Hypercoagulable Genetics

  1. Genetic cause of thrombophilia is suspected when patient meet these criteria:
    • Thrombotic event under 45 years of age without underlying pathology
    • Recurrent unexplained thromboses
    • Positive family history
  2. There are two types of congenital hypercoagulation disorders, which one is more commonly seen: Type I or Type II?
    Type II is more common, having to do with Factor V Leiden and mutateion of prothrombin gene
  3. What is Type I vs Type II congenital hypercoagulation disorders?
    • Thrombosis is more likely in Type I – involving Antithrombin III deficiency and Proteins C and S deficiency
    • Type II is more common and relatively mild, involving Factor V Leiden, prothrombin gene mutation
  4. Type I hypercoagulation disorder involves deficiency in ____, _____ and ____
    • Antithrombin IIII
    • Protein C
    • Protein S
  5. Type II hypercoagulation disorder involves ________ of coagulation factors: ______ and _____
    • Overactivity
    • Factor V Leiden
    • Prothrombin G20210A ( a mutation in prothrombin
  6. Which enzyme is central in the coagulation process? What does it do?
    • Thrombin is a central enzyme in the coagulation process
    • Generates fibrin from fibrinogen, activates a number of enzymes and cofactors, including Factor 13, 11, 5 and 8, TAFI, enchancing the fibrin clot
  7. Which enzyme activates fibrin from fibrinogen?
  8. What are factors that inhibit fibrin clot (fibrinolysis)?
    • Antithrombin (AT3)
    • Protein C (in the presence of Protein S)
  9. What does AT3 do?
    Antithrombin inactivates thrombin, factor IXa, Xa and Xia
  10. What does an activated protein C do?
    Inhibits Factors Va and VIIIa in the presence of Protein S
  11. T/F: in addition to its effects on thrombosis, hypercoagulable states may accelerate the development of atherosclerosis
  12. AT3 inhibits _____ proteases which inhibits factors ____, ___, ___, ____ and ____
    • Serine
    • IX
    • X
    • XI
    • XII
    • II (thrombin)
  13. T/F: when there is 50% reduction of AT activity, you are at risk of developing thrombosis
  14. AT3 deficiency, aka inherited antithrombin deficiency, is a ___________ genetic defect, and it is a Type _____ congenital hypercoagulation disorder
    • Autosomal dominant
    • Type I
  15. T/F: arterial thrombosis are most commonly see in patients with AT3 deficiency?
    False; Deep leg vein and mesenteric vein thrombosis are common, arterial thrombosis are rare in AT 3 deficiency
  16. How does AT 3 deficiency changes the result of PT, PTT?
    No changes in PT, PTT seen, however, there is under-responsiveness seen with heparin use
  17. (PT/ PTT) measure the integrity of the Extrinsic system, while (PT/PTT) measure the integrity of the intrinsic system and the common components
    • PT = extrinsic
    • PTT= intrinsic
  18. Which is a vitamin K dependent protease zymogen?
    Protein C
  19. What does an activated Protein C do?
    Activated PC inactivates clotting factors Va and Viiia, thus downregulating the clotting cascade
  20. T/F: Protein C deficiency, like AT3 deficiency, is an autosomal dominant genetic defect
  21. When do venous thrombosis presents in patients with AT3 or Protein C deficiency?
    Around the third or fourth decade; rarely before puberty
  22. In mild protein C deficiency, an individual can develop ____. In severe protein C deficiency, infants develop a life-threatening blood clotting disorder called ____
    • DVT
    • Purpura Fulminans
  23. A cofactor needed to activated protein C is ____. A 50% reduction of this cofactor would result in ____
    • Protein C
    • Clotting cascade not able to be turned off, because Protein C cannot function
  24. Which factor is identified in patients with hypercoagulation that were resistant to increase in PTT From addition of APC?
    Factor V Leiden
  25. T/F: Factor V Leiden mutation is an autosomal dominant substitution mutation of glutamine for Arginine at 506
    True; point mutation Arg506Gin
  26. Which is the most common cause of inherited hypercoagulation in Caucasians?
    Factor V Leiden
  27. Pt presents with DVT, cerebral vein thrombosis and history of recurrent pregnancy loss, think:
    Factor V Leiden
  28. T/F: thrombosis associated with factor V Leiden appears to be restricted to the venous circulation with only limited controversial evidence for arterial thrombosis or increased risk of MI
  29. What is mutated at G20210A in 3’ untranslated region and lead to mRNA accumulation?
    Prothrombin gene
  30. T/F: antithrombin deficiency has direct effect on PT, PTT or thrombin time
    False; it has no direct effect on them just diminished the increase in PTT following heparin administration
  31. What is the main pathophysiological mechanism for protein C and S deficiency?
    • Mutations causing protein C deficiency do not have enough functional protein C to inactivate clotting proteins Va and VIIIa which results in blood clots.
    • Protein S is a cofactor for Protein C, same mechanism
  32. Which hypercoagulation disorder is most likely to lead to warfarin-induced skin necrosis?
    Protein C deficiency
  33. What mutation characterizes factor V leiden?
    Arg506Gin mutation in factor V making it resistant to degradation by APC
  34. What mutation characterized prothrombin?
    G20210A mutation in the 3’ UTR
  35. The addition of APC does what to the PTT in people with factor V Leiden?
    PTT does NOT increase
Card Set
Hypercoagulable Genetics
HemeOnc Final