for fetal blood type), bilirubin ↑, peripheral smear (↑ reticulocytes, ↑ erythroblasts), and direct Coombs test: Positive.  Maternal tests: Blood typing (ABO, Rh), indirect Coombs test (positive), and anti-Rh IgG titer (serial test fro hight titers >1:16).

§  TREATMENT:  Intrauterine blood transfusion and initiate delivery:  For severe cases with fetal distress when pulmonary maturity has been attained; otherwise, also administer betamethasone to enhance lung maturity.   Maternal plasma exchange:  Reduce circulating antibody up to 75%.  Supportive treatment of the neonate:  Mechanical ventilation, phototherapy, transfusion, sodium bicarbonate (correct the acidosis).  Prevention:  Rh- mothers who have had a pregnancy with/are pregnant with a Rh+ infant are given RhoGAM (RhIgG) at 28 weeks during pregnancy and within 72 hours after delivery.  RhoGAM bind any fetal RBC with the D antigen before the mother is able to produce an immune response and form anti-D IgG.


v PATHOPHYSIOLOGY:  MAHA results from the formation of a fibrin mesh in the microvasculature due to increased activity of the coagulation system. The RBCs are physically sheared by these protein networks, and the fragments are seen as schistocytes on peripheral smear.

v PRESENTATION:  Anemia from intravascular hemolysis.

v TYPES OF MAHA:  THAD (imagine a guy named THAD with MAHA) → T-TTP (thrombotic thrombocytopenic purpura), H-HIT (heparin-induced thrombocytopenia), H-HUS (hemolytic uremic syndrome), H-HELLP (hemolytic anemia, elevated liver enzyme, low platelets) syndrome, A-AS (aortic stenosis), D-DIC (disseminated intravascular coagulopathy).

§  T _______________, _______________, _______________, ______________, ______________

§  H _______________, _______________, _______________, ______________, ______________

§  A _______________, _______________, _______________, ______________, ______________

§  D _______________, _______________, _______________, ______________, ______________





v AS (AORTIC STENOSIS):   Aortic valve stenosis increases breakdown of large vWF multimers by ADAMTS13 due to the high shear stress around the stenosed valve.   SEE Heyde's syndrome.   


I.     HEREDITARY CAUSES OF HEMOLYTIC ANEMIA (Often due to defects in the RBCs, i.e. intraerythrocytic factors): HEMoglobin = HEM → H-hemoglobin disorders, E-enzyme defect, M-membrane defects

v  H _______________, _______________, _______________, _______________, _______________

v  E _______________, _______________, _______________, _______________, _______________

v  M _______________, _______________, _______________, _______________, _______________

Ø  HEMOGLOBIN DISORDERS (extravascular hemolysis): Genetic defect that results in abnormal structure of the hemoglobin molecule. 

PATHOPHYSIOLOGY: Hemo-globin molecule is an assembly a non-protein, iron-containing, heme group associated with four globular protein subunits.

v  TYPES OF HEMOGLOBIN DISORDERSDivided into quantitative defect (i.e. deficiency of production of normal hemoglobin structure as in the case of thalassemia) or qualitative defect (aka hemoglobinopathies and characterized by normal production of abnormal hemoglobin structure as in the case of hemoglobin S, hemoglobin C, hemoglobin E disorder, and methemoglobinemia).

THALASSEMIA (quantitative defect):  Inherited reduced rate of synthesis of one of the globin chains that make up hemoglobin. 

§  EPIDEMIOLOGY:  Generally, thalassemias are prevalent in populations that evolved in humid climates where malaria was endemic.  They are particularly associated with people of Middle Eastern, Mediterranean, Indian, African, and Asian origin.

§  PATHOPHYSIOLOGY:  Autosomal recessive inherited defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin.  The thalassemias are classified according to which chain of the hemoglobin molecule is affected. 

a)    α thalassemias (more common in the african and asian population):  Deletion of ≥ 1 of the 4 α globin gene.  With deletions of  ≥ 3 α globin gene, there is tetramerization of the excess globins chains such as Hb H b4 and Hb Barts g4, which are unstable and have a higher affinity for O2 than normal hemoglobin, resulting in poor O2 delivery to tissues.

b)    β thalassemias (common in Mediterranean populations):  Mutate ≥ 1 of the 2  beta globin gene.  Mutations characterized as:  βo (total lack of β chains synthesis); β+ (partial lack of β synthesis); β (normal).  Inc all cases, the excess α chains do not form tetramers.  Rather, they form intracytoplasmic toxic aggregates, which cause premature erythroblasts death (i.e. ineffective erythropoiesis).

Thalassemias can co-exist with other hemoglobinopathies.  For example:  Hemoglobin  E/thalassemia (common in southEast asia and parts of India; clinically similar to β thalassemia  major or intermedia), hemoglobin S/thalassemia (common in African and Mediterraneans;          clinically similar to sickle cell anemia), hemoglobin C/thalassemia (common in African and   Mediterraneans; hemoglobin C/βo thalassemia causes a moderately severe hemolytic anemia with  splenomegaly; hemoglobin C/β+ thalassemia produces a milder disease).

§  DIAGNOSTIC EVALUATION:  CBC: Anemia. Peripheral smear: Target.  Hemoglobin electrophoresis:  Detect the abnormal haemoglobin. Genetic testing.   

