H.I.T.:
Complications of Heparin Therapy
Heparin comes in many forms and is commonly used in cancer patients. Since its discovery in 1923, heparin has been the primary parenteral anticoagulant used worldwide for the prevention and treatment of blood clots and for maintaining patency of catheters. The most frequent side effect of heparin therapy is bleeding. However, a less common but potentially devastating complication of heparin exposure, immune-mediated heparin-induced thrombocytopenia (HIT), is now well described. Paradoxically, immune-mediated HIT is associated with the development of new thrombosis or worsening of preexisting thromboses rather than bleeding.
A mild decline in the platelet count occurs commonly in patients receiving heparin and is most often non-immune mediated. This generally occurs within 5 days after institution of the drug and is not associated with thrombosis. Heparin can be safely continued and the platelet count generally returns to normal within a few days.
Immune-mediated HIT, on the other hand, is characterized by a more significant decline in platelets defined as either a drop in the platelet count to under 150,000 or greater than 50% decline in the platelet count following the initiation of heparin therapy. It typically develops after 4-10 days of heparin therapy but can suddenly occur within 24 hours of heparin exposure if the patient has been sensitized to heparin within the preceding three months. For these reasons, all patients receiving heparin should have their platelet count monitored.
The frequency of HIT may be as high as 3% in patients treated with heparin for at least 4 days. The likelihood that HIT will develop depends upon the source and dose of heparin. Therapeutic doses of heparin are more likely than prophylactic doses to cause HIT and it is most common with unfractionated heparin. In fact, HIT has only rarely been associated with low molecular weight heparin.
HIT is caused by antibodies directed against an antigen complex that is composed of heparin and platelet factor 4. This antibody-antigen complex binds to the surface of platelets resulting in platelet activation and aggregation. It also indirectly leads to the generation of thrombin, further promoting the onset or extension of thrombosis through activation of the coagulation cascade.
In patients who develop HIT, an alarming 50-60% will develop thrombotic complications within 30 days following the diagnosis without further therapy. Venous thromboses are far more likely than arterial thromboses.
Serologic testing should be ordered to confirm the clinical suspicion. However, the results typically are not available for several days, making HIT a clinical diagnosis initially. Indeed, if one waits for the results of the confirmatory tests to act, it may be too late to prevent or effectively treat thrombosis. Laboratory tests include functional assays (serotonin release assay, heparin-induced platelet activation) and an antigenic assay (ELISA). When the functional and antigenic assays are combined both sensitivity and specificity exceeds 90%.
Once HIT is suspected, all heparin exposures must be immediately discontinued, including heparin flushes and heparin-coated central lines. Those patients who have active thrombosis at the time HIT is diagnosed require an alternative form of anticoagulation. Furthermore, those patients who develop HIT while receiving prophylactic heparin but do not have evident clot are at a high risk of developing thrombosis within 30 days. They should also be considered for an alternative form of anticoagulation until the platelet count normalizes. Longer-term anticoagulation is necessary for those with documented clot. Warfarin should be avoided in the initial management of HIT since it can cause venous limb gangrene, a very rare but devastating complication in this patient population. It can be safely begun once the platelet count has normalized, however. Once HIT develops, low molecular weight heparin should not be substituted for unfractionated heparin since the HIT antibody will cross-react.
Alternative anticoagulants used in patients with HIT include lepirudin and argatroban, both direct thrombin inhibitors, and danaparoid, a compound similar to heparin but effective in patients with HIT. Each has been shown to significantly reduce thrombotic complications associated with HIT.
The development of HIT can be limited by minimizing heparin exposure and using low molecular weight heparin when appropriate.
In summary, immune-mediated HIT is a well recognized complication of heparin therapy and can lead to the development of thrombosis. Any significant drop in platelets in patients receiving heparin should prompt an investigation. If HIT is strongly suspected, all forms of heparin should be stopped and temporary anticoagulation with non-heparin drugs is recommended, at least until the thrombocytopenia has resolved.
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