Heparin-Induced Thrombocytopenia. Introduction
Since it was first used to prevent venous thrombosis in surgicalpatients in 1937, heparin has been the anticoagulant therapy ofchoice for the prevention and early management of arterialand venous thromboembolic disease. Heparin plays a major role in cardiovascular therapy; it is the routine anticoagulant agent used in percutaneous transluminal coronary angioplasty and coronary artery bypass graft surgery and has confirmed value in the management of patients with unstable angina and as adjunctive therapy in patients receiving thrombolysis after myocardial infarction.
Because of the vast clinical experience with heparin, physicians are generally well aware of most of the practical limitations associated with its use, including the potential for bleeding and interpatient variability in anticoagulant response after administration. The focus of this report, however, is one of the potentially most devastating but least well recognized complications of heparin therapy—its propensity to cause thrombocytopenia with associated thrombosis. With the more frequent use of heparin in recent years, the prevalence of this potentially catastrophic complication has prominently increased
Frequency of Thrombocytopenia
Approximately 10% to 20% of patients will develop a transient mild thrombocytopenia after 1 to 4 days of heparin therapy. The platelet count rarely goes below 100,000/ml, often becomes normal despite further heparin administration and is generally without clinical sequelae. This benign form of heparin-induced thrombocytopenia (HIT), attributed to a direct interaction between administered heparin and circulating platelets, is classified as HIT type I The more sinister form of HIT generally develops after 5 to 10 days (mean 7 to 8 ) of heparin therapy. This form is antibody mediated, can be associated with potentially devastating thromboembolic sequelae and is classified as HIT type II and is the topic of this report. A recent prospective, randomized study of 665 patients receiving either subcutaneous unfractionated or low molecular weight (LMW) heparin for thromboprophylaxis after hip surgery reported a frequency rate of HIT of 2.7% in patients receiving unfractionated heparin and 0% in patients receiving LMW heparin. HIT was defined as a decrease in the platelet count ,150,000/ml occurring at least 5 days after beginning heparin therapy, accompanied by heparindependent antiplatelet antibodies detected by the sensitive 14C-serotonin release assay Unfortunately there have not been any comparably designed, prospective, large-scale trials investigating the frequency of HIT in patients receiving full-dose intravenous heparin. However, pooled analyses derived from less rigorous prospective studies suggest that HIT becomes more common after full-dose intravenous heparin than after subcutaneous heparin.
The reported frequency of HIT type II in this patient group ranges from 0% to 30%, reflecting the varying and varying definitions of thrombocytopenia. Although HIT appears to be more common after administration of larger doses of heparin, it may still occur after exposure to very small quantities of the drug. The condition has been described in patients receiving small amounts of heparin in flush solutions used to maintain the patency of indwelling peripheral catheters and in patients with heparin-coated pulmonary artery catheters A number of investigators have observed that patients previously exposed to heparin develop HIT earlier after institution of heparin therapy compared with those with no previous exposure, suggestive of an anamnestic response, although the objective evidence for the existence of immunologic memory in these patients is not strong (see later discussion).
The small, prospective studies to date have not demonstrated an association between previous treatment with heparin and an increased likelihood of developing HIT (21), and it is anticipated that ongoing, adequately sized, prospective trials will provide a clearer perspective of the impact of previous exposure to heparin on the frequency of this syndrome. Most prospective studies comparing porcine mucosal with bovine lung heparin have reported a greater frequency of HIT among patients receiving the latter Individual batches of heparin may have an increased propensity to cause thrombocytopenia even when derived from the same source, giving rise to “epidemics” of HIT Thrombocytopenia and thrombosis are not unique to heparin and have also been described after administration of other sulfated glycosaminoglycans such as LMW heparin, pentosan polysulfate and chondroitin sulfate. The frequency with which it occurs appears to be directly related to the size and degree of sulfation of the molecule.