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Flashcards in Thrombophilia Deck (28):
1

thrombophilia

any condition that results in an imbalance of homeostasis that favors clotting and formation of pathologic thrombosis

2

two causes of thrombophilia

increased procoagulants or decreased anticoagulants

3

what can cause increased procoagulant activity?

gain of function point mutations in clotting factors that increase their activity. Factor V leiden & prothrombin mutations

4

what can cause decreased anticoagulant activity?

protein C, D and antithrombin deficiencies

5

clinical manifestation of thrombophilia

increase risk of deep vein thrombosis and subsequent pulmonary embolism. no increased risk of arterial thrombosis

6

venous thromboembolism

DVT + PE

7

antithrombin

inactivates thrombin and 10a

8

protein C

when activated by thrombin, and paired with cofactor S, inhibits factor 5 & 8

9

antithrombin deficiency

AT usually inactivates thrombin and 10a, so a lack of AT leads to a decrease in clotting regulation.

10

heparin

anticoagulant drug that works by enhancing the anticoagulant activity of antithrombin via conformational changes that cause AT to bind tighter to thrombin and 10a

11

type 1 AT deficiency

reduced levels of functionally normal AT

12

type 2 AT deficiency

functionally abnormal AT

13

how to test for AT deficiency

antigen assays (levels in plasma) and functional assays (measures inhibition of thrombin/10a in presence of heparin)--> distinguish type 1&2

14

how is protein C activated?

by thrombomodulin bound thrombin (negative feedback loop)

15

protein S bound vs unbound

bound=inactive, free=active

16

thrombomodulin

integral protein embedded in luminal endothelium. binds thrombin and causes it to activate protein C, which then cleaves 5/8

17

how can we test protein C in vitro if it requires thrombomodulin in vivo, which is bound to vessel endothelial membrane?

copperhead snake venom mimics thrombin activity

18

protein S type 3 deficiency

reduced levels of free protein S, higher proportion than normal is bound and inactivated. normal levels of total protein

19

neonatal purpura fulminans

autosomal recessive protein C deficiency. presents on day 1 with massive thrombosis of cutaneous vessels.

20

neonatal purpura fulminans treatment

rapid administration of anticoagulation and exogenous source of protein C

21

warfarin

oral anticoagulant that works by sequestering vitamin k in epoxide form and thereby reducing circulation 2,7,9,10, proC/S levels.

22

warfarin induced skin necrosis

complication of warfarin therapy due to different half lives of vitamin k dependent proteins and subsequent cutaneous vessel thrombosis and necrotic skin lesions. protein S/C deficiency is risk factor since balance is already tipped against their concentrations.

23

factor v leiden

point mutation in factor 5 that makes it resistant to cleavage by protein C (thereby rendering protein C inactive)

24

prothrombin mutation

gain of function mutation in which prothrombin is higher concentration than normal

25

what is the best predictor of VTE recurrence?

the cause of the first VTE. surgical

26

low antigen assay and low functional assay

type 1 deficiency

27

normal antigen assay and low functional assay

type 2 deficiency

28

causes of acquired deficiency of AT/ProteinC/S and therefore acquired thrombophilia

acute thrombosis (consumption of all 3 proteins is accelerated), liver disease (all 3 are made in liver), vitamin K deficiency, treatment with warfarin or heparin