Heparin-induced thrombocytopenia: A prospective study

Thrombocytopenia is a well-described complication of heparin therapy. Few studies describe the incidence of thrombocytopenia when low-dose heparin (10,000–15,000 units/day) is used for prophylaxis of deep venous thrombosis. In our study, ten of 66 courses (15%) of heparin prophylaxis in coronary care unit patients were accompanied by a mild thrombocytopenia with platelet counts below 150 ± 10³/mm³. In all cases the platelet count returned to normal despite continued heparin therapy. Patients who became thrombocytopenic had significantly lower initial platelet counts. No cases of severe thrombocytopenia were seen (platelet count below 100 ± 10³/mm³). No patient developed thrombosis, bleeding or elevated fibrin split products. Mild thrombocytopenia occuring after 2–5 days of low-dose heparin is common, but clinically insignificant.     

Heparin-induced thrombocytopenia and thrombosis

Heparin, employed clinically for more than 50 years, is still a widely used anticoagulant. Unfortunately, some patients given this agent develop thrombocytopenia and thrombosis. Because this side effect can have catastrophic consequences, it is imperative that all clinicians caring for patients who receive heparin have at least a basic understanding of its pathogenesis, diagnosis, and management.     

Heparin-induced thrombocytopenia: analysis of risk factors in medical inpatients

Heparin-induced thrombocytopenia (HIT) is an unpredictable reaction to heparin characterized by thrombocytopenia and increased risk of life-threatening venous and/or arterial thrombosis. Data are lacking regarding additional risk factors that may be associated with the development of HIT. This study aimed to identify the risk factors that may be associated with HIT in medical inpatients receiving heparin. Twenty five thousand six hundred and fifty-three patients admitted to the medicine service who received heparin product were reviewed retrospectively. The diagnosis of HIT was confirmed if the platelet count dropped >50% from baseline and there was a positive laboratory HIT assay. Fifty-five cases of in-hospital HIT were observed. Multivariate analysis identified the administration of full anticoagulation dose with unfractionated heparin or exposure to heparin products for more than 5 d with an increased risk of HIT. Moreover, patients who were on haemodialysis, carried a diagnosis of autoimmune disease, gout or heart failure were also at increased risk. The results suggest that when using heparin products in these patient cohorts, increased surveillance for HIT is necessary.     

Heparin-induced thrombocytopenia and recurrent thromboembolism in siblings

Two brothers with heparin-induced thrombocytopenia and multiple arterial and venous thromboembolism affecting peripheral vessels are described. Heparin-dependent antiplatelet antibody was detected using platelet aggregometry in both patients. Although these observations may be coincidental, the possibility of familial occurrence of this adverse reaction to heparin cannot be excluded with certainty.     

Heparin-induced thrombocytopenia (HIT) due to heparin flushes: a report of three cases

Three cases of heparin-induced thrombocytopenia (HIT) are reported that were provoked by daily heparin flushes of central venous access devices. Each case had confounding features that delayed recognition of the problem. A review of the literature revealed only 29 previously reported cases of HIT secondary to heparin flushes. However, the true incidence of this problem is unknown. A high index of suspicion and confirmatory laboratory tests are necessary to make the diagnosis.     

Heparin-induced multiple electrode aggregometry is a promising and useful functional tool for heparin-induced thrombocytopenia diagnosis: Confirmation in a prospective study

