USMLE STEP I Review Week 6: Renal and Hematology Physiology

1. Steven Katz, MSIV USMLE STEP I Review Week 6: Renal and Hematology Physiology

2. Part 1: Hematology and Oncology (p.326-347) • Blood Cell Differentiation

3. Heme Terms (p. 327) • Erythrocyte: anucleate, biconcave cell with large surface area for gas exchange. • Macrophage: mature monocyte, phagocytic cell found in tissues • Platelet: cytoplasmic fragment of megakaryocyte, involved in primary hemostasis. Aggregates and interacts with fibrinogen to form hemostatic plug. 1/3 platelet pool stored in the spleen.

4. Heme terms (p.327) • Leukocyte: two types granulocytes and mononuclear cells. Involved in defense against infections • Basophil: Granulocyte, mediates allergic rxn, in blood • Mast Cell: Granulocyte, binds IgE to membrane, found in tissue • Eosinophil: Granulocyte, causes of eosinophilia (NAACP) Neoplasm, Asthma, Allergy, CollagenVasc. Dz, Parasites • Neutrophil: Granulocyte, acute inflammatory response cell • Monocyte: mononuclear cell, “frosted glass cytoplasm”

5. Heme Terms (p.327) • Dendritic Cells: APC, has MHC II and Fc receptor, main inducer of 10 Ab response • Lymphocyte: mononuclear cells mature into: • B lymphocyte: humoral immunity • Plasma cell: mature B Lymphocyte, produce Ab. (multiple myeloma is a plasma cell neoplasm) • T lymphocyte: cellular immunity, matures in thymus • MHC x CD=8 (MHC2 x CD4 & MHC1 x CD1)

6. Intrinsic Pathway Extrinsic Pathway * * * TF = thromboplastin * * Factor II is prothrombin (IIa is thrombin) * = Ca required

7. Thrombogenesis

8. Coag Cascade and platelet plug (p.330) • Platelet plug formation • Adhesion: vWF mediates linking of platelet Gp1b receptor to subendothelial collagen • Aggregation: balance btw pro-aggregation and anti-aggregation factors • TxA2 released by platelets incr aggregation • PGI2 and NO from endothelial cells decr aggregation • Swelling: binding of ADP on platelet receptor  insertion of G2b/3a on platelet memb which allows platelet cohesion, Ca strengthens platelet plug • ASA inhibits cyclooxygenase which inhibits TxA2 synthesis

9. Coag cascade: pro-coagulation (p.330) • Vitamin K becomes activated by epoxide reductase and acts as a co-factor in the maturation of Factors II, VII, IX,, X, C, and S • Warfarin inhibits epoxide reductase • von Willebrand factor carries/protect VIII • Binds GpIb to subendothelial collagen as well

10. Coag cascade: anti-coagulation (p.330) • Antithrombin III inactivates factors II, VII, IX, X, and XI • Heparin activates ATIII • Protein C is activated by Protein S and thrombomodulin (endothelial cells). • APC (activated protein C) cleaves and inactivates Va and VIIIa • Factor V Leiden mutation produces APC resistant Factor V • Plasminogen –tPA-> plasmin cleavage of fibrin mesh

11. Coag cascade and kinin (p.331)

12. Hereditary Thrombosis Syndromes (p.329) • Factor V Leiden: mutant factor V cannot be degraded by protein C • Prothrombin gene mutation: Mutation in 3’ untranslated region associated with venous clots • AT III deficiency: inherited deficiency of ATIII, reduced increase of PTT with heparin admin • Protein C or S deficiency: decreased ability to inactivate factors V and VIII. Increased risk of hemorrhagic skin necrosis following warfarin admin

13. Blood groups (p.331) • Type A: has A Ag on RBC and B Ab in plasma • Type B: has B Ag on RBC and A Ab in plasma • Type AB: A and B Ag on RBC, no Ab in plasma “universal RECIEPIENT” • Type O: No Ag on RBC, both AB in plasma, “universal DONOR” • Rh: + indicates Ag is present, mothers who are neg, may make anti-Rh IgG that can cross the placenta and cause hemolytic dz of the newborn (in the subsequent pregnancy)

