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Thrombophilia— Hypercoagulable States. Gabriel Shapiro, MD, FACP. Risk Factors for Thrombosis. Acquired thrombophilia. Hereditary thrombophilia. Atherosclerosis. Thrombosis. Surgery trauma. Immobility. Estrogens. Inflammation. Malignancy. Risk Factors for Venous Thrombosis .

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Thrombophilia— Hypercoagulable States

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Thrombophilia—Hypercoagulable States

Gabriel Shapiro, MD, FACP


Risk Factors for Thrombosis

Acquired

thrombophilia

Hereditary

thrombophilia

Atherosclerosis

Thrombosis

Surgery

trauma

Immobility

Estrogens

Inflammation

Malignancy


Risk Factors forVenous Thrombosis

  • Acquired

  • Inherited

  • Mixed/unknown


Advancing age

Prior Thrombosis

Immobilization

Major surgery

Malignancy

Estrogens

Antiphospholipid antibody syndrome

Myeloproliferative Disorders

Heparin-induced thrombocytopenia (HIT)

Prolonged air travel

Risk Factors—Acquired


Risk Factors—Inherited

  • Antithrombin deficiency

  • Protein C deficiency

  • Protein S deficiency

  • Factor V Leiden mutation (Factor V-Arg506Gln)

  • Prothrombin gene mutation (G A transition at position 20210)

  • Dysfibrinogenemias (rare)


Risk Factors—Mixed/Unknown

  • Hyperhomocysteinemia

  • High levels of factor VIII

  • Acquired Protein C resistance in the absence of Factor V Leiden

  • High levels of Factor IX, XI


Genetic Thrombophilic Defects Influence the Risk of a First Episode of Thrombosis


Prevalence of DefectsIn Patients with Venous Thrombosis

Thrombophilic DefectRel. Risk

Antithrombin deficiency8 – 10

Protein C deficiency7 – 10

Protein S deficiency8 – 10

Factor V Leiden/APC resisance3 – 7

Prothrombin 20210 A muation3

Elevated Factor VIII2 – 11

Lupus Anticoagulant11

Anticardiolipin antibodies1.6-3.2

Mild hyperhomocysteinemia2.5


Risk vs. Incidence ofFirst Episode of Venous Thrombosis

RiskIncidence/year (%)

Normal 1.008

Oral Cont. Pills 4x.03

Factor V Leiden 7x.06

(heterozygote)

OCP + Factor V L. 35x.3

Factor V Leiden 80x.5-1

homozygotes


Risk of Recurrent Venous Thromboembolism (VTE) in Thrombophilia Compared to VTE Without a Thrombophilic Defect

Thrombophilic DefectRel. Risk

Antithrombin, protein C, 2.5

or protein S deficiency

Factor V Leiden mutation 1.4

Prothrombin 20210A mutation 1.4

Elevated Factor VIII:c 6 – 11

Mild hyperhomocysteinemia 2.6 – 3.1

Antiphospholipid antibodies 2 – 9


Other Predictors for Recurrent VTE

  • Idiopathic VTE

  • Residual DVT

  • Elevated D-dimer levels

  • Age

  • Sex


FXII

FXI

FVII

FIX

FVIII

FX

FV

Prothrombin

Thrombin

Fibrin Clot

Fibrinogen


J Thromb. Haem.1.525, 2003


Antithrombin,Antithrombin Deficiency

  • Also known as Antithrombin III

  • Inhibits coagulation by irreversibly binding the thrombogenic proteins thrombin (IIa), IXa, Xa, XIa and XIIa

  • Antithrombin’s binding reaction is amplified 1000-fold by heparin, which binds to antithrombin to cause a conformational change which more avidly binds thrombin and the other serine proteases


Protein C andProtein C Deficiency

  • Protein C is a vitamin K dependent glycoprotein produced in the liver

  • In the activation of protein C, thrombin binds to thrombomodulin, a structural protein on the endothelial cell surface

  • This complex then converts protein C to activated protein C (APC), which degrades factors Va and VIIIa, limiting thrombin production

  • For protein C to bind, cleave and degrade factors Va and VIIIa, protein S must be available

  • Protein C deficiency, whether inherited or acquired, may cause thrombosis when levels drop to 50% or below

  • Protein C deficiency also occurs with surgery, trauma, pregnancy, OCP, liver or renal failure, DIC,or warfarin


Protein S, C4b Binding Protein,and Protein S Deficiency

  • Protein S is an essential cofactor in the protein C pathway

  • Protein S exists in a free and bound state

  • 60-70% of protein S circulates bound to C4b binding proten

  • The remaining protein S, called free PS, is the functionally active form of protein S

  • Inherited PS deficiency is an autosomal dominant disorder, causing thrombosis when levels drop to 50% or lower


Causes of Acquired Protein S Deficiency

  • May be due to elevated C4bBP, decreased PS synthesis, or increased PS consumption

  • C4bBP is an acute phase reactant and may be elevated in inflammation, pregnancy, SLE, causing a drop in free PS

  • Functional PS activity may be decreased in vitamin K deficiency, warfarin, liver disease

  • Increased PS consumption occurs in acute thrombosis, DIC, MPD, sickle cell disease


Activated Protein C (APC) ResistanceDue to Factor V Leiden

  • Activated protein C (APC) is the functional form of the naturally occurring, vitamin K dependent anticoagulant, protein C

  • APC is an anticoagulant which inactivates factors Va and VIIIa in the presence of its cofactor, protein S

  • Alterations of the factor V molecule at APC binding sites (such as amino acid 506 in Factor V Leiden) impair, or resist APC’s ability to degrade or inactivate factor Va


J Thromb Haem 1. 525, 2003


Prothrombin G20210A Mutation

  • A G-to-A substitution in nucleotide position 20210 is responsible for a factor II polymorphism

  • The presence of one allele (heterozygosity) is associated with a 3-6 fold increased for all ages and both genders

  • The mutation causes a 30% increase in prothrombin levels.


