23 - Thrombophilia Flashcards
composition of venous thrombi vs arterial thrombi
venous - RBCs
arterial - platelets
virchow’s triad
endothelial injury
abnl blood flow
hypercoagulability
activated protein C affect on PTT
prolong - degrades factor Va and VIIIa
APC resistance gene mutation
factor V Leiden mutation - makes V less susceptible to cleavage by APC
clinical consequences / management of Factor V Leiden
relatively common, risk for venous (not arterial) thrombosis
overall significance not known, prophylactic anticoag NOT recommended
prothrombin gene mutation
inc synth of prothrombin > 3 fold inc thrombotic risk
common in caucasians
protein C
vit K dependent anticoagulant
made in liver
what activates protein C
thrombin/thrombomodulin complex
how does APC reduce coagulation?
inactivates factor Va and VIIIa w/ protein S as cofactor
also a powerful inhibitor of PAI-1 (plasminogen activator inhibitor)
congenital protein C deficiency inheritance pattern
AD inheritance, variable penetrance
clinical presentation/effects of heterozygous and homozygous protein C deficiency
heterozygotes - 5-10 fold inc in venous thrombosis risk, rarely symptomatic until >20yo. assoc w/ pregnancy loss
homozygotes - infants w/ DIC or purpura fulminans
protein S
vit K dependent
60% binds to C4b-BP, no anticoag fn
40% free - cofactor for APC, anticoag
causes of acquired protein C and S deficiency
liver dz DIC acute thromboses post surg BC pill, hormone replacement warfarin / vit K deficiency
L-asparginase - C only
ARDS - C only
nephrotic syndrome - S only
antithrombin
binds w/ heparin-like molecs > conf change
complex inactivates thrombin and F.Xa
accelerates dissoc of F.VIIa-TF complex
causes of antithrombin defi
congenital - AD
acquired - similar to prot C/S
causes of impaired fibrinolysis
congenital plasminogen defi tPA defi high PAI-1 congenital dysfibrinogenemia F.XII defi high lipoprotein (a)
lipoprotein (a)
inc levels > inc risk of venous thromboembolsim
facilitates tissue repair by inhibiting fibrinolysis in damaged area
hyperhomocysteinemia - clinical consequences
risk factor for premature CAD, stroke, venous thrombosis, periph vasc dz
mechanism of homocysteine effect
inc endothelial cell toxicity
promotes proteolyis of F.V > F.Va
blocks protein C activation
may block tPA binding to endothelial cells > dec fibrinolysis
may inc monocytes binding to endothelial cells
MTHFR 677 C>T mutation
homozygous state > mild to mod hyperhomocysteinemia
~10% in caucasians, ~20% asians are hetero
acquired risk factors for venous thrombosis
history of thrombosis central venous cath / cannulation attempt older immobilization / venous stasis malignancy inflammation / severe infxn surgery pregnancy / estrogen therapy obesity smoking antiphospholipid ab syndrome
antiphospholipid ab syndrome (APS)
clinical: thromboses, recurrent miscarriages, pregnancy morbidity
labs: lupus anticoag, anticardiolipin ab (IgG or IgM), anti-beta-2 glycoprotein-1 ab
clinical presentation of venous thromboembolism
unilateral thigh/calf swelling / tenderness, pitting edema, presence of collateral superficial non-varicose veins
2 methods for diagnosis of venous thromboembolism
serial compression ultrasounds - most reliable/practical but cant tell btwn acute and chronic
contrast venography - most sensitive, but painful and can induce thromboembolism
dx of pulm embolism
CXR often normal
ventilation-perfusion scan shows areas not perfused but ventilated
spiral CT pulm angiography
echo may pick up large saddle embolus
