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Heparin induced thrombocytopenia (HIT) is the most significant adverse effect of heparin therapy after bleeding. Two categories of HIT are recognized; a benign form called type I and an immune mediated form associated with thrombosis called type II. Type I HIT is caused be a direct interaction of heparin with platelets. Type II HIT is caused by an antibody directed against heparin-PF4 (platelet factor 4) complexes, which bind to and activate platelets, leading to thrombocytopenia and thrombosis. The interaction of this immune complex with platelet membranes activates platelets, releases additional platelet factor 4, and perpetuates the cycle of platelet activation, thrombocytopenia, and thrombosis. Type I HIT affects up to 10% of patients treated with heparin. Platelet counts decrease rapidly within the first two days of heparin exposure, but usually remain above 100,000/uL. Platelet counts return to normal within two days in spite of continued heparin therapy. This type of HIT is not associated with an increased risk of thrombosis or any other adverse clinical consequences. No intervention is necessary. The incidence of type II HIT remains uncertain. Recent studies suggest that up to 8% of heparinized patients develop the antibodies associated with this type of HIT without becoming thrombocytopenic. Between 1 and 5% of heparinized patients develop antibodies and become thrombocytopenic, and approximately one third of these patients experience thrombosis. Most cases arise in patients who have not been previously exposed to heparin. In this situation, thrombocytopenia usually occurs 5 to 12 days after heparin initiation. In patients who have been previously sensitized to heparin, platelet counts may decrease within the first three days or even hours after re-exposure. Platelet counts usually decrease more than 50% from baseline and typically fall to 20,000 - 100,000/uL. The nadir is usually reached 5 days after onset of the decline. After discontinuing heparin, platelet counts begin to rise within 2-3 days and usually return to normal within 10 days. Antibody decreases to undetectable levels within 2-3 months after cessation of heparin therapy. Future exposure to heparin is contraindicated. The thrombosis associated with type II HIT usually involves major vessels, particularly the distal aorta and femoral arteries. Numerous complications have been reported including stroke, pulmonary embolism, myocardial infarction, mural thrombosis, mesenteric infarction, renal infarction, adrenal infarction, and distal limb gangrene. Patients with preexisting cardiovascular disease or recent cardiovascular surgery are prone to arterial thrombosis, while other postoperative patients are more likely to experience venous thrombosis. Any heparin compound can induce antibody formation, but those forms with the highest molecular weight and highest degree of sulfation are associated with the highest incidence of HIT type II. The types of heparin reported to cause HIT II in order of decreasing frequency are bovine heparin> porcine heparin> low molecular weight heparin> heparinoids. Low molecular weight heparin appears to induce antibody formation about one fourth as often as bovine heparin and seldom causes thrombocytopenia. HIT can be induced by any dose or route of heparin administration, including heparin flushes and heparin coated intra-arterial lines. High dose IV heparin is more likely to induce antibody formation than low dose subcutaneous heparin. Long duration of heparin administration is more likely to cause HIT, but the syndrome can occur after a single bolus. Heparin should be discontinued in any patient with a clinical presentation consistent with HIT type II. Heparin flushes and heparin coated catheters should also be avoided. Platelet transfusions are contraindicated because they may contribute to thrombus formation or extension. If continued anticoagulation is required, Coumadin should be initiated as soon as possible. Low molecular weight heparin should not be used, because antibody cross-reacts with it in 90% of cases. Heparinoids may be a useful alternative because they react with the HIT antibody in only 7 to 20% of cases. Elective procedures requiring heparin therapy should be delayed until antibody is no longer detectable. Patients receiving heparin should have a platelet count performed at least once every three days. If HIT type II is suspected, the diagnosis can be confirmed by laboratory tests that detect the antibody. An ELISA method is used for heparin antibody detection that has a sensitivity of 90% and a specificity of 98% for diagnosis of HIT. HIT antibody is detected by a sensitive enzyme immunoassay. In this assay, presence of the antibody results in a color change, detected as an increase in optical density (OD). The ELISA is reported as positive if the observed OD is above a specific threshold value, and negative if the OD is below the threshold. Until recently, it has not been known whether the actual OD has clinical significance, and specifically if there is any value in repeating the assay if the result is negative but just below the threshold. A recent study addressed this issue (Am J Clin Pathol 2003;119:61-65). Consecutive patients who had negative ELISA tests for HIT were divided into 3 equal groups, according to the OD for the negative result (see Table). The high negative group had borderline negative OD readings that were just below the threshold for positivity. Repeated ELISA tests were ordered at the discretion of the patients' physicians, who were unaware of the OD titer values. The results are shown in the following table.
These results indicate that a significant proportion of patients with a high negative (borderline) HIT ELISA result will convert to positive on repeat testing. Among those that converted to positive in this group, the median interval before the test was repeated was 3 days. The initial platelet counts (low in all except one patient) did not differ significantly among the 3 groups, and platelet counts in those that converted to positive did not change significantly. Among all the patients that converted to a positive HIT result on repeat testing, thrombosis occurred in 28%, and mortality was 44%, confirming the clinical importance of this finding. It is speculated that the initial false negative result in these patients may be due to performance of the test early in the course of HIT, when the antibody concentration may not yet be high enough to be detectable. In view of these findings, it is recommended that an initially negative HIT ELISA test be repeated after an interval of approximately 3 days, if the result is high negative, or if there is a strong clinical suspicion that HIT is present. The sensitivity of the HIT ELISA test is currently approximately 90%, a value that could probably be improved if repeat testing is undertaken. It should also be kept in mind that the ELISA test is not 100% specific - a positive test may occur in a proportion of patients exposed to heparin who do not develop HIT (specificity has varied in different studies from 86-98%). Results are reported as positive or negative. If a negative result falls into the "high/borderline negative" category, this should be noted on the chart, with a comment recommending that the test be repeated after approximately 3 days. Specimen requirement is one red top tube of blood is required. Reference value is no antibody detected. |
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