Hypercoagulable States

1. Hypercoagulable States

2. 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?

3. Virchow’s triad

4. Was VTE “provoked”? • Medical and surgical history • Medications • Travel – air & ground • Review of systems • Cancer screening history

5. 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

6. Was VTE “provoked”? • CBC with diff • CMP • Urinalysis • Fecal occult blood test

7. 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)

8. 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

9. Unusual sites • Cerebral veins • IVC, renal veins • Mesenteric veins • Portal and hepatic veins

10. Recurrent fetal loss • Unexplained death at >10 weeks gestation–morphologically normal • Three or more 1st-trimester pregnancy losses without an intercurrent term pregnancy

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. Antiphospholipid Antibody Syndrome • VTE • Stroke, white matter lesions • MI, nonbacterial endocarditis • Renal failure • Thrombocytopenia, TTP/HUS

20. Livedoreticularis

21. 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

22. 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

23. 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

24. What is this? Why does it happen?

25. 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

26. 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

27. 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

28. 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

29. 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)

30. 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

31. 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

32. 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

33. When to refer to Hematology • Inherited thrombophilia with VTE • Recurrent idiopathic VTE without inherited thrombophilia • Contemplating lifelong anticoagulation • Patient request

34. Questions?