First Aid for USMLE Step 1 2023 PDF

HIGH-YIELD SYSTEMS Hematology and Oncology “You’re always somebody’s type! (blood type, that is)” ` Embryology 410 —BloodLink `...

HIGH-YIELD SYSTEMS Hematology and Oncology “You’re always somebody’s type! (blood type, that is)” ` Embryology 410 —BloodLink ` Anatomy 412 “The best blood will at some time get into a fool or a mosquito.” —Austin O’Malley ` Physiology 416 “A life touched by cancer is not a life destroyed by cancer.” ` Pathology 420 —Drew Boswell, Climbing the Cancer Mountain ` Pharmacology 440 “Without hair, a queen is still a queen.” —Prajakta Mhadnak “Blood can circulate forever if you keep donating it.” —Anonymous When studying hematology, pay close attention to the many cross connections to immunology. Make sure you master the different types of anemias. Be comfortable interpreting blood smears. When reviewing oncologic drugs, focus on mechanisms and adverse effects rather than details of clinical uses, which may be lower yield. Please note that solid tumors are covered in their respective organ system chapters. 409 410 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—EMBRYOLOGY ` HEMATOLOGY AND ONCOLOGY—EMBRYOLOGY Fetal erythropoiesis Fetal erythropoiesis occurs in: Young liver synthesizes blood. ƒ Yolk sac (3–8 weeks) ƒ Liver (6 weeks–birth) ƒ Spleen (10–28 weeks) ƒ Bone marrow (18 weeks to adult) Hemoglobin Embryonic globins: ζ and ε. development Fetal hemoglobin (HbF) = α2γ2. From fetal to adult hemoglobin: Adult hemoglobin (HbA1) = α2β2. Alpha always; gamma goes, becomes beta. HbF has higher affinity for O2 due to less avid binding of 2,3-BPG, allowing HbF to extract O2 from maternal hemoglobin (HbA1 and HbA2) across the placenta. HbA2 (α2δ2) is a form of adult hemoglobin present in small amounts. BIRTH Site of Yolk Liver Bone marrow erythropoiesis sac Spleen 50 α 40 Fetal (HbF) γ Adult (HbA1) % of total 30 globin synthesis HbA2 20 β ε Embryonic globins 10 ζ δ Weeks: 6 12 18 24 30 36 6 12 18 24 30 36 42 >> EMBRYO FETUS (weeks of development) POSTNATAL (months) ADULT >>  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—EMBRYOLOGY SEC TION III 411 Blood groups ABO classification Rh classification A B AB O Rh Rh RBC type A B AB O Group antigens on RBC surface A B A&B Rh (D) NONE NONE Antibodies in plasma Anti-B Anti-A Anti-A Anti-B Anti-D NONE NONE IgG (predominantly), IgM IgM IgM IgG Clinical relevance Compatible RBC types A, O B, O AB, A, B, O O Rh⊕ , Rh⊝ Rh⊝ to receive Compatible RBC types A, AB B, AB AB A, B, AB, O Rh⊕ Rh⊕ , Rh⊝ to donate to Hemolytic disease of Also called erythroblastosis fetalis. the fetus and newborn Rh hemolytic disease ABO hemolytic disease INTERACTION Rh ⊝ pregnant patient; Rh ⊕ fetus. Type O pregnant patient; type A or B fetus. MECHANISM First pregnancy: patient exposed to fetal Preexisting pregnant patient anti-A and/or blood (often during delivery) Ž formation of anti-B IgG antibodies cross the placenta maternal anti-D IgG. Ž attack fetal and newborn RBCs Subsequent pregnancies: anti-D IgG crosses Ž hemolysis. placenta Ž attacks fetal and newborn RBCs Ž hemolysis. PRESENTATION Hydrops fetalis, jaundice shortly after birth, Mild jaundice in the neonate within 24 hours of kernicterus. birth. Unlike Rh hemolytic disease, can occur in firstborn babies and is usually less severe. TREATMENT/PREVENTION Prevent by administration of anti-D IgG to Rh Treatment: phototherapy or exchange ⊝ pregnant patients during third trimester transfusion. and early postpartum period (if fetus Rh ⊕). Prevents maternal anti-D IgG production. 412 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—ANATOMY ` HEMATOLOGY AND ONCOLOGY—ANATOMY Hematopoiesis Multipotent stem cell Myeloid stem cell Lymphoid stem cell Erythropoiesis Thrombopoiesis Granulocytopoiesis Monocytopoiesis Lymphopoiesis Erythroblast Megakaryoblast Myeloblast Monoblast Lymphoblast Bone marrow Reticulocyte Band Megakaryocyte Blood Erythrocyte Platelets Eosinophil Basophil Neutrophil Monocyte B cell T cell NK cell Tissues Macrophage Plasma cell T-helper T-cytotoxic cell cell Neutrophils Acute inflammatory response cells. Phagocytic. Neutrophil chemotactic agents: C5a, IL-8, A Multilobed nucleus A. Specific granules LTB4, 5-HETE (leukotriene precursor), contain leukocyte alkaline phosphatase kallikrein, platelet-activating factor, (LAP), collagenase, lysozyme, and N-formylmethionine (bacterial proteins). lactoferrin. Azurophilic granules (lysosomes) Hypersegmented neutrophils (nucleus has 6+ contain proteinases, acid phosphatase, lobes) are seen in vitamin B12/folate deficiency. myeloperoxidase, and β-glucuronidase. Left shift— neutrophil precursors (eg, band Inflammatory states (eg, bacterial infection) cells, metamyelocytes) in peripheral blood. cause neutrophilia and changes in neutrophil Reflects states of  myeloid proliferation B morphology, such as left shift, toxic (eg, inflammation, CML). granulation (dark blue, coarse granules), Döhle Leukoerythroblastic reaction—left shift bodies (light blue, peripheral inclusions, arrow accompanied by immature RBCs. Suggests in B ), and cytoplasmic vacuoles. bone marrow infiltration (eg, myelofibrosis, metastasis).  