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Hypercoagulable Syndromes

Hypercoagulable Syndromes. Risk Factors For Venous Thrombosis. ACQUIRED INHERITED MIXED/UNKNOWN Advancing age Antithrombin Deficiency  Homocysteine Obesity Protein C Deficiency  Factor VIII Prior thrombosis Protein S Deficiency APC resistance

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Hypercoagulable Syndromes

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  1. Hypercoagulable Syndromes

  2. Risk Factors For Venous Thrombosis ACQUIRED INHERITED MIXED/UNKNOWN Advancing age Antithrombin Deficiency Homocysteine Obesity Protein C Deficiency Factor VIII Prior thrombosis Protein S DeficiencyAPC resistance Immobilization Factor V Leiden (FVL) in the absence Major surgery Prothrombin G20210A of FVL Malignancy Dysfibrinogenemias  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 Genes Acquired Risk Factors + + • • Anticoagulant deficiencies • • Factor V Leiden • Prothrombin 20210A • Age • Previous VTE • Cancer • Obesity Intrinsic Thrombosis Risk Triggering Factors • Estrogens • Pregnancy • Surgery • Immobilization + Prophylaxis – Thrombosis Threshold VTE from Folsom A

  4. The Protein C Pathway CASCADE From Esmon CT

  5. Prothrombin Gene MutationG  A Mutation at Position 20210 in 3´- UT Region GENOTYPE PROTHROMBIN RANGE 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.

  6. 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% Unknown 15-70%

  7. 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

  8. 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

  9. 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

  10. 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.

  11. 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

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

  13. Recurrent VTE risk reduction = 52% p-value = 0.0017 25 20 OAC Probability of Recurrent VTE, % 15 10 dalteparin 5 0 0 30 60 90 120 150 180 210 Days Post Randomization

  14. 100 90 80 70 60 50 40 30 20 10 0 12-month Mortality All patients dalteparin Probability of Survival, % OAC HR 0.94 (0.77 – 1.1) P-value = 0.40 0 30 60 90 120 180 240 300 360 Days Post Randomization

  15. 12-month Mortality Patients without metastases 100 dalteparin 90 80 70 OAC 60 Probability of Survival, % 50 40 30 20 HR 0.5 (0.27 – 0.95) P-value = 0.03 10 0 0 30 60 90 120 180 240 300 360 Days Post Randomization

  16. 40 30 20 10 0 Detection of malignancy in the patient presenting with thrombosis Idiopathic 0.04 Cancer incidence % Secondary 0.012 0.043 <0.001 Monreal 1991 Prandoni 1992 Monreal 1993 Bastounis 1996

  17. 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.

  18. Sites of Thrombosis ABNORMALITY ARTERIAL VENOUS Factor V Leiden - + Prothrombin 20210A - + AT Deficiency - + Protein C Deficiency - + Protein S Deficiency - + Hyperhomocysteinemia + + Lupus Anticoagulant + +

  19. Acquired Deficiencies in Antithrombin,Protein C, or Protein S ANTITHROMBIN PROTEIN C PROTEIN S Pregnancy Pregnancy Liver Disease Liver Disease Liver Disease DIC DIC DIC Nephrotic syndrome Major surgery Inflammation Acute thrombosis Acute thrombosis Acute thrombosis TREATMENT WITH: Heparin WarfarinWarfarin Estrogens Estrogens

  20. Protein S Deficiency PROTEIN S ANTIGEN PS TYPE TOTAL FREE ACT I Low Low Low II Normal Normal Low III Normal Low Low

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

  22. 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

  23. 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

  24. First Episode of Deep Venous Thrombosis(Leiden Thrombophilia Study) INCIDENCE/YEAR (%) Normal 0.008 Oral contraceptives 0.03 Factor V Leiden 0.06 heterozygotes Oral contraceptives 0.3 + Factor V Leiden Factor V Leiden 0.5 - 1 Homozygotes

  25. 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.

  26. Hereditary Thrombophilia andObstetric 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

  27. 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

  28. 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

  29. 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

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

  31. 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

  32. Guidelines on Anticoagulant Therapy RISK CLASSIFICATION MANAGEMENT • Moderate-risk • 1 event with a stimulus Vigorous prophylaxis • Asymptomatic in high-risk settings

  33. 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)

  34. After Initial Anticoagulation Accept the riskof recurrence 6 months Extendwith newstrategies Extend inhigh-risk patients Extend inall patients

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

  36. 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

  37. Thrombophilia and Recurrent VTELeiden 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.”

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