Heparin-induced thrombocytopenia (HIT) is a potentially lethal adverse effect of heparin therapy. Accurate and rapid HIT laboratory diagnosis when HIT is suspected is crucial. The combination of an immunological assay with a functional test improves the accuracy of HIT, but functional assays are currently limited to a few laboratories. Multiplate® analyzer (Dynabyte, Munich, Germany) is a practical, semi-automated and easy-to-perform platelet aggregation assay. The aim of this study is to explore whether heparin-induced platelet aggregation in whole blood assessed by Multiplate® (Heparin-induced multiple electrode aggregometry, HIMEA) can replace platelet aggregation test (PAT) in platelet-rich plasma. For this purpose, HIMEA performance in HIT diagnosis was prospectively evaluated. HIMEA and PAT were compared to serotonin-release assay (SRA) in 200 well-characterized consecutive patients suspected for HIT. HIMEA was found to be more sensitive (81% vs. 76%) and more specific (99% vs. 96%) than PAT compared to SRA. Both tests showed a high negative predictive value while HIMEA had a better positive predictive value. HIMEA has overall better performance characteristics than PAT for the detection of HIT platelet-activating antibodies. The combination of an immunological assay with HIMEA could be a feasible option in non-specialized laboratories for HIT diagnosis optimization.     

Heparin-induced thrombocytopenia: evaluation of IgG and IgGAM ELISA assays

Background: Heparin‐induced thrombocytopenia (HIT) is a rare complication of heparin therapy resulting from antibody production to platelet factor 4 and heparin complexes (H‐PF4). Methods: We have evaluated four enzyme‐linked immunosorbent assay (ELISA)‐based screening tests to identify the best assay(s) with the highest specificity but without underdiagnosis of HIT. As functional assays are difficult to perform, ELISAs are useful to provide clinicians with a timely answer. Over a 10‐month period, all samples (N = 107) referred to our laboratory were tested for HIT antibodies using four commercially available ELISA kits, two detecting IgG/A/M anti‐H‐PF4 antibodies and the other two IgG specific. Results: Twenty‐eight samples were positive by at least one assay; IgGAM ELISAs were found to be more sensitive with 24 samples positive by Asserachrom IgGAM and 23 by Zymutest IgGAM. Only 18 samples were positive by GTI‐PF4‐IgG and Zymutest IgG. The gold standard serotonin release assay (SRA) was used as a confirmation assay, and 11/28 samples tested positive. All these SRA‐positive samples were positive by all four assays. None of the IgGAM‐only‐positive samples was found to be positive by SRA suggesting a better specificity for the IgG‐only assays. Conclusion: Our data strongly support the use of IgG‐only assays for the detection of HIT antibodies.     

Heparin-induced thrombocytopenia: recent experience in a large teaching hospital

Background: Heparin‐induced thrombocytopenia (HIT) is a potentially serious adverse reaction caused by platelet‐activating antibodies. Aim: To describe experience with HIT. Methods: Twenty‐two patients identified by laboratory records of heparin‐associated antibodies with a 50% or greater decrease in platelet count were reviewed in our 600‐bed metropolitan teaching hospital from 1999 to April 2005. Results: There was an increase in the frequency of HIT diagnosed during the review period, which was associated with a rise in the number of requests for HIT antibodies. Thrombotic complications were identified in 14 of 22 patients with HIT. Mean age was 65 years, and 11 patients were men. Seven patients died and HIT was considered contributory in four. One patient required mid‐forearm amputation. Unfractionated heparin was used in all cases and five patients also received enoxaparin. Mean time to HIT screen, reflecting when the diagnosis was first suspected, was 14 days. Platelet nadir ranged from 6 × 10⁹/L to 88 × 10⁹/L, with a percentage drop in platelet count of 67–96%. Alternative anticoagulation (danaparoid) was not used in three patients, two of whom died. Conclusions: HIT is a potentially life‐threatening complication of heparin therapy, associated with a fall in platelet count and a high incidence of thromboembolic complications. It is most frequently seen using unfractionated heparin therapy. The increase in frequency of HIT diagnosed in our hospital appears to be associated with a greater awareness of the entity, although detection is often delayed. Platelet count should be monitored in patients on heparin and the presence of antiplatelet antibodies determined if HIT is suspected. Treatment involves both discontinuation of heparin and the use of an alternative anticoagulant such as danaparoid because of the persisting risk of thrombosis.     