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—ANATOMY SEC TION III 413 Erythrocytes Carry O2 to tissues and CO2 to lungs. Anucleate Erythro = red; cyte = cell. A and lack organelles; biconcave A , with large Erythrocytosis = polycythemia =  Hct. surface area-to-volume ratio for rapid gas Anisocytosis = varying sizes. exchange. Life span of ~120 days in healthy Poikilocytosis = varying shapes. adults; 60–90 days in neonates. Source of energy is glucose (90% used in glycolysis, 10% Reticulocyte = immature RBC; reflects used in HMP shunt). Membranes contain erythroid proliferation. Cl−/HCO3− antiporter, which allow RBCs to Bluish color (polychromasia) on Wright-Giemsa export HCO3− and transport CO2 from the stain of reticulocytes represents residual periphery to the lungs for elimination. ribosomal RNA. Thrombocytes Involved in 1° hemostasis. Anucleate, small Thrombocytopenia or  platelet function results (platelets) cytoplasmic fragments A derived from in petechiae. A megakaryocytes. Life span of 8–10 days vWF receptor: GpIb. (pl8lets). When activated by endothelial injury, Fibrinogen receptor: GpIIb/IIIa. aggregate with other platelets and interact Thrombopoietin stimulates megakaryocyte with fibrinogen to form platelet plug. Contain proliferation. dense granules (Ca2+, ADP, Serotonin, Alfa granules contain vWF, fibrinogen, Histamine; CASH) and α granules (vWF, fibronectin, platelet factor four. fibrinogen, fibronectin, platelet factor 4). Approximately 1/3 of platelet pool is stored in the spleen. Monocytes Found in blood, differentiate into macrophages Mono = one (nucleus); cyte = cell. A in tissues. Large, kidney-shaped nucleus A. Extensive “frosted glass” cytoplasm. Macrophages A type of antigen-presenting cell. Phagocytose Macro = large; phage = eater. A bacteria, cellular debris, and senescent Macrophage naming varies by specific tissue RBCs. Long life in tissues. Differentiate from type (eg, Kupffer cells in liver, histiocytes circulating blood monocytes A. Activated by in connective tissue, osteoclasts in bone, IFN-γ. Can function as antigen-presenting microglial cells in brain). cell via MHC II. Also engage in antibody- Lipid A from bacterial LPS binds CD14 on dependent cellular cytotoxicity. Important macrophages to initiate septic shock. cellular component of granulomas (eg, TB, sarcoidosis), where they may fuse to form giant cells. 414 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—ANATOMY Dendritic cells Highly phagocytic antigen-presenting cells (APCs) A. Function as link between innate and A adaptive immune systems (eg, via T-cell stimulation). Express MHC class II and Fc receptors on surface. Can present exogenous antigens on MHC class I (cross-presentation). Eosinophils Defend against helminthic infections (major Eosin = pink dye; philic = loving. A basic protein). Bilobate nucleus. Packed Causes of eosinophilia (PACMAN Eats): prot with large eosinophilic granules of uniform Parasites size A. Highly phagocytic for antigen- Asthma antibody complexes. Chronic adrenal insufficiency Produce histaminase, major basic protein (MBP, Myeloproliferative disorders a helminthotoxin), eosinophil peroxidase, Allergic processes eosinophil cationic protein, and eosinophil- Neoplasia (eg, Hodgkin lymphoma) derived neurotoxin. Eosinophilic granulomatosis with polyangiitis Basophils Mediate allergic reaction. Densely basophilic Basophilic—stains readily with basic stains. A granules A contain heparin (anticoagulant) Basophilia is uncommon, but can be a sign of and histamine (vasodilator). Leukotrienes myeloproliferative disorders, particularly CML. synthesized and released on demand. Mast cells Mediate local tissue allergic reactions. Contain Involved in type I hypersensitivity reactions. A basophilic granules A. Originate from same Cromolyn sodium prevents mast cell precursor as basophils but are not the same degranulation (used for asthma prophylaxis). cell type. Can bind the Fc portion of IgE to Vancomycin, opioids, and radiocontrast dye can membrane. Activated by tissue trauma, C3a elicit IgE-independent mast cell degranulation. and C5a, surface IgE cross-linking by antigen Mastocytosis—rare; proliferation of mast cells in (IgE receptor aggregation) Ž degranulation skin and/or extracutaneous organs. Associated Ž release of histamine, heparin, tryptase, and with c-KIT mutations and  serum tryptase. eosinophil chemotactic factors.  histamine Ž flushing, pruritus, hypotension, abdominal pain, diarrhea, peptic ulcer disease.  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—ANATOMY SEC TION III 415 Lymphocytes Refer to B cells, T cells, and natural killer (NK) cells. B cells and T cells mediate adaptive A immunity. NK cells are part of the innate immune response. Round, densely staining nucleus with small amount of pale cytoplasm A. Natural killer cells Important in innate immunity, especially against intracellular pathogens. NK cells are larger than CD56 B and T cells, with distinctive cytoplasmic lytic granules (containing perforin and granzymes) CD16 (FcR) that, when released, act on target cells to induce apoptosis. Distinguish between healthy and Lytic granules infected cells by identifying cell surface proteins (induced by stress, malignant transformation, or microbial infections). Induce apoptosis (natural killer) in cells that do not express class I MHC NK cell cell surface molecules, eg, virally infected cells in which these molecules are downregulated. B cells Mediate humoral immune response. Originate B = bone marrow. CD20 CD21 from stem cells in bone marrow and matures in CD19 marrow. Migrate to peripheral lymphoid tissue B cell (follicles of lymph nodes, white pulp of spleen, unencapsulated lymphoid tissue). When antigen is encountered, B cells differentiate into plasma cells (which produce antibodies) and memory cells. Can function as an APC. T cells Mediate cellular immune response. Originate T = thymus. CD8 CD4 from stem cells in the bone marrow, but mature CD4+ helper T cells are the primary target of CD3 CD3 in the thymus. Differentiate into cytotoxic HIV. T cells (express CD8, recognize MHC I), Rule of 8: MHC II × CD4 = 8; Tc Th helper T cells (express CD4, recognize MHC MHC I × CD8 = 8. II), and regulatory T cells. CD28 (costimulatory signal) necessary for T-cell activation. Most circulating lymphocytes are T cells (80%). Plasma cells Produce large amounts of antibody specific to Multiple myeloma is a plasma cell dyscrasia. A a particular antigen. “Clock-face” chromatin distribution and eccentric nucleus, abundant RER, and well-developed Golgi apparatus (arrows in A ). Found in bone marrow and normally do not circulate in peripheral blood. 