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  1. Subunits in Hb
    • Adult: 2α2β
    • Fetal: 2α2γ
    • Embryonic: 2ζ2ε
    • Semi-embryonic: 2ζ2β, 2α2ε
  2. Timeframes of Hb Subunits
    • Epsilon ε: 0-12 weeks gestation, start 50%
    • Zeta ζ: 0-12 weeks gestation, start 100%
    • Alpha α: 0 weeks gestation-adult, reaches 100% at birth
    • Gamma γ: 0 weeks gestation-6 months infant, 30% to 100% mid gestation
    • Beta β: 6 weeks gestation-adult, exponential INC around 3 month infant
  3. Hepcidin
    • Protein synthesized by hepatocytes and induced by dietary iron overload, acts at enterocytes and macrophages and crypt cells
    • Downregulated by EPO

    Binds ferroportin on intestinal mucosal cells and macrophages thus inhibiting iron transport
  4. Bone Marrow Function
    • Produces vast majority of blood cells that circulate, however precursor cells in marrow don't appear in peripheral blood unless there is a pathological process
    • Is found in most bones at birth → in adults only in flat bones
  5. Erythropoietin (EPO)
    • Controls erythropoiesis and is produced in kidneys
    • Tissue hypoxia INCs production
    • No EPO = RBC progenitor death
    • Downregulates hepcidin (can ⇒ iron overload)
  6. Hypoxia Inducing Factor 1 (HIF-1)
    ↑s gene expression of EPO producing cells ⇒ ↑ EPO
  7. Myeloid:Erythroid ratio
    • In normal marrow, 5:1
    • Erythroid hyperplasia will reverse this ratio (hemorrhage, hemolytic anemias, hemoglobinopathies, etc)
  8. Measure Reticulocyte Count to measure erythropoiesis
    • Reticulocytes are young RBCs and still have ER after nucleus is shed, still produce Hb
    • Count can be given as a percentage per 100 RBCs or as an absolute #

    Low count: 1° marrow disorders, aplastic anemia, deficiency anemias, renal failure, chemo/radition

    High count: hemorrhage, hemolysis, hemoglobinopathies
  9. Mean Corpuscular Volume (MCV)
    Measure of average red blood cell volume/size

    • RBCs ↓ volume as they age, so reticulocytes are biggest
    • If have high MCV, could be due to ↑ed reticulocytes

    • RRs:
    • Adults: 80-100
    • Children: 72-85
  10. GM-CSF
    • Growth factor that stimulates production of neutrophils, eosinophils, and monocytes
    • Important in monocyte funct
    • Produced by activated lymphocytes
  11. G-CSF
    • Growth factor that stimulates neutrophil production only
    • Critical for maintaining neutrophil count
    • ↑s with ↓ing neutrophil counts
    • IL-1, TNF, and endotoxins stimulate monocytes and endothelial/mesenchymal cells → produce G-CSF
  12. c-kit
    • Stem cell growth factor for WBCs
    • Acts with IL-3 and/or GM-CSF
    • Produced by marrow stromal cells
  13. IL-3
    • Multi-CSF growth factor that acts on early stem cells and on mature eosinophils and monocytes
    • Produced by activated T cells
  14. Circulating vs Marginated Neutrophils
    The 2 different pools upon leaving marrow

    Marginated: neutrophils that adhere to endothelium in low flow exchange vessels, ↑ when adhesion molecules ↑

    Circulating: neutrophils that freely move around in the blood, the only ones accessible in blood samples, ↑ when adhesion molecules ↓

    Exercise, catecholamine, and stress ⇒ shift from marginated→circulating ⇒ ↑ measured count of neutrophils
  15. Left Shift of Neutrophils
    Situations of rapid neutrophil production like during acute inflammation or marked stress⇒ ↑ of band neutrophils

    Band neutrophils are mature neutrophils that have horseshoe-shaped nuclei but aren't segmented
  16. IT Ratio
    • Ratio of immature to total neutrophils
    • Useful in screening for infections
  17. Monocytes
    • Circulate in blood for ~ 24 hrs
    • Continue to differentiate in tissues
    • Production regulated by GM-CSF, G-CSF, ILs, TNF
  18. Different Forms of Monocytes
    • Connective tissues: Macrophages
    • Bone: Osteoclasts
    • Liver: Kupfer cells
    • CNS: Microglia
  19. Eosinophils
    • Role not known but presence in helminthic infections and allergies is widely recognized
    • Production controled by various ILs and GM-CSF from activated T cells
    • ↓ eosinophils doesn't have marked effect on therapy for eosinophil disorders
  20. Basophils
    • Mediates allergic rxns
    • Don't normally reside in tissues
    • Production stimulated by IL-4 from T cells
    • Have high affinity IgE receptors
    • Release histamine (vasodilator), heparin (anticoagulant), and leukotriene D4 (modulators for allergic rxns and asthma)
  21. Mast Cells
    • Mediate allergic rxns in local tissues
    • Have high affinity IgE receptors
    • Release histamine (vasodilator), heparin (anticoagulant), and leukotriene D4 (modulators for allergic rxns and asthma)
    • Involved in Type I hypersensitivity