§  TREATMENT:  Usually reserve for severe cases such as with b thalassemia major.  Blood transfusions:  Improve symptoms and prevents skeletal deformities.  Splenectomy: Improve anemia by removing the primary site of extravascular hemolysis.  Iron chelators (e.g. deferoxamine SC): Prevent iron overload damage to internal organs, but require annual vision and hearing exam due to risk of optic neuropathy and sensorineural hearing loss.  Bone marrow transplant: The definitive treatment.

HEMOGLOBINOPATHIES (qualitative defect):  Normal production of abnormal hemoglobin structure.  Commonly found hemoglobinopathies in the US include hemoglobin S, hemoglobin C, hemoglobin E disorder.  We will also discuss methemoglobinemia.

§  DIAGNOSTIC EVALUATION CBC: Anemia. Peripheral smear: Sickled RBC (sickling can be induced by sodium metabisulfite), target cells, Howell-Jolly bodies (basophilic remnants of nuclear DNA in individuals with functional hyposplenia or asplenia), and reticulocytosis (bone marrow compensates for the destruction of sickle cells).  Hemoglobin electrophoresis:  Abnormal hemoglobin forms. Genetic testing.   

Sickle-cells in human blood: both normal red blood cells and sickle-shaped cells are present.

By Dr Graham Beards - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18421017

Normal blood cells next to a sickle-blood cell, colored scanning electron microscope image

By OpenStax College - Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/, Jun 19, 2013., CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=30148180

§  SICKLE CELL ANEMIA (SCA) COMPLICATIONS:   SCA → S-splenic S-sequestration crisis (acute, painful splenomegaly due to blood pooling causing severe anemia; manage with hemodynamic support, blood transfusion and rarely splenectomy), S-splenic infarction (autosplenectomy), S-stroke (most in patient < 10 y/o and from occlusion of cerebral vasculature), S-salmonella osteomyelitis; C-cholelithiasis (from excessive bilirubin production due to prolonged hemolysis), C-CHF, C-CRD (occur in 4.2%), A-acute chest syndrome (can be caused by respiratory infection, pain crises, atelectasis, and is characterised by fever, chest pain, dyspnea, and pulmonary infiltrate indistinguishable from pneumonia; manage with IV antibiotics, O2, analgesia, blood transfusion), A-aplastic crises (parvovirus B19 infection complete suppression of erythropoiesis causing sudden worsening anaemia and ↓ reticulocyte count; manage with blood transfusion and most cases recover in 2 weeks), A-avascular necrosis of the femoral bone.  Other complications: Vaso-occlusive pain crises (this is the most common manifestatiof of SCA and often present with pain in the back, ribs and limbs lasting for ~ 1 week; manage with hydration and analgesics), Overwhelming post-(auto)splenectomy infection (functional asplenia predisposed to infection by encapsulated organisms such as S. pneumonia, H. influenza, N. meningitidis; manage with routine vaccination), Priapism and penile infarction, Leg ulcers (treat with leg elevation, wound care), proliferative retinopathy (manage with annual eye exam/laser photocoagulation), and Pulmonary hypertension.   

§  S _______________, _______________, _______________, _______________, _____________

§  C _______________, _______________, _______________, ______________, ______________

§  A _______________, _______________, _______________, ______________, ______________

§  TREATMENT:  Blood transfusion: Indicated for severe hemoglobinopathies. Hydroxyurea: Indicated for SCA.  It acts to increase Hb F and has been shown to decrease the severity and frequency of sickle cell crises.  Bone marrow transplants:  Effective in children.

Ø  ENZYME DEFECTS (intravascular hemolysis):  Including Glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase deficiency.

v  GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY:  X-linked nonimmune hemolytic anemia in response to oxidant stress.

§  EPIDEMIOLOGY:  The most common hereditary enzyme deficiency disease in the world.  Worldwide prevalence: 400 million.  The high prevalence is thought to arise from an evolutional selection as this disease confers protection against malaria.  Namely, cells infected with the Plasmodium parasite are cleared more rapidly by the spleen.

§  PATHOPHYSIOLOGY:  G6PD is an enzyme in the pentose phosphate pathway that supplies reducing energy to RBCs by producing NADPH. The NADPH in turn maintains the level of glutathione, which serve to protect the RBCs against oxidative damage.  Thus, G6PD deficiency increases the risk of hemolytic anemia in states of oxidative stress. Enzymes and other proteins are damaged by the oxidants, leading to phagocytosis and splenic sequestration of RBCs. The hemolysis releases hemoglobin, which is excreted by the kidney (can cause ARF) or is metabolized to bilirubin (causing jaundice).  G6PD deficiency also increases the risk for diabetes mellitus (due to the back up of glucose) and hypertension (from ↓ NADPH which is necessary for NO systhesis).  Episodes of hemolysis can be triggered by severe infection, medication and certain foods (e.g. fava beans).  Medications that should be avoided include NADPH’S → N-nitrofurantoin, N-niridazole (and other antihelminthics), A-aspirin (and other NSAIDs), D-dapsone, D-darvocet, D-dimercaprol, P-primaquine (and other antimalarials), P-phenothiazines, P-probenecid, H-henna, S-sulfones.     

§  PRESENTATION:  Prolonged neonatal jaundice and hemolytic crises. 

