SM_257b: Thrombophilia Flashcards
____ is the way blood vessels, blood components, and procoagulants stop bleeding
Hemostasis is the way blood vessels, blood components, and procoagulants stop bleeding
____ is physiologic control of bleeding by clot formation
Coagulation is physiologic control of bleeding by clot formation
___ is pathological occlusion of blood vessels
Thrombosis is pathological occlusion of blood vessels
___ is increased tendency to form thrombi
Thrombophilia is increased tendency to form thrombi
____ is bleeding tendency
Hemophilia is bleeding tendency
Describe hemostatic balance
Hemostatic balance
- Maintaining blood flow while preserving ability to respond to vessel injury
- Designed to prevent clots within vessels
- When vessel injury occurs, coagulation system is activated to prevent or lessen hemorrhage
Procoagulant factors include ____ and ____
Procoagulant factors include primary hemostasis and secondary hemostasis
Describe anticoagulant factors
Anticoagulant factors
- Rapid pulsatile blood flow
- Endothelial surface: non-wettable, NO, prostacyclin, ecto-ADPase, TFPI, thrombomodulin, proteoglycans
- Natural anticoagulants
- Fibrinolytic system
Coagulation is ___, ___, and ___
Coagulation is rapid, self-limited, and reversible
- Cells and plasma proteins form a clot in response to vessel injury
Describe phases of clot formation
Clot formation
- Primary hemostasis: formation of platelet plug at site of endothelial injury, involves endothelium (collagen) / platelets / vWF
- Secondary hemostasis: strengthening of clot by coagulation cascade, interaction of platelets / proteins / fibrin
- Termination: natural anticoagulants
- Breakdown of clot: fibrinolysis
Thrombosis occurs when ___
Thrombosis occurs when hemostatic balance is shifted in favor of procoagulants
- Artery: MI, stroke
- Vein: PE, DVT
Virchow’s triad consists of ____, ____, and ____
Virchow’s triad consists of endothelial injury, alterations in normal blood flow, and hypercoagulability of blood
- Endothelial injury: physical distribution of endothelium, disruption of balance of pro- and anti-thrombotic effects of endothelium
- Alterations in normal blood flow: stasis, turbulence
- Hypercoagulability of blood
Describe arterial thrombosis
Arterial thrombosis
- High flow state
- Typically more dependent on vascular abnormalities and more rarely a result of coagulation abnormality
- Platelet rich thrombus (white)
Describe mechanisms of arterial thrombosis
Arterial thrombosis mechanisms
- Injury to vessel wall (most common)
- Embolism from other source (less common): majority from arteries, rarely “paradoxical” embolism from venous circulation
Describe arterial thrombus on disrupted plaque
Arterial thrombus on disrupted plaque
- Many arterial thrombi form on top of disrupted atherosclerotic plaques
- Thin fibrous cap and lipid-ruch core prone to disruption
- Plaque rupture exposes thrombogenic material in lipid core to blood
- Triggers platelet activation and thrombin generation
Describe examples of arterial thrombi
Arterial thrombi
- Coronary artery: MI, unstable angina (temporary occlusion)
- Cerebral artery: stroke, TIA (temporary occlusion)
- Peripheral / lower extremity artery: limb ischemia / gangrene
- Small vessel peripheral arteries: digital ischemia
Describe venous thrombosis
Venous thrombosis
- Low flow state
- Occurs with venous stasis: valve cusps, muscular sinuses
- Red thrombi: contain more RBCs that accumulate on fibrin strands
- More dependent on coagulation factors than platelets
Describe examples of venous thrombosis
Venous thrombosis
- DVT of legs and arms
- Pulmonary embolus
- Portal vein thrombosis
- Cerebral sinus thrombosis
Compare arterial and venous thrombsis
Comparison
- Arterial thrombosis: rich in platelets (white clot), high shear, antiplatelet drugs are first-line
- Venous: mostly fibrin and trapped RBCs with fewer platelets (red clot), low shear, anticoagulants are first-line
Describe loss of function inherited thrombophilias
Loss of function inherited thrombophilias: loss of anticoagulant activity
- Protein C deficiency
- Protein S deficiency
- Antithrombin deficiency
Describe gain of function inherited thrombophilias
Gain of function inherited thrombophilias: procoagulant activity
- Factor V Leiden
- Prothrombin gene mutation 20210
- Increased clotting factor VIII
Factor V Leiden results from ____
Factor V Leiden results from a substitution in base 1691 position 506 resulting in glutamic acid instead of the normal arginine
Factor V Leiden mutation renders ___
Factor V Leiden mutation renders FVa relatively resistant to cleavage by APC
- Factor V Leiden does not function as a cofactor for the cleavage of FVIIIa by APC
- Persistence of activated factors V and VIII increases risk of thrombosis
Prevalence of heterozygous Factor V Leiden is ___ than that of homozygous Factor V Leiden
Prevalence of heterozygous Factor V Leiden is greater than that of homozygous Factor V Leiden
(overall most commonly found in Caucasians)
____ is the most common inherited thrombophilic mutation
Factor V Leiden is the most common inherited thrombophilic mutation
- Risk for venous thrombosis, arterial thrombosis, pregnancy complications
