Hereditary or acquired conditions associated with a tendency for thrombosis

HEMOSTATIC BALANCE IN THROMBOPHILIA

FIBRINOLYSIS

COAGULATION

HEREDITARY THROMBOPHILIC CONDITIONS

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

ACQUIRED THROMBOPHILIC CONDITIONS

Major surgery Immobilization Cancer Estrogens Antiphospholipid antibodies Myeloproliferative disorders Hyperhomocysteinemia Heparin-induced thrombocytopenia Prolonged air travel

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

DVT Deep vein thrombosis

Pulmonary Emboli

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

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

Should be suspected in anyone who:

Presents with an unprovoked venous or arterial thromboembolic disease at <45 yrs 2 or more thrombotic episodes in the absence of a risk factor for thrombosis History of objectively confirmed idiopathic thrombosis in firstdegree relative Thrombosis in an unusual site
Mesenteric veins, dural sinus

Neonatal thromobosis or stroke History of recurrent fetal loss

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

ESTIMATED PREVALENCE OF HEREDITARY THROMBOPHILIC CONDITIONS IN CAUCASIANS

POPULATION PROTEIN C DEFICIENCY PROTEIN S ANTITHROMBIN DEFICIENCY DEFICIENCY FV LEIDEN G20210A MUTATION

Normal

0.3

0.3

0.04

Consecutive patients with first VTE Relative risk of first VTE

16

10

10

25

2.5

PREVALENCE OF FACTOR V LEIDEN AND PROTHROMBIN G20210A MUTATIONS IN VARIOUS POPULATIONS

POPULATION

FACTOR V LEIDEN

G20210A

% EUROPEAN NORTHERN SOUTHERN AFRICAN/ASIAN

5-10 2-3 <1

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

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

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

Prothrombin G20210A Mutation

A Vitamin K-dependant protein synthesized in the liver Due to substitution of adenine for guanine Results in 30% higher prothrombin levels
This promotes generation of thrombin and impairs inactivation of Factor Va by APC

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 deficiency Warfarin induced skin necrosis

Seen in heterozygotes when giving large loading doses of warfarin and heparin not given concomitantly Occurs within days of starting therapy and develops over fatty tissue (thigh, buttocks, breasts) or extremities Begins as a painful erythematous lesion and leads to necrosis Occurs because of the shorter half life of Protein C verses the other vitamin K-dependent proteins As a result, protein C levels decrease rapidly once warfarin therapy has been initiated (reduced to 50% of normal within one day)
This effect is even more pronounce in Protein C deficiency

Protein C is lost before the anticoagulant effects of warfarin are established and thrombosis develops

Protein C deficiency Warfarin induced skin necrosis

Treatment: stop warfarin, give heparin, Vitamin K, protein C concentrate Can restart warfarin once skin lesions resolve, restart in low doses and give with heparin

Histopathologically, will see fibrin deposition within the blood vessels

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

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

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

Antithrombin III Deficiency

A vitamin K-independent protein that works inhibit thrombin Prevalence: 1:2000-1:5000 persons 30% of heterozygotes develop a thrombosis by 30yrs, 65% by age 50yrs Homozygous deficiency is almost always incompatible with life 60% will have recurrent thrombosis
Risk of thrombosis is particularly high in pregnancy Heparin prophylaxis recommended throughout pregnancy and coumadin for 6 weeks postpartum

Methylenetetrahydropholate reductase (MTHFR)

Homozygotes: increased homocysteine levels Heterozygotes: normal homocysteine levels 12%- asymptomatic 2-fold increased risk of venous thrombosis (controversial) Risk factor for MI (controversial)


43, ..., Acute Inferoposterior MI :
FV FII MTHFR Anticardiolipin Circulating anticoagulant - 8.02; ? APL syndrome

Antiphospholipid Syndrome (APL)

Frequency of APL Ab in the general population: 310% (Thromb Haemost 1997, 77:444) Clinical manifestations: Venous (DVT + PE 55%) and arterial thrombosis (CVA + TIA 50%; MI 25%) Recurrent pregnancy loss Laboratory findings: Ab against phospholipids (PL)-binding proteins: 2GP1, (FII, annexin 5) APL Ab increase the risk for VTE 9-fold (Blood 1995 85:3685)

Hypercoaguable workup
APC resistance screen
Clotting assay, then confirm with a genetic test

Prothrombin G20210A mutation

Genetic test (PCR)

Functional assay for Protein C + S, antithrombin III deficiency

Heterozygous deficiencies are from many different mutations and abnormalities Measure both free and total Protein S Affected by acute thrombosis and anticoagulation, so check levels at least 2 weeks after completing therapy

Anticardiolipin and lupus anticoagulant clotting assay

Testing should be done at least 2 weeks after completion of anticoagulation

Approach to the Diagnosis and Treatment of Thrombophilia in Patients with Venous Thrombosis

Seligsohn U and Lubetsky A. N Engl J Med 2001;344:1222-1231

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

SITES OF THROMBOSIS IN VARIOUS THROMBOPHILIC CONDITIONS

THROMBOPHILIC CONDITION VENOUS ARTERIAL

Protein C deficiency Protein S deficiency Antithrombin deficiency Factor V leiden Prothrombin G20210A Hyperhomocysteinemia Lupus anticoagulant

+ + + + + + +

+ +

DO HEREDITARY THROMBOPHILIC CONDITIONS INCREASE THE RISK OF RECURRENT VTE?

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

1-2 4 1-2 2-5 2-4

ASSUMPTIONS INFLUENCING DURATION OF ANTICOAGULATION

Annual risk of recurrent VTE if anticoagulant treatment is stopped is 10%, of which 0.5% are fatal Annual risk of major bleeding is 2%, of which 0.4% are fatal

FACTORS THAT INFLUENCE DURATION OF ANTICOAGULATION

Site and severity of thrombosis (PE tends to recur as PE and DVT recurs as DVT)
Bleeding risk

Identification of a prothrombotic defect coupled with family history of thrombosis

Patient preference

DURATION OF ANTICOAGULATION AS A FUNCTION OF RISK FACTOR

RISK FACTORS DURATION

TRANSIENT IDIOPATHIC CONTINUING

3 MONTHS (OR LESS) 6 MONTHS (OR LONGER) UNTIL RISK FACTOR RESOLVES

DURATION OF ANTICOAGULANT THERAPY

SYMPTOMATIC VTE

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

AT LEAST 12 MONTHS, OR INDEFINITE

3 MONTHS, OR UNTIL RISK FACTORS HAVE RESOLVED

SCREENING FOR THROMBOPHILIA

Who should be screened?

WHO SHOULD BE SCREENED?

Clinical features highly suggestive of thrombophilia thrombosis at a young age positive family history recurrent thrombosis
Diagnosis of thrombophilia will alter management of patients or their relatives