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Afibrinogenemia

Afibrinogenemia. Prevalence approx 1:1,000,000 Recessive inheritance Most reported cases from consanguineous parents Parents typically have asymptomatic hypofibrinogenemia Genetically heterogeneous (>30 mutations)

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Afibrinogenemia

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  1. Afibrinogenemia • Prevalence approx 1:1,000,000 • Recessive inheritance • Most reported cases from consanguineous parents • Parents typically have asymptomatic hypofibrinogenemia • Genetically heterogeneous (>30 mutations) • May be due to failure of synthesis, intracellular transport or secretion of fibrinogen • Moderate to severe bleeding (typically less than in severe hemophilia) • Death from intracranial bleeding in childhood may occur • GI and other mucosal hemorrhage • Menorrhagia • Placental abruption • Treat with purified fibrinogen concentrate or cryoprecipitate for bleeding, during pregnancy

  2. Inherited dysfibrinogenemia • Prevalance uncertain (most cases asymptomatic) • Usually exhibits dominant inheritance • Most cases due to missense mutations • Mutations may affect fibrin polymerization, fibrinopeptide cleavage, or fibrin stabilization by FXIIIa • Variable clinical manifestations (mutation-dependent): • Over 50% asymptomatic • Approx 25% with bleeding tendency (mild to severe) • 20% have a thrombotic tendency (arterial, venous, or both) • Decreased thrombin-binding (antithrombin effect) of fibrin? • Altered fibrin clot structure?

  3. JCI 1978;61:535 Acquired dysfibrinogenemia • Usually associated with liver disease • Cirrhosis • Acute hepatitis • Hepatoma • Fibrinogen has higher than normal sialic acid content • Diseased liver has increased levels of sialyltransferase and other enzymes that control oligosaccharide content

  4. Diagnosis of dysfibrinogenemia • Prolonged thrombin & reptilase times • PT, aPTT may be prolonged • Disparity (>30%) between fibrinogen activity and antigen • Family testing • Evaluate for liver disease

  5. Arch Pathol Lab Med 2002;126:499

  6. Other acquired abnormalities of fibrin formation • High fibrinogen • High levels of FDP • Myeloma proteins (IgM > IgA > IgG) • Autoantibodies

  7. Recessively inherited clotting factor deficiencies • Rare • Exceptions: XI, XII deficiency • Homozygotes (often consanguineous parents) or compound heterozygotes • Heterozygous parents usually asymptomatic • Quantitative (“type 1”) deficiency: parallel reduction in antigen and activity • Qualitative (“type 2”) deficiency: reduced activity with near-normal antigen • Genetically heterogeneous • Complete deficiency of II, X not described (lethal?) • Mutation usually in gene encoding clotting factor Exceptions: Combined V, VIII deficiency Combined deficiency of vitamin K-dependent factors

  8. Combined deficiency of factors V and VIII • Levels of affected factors 5-20% of normal • Associated with mutations of LMAN-1 (ERGIC-53) or MCFD2, both of which regulate intracellular trafficking of V and VIII

  9. Deficiency of multiple vitamin-K dependent clotting factors • Levels of II, VII, IX, X, proteins C and S range from <1% to 30% of normal • Bleeding symptoms proportional to degree of deficiency • Usually associated with missense mutations in vitamin K epoxide reductase subunit 1 (VKORC1)

  10. Relative frequencies of recessively inherited factor deficiencies Blood 2004; 104:1243

  11. Clinical features of recessively inherited factor deficiencies Blood 2004; 104:1243

  12. Patterns of bleeding in recessively inherited factor deficiency vs hemophilia Blood 2004; 104:1243

  13. Treatment of rare clotting factor deficiencies • FFP • Prothrombin complex concentrate (II, VII, IX, X) or specific factor concentrate (XIII – others available in Europe) when appropriate • Goal is to maintain “minimal hemostatic levels” • Antifibrinolytic drugs may be helpful in patients with mucosal hemorrhage • Routine prophylaxis appropriate for F XIII deficiency (long half-life, low levels adequate for hemostasis) • Otherwise treatment appropriate for active bleeding or pre-procedure

  14. Factor XI

  15. Factor XI deficiency • Recessively inherited • Most common in individuals of Ashkenazi Jewish descent • 2 common mutations (one nonsense, one missense) • Allele frequency as high as 10%, 0.1-0.3% homozygous • Most affected patients compound heterozygotes with low but measurable levels of XI activity • Long aPTT, normal PT • XI activity < 10% in most patients with bleeding tendency