§  DIAGNOSTIC EVALUATION:  CBC. CMP: Exclude hepatic cause of anemia. Peripheral smear: Heinz bodies (denatured Hb inclusions), Bite cells (splenic macrophages trying to remove Heinz bodies).  LDH: ↑ with hemolysis.  Haptoglobin: ↓ with hemolysis.  Coombs test: Negative as G6PD is not immune-mediated.  G6PD levels (diagnostic): Beutler flourescent spot test visualize NADPH produced by G6PD under UV light. This test should be done 2-3 week after a hemolytic episode because in acute hemolysis old RBCs with less G6PD are selective destroyed, leaving behind relatively normal young RBCs.  DNA testing. 

§  TREATMENT:  Avoidance of the drugs and foods that cause hemolysis. Folic acid supplement. Vaccination against some common pathogens (e.g. hepatitis A) may prevent infection-induced attacks.  Hydration, blood transfusions &/or dialysis: Indicated in acute hemolysis to prevent ARF.  Splenectomy.

PYRUVATE KINASE DEFICIENCY:  Autosomal recessive disorder that cause hemolytic anemia. 

§  EPIDEMIOLOGY:  The second most common cause enzyme deficient hemolytic anemia. 

§  PATHPHYSIOLOGY:  RBCs primarily depend on glycolysis to manufacture ATP required for cellular function. With mutations that lead to lowered pyruvate kinase, the cells become ATP deficient.and unable to maintain Na+/K+-ATPase activity. This results in elevated intracellular [Na+], causing water to diffuse passively into RBCs and eventual lysis. Complete absence of pyruvate kinase is lethal in utero.

§  PRESENTATION: Hemolytic anemia usually limited to early life and times of physiologic stress or infection. 

§  TREATMENT:  Depend on severity.  Most affected individuals do not require treatment. Blood transfusions or splenectom:  For severe disease.

Ø  MEMBRANE DEFECTS: Including hereditary spherocytosis, hereditary stomatocytosis, hereditary pyropoikilocytosis, and hereditary elliptocytosis.  PNH is an acquired membrane defect SEE HYPERCOAGULABLE STATES.

§  PATHOPHYSIOLOGY:  Inherited defects of a variety of RBC membrane proteins (e.g. spectrin, ankyrin, protein 4.1) required to maintain the normal biconcave-disk shape of the RBC. The abnormally shaped RBC are either hemolysed or selectively targeted by the spleen for disposal. 

§  PRESENATATION:  Hemolytic anemia: Fatigue, pallor, jaundice.  Secondary hemochromatosis: Cardiomyopathy and liver disease may be seen in severe cases requiring chronic transfusion. Cholelithiasis: Bilirubin stones.

§  DIAGNOSTIC EVALUATION:  CBC.  Peripheral smear.   Measuring iron stores.  

§  TREATMENT:  Iron and Vitamins  supplement. Blood transfusions or exchanges.  Splenectomy.  

Peripheral blood smear from patient with hereditary spherocytosis

By Paulo Henrique Orlandi Mourao - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9793806


By Jarkeld - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=23702385

Peripheral blood smear showing an abundant number of elliptocytes

By Gabriel Caponetti - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=23284278

o   ANEMIA WITH REDUCED CRC: HALF, M.D. CHARMS CLITSHALF, M.D. (macrocytic anemia MCV > 100 fL); CHARMS (normocytic anemia MCV 80-100 fL); CLITS (microcytic anemia MCV < 80 fL).

o   MACROCYTIC ANEMIA (MCV > 100 fL)HALF, M.D. → H-hypothyroidism, A-alcoholism, L-liver disease, F-folate &/or Vit B12 deficiency, M-myelodysplastic syndrome, D-drugs (e.g. MTX, zidovudine inhibits DNA replication).

Ø  H _______________, _______________, _______________, _______________, _______________

Ø  A _______________, _______________, _______________, _______________, _______________

Ø  L _______________, _______________, _______________, _______________, _______________

Ø  F _______________, _______________, _______________, _______________, _______________

Ø  M _______________, _______________, _______________, _______________, _______________

Ø  D _______________, _______________, _______________, _______________, _______________

Ø  HYPOTHYROIDISM:  May cause macrocytic anemia by 1) ↓ EPO → impaired hemoglobin synthesis, 2) Impaired folate absorption or 3) Pernicious anemia and related B12 deficiency. 

Ø  ALCOHOLISM: Suppress hematopoiesis and produces a mild macrocytosis

Ø  LIVER DISEASE:  Cause accelerated erythropoiesis and resulting macrocytosis.

Ø  FOLATE & VITAMIN B12 DEFICIENCY:  Lead to MEGALOBLASTIC ANEMIA, which is a group of disorders with altered morphology of hematopoietic cells resulting from inhibition of DNA synthesis.  Almost all cases are caused by deficiency of vitamin B12 &/or folic acid.

1.     Folate deficiency:  May develop within a few months, and can be caused by deficient intake, increased needs (e.g. pregnancy, infant, rapid cellular proliferation and cirrhosis), and malabsorption (e.g. congenital, drugs, intestinal resection).

2.     Vitamin B12 deficiency: Take years to develop because there is a relatively large hepatic storage.  It can be caused by deficient intake, deficient intrinsic factor (e.g. pernicious anaemia, gastrectomy), bilogical competition for vitamin B12 (e.g. intestinal parasites such as the fish tape worm diphyllobothrium, H. pylori, GI bacterial overgrowth in blind loop syndrome), and malabsorption (e.g. chronic pancreatitis, ileitis or ieleal resection, celiac sprue, Giardia infection).

