RBC and BLEEDING DISORDERS

1. RBC and BLEEDING DISORDERS

2. RBC and Bleeding Disorders • NORMAL • Anatomy, histology • Development • Physiology • ANEMIAS • Blood loss: acute, chronic • Hemolytic • Diminished erythropoesis • POLYCYTHEMIA • BLEEDING DISORDERS

8. WHERE is MARROW? • Yolk Sac: very early embryo • Liver, Spleen: NEWBORN • BONE • CHILDHOOD: AXIAL SKELETON & APPENDICULAR SKELETON BOTH HAVE RED (active) MARROW • ADULT: AXIAL SKELETON RED MARROW, APPENDICULAR SKELETON YELLOW MARROW

9. MARROW FEATURES • CELLULARITY 50% • MEGAKARYOCYTES at least 1-2/hpf • M:E RATIO  3:1 • MYELOID MATURATION  1/3 bands or more • ERYTHROID MATURATION  nucleus/cytoplasm • LYMPHS, PLASMA CELLS  small percentage • STORAGE IRON, i.e., HEMOSIDERIN present • “FOREIGN CELLS”

10. MARROW “DIFFERENTIATION”

12. ANEMIAS* • BLOOD LOSS • ACUTE • CHRONIC • IN-creased destruction (HEMOLYTIC) • DE-creased production * A good definition would be a decrease in OXYGEN CARRYING CAPACITY, rather than just a decrease in red blood cells, because you need to have enough blood cells THAT FUNCTION, and not just enough blood cells.

13. Featuresof ALL anemias • Pallor, where? • Tiredness • Weakness • Dyspnea, why? • Palpitations • Heart Failure (high output), why?

15. HEMOLYTIC • HEREDITARY • MEMBRANE disorders: e.g., spherocytosis • ENZYME disorders: e.g., G6PD deficciency • HGB disorders (hemoglobinopathies) • ACQUIRED • MEMBRANE disorders (PNH) • ANTIBODY MEDIATED, transfusion or autoantibodies • MECHANICAL TRAUMA • INFECTIONS • DRUGS, TOXINS • HYPERSPLENISM

16. IMPAIRED PRODUCTION • Disturbance of proliferation and differentiation of stem cells: aplastic anemias, pure RBC aplasia, renal failure • Disturbance of proliferation and maturation of erythroblasts • Defective DNA synthesis: (Megaloblastic) • Defective heme synthesis: (Fe) • Deficient globin synthesis: (Thalassemias)

17. MODIFIERS • MCV, microcytosis, macrocytosis • MCH • MCHC, hypochromic • RDW, anisocytosis

18. HEMOLYTIC ANEMIAS • Life span LESS than 120 days • Marrow hyperplasia (M:E), EPO+ • Increased catabolic products, e.g., bilirubin, serum HGB, hemosiderin, haptoglobin-HGB

19. HEMOLYSIS • INTRA-vascular (vessels) • EXTRA-vascular (spleen)

20. M:E Ratio normally 3:1

21. HEREDITARY SPHEROCYTOSIS Genetic defects affecting ankyrin, spectrin, usually autosomal dominant Children, adults Anemia, hemolysis, jaundice, splenomegaly, gallstones (what kind?)

22. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency • A- and Mediterranean are most significant types

23. FEATURES of G6PD Defic. • Genetic: Recessive, X-linked • Can be triggered by foods (fava beans), oxidant substances drugs (primaquine, chloroquine), or infections • HGB can precipitate as HEINZ bodies • Acute intravascular hemolysis can occur: • Hemoglobinuria • Hemoglobinemia • Anemia

24. Sickle Cell Disease • Classic hemoglobinopathy • Normal HGB is α2 β2: β-chain defects (Val->Glu) • Reduced hemoglobin “sickles” in homozygous • 8% of American blacks are heterozygous

25. Clinical features of HGB-S disease • Severe anemia • Jaundice • PAIN (pain CRISIS) • Vaso-occlusive disease: EVEREWHERE, but clinically significant bone, spleen (autosplenectomy) • Infections: Pneumococcus, Hem. Influ., Salmonella osteomyelitis

27. THALASSEMIAS • A WIDE VARIETY of diseases involving GLOBIN synthesis, COMPLEX genetics • Alpha or beta chains deficient synthesis involved • Often termed MAJOR or MINOR, depending on severity, silent carriers and “traits” are seen • HEMOLYSIS is uniformly a feature, and microcytic anemia, i.e, LOW MCV (just like iron deficiency anemia has a low MCV) • A “crew cut” skull x-ray appearance may beseen in severe erythroid hyperplasia.

