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

Treatment of HIT involves prompt withdrawal of heparin or heparinoid 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. Clinical practice guidelines are available from the American College of Chest Physicians to direct treatment.

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. Thus, it is the anticoagulant of choice for HIT in patients with renal dysfunction (Grade 2C recommendation). The infusion is initiated at 2 mcg/kg/min, but patients with hepatic impairment require dose reduction to 0.5 mcg/kg/min, since argatroban is excreted by the liver. Adjustment is made to a steady state activated partial thromboplastin time (aPTT) of 1.5-3X the baseline. 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. 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 . Platelet transfusion can also be given if an active procedure with high bleeding risk is planned and if the benefits of the procedure outweigh the risks of further HIT-related complications.

• 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). Warfarin can contribute to ongoing thrombotic risk in the acute setting via inhibition of protein C and protein S, which are natural anticoagulants that inhibitor factors V and VIII. It is appropriate to eventually begin warfarin after the acute phase of HIT is over. Once warfarin is started, it should be overlapped with a non-heparin anticoagulant for at least 5 days.

Long-Term Pharmacotherapies

• Warfarin: This ia a vitamin K antagonist that inhibits epoxide reductase, which prevents regeneration of vitamin K and thus prevents activation of clotting factors II, VII, IX, and X. It 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 since it can cause thrombotic complications via inhibition of protein C and protein S. . It is important not to initiate coumadin treatment until the platelet count has recovered due to the threat of skin necrosis or gangrene. Typically, warfarin should be overlapped with a non-heparin anticoagulant, such as argatroban for at least 5 days to prevent the acute hypercoaguable state that warfarin can induce. Once the INR is greater than 4 while a patient is simultaneously on warfarin and a non-heparin anticoagulant, the non-heparin anticoagulant should be stopped and the warfarin should be continued. If the INR after 6 hours is less then 2, the non-heparin anticoagulant should be restarted. Warfarin should then be continued for at least 3 months. Please see "Acute Pharmacotherapies" section above.

Special conditions

Pregnancy

Pregnancy is a hypercoaguble physiological state by itself, so pregnant patients with HIT are at a particularly high risk for thrombosis. Management of HIT in pregnant patients warrants special consideration to prevent morbidity associated with thrombus formation, which can affect the health of the mother and fetus. The preferred anticoagulant for treatment of HIT in pregnancy is danaparoid (grade 2C recommendation from the American College of Chest Physicians). Alternatively, lepirudin or fondaparinux can be used.

Cardiopulmonary Bypass

• The management of cardiopulmonary bypass (CPB) patients with active HIT is controversial. Direct thrombin inhibitors such as argatroban and hirudin are used (and increase the aPTT in a dose dependent manner). However, in the large doses required for cardiopulmonary bypass surgery, hirudin's effects cannot be monitored well.
• Following cardiopulmonary bypass surgery, platelet counts can decrease to about 40-60% of normal within the first 2-3 days post-operatively due to hemodilution, platelet consumption, and other factors which may be unrelated to HIT. However, there is also a significant risk of HIT since HIT prevalence is highest for this patient group.
• Approximately 20-50% of patients develop heparin antibodies during the first 5-10 days following cardiopulmonary bypass surgery and some develop HIT. In patients with a history of HIT who have no detectable HIT antibodies, the American College of Chest Physicians recommends use of heparin over non-heparin anticoagulants. If HIT antibodies are present, however, non-heparin anticoagulants should be used.

Percutaneous Coronary Intervention

• The American College of Chest Physicians recommends use of bivalirudin or agratroban for patients with HIT undergoing percutaneous coronary intervention.

Renal Replacement Therapy

• For patients with HIT who are also on dialysis who require anticoagulation of the dialysis circuit, the American College of Chest Physicians recommends use of a non-heparin anticoagulant, such as argatroban or danaparoid. Regional citrate can be used an anticoagulant for catheter locking, instead of heparin locking or heparin flushes. Citrate works via calcium chelation, preventing activation of the clotting cascade.