Thrombophilia

Question 1

thrombophilia

Answer 1

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

Question 2

two causes of thrombophilia

Answer 2

increased procoagulants or decreased anticoagulants

Question 3

what can cause increased procoagulant activity?

Answer 3

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

Question 4

what can cause decreased anticoagulant activity?

Answer 4

protein C, D and antithrombin deficiencies

Question 5

clinical manifestation of thrombophilia

Answer 5

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

Question 6

venous thromboembolism

Answer 6

DVT + PE

Question 7

antithrombin

Answer 7

inactivates thrombin and 10a

Question 8

protein C

Answer 8

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

Question 9

antithrombin deficiency

Answer 9

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

Question 10

heparin

Answer 10

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

Question 11

type 1 AT deficiency

Answer 11

reduced levels of functionally normal AT

Question 12

type 2 AT deficiency

Answer 12

functionally abnormal AT

Question 13

how to test for AT deficiency

Answer 13

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

Question 14

how is protein C activated?

Answer 14

by thrombomodulin bound thrombin (negative feedback loop)

Question 15

protein S bound vs unbound

Answer 15

bound=inactive, free=active

Question 16

thrombomodulin

Answer 16

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

Question 17

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

Answer 17

copperhead snake venom mimics thrombin activity

Question 18

protein S type 3 deficiency

Answer 18

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

Question 19

neonatal purpura fulminans

Answer 19

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

Question 20

neonatal purpura fulminans treatment

Answer 20

rapid administration of anticoagulation and exogenous source of protein C

Question 21

warfarin

Answer 21

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

Question 22

warfarin induced skin necrosis

Answer 22

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.

Question 23

factor v leiden

Answer 23

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

Question 24

prothrombin mutation

Answer 24

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

Question 25

what is the best predictor of VTE recurrence?

Answer 25

the cause of the first VTE. surgical<unprovoked

Question 26

low antigen assay and low functional assay

Answer 26

type 1 deficiency

Question 27

normal antigen assay and low functional assay

Answer 27

type 2 deficiency

Question 28

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

Answer 28

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