14. RBC pathologies (p.332) Type Biconcave Spherocyte Elliptocyte Macro-ovalocyte Helmet cell, shistocyte Sickle Cell Bite Cell Teardrop cell Acanthocyte (spur cell) Target cell Burr Cell Basophilic stippling Pathology Normal spherocytosis, autoimmune hemolysis Hereditary elliptocytosis Megaloblastic anemia, marrow failure DIC, TTP/HUS, traumatic, hemolysis Sickle Cell anemia G6PD deficiency Myeloid metaplasia with myelofibrosis “Spiny”, in liver dz and abetalipoproteinemia HbC dz, Asplenia, Liver dz, Thalassemia (HALT) TTP/HUS Thalassemia, Anemia of chronic dz, IDA, Lead (TAIL)

15. Anemias-VERY IMPORTANT (p.332) • Microcytic Hypochromic: MCV <80 • Iron deficiency anemia: serum iron, TIBC, ferritin (intracellular iron store) • Decreased heme synthesis • Thalassmia: target cells • Mut leads to decr globin synthesis • Lead poisioning • Inhibits ferrochelatase and ALA dehydrase (heme synthesis) • Some sideroblastic anemias • Anemia of chronic dz: release of iron to transferrin

16. Anemias-VERY IMPORTANT (p.332) • Macrocytic: MCV >100 • Megaloblastic-vit B12 and/or folate deficiency • Drugs that block DNA synthesis (e.g sulfa, phenytoin, AZT) • Marked reticulocytosis (bigger than mature RBC’s)

17. Anemias-VERY IMPORTANT (p.332) • Normocytic, normochromic • Acute hemorrhage • Enzyme defects (e.g. G6PD) • RBC membrane defects (e.g. spherocytosis) • Bone marrow disorders (e.g. aplastic anemia, leukemia) (macrocytic as well) • Hemoglobinopathies (e.g. sickle cell) • Autoimmune hemolytic anemia • Anemia of chronic dz: TIBC, ferritin, increased storage in marrow macrophages

18. Lab values in anemia Ferritin=iron storage; Transferrin=iron transport in blood

19. Porphyria (p.333) • Lead poisioning: build up coproporphyrin and ALA 2/2 inhibition of ferrochelatase and ALAL dehydrase • Acute intermittent porphyria: build up of porphobilinogen and d-ALA 2/2 inhibition of iroporphyrinogen I synthase • Porphyria Cutanea Tarda: build up of uroporphyrin (tea-colored) 2/2 inhibition of uroporphyrinogen decarboxylase

20. Hemoglobin synthesis

21. Blood Dyscrasias (p.334) • Sickle Cell: mut of beta-globin chain. Low O2 or dehydration precipitates sickling. • Complications: • aplastic anemia (parvo B19) • Autosplenectomy • incr risk of encapsulated org infect • Salmonella osteomyelitis • vaso-occlusive crises • renal papillary necrosis, etc. • Therapies include hydroxyurea (incr HbF), bone marrow transplant, folate, etc. • “Crew cut” on skull XR 2/2 marrow expansion from incr erythropoeisis • Newborns are initially asymptomatic 2/2 high HbF levels

22. Blood Dyscrasias (p.334) • a-thalassemia: there are 4 a-globin chains and clinical dz depends on how many chains are under-produced. • HbH: b4-tetramers, lacks 3 a-globin genes • Hb Barts: g4-tetramers, lacks all 4 a-globin genes • Results in hydrops fetalis and intrauterine fetal death • Most prevalent in Asian and African populations

23. Blood Dyscrasias (p.334) • b-thalassemia: • Minor (heterozygotes): beta-chain is under-produced • Major (homozygotes): beta-chain is absent • Require transfusions and get 2ndary hemochromatosis (need iron chelator) • HbF production is increased but inadequate • HbS/B-thal heterozygotes have increased propensity to have sickling.

