1. Hypercoagulable Syndromes

2. Risk Factors For Venous Thrombosis ACQUIREDINHERITEDMIXED/UNKNOWN Advancing ageAntithrombin Deficiency  Homocysteine ObesityProtein C Deficiency  Factor VIII Prior thrombosisProtein S DeficiencyAPC resistance ImmobilizationFactor V Leiden (FVL) in the absence Major surgeryProthrombin G20210A of FVL MalignancyDysfibrinogenemias  Factor IX Estrogens (rare)  Factor XI (OCP, HRT, SERMs)  TAFI Antiphospholipid  Free TFPI antibody syndrome  fibrinolytic activity Myeloproliferative disorders IBD, Nephrotic syndrome Heparin-induced thrombocytopenia Prolonged air travel

3. VTE Risk Factor Model Intrinsic Thrombosis Risk Acquired Risk FactorsGenes ++ VTE Triggering Factors Prophylaxis + – Thrombosis Threshold Anticoagulant deficiencies Factor V Leiden Prothrombin 20210A Age Previous VTE Cancer Obesity Estrogens Pregnancy Surgery Immobilization from Folsom A

4. CASCADE The Protein C Pathway From Esmon CT

5. Prothrombin Gene Mutation G  A Mutation at Position 20210 in 3´- UT Region GENOTYPEPROTHROMBINRANGE 20210 AG 132%95-178 20210 GG 105%55-156 From Poort et al, Blood 1996 Mutation leads to increased efficiency of prothrombin mRNA 3’-end formation and increased prothrombin biosynthesis without affecting the rate of transcription.

7. Prevalence of Defects in Patients with Venous Thrombosis APC Resistance (Factor V Leiden)12-40% Hyperhomocysteinemia 10% Prothrombin Gene Mutation 6-18% Deficiencies of AT, Protein C, Protein S 5-15% Antiphospholipid Antibody Syndrome 5-10% Unknown15-70%

8. The “Hypercoagulable Workup” Genetic test for Factor V Leiden mutation or coagulation assay for Activated Protein C Resistance (if abnormal, confirm genetically) Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin* Functional assay of Protein C* Protein S assays* Functional assay Measurements of total and free Protein S Tests for Antiphospholipid Antibody Syndrome ± Measurement of fasting plasma homocysteine (hcy) level ± Factor VIII Coagulant Activity Level *Can omit in patients with a first VTE at age > 50 and a negative family history

9. Hcy lowering by B-vitamin supplements does not lower risk of recurrent thrombosis Arterial Thrombosis NORVIT Trial (N Eng J Med 2006) 3,479 patients with acute MI Trend toward increased risk with combined B vitamin treatment HOPE 2 Investigators (N Eng J Med 2006) 5,522 patients > age 55 with vascular disease or diabetes Venous Thrombosis VITRO Study (Bos GMJ, et al. ASH Abstract 2004) Patients ages 20-80 with unprovoked proximal DVT or PE Recurrences: 43/348 vitamins, 50/353 placebo

10. Antiphospholipid Antibody Syndrome (APLS) A clinical diagnosis characterized by a thrombotic event (venous or arterial thrombosis, recurrent fetal loss) in association with a persistent LA in specialized clotting assays or persistently elevated titers of cardiolipin (IgG or IgM) or  2 -glycoprotein I antibodies Clinical manifestations include thrombocytopenia, and livedo reticularis. Associated with SLE, cancer, infections, drugs, idiopathic

11. Antiphospholipid Antibody Syndrome (APLS) LA result from the presence of immunoglobulins which bind to phospholipids and plasma proteins (  2- glycoprotein 1, prothrombin) in vitro and prolong clotting times (critically dependent on the amount of phospholipid in assay). LA do not cause bleeding, but confer an increased risk for recurrent thrombosis. Retrospective studies indicated that patients with APLS require a target INR range of >3 to obtain adequate antithrombotic protection. Two randomized trials have shown that an INR of 2-3 is adequate in patients with venous thrombosis.

12. Venous Thromboembolism in Cancer Common (~20% of all patients with VTE) Increased risk of recurrent VTE Can occur with an adequate INR (“warfarin resistance”) Increased risk of bleeding during anticoagulant therapy Rx: Consider chronic low molecular weight heparin

13. multicenter, randomized, open-label study Initial Rx 6 months R Cancer patients with proximal DVT, PE or both dalteparin OAC dalteparin CLOT in Cancer Trial Lee A. New Eng J Med 2003

14. Recurrent VTE 0 5 10 15 20 25 Days Post Randomization 0306090120150180210 Probability of Recurrent VTE, % risk reduction = 52% p-value = 0.0017 dalteparin OAC

15. 0 10 20 30 40 50 60 70 80 90 100 Days Post Randomization 0306090120180240300360 dalteparin OAC Probability of Survival, % 12-month Mortality All patients HR 0.94 (0.77 – 1.1) P-value = 0.40

16. 0 10 20 30 40 50 60 70 80 90 100 0306090120180240300360 OAC dalteparin 12-month Mortality Patients without metastases Probability of Survival, % Days Post Randomization HR 0.5 (0.27 – 0.95) P-value = 0.03

17. Prandoni 1992 0.012 0.043 0.04 <0.001 40 30 20 10 0 Idiopathic Secondary Cancer incidence % Monreal 1991 Monreal 1993 Bastounis 1996 Detection of malignancy in the patient presenting with thrombosis

18. Evaluation for malignancy in the patient presenting with thrombosis Available data do not support an extensive search for occult malignancy; it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age- appropriate screening tests have been performed.

