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
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
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
Type I hypercoagulation disorder involves deficiency in ____, _____ and ____
Antithrombin IIII
Protein C
Protein S
Type II hypercoagulation disorder involves ________ of coagulation factors: ______ and _____
Overactivity
Factor V Leiden
Prothrombin G20210A ( a mutation in prothrombin
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
Which enzyme activates fibrin from fibrinogen?
Thrombin
What are factors that inhibit fibrin clot (fibrinolysis)?
Antithrombin (AT3)
Protein C (in the presence of Protein S)
What does AT3 do?
Antithrombin inactivates thrombin, factor IXa, Xa and Xia
What does an activated protein C do?
Inhibits Factors Va and VIIIa in the presence of Protein S
T/F: in addition to its effects on thrombosis, hypercoagulable states may accelerate the development of atherosclerosis
True
AT3 inhibits _____ proteases which inhibits factors ____, ___, ___, ____ and ____
Serine
IX
X
XI
XII
II (thrombin)
T/F: when there is 50% reduction of AT activity, you are at risk of developing thrombosis
True
AT3 deficiency, aka inherited antithrombin deficiency, is a ___________ genetic defect, and it is a Type _____ congenital hypercoagulation disorder
Autosomal dominant
Type I
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
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
(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
Which is a vitamin K dependent protease zymogen?
Protein C
What does an activated Protein C do?
Activated PC inactivates clotting factors Va and Viiia, thus downregulating the clotting cascade
T/F: Protein C deficiency, like AT3 deficiency, is an autosomal dominant genetic defect
True
When do venous thrombosis presents in patients with AT3 or Protein C deficiency?
Around the third or fourth decade; rarely before puberty
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
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
Which factor is identified in patients with hypercoagulation that were resistant to increase in PTT From addition of APC?
Factor V Leiden
T/F: Factor V Leiden mutation is an autosomal dominant substitution mutation of glutamine for Arginine at 506
True; point mutation Arg506Gin
Which is the most common cause of inherited hypercoagulation in Caucasians?
Factor V Leiden
Pt presents with DVT, cerebral vein thrombosis and history of recurrent pregnancy loss, think:
Factor V Leiden
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
True
What is mutated at G20210A in 3’ untranslated region and lead to mRNA accumulation?
Prothrombin gene
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
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
Which hypercoagulation disorder is most likely to lead to warfarin-induced skin necrosis?
Protein C deficiency
What mutation characterizes factor V leiden?
Arg506Gin mutation in factor V making it resistant to degradation by APC
What mutation characterized prothrombin?
G20210A mutation in the 3’ UTR
The addition of APC does what to the PTT in people with factor V Leiden?