3.     Pernicious anemia (Addison-Biermer anaemia): The most common form of Vitamin B12 deficiency anemia. It is an autoimmune disease characterized by anti-intrinsic factor and anti-parietal cell antibodies, leading to atrophic gastritis, Vitamin B12 malabsorption, achlorhydia, and increase risk of gastric carcinoma.  Normally, vitamin B12 can only be absorbed by the terminal ileum when it is bound to intrinsic factor produced by parietal cells.

PATHOPHYSIOLOGY:  Only 2 known biological enzymes require Vitamin B12, methylmalonyl-CoA and methionine synthase.  Methionine synthase also requires 5-methyl THF as a subtrates.  Both folate and Vitamin B12 play important roles in the synthesis of pyrimidine DNA bases.  Thus, deficiency of folate &/or Vitamin B12 lead to delay nuclear division of hematopoietic cells (causing pancytopenia) with a relatively unimpeded cytoplasmic maturation (causing macrocytosis). 

PRESENTATION:  Anemia (e.g. pallor, fatigue, SOB, palpitations), stomatitis, glossitis, jaundice, digestive disturbances (e.g. bloating, weight loss, diarrhea/constipation, abdominal pain).  Vitamin B12 deficiency is distinguished from folate deficiency by the present of neurologic disease in the former.  The characteristic lesion with Vitamin B12 deficiency is subacute combined degeneration (SCD), which involve lesions in SCD → S-spinocerebellar tract (ataxic gait), C-corticospinal tract (spasticity), D-dorsal column (unsteadiness, paresthesia).  Other neurologic symptoms: Personality changes, weakness, and muscle spasm.  Irreversible neurologic damage may occur even in the absence of clinically significant anemia.

§  S _______________, _______________, ______________, ______________, ______________

§  C _______________, _______________, ______________, ______________, ______________

§  D _______________, _______________, ______________, ______________, ______________

DIAGNOSTIC EVALUATION:  CBC:  Macrocytic anemia with or without thrombocytopenia and leukopenia.  CMP.  TSH: Pernicious anemia is associated with hypothyroidism.  LDH & indirect bilirubin: ↑.  Folate & vitamin B12 levels.  Methylmalonic acid (MMA) and homocystein (HC) level:  Both are elevated with vitamin B12 deficiency, but only HC is elevated with folate deficiency.  Schilling test:  Impaired absorption of vitamin B12 correctable by intrinsic factor is specific for pernicious anemia.  Peripheral smear:  Hypersegmented neutrophils, Howell-Jolly bodies.  EGD with biopsy:  Diagnose atrophic gastritis in case of pernicious anemia and rule out gastric cancer. Bone marrow biopsy:  Rule out MDS and other hematopoietic malignancy.

Peripheral blood smear showing hypersegmented neutrophils, characteristic of megaloblastic anemia.

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Immunofluorescence staining pattern of gastric parietal cell antibodies on a stomach section

By Simon Caulton - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20538616

MRI image of the brain in an axial view showing the “precontrast FLAIR image”. Note the abnormal lesions (circled) in the per ventricular area suggesting white matter pathology in someone with vitamin B12 deficiency.

By Hemlata Bhaskar and Rekha Chaudhary - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065218/, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=44387412

TREATMENT:  Vitamin replacement:  Folic acid 1 mg PO daily; vitamin B12 1 mg IM weekly. Reticulocytosis should be seen within 1 week of initiation of treatment followed by gradual rising of Hb over 6-8 weeks.  Intrinsic factor replacement:  For pernicious anemia.  Blood transfusion and iron replacement as needed.


Ø  DRUG-INDUCED MACROCYTIC ANEMIA:  Caused by drugs that inhibits DNA synthesis such as Folic acid antagonists (methotrexate), Purine antagonists (6-mercaptopurine), Pyrimidine antagonists (cytosine arabinoside).

o   NORMOCYTIC ANEMIA (MCV 80-100 fL)CHARMS → C-chronic disease anemia, H-hypothyroidism, A-aplastic anemia, R-renal failure-induced anemia, M-multiple myeloma, M-myelopthisis, S-sideroblastic anemia

Ø  C _______________, _______________, _______________, _______________, _______________

Ø  H _______________, _______________, _______________, _______________, _______________

Ø  A _______________, _______________, _______________, _______________, _______________

Ø  R _______________, _______________, _______________, _______________, _______________

Ø  M _______________, _______________, _______________, _______________, _______________

Ø  S _______________, _______________, _______________, _______________, _______________

Ø  CHRONIC DISEASE ANEMIA (CDA):  A form of anemia seen in chronic illness (e.g. chronic infection such as TB, osteomyelitis; chronic inflammatory states such as with rheumatoid arthritis; or malignancy).   

EPIDEMIOLOGY: #2 most common form of anemia (#1 is iron deficiency anemia).

PATHOPHYSIOLOGY:  Inflammatory cytokines are elevated in chronic disease.  CDA is primarily the result of the hepatic production of hepcidin, a master regulator of human iron metabolism, in response to inflammatory cytokines.  Hepcidin prevent ferroportin from releasing its iron stores.  Inflammatory cytokines also blunt erythropoiesis by decreasing the ability of the bone marrow to respond to EPO, which leads to a relative upregulation of WBCs production as more stem cells are available to diffentiate into WBCs.  In the case of chronic infection, the short-term benefit is apparent; allows the body to keep iron, an essential nutrients, away from bacterial pathogens, while producing more immune cells to fight off infection. However, if inflammation continues, iron is locked away, unavailable for heme synthesis, and erythropoiesis is blunted. 

