ThrombophiliasSharon Sams

Objectives

Overview of etiology of hypercoagulability Available tests Clinical correlation or “What do I do with

these results?” Inconclusive conclusions: To test or not to

test…

Risk Factors: Acquired

Age: largest gradient of risk Malignancy: prevalence ranges from 3-18% Surgery:

Orthopedic surgery:30 - 50% Abdominal surgery: 30% With anticoagulants: 18%

Major trauma: 50-60% Immobilization

Risk Factors: Acquired

Oral contraceptives: 4 X increase in risk Hormonal replacement therapy: 2-4 X

increase Pregnancy and post-partum: 10 X increase Antiphospholipid antibodies: 10 X increase

Genetic causes of Thrombosis

Deficiencies of natural coagulation inhibitors Antithrombin, protein C, and Protein S

deficiencies; < 1% of the population Quantitative (type I): normal protein but

reduced quality Qualitative (Type II): Normal amounts of a

defective protein Heterozygote: Increased risk 10 X Homozygote: purpura fulminans

Genetic Causes: Factor V Leiden

Most common genetic defect causing thrombosis among Caucasians

Prevalence of carriers: 5 % Found in 15 % of patients with venous

thrombosis Causes thrombosis via resistance to activated

Protein C Heterozygote: Increased risk 3-8 X Homozygote: Increased risk 50-80 X; Found

in 1 per 5000 people in general population

Genetic causes of Thrombosis

Prothrombin G20210A Mutation Prevalence: 3% of Caucasians Increased risk 3 X

ABO Blood Group Non-O blood groups: 2-4 X increased risk Higher von Willebrand factor levels and higher

factor VIII levels

Plasma Abnormalities

Hyperhomocysteinemia Homozygous deficiency of cystathionine beta-synthase

(CS): Homocystinuria→ atherosclerosis, arterial disease and venous thrombosis

Mildly elevated homocystine: 5-10% of the population; Increased risk 2 X; usually due to low intake of folate, B6 or B12

High levels of clotting factors Elevated levels (above 90th percentile) of prothrombin,

Factor VIII, Factor IX, and Factor XI: Increased risk: 2-4 x

Multi-Casual Model

The thrombotic event is the result of gene- gene interaction and/or gene-environment interaction.

Variable RR Annual Incidence%

Normal 1 0.008

Hyperhomocysteinemia 2.5 0.02

Prothrombin G20210A 2.8 0.02

Oral contraceptives 4 0.03

Factor Leiden heterozygote 7 0.06

OCT and Factor Leiden 35 0.3

Factor Leiden homozygote 80 0.5-1

Lab evaluation

Timing: Acute thrombotic event or anticoagulation

therapy will affect the parameters of functional assays.

Wait 6 months after acute event 10 days after the discontinuation of oral

anticoagulation therapy

Lab testing: APC Resistance

APC Resistance Factor Leiden V: DNA analysis via PCR is the

gold standard Acquired APC: Paired PTT’s performed in the

presence and absence of exogenous activated Prot C; →dilute patient plasma with Factor V deficient plasma: specificity and sensitivity approach 100%

Lab Testing: Protein C, Protein S and Antithrombin DNA testing not available Functional assay to measure protein activity is the

initial screen– low specificity Antigenic assays are immunoassays that measure

the quantity of the protein Conditions that affect assay:

Negative influence: Oral anticoagulants, Vitamin K deficiency, liver disease, recent thrombosis, surgical

procedures, DIC, L- Asparaginase therapy, oral contraceptives, estrogen replacement therapy, pregnancy, elevated acute phase reaction, heparin and nephrotic syndrome

Lab Testing:

Prothrombin (G20210A) Mutation DNA test via PCR

Homocysteine Immunoassay methods

Coagulation Factors

Lab testing: Antiphospholipid antibodies Low specificity: clinical correlation required Solid phase antiphospholipid antibodies

Anticardiolipin Antibeta2glycoprotien I

Lupus anticoagulants Clotting time based assays such as Russell

viper venom test, kaolin clotting time, or PTT Improved sensitivity by use of two screening

tests

Current Treatment

Acute events: Management of acute thrombosis is the same for patients with and without inherited thrombophilia Anticoagulation with warfarin for 3-6 months

Secondary prophylaxis: No controlled trials have evaluated the

duration of anticoagulation in pts with hereditary thrombophilias thus no standard protocols.