    For asthma prophylaxis, use cromolyn sodium to prevent mast cell degranulation
  22. Lymphocytes
    • Undifferentiated B and T cells
    • Mediates adaptive immunity
    • Round, densely staining nucleus with small amount of pale cytoplasm
  23. Platelet Count
    RR = 150-400 x 10^9/L
  24. Erythrocyte
    • Anucleate and biconcave
    • Lifespan = 120 days
    • Glucose is source of energy
    • Membrane contains chloride HCO3- antiporter, allows RBCs to sequester HCO3- and transport CO2 from periphery to lungs for elimination
  25. Erythrocytosis
    • Polycythemia = ↑ hematocrit
    • An actual ↑ in RBCs, not just an ↑ in relative mass
  26. Anisocytosis
    Varying sizes of RBCs
  27. Poikilocytosis
    Varying shapes in RBCs
  28. Reticulocyte
    Immature erythrocyte, marker of erythroid proliferation
  29. Platelet (Thrombocyte)
    • Small cytoplasmic fragment derived from megakaryoytes
    • Lifespan = 8-10 days
    • Endothelial injury ⇒ platelets aggregate ⇒ interact with fibrin ⇒ form platelet plug
    • Contain dense granules like ADP and calcium
    • Contain α granules like vWF and fibrinogen
    • 1/3 of platelet store is in spleen
  30. vWF receptor on platelet
    GpIb (Gp 1b)
  31. Fibrinogen receptor on platelet
    GpIIb/GpIIIa (Gp2b/Gp3a)
  32. Leukocyte
    • Granulocytes: neutrophils, eosinophils, basophils
    • Mononuclear cells: monoytes, lymphocytes
    • Responsible for defense against infx
    • Normal range: 4000 - 10,000 cells/mm3
  33. WBC percentages in blood (order better than actual #)
    • Neutrophils = 54-62%
    • Lymphocytes = 25-33%
    • Monocytes = 3-7%
    • Eosinophils = 1-3%
    • Basophils = 0-0.75%

    Neutrophils Like Making Everything Better
  34. Blood Group A
    A Ag on RBC surface and anti-B Ab in plasma
  35. Blood Group B
    B Ag on RBC surface and anti-A Ab in plasma
  36. Blood Group AB
    • A and B Ags on RBC surface, no Abs in plasma
    • Universal recipient of RBC
    • Universal donor of plasma
  37. Blood Group O
    • No A or B Ags on RBC surface, anti-A and anti-B Abs in plasma
    • Universal donor of RBCs
    • Universal recipient of plasma
  38. Blood Group Rh
    Rh Ag on RBC surface

    Rh- mothers exposed to fetal Rh+ blood during delivery may make anti-Rh IgG. In subsequent pregnancies, anti-Rh IgG crosses the placenta ⇒ hemolytic disease of the newborn (erythroblastosis fetalis) in the next fetus that is Rh+
  39. Treatment for Rh- Mothers
    Rho(D) immune globulin for mothers at first delivery to prevent initial sensitization of Rh- mother to Rh Ag

    It's a sltn of IgG anti-D Abs that suppress mother's immune system from attacking Rh+ blood cells that have entered the maternal blood stream from fetal circulation
  40. Outcome of incompatible blood transfusions
    Immunologic response, hemolysis, renal failure, shock, and death
  41. Type of Ig in anti-A and anti-B Abs
    • IgM
    • (pentamer, too big to cross placenta)
  42. Type of Ig in anti-Rh
    • IgG
    • (can cross placenta)
  43. Draw Coagulation Cascade
    Intrinsic: XIIa, XIa, IXa, VIIIa (cofactor), Xa, V (cofactor), II (prothrombin) → IIa (thrombin) → activates fibrinogen to fibrin which is stabilized by XIIIa

    Extrinsic: VII activated by thromboplastin → Xa, V (cofactor), II (prothrombin) → IIa (thrombin) → activates fibrinogen to fibrin which is stabilized by XIIIa

    see pg 348 in First Aid
  44. Kinin Pathway
    High-molecular Weight Kininogen assists in activating coag factor XII, and XIIa converts prekallikrein → kallikrein which converts plasminogen → plasmin (breaks up fibrin plug) AND activates bradykinin → INC vasodilation, INC permeability, and INC pain

    see pg 348 First Aid
  45. Hemophilia A
    • Genetic deficiency (but can arise from new mutation without FHx) in coag factor Vlll, intrinsic
    • Presentation: bleeding in deep tissues, joints (hemarthroses), and post surgeries
    • Lab findings: ↑ PTT, normal PT, ↓ factor VIII, normal platelet count and bleeding time
    • Treatment: recombinant factor VIII

    "hemophilia 8"
  46. Hemophilia B
    • Genetic deficiency in coag factor IX, intrinsic
    • Presentation: bleeding in deep tissues, joints (hemathroses), and post surgeries
    • Lab findings: ↑ PTT, normal PT, ↓ factor IX, normal platelet count and bleeding time
    • Treatment: recombinant factor IX
  47. Procoagulation
    Oxidized Vitamin K →(epoxide reductase)→ reduced Vitamin K is a cofactor that activates factors II, VII, IX, X, and proteins C and S
  48. How does Warfarin affect coagulation factors?
    Warfarin inhibits epoxide reductase → can't reduce Vitamin K ⇒ no activation of factors II, VII, IX, X, and proteins C and S
  49. Which coag factor does vWF carry?
    factor VIII
  50. Anticoagulation
    Thrombomodulin from endothelial cells activates Protein C. With help of Protein S, Protein C cleaves and inactivates coag factors Va and VIIIa