DIAGNOSTIC EVALUATION:  Hemogram:  CDA is often a mild normocytic anemia, but can be severe, or microcytic, thus, resembling iron-deficiency anemia (IDA).  Serum iron: ↓ in CDA (similar to IDA). Ferritin level (i.e. the main intracellular iron storage protein): ↑ in CDA (vs. ↓ in IDA).  TIBC:  ↓ in CDA (vs. ↑ in IDA).  Transferrin saturation (i.e. the main serum iron-transporting protein): ↑ with CDA (vs. ↓ in IDA). Bone marrow exam:  ↑ staining for hemosiderin. 

TREATMENT:  Treat the underlying chronic disease.  EPO:  Considered for Hb ≤ 10 g/dL.  Blood transfusion as needed. 

Ø  HYPOTHYROIDISM:  Can lead to macrocytic or normocytic anemia.

Ø  APLASTIC ANEMIA:  Acquired bone marrow hypocellularity resulting in peripheral pancytopenia (i.e. anemia, leukopenia, and thrombocytopenia).   

PATHOPHYSIOLOGY:  T-lymphocytes are believed to be the main cells that attack the bone marrow.  Most cases are idiopathic.  Known causes include: Thepeutic drugs (e.g. CAPS → C-chloramphenicol, C-carbamazepine, A-acetazolamide, A-alkylating agents, P-phenytoin, P-penicillamine, P-phenylbutazone, S-sulfones), chemical exposure (e.g. benzene), radiation, viral infection (e.g. parvovirus B19, viral hepatitis, EBV, CMV), autoimmune disorder (dysfunctional cytotoxic T cells attack the bone marrow).  Aplastic anemia is also associated with FDA → F-fanconi anemia, D-diamond-blackfan anemia, and A-acquired pure red cell aplasia.

PRESENTATION:  Anemia (malaise, pallor, palpitations), thrombocytopenia (easy bruising to hemorrhage), and leukopenia (fever and other signs of infection.  10-33% of all patients also develop PNH. 

DIAGNOSTIC EVALUATION:  CBC.  CMP: RFTs, LFTs.  TSH. Folic acid & Vitamin B12 levels.  Peripheral smear.  Bone marrow exam (required for diagnosis):  Hypocellularity with almost total loss of hematopietic cells (e.g. erythroid and myeloid precursors, and megakaryocytes) with relative lymphocytosis.

TREATMENT:  Stop the offending triggers:  The first step.  Immunosuppressants (generally for those not undergoing BMT):  Often includes a short course of anti-thymocyte globulin (ATG) + several months cyclosporine to modulate the immune system.  Cyclophosphamide and vincristine may also be effective, but corticosteroids are generally ineffective.  Bone marrow transplant:  Potentially curative but is risky.  Transfusion with PRBC &/or platelets:  As needed. 

PROGNOSIS:  Untreated cases can leads to rapid death, typically within six months. However, with early diagnosis and treatment, the survival rate improves substantially improved.  With BMT, the 5-year survival rate is as high as 80%-90%.

CONDITIONS ASSOCIATED WITH APLASTIC ANEMIA:  FDA → F-fanconi anemia, D-diamond-blackfan anemia, A-acquired pure red cell aplasia.

§  F ______________, ______________, ______________, ______________, ______________

§  D ______________, ______________, ______________, ______________, ______________

§  A ______________, ______________, ______________, ______________, ______________

Aplastic Anemia seen in bone marrow:  Fatty replacement of normal marrow cellularity

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§  EPIDEMIOLOGY:  Worldwide incidence: ~ 1/360,000.  Most common in Ashkenazi Jewish population.  Median age of diagnosis is 7 y/o.

§  PATHOPHYSIOLOGY:  At least 13 genes of which mutations are known to cause FA (FANC-A, B, C, D1, D2, E, F, G, I, J, L, M and N).  All are autosomal recessive inherited, except for FANCB, which is on the X chromosome.  It is thought that replicative stress, particularly that resulting from DNA damage caused by cross-linking agents or ROS, trigger the assembly of 8 of these proteins, FANCA, -B, -C, -E, -F, -G, -L and –M, to form a core protein complex in the cytoplasm.  Subsequently, the protein complex translocate into the nucleus (nuclear localization signals is thought to be from FANCA and FANCE), where it involves in genome surveillance and associates with a variety of proteins implicated in DNA repair and chromosomal stability (e.g. the protein complex activates FANCL-an E3 ubiquitin-ligase and FANCD2- a monoubiquitinases).  Mutation in any of the FANC gene renders DNA repair much less effective, as can be seen from the damage caused by cross-linking agents such as cisplatin, diepoxybutane and Mitomycin C.  FANC genes are thought to also play a major role in many other tumor suppression and ROS detoxification pathways. 

Recombinational repair of DNA double-strand damage - some key steps. ATM (ATM) is a protein kinase that is recruited and activated by DNA double-strand breaks. DNA double-strand damages also activate the Fanconi anemia core complex (FANCA/B/C/E/F/G/L/M).[11] The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI.[12] ATM activates (phosphorylates) CHEK2 and FANCD2[13] CHEK2 phosphorylates BRCA1.[14] Ubiquinated FANCD2 complexes with BRCA1 and RAD51.[15] The PALB2 protein acts as a hub,[16] bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.[17] RAD51 plays a major role in homologous recombinational repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.

