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Coagulation Disorders

Coagulation Disorders. FACTOR VIII DEFICIENCY HEMOPHILIA A. Factor VIII: Regulates the activation of factor X by proteases. Synthesized in liver, complexed to vWF. On the X chromosome. HEMOPHILIA A. Female carriers have sufficient factor VIII.

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Coagulation Disorders

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  1. Coagulation Disorders

  2. Coagulation Disorders Coagulation Disorders

  3. Coagulation Disorders

  4. FACTOR VIII DEFICIENCY HEMOPHILIA A Factor VIII: • Regulates the activation of factor X by proteases. • Synthesized in liver, complexed tovWF. • On the X chromosome. Coagulation Disorders

  5. HEMOPHILIA A • Female carriers have sufficient factor VIII. • However, occasional hemophilia carriers will have factor VIII levels far below 50% due to random inactivation of normal X chromosomes in tissue producing factor VIII. • Rarely, true female hemophiliacs arise from consanguinity within families with hemophilia or from concomitant Turner's syndrome or XO mosaicism in a carrier female. Coagulation Disorders

  6. HEMOPHILIA A • One in 5,000 males is born with deficiency or dysfunction of the factor VIII molecule (one in 10,000 in both FVIII and IX def.). Coagulation Disorders

  7. HEMOPHILIA A • <5% FVIII: symptomatic. • <1%: severe disease. • 1-5%: moderate disease. • >5%: mild disease. Coagulation Disorders

  8. HEMOPHILIA A • The majority of patients with hemophilia A have factor VIII levels below <5%. Coagulation Disorders

  9. HEMOPHILIA A • Hemophilic bleeding occurs hours or days after injury. • This can result in large collections of partially clotted blood putting pressure on adjacent normal tissues. Coagulation Disorders

  10. HEMOPHILIA A • Retroperitoneal hematoma • Large calcified masses (pseudotumor syndrome). • Cephalhematoma or profuse bleeding at circumcision • Hemarthrosis • Hematuria, usually self-limited • Oropharyngeal and central nervous system bleeding (the most feared complications of hemophilia) Coagulation Disorders

  11. HEMOPHILIA A Laboratory Diagnosis • Typically, the patient will have a prolonged PTT with all other tests normal. • Any male with an appropriate bleeding history and a prolonged PTT should have specific assays for factor VIII and factor IX. Coagulation Disorders

  12. HEMOPHILIA A Treatment • Avoid the use of aspirin or aspirin-containing drugs, which impair platelet function and may cause severe hemorrhage. COX-2 inhibitors can be used, as they do not impair platelet function. • Factor VIII replacement Coagulation Disorders

  13. HEMOPHILIA A Plasma products: • Fresh frozen plasma • Cryoprecipitate (around 80U per bag) • Factor VIII concentrates Coagulation Disorders

  14. HEMOPHILIA AManagement Calculation of FVIII replacement • 1 U of FVIII = 1 ml of normal plasma. • Normal plasma volume: 50 ml/kg of BW. • A healthy person has 50U FVIII/kg of BW • Half-life of 8 to 12 h • FVIII replacement: target level - baseline level x wt(kg) x 0.5 Coagulation Disorders

  15. HEMOPHILIA AManagement • In patients with mild hemophilia, an alternative treatment is desmopressin (DDAVP), which transiently increases the factor VIII level. DDAVP will increase the factor level two- to threefold. Coagulation Disorders

  16. HEMOPHILIA AManagement • Skilled orthopedic care. • Antifibrinolytic therapy: e-aminocaproic acid (EACA), and tranexamic acid. • Gene therapy Coagulation Disorders

  17. HEMOPHILIA AComplications • Viral Hepatitis • AIDS • Factor inhibitors Coagulation Disorders

  18. FACTOR IX DEFICIENCY Hemophilia B (Christmas disease ) • Occurs in 1 in 100,000 male births. • Indistinguishable clinically from factor VIII deficiency. • Therapy: FFP or a plasma fraction enriched in the prothrombin complex proteins. • Monoclonally purified or recombinant factor IX preparations are now available. • Replacement: target-baseline x wt(kg) x 1U/kg Coagulation Disorders

  19. OTHER FACTOR DEFICIENCIES • Deficiencies in factors V, VII, X, and prothrombin (factor II) are exceedingly rare autosomal recessive disorders. • Therapy: FFP, Prothrombin concentrates Coagulation Disorders

  20. OTHER FACTOR DEFICIENCIES Hageman factor (factor XII), HMWK, and PK • PTT often >100 • Normal hemostasis • No clinical bleeding. • Direct activation of factor IX by the tissue factor-VIIa complex may bypass this defective step in coagulation . Coagulation Disorders

  21. FACTOR XIII DEFICIENCY AND DEFECTIVE FIBRIN CROSS-LINKING • Usually bleed in the neonatal period from their umbilical stump or circumcision. • Poor wound healing • A high incidence of infertility among males and abortion among affected females. • Enzyme may be important in placental implantation, spermatogenesis, and wound healing. • Drugs: Isoniazid • Normal hemostasis requires only 1% of normal enzyme activity, which can be achieved with a single infusion of fresh-frozen plasma or a purified factor XIII-rich product • Factor XIII has a 14-day half-life. Coagulation Disorders

  22. Acquired Coagulation Disorders • More frequent and more complex • Affecting both primary and secondary hemostasis. DIC Liver disease Vitamin K deficiency Anticoagulant therapy Coagulation Disorders

  23. VITAMIN K DEFICIENCY • Following absorption and transport, vitamin K is converted to an active epoxide in liver microsomes and serves as a cofactor in the enzymatic carboxylation of glutamic acid residues on prothrombin complex proteins. Coagulation Disorders

  24. VITAMIN K DEFICIENCY • Inadequate dietary intake • Intestinal malabsorption • Loss of storage sites due to hepatocellular disease. • Neonatal vitamin K deficiency • Warfarin usage Coagulation Disorders

  25. VITAMIN K DEFICIENCY • Decrease in factors II, VII, IX, X; proteins C and S. • Factor VII and protein C, which have the shortest half-lives, decrease first. Coagulation Disorders

  26. COAGULATION DISORDERS IN LIVER DISEASE • Prolongation of the PT and PTT. • Mild thrombocytopenia. • Normal fibrinogen level. • Therapy: fresh-frozen plasma. Coagulation Disorders

  27. CIRCULATING ANTICOAGULANTS • Circulating anticoagulants, or inhibitors, are usually IgG. • They arise in 15 to 20% of patients with factor VIII or factor IX deficiency who have received plasma infusions. • Specific inhibitors also occur in previously normal individuals. • In addition to hemophiliacs, anti-factor VIII antibodies are seen in postpartum females, in patients on various drugs, as part of the spectrum of autoantibodies in SLE patients, and in normal elderly individuals and in patients with AIDS. Coagulation Disorders

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