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 & thrombophiliaGenefrequency

Cause ofhypercoagula-bililty

APC resistance 3.6-6% 10-64%

PC deficiency 0.3% 1.4-8.6%

PS deficiency 0.5% 1.4-7.5%

Antithrombindeficiency

0.1% 0.5-4.9%

Prothrombin20210A

0.7-6% 5.0-7.1%

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 50-100x 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 2.0-3.0)– 1 episode of VTE in the presence of another triggering

event - 3-6 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