By Chaya5260 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49350123

§  PRESENTATION:  Short stature, skin abnormalities (hyper or hypopigmentation, café au lait spots), skeletal anomalies (90% with absent of thumb; absent radius, clinodactyly, syndactyly, congenital hip dislocation), anatomic abnormalities (hypogenitalia, blindness, deaf, hypoplastic kidney, duodenal atreasia, tetralogy of Fallot, and many others), hematological abnormalities (occur in 98% of patients by the age of 40; initially with macrocytic anemia often progressing to bone marrow failure, aplastic anemia, MDS, and AML), and solid tumors (most commonly liver adenomas and hepatomas, head and neck tumors, GI cancers, and gynecologic tumors).       

§  DIAGNOSTIC EVALUATION:  CBC: Trilineage pancytopenia. Flow cytometry of FA cells cultured with clastogens (e.g. nitrogen mustard) demonstrates an arrest in G2/M. RBC adenosine deaminase (ADA): Normal in FA (vs. ↑ Diamond-Blackfan anemia). EPO level: ↑.  Skeletal survey:  Identify skeletal defects involving bone.  Abdominal US:  Document size and location of kidneys and monitor for liver tumors or peliosis hepatis. Echocardiography:  Evaluate for congenital anomalies.  Head MRI:  Identify any structural defects (e.g. absence of the corpus callosum).  Molecular techniques:  Identify FANC gene mutation. Bone marrow biopsy:  Hypocellularity or full-blown aplasia, signs of MDS or AML.   

§  TREATMENT:  Bone marrow transplant:  The first-line therapy.  One great setback is that pre-transplant conditioning cannot include high doses of radiations or immunosuppressants because of the high susceptibility of FA patients to chromosomal damage.  Thus, the risk of GVHD is high.  Long-term survival after BMT is better in cases that were performed within the first decade of life (2-year survival up 89% vs. 54% in older patients).  Androgen therapy (oxymetholone) and haemopoietic growth factors (EPO, G-CSF):  For patients who are not candidates for BMT.  Other as needed therapy: PRBC and platelets (should be leukodepleted and are not from family members, to avoid sensitization in case of a future BMT), and surgery and medical care for other associated condition.  

§  SUMMARY OF FANCONI ANEMIA: FANC (the involved genes) → F-FANC genes mutation resulting in susceptibility to DNA damage by A-alkylating agents, A-anatomic abnormalities (short stature, hyper or hypopigmentation, café au lait spots, absent of thumb; absent radius, clinodactyly, syndactyly, congenital hip dislocation, hypogenitalia, blindness, deaf, hypoplastic kidney, duodenal atreasia, tetralogy of Fallot, and many others), A-aplastic anemia, A-AML, N-neoplasia (leukemia, hepatomas, head and neck tumors, GI cancers, and gynecologic tumors), F-FANC genes form a N-nuclear C-complex that is involved in DNA repair.

§  F ______________, ______________, ______________, ______________, ______________

§  A ______________, ______________, ______________, ______________, ______________

§  N ______________, ______________, ______________, ______________, ______________

§  C ______________, ______________, ______________, ______________, ______________

v  DIAMOND-BLACKFAN ANEMIA (DBA):  A congenital erythroid aplasia that usually presents in infancy. Only the erythroid lineage is affected, the rest hematopoietic cells, platelets and leukocytes, are normal.

§  PATHOPHYSIOLOGY:  Current evidence suggests the existence of at least three autosomal dominant genes mutations in DBA.  In ~ 20-25% of cases, there is mutation in the ribosome protein S19 (RPS19) gene on chromosome 19, which affects translation and protein biosynthesis. The other genes have yet to be identified, but are suspected to be on chromosome 8. It is not known how these mutations lead to the hematological stem cell defect specifically affecting the erythroid progenitor population, as seen in DBA.

§  PRESENTATION:  Congenital abnormalities (occur in 47% of patients and include craniofacial malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate),  anemia with decreased erythroid progenitors in the bone marrow (usually become apparent during the neonatal period), and increase risk of developing leukemia and other malignancies.

§  DIAGNOSTIC EVALUATION:  CBC:  Anemia, low reticulocyte.  Hb F: ↑.  Adenosine deaminase: ↑.  Bone marrow exam:  ↓ erythroid precursors in bone marrow.  Genetic test:  Identify RPS19 mutation, which occurs in 20-25% of cases.

§  TREATMENT: Corticosteroids:  82% of patient respond to this therapy; however, efficacy may wane overtime.  Blood transfusions:  As needed for severe anemia in DBA.  BMT:  Potentially curative and is considered when patients become transfusion-dependent to prevent iron overloading and organ damage.

§  SUMMARY OF DBA: C-congenital E-erythroid A-aplasia (this is the pathophysiologic description) = CEA → C-congenital anomolies (e.g. C-craniofacial malformations, C-cardiac defects, C-cleft palate, and GU malformations), C-cancers ↑ (e.g. leukemia), E-extremities defect (e.g triphalangeal thumb or other UE abnormalities), E-erythroid progenitors are reduced in the BM, A-adenosine deaminase ↑ in RBCs is characteristic.

§  C ______________, ______________, ______________, ______________, ______________

§  E ______________, ______________, ______________, ______________, ______________

§  A ______________, ______________, ______________, ______________, ______________

ACQUIRED PURE RED CELL APLASIA (PRCA):  A condition affecting the erythroid precursors but not other hematopoietic stem cells. In PRCA, the bone marrow ceases to produce RBCs.