416 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY ` HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY Hemoglobin electrophoresis Origin During gel electrophoresis, hemoglobin AA Normal adult migrates from the negatively charged cathode ↑ to the positively charged anode. HbA migrates AF Normal newborn ↑ the farthest, followed by HbF, HbS, and HbC. AS Sickle cell trait This is because the missense mutations in HbS ↑ and HbC replace glutamic acid ⊝ with valine SS Sickle cell disease ↑ (neutral) and lysine ⊕, respectively, making AC Hb C trait ↑ HbC and HbS more positively charged than CC Hb C disease HbA. ↑ SC Hb SC disease ↑ C S F A Cathode A: normal hemoglobin β chain (HbA, adult) Anode F: normal hemoglobin γ chain (HbF, fetal) A Fat Santa Claus can’t (cathode Ž anode) go S: sickle cell hemoglobin β chain (HbS) C: hemoglobin C β chain (HbC) far. Antiglobulin test Also called Coombs test. Detects the presence of antibodies against circulating RBCs. Direct antiglobulin test—anti-human globulin (Coombs reagent) added to patient’s RBCs. RBCs agglutinate if RBCs are coated with anti-RBC Abs. Used for AIHA diagnosis. Indirect antiglobulin test—normal RBCs added to patient’s serum. If serum has anti-RBC Abs, RBCs agglutinate when Coombs reagent is added. Used for pretransfusion testing. Does this patient have AIHA? Will recipient react against donor RBCs? Perform direct antiglobulin test (direct Coombs) Perform indirect antiglobulin test (indirect Coombs) + + Patient RBCs with or Anti-human globulin Patient serum with or Anti-human globulin without anti-RBC Abs (Coombs reagent) without anti-RBC Abs and donor blood Positive Negative Positive Negative AIHA No AIHA Reaction No reaction Agglutination No agglutination Agglutination No agglutination indicates presence of indicates absence of indicates presence of indicates absence of anti-RBC Ab anti-RBC Ab anti-RBC Ab anti-RBC Ab  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY SEC TION III 417 Platelet plug formation (primary hemostasis) 4 5 INJURY EXPOSURE ADHESION ACTIVATION AGGREGATION Endothelial damage vWF binds to exposed Platelets bind vWF via GpIb ADP binding to P2Y12 Fibrinogen binds GpIIb/IIIa receptors and links platelets → transient collagen receptor at the site of injury receptor induces GpIIb/IIIa Balance between vasoconstriction via (vWF is from Weibel-Palade only (specific) → platelets expression at platelet Pro-aggregation factors: Anti-aggregation factors: neural stimulation reflex bodies of endothelial undergo conformational surface → rapid and endothelin (released cells and α-granules change irreversible platelet TXA2 (released PGI2 and NO (released from damaged cell) of platelets) aggregation by platelets) by endothelial cells) ↓ blood flow ↑ blood flow Platelets release ADP and ↑ platelet aggregation ↓ platelet aggregation Ca2+ (necessary for coagulation cascade), TXA2 Temporary plug stops bleeding; unstable, easily dislodged ADP helps platelets adhere to endothelium Coagulation cascade (secondary hemostasis) Thrombogenesis Formation of insoluble fibrin mesh. Aspirin irreversibly inhibits cyclooxygenase, Vascular thereby inhibiting TXA2 synthesis. endothelial cell Clopidogrel, prasugrel, and ticagrelor inhibit ADP-induced expression of GpIIb/IIIa by P-selectin Deficiency: vWF blocking P2Y12 receptor. Weibel Palade von Willebrand disease body Eptifibatide and tirofiban inhibit GpIIb/IIIa directly. PGI2 Anti-aggregation Ristocetin activates vWF to bind GpIb. Failure NO of aggregation with ristocetin assay occurs in von Willebrand disease and Bernard-Soulier Clopidogrel, prasugrel, INJURY ticagrelor syndrome. Desmopressin promotes the release of vWF and factor VIII from endothelial cells. ADP vWF carries/protects factor VIII; volksWagen Desmopressin Factories make gr8 cars. Subendothelial ADP (P2Y12) collagen receptor ACTIVATION EXPOSURE GpIIb/IIIa ADHESION insertion Ristocetin GpIb AGGREGATION Fibrinogen Arachidonic TXA2 Platelet acid TXA2 (pro-aggregation) GpIIb/IIIa COX Deficiency: Bernard-Soulier syndrome Abciximab, Deficiency: eptifibatide, Glanzmann Aspirin tirofiban thrombasthenia 418 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY Coagulation and kinin PT monitors extrinsic and common pathway, reflecting activity of factors I, II, V, VII, and X. pathways PTT monitors intrinsic and common pathway, reflecting activity of all factors except VII and XIII. Collagen, HMWK basement membrane, Kallikrein ↑ vasodilation activated platelets –# Contact C1-esterase inhibitor Bradykinin ↑ permeability activation – (intrinsic) XII XIIa – Kinin cascade ↑ pain pathway XI XIa REGULATORY ANTICOAGULANT PROTEINS: IX IXa - proteins C and S Tissue factor * VIII * VIIIa with vWF Tissue factor VII VIIa – ANTICOAGULANTS: (extrinsic) * * - heparin pathway X * Xa - LMWH – Va V - direct thrombin inhibitors (eg, argatroban, bivalirudin, * dabigatran) ANTICOAGULANTS: - LMWH (eg, dalteparin, enoxaparin) II * IIa – - heparin Prothrombin Thrombin Plasminogen - direct Xa inhibitors (eg, apixaban) THROMBOLYTICS: - fondaparinux - alteplase, reteplase, I Ia tPA tenecteplase Fibrinogen Fibrin monomers – ANTIFIBRINOLYTICS: Aggregation Plasmin - aminocaproic acid, tranexamic acid Hemophilia A: deficiency of factor VIII (XR) Common Hemophilia B: deficiency of factor IX (XR) pathway Ca2+ XIIIa XIII Fibrinolytic system Hemophilia C: deficiency of factor XI (AR) Fibrin stabilizing Note: Kallikrein activates bradykinin factor ACE inactivates bradykinin # = C1-esterase inhibitor deficiency hereditary angioedema * = require Ca2+ , phospholipid; Fibrin degradation = vitamin K-dependent factors products (eg, D-dimer) = cofactor