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FIBRINOLYSIS
COAGULATION
DECREASED ANTICOAGULANT PROTEINS Antithrombin deficiency Protein C deficiency Protein S deficiency INCREASED PROCOAGULANT PROTEINS Factor V Leiden Prothrombin gene mutation (G20210A) Increased levels of factors VIII, IX, XI
Venous Thromboembolism
Most common presentation is DVT of the lower extremity and PE A risk factor for thromboembolism is found in 80% of patients Often more than one factor at play Divided into hereditary and acquired
Pulmonary Emboli
Inherited Thrombophilias
In the recent past, a genetic cause for thrombophilia was detected in only 5-15% of patients
Limited to antithrombin gene deficiency, protein C+S deficiency, dysfibrogenemia 1993: Discovered Factor V gene mutation (Factor V Leiden) 1996: Discovered the prothrombin G20210A gene mutation
Inherited thrombophilias are most common in Caucasians, rare in African or Asian In all comers with DVT, the incidence of inherited thrombophilias is 24- 37% Of Caucasian patients who present with initial symptomatic DVT, 12-20% are heterozygous for factor V Leiden and 6% heterozygous for prothrombin G20210A mutation
Inherited Thrombophilias
Inherited hypercoaguable states
A genetic tendency for venous thromboembolism
Inherited thrombophilias
Will often present with DVT or PE More than 50% of cases, thrombosis is provoked by surgery, pregnancy, immobilization, OCP, HRT, or old age Recurrent venous thrombosis is highest in deficiency of antithrombin, protein C, protein S, greater than one inherited thrombophilia, homozygous for factor V Leiden
Those heterozygous for factor V Leiden and prothrombin gene mutation have not been shown to have a higher rate of recurrent venous thrombosis verses the general population
Normal
0.3
0.3
0.04
16
10
10
25
2.5
POPULATION
FACTOR V LEIDEN
G20210A
2 3 <1
Major Mechanisms Involved in the Normal Control of Coagulation and Inherited Thrombophilias
In inherited thrombophilias, thrombosis is most often Seligsohn U and Lubetsky A. N Engl J Med caused by impaired neutralization 2001;344:1222-1231 of thrombin or failure to control the generation of thrombin
Factor V Leiden
Factor V is activated to Va, which acts as a cofactor in the conversion of prothrombin to thrombin Normally, Factor Va is degraded by APC and limits prothrombin conversion to thrombin Arginine is replaced by Glutamine (Arg506Gln) on the factor V gene, resulting in a protein called factor V Leiden Factor V Leiden is less susceptible to inactivation by APC and is now considered resistant to APC
This results in a prothrombotic state
Factor V Leiden
Most common - 40-50% of inherited thrombophilias
Found in 5% of the Caucasian population
Found in 10-20% of patients with first episode of idiopathic DVT Found in 50% of patients with recurrent DVT 90-95% of those with factor V Leiden are heterozygous
Homozygotes have a more severe course
Acquired forms of APC resistance found in pregnancy, use of OCPs, elevated Factor VIII or those with antiphospholipid antibodies
Factor V Leiden
Anticoagulation therapy
Long term therapy not recommended in heterozygotes
At no higher risk of recurrent thrombosis than those without the mutation
In homozygotes, should use prophylaxis in high risk settings Heterozygous, pregnant women with no history of thrombosis are at low risk for thrombosis
Anticoagulation is not recommended Recommendations differ if have a history of thrombosis or if Pt is homozygous
Found in 2% of the Caucasian population Seen in 6-10% of patients presenting with first episode of unprovoked DVT Like with factor V Leiden, there is no increased risk of recurrent DVT in those with the mutation
Protein C deficiency
Vitamin K-dependant protein made by the liver Many different gene mutations are found on the Protein C gene Among those with mutations on the Protein C gene, levels of Protein C vary widely
Some heterozygotes actually have normal levels
Homozygotes manifest shortly after birth with neonatal purpura fulminans Heterozygotes are prone to venous thrombosis, but not at increased risk for arterial thrombosis
Protein C is lost before the anticoagulant effects of warfarin are established and thrombosis develops
Protein S Deficiency
Vitamin K-dependant protein Circulates as both a free protein (40%) and bound C4b-binding protein (60%), which is part of the classic complement system
Only free Protein S can act as a cofactor to APC for the inhibition of Factors Va and VIIIa
C4b is increased in acute phase reactions, causing free Protein S to be decreased Like in Protein C deficiency, homozygous patients present soon after birth with neonatal purpura fulminans
Protein S Deficiency
Decreased levels of Protein S in Liver disease Renal disease Women especially those on OCPs or pregnant IBD Neonates, infants 50% of heterozygotes experience DVT by 35yrs May have atypical presentation: migraine headache, mesenteric vein thrombosis
43, ..., Acute Inferoposterior MI :
FV FII MTHFR Anticardiolipin Circulating anticoagulant - 8.02; ? APL syndrome
Hypercoaguable workup
APC resistance screen
Clotting assay, then confirm with a genetic test
Approach to the Diagnosis and Treatment of Thrombophilia in Patients with Venous Thrombosis
Review
Thrombosis due to acquired and inherited causes:
**Factor V Leiden
Less susceptible to inhibition of APC Resistant to APC
**Prothrombin gene mutation Protein C deficiency Protein S deficiency Antithrombin III deficiency
Protein C deficiency Protein S deficiency Antithrombin deficiency Factor V leiden Prothrombin G20210A Hyperhomocysteinemia Lupus anticoagulant
+ + + + + + +
+ +
RELATIVE RISK OF RECURRENT VTE AFTER STOPPING ANTICOAGULANT THERAPY WITH VARIOUS THROMBOPHILIC CONDITIONS
THROMBOPHILIC CONDITION Protein C, protein S, or antithrombin deficiency Factor V Leiden (heterozygous) Factor V Leiden (homozygous) G20210A (heterozygous) Factor V Leiden and G20210A Antiphospholipid Antibody RELATIVE RISK 1-3
3 MONTHS (OR LESS) 6 MONTHS (OR LONGER) UNTIL RISK FACTOR RESOLVES
IDIOPATHIC
THROMBOPHILIA
RISK FACTORS
HETEROZYGOUS FV LEIDEN
HOMOZYGOUS FV LEIDEN ANTITHROMBIN, PROTEIN TRANSIENT CONTINUING C OR S DEFICIENCY ANTIPHOSPHOLIPID ANTIBODY INDEFINITE, OR AT LEAST 6 MONTHS IF RISK FACTORS RESOLVE
AT LEAST 6 MONTHS FOR FIRST EPISODE; INDEFINITE FOR TWO OR MORE EPISODES