Antiphospholipid Syndrome


Antiphospholipid Syndrome—Diagnosis

  • Clinical Criteria

    -Arterial or venous thrombosis

    -Pregnancy morbidity

  • Laboratory Criteria

    -IgG or IgM anticardiolipin antibody-medium

    or high titer

    -Lupus Anticoagulant


Antiphospholipid Syndrome—Clinical

  • Thrombosis—arterial or venous

  • Pregnancy loss

  • Thrombocytopenia

  • CNS syndromes—stroke, chorea

  • Cardiac valve disease

  • Livedo Reticularis


Antiphospholipid Syndrome—The Lupus Anticoagulant (LAC)

  • DRVVT- venom activates F. X directly;

    prolonged by LAC’s

  • APTT- Usually prolonged, does not correct in 1:1 mix

  • Prothrombin Time- seldom very prolonged


Antiphospholipid Syndrome—Anticardiolipin Antibodies

  • ACAs are antibodies directed at a protein-phosholipid complex

  • Detected in an ELISA assay using plates coated with cardiolipin and B2-glycoprotein


Antiphospholipid Syndrome—Treatment

  • Patients with thrombosis- anticoagulation, INR 3

  • Anticoagulation is long-term—risk of thrombosis is 50% at 2 years after discontinuation

  • Women with recurrent fetal loss and APS require LMW heparin and low-dose heparin during their pregnancies


Heparin-Induced Thrombocytopenia(HIT)

  • HIT is mediated by an antibody that reacts with a heparin-platelet factor 4 complex to form antigen-antibody complexes

  • These complexes bind to the platelet via its Fc receptors

  • Cross-linking the receptors leads to platelet aggregation and release of platelet factor 4 (PF4)

  • The released PF4 reacts with heparin to form heparin-PF4 complexes, which serve as additional sites for HIT antibody binding


J Thromb Haem 1,1471, 2003


Diagnosis of HIT

  • Diagnosis made on clinical grounds

  • HIT usually results in thrombosis rather than bleeding

  • Diagnosis should be confirmed by either immunoassay (ELISA) or functional tests (14C serotonin release assay)

  • Treatment involves cessation of heparin, treatment with an alternative drug, e.g. argatroban, and switching to warfarin


Thrombophilia:How Do You DecideWho to Test?


Site of Thrombosis vs. Coag. Defect

AbnormalityArterialVenous

Factor V Leiden - +

Prothrombin G20210A - +

Antithrombin deficiency - +

Protein C deficiency - +

Protein S deficiency - +

Hyperhomocysteinemia + +

Lupus Anticoagulant + +


Stratification of Potentially Thombophilic Patients

Clinical History“Weekly”“Strongly”

Age of onset <50 - +

Recurrent thrombosis - +

Positive family history - +


Testing for Hereditary Defectsin Patients With ThrombosisWith No Family History

Pro

Improve understanding of pathogenesis of thrombosis

Identify and counsel affected family members

Obviate expensive diagnostic testing (e.g. CT scans) looking for a malignancy

Con

Infrequent identification of patients with defects whose management would change

Potential for overaggressive management

Insurance implications

Cost of testing


Clinical Implications In Treatment of Thrombophilia

  • Routine screening of patients with VTE for an underlying thrombophilic defect “is not justified”

  • However, the risk of subsequent thrombosis over 5 years in men with idiopathic VTE is 30%

  • Any additional defect adds to risk and to possible need for prolongation of anticoagulation

  • Furthermore, women with a history of VTE who wish to become pregnant will be treated differently if a defect were found


Screening EvaluationFor “Strongly Thrombophilic” Patients

  • Test for Factor V Leiden

  • Genetic test for prothrombin gene mutation 20210A

  • Functional assay of antithrombin

  • Functional assay of protein C

  • Functional assay of protein S

  • Clotting test for lupus anticoagulant/ELISA for cardiolipin antibodies

  • Measurement of fasting total plasma homocysteine


Screening Laboratory EvaluationFor “Weekly Thrombophilic” Patients

  • Test for Factor V Leiden

  • Genetic test for prothrombin gene mutation G20210A

  • Measurement of fasting total plasma homocysteine

  • Clotting assay for lupus anticoagulant/ELISA for cardiolipin antibodies


Management of PatientsWith Thrombophilia

Risk ClassificationManagement

High Risk

2 or more spontaneous eventsIndefinite Anticoagulation

1 spontaneous life-threatening

event (near-fatal pulmonary

embolus, cerebral, mesenteric,

portal vein thrombosis)

1 spontaneous event in association

with antiphospholipid antibody

syndrome, antithrombin deficiency,

or more than 1 genetic defect

Moderate Risk

1 event with a known provocativeVigorous prophylaxis in

stimulus high-risk settings

Asymptomatic


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