Warfarin Institute of America

Dedicated To Your Health

By Heather Klug, Pharm.D. Candidate

Heparin-induced thrombocytopenia (HIT), also known as "white clot syndrome" or heparin-associated thrombocytopenia (HAT), is a severe immune-mediated drug reaction that can occur in anyone exposed to unfractionated heparin or low-molecular weight heparin (LMWH) products. However, the incidence of HIT in patients exposed to LMWH is less than that of patients receiving unfractionated heparin. Heparin or LMWH is mostly used to prevent or treat various clotting diseases but can be used for many other conditions. HIT is characterized by the formation of antibodies (heparin-dependent antibodies) in the blood that lead to the destruction of blood cells that are responsible for forming clots, called platelets. In later stages of the reaction, the platelets increase in number and can make patients more susceptible to forming clots in the extremities or cardiovascular system.

Complications of HIT can result in life- or limb- threatening clots or death. More specifically, clots can form in the legs or arms (deep vein thromboses or DVT) or lungs (pulmonary embolism or PE) or brain (stroke), arteries can become blocked and lead to limb amputation, or skin necrosis may occur.

Any patient exposed to heparin or LMWH at any dose is at risk for developing HIT. This includes, unfractionated heparin at full therapeutic doses, preventative doses, heparin flushes, or heparin coated catheters.

About 50% of patients exposed to heparin will develop heparin-dependent antibodies. Approximately 3% of patients exposed to heparin will develop HIT. Complications are estimated to occur in 50% of patients with HIT.

Patients that are at a higher risk for developing HIT include those with previous exposure to heparin, a past history of HIT, presence of heparin-dependent antibodies, or patients undergoing cardiovascular or orthopedic surgeries.

It is recommended that all heparin or LMWH be discontinued, including heparin flushes and heparin coated catheters. Switching to LMWH is not recommended in patients that develop HIT due to the presence of heparin-dependent antibodies and the likelihood that there is cross-sensitivity between unfractionated heparin and LMWH. The recommended treatment for HIT in a patient that requires anticoagulation is a direct thrombin inhibitor such as lepirudin (RefludanÒ ) or argatroban (ArgatrobanÒ ), or danapariod, which is a heparin derivative. Both lepirudin and argatroban are FDA approved for the treatment of HIT, but danapariod is only indicated for clot prevention in hip replacement surgery. These agents are effective for the treatment of HIT and prevent complications associated with HIT. Warfarin is not recommended for initial treatment of HIT due to the possibility of further complications. Once platelet levels return to the normal range and a direct thrombin inhibitor is started, warfarin may be an option for long-term anticoagulation.

In a review article titled, Treatment of Heparin-Induced Thrombocytopenia, researchers assessed the risk associated with clots after stopping heparin in a patient with HIT, the current evidence supporting the use of direct thrombin inhibitors, the use of direct thrombin inhibitors in patients with a past history of HIT requiring anticoagulation for coronary procedures, and the risk for bleeding when direct thrombin inhibitors were used. Researchers found nine studies that provided information about HIT and treatment alternatives. They found that the risk of developing a clot after stopping heparin therapy due to HIT is at least 20% and may be as high as 50%. Therefore, a rapid acting anticoagulant should be initiated once heparin therapy is stopped. The direct thrombin inhibitors evaluated were argatroban and lepirudin. Danaparoid is another alternative, but the studies did not meet the criteria for this review. Both argatroban and lepirudin were found to reduce the incidence of clots, death, and amputations related to HIT. The use of direct thrombin inhibitors in patients with a past history of HIT undergoing coronary procedures were found to have a complication rate relative to patients without a history of HIT. Finally, the risk of bleeding associated with direct thrombin inhibitors used in patients with HIT was found to be 6-18%. The result is consistent with the expected risk of bleeding related to these agents. Therefore, the researchers conclude that the use of direct thrombin inhibitors in patients with HIT has been shown to be beneficial in reducing complications related to HIT.

Since the incidence of HIT in patients exposed to LMWH is lower than the incidence of HIT in patients exposed to unfractionated heparin, LMWH heparin may be a consideration as first line therapy. If heparin is necessary, the duration of therapy should be limited to less than 5 days and the patient should be switched to warfarin if long-term anticoagulation is required. However, warfarin should not be started in a patient who has had HIT until the platelet levels are within the normal range. LMWH should not be substituted for unfractionated heparin if HIT should develop.

1. Coutre S. Heparin-induced thrombocytopenia. UpToDateÒ Online 11.1. Available at: http://uptodateonline.com. Accessed March 20, 2004.
2. HIT information page. Argatroban web site. Available at: http://www.argatroban.com. Accessed March 21, 2004.
3. Hirsh J, Heddle N, Kelton J. Treatment of heparin-induced thrombocytopenia. A critical review. Arch Intern Med 2004;164:361-9.