  16. Factor XI deficiencyClinical features & treatment • Variable, generally mild bleeding tendency • Bleeding after trauma & surgery • Spontaneous bleeding uncommon • Bleeding risk does not correlate well with XI level • Treatment: FFP • 15 ml/kg loading, 3-6 ml/kg q 12-24h • Half life of factor >48 hours • Amicar useful after dental extraction, surgery • rVIIa is effective but expensive; thrombotic complications reported

  17. Factor XIII • Transglutaminase: forms amide bonds between lysine and glutamic acid residues • Heterotetramer (A2B2) in plasma • A chains made by megakaryocytes and monocyte/macrophage precursors • Platelet XIII (50% of total XIII) has only A chains • B chains (non-catalytic) made in liver • Proenzyme activated by thrombin • Crosslinks fibrin

  18. Inherited factor XIII deficiency • Autosomal recessive, rare (consanguineous parents) • Heterozygous woman may have higher incidence of spontaneous abortion • Most have absent or defective A subunit • F XIII activity < 1%

  19. Inherited factor XIII deficiencyClinical features & treatment • Bleeding begins in infancy (umbilical cord) • Poor wound healing • Intracranial hemorrhage • Oligospermia, infertility • Diagnosis: • Urea solubility test • Quantitative measurement of XIII activity • Rule out acquired deficiency due to autoantibody • F XIII concentrates available (long half life, can administer every 4-6 weeks as prophylaxis)

  20. Acquired factor XIII deficiency • Autoantibody-mediated • Very rare • Most patients elderly • May be drug-induced (isoniazid, other antibiotics) • Bleeding may be severe • Diagnosis: • Urea solubility • F XIII activity • Mixing study?

  21. Factor XII deficiency • Recessive inheritance, but fairly common • Markedly prolonged aPTT • No bleeding tendency • Deficiency of other contact factors (HMWK, prekallikrein) less common, but has similar phenotype

  22. PLATELET DISORDERS

  23. Platelet structure 1 • Membrane glycoproteins • IIb-IIIa: integrin, cryptic in resting platelet, after platelet activation binds fibrinogen and other adhesive proteins, necessary for aggregation • Ib-IX-V: binds VWF, necessary for platelet adhesion at high shear rates • Ia-IIa: integrin, binds collagen, mediates adhesion at low shear rates and platelet spreading (also acts as receptor)

  24. Platelet structure 2 • Membrane receptors • Thrombin receptors (2): cleaved and activated by thrombin • Thromboxane A2 receptor • ADP receptors (3) • Epinephrine receptor • Serotonin receptor • Cytokine, chemokine receptors • Fc receptor

  25. Platelet structure 3 • Membrane phospholipids • Procoagulant lipids (phosphatidyl serine) sequestered on inner leaflet, transferred to outer leaflet by “scramblase” enzyme with platelet activation • Arachidonic acid cleaved from inner leaflet by phospholipase, converted to thromboxane by cyclooxygenase & thromboxane synthase

  26. Platelet structure 4 • Granules • Dense granules: small molecules involved in platelet activation (ATP/ADP, serotonin) • Alpha granules: fibrinogen, fibronectin, thrombospondin, P-selectin, plasminogen, alpha-2 antiplasmin, factor V, PF4, PDGF, TGF-alpha and beta, ECGF

  27. Bernard-Soulier syndrome • Pathophysiology: • Deficiency of platelet membrane glycoprotein Ib-IX (VWF “receptor”) • Defective platelet adhesion • Clinical: Moderate to severe bleeding • Inheritance: autosomal recessive • Morphology: • Giant platelets • Thrombocytopenia (20-100K) • Diagnosis: • No agglutination with ristocetin, decr thrombin response, responses to other agonists intact • Morphology • Decreased GP Ib expression

  28. Bernard-Soulier syndrome

  29. Glanzmann thrombasthenia • Pathophysiology: • Deficiency of platelet membrane GPIIb-IIIa • Absent platelet aggregation with all agonists; agglutination by ristocetin intact • Clinical: Moderate to severe bleeding • Inheritance: autosomal recessive • Morphology: normal • Diagnosis: • Defective platelet aggregation • Decreased GP IIb-IIIa expression

  30. Gray platelet syndrome • Pathophysiology: Empty platelet alpha granules • Clinical: Mild bleeding • Inheritance: Autosomal dominant or recessive • Morphology: • Hypogranular platelets • Giant platelets • Thrombocytopenia (30-100K) • Myelofibrosis in some patients • Diagnosis • Variably abnormal platelet aggregation (can be normal) • Abnormal platelet appearance on blood smear • Electron microscopy showing absent alpha granules

