thrombophilia. definition –tendency to develop clots due to predisposing factors that may be...
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Thrombophilia
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• Definition– Tendency to develop clots due to predisposing
factors that may be genetically determined
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• Classification– Inherited– Acquired– Inherited + acquired
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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
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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%
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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
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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
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• Drugs
• Disease states:– Malignancy– connective tissue diseases – myeloproliferative disorders– pregnancy– surgery– trauma
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Mixed hereditary + acquired
• Acquired conditions amplify the risk of clotting in those with underlying hereditary coagulatory defects
• Examples: oral contraceptives, HRT, pregnancy, surgery
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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
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• Arterial thrombosis– anticoagulation pathway anomalies rarely cause
arterial events– Main differentials
• Antiphospholipid syndrome• Hyperhomocysteinaemia• Dysfibroginaemia
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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
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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
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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
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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
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• Assays for Protein C/ protein S– Antigen level– Functional assay
• Homocystein level
• DNA analysis – factor V Leiden– Prothrombin 20210A
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Investigations
• Results affected by:– acute thrombotic event– pregnancy– Disease states: liver, DIC, inflammation,
surgery – Drugs: anticoagulants, OCPs
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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
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Treatment- Acute
• DVT– below knee
• TED stockings • Re- scan in 7-10 days• Anticoagulate if there is progression
– above knee- anticoag x 3 months
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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
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• 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
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• IVC filter– consider if patient still has recurrent VTEs
despite adequate anticoagulation
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Prophylaxis
• Pre-op LMWH– major op: give for 5-10 days – Aspirin not as effective as LMWH
• Pregnancy -subcut. LMWH rather than warfarin