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

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

• 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)

• TreatmentHeparin x 5-10 days until at least 5 days of warfarinWarfarin x 6 months ( indefinite for second thrombosis)