  31. Gray platelet syndrome

  32. Giant platelet syndromes associated with MYH9 mutations • May-Hegglin anomaly • Fechtner syndrome • Sebastian syndrome • Epstein syndrome • All associated with mutations in the non-muscle myosin heavy chain gene MYH9 • Thrombocytopenia with giant platelets, but mild bleeding • Autosomal dominant inheritance • No consistent defects of platelet function detectable in the clinical laboratory • Diagnosis usually based on clinical picture, family history, examination of blood smear for neutrophil inclusions

  33. Giant platelet syndromes associated with MYH9 mutations *Neutrophil inclusions have different structure from those in May-Hegglin

  34. Neutrophil inclusions in May-Hegglin anomaly

  35. Wiskott-Aldrich syndrome • Pathophysiology • Mutation in WASP signaling protein • Decreased secretion and aggregation with multiple agonists; defective T-cell function • Clinical: • Mild to severe bleeding • Eczema, immunodeficiency • Inheritance: X-linked • Morphology: • Thrombocytopenia (20-100K) • Small platelets with few granules • Diagnosis: Family hx, clinical picture, genetic testing

  36. Wiskott-Aldrich syndrome

  37. Hermansky Pudlak syndrome Chédiak-Higashi syndrome • Pathophysiology: • Platelet dense granule deficiency: decreased aggregation & secretion with multiple agonists • Defective pigmentation • Defective lysosomal function in other cells • Clinical: • Mild to moderate bleeding • Oculocutaneous albinism (HPS) • Lysosomal storage disorder with ceroid deposition, lung & GI disease (HPS) • Immunodeficiency, lymphomas (CHS) • Inheritance: autosomal recessive • Morphology • Reduced dense granules • Abnormal neutrophil granules (CHS) • Diagnosis: clinical picture, neutrophil inclusions (CHS), genetic testing

  38. HPS, with oculocutaneous albinism Chédiak-Higashi, showing neutrophil inclusions

  39. Hermansky-Pudlak syndrome Br J Haematol 2007;138:671 Disaggregation after primary aggregation with ADP Dense granule deficiency Control platelet

  40. Platelet type von Willebrand disease • Pathophysiology: Gain of function mutation in GP Ib, with enhanced binding to VWF and clearance of largest multimers from blood • Clinical: Mild to moderate bleeding • Inheritance: Autosomal dominant • Morphology: Normal, but platelet count often low • Diagnosis: Variably low VWF antigen, disproportionately low ristocetin cofactor activity, loss of largest VWF multimers on electrophoresis, enhanced platelet agglutination by low dose ristocetin (indistinguishable from type 2B VWD) • Can distinguish from 2B VWD by mixing studies with normal/pt platelets and plasma and low dose ristocetin, or by genetic testing

  41. Treatment of patients with platelet disorders • Platelet transfusions • DDAVP • Antifibrinolytic drugs (Amicar) • rVIIa? • Treatment decisions must be individualized

  42. VASCULAR DISORDERS

  43. Hereditary Hemorrhagic Telangiectasia • Autosomal dominant inheritance • Mutation in endoglin gene that controls vascular remodeling • Molecular diagnosis possible • Multiple small AVMs in skin, mouth, GI tract, lungs

  44. Endoglin and vascular remodeling J Thromb Haemost 2010;8:1447

  45. Hereditary hemorrhagic telangiectasia J Thromb Haemost 2010;8:1447

  46. Hereditary Hemorrhagic TelangiectasiaClinical features • Epistaxis, GI bleeding – may be severe • Severe iron deficiency common • Pulmonary or CNS bleeding often fatal • Gradual increase in bleeding risk with age • AVMs enlarge during pregnancy • Risk of brain abscess • Hypoxemia from pulmonary HTN and R→L shunting in lung

  47. Hereditary Hemorrhagic TelangiectasiaTreatment • No consistently effective method for preventing bleeding • Aggressive iron replacement • Antibiotic prophylaxis for dental work etc • Screen for CNS lesions → consider surgical intervention

  48. Ehlers-Danlos syndrome • Defective collagen structure • Mutations in genes for various types of collagen • 9 variants • Type IV (mutation in type III collagen gene) most likely to cause bleeding • Bleeding due to weakening of vessel wall → vessel rupture • Conventional tests of hemostatic integrity normal

  49. Ehlers-Danlos syndrome • Thin, weak skin with poor healing • “Cigarette paper” scars • Bruising • Hypermobile joints • Spontaneous joint dislocation • Median survival 48 years in type IV EDS • Death from rupture of large vessels or colon perforation

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