A diagnostic test for heparin-induced thrombocytopenia: detection of platelet microparticles using flow cytometry

Based on our previous observation that heparin-induced thrombocytopenia (HIT) sera can generate platelet microparticles from washed platelets in a heparin-dependent fashion, we developed a test for HIT using flow-cytometry to measure heparin-dependent platelet microparticle formation. During the developmental phase of the assay the optimal physical conditions for microparticle generation were defined. 133 sera were then evaluated using the microparticle assay and the serotonin release assay to determine the threshold for defining a positive result that gave optimal sensitivity and specificity. The microparticle assay was then prospectively evaluated against the serotonin release assay in 202 sera referred to our laboratory for HIT testing. Overall agreement between the two assays was 96% (Cohen's kappa = 0.91). When the clinical data were reviewed on patients whose sera gave discrepant results between the two assays, no case of HIT was detected by one assay and missed by the other. The platelet microparticle assay is as accurate as the serotonin release assay and may be a useful non-radioactive test for HIT.     

Heparin-induced thrombocytopenia

Thrombocytopenia is a common adverse effect of heparin therapy. Two types of heparin^linduced thrombocytopenia (HIT) are observed clinically - an early onset mild thrombocytopenia (Type I) in which the patients remain asymptomatic and a delayed onset severe thrombocytopenia (Type II). Patients with Type II HIT have an increased risk of thrombotic complications which frequently cause crippling disability e.g. limb amputation or even death. Type I HIT, the commoner of the two types, is believed to be due to the platelet proaggregating effect of heparin itself but Type II HIT is generally agreed to be caused by an immune mechanism, in which heparin-antibody complexes bind to platelets resulting in platelet activation, reduced platelet survival, thrombocytopenia and, in some cases, thrombosis. The diagnosis of HIT is made mainly on a clinical basis but in patients with suspected Type II HIT, laboratory test for the heparin-dependent antibody using platelet aggregometry or the two-point ¹⁴C-serotonin release method, allows confirmation of the diagnosis. In most Type I and all Type II patients, heparin should be stopped and warfarin commenced if there is a recent or new thrombosis requiring continuing anticoagulation. An alternative antithrombotic drug such as low molecular weight heparinoid (Org 10172) or dextran should be given at the same time until warfarin becomes therapeutic. The use of low molecular weight heparins (e.g. Fragmin) should be avoided unless it can be demonstrated that the HIT antibody does not cross-react with these drugs. (Aust NZ J Med 1992; 22: 145–152.)     

Heparin-induced thrombocytopenia and thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases

Heparin-induced thrombocytopenia and/or thrombosis (HITT) are serious complications of heparin treatment. The incidence, as previously reported, varies widely and, in consequence, is not precisely known. Moreover, most reports only concern clinically defined heparin-induced thrombocytopenia. Therefore we carried out a prospective study of the incidence of serologically confirmed HITT.
All patients admitted to the Departments of Cardiology and Neurology of our institution with an indication for treatment with therapeutic-dose intravenous unfractionated heparin were enrolled in the study. The patients were examined daily for the occurrence of thromboembolic complications. Regular platelet counts and tests for the presence of heparin-dependent antibodies were carried out using two different tests: a quantitative platelet factor 4/heparin (PF4/hep) Elisa, and a functional test, the heparin-induced platelet activation assay (HIPAA). HITT was defined as a rapidly occurring (within 5 d) decrease of the platelet count from normal values of >120 ×10⁹ l to <60 ×10⁹ l or to <100 ×10⁹ l if there was a rapid fall of >50% of starting value or >30% with concomitant acute thrombosis.
The observed incidence of HITT was 1/358 patients (0.3%, 95% confidence limits 0.01–1.5%). However, Elisa PF4/hep specific IgG antibodes were demonstrated in nine (2.5%) and IgM antibodies in seven (2.0%) of 358 patients. 30/358 patients (8.4%) had platelet activating antibodies in the HIPAA.
We conclude that the incidence of serologically confirmed HITT in this study is very low (0.3%) in patients with cardiac and neurologic diseases treated with intravenous unfractionated heparin. The frequency of heparin-dependent antibodies without concomitant occurrence of thrombocytopenia is much higher.     