Treatment Proposal I

Risk Classification ManagementHigh Risk Indefinite Anticoagulation Two or more spontaneous events One spontaneous life-threatening event One spontaneous event is association with

the antiphospholipid syndrome, antithrombin def

or more than one genetic or allelic abnormality

Moderate Risk Vigorous prophylaxis in high- risk setting

One event with a known provocative stimulus Asymptomatic

Association Studies

In patients presenting with a first venous thrombosis (adults) 5% have a deficiency of a natural

anticoagulant by phenotypic testing 15% Factor Leiden V deficiency 3-5% Prothrombin G20210A Mutation >70% have no inheritable abnormality

Risk of Reoccurrence

Two year cumulative incidence of recurrent thrombosis ~ 15%

Five year cumulative incidence of recurrent thrombosis ~ 25%

Early studies: 2-4 X increase in risk in Factor V Leiden carriers However these studies were small in number

and retrospective

Cambridge Venous Thromboembolism Study (CVTE) (2003) Two year Prospective Study:

570 patients Recurrence rate was 11%

Lowest incidence after surgery related VTE (0%) Highest incidence with unprecipitated VTE (19.4%)

85% of patients were tested for heritable thrombophilic defects→ recurrence rates were not related to presence or absence of heritable thrombophilia.

CONCLUSION: Thrombophilia testing had no predictive value for reoccurrence (hazard ration 1.5 [95% CI 0.82-2.77]; p=0.187)

Baglin et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. The Lancet 2003, (362):523-526.

Leiden Thrombophilia study (LETS) JAMA 2005 Prospective follow up study of LETS pts

447 patients followed for a mean of 7.3 years Incidence rate of recurrence was highest during the

first two years: annual rate of 3.2%; cumulative recurrence of 12.4% at 5 years

Risk of recurrence was 2.7 x higher in men than women (95% CI , 1.8-4.2)

Higher risk of recurrence with idiopathic initial VTE Lower risk of recurrence with provoked initial VTE OCT use during follow up had a higher recurrence rate

(28 per 1000 pt-yrs vs 12.9 per 1000 pt-yrs)

Copyright restrictions may apply.

Christiansen, S. C. et al. JAMA 2005;293:2352-2361.

Recurrence Rates by Sex and Type of First Thrombotic Event

Copyright restrictions may apply.

Christiansen, S. C. et al. JAMA 2005;293:2352-2361.

Recurrence Rates by Oral Contraceptive Use in 215 Women Between 16 and 55 Years

Copyright restrictions may apply.

Christiansen, S. C. et al. JAMA 2005;293:2352-2361.

Recurrence Rates for Prothrombotic Laboratory Abnormalities in 474 Patients

Leiden Thrombophilia study (LETS) JAMA 2005 Conclusion:

Hazard ratios calculated for reoccurrence according to individual defect → no defects were associated with a statistically significant hazard ratio

Clinical factors (male sex, use of OCT’s, idiopathic initial VTE) have a more significant role in risk of reoccurrence than lab abnormalities

Multi-causal disease. Combined defects at greater risk of reoccurrence?

Candidates for screening(Stefano et al 2002) All patients with venous thromboembolism,

independent of the age of onset, the circumstances and the severity

Cancer pts may be excluded Women with complications of a pregnancy All asymptomatic individuals who are a first degree

relative of a diagnosed carrier of a thrombophilic trait Asymptomatic women with a family history of venous

thromboembolism prior to use of oral contraceptives, HRT or pregnancy

Candidates for screening(Baglin 2004) Patient presents with first thromboembolism

Family history? If positive, testing is recommended Clinical circumstances- surgery or cancer? Testing not

indicated Clinical circumstance not associated with surgery or

cancer-acquired antiphospholipid activity is recommended

Screening asymptomatic relatives has no clinical utility Annual absolute incidence of venous

thromboembolism was very low

References:

1. Baglin T, Management of Thrombophilia: Who to Screen? Pathophysiol Haemost Thromb 2003/2004;33:401-404

2. Bauer KA, The Thrombophilias: Well defined risk factors with uncertain therapeutic implications. Ann Intern Med. 2001;135:367-373

3. Christiansen et al. Thrombophilia, Clinical Factors, and Recurrent Venous Thrombotic Events. JAMA 2005;293:2352-2361

4. Tripodi A, Laboratory diagnosis of thrombophilic states: where do we stand? Pathophysiol Haemost Thromb, 2002;32:245-248

5. Bauer et al. Hypercoagulability: Too many test, Too much conflicting data. Hematology 2002; 353-368

6. Stefanoe et al. Screeninf for inherited thrombophilia: indications and therapeutic implications. Haematologica 2002;87:1095-1108

7. Henry. Clinical Diagnosis and Management by Laboratory Methods. 20th ed. 2001 W.B. Saunders Co. Philadelphia

8. Baglin et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. The Lancet 2003, (362):523-526.