Hypercoagulable states
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Hypercoagulable States. Hypercoagulable States. Acquired versus inherited “Provoked” vs idiopathic VTE Who should be tested for inherited thrombophilia ? What tests should be done & when? Anticoagulation recommendations Should family members be tested?. Virchow’s triad.

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Hypercoagulable states1
Hypercoagulable States

  • Acquired versus inherited

  • “Provoked” vs idiopathic VTE

  • Who should be tested for inherited thrombophilia?

  • What tests should be done & when?

  • Anticoagulation recommendations

  • Should family members be tested?

Was vte provoked
Was VTE “provoked”?

  • Medical and surgical history

  • Medications

  • Travel – air & ground

  • Review of systems

  • Cancer screening history

Was vte provoked1
Was VTE “provoked”?

  • Physical exam – including breast exam, rectal exam, pelvic exam for females, prostate exam for males

  • Age-appropriate cancer screening – MMG, Pap smear, colonoscopy, PSA

  • Do not recommend CT scans, etc.

  • Chest x-ray is reasonable

Was vte provoked2
Was VTE “provoked”?

  • CBC with diff

  • CMP

  • Urinalysis

  • Fecal occult blood test

Inherited thrombophilia
Inherited thrombophilia

  • Factor V Leiden (2.2)

  • Prothrombin gene mutation (2.8)

  • Protein C deficiency (7.3)

  • Protein S deficiency (8.5)

  • Antithrombin III deficiency (8.1)

  • Acquired – antiphospholipid antibody syndrome (APS)

Who to test
Who to test

  • <45 years old with unprovoked venous or arterial thromboembolic disease

  • >2 idiopathic thrombotic episodes

  • Thrombosis in unusual site

  • VTE & strong family history of VTE

  • History of recurrent fetal loss

  • ? VTE in reproductive age female

Unusual sites
Unusual sites

  • Cerebral veins

  • IVC, renal veins

  • Mesenteric veins

  • Portal and hepatic veins

Recurrent fetal loss
Recurrent fetal loss

  • Unexplained death at >10 weeks gestation–morphologically normal

  • Three or more 1st-trimester pregnancy losses without an intercurrent term pregnancy

Who to test1
Who to test

  • What about a strong family history without personal history of VTE?

  • Test affected family member first

  • If history is very suggestive of inherited thrombophilia and there is no affected family member alive to be tested – needs appropriate counseling

Hypercoagulable work up
Hypercoagulable Work-up

  • “Hypercoag panel”

    -Protein C, protein S, AT III (functional)

    -Lupus anticoagulant

    -APC resistance

  • Factor V Leiden (if APC resistance low)

  • Prothrombin gene mutation

  • Anticardiolipin antibodies

Timing of tests
Timing of tests

  • Factor V Leiden and prothrombin mutation can be checked at any time

  • Wait at least 4-6 weeks after acute event to check lupus anticoagulant and cardiolipin antibodies (or later)

  • Most efficient to check all other tests >2 weeks after course of anticoagulation is completed

Timing of tests1
Timing of Tests

  • In setting of acute VTE, proteins C & S and AT III may be decreased

  • Cardiolipin antibodies may be present as an acute phase reactant

  • Heparin interferes with AT III activity and lupus anticoagulant assays

  • Coumadin lowers proteins C & S

Timing of tests2
Timing of Tests

  • In acute phase, if protein C or S is normal, that test does not need to be repeated

  • Some evidence that coumadin may increase AT III levels – if AT III is at low end of normal range, then test needs to be repeated off coumadin

  • Never need to repeat FVL or PTM test

Antiphospholipid antibody syndrome aps
Antiphospholipid Antibody Syndrome (APS)

  • Clinical criteria: One or more episodes of venous, arterial, or small vessel thrombosis and/or morbidity with pregnancy

  • Laboratory criteria: Presence of anti-phospholipid antibodies on 2 or more occasions at least 12 weeks apart and <5y prior to clinical manifestations

Aps clinical criteria
APS Clinical Criteria

  • Imaging or histologic evidence of thrombosis in any tissue or organ

  • Fetal death at >10 wks gestation

  • Premature birth before 34 weeks because of eclampsia, preeclampsia or placental insufficiency