    Tissue plasimogen activator activates plasminogen → plasmin ⇒ cleavage of fibrin plug
  51. Heparin and antithrombin
    Heparin activates antithrombin → inhibits active forms of coag factors II, VII, IX, X, XI, and XII
  52. Factor V Leiden
    • Mutation that produces a coag factor V that is resistant to inhibition by activated Protein C⇒ too much clotting
    • Most common cause of inherited hypercoaguability in whites
  53. How is tissue plasminogen activator (tPA) used clinically?
    As a thrombolytic
  54. Platelet Plug Formation: Injury
    • vWF binds to exposed collagen upon endothelial damage
    • Endothelial cells release endothelin ⇒ vasoconstriction
  55. Platelet Plug Formation: Adhesion
    • Platelets bind vWF via GpIb receptor at site of injury
    • Platelets release ADP and Ca2+, necessary for coag cascade
    • ADP helps platelets adhere to endothelium
  56. What is vWF derived from?
    Weibel-Palade bodies of endothelial cells and α-granules of platelets
  57. Platelet Plug Formation: Activation
    • Platelets release ADP ⇒ exposure of GpIIB/IIIa receptors on platelet surface
    • Thromboxane A2 (TXA2) is synthesized by cyclooxygenase (COX) in platelets → released ⇒ promotes platelet aggregation and ↓es blood flow
  58. Platelet Plug Formation: Aggregation
    • Fibrinogen binds GpIIb/IIIa receptors and links platelets
    • Weak plug is formed, coagulation cascade needed to stabilize it
  59. For platelet aggregation, what is the balance between?
    • Pro-aggregation factors: TXA2 released by platelets ��� ↓ blood flow and ↑ aggregation
    • Anti-aggregation factors: PGI2 and NO released by endothelial cells ⇒ ↑ blood flow and ↓ aggregation
  60. Erythrocyte Sedimentation Rate (↑ and ↓)
    Fibrinogen and other reactants can cause RBC aggregation, thereby ↑ing RBC sedimentation rate

    • ↑: infxs, autoimmune disease (SLE, rheumatoid arthritis, temporal arteritis), malignant neoplasms, GI disease, pregnancy
    • ↓: polycythemia, sickle cell anemia, congestive ♡ failure, microcytosis, hypofibrinogenemia
  61. Acanthocyte (spur cell)
    • Pathological RBC
    • Associated Path: liver disease, abetalipoproteinemia (states of cholesterol dysregulation)

    Acantho = spiny
  62. Basophilic stippling
    • Pathological RBC
    • Associated Path: Thalassemias, Anemia of chronic disease, Lead poisoning

    BASte the ox TAiL
  63. Bite Cell
    • Pathological RBC
    • Associated Path: G6PD deficiency
  64. Elliptocyte
    • Pathological RBC
    • Associated Path: Hereditary elliptocytosis
  65. Macro-ovalocyte
    • Pathological RBC
    • Associated Path: Megaloblastic anemia (also hypersegmented neutrophils), marrow failure
  66. Ringed sideroblasts
    • Pathological RBC
    • Associated Path: Sideroblastic anemia (excess iron in mito)
  67. Schistocyte (helmet cell)
    • Pathological RBC
    • Associated Path: DIC, TTP/HUS, traumatic hemolysis ex) metal heart valve prosthesis
  68. Spherocyte
    • Pathological RBC
    • Associated Path: Hereditary spherocytosis, autoimmune hemolysis
  69. Teardrop cell
    • Pathological RBC
    • Associated Path: bone marrow infiltration ex) myelofibrosis

    "RBC sheds a tear because it's been forced out of its home in bone marrow"
  70. Target cell
    • Pathological RBC
    • Associated Path: HbC disease, Asplenia, Liver disease, Thalassemia

    HALT said the hunter to the target
  71. Heinz bodies
    • Pathological RBC
    • Process: Oxidation of iron from ferrous to ferric form ⇒ denatured hemoglobin precipitation and damage to RBC membrane ⇒ formation of bite cells
    • Associated Path: G6PD deficiency, Heinz body-like inclusions seen in alpha-thalassemia
  72. Iron Deficiency Anemia
    • Microcytic, hypochromic anemia
    • ↓ iron due to chronic bleeing (GI loss, menorrhagia), malnutrition/absorption disorders, or ↑ demand (pregnancy) ⇒ ↓ final step in heme synthesis

    Findings: ↓ iron, ↑ TIBC, ↓ ferritin. May manifest as Plummer-Vinson syndrom, a triad of iron deficiency anemia, esophageal webs, and atrophic glossitis
  73. Howell-Jolly bodies
    • Pathological RBC
    • Process: Basophilic nuclear remnants found in RBCs. Are normally removed from RBCs by splenic macrophages
    • Associated Path: functional hyposplenia or asplenia, or after mothball ingestion (naphthalene)
  74. The Prophyrias
    Hereditary or acquired conditions of defective heme synthesis that ⇒ accumulation of heme precursors.
  75. Lead Poisoning
    • Lead inhibits specific enzymes needed in heme synthesis ⇒ accumulation of heme precursors
    • Affected enzyme: Ferrochelatase and ALA dehydrogenase
    • Accumulated substrate: protoporphyrin, delta-ALA (in blood)
    • Presenting symptoms: Microcytic anemia, GI and kidney disease.

