Flashcards in Thrombophilia Deck (28):
any condition that results in an imbalance of homeostasis that favors clotting and formation of pathologic thrombosis
two causes of thrombophilia
increased procoagulants or decreased anticoagulants
what can cause increased procoagulant activity?
gain of function point mutations in clotting factors that increase their activity. Factor V leiden & prothrombin mutations
what can cause decreased anticoagulant activity?
protein C, D and antithrombin deficiencies
clinical manifestation of thrombophilia
increase risk of deep vein thrombosis and subsequent pulmonary embolism. no increased risk of arterial thrombosis
DVT + PE
inactivates thrombin and 10a
when activated by thrombin, and paired with cofactor S, inhibits factor 5 & 8
AT usually inactivates thrombin and 10a, so a lack of AT leads to a decrease in clotting regulation.
anticoagulant drug that works by enhancing the anticoagulant activity of antithrombin via conformational changes that cause AT to bind tighter to thrombin and 10a
type 1 AT deficiency
reduced levels of functionally normal AT
type 2 AT deficiency
functionally abnormal AT
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
how is protein C activated?
by thrombomodulin bound thrombin (negative feedback loop)
protein S bound vs unbound
integral protein embedded in luminal endothelium. binds thrombin and causes it to activate protein C, which then cleaves 5/8
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
protein S type 3 deficiency
reduced levels of free protein S, higher proportion than normal is bound and inactivated. normal levels of total protein
neonatal purpura fulminans
autosomal recessive protein C deficiency. presents on day 1 with massive thrombosis of cutaneous vessels.
neonatal purpura fulminans treatment
rapid administration of anticoagulation and exogenous source of protein C
oral anticoagulant that works by sequestering vitamin k in epoxide form and thereby reducing circulation 2,7,9,10, proC/S levels.
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.
factor v leiden
point mutation in factor 5 that makes it resistant to cleavage by protein C (thereby rendering protein C inactive)
gain of function mutation in which prothrombin is higher concentration than normal
what is the best predictor of VTE recurrence?
the cause of the first VTE. surgical
low antigen assay and low functional assay
type 1 deficiency
normal antigen assay and low functional assay
type 2 deficiency