Heparin-induced thrombocytopenia medical therapy

Heparin-induced thrombocytopenia
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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], Priyamvada Singh, M.B.B.S. [3], Aric C. Hall, M.D., [4] Shyam Patel [5]

Overview

Clinical practice guidelines are available to direct treatment.

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

The most important initial step in the management of HIT is withdrawal of heparin. This includes avoiding heparin in catheter flushes and documenting a heparin reaction in a patient's chart to ensure that other clinicians do not inadvertently administer heparin. Heparin should be replaced with a suitable alternative anticoagulant like a direct thrombin inhibitor.

• 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

• Argatroban: This is a direct thrombin inhibitor derived from arginine. It is hepatically eliminated (half life of 1 hour) so requires dose adjustment in liver failure. It acts immediately and steady state can be achieved in 1-3 hours. The advantage is that 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. However, it is contraindicated in patients with hemorrhage and one should avoid intramuscular injections during its use. Abrupt discontinuation of agatroban can lead to a hypercoagulable state, there is loss of thrombin inhibition. The infusion is initiated at 2 mcg/kg/min, but patients with hepatic impairment requires dose reduction to 0.5 mcg/kg/min. Adjustment is made to a steady state activated partial thromboplastin time (aPTT) of 1.5-3X the baseline. When argatroban is given, warfarin should be started simultaneously as long as the platelet count is greater than 150,000 per microliter. When the INR is > 4, argatroban should be stopped, and INR should be re-checked 4-6 hours later. If the INR is below the therapeutic range of INR 2-3, then argatroban should be resumed. The process should be repeated until a therapeutic INR is achieved when off argatroban.

• Lepirudin: This is an irreversible direct thrombin inhibitor. It is renally eliminated (half-life of 80 min). Dose reduction is required in patients with renal failure. The dose is 0.4 mg/kg intravenously, followed by an initial maintenance infusion of 0.15 mg/kg/hr. The activated partial thromboplastin time (aPTT) should be kept at 1.5-2.5 times the baseline. aPTT monitoring should be done every 4 hours.. Note that fatal anaphylactic reactions has been reported in some patients after after previous exposure.

• Hirudin: This is a thrombin inhibitor that binds to the active site of thrombin by exosite 1, the site at which thrombin binds to its substrates. It is not commonly used in clinical practice.

• Bivalirudin: This is similar to hirudin and binds to the active site of thrombin/exostie 1. It is not commonly used in clinical practice.

• Danaparoid: This 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%.

Contraindicated Pharmacotherapies

• '''Heparin''': This should be avoided since this serves as the antigen to which HIT antibodies are produced. Heparin can exposure contribute to ongoing thrombosis and worsening morbidity.

• '''Low molecular weight heparin''' (LMWH): It is thought that LMWH is contraindicated for patients who develop HIT because of this cross-reactivity, but some clinicians use this for treatment of HIT. 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.

• '''Platelet transfusions''': This worsens thrombosis and should be reserved for patients with active bleeding .

• '''Warfarin''': Warfarin is a vitamin K antagonist and should be avoided for 3-5 days after heparin cessation and/or until thrombocytopenia resolves (>150,000 per microliter).

Long term pharmacotherapy

• Warfarin, a vitamin K antagonist is recommended for long-term anticoagulation after the acute issues resolve and the INR is at goal 2-3 with use of a direct thrombin inhibitor as above. It should not be administered too early., . 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.

• 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.

Special conditions

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.