    • Children: exposure to lead paint ⇒ mental deterioration
    • Adults: environmental exposure (battery, ammunition, etc)⇒ headache, memory loss, demyelination
  76. Acute intermittent porphyria
    • Affected enzyme: porphobilinogen deaminase
    • Accumulated substrate: porphobilinogen, delta-ALA, uroporphyrin (in urine)
    • Presenting symptoms: The 5 Ps painful abdomen, port wine-colored urine, polyneuropathy, psychological disturbances, precipitated by drugs

    Treatment: glucose and heme, which inhibit ALA synthase
  77. Porphyria cutanea tarda
    • Affected enzyme: uroporphyrinogen decarboxylase
    • Accumulated substrate: uroporphyrin (tea-colored urine)
    • Presenting symptoms: blistering cutaneous photosensitivity. Most common porphyria.
  78. Draw heme synthesis
    Location: mito→ cytoplasm→ mito

    Intermediates: glycine + succinyl-CoA → δ-aminolevulinic acid → porphobilinogen → hydroxymethylbilane →uroporphyrinogen III → coproporphyrinogen III → protoporphyrin→ (Fe2+) heme

    Enzymes: δ-aminolevulinic acid synthase (rate-limiting step), δ-aminolevulinic acid dehydratase, porphobilinogen deaminase, uroporphyrinogen decarboxylase, ferrochelatase

    Diseases: x-linked sideroblastic anemia, lead poisoning (x2), acute intermittent porphyria, porphyria cutanea tarda

    see pg 358 First Aid
  79. Relationship b/w heme and ALA synthase
    • ↓ heme = ↑ ALA synthase activity
    • ↑ heme = ↓ ALA synthase activity
  80. PT Test
    • Tests funct of common and extrinsic pathway
    • Factors I, II, V, VII, and X
    • Defects in these factors ⇒ ↑ PT
  81. PTT Test
    • Tests funct of common and intrinsic pathway
    • All factors except VII and XIII
    • Defects in these ⇒ ↑ PTT
  82. Vitamin K Deficiency
    • General coagulation defect ⇒ ↓ synthesis of factors II, VII, IX, X, and proteins C and S
    • PTT ↑ , PT ↑ 
    • Deficiency occurs in newborns, long-term antibiotic therapy, and malabsorption
  83. Bernard-Soulier Syndrome
    • Defect in platelet plug formation (qualitative)
    • Genetic GpIb deficiency that ⇒ defect in platelet-to-vWF adhesion ⇒ impaired platelet adhesion
    • Blood smear: mild thrombocytopenia (b/c platelets w/o GpIb get destroyed), enlarged (immature) platelets
    • Presentation: microhemorrhage (mucous membrane bleeding, epitaxis, petechiae, purpura)
    • Platelet count: ↓
    • Bleeding time: ↑

    St Bernards are enlarged dogs
  84. Glanzmann's Thrombasthenia
    • Defect in platelet plug formation (qualitative)
    • Genetic GIIb/IIIa deficiency ⇒ defeat in platelet-to-platelet aggregation
    • Blood smear: no platelet clumping
    • Presentation: microhemorrhage (mucous membrane bleeding, epitaxis, petechiae, purpura)
    • Platelet count: normal
    • Bleeding time: ↑
  85. Idiopathic Thrombocytopenia Purpura (ITP)
    • Autoimmune production of IgG against GpIIb/IIIa ⇒ splenic macrophage consumption of platelet/Ab complex (quantitative)
    • Children: acute, after viral infx or immunization
    • Adults: chronic, 1° or 2°, in pregnant women may ⇒ short-lived thrombocytopenia in infants b/c IgG can cross placenta
    • Marrow biopsy: ↑ megakaryocytes
    • Presentation: microhemorrhage (mucous membrane bleeding, epitaxis, petechiae, purpura)
    • Platelet count: ↓
    • Bleeding time: ↑ 
    • Treatment: corticosteroids (adults often relapse), splenectomy (removes 1° source of self-Ab and site of destruction)
  86. Thrombotic Thrombocytopenic Purpura (TTP)
    • Deficiency of ADAMTS 13 (vWF metalloprotease) ⇒ ↓ cleavage of vWF multimers to monomers ⇒ ↑ of large multimers ⇒↑ platelet aggregation and thrombosis (quantitative)
    • Generally due to acquired Ab against ADAMTS 13, in adult females
    • Blood smear: schistocytes (helmet cells), ↑ LDH
    • Marrow biopsy: ↑ megakayocytes
    • Presentation: microhemorrhage (mucous membrane bleeding, epitaxis, petechiae, purpura), pentad of neurologic and renal symptoms, fever, microangiopathic hemolytic anemia
    • Platelet count: ↓
    • Bleeding time: ↑
    • Treatment: plasmapheresis (remove auto-Abs), corticosteroids (↓production of Abs)
  87. von Willebrand's Disease
    • Genetic (autosomal dominant) intrinsic pathway coag defect, most common inherited coagulation disorder
    • ↓ vWF ⇒ defect in platelet-to-vWF adehsion
    • Presentation: mild mucosal and skin bleeding
    • Platelet count: normal
    • Bleeding time: ↑
    • PT: normal
    • PTT: normal or ↑ depending on severity (b/c need vWF to stabilize factor VIII)
    • Abnormal ristocetin test
    • Treatment: DDAVP (desmopressin) which ↑es vWF release from Weibel-Palade bodies of endothelial cells
  88. Ristocetin Cofactor Assay
    • Normally, ristocetin causes platelets to aggregate together
    • Abnormal test when platelets don't aggregate
  89. Disseminated Intravascular Coagulation (DIC)
    • Widespread activation of clotting ⇒deficiency of clotting factors ⇒ bleeding state
    • Also ⇒ widespread microthrombi ⇒ischemia and infarction
    • Causes: Sepsis (gram-neg), Trauma, Obstetric complications, acute Pancreatitis, Malignancy, Nephrotic syndrome, Transfusion ((STOP Making New Thrombi)), and rattlesnake bite
    • Platelet count: ↓
    • Bleeding time: ↑
    • PT: ↑
    • PTT: ↑
    • Findings: schistocytes (helmet cells), ↑ fibrin split products (D-dimers), ↓ fibrinogen, ↓ factors V and VIII
  90. D-dimer
    • The product released at end of coag cascade and healing is done and clot is lysed
    • Lysing causes release of D-dimer
  91. Prothrombin gene mutation
    • Syndrome ⇒ hypercoagulability
    • Mutation in 3' untranslated region ⇒ ↑ production of prothrombin ⇒ ↑ plasma levels and venous clots
  92. Antithrombin deficiency
    • Syndrome ⇒ hypercoagulability
    • Inherited deficiency of antithrombin
    • ↑ in PTT, blunted after heparin administration
  93. Protein C or S deficiency
    • Syndrome ⇒ hypercoagulability
    • ↓ ability to inactivate factors V and VIII
    • ↑ risk of thrombotic skin necrosis with hemorrhage following administration of warfarin
  94. Blood transfusion: Packed RBCs
    • Dosage effect: ↑ Hb and oxygen carrying capacity
    • Clinical Use: acute blood loss, severe anemia
  95. Blood transfusion: Platelets
    • Dosage effect: ↑ platelet count (~5000/mm3/unit)
    • Clinical Use: stop significant bleeding (thrombocytopenia, qualitative platelet defects)
  96. Blood transfusion: Fresh frozen plasma
    • Dosage effect: ↑ coag factor levels
    • Clinical Use: DIC, cirrhosis, Warfarin overdose
  97. Blood transfusion: Cryoprecipitate
    • Dosage effect: contains fibrinogen, factor VIII, factor XIII, vWF, and fibronectin
    • Clinical Use: treat coag factor deficiencies involving fibrinogen and factor VIII
  98. Blood transfusion risks
    • Infx transmission
    • Transfusion rxns
    • Iron overload
    • Hypocalcaemia
    • Hyperkalemia
  99. Heparin-induced thrombocytopenia (HIT)
    • Development of IgG Ab agents heparin bound to platelet factor 4 (PF4)
    • Ab-heparin-PF4 complex activates platelets ⇒ thrombosis and thrombocytopenia
  100. 5 Types of Microcytic Anemia
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  101. 3 Types of Megaloblastic, Microcytic Anemia
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  102. 3 Types of Nonmegaloblastic, Microcytic Anemia
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  103. 3 Types of Nonhemolytic, Normocytic Anemias
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  104. 5 Types of Intrinsic Hemolytic, Normocytic Anemias
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  105. 4 Types of Extrinsic Hemolytic, Normocytic Anemia
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  106. Iron deficiency: type of anemia and description
    Microcytic and hypochromic 