Fibrin mesh stabilizes = activates but not part of coagulation cascade platelet plug LMWH = low-molecular-weight heparin HMWK = high-molecular-weight kininogen  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PHYSIOLOGY SEC TION III 419 Vitamin K–dependent coagulation Procoagulation Vitamin K deficiency— synthesis of factors II, VII, IX, X, protein C, protein S. Warfarin inhibits vitamin K epoxide reductase. Vitamin K administration can potentially reverse inhibitory effect of warfarin on clotting factor synthesis (delayed). FFP or PCC Reduced administration reverses action of warfarin vitamin K Inactive II, VII, IX, X, C, S (active) immediately and can be given with vitamin K -glutamyl carboxylase (vitamin K-dependent) in cases of severe bleeding. Warfarin, Epoxide Mature, carboxylated Neonates lack enteric baKteria, which produce liver failure reductase C, S II, VII, IX, X vitamin K. Early administration of vitamin K Oxidized overcomes neonatal deficiency/coagulopathy. vitamin K Suppression of gut flora by broad spectrum (inactive) Anti- Clotting coagulants factors antibiotiKs can also contribute to deficiency. Liver Factor VII (seven)—shortest half-life. Factor II (two)—longest (too long) half-life. Anticoagulation Antithrombin inhibits thrombin (factor IIa) and Activated factors VIIa, IXa, Xa, XIa, XIIa. protein C Heparin enhances the activity of antithrombin. Requires I Ia Principal targets of antithrombin: thrombin and protein S Fibrinogen Fibrin X factor Xa. VIIIa Factor V Leiden mutation produces a factor V IXa resistant to inhibition by activated protein C. Va Heparin, LMWH, Direct factor II IIa direct thrombin tPA is used clinically as a thrombolytic. Xa Prothrombin Xa inhibitors Thrombin inhibitors Antithrombin III = vitamin K-dependent factors = activates but not part of coagulation cascade = cofactor LMWH = low-molecular-weight heparin 420 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY RBC morphology TYPE EXAMPLE ASSOCIATED PATHOLOGY NOTES Acanthocytes Liver disease, abetalipoproteinemia, Projections of varying size at (“spur cells”) vitamin E deficiency irregular intervals (acanthocytes are asymmetric). Echinocytes Liver disease, ESRD, pyruvate Smaller and more uniform (“burr cells”) kinase deficiency projections than acanthocytes (echinocytes are even). Dacrocytes Bone marrow infiltration (eg, RBC “sheds a tear” because it’s (“teardrop cells”) myelofibrosis) mechanically squeezed out of its home in the bone marrow Schistocytes MAHAs (eg, DIC, TTP/HUS, Fragmented RBCs (“helmet” cells) HELLP syndrome), mechanical hemolysis (eg, heart valve prosthesis) Degmacytes (“bite G6PD deficiency Due to removal of Heinz bodies cells”) by splenic macrophages (they “deg” them out of/bite them off of RBCs) Elliptocytes Hereditary elliptocytosis Caused by mutation in genes encoding RBC membrane proteins (eg, spectrin)  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY SEC TION III 421 RBC morphology (continued) TYPE EXAMPLE ASSOCIATED PATHOLOGY NOTES Spherocytes Hereditary spherocytosis, Small, spherical cells without autoimmune hemolytic anemia central pallor  surface area-to-volume ratio Macro-ovalocytes Megaloblastic anemia (also hypersegmented PMNs) Target cells HbC disease, Asplenia, “HALT,” said the hunter to his Liver disease, Thalassemia target  surface area-to-volume ratio Sickle cells Sickle cell anemia Sickling occurs with low O2 conditions (eg, high altitude, acidosis), high HbS concentration (ie, dehydration) 422 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY RBC inclusions TYPE EXAMPLE ASSOCIATED PATHOLOGY NOTES Bone marrow Iron granules Sideroblastic anemias (eg, lead Perinuclear mitochondria with poisoning, myelodysplastic excess iron (forming ring in syndromes, chronic alcohol ringed sideroblasts) overuse) Require Prussian blue stain to be visualized Peripheral smear Howell-Jolly bodies Functional hyposplenia (eg, sickle Basophilic nuclear remnants (do cell disease), asplenia not contain iron) Usually removed by splenic macrophages Basophilic stippling Sideroblastic anemia, thalassemias Basophilic ribosomal precipitates (do not contain iron) Pappenheimer bodies Sideroblastic anemia Basophilic granules (contain iron) “Pappen-hammer” bodies Heinz bodies G6PD deficiency Denatured and precipitated hemoglobin (contain iron) Phagocytic removal of Heinz bodies Ž bite cells Requires supravital stain (eg, crystal violet) to be visualized  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY SEC TION III 423 Anemias Anemias Microcytic Normocytic Macrocytic (MCV < 80 fL) (MCV 80–100 fL) (MCV > 100 fL) Hemoglobin affected (TAIL) Nonhemolytic Hemolytic Megaloblastic Nonmegaloblastic Defective globin chain: (low reticulocyte index) (high reticulocyte index) Thalassemias DNA affected Iron deficiency (early) Defective heme synthesis: Defective DNA synthesis Anemia of chronic disease Diamond-Blackfan anemia Anemia of chronic disease Folate deficiency Aplastic anemia Liver disease Iron deficiency (late) Vitamin B12 deficiency Chronic kidney disease Chronic alcohol overuse Lead poisoning Orotic aciduria Acute blood loss (hemorrhage) Defective DNA repair Fanconi anemia Intrinsic Extrinsic Membrane defects Autoimmune Hereditary spherocytosis Microangiopathic Paroxysmal nocturnal Macroangiopathic hemoglobinuria Infections Enzyme deficiencies G6PD deficiency Pyruvate kinase deficiency Hemoglobinopathies Sickle cell anemia HbC disease Reticulocyte Also called corrected reticulocyte count. Used to correct falsely elevated reticulocyte count production index in anemia. Measures appropriate bone marrow response to anemic conditions (effective erythropoiesis). High RPI (> 3) indicates compensatory RBC production; low RPI (< 2) indicates inadequate response to correct anemia. Calculated as: actual Hct RPI = % reticulocytes × normal Hct ( / maturation time ) Interpretation of iron studies Iron Chronic Pregnancy/ deficiency disease Hemochromatosis OCP use Serum iron    — Transferrin or TIBC   a   Ferritin    — % transferrin saturation  —/   (serum iron/TIBC)  = 1° disturbance. Transferrin—transports iron in blood. TIBC—indirectly measures transferrin. Ferritin—1° iron storage protein of body. a Evolutionary reasoning—pathogens use circulating iron to thrive. The body has adapted a system in which iron is stored within the cells of the body and prevents pathogens from acquiring circulating iron. 424 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY Microcytic, hypochromic anemias MCV < 80 fL. Iron deficiency  iron due to chronic bleeding (eg, GI loss, heavy menstrual bleeding), malnutrition, absorption disorders, GI surgery (eg, gastrectomy), or  demand (eg, pregnancy) Ž  final step in heme synthesis. Labs:  iron,  TIBC,  ferritin,  free erythrocyte protoporphyrin,  RDW,  RI. Microcytosis and hypochromasia ( central pallor) A. Symptoms: fatigue, conjunctival pallor B , restless leg syndrome, pica (persistent craving and compulsive eating of nonfood substances), spoon nails (koilonychia). May manifest as glossitis, cheilosis, Plummer-Vinson syndrome (triad of iron deficiency anemia, esophageal webs, and dysphagia). α-thalassemia α-globin gene deletions on chromosome 16 Ž  α-globin synthesis. May have cis deletion (deletions occur on same chromosome) or trans deletion (deletions occur on separate chromosomes). Normal is αα/αα. Often  RBC count, in contrast to iron deficiency anemia.  prevalence in people of Asian and African descent. Target cells C on peripheral smear. # OF α-GLOBIN GENES DELETED0 DISEASE CLINICAL OUTCOME 1 α-thalassemia minima No anemia (silent carrier) Minima α α α α β β 2 α-thalassemia minor Mild microcytic, hypochromic anemia Minor α α α α β β Cis or α α α α β β Trans 3 Hemoglobin H disease Moderate to severe microcytic α α (HbH); excess β-globin hypochromic anemia α α forms β4 β β 4 Hemoglobin Barts Hydrops fetalis; incompatible with life Hb Barts α α disease; no α-globin, α α excess γ-globin forms γ4 β β  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY SEC TION III 425 Microcytic, hypochromic anemias (continued) β-thalassemia Point mutation in splice sites or Kozak consensus sequence (promoter) on chromosome 11 Ž  β-globin synthesis (β+) or absent β-globin synthesis (β0).  prevalence in people of Mediterranean descent. # OF β-GLOBIN GENES MUTATED+ DISEASE CLINICAL OUTCOME 1 β-thalassemia minor Mild microcytic anemia.  HbA2. β β 2 (β+/β+ or β+/β0) β-thalassemia intermedia Variable anemia, ranging from mild/ asymptomatic to severe/transfusion- dependent. 2 β-thalassemia major Severe microcytic anemia with target β β (Cooley anemia) cells and  anisopoikilocytosis requiring blood transfusions ( risk of 2º hemochromatosis), marrow expansion (“crew cut” on skull x-ray) Ž skeletal deformities, extramedullary hematopoiesis Ž HSM.  risk of parvovirus B19-induced aplastic crisis.  HbF and HbA2, becomes symptomatic after 6 months when HbF declines (HbF is protective). Chronic hemolysis Ž pigmented gallstones. 1 (β+/HbS or β0/HbS) Sickle cell β-thalassemia Mild to moderate sickle cell disease depending on whether there is  (β+/HbS) or absent (β0/HbS) β-globin synthesis. Lead poisoning Lead inhibits ferrochelatase and ALA dehydratase Ž  heme synthesis and  RBC protoporphyrin. Also inhibits rRNA degradation Ž RBCs retain aggregates of rRNA (basophilic stippling). Symptoms of LLEEAAD poisoning: ƒ Lead Lines on gingivae (Burton lines) and on metaphyses of long bones D on x-ray. ƒ Encephalopathy and Erythrocyte basophilic stippling. ƒ Abdominal colic and sideroblastic Anemia. ƒ Drops—wrist and foot drop. Treatment: chelation with succimer, EDTA, dimercaprol. Exposure risk  in old houses (built before 1978) with chipped paint (children) and workplace (adults). Sideroblastic anemia Causes: genetic (eg, X-linked defect in ALA synthase gene), acquired (myelodysplastic syndromes), and reversible (alcohol is most common; also lead poisoning, vitamin B6 deficiency, copper deficiency, drugs [eg, isoniazid, linezolid]). Lab findings:  iron, normal/ TIBC,  ferritin. Ringed sideroblasts (with iron-laden, Prussian blue–stained mitochondria) seen in bone marrow. Peripheral blood smear: basophilic stippling of RBCs. Some acquired variants may be normocytic or macrocytic. Treatment: pyridoxine (B6, cofactor for ALA synthase). A B C D 426 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY Macrocytic anemias MCV > 100 fL. DESCRIPTION FINDINGS Megaloblastic anemia Impaired DNA synthesis Ž maturation of RBC macrocytosis, hypersegmented neutrophils A nucleus of precursor cells in bone marrow (arrow in A ), glossitis. delayed relative to maturation of cytoplasm. Causes: vitamin B12 deficiency, folate deficiency, medications (eg, hydroxyurea, phenytoin, methotrexate, sulfa drugs). Folate deficiency Causes: malnutrition (eg, chronic alcohol  homocysteine, normal methylmalonic acid. overuse), malabsorption, drugs (eg, No neurologic symptoms (vs B12 deficiency). methotrexate, trimethoprim, phenytoin),  requirement (eg, hemolytic anemia, pregnancy). Vitamin B12 Causes: pernicious anemia, malabsorption  homocysteine,  methylmalonic acid. (cobalamin) (eg, Crohn disease), pancreatic insufficiency, Neurologic symptoms: reversible dementia, deficiency gastrectomy, insufficient intake (eg, veganism), subacute combined degeneration (due to Diphyllobothrium latum (fish tapeworm). involvement of B12 in fatty acid pathways and myelin synthesis): spinocerebellar tract, lateral corticospinal tract, dorsal column dysfunction. Folate supplementation in vitamin B12 deficiency can correct the anemia, but worsens neurologic symptoms. Historically diagnosed with the Schilling test, a