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Thrombophilia

Thrombophilia. Barry White National Haemophilia Director Director, National Centre for Hereditary Coagulation Disorders, St James’s Hospital. Virchow’s Triad. Disorder of blood vessel wall Disordered blood flow (stasis) Abnormality of blood constituents.

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Thrombophilia

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  1. Thrombophilia Barry White National Haemophilia Director Director, National Centre for Hereditary Coagulation Disorders, St James’s Hospital

  2. Virchow’s Triad • Disorder of blood vessel wall • Disordered blood flow (stasis) • Abnormality of blood constituents

  3. Venous thrombosis - a multifactorial disease • Acquired risk factors pregnancy, surgery, hormonal therapy, malignancy • Inherited risk factors single gene defects e.g. antithrombin multigenic defects e.g. antithrombin + FV leiden

  4. Thrombophilia • Inherited or acquired predisposition to venous thrombosis • Laboratory abnormalities

  5. Increased procoagulants • FVIII • FIX • FXI • Prothrombin 20210A • Fibrinogen • Thrombin activator fibrinolysis inhibitor (TAFI)

  6. Decreased anticoagulants • Antithrombin deficiency • Protein C deficiency • Protein S deficiency • Activated PC resistance (FV Leiden)

  7. Unknown mechanism • Antiphospholipid syndrome • Hyperhomocysteinemia

  8. Activated protein C resistance • Activated protein C resistance • Factor V leiden (R506Q) in 90% of cases • Coagulation based assay (+/-FV def plasma) • PCR based assay • 2%-15% • 2.0 –2.3% of Irish population are heterozygous FVL Livingstone et al 2000 • 20% of unselected VTE • Relative risk 3-8 fold for heterozygotes

  9. APC Factor V (normal) APC Factor V Leiden

  10. Prothrombin G20210A • Poort 1996 • Mutation in 3’ UTR associated with increased prothrombin levels • 1.3% of Irish population heterozygous (Keenan et al 2000) • 6-8% of unselected VTE • 16% of familial VTE

  11. Hyperhomocysteinemia • Definite risk factor for arterial vascular disease • >18.5 mol/l in 5% of normal population • >18.5 mol/l in 10% of VTE • Homozygous MTHFR (C677T) - 10% Irish population • Acquired B12, folate, B6 deficiency

  12. Antiphospholipid syndrome • Venous, arterial or small vessel except superficial venous thrombosis • 3 consecutive unexplained fetal loss • Severe pre-eclampsia or placental insufficiency leading to prematurity (<34w) • Unexplained single fetal loss >10 wks with normal morphology

  13. APLS - laboratory diagnosis • ACL IgG or IgM (> 3SD above normal) • Lupus anticoagulant • Need 2 positive tests (either test will do) at least 6 weeks apart • Anti B2-Glycoprotein I

  14. Hormonal therapy • OCP risk of VTE increased x 2-3 fold (baseline risk 1:10,000) • FVL risk of VTE increased x 3-7 fold • OCP + FVL risk of VTE increased x 33 fold (30:10,000 = 0.3%) • Need to screen 2 million to save one life • Similar synergistic interaction with other thrombophilic defects • HRT likely to be similar

  15. Pregnancy and Virchow’s triad • Venous stasis - changes in tone and obstruction • Vascular damage at time of delivery •  APTT, PS (free and total), APCr •  FVIII:C, VWF, Fibrinogen •  PAI-1 and PAI-2

  16. Pregnancy and venous thromboembolic disease • Pregnancy increases risk x 5-10 fold • 0.86/1000 deliveries • 0.71/1000 (DVT) : 0.15/1000 (PE) • Left leg >80% • Ileofemoral more common than calf vein (72% versus 9%) • Increased with age, caesarian section, bed rest and prior history of DVT/PE

  17. Clinical practice – DVT/PE • Diagnosis DVT – doppler ultrasound primarily (venogram gold standard) PE – ventilation perfusions scan primarily (pulmonary angiogram is gold standard) • Treatment Heparin x 5-10 days until at least 5 days of warfarin Warfarin x 6 months ( indefinite for second thrombosis)

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