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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 l.jpg

Thrombophilia—Hypercoagulable States

Gabriel Shapiro, MD, FACP


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Risk Factors for Thrombosis

Acquired

thrombophilia

Hereditary

thrombophilia

Atherosclerosis

Thrombosis

Surgery

trauma

Immobility

Estrogens

Inflammation

Malignancy


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Risk Factors forVenous Thrombosis

  • Acquired

  • Inherited

  • Mixed/unknown


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Advancing age

Prior Thrombosis

Immobilization

Major surgery

Malignancy

Estrogens

Antiphospholipid antibody syndrome

Myeloproliferative Disorders

Heparin-induced thrombocytopenia (HIT)

Prolonged air travel

Risk Factors—Acquired


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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)


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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



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Prevalence of DefectsIn Patients with Venous Thrombosis

Thrombophilic DefectRel. Risk

Antithrombin deficiency 8 – 10

Protein C deficiency 7 – 10

Protein S deficiency 8 – 10

Factor V Leiden/APC resisance 3 – 7

Prothrombin 20210 A muation 3

Elevated Factor VIII 2 – 11

Lupus Anticoagulant 11

Anticardiolipin antibodies 1.6-3.2

Mild hyperhomocysteinemia 2.5


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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


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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


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Other Predictors for Recurrent VTE Thrombophilia Compared to VTE Without a Thrombophilic Defect

  • Idiopathic VTE

  • Residual DVT

  • Elevated D-dimer levels

  • Age

  • Sex


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FXII Thrombophilia Compared to VTE Without a Thrombophilic Defect

FXI

FVII

FIX

FVIII

FX

FV

Prothrombin

Thrombin

Fibrin Clot

Fibrinogen


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J Thromb. Haem Thrombophilia Compared to VTE Without a Thrombophilic Defect.1.525, 2003


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Antithrombin, Thrombophilia Compared to VTE Without a Thrombophilic DefectAntithrombin 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


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Protein C and Thrombophilia Compared to VTE Without a Thrombophilic DefectProtein 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


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Protein S, C4b Binding Protein, Thrombophilia Compared to VTE Without a Thrombophilic Defectand 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


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Causes of Acquired Protein S Deficiency Thrombophilia Compared to VTE Without a Thrombophilic Defect

  • 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


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Activated Protein C (APC) Resistance Thrombophilia Compared to VTE Without a Thrombophilic DefectDue 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


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J Thromb Haem 1. 525, 2003 Thrombophilia Compared to VTE Without a Thrombophilic Defect


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Prothrombin G20210A Mutation Thrombophilia Compared to VTE Without a Thrombophilic Defect

  • 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.


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Antiphospholipid Thrombophilia Compared to VTE Without a Thrombophilic DefectSyndrome


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Antiphospholipid Syndrome— Thrombophilia Compared to VTE Without a Thrombophilic DefectDiagnosis

  • Clinical Criteria

    -Arterial or venous thrombosis

    -Pregnancy morbidity

  • Laboratory Criteria

    -IgG or IgM anticardiolipin antibody-medium

    or high titer

    -Lupus Anticoagulant


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Antiphospholipid Syndrome— Thrombophilia Compared to VTE Without a Thrombophilic DefectClinical

  • Thrombosis—arterial or venous

  • Pregnancy loss

  • Thrombocytopenia

  • CNS syndromes—stroke, chorea

  • Cardiac valve disease

  • Livedo Reticularis


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Antiphospholipid Syndrome— Thrombophilia Compared to VTE Without a Thrombophilic DefectThe 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


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Antiphospholipid Syndrome— Thrombophilia Compared to VTE Without a Thrombophilic DefectAnticardiolipin Antibodies

  • ACAs are antibodies directed at a protein-phosholipid complex

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


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Antiphospholipid Syndrome— Thrombophilia Compared to VTE Without a Thrombophilic DefectTreatment

  • 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


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Heparin-Induced Thrombocytopenia Thrombophilia Compared to VTE Without a Thrombophilic Defect(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


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J Thromb Haem 1,1471, 2003 Thrombophilia Compared to VTE Without a Thrombophilic Defect


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Diagnosis of HIT Thrombophilia Compared to VTE Without a Thrombophilic Defect

  • 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


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Thrombophilia: Thrombophilia Compared to VTE Without a Thrombophilic DefectHow Do You DecideWho to Test?


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Site of Thrombosis vs. Coag. Defect Thrombophilia Compared to VTE Without a Thrombophilic Defect

AbnormalityArterialVenous

Factor V Leiden - +

Prothrombin G20210A - +

Antithrombin deficiency - +

Protein C deficiency - +

Protein S deficiency - +

Hyperhomocysteinemia + +

Lupus Anticoagulant + +


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Stratification of Thrombophilia Compared to VTE Without a Thrombophilic DefectPotentially Thombophilic Patients

Clinical History“Weekly” “Strongly”

Age of onset <50 - +

Recurrent thrombosis - +

Positive family history - +


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Testing for Hereditary Defects Thrombophilia Compared to VTE Without a Thrombophilic Defectin 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


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Clinical Implications Thrombophilia Compared to VTE Without a Thrombophilic Defect 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


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Screening Evaluation Thrombophilia Compared to VTE Without a Thrombophilic DefectFor “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


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Screening Laboratory Evaluation Thrombophilia Compared to VTE Without a Thrombophilic DefectFor “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


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Management of Patients Thrombophilia Compared to VTE Without a Thrombophilic DefectWith Thrombophilia

Risk Classification Management

High Risk

2 or more spontaneous events Indefinite 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 provocative Vigorous prophylaxis in

stimulus high-risk settings

Asymptomatic


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