    ↓ iron due to chronic bleeding (GI loss, menorrhagia), malnutrition/absorption disorders or ↑ demand (like pregnancy) ⇒ ↓ final step in heme synthesis
  107. Iron deficiency: findings
    (Microcytic and hypochromic)

    • ↓ iron
    • ↑ TIBC
    • ↓ ferritin
    • Microcytosis
    • Hypochromia
    • May manifest as Plummer-Vinson syndrome
  108. Plummer-Vinson Syndrome
    • Triad of:
    • Iron deficiency anemia
    • Esophageal webs
    • Atrophic glossits
  109. α thalassima: type of anemia and defect causing it
    Microcytic and hypochromic

    • α-globin gene mutation ⇒ ↓ α-globin synthesis
    • cis deletion = Asian
    • trans deletion = African
  110. α thalassemia: 4 gene deletion outcome
    • No α-globin
    • Excess γ-globin form γ4 (Hb Barts)
    • Incompatible with life (⇒ hydrops fetalis)
  111. α thalassemia: 3 gene deletion outcome
    (Microcytic and hypochromic)

    • HbH disease
    • Very little α-globin
    • Excess β-globin forms β4 (HbH)
    • Splenomegaly
    • Target cells
  112. α thalassemia: 1 or 2 gene deletion outcome
    No clinically significant anemia
  113. β thalassemia: type of anemia and description
    Microcytic and hypochromic

    • Point mutations in splice sites and promoter sequences ⇒ ↓ β-globin synthesis
    • Prevalent in Mediterranean populations
  114. β thalassemia: findings with β-thalassemia minor
    (Microcytic and hypochromic)

    • Heterozygote mutation (B/B+)
    • β chain is underproduced
    • Usually asymptomatic
    • Diagonsis confirmed by ↑ HbA2 (α2δ2) >3.5% on electrophoresis
  115. β thalassemia: findings with β-thalassemia major
    (Microcytic and hypochromic)

    • Homozygote for mutation (B/B)
    • β chain is absent ⇒ severe anemia requiring blood transfusions (can ⇒ 2° hemochromatosis)
    • Marrow expansion ("crew cut" on skull xray) ⇒ skeletal deformations like "chipmunk" facies
    • ⇒ ↑ HbF (α2γ2)
  116. β thalassemia: findings with β-thalassemia heteroygote/HbS
    (Microcytic and hypochromic)

    Mild to moderate sickle cell disease depending on amount of β-globin production
  117. Lead poisoning: type of anemia and description
    Microcytic and hypochromic

    • Lead inhibits ferrochelatase and ALA dehydratase ⇒ ↓ heme synthesis
    • Lead also inhibits rRNA degradation ⇒ RBCs to retain aggregates of rRNA ⇒ basophilic stippling
    • High risk in houses with chipped paint
  118. Lead Poisoning: findings
    (Microcytic and hypochromic)

    • Lead lines on gingivae (Burton's lines) and on metaphyses of long bones on x-ray
    • Encephalophy
    • Erythrocyte basophilic stippling
    • Abdominal colic
    • Anemia (sideroblastic)
    • Drops of wrist and foot

  119. Lead Poisoning: treatment
    (Microcytic and hypochromic)

    • Adults: Dimercaprol and EDTA
    • Children: Succimer (it sucks to be a kid who eats lead)
  120. Sideroblastic Anemia: type of anemia and description
    Microcytic and hypochromic