  • >3 pregnancy losses <10 weeks

Aps laboratory criteria
APS Laboratory Criteria

  • Positive lupus anticoagulant

  • Moderate or high titer IgG and/or IgManticardiolipin antibodies

  • IgG or Ig M antibodies to beta2-glycoprotein-1

  • On two or more occasions at least 12 weeks apart

Antiphospholipid antibody syndrome
Antiphospholipid Antibody Syndrome

  • VTE

  • Stroke, white matter lesions

  • MI, nonbacterial endocarditis

  • Renal failure

  • Thrombocytopenia, TTP/HUS

Livedo reticularis

Catastrophic aps
Catastrophic APS

  • Involvement of 3 or more organs, systems, or tissues

  • Develop simultaneously or in <1 week

  • Histopathologic evidence of small vessel occlusion

  • Presence of antiphospholipid antibodies

    Asherson et al., Lupus, 2003, 12:530

Catastrophic aps1
Catastrophic APS

  • Treatment of underlying illness

  • Heparin acutely then warfarin

  • High dose steroids

  • Plasma exchange +/- IVIG if there is evidence of TTP/HUS

  • For survivors, lifelong warfarin


  • Low molecular weight heparin acutely until INR therapeutic for 2 days

  • Warfarin for 3-6 months

  • INR 2.0-3.0

  • For idiopathic DVT or inherited thrombophilia can discuss prolonged therapy – delays risk of recurrence

What is this why does it happen
What is this? Why does it happen?

Warfarin skin necrosis
Warfarin skin necrosis

  • Protein C deficiency

  • Vitamin K dependent protein with relatively short half-life

  • Start warfarin after full heparinization documented by PTT or anti-Xa assay

  • Start at a low dose (2 mg a day) then gradually increase

Warfarin skin necrosis1
Warfarin skin necrosis

  • Stop warfarin

  • Give vitamin K

  • Heparinize

  • Consider protein C administration (FFP, protein C concentrate)

  • Can retreat with warfarin in setting of protein C administration

At iii deficiency
AT III deficiency

  • Sometimes show resistance to heparin

  • May require larger doses

  • Consider antithrombin concentrate

    -Unusually severe thrombosis

    -Recurrent thrombosis in setting of adequate anticoagulation

    -Inability to adequately anticoagulate

Discussion of lifelong anticoagulation
Discussion of lifelong anticoagulation

  • Recurrent idiopathic VTE

  • Idiopathic life-threatening VTE

  • Antiphospholipid antibody syndrome (with persistently elevated antibodies)

  • Antithrombin III deficiency

  • Homozygous or compound heterozygous defects

Inherited thrombophilia surgical prophylaxis
Inherited thrombophilia & surgical prophylaxis

  • Consider as “high risk” group

  • Exception may be Factor V Leiden – prophylaxis based on risk of surgery

  • AT III deficiency – could consider antithrombin concentrate (retrospective & case reports only)

Inherited thrombophilia and pregnancy
Inherited thrombophilia and pregnancy

  • Anticoagulate during pregnancy and 6 weeks post-partum

  • AT III deficiency, homozygous FVL or PTM, compound heterozygotes

  • Personal history of VTE or strong family history of VTE use therapeutic dose, otherwise prophylactic dose

Inherited thrombophilia and pregnancy1
Inherited thrombophilia and pregnancy

  • Heterozygous FVL or PTM, protein C or S deficiency

  • Prophylaxis if personal history of VTE

  • Consider if 1st degree relative with VTE at age <50

  • If no prior history of VTE then only postpartum prophylaxis if C-section

Should family members be tested
Should family members be tested?

  • Need to be counseled on how result will be used

  • Females of reproductive age

  • Protein C deficiency

  • If there is more than one inherited thrombophilia in the family

  • Usually we do

When to refer to hematology
When to refer to Hematology

  • Inherited thrombophilia with VTE

  • Recurrent idiopathic VTE without inherited thrombophilia

  • Contemplating lifelong anticoagulation

  • Patient request