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Thrombophilia

Thrombophilia. Acquired or inherited tendency toward accelerated thrombosis. Hemophilia is to Hemophiliac as Thrombophilia is to ………? THROMBOPHILIAC?. Prevalence of thrombophilia. Relative risk of first episode DVT. APLA 20 Antithrombin deficiency 20

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Thrombophilia

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  1. Thrombophilia • Acquired or inherited tendency toward accelerated thrombosis

  2. Hemophilia is to Hemophiliac as • Thrombophilia is to ………? • THROMBOPHILIAC?

  3. Prevalence of thrombophilia

  4. Relative risk of first episode DVT • APLA 20 • Antithrombin deficiency 20 • Protein C deficiency (Hetero) 10 • Protein S deficiency 10 • Homozygous Factor V Leiden 80 • Heterozygous Factor V Leiden 7 • Elevated FVIII 5 • Prothrombin gene mutation 20210 3 • Homocystenemia 3 • OBCP 4 • OBCP and heterozygous Factor V 35

  5. ? XII XIIa

  6. XII XIIa XI XIa

  7. XII XIIa XI XIa IX IXa

  8. XII XIIa TENASE Complex XI XIa IX IXa Ca++ VIIIa PL VIII X Xa

  9. XII XIIa XI XIa Tissue Factor VIIa VII IX IXa X Xa

  10. XII XIIa XI XIa IX IXa X Xa

  11. XII XIIa XI XIa PROTHROMBINASE Complex IX IXa X Xa Ca++ Va PL Va II IIa (Thrombin)

  12. XII XIIa XI XIa Thrombin is the central bioregulatory enzyme in hemostasis IX IXa X Xa Ca++ Va PL Va II IIa (Thrombin)

  13. vWF(ADAMST13) XII XIIa Platelets PARS 1 &4 XI XIa IX IXa X Xa VIIIa II IIa (Thrombin) Va I Ia (Fibrin) XIIIa XIII TAFI Cross-linked Ia (Fibrin) Pro-thrombotic actions of THROMBIN

  14. XII XIIa XI XIa Tissue Factor VIIa VII IX IXa X Xa VIII VIIIa II IIa (Thrombin) V Va I Ia (Fibrin) XIIIa XIII Cross-linked Ia (Fibrin)

  15. Anti-thrombotic actions of ECs • Binding of thrombin to thrombomodulin • Activation of protein C • Release of tPA • Prostacyclin

  16. ECPR TM Activated Protein C Thrombin Protein C

  17. XII XIIa XI XIa Tissue Factor VIIa VII IX IXa aPC Vac X Xa aPC VIII VIIIa aPC II IIa (Thrombin) V Va I Ia (Fibrin) (PS and FV are cofactors for aPC)

  18. XII XIIa XI XIa Tissue Factor VIIa VII IX IXa X Xa aPC VIII VIIIa aPC II IIa (Thrombin) V Va I Ia (Fibrin) Plasmin Plasminogen tPA EC PAR1

  19. XII XIIa Tissue Factor XI XIa VIIa VII IX IXa aPC X Xa VIII VIIIa II IIa (Thrombin) V LEIDEN Va I Ia (Fibrin) FV Leiden is NOT deactivated by APC and does not act as cofactor (FVac) for FVIIIa inactivation

  20. XII XIIa Tissue Factor TFPI XI XIa VIIa VII IX IXa VIIa Inhibitor X Xa VIII VIIIa II IIa (Thrombin) V Va I Ia (Fibrin)

  21. XII XIIa Tissue Factor XI XIa VIIa VII IX IXa Antithrombin X Xa VIII VIIIa II IIa (Thrombin) V Va I Ia (Fibrin)

  22. XII XIIa Tissue Factor XI XIa VIIa VII IX IXa Heparin X Xa Antithrombin VIII VIIIa II IIa (Thrombin) V Va I Ia (Fibrin)

  23. Antithrombin deficiency • Auto dom (males=females) • 1% of VTE • Homozygous lethal in utero • Heterozygous 40-70% of normal AT level • Clinical presentation late teens and early adulthood • 20-fold relative risk • May be acquired – nephrotic syndrome

  24. Clinical detection • Functional assay (HCII based) • Immunogenic assay for protein components • One or both assays may be deficient

  25. Protein C deficiency • Auto Dom • Vit K dependent (II, VII, IX, X, C & S) • aPC inactivates Va and VIIIa • 3-5% of pts with VTE • 10 fold relative risk • Both functional and immunogenic deficiencies have been described • Warfarin-induced skin necrosis • Homozygous neonatal purpura fulminans

  26. Protein S Deficiency • Auto Dom • Co-factor for aPC inactivation of Va and VIIIa • Low level direct (aPC independent) inactivation of Va and VIIIa • Produced by liver (vit K dependent), ECs and megakaryocytes • Free (40%) and bound (60%) to C4bBP • C4bBP increased in pregnancy, OBCP, inflammation and acute thrombosis results in decreased free S • Warfarin-induced skin necrosis • Homozygous neonatal purpura fulminans