Heparin-induced thrombocytopenia and thrombosis: reversal with streptokinase. A case report and review of literature

Heparin-induced thrombocytopenia and thrombosis is associated with a significant incidence of morbidity and mortality. Prompt recognition of this complication and immediate withdrawal of heparin therapy are imperative. This report describes a case of heparin-induced thrombosis and thrombocytopenia with major vascular insufficiency of the extremities. This is the first reported instance of the use of intravenous streptokinase for the treatment of heparin-induced venous thrombosis.     

The use of low dose Orgaran in heparin-induced thrombocytopenia associated with in vitro platelet aggregation at higher Orgaran concentrations

We report a case of heparin-induced thrombocytopenia with in vitro antibody cross-reactivity by platelet aggregometry to both low molecular weight heparin and the heparinoid Org 10172 (Orgaran). The in vitro reactivity with Orgaran was only present at the upper limit of concentrations that would normally be used therapeutically. Low dose Orgaran therapy was initiated, allowing successful renal replacement therapy without invoking further thrombocytopenia or thrombosis. Interestingly, in vitro platelet aggregometry following treatment did not reveal increasing sensitivity to Orgaran. This case indicates that negative in vitro platelet aggregometry at defined lower concentrations of Orgaran may predict in vivo safety at the same levels despite positive platelet aggregometry reactions at higher concentrations of Orgaran.     

Danaparoid for heparin-induced thrombocytopenia: an analysis of treatment failures

BACKGROUND: Patients with heparin-induced thrombocytopenia (HIT) (with or without thrombosis) require alternative anticoagulation because of their extreme risk of new thromboembolic complications. The first effective agent for this purpose may be danaparoid, a less-sulfated low molecular weight heparinoid. Recently, direct thrombin inhibitors have been used. OBJECTIVE: Five HIT patients, who developed new thromboembolic complications while receiving danaparoid, were analyzed to consider possible reasons for treatment failure and to promulgate strategies that improve efficacy. RESULTS: Three patients had acute HIT, one had recent HIT, and one with remote HIT was re-exposed to heparin during heart surgery. Danaparoid was started as intravenous bolus and infusion in one patient, and as 1250 units subcutaneously twice daily in four patients. The new complications that emerged on danaparoid were new venous thrombi in three patients (one with pulmonary emboli), lower extremity arterial thrombosis in one, myocardial ischemia in one, thromboembolic cardiovascular accidents in one, and fatal bowel necrosis in one (two patients suffered more than one complication). Platelet counts did not improve or worsened in four, improved partially in the other, and parameters of disseminated intravascular coagulation failed to improve in one patient. Four patients responded relatively dramatically when direct thrombin inhibitors were substituted. Possible reasons for danaparoid failure include that: 1) no treatment is expected to completely prevent complications, 2) antithrombin III consumption can blunt efficacy in some patients, 3) low or intermediate doses may be insufficient, and 4) there was clinically significant cross-reactivity of the pathogenic HIT antibodies. CONCLUSIONS: It is emphasized that the possibility of clinically significant antibody cross-reactivity and that low or intermediate dosage may be inadequate when using danaparoid in therapy of HIT. The latter problem probably extrapolates to other anticoagulants used for HIT.     