29. Hemoglobin H Disease • Deletion of THREE alpha chain genes • HGB-H is primarilly Asian • HGB-H has a HIGH affinity for oxygen • HGB-H is unstable and therefore has classical hemolytic behavior

30. HYDROPS FETALIS • FOUR alpha chain genes are deleted, so this is the MOST SEVERE form of thalassemia • Many/most never make it to term • Children born will have a SEVERE hemolytic anemia as in the erythroblastosis fetalis of Rh disease: • Pallor (as in all anemias), jaundice, kernicterus • Edema (hence the name “hydrops”) • Massive hepatosplenomegaly (hemolysis)

31. Paroxysmal Nocturnal Hemoglobinuria (PNH) • ACQUIRED, NOT INHERITED like all the previous hemolytic anemias were • ACQUIRED mutations in phosphatidylinositol glycan A (PIGA) • Note: It is “P” and “N” only 25% of the time! GlycosylphosPhatidylInositol (lipid rafts)

32. Immunohemolytic Anemia • All of these have the presence of antibodies and/or compliment present on RBC surfaces • NOT all are AUTOimmune, some are caused by drugs • Antibodies can be • WARM (IgG) • COLDAGGLUTININ (IgM) • COLD HEMOLYSIN (paroxysmal) (IgG)

33. IMMUNOHEMOLYTIC ANEMIAS • WARM AGGLUTININS (IgG), will NOT hemolyze at room temp • Primary Idiopathic (most common) • Secondary (Tumors, especially leuk/lymph, drugs) • COLD AGGLUTININS: (IgM), WILL hemolyze at room temp • Mycoplasma pneumoniae, HIV, mononucleosis • COLD HEMOLYSINS: (IgG) Cold Paroxysmal Hemoglobinuria, hemo-LYSIS in body, ALSO often follows mycoplasma pneumoniae

34. COOMBSTEST • DIRECT: Patient’s CELLS are tested for surface Ab’s • INDIRECT: Patient’s SERUM is tested for Ab’s.

35. HEMOLYSIS/HEMOLYTIC ANEMIAS DUE TO RBC TRAUMA • Mechanical heart valves breaking RBC’s • MICROANGIOPATHIES: • TTP • Hemolytic Uremic Syndrome

36. NON-Hemolytic Anemias:i.e., DE-creased Production • “Megaloblastic” Anemias • B12 Deficiency (Pernicious Anemia) • Folate Deficiency • Iron Deficiency • Anemia of Chronic Disease • Aplastic Anemia • “Pure” Red Cell Aplasia • OTHER forms of Marrow Failure

37. MEGALOBLASTIC ANEMIAS • Differentiating megaloblasts (marrow) from macrocytes (peripheral smear, MCV>94) • Impaired DNA synthesis • For all practical purposes, also called the anemias of B12 and FOLATE deficiency • Often VERY hyperplastic/hypercellular marrow

39. Vit-B12 Physiology • Oral ingestion • Combines with INTRINSIC FACTOR in the gastric mucosa • Absorbed in the terminal ileum • DEFECTS at ANY of these sites can produce a MEGALOBLASTIC anemia

40. Please remember that ALL megaloblastic anemias are also MACROCYTIC (MCV>94 or MCV~100), and that not only are the RBC’s BIG and hyperplastic/hypercellular, but so are the neutrophils, and neutrophilic precursors in the bone marrow too, and even more so, HYPERSEGMENTED!!!

41. PERNICIOUS ANEMIA • MEGALOBLASTIC anemia • LEUKOPENIA and HYPERSEGS • JAUNDICE • NEUROLOGIC posterolateral spinal tracts • ACHLORHYDRIA • Can’t absorb B12 • LOW serum B12 • Flunk Schilling test, i.e., can’t absorb B12, using a radioactive tracer

42. FOLATE DEFICIENCY MEGALOBLASTIC AMEMIAS • Decreased Intake: diet, etoh-ism, infancy • Impaired Absorption: intestinal disease • DRUGS: anticonvulsants, BCPs, CHEMO • Increased Loss: Hemodialysis • Increased Requirement: Pregnancy, infancy • Impaired Usage

43. Fe Deficiency Anemia • Due to increased loss or decreased ingestion, almost always, in USA, nowadays, increased loss is the reason • Microcytic (low MCV), Hypochromic (low MCHC) • THE ONLY WAY WE CAN LOSE IRON IS BY LOSING BLOOD, because FE is recycled!

44. Fe Transferrin Ferritin (GREAT test) Hemosiderin

45. Clinical Fe-Defic-Anemia • Adult men: GI Blood Loss • PRE menopausal women: menorrhagia • POST menopausal women: GI Blood Loss

47. 2 BEST lab tests: • Serum Ferritin • Prussian blue hemosiderin stain of marrow (also called an “iron” stain)

49. Anemia of Chronic Disease* • CHRONIC INFECTIONS • CHRONIC IMMUNE DISORDERS • NEOPLASMS • LIVER, KIDNEY failure * Please remember these patients may very very much look like iron deficiency anemia, BUT, they have ABUNDANT STAINABLE HEMOSIDERIN in the marrow!

50. APLASTIC ANEMIAS • ALMOST ALWAYS involve platelet and WBC suppression as well • Some are idiopathic, but MOST are related to drugs, radiation • FANCONI’s ANEMIA is the only one that is inherited, and NOT acquired • Act at STEM CELL level, except for “pure” red cell aplasia