  27. Prothrombin Gene g20210a • 2-5% in healthy population • 7-18% in VTE patients • Mutation in non-transcribed portion of prothrombin gene resulting in elevated levels of prothrombin • Common in association with FV Leiden • May have higher risk of PE than FV Leiden • 1-3 fold increased risk of first VTE

  28. Factor V • Single chain 330kda glycoprotein • 25% of FV is stored in platelet alpha granules • Essential co-factor for Xa activation of prothrombin • Also acts as co-factor for aPC inactivation of VIIIa

  29. Factor V Leiden • Arg506gln • Most common inherited thrombophilia • 2-10% of healthy population • 20-50% of first-time VTE • Common in Caucasians, but not found in other ethnic groups such as African, Chinese or Japanese • A single mutational event occurred approximately 21,000 years ago • 5-10 fold increased risk of first VTE • Gene assay

  30. APC resistance • Addition of aPC does not prolong routine clotting assays (aPTT) • 90% - due to FV Leiden (point mutation preventing Va inactivation by APC) • 10% - due to increased plasma levels of factor VIII, the presence of antiphospholipid antibodies, older age, pregnancy, and the use of estrogens

  31. Factor elevations (VII, VIII, IX, XI) • FVIII elevation has been associated with 6-10 fold increased risk of VTE • Some believe it should be included in thrombophilia workup • Elevations of FVII, IX and XI of uncertain clinical relevance

  32. Dysfibrinogenemia • Variable susceptibility to degradation by plasmin • Over 250 fibrinogen mutations have been described

  33. Hyperhomocysteinemia • Produced in metabolism of methionine • Associated with arterial disease and venous thrombosis • Acquired due to vitamin deficiency (B6, B12 and folate) or genetic (MTHFR or CBS)

  34. Lupus anticoagulant • First detected prolongation of PT in a patient with SLE • Most result in prolongation of aPTT • Not an anticoagulant • Not only in SLE

  35. APLA Syndrome • LA and/or APLA • Arterial or venous thrombosis • Thrombocytopenia • Recurrent fetal loss

  36. APLA and Risk of Recurrent VTE • Marked elevation in the risk of recurrent thrombosis –20 fold • With anti-coagulants • 3 – 10% risk at 3 years • Without anti-coagulants • 10 -29% risk at 3 years

  37. High risk for thrombosis:Prolonged duration of anticoagulation • Antiphospholipid syndrome • More than one thrombophilic defect (e.g. FV Leiden and Prothrombin gene mutation)) • Previous VTE at unusual site • Strong family history of thrombosis

  38. Treatment (1) • First time VTE with transient risk factor • E.g. surgery, immobilization • 3 months VKA

  39. Treatment (2) • First time IDIOPATHIC VTE • Recommend – 6-12 months VKA • Suggest – indefinite (esp PE) • Reliable patient • Risk factors for bleeding

  40. Treatment (3) • First time VTE and cancer • Recommend – 3-6 months LMWH • Then indefinite VKA • CLOT - Fragmin study LEE • LITE - Hull

  41. Treatment (4) • First time VTE • APLA • Combined (e.g. FV Leiden and PG20210) • Single factor and STRONG Family history • Recommend 12 months vs indefinite

  42. Treatment (5) • First time VTE • ATIII deficiency • PC deficiency • PS deficiency • FV Leiden • Prothrombin gene 20210 • Homocysteine • Elevated FVIII • Recommend 6-12 months • Prevent Low dose warfarin

  43. Treatment (6) • Recurrent VTE • Recommend indefinite VKA

  44. Screening for thrombophilia The main argument in favor of screening asymptomatic relatives of patients with thrombophilia is the possibility of giving advice for primary antithrombotic prevention during circumstances potentially leading to VTE but not usually covered with prophylaxis in normal individuals (e.g. low-risk surgery or pregnancy and pueperium)

  45. Against screening • Expensive • Does not alter treatment • Stigmatizes patient/anxiety • May have insurance/employer ramifications

  46. Screening SOMMA J, SUSSMAN II , RAND JH. An evaluation of thrombophilia screening in an urban tertiary care medical center: a ‘‘real world’’ experience. Am J Clin Pathol 2006 July;126(1):120e127.

  47. Who should be tested for inherited thrombophilia? • No one

  48. Who should be tested for inherited thrombophilia? • Idiopathic first time VTE • Recurrent VTE • Venous thromboembolism at early age • Thrombosis in an unusual site, eg mesenteric vein, cerebral vein etc • Unexplained neonatal thrombosis • Skin necrosis, particularly if on VKA • Arterial thrombosis before the age 30 years • Unexplained prolonged activated partial thromboplastin time • Patients with recurrent fetal loss • Relatives of patients with thrombophilic abnormality – very controversial

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