Thrombophilia National Haemophilia Director 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

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

Thrombophilia Inherited or acquired predisposition to venous thrombosis Laboratory abnormalities

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

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

Unknown mechanism Antiphospholipid syndrome Hyperhomocysteinemia

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

APC Factor V (normal) APC Factor V Leiden

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

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

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

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

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

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

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

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)