    • Defect in heme synthesis
    • Hereditary: X-linked defeat in δ-ALA synthase gene
    • Reversible causes: alcohol, lead, isoniazid
  121. Sideroblastic Anemia: findings
    (Microcytic and hypochromic)

    • Ringed sideroblasts with iron-laden mitochondria
    • ↑ iron
    • Normal TIBC
    • ↑ ferritin
  122. Sideroblastic anemia: treatment
    (Microcytic and hypochromic)

    Pyridoxine which is Vit B6, a cofactor for δ-ALA syntase
  123. Megaloblastic anemia: type of anemia and description
    Macrocytic, has 3 subtypes (folate deficiency, B12 deficiency, orotic aciduria)

    • Impaired DNA synthesis ⇒ maturation of nucleus delayed relative to maturation of cytoplasm
    • Ineffective erythropoiesis ⇒ pancytopenia
  124. Folate deficiency: type of anemia and description
    Macrocytic and megaloblastic

    • Develops within months because body stores are minimal
    • Caused by:
    • Malnutrition (alcoholics)
    • Malabsorption
    • Antifolates (methotrexate, trimethoprim, phenytoin)
    • ↑ requirement (hemolytic anemia, pregnancy)
  125. Normal absorption and action of folate
    Folate obtained from green vegetables and fruits → absorbed in jejunum

    Enters body as tetrahydrofolate → is methylated → Vit B12 removes methyl group → folate can now participate in DNA precursor synthesis
  126. Normal action of Vit B12
    Vit B12 removes methyl group from methylated tetrahydrofolate → passes methyl group to homocysteine → homocysteine is now methienine (important compound that transfers methyl groups to other molecules)
  127. Folate deficiency: findings
    (Macrocytic and megaloblastic)

    • Hypersegmented neutrophils
    • Glossitis
    • ↓ folate
    • ↑ homocysteine
    • Normal methylmalonic acid (substance that is converted to succinyl CoA by Vit B12)
  128. Normal absorption of Vit B12
    B12 is complexed to animal-derived proteins → is cleaved off when enters body → binds to R-binder protein (made by salivary glands) → in small intestines, pancreatic proteases cleave B12 from R-binder → B12 binds to intrinsic factor (made by parietal cells in body of stomach) → complex absorbed in ileum
  129. Vitamin B12 deficiency: type of anemia and description
    Macrocytic and megaloblastic

    • Takes years to develop b/c of large liver stores
    • Causes:
    • Insufficient intake (strict vegans)
    • Malabsorption (Crohn's disease, pernicious anemia, Diphyllobothrium latum [fish tapeworm])
    • Proton pump inhibitors (proton pumps on parietal cells make HCl)
    • Pancreatic insufficiency (↓ proteases ⇒ can't cleave R-binder protein from B12)
  130. Pernicious anemia
    Autoimmune destruction of parietal cells in stomach body ⇒ intrinsic factor deficiency ⇒ inability to absorb Vit B12
  131. Vitamin B12 deficiency: findings
    (Macrocytic and megaloblastic)

    • Hypersegmented neutrophils
    • Glossitis
    • ↓ B12
    • ↑ homocysteine
    • ↑ methylmalonic acid (substance that is converted to succinyl CoA by Vit B12)
    • Neurologic symptoms b/c of subacute combined degeneration (peripheral neuropathy with sensorimotor dysfunction, posterior columns [vibration and proprioception], lateral corticospinal [spasticity], dementia)
  132. Why is subacute combined degeneration seen in Vitamin B12 deficiency?
    No B12 → methylmalonic acid is not converted to succinyl CoA → methylmalonic acid builds up in myelin of spinal cord ⇒ cord degeneration
  133. If person has B12 and folate deficiency, which should be treated first? Why?
    • B12
    • If treat folate deficiency first, might convert the small amount of B12 in the body to methylcobalamin, which does not assist in fatty acid metabolism, so can inadvertently ⇒ subacute combined degeneration
  134. Orotic aciduria: type of anemia and description
    Macrocytic and megaloblastic

    • Genetic mutation (autosomal recessive) in enzyme that synthesizes uridine from orotic acid ⇒ excess orotic acid excreted in urine
    • Orotic acid is needed in pyrimidine synthesis, eventually plays a role in converting dihydrofolate to tetrahydrofolate
    • Presents in children as megaloblastic anemia that is not treated by folate or Vit B12
  135. Orotic aciduria: findings
    (Macrocytic and megaloblastic)

    • Hypersegmented neutrophils
    • Glossitis
    • Orotic acid in urine
    • Failure to thrive
    • Mental and physical disabilities
  136. Nonmegaloblastic anemias: type of anemia and description

    • Anemia in which DNA synthesis is not impaired
    • Causes:
    • Liver disease
    • Alcoholism
    • Reticulocytosis → ↑ MCV
    • Drugs like 5-FU, AZT, hydroxyurea
  137. Nonmegaloblastic anemias: findings

    • Macrocytosis
    • Bone marrow suppression
  138. Orotic aciduria: treatment
    (Macrocytic and megaloblastic)

    Uridine monophosphate to bypass mutated enzyme that cannot convert orotic acid to uridine
  139. Classifications of normocytic, normochromic anemias
    • Nonhemolytic
    • Hemolytic; Intrinsic vs Extrinsic and Intravascular vs Extravascular
  140. Intravascular hemolytic anemia: type of anemia and findings
    Normocytic and normochromic