§  PATHOPHYSIOLOGY:  PRCA is regarded as an autoimmune disease. The acute self-limited form is secondary to virus (e.g. HIV, herpes, parvovirus B19, hepatitis virus), drug (e.g. chloramphenicol, azathiprine), and leukemia (e.g. T large granular lymphocyte leukemia).  The acquired chronic form of pure red cell aplasia is associated with thymomas and autoimmune disorders. The mechanism is believed to be through a T-cell mediated impairment of erythroid progenitor cells.  SUMMARY OF CAUSES OF PRCA: PRCA → P-parvovirus, R-retroviral viruses, C-chloramphenicol & other drugs, A-autoimmune disease.

§  C ______________, ______________, ______________, ______________, ______________

§  E ______________, ______________, ______________, ______________, ______________

§  A ______________, ______________, ______________, ______________, ______________


§  PRESENTATON: Anemia without associated congenital abnormalities (vs. its counter-part Diamond-Blackfan syndrome).

§  TREATMENT:  Immunosuppresants:  Cyclosporine, rituximab.

Ø  RENAL FAILURE:  Normochromic anemia arises from ↓ renal EPO synthesis.  SEE FAILURE OF KIDNEY.

Ø  MYELOPHTHISIS ANEMIA:   A from of bone marrow failure that results from the destruction of bone marrow precursor cells and their stroma.

PATHOPHYSIOLOGY:  Myelophythisis can occur with infection (e.g. TB granuloma), metastatic carcinoma (e.g. small-cell lung cancer, breast cancer, prostate cancer), leukemia, lymphoma, multiple myeloma, or myelofibrosis.  It is related to the release of cytokines that damage hematopoietic stem cells and stimulate fibroblastic proliferation in the marrow.

PRESENTATION: Anemia, thrombocytopenia, &/or leukopenia, and signs and symptoms of the underlying disease.

DIAGNOSTIC EVALUATION:  Peripheral smear:  Leukoerythroblastic picture (i.e. Immature leukocytes-myelocytes, metamyelocytes, promyelocytes &/or myeloblasts, gian megakaryocyte,  nucleated erythrocytes, and tearshaped erythrocytes); caseating granulomas with positive acid-fast organisms (in case of TB).

TREATMENT:  Treat the underlying cancer.  Supportive: PRBC, EPO. 

Ø  SIDEROBLASTIC ANEMIA:  Characterized by abnormal iron metabolism. 

PATHOPHYSIOLOGY:  Arises from many etiologies, but the common feature is a failure to incorporate iron into heme. This leads to intra-cytoplasmic iron depositions that form a ring around the nucleus of the developing RBC.  Hereditary causes: X-linked d-aminolevulinic Acid Synthase deficiency.  Acquired causes: MT DNA (mitochrondria DNA) → M-Mt DNA chromosomal abnormalities, T-toxins (Pb2+ or Zn2+ poisoning, EtOH), D-drugs (e.g. PIC → P-pyrazinamide, I-INH, C-chloramphenicol, C-cycloserine), N-nutrition (Vitamin B6-pyridoxine or Cu2+ deficiency), A-alcoholism.  Sometimes, the disorder represents a stage in evolution of a generalized bone marrow disorder that may ultimately terminate in acute leukemia. 

§  M ______________, ______________, ______________, ______________, ______________

§  T ______________, ______________, ______________, ______________, ______________

§  D ______________, ______________, ______________, ______________, ______________

§  N ______________, ______________, ______________, ______________, ______________

§  A ______________, ______________, ______________, ______________, ______________

DIAGNOSTIC EVALUATION:  CBC: Anemia. RDW: ↑.  Serum iron: ↑. Ferritin: ↑. Transferrin saturation: ↑.  TICB: ↓.  Peripheral smear: Marked anisocytosis and poikilocytosis, target cells, Pappenheimer bodies (distinctive granules that can indicate an excess of iron), coarse basophilic stippling (with lead poisoning).  Prussian blue stain of bone marrow (specific test):   > 40% ringed sideroblasts, erythroid hyperplasia with a maturation arrest, and normal leukocytes and platelets. Stainable marrow hemosiderin is also increased.

TREATMENT:  Treat the underlysing disorder (e.g. pyridoxine supplement).  Supportive therapy:  Blood transfusion as needed.  Patients usually will not respond to EPO.  Bone marrow transplant:  Considered for severe cases.   

Bone marrow aspirate: ring sideroblasts

By Paulo Henrique Orlandi Mourao - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9024399

o   MICROCYTIC ANEMIA (MCV < 80 fL):  CLITS → C-chronic disease anemia, L-lead poisoning, I-iron deficiency anemia, T-thalassemia, S-sideroblastic anemia

Ø  C _______________, _______________, _______________, _______________, _______________

Ø  L _______________, _______________, _______________, _______________, _______________

Ø  I _______________, _______________, _______________, _______________, _______________

Ø  T _______________, _______________, _______________, _______________, _______________

Ø  S _______________, _______________, _______________, _______________, _______________

Ø  LEAD POISONING (aka saturnism, plumbism or painter's colic): 

PATHOPHYSIOLOGY:  Lead (Pb2+) may be ingested (e.g. from paint) or inhaled (e.g. from automobile emissions).  Lead has no known physiologically role in the body. The toxicity of lead comes from its ability to mimic other biologically important metals, most notably Ca2+, Fe2+ and Zn2+, which act as cofactors in many enzymatic reactions. Lead is able to bind to and interact with many of the same enzymes as these metals but, due to its differing chemistry, does not properly function as a cofactor, thus interfering with the enzyme's ability to catalyze its normal reaction(s).  Lead is known to 1) Inhibits the enzyme d-aminolevulinic acid dehydratase and ferrochelatase:  Resulting in anemia from the failure to synthesize heme 2) Interferes with excitatory neurotransmission by glutamate at NMDA receptors in the hippocampal area:  Resulting in the disruption of long-term potentiation, which compromises the permanent retention of newly learned information. 