24. Hemolytic Anemias (p.335) • Usually results in increased serum bilirubin (indirect/unconjugated) and reticulocytosis • INTRAvascular hemolysis  hemoglobinuria • EXTRAvascular  jaundice

25. Hemolytic Anemias (p.335) • Autoimmune • Warm agglutinin (IgG) chronic anemia seen in SLE, CLL, and with certain drugs (e.g. a-methyldopa). Mostly extravascular hemolysis (RBC’s destroyed by Kupffer cells and spleen) • Cold agglutinin (IgM) ACUTE anemia triggered by cold, seen with Mycoplasma pneumoniae or mono (EBV). • Erythroblastosis fetalis: in newborns 2/2 Rh or other blood group incompatibility. Ab from Mom destroy baby’s RBC’s.

26. Hemolytic Anemias (p.335) • Hereditary spherocytosis: Extravascular hemolysis 2/2/ defect in ankyrin, band 3.1, or spectrin. • RBC are round and have no central pallor • Increased MCHC and RDW • Associated with splenomegaly, aplastic crisis, and Howell-Jolly bodies • Coombs negative, use osmotic fragility test for confirmation of disease

27. Howell-Jolly Body

28. Hemolytic Anemias (p.335) • Paroxysmal nocturnal hemoglobinuria: • Intravascular hemolysis 2/2 membrane defect. The RBC’s have an increased sensitivity to the lytic activity of complement (impaired synthesis of GPI anchor/decay-accelerating factor in RBC membranes) • Lab tests show increased urine hemosiderin (iron storage complex similar to ferritin)

29. Hemolytic Anemias (p.335) • Microangiopathic Anemia: Intravasular hemolysis seen in • DIC • TTP/HUS • SLE • Malignant hypertension

30. Disseminated Intravascular Coagulation (DIC) (p.335) • Activation of the coagulation cascade leading to microthrombi and global consumption of platelets, fibrin, and coagulation factors. • Causes: • Sepsis, Trauma, Obstetric complications, acute Pancreatitis, Malignancy, Nephrotic syndromes, Transfusion (STOP Making New Thrombi) • Lab Findings: • Incr PT, PTT, fibrinogen, and fibrin split products (D-dimer) • Decr platelet count • Helmet cells and shistocytes on blood smear

31. Bleeding disorders (p.336) • Platelet abnormality causes: • ITP: peripheral platelet destruction, anti-GpIIb/IIIa Ab, incr megakaryocytes) • May have onset after a viral infection • Definitive treatment in splenectomy • TTP: deficiency in vWF cleaving metalloproteinase, incr platelet aggregation, thrombosis and shistocyte formation, incr LDH, neurologic and renal sx, fever • Aplastic anemia • Drugs: immunosuppressive agents

32. Bleeding disorders (p.336) • Coagulation Factor Defects/Coagulopathies: • Hemophilia A: factor VIII deficiency • Hemophilia B: Factor IX deficiency • Von Willebrand’s disease: fairly mild it is the most common bleeding disorder • Cause of bleeding is deficiency of von Willebrand’s factor which leads to a defect of platelet adhesion and decreased factor VIII survival • *Remember vWF helps protect Factor VIII!

33. Hemorrhagic Disorders (p.336)

34. Hemorrhagic Disorders • Defects in platelet plug formation lead to increased bleeding time • GT: decr GpIIb/IIIa (defect in platelet-platelet adhesion) • BS: decr GpIb (defect in platelet-collagen adhesion) • vWD: decr vWF (defect in platelet-collagen adhesion) • DIC and thombrocytopenia: decreased platelet count • Defects in extrinsic coag cascade lead to increased PT • Defects in intrinsic coag cascade lead to increased PTT

35. Reed-Sternberg cells (p. 337) • Distinctive giant cell associate with Hodgkin’s lymphoma • Bilobed or binucleate cell appear as “owl eyes” • The cells are CD30+ and CD15+ of B-cell origin • Necessary but not sufficient for dx of Hodgin’s dz