    • ↓ haptoglobin (scavenger molecule in blood that binds free Hb)
    • ↑ LDH
    • Hb in urine
    • Hemosiderinuria (Fe in renal tubules are excreted)
    • Mechanical destruction of RBCs
  141. Extravascular hemolytic anemia: type of anemia and findings
    Normocytic and normochromic

    • Macrophages in spleen clear RBC ⇒ splenomegaly
    • ↑ LDH
    • ↑ unconjugated bilirubin ⇒ jaundice
  142. Anemia of Chronic Disease (ACD): type of anemia and description
    Nonhemolytic, normocytic and normochromic

    Inflammation → ↑ hepcidin (released by liver, binds ferroportin on intestinal mucosal cells and macrophages ⇒ inhibiting iron transport) ⇒ ↓ release of iron from macrophages
  143. Anemia of Chronic Disease (ACD): findings
    (Nonhemolytic, normocytic and normochromic)

    • ↓ iron
    • ↓ TIBC
    • ↑ ferritin

    can ⇒ microcytic hypochromic anemia
  144. Aplastic anemia: type of anemia and description
    Nonhemolytic, normocytic and normochromic

    • Caused by failure or destruction of myeloid stem cells due to:
    • Radiation and drugs (benzene, chloramphenicol, alkytaling agents, antimetabolites)
    • Viral agents (parvovirus B19, EBV, HIV, HCV)
    • Fanconi's anemia (DNA repair defect)
    • Idiopathic (immune mediated, 1° stem cell defect), can follow acute hepatitis
  145. Aplastic anemia: findings and symptoms
    (Nonhemolytic, normocytic and normochromic)

    • Findings:
    • Severe pancytopenia
    • ↓ reticulocytes
    • Normal cell morphology
    • Hypocellular bone marrow with fatty infiltration (dry tap)

    • Symptoms:
    • Fatigue
    • Malaise
    • Pallor
    • Purpura
    • Mucosal bleeding
    • Petechiae
    • Infx
  146. Aplastic anemia: treatment
    (Nonhemolytic, normocytic and normochromic)

    • Cessation of causative drugs
    • Immunosuppression (with antithymocyte globin, cyclosporine)
    • Allogenic bone marrow transplant
    • RBC and platelet transfusion
    • G-CSF or GM-CSF (marrow stimulating factors)
  147. Chronic kidney disease: type of anemia it causes and description
    Nonhemolytic, normocytic and normochromic

    ↓ erythropoietin ⇒ ↓ hematopoiesis
  148. Hereditary spherocytosis: type of anemia and description
    Extravascular, intrinsic hemolytic normocytic anemia

    Defect in proteins (ankyrin, band 3, protein 4.2, specterin) interacting with RBC membrane skeleton and plasma membrane ⇒ blebs formed and lost ⇒ loss of membrane ⇒ sphere-shaped RBC with no central pallor that have harder time moving through spleen ⇒ consumed by splenic macrophages
  149. Hereditary spherocytosis: findings, labs, and treatment
    (Extravascular, intrinsic hemolytic normocytic anemia)

    • Findings:
    • Splenomegaly
    • Aplastic crisis (parvovirus B19 infx of erythroid precursors)
    • Jaundice (↑ unconjugated bilirubin)

    • Labs:
    • (+) osmotic fragility test
    • ↑ red cell distribution width
    • ↑ mean corpuscular Hb concentration (higher conc b/c of shrinking RBC)

    • Treatment:
    • Splenectomy
  150. G6PD deficiency: type of anemia and description and 2 variants
    Intravascular or extravascular, intrinsic hemolytic normocytic anemia

    • X-linked recessive
    • Defect in G6PD → ↓ G6PD half life → ↓ glutathione ⇒ ↑ RBC susceptibility to oxidant stress
    • Oxidant stress from things like sulfa drugs, infx, fava beans ⇒ hemolytic anemia

    • African variant: mildly ↓ed G6PD half life
    • Mediterranean variant: markedly ↓ed GGPD half life
  151. G6PD deficiency: findings and labs
    (Intravascular or extravascular, intrinsic hemolytic normocytic anemia)

    • Findings:
    • Back pain
    • Hemoglobinuria a few days later

    • Labs:
    • Heinz bodies (Hb precipitation ⇒ damage to RBC)
    • Bite cells
  152. Pyruvate kinase deficiency: type of anemia and description
    Extravascular, intrinsic hemolytic normocytic anemia

    • Autosomal recessive
    • Defeat in pyruvate kinase → ↓ ATP ⇒ rigid RBCs
  153. Pyruvate kinase deficiency: findings
    (Extravascular, intrinsic hemolytic normocytic anemia)

    Hemolytic anemia in a newborn
  154. HbC defect: type of anemia and description
    Extravascular, intrinsic hemolytic normocytic anemia

    • Autosomal recessive
    • Glutamic acid-to-lysine mutation at residue 6 in β-globin
  155. HbC defect: finding
    (Extravascular, intrinsic hemolytic normocytic anemia)

    HbC crystals in blood smear
  156. Paroxysmal nocturnal hemoglobinuria: type of anemia and description
    Intravascular, intrinsic hemolytic normocytic anemia

    • Aqured defect in myeloid stem cells ⇒ absent GPI anchor which binds decay accelerating factor (DAF, deactivates complements) ⇒ ↑ complement-mediated RBC lysis b/c RBC don't have protective DAF anymore
    • Nocturnal b/c shallow breathing → retain CO→ some acidosis ⇒ complement activation
  157. Paroxysmal nocturnal hemoglobinuria: triad
    (Intravascular, intrinsic hemolytic normocytic anemia)

