Kevin P. Hubbard, DO, FACOI

Clinical Professor of MedicineKansas City University of Medicine and Biosciences-College of Osteopathic

MedicineKansas City, Missouri

ThrombophiliaThrombophiliaDiagnosis and ManagementDiagnosis and Management

Thrombophilia

• Hereditary and acquired risk factors for thrombosis

• Venous thromboembolism• Arterial thromboembolism• Pregnancy complications

Virchow’s Triad1850

FactorsContributing

toThrombosis

Vessel WallDamage

Altered Blood Flow(Stasis)

Blood Coagulability

Factor V LeidenProthrombin 20210AProtein C deficiencyProtein S deficiencyAntithrombin deficiency

Antiphospholipid antibodiesMalignancyImmobilizationSurgeryPregnancyEstrogenHyperhomocysteinemiaHeparin-induced thrombocytopenia

AcquiredProthrombotic

Stimulus

One or moreInherited

ProthromboticMutation(s)

Thrombosis

After Schafer

Prevalence of Hereditary Risk Factorsin Venous Thromboembolism (VTE)

Asymptomatic Unselected FamilialMutation (N) Controls VTE VTEFactor V Leiden (1) 4% 20% 45%Prothrombin 20210A (1) 2% 6% 18%Protein C (>160) 0.8% 3% 6%Protein S (>13) 0.5% 1% 6%Antithrombin (>80) 0.2% 1% 4%

(All Autosomal Dominant)

Factor V Leiden

•Most common hereditary risk factor for venous thrombosis

•Present in 4% of Caucasian population

•Caused by a point mutation in Factor V(R506Q)

•Poor anticoagulant response to activated protein C (APC Resistance)

The Protein C Anticoagulant Pathway

Blood Flow

Thrombomodulin

Protein C

APC

Anticoagulationdownstream

ThrombinThrombin

Thrombus

Thrombusat site of injury

VIIIai

The Protein C Anticoagulant Pathway

Blood Flow

VIIIaVa

Thrombus

Vai

APC APCPS

PS

Factor V Leiden

1 2 3 4 50

1

2

3

APC (µg/ml)

APTTRatio

Control

Factor V Leiden

Activated Protein C Resistance

Prothrombin Gene Mutation

• Second most common hereditary risk factor for venous thrombosis

• Present in 2% of Caucasian population

• Caused by a point mutation (G20210A) in the 3’ UTR of prothrombin gene

• Elevated levels of prothrombin in plasma

Antithrombin Deficiency

• Antithrombin (also called AT III) inhibits thrombin, factor Xa and other clotting factors

• Activity enhanced by heparin• Risk factor for venous thrombosis,

especially during pregnancy

Risk Factor Relative RiskGeneral population 1Heterozygous factor V Leiden 5Heterozygous prothrombin 20210A 5Protein C deficiency ∼10Protein S deficiency ∼10Antithrombin deficiency ∼20Homozygous factor V Leiden ∼80

Influence of Hereditary Risk Factors on Probability of First

DVT or PE

Age (years)0 20 40 60 80

Thro

mbo

sis-

free

Sur

viva

l (%

)

0

20

40

60

80

100 general population (RR=1)

heterozygous FVL (RR=5)

protein C def (RR=10)

antithrombin def (RR=20)

homozygous FVL (RR=80)

Influence of Hereditary Risk Factors on Probability of First

DVT or PE

After Miletich (1998)Semin Thromb Hemost

Risk Factor Relative RiskGeneral population 1Hyperhomocysteinemia 2Estrogen therapy 4Active cancer ~7Lupus anticoagulant

or antiphospholipid antibody ~10

Influence of Acquired Risk Factors on Probability of First

DVT or PE

Hyperhomocysteinemia

• Elevated level of homocysteine in plasma• Multiple causes

Genetic factors – uncommonNutritional factors (folate, B12, B6) – commonRenal dysfunction – common

• Cardiovascular disease, stroke, peripheral vascular disease

• Neural tube defects• Dementia

Treatment of Hyperhomocysteinemia

•Folic acid

•Other B vitamins (B12, B6)

•Methionine restriction

Foltx®

Antiphospholipid Antibodies

Clinically-Important APLA

AnticardiolipinAntibodies

LupusAnticoagulants

Clinically Important Antiphospholipid

Antibodies

•High titer (>30 GPL or MPL)anticardiolipin antibodies (IgG or IgM)

•Lupus anticoagulant

•Systemic lupus erythematosus or lupus-like syndrome

Management of Patients with Antiphospholipid

Antibodies•Chronic anticoagulation not necessary if no

history of thrombosis•Long-term anticoagulation with warfarin after first thrombotic event