PRESENTATION:  History:  PNS problems (painless wristdrop/footdrop is the most common), CNS problems (reduced cognitive abilities, irritability, insomnia, excess lethargy or hyperactivity, headache, learning disabillity, seizure and coma), GI problems (N/V, metal taste in oral cavity, anorexia, abdominal pain, constipation, diarrhea, weight loss), Hematologic problems (anemia), Kidney problems (Fanconi syndrome characterized by impaired PCT reabsorption of phosphate, amino acids, glucoses),  Reproductive problems.  Physical exam:  Burton’s line (bluish line along the gums).  

Symptoms of lead poisoning.

By Mikael Häggström - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=40804069

DIAGNOSTIC EVALUATION:  Hemogram: Microcytic hypochromic anemia.  Peripheral smear: Basophilic stippling of RBCs. Blood lead level (BLL):  ≥ 10 μg/dL is a cause for concern. However, BLL measures current exposure to lead, but lead may also be incorporated into bone from prior exposures that will not show in BLLs until this bone-lead becomes "mobilized" through pregnancy or fracture healing. K-fluorescent X-ray metering:  Measures bone-lead as increased radiodensity of the epiphyses of long bones.  

TREATMENT:  Decrease lead exposure:  The most important part of therapy.  Chelation therapy:  EDTA or DMSA are used to reduce BLL levels.  Ascorbic acid supplement:   Shown decrease lead levels due to an inhibition of lead absorption.

Basophilic stippling (arrows) of red blood cells in a 53-year-old who had elevated blood lead levels

By Herbert L. Fred, MD and Hendrik A. van Dijk - http://cnx.org/content/m15003/latest/, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5038848

An X ray demonstrating the characteristic finding of lead poisoning in humans—dense metaphyseal lines.

By Dr Abhijit Datir - http://radiopaedia.org/cases/lead-poisoning, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11343872

Ø  IRON DEFICIENCY ANEMIA (IDA):  AKA sideropenic anemia.

EPIDEMIOLOGY:  The most common type of anemia.  US prevalence:  20% all childbearing age women (mostly due to blood lost during menses) and 2% of adult men.

PATHOPHYSIOLOGY:  IDA occurs when the dietary intake or absorption of iron is insufficient, thus hemoglobin cannot be formed.  Most cases are caused by menstrual blood loss and increased iron requirements during pregnancy.  In the absence of menstrual loss, GI blood loss is the most common and presumed etiology in most patients.  Causes of GI blood loss:  Parasitic infections (e.g. hookworms), UGIB (e.g. PUD and gastritis), LGIB (e.g. diverticulosis and colon cancer).  IDA can be the result of malabsorption phenomena associated with celiac disease. 

PRESENTATION:  Anemia (pallor, fatigue, dyspnea, palpitations, syncope), pica (peculiar food cravings such as for dirt, ice), glossitis, angular cheilosis, and koilonychia (spoon nails).  Other reported manifestations:  Hair loss, tinnitus, visual disturbances (e.g. seeing bright colors), depression, paresthesia (twitching, tingling, numbness, burning), sleep apnea, irregular menses, weak/ brittle nails, weakened immune system, and Plummer-Vinson syndrome.  The affects of IDA are much more serious in young children.  It has been shown to decrease learning ability, alter motor functions, and stunt physical growth.

DIAGNOSTIC EVALUATION:  Hemogram:  ↑ RDW, ↓ MCV, MCH and MCHC.  Peripheral smear: Microcytic hypochromic anemia, target cells.  Serum iron: ↓.  Serum ferritin (considered the most sensitive lab test for IDA): ↓.  Serum transferrin: ↑.  TIBC: ↑.  Hemoglobin electrophoresis:  May be indicated to rule out thalasemia.  Bone marrow exam and stain for iron (definitive diagnosis):  ↓ hemosiderin staining.  FOBT, EGD and colonoscopy: May be needed to rule out cancers. 

Blood smear of a person with iron-deficiency anemia.  The increase RDW is manifested as anisopoikilocytosis.

By Rjgalindo from es, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2119309

TREATMENT:  Repleting iron stores with iron supplement. With adequate therapy, reticulocyte count peaks in 1-2 weeks and Hb rises over 1-2 months.  Oral therapy:  Ferrous sulfate 325 mg tid X 6 months or until serum ferritin reaches 50 ng/L.  Patient should be advised that concomitant use of acid-neutralizing substances (e.g. milk, tea, coffe, PPI) may impair iron absorption, while ascorbic acid may enhance iron absorption. IV therapy (e.g. iron dextran): For patients with poor absorption (e.g. IBD, celiac disease) or intolerance to oral preprations.  Side effects of iron supplement:  Oral iron (constipation, cramping, nausea); IV iron (fever, chills, backache, myalgia, dizziness, syncope, rash, anaphylactic shock).  The most common cause of therapy failure is noncompliance.