257. Thrombophilia Flashcards
What is Virchow’s Triad?
3 factors that lead to a pro-coagulated state
- Endothelial Injury
- physical membrane disruption
- disruption of balance of pro and thrombotic effects of endothelium - Alterations in normal blood flow
- stasis
- turbulence - Hypercoagulability of blood
Arterial Thrombosis
- causes
- RFs
- type of flow
- type of clot
- first line tx
Cause:
- injury to the vessel wall
- embolism from other source
RF:
- HTN, Hyperlipidemia, DM, Obesity
- comorbid diseases
- TTP, Heparin-induced thrombocytopenia, Sickle-Cell Disease
- FamHx
- presence of atherosclerotic plaque
HIGH flow, HIGH shear
“White” clot (platelet rich)
tx: antiplatelet drugs
Venous Thrombosis
- type of flow
- cause
- type of clot
- difference from arterial thrombosis
- first line tx
LOW flow, low shear
Cause: venous stasis (valve cusps, muscular sinuses)
“Red” thrombi - more RBCs accumulate on fibrin strands (less platelet dense)
- more dependent on coag factors than platelets
tx: anticoagulants
Factor V Leiden
- what is it (genetics, mechanism)
- epidemiology
- risks
FVL mutation: substitution of glutamic acid instead of arginine (change one base pair) = FVa resistant to cleavage by APC (activated protein C) AND FVa does not fx as cofactor for cleavage of FVIIIa = persistent active FVa and FVIIIa
Epi: most commonly inherited thrombophilic mutation, highest inheritance of heterozygous FVL in EU ancestry = 3-7% (rare hmozygous)
Risks: increased risk of first VTE, less increased risk of recurrent VTE, thrombosis in pregnancy
Prothrombin G20210A Mutation
- what is it (mechanism)
- epidemiology
- risks
Mutation in promotor region of prothombin synthesis = increased circulating FII, protects FXa from antithrombin, more inhibition of fibrinolysis by activating TAF
Higher prevalence in Caucasian population (0.7-4% EU)
Risks: moderately increased risk of first VTE, less increased risk of recurrent VTE, mixed data on OB complications (similar to FVL)
Elevated Factor VIII
- mechanism
- risk
Elevated = top decile of population of F8 values
F8 has role as acute phase reactant = hard to sort out genetic basis
Risk: DOSE-DEPENDENT = more F8 = more risk for first VTE
What are the results of two tests that can be used to determine if thrombophilia is due to quantitative or qualitative protein deficiency?
Quantitative: low antigen, low activity
Qualitative: normal antigen, low activity
Deficiency of Protein C and Protein S
- function of PC and PS
- type of mutation, causes of acquired deficiency
- complications (include homozygous vs. heterozygous)
PC: inactivates F5, F8
PS: cofactor of APC (active when not bound to C4b-binding protein in blood)
Mutation: >100 mutations affecting quantity and quality
Acquired:
- decreased synthesis: liver disease, Vit K deficiency, warfarin therapy
- increased consumption: sepsis, DIC
- increase in C4BP and resultant decrease in Free PS: Estrogens/OCPs, pregnancy, sickle cell disease, HIV
Complications
Homozygous: purpura fulminans: life threatening extensive tissue thrombosis, hemorrhagic skin necrosis
Heterozygous: high risk of first VTE, esp if +FHx
- risk of warfarin-induced skin necrosis upon initiation of warfarin (PC half life shorter than clotting factors) - need overlap with short term heparin
ATIII Deficiency
- mechanism
- type of mutation, causes of acquired deficiency
- risk
Mech: lose ATIII ability to inactivate thrombin, relative heparin resistance
Mutation: in regions that inactivate thrombin or cause defects in heparin binding = decreased AT activity
Acquired: prematurity, liver disease, nephrosis, malnutrition, IBD, Estrogen therapy, l-asparaginase (Tx for leukemia)
risk: increased risk for first VTE, mildly increased risk for recurrent VTE
Antiphospholipid Antibody Syndrome
- mechanism of disease
- types
- primary cause if secondary APS
- assoc
Mech: ACQUIRED auto-Ab's against phospholipids and PL-binding proteins 1. Lupus Anticoagulant 2. anti-cardiolipin 3. anti-beta2-glycoprotein Secondary: SLE or autoimmune disorder
Assoc: Arterial and Venous thrombosis, pregnancy complications
Dx: needs BOTH lab (Ab’s) and Clinical Criteria (spontaneous pregnancy loss, thrombosis)
Hyperhomocysteinemia and MTHFR gene mutation
- mechanism
- risks
High homocysteine = marker for venous/arterial thrombosis (not cause - no decrease in VTE risk with lowering homocysteine)
Screening for MTHFR gene mutation should not be done because alone it does not increase risk of VTE/pregnancy complications
When should you test for inherited thrombophilia?
- NO TEST IF MAJOR TRANSIENT RF
- only if unprovoked
- weeks after acute event (rebuild protein levels), with patient NOT on anticoagulant tx