Target INR 2-3 (hematologists)Target INR 3-4 (rheumatologists)•Some antiphospholipid antibodies interfere

with INR (may need higher target INR or alternative method to monitor anticoagulation)

Risk Factor Relative RiskGeneral population 1Hyperhomocysteinemia 2Heterozygous factor V Leiden 5Hyperhomocysteinemia

and heterozygous factor V Leiden 20

Influence of Combinations of Risk Factors on Probability of First

DVT/PE

Risk Factor Relative RiskGeneral population 1Oral contraceptives 4Heterozygous factor V Leiden 5Oral contraceptives and

heterozygous factor V Leiden 35

Influence of Combinations of Risk Factors on Probability of First DVT

or PE

Influence of Oral Contraceptives and Factor V Leiden on Probability

of First DVT or PE

Age (years)15 20 25 30 35 40

Thro

mbo

sis-

free

Sur

viva

l (%

)

80

90

100 general population (RR=1)oral contraceptives (RR=4)pregnancy (RR=10)

oral contraceptives andheterozygous FVL (RR=35)

Hereditary Risk Factors andArterial Thrombosis (Stroke or MI)

Risk Factor Relative RiskHeterozygous Factor V Leiden 1Heterozygous Prothrombin 20210A 1Protein S deficiency 1Protein C deficiency 1Antithrombin deficiency 1

Possible exception: young patients, especially in association with smoking or hypertension

• Fibrinogen• Lipoprotein (a)• Factor VIII• Von Willebrand factor• Thrombomodulin• Heparin Cofactor II• Factor XII

Other Putative Risk Factors(Not Ready for Prime Time)

• GPIa C807T• GPIIIa PLA2• PAI-1 4G/5G• D-dimer• TFPI• MTHFR• Protein Z

Laboratory Testing for Thrombophilia

• Factor V Leiden• Prothrombin 20210A gene mutation• Anticardiolipin antibodies• Lupus anticoagulant workup• Plasma total homocysteine• Antithrombin

(not reliable in patients receiving heparin)

Other Tests to ConsiderOther Tests to Considerin Convalescent Periodin Convalescent Period

• Protein C• Protein S• These tests are not reliable in acute

setting or in patients receiving warfarin

Rationale for Thrombophilia Testing

• Prophylactic anticoagulation during high risk situations (surgery, pregnancy, immobilization)

• Extended duration of anticoagulation after a thrombotic event

Antiphospholipid antibodyAntithrombin deficiencyTwo or more thrombophilic alleles(Factor V Leiden, Prothrombin 20210A, Protein C deficiency, Protein S deficiency)

• Family genetic counseling

Relative RiskTemporary risk factor 1Heterozygous factor V Leiden 2Homozygous factor V Leiden 4Antiphospholipid antibody 4Unprovoked DVT or PE 8Recurrent DVT or PE 8Active Cancer 8

Probability of RecurrenceAfter First DVT or PE

RecurrentDVT/PE

(%)

Days300100 200

unprovoked

temporary risk factor

30

10

20

warfarin

Recurrence after First DVT or PE

Levine et al. Thromb Haemost 1995; 74:606

Years

Rec

urre

nce

(%)

1 2 3

10

20

303 months (INR 2-3)

Indefinite (INR 2-3)

12 months (INR 2-3)

Indefinite (INR 1.5-2)

Duration of Anticoagulation forFirst Unprovoked DVT

My Approach to Prevention ofMy Approach to Prevention ofRecurrent Venous ThromboembolismRecurrent Venous Thromboembolism

• Low Risk (anticoagulate for 6 weeks to 3 months)Superficial venous thrombosisSecondary DVT or PE

• Intermediate Risk (anticoagulate for at least 3 to 6 months; consider indefinite anticoagulation at INR 1.5-2 or 2-3)

Unprovoked DVT or PEUnprovoked DVT or PE with one genetic risk factor

• High Risk (anticoagulate indefinitely at target INR 2-3)Recurrent unprovoked DVT or PELife-threatening venous thrombosisUnprovoked DVT or PE with antiphospholipid antibody,

two or more genetic risk factors, or active cancer

References

Kearon et al. Management of patients with hereditary hypercoagulable disorders. Annu Rev Med 51:169-185, 2000

Kupferminc, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. New Eng J Med340:9-13, 1999

Gerhardt, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the peurperium. New Eng J Med 342:374-380, 2000

Gordy et al. American College of Medical Genetics Consensus Statement on Factor V Leiden mutation testing. Genetics in Medicine 3:139-148, 2001

Ridker et al. Long-term low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. New Eng J Med 348:1425-1434, 2003

Lopez et al. Deep venous thrombosis. American Society of Hematology Education Book, 2004