    • Hemolytic anemia
    • Pancytopenia
    • Venous thrombosis (b/c platelets that are lysed release their contents, most common CoD)
  158. Paroxysmal nocturnal hemoglobinuria: labs and treatment
    (Intravascular, intrinsic hemolytic normocytic anemia)

    • Labs:
    • Hemosiderinuria
    • Hemoglobinuria
    • No CD55 RBCs on flow cytometry (CD55 = DAF)

    • Treatment:
    • Eculizumab
  159. Sickle cell anemia: type of anemia and description
    Extravascular, intrinsic hemolytic normocytic anemia

    • Hb point mutation glutamic acid to valine at position 6 ⇒ defected β-globin
    • ↓ O2 or dehydration precipitates sickling (deoxygenated HbS polymerizes, reversible) ⇒ anemia and vaso-occlusion
    • RBC membrane damage occurs from constant sickling and desickling ⇒ splenic removal
    • Newborns initially asymptomatic due to ↑ HbF
    • Heterozygotes for sickle cell trait are resistant to malaria
    • 8% of African Americans carry HbS
  160. Sickle cell anemia: findings and treatment
    (Extravascular, intrinsic hemolytic normocytic anemia)

    • Findings:
    • Sickled cells and target cells (only in sickle cell disease, not trait)
    • Positive metabisulfite screen (cells with any HbS will sickle)
    • Crew cut on skull x-ray (due to marrow expansion from ↑ erythropoiesis)

    • Treatment:
    • Hydroxyurea (↑es HbF)
    • Bone marrow transplant
  161. Sickle cell anemia/disease: 7 complications in homozygotes
    • Aplastic crisis (parvovirus B19)
    • Autosplenectomy (Howell-Jolly bodies) ⇒ ↑ risk of infx w/ encapsulated organisms (most common CoD in children)
    • Splenic sequestration crisis
    • Salmonella paratyphi osteomyelitis
    • Painful crisis from vaso-occlusion (dactylitis aka painful hand or feet swelling, common presenting sign in infants) (acute chest syndrome, occlusion of pulmonary microcirculation often precipitated by pneumonia,most common CoD of adults)
    • Renal papillary necrosis (due to ↓ O2 in papilla)
    • Microhematuria (medullay infarcts)
  162. Autoimmune hemolytic anemia: type of anemia and description of warm agglutinin
    Extrinsic hemolytic normocytic anemia

    • IgG
    • Chronic anemia seen in SLE, CLL, or with certain drugs like α-methyldopa
    • Many are idiopathic
    • ⇒ spherocytes because of RBC membrane destruction by splenic macrophages

    Warm weather is Great
  163. Autoimmune hemolytic anemia: type of anemia and description of cold agglutinin
    Extrinsic hemolytic normocytic anemia

    • IgM
    • Acute anemia triggered by cold
    • Seen in CLL, Mycoplasma pneumonia infx, or infectious mononucleosis
    • Many are idiopathic
    • ⇒ spherocytes because of RBC membrane destruction by splenic macrophages

    Cold ice cream is yuM
  164. Direct Coomb's Test
    Tests for autoimmune hemolytic anemia

    • Anti-Ig Ab added to pt's serum
    • RBCs agglutinate if RBCs are coated with Ig
  165. Indirect Coomb's Test
    Test for autoimmune hemolytic anemia

    Normal RBCs added to pt's serum will agglutinate if the serum has anti-RBC surface Ig
  166. Autoimmune hemolytic anemia: diagnostic test and treatment
    • Diagnosis:
    • Coomb's test (+)

    • Treatment:
    • Cessation of offending drug
    • Steroids (↓ production of Ab)
    • IVIG (splenic macrophages consume these Igs instead of Igs on RBCs)
    • Splenectomy
  167. Microangiopathic anemia: type of anemia and description
    Extrinsic hemolytic normocytic anemia

    • RBCS are damaged when passing through obstructed or narrowed vessel lumina ⇒ schistocytes
    • Seen in DIC, TTP-HUS, SLE, and malignant HTN
  168. Microangiopathic anemia: finding
    Schistocytes on blood smear
  169. Macroangiopathic anemia: type of anemia and description
    Extrinsic hemolytic normocytic anemia

    Prosthetic heart valves and aortic stenosis may cause hemolytic anemia 2° to mechanical destruction of RBCs
  170. Macroangiopathic anemia: finding
    Schistocytes on blood smear
  171. Can some infections cause anemia? If so, what type and how?

    • Extrinsic hemolytic normocytic anemia
    • ↑ destruction of RBCs by things like malaria or Babesia
  172. Lab values in iron defiency anemia
    • Serum iron: ↓ (1°)
    • Transferrin or TIBC: ↑
    • Ferritin: ↓
    • % tranferrin saturation: ↓↓
  173. Lab values in anemia of chronic disease
    • Serum iron: ↓
    • Transferrin or TIBC: ↓
    • Ferritin: ↑ (1°)
    • % tranferrin saturation: normal
  174. Why do transferrin and TIBC values drop in anemia of chronic disease?
    • Evolutionary reasoning
    • Pathogens use circulating iron to thrive
    • Body stores iron within cells to prevent pathogens from acquiring circulating iron
  175. Lab values of anemia caused by hemochromatosis
    • Serum iron: ↑ (1°)
    • Transferrin or TIBC: ↓
    • Ferritin: ↑
    • % tranferrin saturation: ↑↑
  176. Lab values of anemia caused by pregnancy or OCP use
    • Serum iron: normal
    • Transferrin or TIBC: INC (1°)
    • Ferritin: normal
    • % tranferrin saturation: ↳
  177. Transferrin
    Iron transporter in blood
  178. Ferritin
    1° iron storage protein of body
Card Set:
2014-03-20 02:03:08

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