test that determines if the cause is dietary insufficiency vs malabsorption. Anemia 2° to insufficient intake may take several years to develop due to liver’s ability to store B12 (vs folate deficiency, which takes weeks to months). Orotic aciduria Inability to convert orotic acid to UMP Orotic acid in urine. (de novo pyrimidine synthesis pathway) Treatment: uridine monophosphate or uridine because of defect in UMP synthase. triacetate to bypass mutated enzyme. Autosomal recessive. Presents in children as failure to thrive, developmental delay, and megaloblastic anemia refractory to folate and B12. No hyperammonemia (vs ornithine transcarbamylase deficiency— orotic acid with hyperammonemia). Nonmegaloblastic Macrocytic anemia in which DNA synthesis is RBC macrocytosis without hypersegmented anemia normal. neutrophils. Causes: chronic alcohol overuse, liver disease. Diamond-Blackfan A congenital form of pure red cell aplasia  % HbF (but  total Hb). anemia (vs Fanconi anemia, which causes Short stature, craniofacial abnormalities, and pancytopenia). Rapid-onset anemia within 1st upper extremity malformations (triphalangeal year of life due to intrinsic defect in erythroid thumbs) in up to 50% of cases. progenitor cells.  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY SEC TION III 427 Normocytic, Normocytic, normochromic anemias are classified as nonhemolytic or hemolytic. The hemolytic normochromic anemias are further classified according to the cause of the hemolysis (intrinsic vs extrinsic to the anemias RBC) and by the location of hemolysis (intravascular vs extravascular). Hemolysis can lead to  in LDH, reticulocytes, unconjugated bilirubin, pigmented gallstones, and urobilinogen in urine. Extravascular Hemolysis Intravascular Hemolysis Red blood cell Blood vessel Dimers bind Hemoglobin haptoglobin Conjugated bilirubin Enterohepatic Unconjugated recirculation bilirubin Splenic macrophage Red blood Circulated to kidneys Dimers cell (if haptoglobin capacity exceeded) Urobilinogen Urobilinogen Hemoglobinuria Stercobilinogen Intravascular Findings:  haptoglobin,  schistocytes on blood smear. Characteristic hemoglobinuria, hemolysis hemosiderinuria, and urobilinogen in urine. Notable causes are mechanical hemolysis (eg, prosthetic valve), paroxysmal nocturnal hemoglobinuria, microangiopathic hemolytic anemias. Extravascular Mechanism: macrophages in spleen clear RBCs. Findings: splenomegaly, spherocytes in peripheral hemolysis smear (most commonly due to hereditary spherocytosis and autoimmune hemolytic anemia), no hemoglobinuria/hemosiderinuria. Can present with urobilinogen in urine. Nonhemolytic, normocytic anemias DESCRIPTION FINDINGS Anemia of chronic Inflammation (eg,  IL-6) Ž  hepcidin  iron,  TIBC,  ferritin. disease (released by liver, binds ferroportin on Normocytic, but can become microcytic. intestinal mucosal cells and macrophages, Treatment: address underlying cause of thus inhibiting iron transport) Ž  release of inflammation, judicious use of blood iron from macrophages and  iron absorption transfusion, consider erythropoiesis- from gut. Associated with conditions such stimulating agents such as EPO (eg, in chronic as chronic infections, neoplastic disorders, kidney disease). chronic kidney disease, and autoimmune diseases (eg, SLE, rheumatoid arthritis). Aplastic anemia Failure or destruction of hematopoietic stem cells.  reticulocyte count,  EPO. A Causes (reducing volume from inside diaphysis): Pancytopenia characterized by anemia, ƒ Radiation leukopenia, and thrombocytopenia (vs aplastic ƒ Viral agents (eg, EBV, HIV, hepatitis viruses) crisis, which causes anemia only). Normal cell ƒ Fanconi anemia (autosomal recessive DNA morphology, but hypocellular bone marrow repair defect Ž bone marrow failure); with fatty infiltration A. normocytosis or macrocytosis on CBC. Symptoms: fatigue, malaise, pallor, purpura, Common associated findings include short mucosal bleeding, petechiae, infection. stature, café-au-lait spots, thumb/radial Treatment: withdrawal of offending defects, predisposition to malignancy. agent, immunosuppressive regimens (eg, ƒ Idiopathic (immune mediated, 1° stem cell antithymocyte globulin, cyclosporine), bone defect); may follow acute hepatitis marrow allograft, RBC/platelet transfusion, ƒ Drugs (eg, benzene, chloramphenicol, bone marrow stimulation (eg, GM-CSF). alkylating agents, antimetabolites) 428 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY Intrinsic hemolytic anemias DESCRIPTION FINDINGS Hereditary Primarily autosomal dominant. Due to defect Splenomegaly, pigmented gallstones, aplastic spherocytosis in proteins interacting with RBC membrane crisis (parvovirus B19 infection). skeleton and plasma membrane (eg, ankyrin, Labs:  mean fluorescence of RBCs in eosin band 3, protein 4.2, spectrin). 5-maleimide (EMA) binding test,  fragility Small, round RBCs with no central pallor. in osmotic fragility test (RBC hemolysis with  surface area/dehydration Ž  MCHC exposure to hypotonic solution). Normal to Ž premature removal by spleen (extravascular  MCV with abundance of RBCs. hemolysis). Treatment: splenectomy. Paroxysmal nocturnal Hematopoietic stem cell mutation Triad: Coombs ⊝ hemolytic anemia (mainly hemoglobinuria Ž  complement-mediated intravascular intravascular), pancytopenia, venous hemolysis, especially at night. Acquired PIGA thrombosis (eg, Budd-Chiari syndrome). mutation Ž impaired GPI anchor synthesis Pink/red urine in morning. Associated with for decay-accelerating factor (DAF/CD55) and aplastic anemia, acute leukemias. membrane inhibitor of reactive lysis (MIRL/ Labs: CD55/59 ⊝ RBCs on flow cytometry. CD59), which protect RBC membrane from Treatment: eculizumab (targets terminal complement. complement protein C5). G6PD deficiency X-linked recessive. G6PD defect Back pain, hemoglobinuria