Heparin-induced thrombocytopenia medical therapy


 * Associate Editor-In-Chief:, Priyamvada Singh, M.B.B.S. [mailto:psingh@perfuse.org], Aric C. Hall, M.D., [mailto:achall@bidmc.harvard.edu]

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. Out of these lepirudin and argatroban are available for use in USA.

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.

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.

Mechanism of benefit
Inhibits the effect of thrombin by forming irreversible complexes with thrombin.

Pharmacokinetics

 * It is a DTI but, unlike agatroban, it is eliminated by the kidneys (half-life 80 min). Dose reduction is required in patients with renal failure

Dose and administration

 * Dose is 0.4 mg/kg via i/v bolus, followed by an initial maintenance infusion of 0.15 mg/kg/h
 * Activated partial thromboplastin time (aPTT) should be kept at 1.5-2.5 times the baseline.
 * aPTT monitoring should be done every 4 hours.

Contraindications

 * Fatal anaphylactic reactions has been reported in some patients after after previous exposure.

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.

Duration of treatment
Following considerations should be kept in mind while deciding the duration of treatment of different drugs in this condition:


 * Isolated thrombocytopenia
 * Continue DTIs until platelet counts reaches a stable levels.
 * Warfarin can be administered to patients for 4 weeks as the risk of thrombosis remains high for 2-4 weeks after treatment is initiated
 * Heparin-induced thrombocytopenia (HIT) with thrombosis
 * Anticoagulation with DTIs until platelets recovered to above 150 x 109/L.
 * Oral anticoagulation with warfarin should be started at low doses and an overlap with a DTIs for at least 5 days should be planned until the INR stays at therapeutic range for at least 2days.

Cardiopulmonary bypass

 * The management of cardiopulmonary bypass (CPB) patients with active HIT is controversial. Direct Thrombin Inhibitors such as agatroban and hirudin are used (and increase the aPTT in a dose dependent manner).  However, in the large doses required for CPB hirudin's effects cannot be monitored well.  Following CPB surgery the platelet count drops to about 40-60% of normal within the first 2-3 days postop due to hemodilution and platelet consumption.  But there is also a risk of HIT.  20-50% of patients develop heparin antibodies during the first 5-10 days following CPB and some develop HIT (1-3% if UFH is continued through the postop period).

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.

Additional Reading

 * Aouifi A, Blanc P, Piriou V, Bastien OH, French P, Hanss M, Lehot JJ. Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia. Ann Thoracic Surg 2001;71:678-683.
 * Follis F, Filippone G, Montalbano G, Floriano M, LoBianco E, D'Ancona G, Follis M. Argatroban as a substitute of heparin during cardiopulmonary bypass: a safe alternative? Interact CardioVas Thorac Surg 2010;10:592-596.
 * Gates R, Yost P, Parker B. The use of bivalirudin for cardiopulmonary bypass anticoagulation in pediatric heparin-induced thrombocytpenia patients. Artificial Organs. 2010;34(8):667-669.