1. Hypercoagulable States

2. Acquired versus inherited Acquired versus inherited “Provoked” vs idiopathic VTE “Provoked” vs idiopathic VTE Who should be tested for inherited thrombophilia? Who should be tested for inherited thrombophilia? What tests should be done & when? What tests should be done & when? Anticoagulation recommendations Anticoagulation recommendations Should family members be tested? Should family members be tested?

3. Virchow’s triad

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

5. Was VTE “provoked”? Physical exam – including breast exam, rectal exam, pelvic exam for females, prostate exam for males Physical exam – including breast exam, rectal exam, pelvic exam for females, prostate exam for males Age-appropriate cancer screening – MMG, Pap smear, colonoscopy, PSA Age-appropriate cancer screening – MMG, Pap smear, colonoscopy, PSA Do not recommend CT scans, etc. Do not recommend CT scans, etc. Chest x-ray is reasonable Chest x-ray is reasonable

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

7. Inherited thrombophilia Factor V Leiden (2.2) Factor V Leiden (2.2) Prothrombin gene mutation (2.8) Prothrombin gene mutation (2.8) Protein C deficiency (7.3) Protein C deficiency (7.3) Protein S deficiency (8.5) Protein S deficiency (8.5) Antithrombin III deficiency (8.1) Antithrombin III deficiency (8.1) Acquired – antiphospholipid antibody syndrome (APS) Acquired – antiphospholipid antibody syndrome (APS)

8. Who to test <45 years old with unprovoked venous or arterial thromboembolic disease <45 years old with unprovoked venous or arterial thromboembolic disease >2 idiopathic thrombotic episodes >2 idiopathic thrombotic episodes Thrombosis in unusual site Thrombosis in unusual site VTE & strong family history of VTE VTE & strong family history of VTE History of recurrent fetal loss History of recurrent fetal loss ? VTE in reproductive age female ? VTE in reproductive age female

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

10. Recurrent fetal loss Unexplained death at >10 weeks gestation–morphologically normal Unexplained death at >10 weeks gestation–morphologically normal Three or more 1st-trimester pregnancy losses without an intercurrent term pregnancy 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? What about a strong family history without personal history of VTE? Test affected family member first 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 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” “Hypercoag panel” -Protein C, protein S, AT III (functional) -Lupus anticoagulant -APC resistance Factor V Leiden (if APC resistance low) Factor V Leiden (if APC resistance low) Prothrombin gene mutation Prothrombin gene mutation Anticardiolipin antibodies Anticardiolipin antibodies

13. Timing of tests Factor V Leiden and prothrombin mutation can be checked at any time 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) 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 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 In setting of acute VTE, proteins C & S and AT III may be decreased Cardiolipin antibodies may be present as an acute phase reactant Cardiolipin antibodies may be present as an acute phase reactant Heparin interferes with AT III activity and lupus anticoagulant assays Heparin interferes with AT III activity and lupus anticoagulant assays Coumadin lowers proteins C & S 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 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 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 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 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 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 Imaging or histologic evidence of thrombosis in any tissue or organ Fetal death at >10 wks gestation Fetal death at >10 wks gestation Premature birth before 34 weeks because of eclampsia, preeclampsia or placental insufficiency Premature birth before 34 weeks because of eclampsia, preeclampsia or placental insufficiency >3 pregnancy losses 3 pregnancy losses <10 weeks

18. APS Laboratory Criteria Positive lupus anticoagulant Positive lupus anticoagulant Moderate or high titer IgG and/or IgM anticardiolipin antibodies Moderate or high titer IgG and/or IgM anticardiolipin antibodies IgG or Ig M antibodies to beta2- glycoprotein-1 IgG or Ig M antibodies to beta2- glycoprotein-1 On two or more occasions at least 12 weeks apart On two or more occasions at least 12 weeks apart

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

20. Livedo reticularis

21. Catastrophic APS Involvement of 3 or more organs, systems, or tissues Involvement of 3 or more organs, systems, or tissues Develop simultaneously or in <1 week Develop simultaneously or in <1 week Histopathologic evidence of small vessel occlusion Histopathologic evidence of small vessel occlusion Presence of antiphospholipid antibodies Presence of antiphospholipid antibodies Asherson et al., Lupus, 2003, 12:530

22. Catastrophic APS Treatment of underlying illness Treatment of underlying illness Heparin acutely then warfarin Heparin acutely then warfarin High dose steroids High dose steroids Plasma exchange +/- IVIG if there is evidence of TTP/HUS Plasma exchange +/- IVIG if there is evidence of TTP/HUS For survivors, lifelong warfarin For survivors, lifelong warfarin

23. Anticoagulation Low molecular weight heparin acutely until INR therapeutic for 2 days Low molecular weight heparin acutely until INR therapeutic for 2 days Warfarin for 3-6 months Warfarin for 3-6 months INR 2.0-3.0 INR 2.0-3.0 For idiopathic DVT or inherited thrombophilia can discuss prolonged therapy – delays risk of recurrence 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 Protein C deficiency Vitamin K dependent protein with relatively short half-life Vitamin K dependent protein with relatively short half-life Start warfarin after full heparinization documented by PTT or anti-Xa assay Start warfarin after full heparinization documented by PTT or anti-Xa assay Start at a low dose (2 mg a day) then gradually increase Start at a low dose (2 mg a day) then gradually increase

26. Warfarin skin necrosis Stop warfarin Stop warfarin Give vitamin K Give vitamin K Heparinize Heparinize Consider protein C administration (FFP, protein C concentrate) Consider protein C administration (FFP, protein C concentrate) Can retreat with warfarin in setting of protein C administration Can retreat with warfarin in setting of protein C administration

27. AT III deficiency Sometimes show resistance to heparin Sometimes show resistance to heparin May require larger doses May require larger doses Consider antithrombin concentrate 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 Recurrent idiopathic VTE Idiopathic life-threatening VTE Idiopathic life-threatening VTE Antiphospholipid antibody syndrome (with persistently elevated antibodies) Antiphospholipid antibody syndrome (with persistently elevated antibodies) Antithrombin III deficiency Antithrombin III deficiency Homozygous or compound heterozygous defects Homozygous or compound heterozygous defects

29. Inherited thrombophilia & surgical prophylaxis Consider as “high risk” group Consider as “high risk” group Exception may be Factor V Leiden – prophylaxis based on risk of surgery Exception may be Factor V Leiden – prophylaxis based on risk of surgery AT III deficiency – could consider antithrombin concentrate (retrospective & case reports only) AT III deficiency – could consider antithrombin concentrate (retrospective & case reports only)

30. Inherited thrombophilia and pregnancy Anticoagulate during pregnancy and 6 weeks post-partum Anticoagulate during pregnancy and 6 weeks post-partum AT III deficiency, homozygous FVL or PTM, compound heterozygotes 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 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 Heterozygous FVL or PTM, protein C or S deficiency Prophylaxis if personal history of VTE Prophylaxis if personal history of VTE Consider if 1 st degree relative with VTE at age <50 Consider if 1 st degree relative with VTE at age <50 If no prior history of VTE then only postpartum prophylaxis if C-section 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 Need to be counseled on how result will be used Females of reproductive age Females of reproductive age Protein C deficiency Protein C deficiency If there is more than one inherited thrombophilia in the family If there is more than one inherited thrombophilia in the family Usually we do Usually we do

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

34. Questions?