Thrombophilia

Definition –Tendency to develop clots due to predisposing factors that may be genetically determined

Classification –Inherited –Acquired –Inherited + acquired

Inherited Thrombophilia Caused by defective gene –Activated protein C resistance (factor V Leiden)- least severe –Inhibitor deficiencies: protein S, proteinC, antithrombin (intermediate severity) –Prothrombin 20210A allele mutation  hyperprothrombinaemia (v. severe) –Hyperhomocysteinaemia

Inherited defects & thrombophilia

Activated protein C resistance Factor V Leiden –Gene mutation in chromosome 1 –Accounts for most but not all cases of APC resistance –Factor Va unresponsive to protein C –15% of Causasians are carriers –Rare in Asians & Africans heterozygotes 5-10x  risk of clotting homozygotes x  risk

Acquired thrombophilia Antiphospholipid syndrome –lupus anticoagulant: anticoag in vitro, but pro- coag. in vivo –Suspect if : a young person presents with MI, CVA, hepatic vein thrombosis (Budd- Chiari syndome) Recurrent miscarriages Incidental finding of prolonged APTT +  platelets

Drugs Disease states: – Malignancy –connective tissue diseases –myeloproliferative disorders – pregnancy – surgery –trauma

Mixed hereditary + acquired Acquired conditions amplify the risk of clotting in those with underlying hereditary coagulatory defects Examples: oral contraceptives, HRT, pregnancy, surgery

When to suspect thrombophilia +ve family history occlusion at unusual sites e.g. brain, portal veins recurrent thrombosis unexpected VTE unexpected occlusion of arterial tree e.g. young ppl with MI or CVA

Arterial thrombosis –anticoagulation pathway anomalies rarely cause arterial events –Main differentials Antiphospholipid syndrome Hyperhomocysteinaemia Dysfibroginaemia

Evaluation History –VTE or arterial occlusive disease in <50 –Recurrent VTEs Family history- VTE in 1st degree relatives Screen if >1 of the above is +ve

Investigations Screening of population is not justified because overall incidence of thrombosis is low Screen people in whom an occlusive event has occurred and has unusual circumstances e.g. young age, recurrent episodes, family hx

Acute Event No need to investigate fully at this stage Management the same regardless of cause VTE –FBC, blood gas –D-dimer- good -ve predictive valuebut +ve test not specific –CXR –U/S –CTPA

Investigations FBC-  platelets,  RBCs APTT –good for picking up APC resistance –Patient’s plasma + Factor V deficient plasma: v. sensitive & specific for factor V Leiden Thrombin time Lupus anticoagulant, anticardiolipin & antiphospholipid antibodies

Assays for Protein C/ protein S –Antigen level –Functional assay Homocystein level DNA analysis –factor V Leiden –Prothrombin 20210A

Investigations Results affected by: –acute thrombotic event –pregnancy –Disease states: liver, DIC, inflammation, surgery –Drugs: anticoagulants, OCPs

Treatment- Acute Pulmonary Embolism O2 Inotrope support Fluids IV heparin- bolus followed by infusion, then oral warfarin after 24 hrs Thrombolysis - consider in massive PE

Treatment- Acute DVT –below knee TED stockings Re- scan in 7-10 days Anticoagulate if there is progression –above knee- anticoag x 3 months

Treatment- Long term +ve family hx but asymptomatic –Counselling –No action required Anticoagulation (INR ) –1 episode of VTE in the presence of another triggering event months anticoagulation. Stop when triggering factor is gone –VTE without triggering factors- anticoagulant for 6 months, but indefinite if the episode was life-threatening

Indefinite coagulation –> 2 spontaneous thrombotic events –Event AND > 1 hereditary defects –life-threatening thrombotic episode –? Hereditary defect with 1st thrombotic episode- benefit unclear. But yes if patient is heterozygote for antithrombin deficiency (  risk of clotting compared to other herditary conditions). Maybe yes if there is protein C/S defect

IVC filter –consider if patient still has recurrent VTEs despite adequate anticoagulation

Prophylaxis Pre-op LMWH –major op: give for 5-10 days –Aspirin not as effective as LMWH Pregnancy -subcut. LMWH rather than warfarin