a few days after Ž  NADPH Ž  reduced glutathione oxidant stress. Ž  RBC susceptibility to oxidative stress Labs:  G6PD activity (may be falsely normal (eg, sulfa drugs, antimalarials, fava beans) during acute hemolysis), blood smear shows Ž hemolysis. RBCs with Heinz bodies and bite cells. Causes extravascular and intravascular hemolysis. “Stress makes me eat bites of fava beans with Heinz ketchup.” Pyruvate kinase Autosomal recessive. Pyruvate kinase defect Hemolytic anemia in a newborn. deficiency Ž  ATP Ž rigid RBCs Ž extravascular Labs: blood smear shows burr cells. hemolysis. Increases levels of 2,3-BPG Ž  hemoglobin affinity for O2. Sickle cell anemia Point mutation in β-globin gene Ž single amino Complications: A acid substitution (glutamic acid Ž valine) ƒ Aplastic crisis (transient arrest of alters hydrophobic region on β-globin chain erythropoiesis due to parvovirus B19). Ž aggregation of hemoglobin. Causes ƒ Autosplenectomy (Howell-Jolly bodies) extravascular and intravascular hemolysis. Ž  risk of infection by encapsulated Pathogenesis: low O2, high altitude, or acidosis organisms (eg, Salmonella osteomyelitis). precipitates sickling (deoxygenated HbS ƒ Splenic infarct/sequestration crisis. polymerizes) Ž vaso-occlusive disease. ƒ Painful vaso-occlusive crises: dactylitis Newborns are initially asymptomatic because of (painful swelling of hands/feet), priapism,  HbF and  HbS. acute chest syndrome (respiratory distress, Heterozygotes (sickle cell trait) have resistance new pulmonary infiltrates on CXR, common to malaria. cause of death), avascular necrosis, stroke. Sickle cells are crescent-shaped RBCs A. ƒ Sickling in renal medulla ( Po2) Ž renal “Crew cut” on skull x-ray due to marrow papillary necrosis Ž hematuria (also seen in expansion from  erythropoiesis (also seen in sickle cell trait). thalassemias). Hb electrophoresis:  HbA,  HbF,  HbS. Treatment: hydroxyurea ( HbF), hydration. HbC disease Glutamic acid–to-lycine (lysine) mutation in HbSC (1 of each mutant gene) milder than HbSS. β-globin. Causes extravascular hemolysis. Blood smear in homozygotes: hemoglobin crystals inside RBCs, target cells.  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY SEC TION III 429 Extrinsic hemolytic anemias DESCRIPTION FINDINGS Autoimmune A normocytic anemia that is usually idiopathic Spherocytes and agglutinated RBCs A on hemolytic anemia and Coombs ⊕. Two types: peripheral blood smear. A ƒ Warm AIHA–chronic anemia in which Warm AIHA treatment: steroids, rituximab, primarily IgG causes extravascular splenectomy (if refractory). hemolysis. Seen in SLE and CLL and with Cold AIHA treatment: cold avoidance, certain drugs (eg, β-lactams, α-methyldopa). rituximab. “Warm weather is Good.” ƒ Cold AIHA–acute anemia in which primarily IgM + complement cause RBC agglutination and extravascular hemolysis upon exposure to cold Ž painful, blue fingers and toes. Seen in CLL, Mycoplasma pneumoniae infections, infectious mononucleosis. Drug-induced Most commonly due to antibody-mediated Spherocytes suggest immune hemolysis. hemolytic anemia immune destruction of RBCs or oxidant injury Bite cells suggest oxidative hemolysis. via free radical damage (may be exacerbated in Can cause both extravascular and intravascular G6PD deficiency). hemolysis. Common causes include antibiotics (eg, penicillins, cephalosporins), NSAIDs, immunotherapy, chemotherapy. Microangiopathic RBCs are damaged when passing through Schistocytes (eg, “helmet cells”) are seen on hemolytic anemia obstructed or narrowed vessels. Causes peripheral blood smear due to mechanical intravascular hemolysis. destruction (schisto = to split) of RBCs. Seen in DIC, TTP/HUS, SLE, HELLP syndrome, hypertensive emergency. Macroangiopathic Prosthetic heart valves and aortic stenosis may Schistocytes on peripheral blood smear. hemolytic anemia also cause hemolytic anemia 2° to mechanical destruction of RBCs. Hemolytic anemia due  destruction of RBCs (eg, malaria, Babesia). to infection Leukopenias CELL TYPE CELL COUNT CAUSES 3 Neutropenia Absolute neutrophil count < 1500 cells/mm Sepsis/postinfection, drugs (including Severe infections typical when < 500 cells/mm3 chemotherapy), aplastic anemia, SLE, radiation, congenital Lymphopenia Absolute lymphocyte count < 1500 cells/mm3 HIV, DiGeorge syndrome, SCID, SLE, (< 3000 cells/mm% in children) glucocorticoidsa, radiation, sepsis, postoperative Eosinopenia Absolute eosinophil count < 30 cells/mm3 Cushing syndrome, glucocorticoidsa a Glucocorticoids cause neutrophilia, despite causing eosinopenia and lymphopenia. Glucocorticoids  activation of neutrophil adhesion molecules, impairing migration out of the vasculature to sites of inflammation. In contrast, glucocorticoids sequester eosinophils in lymph nodes and cause apoptosis of lymphocytes. 430 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY Heme synthesis, The porphyrias are hereditary or acquired conditions of defective heme synthesis that lead to the porphyrias, and lead accumulation of heme precursors. Lead inhibits specific enzymes needed in heme synthesis, poisoning leading to a similar condition. CONDITION AFFECTED ENZYME ACCUMULATED SUBSTRATE PRESENTING SYMPTOMS Lead poisoning Ferrochelatase and Protoporphyrin, ALA Microcytic anemia (basophilic stippling in A ALA dehydratase (blood) peripheral smear A , ringed sideroblasts in bone marrow), GI and kidney disease. Children—exposure to lead paint Ž mental deterioration. Adults—environmental exposure (eg, batteries, ammunition) Ž headache, memory loss, demyelination (peripheral neuropathy). Acute intermittent Porphobilinogen Porphobilinogen, ALA Symptoms (5 P’s): porphyria deaminase (autosomal ƒ Painful abdomen dominant mutation) ƒ Port wine–colored Pee ƒ Polyneuropathy ƒ Psychological disturbances ƒ Precipitated by factors that  ALA synthase (eg, drugs [CYP450 inducers], alcohol, starvation) Treatment: hemin and glucose. Porphyria cutanea Uroporphyrinogen Uroporphyrin (tea- Blistering cutaneous photosensitivity and tarda decarboxylase colored urine) hyperpigmentation B. B Most common porphyria. Exacerbated with alcohol consumption. Causes: familial, hepatitis C. Treatment: phlebotomy, sun avoidance, antimalarials (eg, hydroxychloroquine). MITOCHONDRIA Glucose, hemin CYTOPLASM Sideroblastic anemia (X-linked) Lead poisoning Aminolevulinic Succinyl CoA + glycine Porphobilinogen B₆ acid ALA synthase ALA dehydratase Porphobilinogen (rate-limiting step) deaminase Acute intermittent Hydroxymethylbilane porphyria Mitochondrial membrane Uroporphyrinogen III Heme Uroporphyrinogen decarboxylase Ferrochelatase Porphyria cutanea tarda Lead poisoning Fe2+ Protoporphyrin Coproporphyrinogen III  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY SEC TION III 431 Iron poisoning Acute Chronic FINDINGS High mortality rate associated with accidental Seen in patients with 1° (hereditary) or 2° (eg, ingestion by children (adult iron tablets may chronic blood transfusions for thalassemia or look like candy). sickle cell disease) hemochromatosis. MECHANISM Cell death due to formation of free radicals and peroxidation of membrane lipids. SYMPTOMS/SIGNS Abdominal pain, vomiting, GI bleeding. Arthropathy, cirrhosis, cardiomyopathy, diabetes Radiopaque pill seen on x-ray. May progress to mellitus and skin pigmentation (“bronze anion gap metabolic acidosis and multiorgan diabetes”), hypogonadism. failure. Leads to scarring with GI obstruction. TREATMENT Chelation (eg, deferoxamine, deferasirox), Phlebotomy (patients without anemia) or gastric lavage. chelation. Coagulation disorders PT—tests function of common and extrinsic pathway (factors I, II, V, VII, and X). Defect Ž  PT (Play Tennis outside [extrinsic pathway]). INR (international normalized ratio) = patient PT/control PT. 1 = normal, > 1 = prolonged. Most common test used to follow patients on warfarin, which prolongs INR. PTT—tests function of common and intrinsic pathway (all factors except VII and XIII). Defect Ž  PTT (Play Table Tennis inside). TT—measures the rate of conversion of fibrinogen Ž fibrin. Prolonged by anticoagulants, hypofibrinogenemia, DIC, liver disease. Coagulation disorders can be due to clotting factor deficiencies or acquired factor inhibitors (most commonly against factor VIII). Diagnosed with a mixing study, in which normal plasma is added to patient’s plasma. Clotting factor deficiencies should correct (the PT or PTT returns to within the appropriate normal range), whereas factor inhibitors will not correct. DISORDER PT PTT MECHANISM AND COMMENTS Hemophilia A, B, or C —  Intrinsic pathway coagulation defect ( PTT). A ƒ A: deficiency of factor VIII; X-linked recessive. Pronounce “hemophilia Ate (eight).” ƒ B: deficiency of factor IX; X-linked recessive. ƒ C: deficiency of factor XI; autosomal recessive. Hemorrhage in hemophilia—hemarthroses (bleeding into joints, eg, knee A ), easy bruising, bleeding after trauma or surgery (eg, dental procedures). Treatment: desmopressin, factor VIII concentrate, emicizumab (A); factor IX concentrate (B); factor XI concentrate (C). Vitamin K deficiency   General coagulation defect. Bleeding time normal.  activity of factors II, VII, IX, X, protein C, protein S. 432 SEC TION III HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY Platelet disorders All platelet disorders have  bleeding time (BT), mucous membrane bleeding, and microhemorrhages (eg, petechiae, epistaxis). Platelet count (PC) is usually low, but may be normal in qualitative disorders. DISORDER PC BT NOTES Bernard-Soulier –/  Autosomal recessive defect in adhesion.  GpIb Ž  platelet-to-vWF adhesion. syndrome Labs:  platelet aggregation, Big platelets. Glanzmann –  Autosomal recessive defect in aggregation.  GpIIb/IIIa ( integrin αIIbβ3) Ž  thrombasthenia platelet-to-platelet aggregation and defective platelet plug formation. Labs: blood smear shows no platelet clumping. Immune   Destruction of platelets in spleen. Anti-GpIIb/IIIa antibodies Ž splenic thrombocytopenia macrophages phagocytose platelets. May be idiopathic or 2° to autoimmune disorders (eg, SLE), viral illness (eg, HIV, HCV), malignancy (eg, CLL), or drug reactions. Labs:  megakaryocytes on bone marrow biopsy,  platelet count. Treatment: glucocorticoids, IVIG, rituximab, TPO receptor agonists (eg, eltrombopag, romiplostim), or splenectomy for refractory ITP. Uremic platelet –  In patients with renal failure, uremic toxins accumulate and interfere with dysfunction platelet adhesion. Thrombotic Disorders overlap significantly in symptomatology. May resemble DIC, but do not exhibit lab microangiopathies findings of a consumptive coagulopathy (eg,  PT,  PTT,  fibrinogen), as etiology does not involve widespread clotting factor activation. Thrombotic thrombocytopenic purpura Hemolytic-uremic syndrome EPIDEMIOLOGY Typically females Typically children PATHOPHYSIOLOGY Inhibition or deficiency of ADAMTS13 (a Predominately caused by Shiga toxin–producing vWF metalloprotease) Ž  degradation of Escherichia coli (STEC) infection (serotype vWF multimers Ž  large vWF multimers O157:H7), which causes profound endothelial Ž  platelet adhesion and aggregation dysfunction. (microthrombi formation) PRESENTATION Triad of thrombocytopenia ( platelets), microangiopathic hemolytic anemia ( Hb, schistocytes,  LDH), acute kidney injury ( Cr) DIFFERENTIATING SYMPTOMS Triad + fever + neurologic symptoms Triad + bloody diarrhea LABS Normal PT and PTT helps distinguish TTP and HUS (coagulation pathway is not activated) from DIC (coagulation pathway is activated) TREATMENT Plasma exchange, glucocorticoids, rituximab Supportive care  HEMATOLOGY AND ONCOLOGY ` HEMATOLOGY AND ONCOLOGY—PATHOLOGY