1. Thrombophilia National Haemophilia Director
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

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

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

9. Unknown mechanism
Antiphospholipid syndrome
Hyperhomocysteinemia

10. 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

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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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)