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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
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
anticoagulation
Anticoagulation
  • 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
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
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