36. Lymphomas (p.337)

37. Hodgkin’s Lymphoma (p. 337)

38. Non-Hodgkin’s Lymphoma (p.339)

39. Non-Hodgkin’s Lymphoma (p.339)

40. Multiple Myeloma (p.338) • Monoclonal plasma cell cancer that arises in the marrow and produces IgG (55%) or IgA (45%). • Most common 10 tumor arising within the bone in the elderly (> 40-50 y/o) • Symptoms: • destructive bone lesions and consequent hypercalcemia • Renal insufficiency • Increased susceptibility to infection • Anemia • Also associated with 10 amyloidosis and punched out lytic lesions on x-ray. • Think CRAB: hyperCalcemia, Renal insuff, Anemia, Back and Bone pain

41. Multiple Myeloma (p.338) • Labs: • SPEP (serum protein electrophoresis) shows monoclonal Ig spike (M protein) • UPEP (urine protein electrophoresis) shows Ig light chains (aka Bence Jones protein) • Peripheral Smear shows RBC’s stacked like poker chips (Rouleaux formation) • Compare to Waldenström’s macroglobulinemia • M spike is IgM (not IgG or IgA) • Also hyperviscosity symptoms, no lytic bone lesions • If asymptomatic dx is monoclonal gammopathy of undetermined significance (MGUS)

42. Chromosomal Translocations (p. 339)

43. Leukemoid Rxn (p.340) • Increased white blood count with LEFT shift (e.g. 80% bands) • Increased leukocyte alkaline phosphatase

44. Leukemias (p.340) • General signs and symptoms: • Increased number of circulating leukocytes • Bone marrow infiltrates of leukemic cells • Marrow failure can cause anemia • Infection (decreased mature WBC’s) • Hemorrhage (decreased platelets) • Leukemic cell infiltrates in liver, spleen and lymph nodes are possible as well

45. Leukemias (p.340) • ALL: Most common in < 15 y/o • Bone marrow replaced by large increase in lymphoblasts • TdT+ (marker of pre-T and pre-B cells) • Most responsive to therapy • May spread to CNS and testes • AML: Median onset ~60 y/o, Auer rods seen on smear • Large increase in circulating myeloblasts • M3 responds to all-trans retinoic acid (Vit A) (induces differentiation of myeloblasts)

46. Leukemias (p.340) • CLL: seen in > 60 y/o • Lymphadenopathy, hepatosplenomegaly • Few symptoms and generally indolent course • Smudge cells on smear • Warm Ab autoimmune anemia • Similar to SLL (small lymphocytic lymphoma) • CML: Age range 30-60 y/o • Defined by the Philadelphia chrom, myeloid stem cell proliferation • Presents with increased neutrophils, metamyelocytes, basophils, splenomegaly • May accelerate and transform into ALL (1/3) or AML (2/3) “blast crisis” • Left shift with all stages of myeloid maturation on smear • Very low leukocyte alk phos (vs. leukomoid rxn) • Responds to imatinib (anti bcr-abl)

47. Leukemias (p.340) • Hairy cell leukemia—mature B-cell tumor in the eldery. Cells have filamentous, hair like projections. • Stains TRAP (tartrate-resistant acid phosphatase) positive

48. Auer rods (p.340) • Peroxidase positive cytoplasmic inclusions in granulocytes and myeloblasts • Commonly seen in acute promyelocytic leukemia (M3) • Treatment of M3 AML can release Auer rods

49. Langerhans cell histiocytoses/Histocytosis X (p.340) • Proliferative disorders of dendritic (Langerhans) cells from the monocyte lineage • Defective cells express S-100 and CD1a • Birbeck granules (“tennis rackets” on EM) are characteristics • Older terms for different clinical conditions with same basic disorder • Letterer-Siwe dz, Hand-Schuller-Christian dz, eosinophilic granulomas

50. Myeloproliferative disorders (p.341) • The myelofibroproliferative disorders represents an overlapping spectrum classic findings below: • PCV-Abnl hematopoeitic stem cells that are sensitive to growth factors • ET-Similar to PCV, but specific for megakaryocytes • Myelofibrosis-Fibrotic obliteration of bone marrow • CML-bcr-abl transformation leads to incr cell division and inhib of apoptosis. JAK2 is involved in hematopoeitic growth factor signaling. Mutations are important in disorders other than CML