19. Sites of Thrombosis ABNORMALITYARTERIALVENOUS Factor V Leiden - + Prothrombin 20210A - + AT Deficiency - + Protein C Deficiency - + Protein S Deficiency - + Hyperhomocysteinemia + + Lupus Anticoagulant + +

20. Acquired Deficiencies in Antithrombin, Protein C, or Protein S ANTITHROMBINPROTEIN CPROTEIN SPregnancy Liver DiseaseLiver DiseaseLiver Disease DICDICDIC Nephrotic syndrome Major surgeryInflammation Acute thrombosisAcute thrombosisAcute thrombosis TREATMENT WITH: HeparinWarfarinWarfarinEstrogens

21. Protein S Deficiency PROTEIN S ANTIGENPS TYPETOTALFREEACT ILowLowLow IINormalNormalLow IIINormalLowLow

22. Prevalence of the Factor V Leiden (FVL) and Prothrombin G20210A Mutations POPULATIONFVL (%)G20210A (%) European Northern 5-10 1.7 Southern 2-3 3 African EXTREMELY RARE Asian

23. Leiden Thrombophilia Study: A Population Based Study Koster T et al, Lancet 1993 Patients: Inclusion Criteria Consecutive outpatients < age 70 referred for warfarin treatment to thrombosis centers with a first DVT Laboratory evaluation > 3 months after discontinuation of oral anticoagulants Patients: Exclusion Criteria Malignancy Controls: Healthy matched unrelated subjects

24. First Episode of Deep Venous Thrombosis (Leiden Thrombophilia Study) RISK Normal 1 Prothrombin 20210A 2.8  heterozygotes Oral contraceptives 4x  Factor V Leiden 7x  heterozygotes Oral contraceptives 35x  + Factor V Leiden Factor V Leiden 80x  Homozygotes

25. First Episode of Deep Venous Thrombosis (Leiden Thrombophilia Study) INCIDENCE/YEAR (%) Normal0.008 Oral contraceptives 0.03 Factor V Leiden 0.06 heterozygotes Oral contraceptives0.3 + Factor V Leiden Factor V Leiden0.5 - 1 Homozygotes

26. Should we screen women for factor V Leiden prior to starting OCPs? If all women with factor V Leiden did not take OCPs, their risk of VTE would decrease from 30 to 6 VTE events per 10,000 women/year.  prevent 1 event per 417 women To find 417 women with factor V Leiden, you would have to screen 6,770 women given a prevalence of 6%. Costs of screening exceed benefits.

27. Hereditary Thrombophilia and Obstetric Complications Significantly increased risk for second and third trimester fetal loss (~3-fold  ) Conflicting data regarding association with other obstetric complications Few randomized trials of anticoagulant therapy

28. Treatment of DVT/PE Heparin Unfractionated or Low Molecular Weight Heparin for at least 5 days Warfarin Start on day 1 to achieve INR of 2-3, treat for 3-6 months

29. Recurrent Venous Thrombosis is Common Following a First Episode of Symptomatic DVT Cumulative Incidence (%) Years Prandoni et al, Ann Intern Med 1996;125:1-7

30. Risk of Recurrent Venous Thrombosis in Patients with Hereditary Thrombophilia Heterozygosity for Factor V Leiden (FVL) or Prothrombin (PT) G20210A do not increase risk. Higher in heterozygotes with both FVL and PT G20210A (retrospective studies); probably higher in homozygotes with FVL Antithrombin, Protein C, Protein S Deficiency High in selected kindreds with strong clinical penetrance (retrospective studies) Little data in unselected patients

31. Factors Influencing Duration of Anticoagulation Recurrent VTE Risk ( % / year)~10% Consequences (case fatality)0.5% Bleeding Risk ( % / year)~2% Consequences (case fatality)0.4%

32. Guidelines on Duration of Anticoagulant Therapy First event with reversible or time limited risk factor 3-6 months at INR 2-3 Unprovoked VTE, first or second event 6 months at INR 2-3, then consider indefinite anticoagulation at INR 2-3 weighing recurrence versus bleeding risk Special Situations - indefinite anticoagulation First event with Cancer until resolved (consider chronic LMWH) Antiphospholipid antibody syndrome Antithrombin deficiency or multiple genetic defects, ? deficiencies of protein C or protein S

33. Guidelines on Anticoagulant Therapy RISK CLASSIFICATIONMANAGEMENT Moderate-risk 1 event with a stimulusVigorous prophylaxis Asymptomaticin high-risk settings

34. Criteria for Long-Term Oral Anticoagulation in Patients with Venous Thrombosis Resolution of triggering risk factor Sites and severity of thrombosis Bleeding risk Identification of a prothrombotic defect coupled with family’s thrombotic history PATIENT PREFERENCE (role of lifestyle and occupation)

35. 6 months After Initial Anticoagulation Accept the risk of recurrence Extend in all patients Extend with new strategies Extend in high-risk patients

36. D-dimer and Recurrent VTE (PREVENT) Warfarin, INR 1.5-2Placebo

37. Testing for Hereditary Defects in Patients with Thrombosis and No Family History PRO Improve understanding of pathogenesis of VTE Identify and counsel affected family members CON Infrequently Identify patients with defects carrying specific management implications (multiple defects are uncommon) Potential for overaggressive management of propositus and asymptomatic affected relatives Negative insurance implications Cost of testing/consultations

38. Thrombophilia and Recurrent VTE Leiden Thrombophilia Study (JAMA 2005) Conclusions “Prothrombotic abnormalities do not appear to play an important role in the risk of a recurrent thrombotic event. Testing for prothrombotic defects has little consequence with respect to prophylactic strategies. Clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.”