Simultaneous binding of heparin and platelet factor-4 to platelets: Further insights into the mechanism of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is mediated by antibody against complexes of platelet factor-4 (PF4) and heparin. Although it has been assumed that these complexes bind to platelets and provide a target for the antibody, this has never been demonstrated. Furthermore, there is evidence suggesting that heparin-PF4 complexes do not bind to platelets. We have analyzed the effect of each ligand on the platelet binding of the other. We particularly focused on the result when heparin and PF4 are in equimolar concentration because we had previously shown that this was the condition under which HIT-IgG increased on the platelet surface. We found that when the molar concentration of PF4 approximates or exceeds that of heparin, the ligands bind simultaneously to the cells and HIT-IgG binds also. However, when heparin is in molar excess, both PF4 binding and HIT-IgG binding are diminished. Our data are consistent with the hypothesis that heparin-PF4 complexes bind via their heparin component to heparin binding sites on the platelet membrane rather than by their PF4 component to PF4 sites. The conditions promoting the binding of the complexes also lead to binding of HIT-IgG. Am. J. Hematol. 58:24–30, 1998. © 1998 Wiley-Liss, Inc.     

Heparin-induced thrombocytopenia associated with interleukin-8-dependent platelet activation in a patient with antiphospholipid syndrome

Platelet factor 4 heparin enzyme immunoassay, platelet aggregation test, and serotonin release assay are commonly used to diagnose and confirm heparin-induced thrombocytopenia. We describe a case of recurrent thrombocytopenia appearing in a few hours after each heparin administration and who tested negative for the three assays. Further analysis revealed anti-interleukin (IL)-8 antibodies and IL-8-dependent platelet activation facilitated by heparin, which may explain this unusual case of heparin-induced thrombocytopenia.     

Heparin-induced thrombocytopenia with thrombosis: Incidence,analysis of risk factors,and clinical outcomes in 108 consecutive patients treated at a single institution

Heparin-induced thrombocytopenia with thrombosis (HITT) can lead to serious morbidity and may be potentially fatal. We reviewed our experience with this entity over a 4-year period, to determine the following: 1) incidence and type of thrombosis in patients with heparin-induced thrombocytopenia (HIT), 2) clinical consequences of thrombosis, i.e., amputation, cerebrovascular accidents and death, 3) risk factors associated with development of thrombosis, and 4) impact of therapy on clinical outcomes in patients with HITT. Between 1991–1994, 108 patients were diagnosed to have HIT by heparin-induced platelet aggregation test. Thirty-two (29%) of these developed thrombotic complications, of which 20 were venous, 8 arterial, and 4 both. Five of the 32 died, 3 underwent amputations, and 3 had cerebrovascular accidents. The patients who developed thrombotic complications, when compared to those with HIT alone, were older (68.7 ± 11.5 vs. 63.3 ± 16 years, P = .05), had more severe thrombocytopenia (platelet count 46,300 ± 30,400/mm³ vs. 62,500 ± 34,400/mm³, P = .02), and developed it earlier (6.0 ± 2.9 vs. 7.4 ± 3.1 days, P = .03). Multivariate analysis showed that severity of thrombocytopenia and early fall in platelet count were independent risk factors for development of thrombotic complications. We did not find an association between development of thrombosis and clinical events (myocardial infarction, cardiac procedures or surgery, noncardiac surgery, and sepsis) that occurred immediately prior to onset of thrombocytopenia. Heparin was stopped in all 32 patients with HITT. Six received no additional therapy, and one received a single dose of aspirin. Three of these 7 died. The other 25 received anticoagulant or multiagent therapy, with 2 deaths. The death rate was lower in those who were treated with anticoagulant or multiagent therapy (P = .05). We conclude that: 1) Thrombotic complications occur in about 29% of hospitalized patients who develop HIT. 2) Early, severe fall in platelet count in elderly patients receiving heparin appears to be associated with development of thrombotic complications. 3) Our data do not show an association between development of thrombotic complications and clinical events immediately preceding the diagnosis of HIT. 4) In addition to discontinuation of heparin, anticoagulant or thrombolytic therapy should be considered in patients with HITT. Am. J. Hematol. 56:12–16, 1997. © 1997 Wiley-Liss, Inc.