Heparin-induced thrombocytopenia medical therapy
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Heparin-induced thrombocytopenia |
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Differentiating Heparin-induced thrombocytopenia from other Diseases |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2], Aric C. Hall, M.D., [3]
Overview
Heparin-induced thrombocytopenia is diagnosed when the platelet count falls by > 50% typically after 5-10 days of heparin therapy. Treatment is by prompt withdrawal of heparin and replacement with a suitable alternative anticoagulant. Lepirudin, fondaparinux, bivalirudin, argatroban, danaparoid or other direct thrombin inhibitors are used to treat the thrombotic state.
Treatment
- Check platelet counts twice weekly while on heparin.
- Treatment is by prompt withdrawal of heparin (heparin use even to flush catheters should not be done) and replacement with a suitable alternative anticoagulant.
- To block the thrombotic state, lepirudin, fondaparinux, bivalirudin, argatroban, danaparoid or other direct thrombin inhibitors are used.
- Low molecular weight heparin is deemed contraindicated in HIT.
Acute Pharmacotherapies
Direct thrombin inhibitors
- Use of direct thrombin inhibitors (DTIs; agatroban, hirudin & bivalirudin) is the safest and most effective therapeutic approach to HIT for both those who need ongoing anticoagulation and for thrombosis prevention.
Agatroban
- Agatroban (Novastan) don't resemble heparin and therefore no cross-reaction with heparin antibodies is seen.
Pharmacokinetics
- It is hepatically eliminated (t1/2 = 1 hour).
Pharmacodyanamics
- With administration its effects are immediate and a steady state can be achieved in 1-3 hours.
Advantages
- With this regimen greater than half of patients had platelet counts recover by day 3 (in HIT).
- It has no cross-reactivity with HIT antibodies (to PF4). There is no antibody formation after repeated administration.
- It does not require dose adjustment in renal impairment.
Contraindications
- It is contraindicated in patients with problems of hemorrhage and one should avoid intramuscular injections during its use.
- Abrupt discontinuation of agatroban can lead to a hypercoagulable state.
Dose and administration
- It is a medication specifically designed as a synthetic intravenous thrombin inhibitor, derived from arginine, to be an anticoagulant in patients with HIT.
- The infusion is initiated at 2 ug/kg/min.
- In patients with hepatic impairment it is recommended to reduce the dose to 0.5 ug/kg/min.
- Adjustment is made to a steady state aPTT of 1.5-3X the baseline.
- When agatroban is given it is advised to begin coumadin.
- When the INR is >4 discontinue the agatroban and recheck the INR 4-6 hours later.
- If the INR is below the therapeutic range then resume agatroban.
- Avoid prothrombotic problems by overlapping the coumadin and agatroban.
Lepirudin
- It is a DTI but, unlike agatroban, it is eliminated by the kidneys.
Hirudin
- It binds to the active site of thrombin by exosite 1, the site at which thrombin binds to its substrates.
Bivalrirudin
- Bivalrirudin like hirudin, binds to the active site of thrombin/exostie 1.
Danaproid
- Danaproid (Orgaran) is a heparinoid composed of 85% heparan sulphate, 10% dermatan sulphate and 5% chondroitin sulphate.
- It has approximately 10% cross reactivity with heparin.
- It has been shown to reduce mortality from thrombotic complications to 5% from 28%.
Low molecular weight heparin
- The in vitro cross reactivity of Low molecular weight heparinLMWH with heparin dependent antibodies is approximately 60-100%. * Some argue that LMWH is contraindicated for patients who develop HIT because of this cross-reactivity. Nonetheless, a theoretical argument for the use of LMWH in therapy for HIT has been made. The theory is that the LMWH overall interaction of heparin with PF4 will diminish. Though there are reports of LMWH being effective in controlling HIT in the presence of cross-reacting antibodies, the consensus is not to administer LMWH unless the absence of cross reactivity has been determined.
- As stated before when HIT is suspected it is recommended to discontinue the heparin and initiate other agents such as direct thrombin inhibitors (DTIs; agatroban, hirudin & bivalirudin).
- Platelet transfusion worsens thrombosis and should be reserved for patients with active bleeding.
Warfarin
- Warfarin therapy should be avoided for 3-5 days after heparin cessation and/or until thrombocytopenia resolves (>100,000).
- Vitamin K should be given when warfarin is started.
Long term pharmacotherapy
- Coumadin (and vitamin K antagonists generally) are recommended for long-term anticoagulation however they should not be administered too early, unopposed or in excessive doses. It is important not to initiate coumadin treatment until the platelet count has recovered due to the threat of skin necrosis or gangrene.
- Discontinuing the heparin and giving Coumadin doesn't prevent the onset of thrombosis in ~50% of patients. Once thrombocytopenia has resolved the coumadin can then be given at a low maintenance dose and alternative anticoagulation should be continued along with coumadin for at least 5 days.
- The alternative anticoagulant should not be discontinued until the platelet count has achieved a stable plateau and the INR has been the therapeutic range for at least 2 days. The optimal duration of the anticoagulation has not been established.
Patients Undergoing Surgery or PCI
Patients with HIT should be treated with Bivalirudin, a direct thrombin inhibitor to support these procedures.
Trial supportive data
According to past reviews, patients treated with lepirudin for heparin-induced thrombocytopenia showed a relative risk reduction of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42 when compared to patient controls. In addition, patients treated with argatroban for HIT showed a relative risk reduction of the above clinical outcomes to be 0.20 and 0.18. [1]