Prothrombin G20210A gene mutation results in ___
Prothrombin G20210A gene mutation results in gain of function inherited thrombophilia
- Heterozygous is more common than homozygous
- Most common in Caucasian population
Prothrombin G20210A gene mutation is ___
Prothrombin G20210A gene mutation is mutation in the promoter region of gene leading to an increase in prothrombin synthesis
Prothrombin G20210A gene mutation leads to ___
Prothrombin G20210A gene mutation leads to increased circulating levels of prothrombin (Factor II)
- Precursor to thrombin
- Protects factor Xa from antithrombin
- Higher levels of prothrombin result in greater inhibition of fibrinolysis by activating TAF
Elevated factor VII is a ___ inherited thrombophilia
Elevated factor VII is a gain of function inherited thrombophilia
- Found in top decile of population
- Baseline levels affected by role of FVIII as acute phase reactant
Describe quantitative vs qualitative loss of function thrombophilia
Quantitative vs qualitative loss of function thrombophilia
- Quantitative: reduced amounts of protein
- Qualitative: reduced functional activity, can have normal protein levels but abnormal function
- Both can cause reduced activity levels
Activated protein C ___
Activated protein C inactivates factors Va and VIIIa
Protein S is a ___
Protein S is a co-factor of APC
- Exists as a free form (1/3) and bound to C4b-binding protein (2/3): free is active form
Deficiencies of Protein C and Protein S shift balance toward ___
Deficiencies of Protein C and Protein S shift balance toward thrombosis
- Protein C and Protein S are natural anticoagulants
- Congenital: quantitative deficiency or qualitative loss
- Acquired: decreased synthesis, increased consumption, increase in C4BP and resultant decrease in free Protein S
Homozygous Protein C or S deficiency leads to ___
Homozygous Protein C or S deficiency leads to purpura fulminans
- Rare, life-threatening
- Characterized by extensive tissue thrombosis and hemorrhagic skin necrosis
Heterozygous Protein C or S deficiency leads to ___
Heterozygous Protein C or S deficiency leads to increased risk of first thrombosis
Protein C or Protein S deficiency confers risk for ____ upon initiation of warfarin
Protein C or Protein S deficiency confers risk for warfarin-induced skin necrosis upon initiation of warfarin
- Levels of protein C drop faster than other clotting factors inducing a transient hypercoagulable state
Homozygous antithrombin deficiency is ___
Homozygous antithrombin deficiency is fatal in utero
Antithrombin ____
Antithrombin binds to pentasaccharide sequence on heparin and proteoglycans, forming trimolecular complex that inactivates thrombin
Congenital mutations leading to antithrombin deficiency can be in ___
Congenital mutations leading to antithrombin deficiency can be in regions that inactivate thrombin or cause defects in heparin binding to decrease antithrombin deficiency
- Lose natural anticoagulant activity
Describe when acquired antithrombin deficiency occurs
Acquired antithrombin deficiency
- Prematurity
- Liver disease
- Nephrosis
- Malnutrition
- IBD
- L-asparaginase
- Estrogen therapy
Antithrombin deficiency leads to ___
Antithrombin deficiency leads to relative heparin resistance
Antiphospholipid antibody syndrome is ___
Antiphospholipid antibody syndrome is acquired
- can be primary or secondary
- Associated with arterial and venous thrombosis and pregnancy complications
Antiphospholipid antibody syndrome involves autoantibodies directed against ___ and ___
Antiphospholipid antibody syndrome involves autoantibodies directed against phospholipids and phospholipid binding proteins
- Lupus anticoagulant, anti-beta-2 glycoprotein antibody, and anti-cardiolipin antibody
- Precise pathogenesis resulting in clinical complications is unknown
Diagnosis of antiphospholipid antibody syndrome requires ____ and ____
Diagnosis of antiphospholipid antibody syndrome requires lab and clinical criteria
- Positive on 2 occasions separated by at least 12 weeks
Describe lupus anticoagulant testing process
Lupus anticoagulant testing
- Prolongation of clot based assay
- Does not correct with mixing study
- Phospholipid dependence
- Lupus anticoagulant positive
Lupus anticoagulant testing can be falsely positive in setting of ____
Lupus anticoagulant testing can be falsely positive in setting of anticoagulation
(UFH, warfarin, DOAC)
Polymorphisms in MTHFR gene may but do not necessarily ____ so ____ screen
Polymorphisms in MTHFR gene may but do not necessarily increase levels of homocysteine so do NOT screen
- Thermolabile variant present in 37% of Caucasians does not increase risk of venous thrombosis or pregnancy complications
Describe when to test for inherited thrombophilias
When to test for inherited thrombophilias
- Only if information obtained will influence management and outweigh potential risks of testing
- Timing of testing: proteins consumed during acute event, take weeks to return to baseline
- Testing can also be affected by anticoagulants
____ test for inherited thrombophilia if thrombosis occurs in the setting of a major transient risk factor
Do NOT test for inherited thrombophilia if thrombosis occurs in the setting of a major transient risk factor
