Diagnosis and management of heparin-induced thrombocytopenia

Heparin use is ubiquitous, wherein 1 to 5% of patients exposed to standard unfractionated heparin develop thrombocytopenia due to antibodies to a complex of heparin and platelet factor 4. Classic features include onset of thrombocytopenia after 5 to 10 days of ongoing heparin exposure, a 50% fall in the platelet count from baseline, resolution of the thrombocytopenia 5 to 10 days after cessation of heparin and a high risk of thrombosis noted in 30 to 75% of patients with heparin-induced thrombocytopenia (HIT) in terms of every-other-day platelet-count monitoring in patients on standard unfractionated heparin. And those patients developing thrombocytopenia necessitate an accurate, readily accessible diagnostic test for HIT. Diagnosis has been recently facilitated by the development of an enzyme-linked immunosorbent assay (ELISA) test for the heparin-P4 antibody complex, although this test carries a relatively low specificity. Widespread use of the ELISA demonstrates a relatively high prevalence of the antibody in patients exposed to heparin in certain settings, such as cardiopulmonary bypass, wherein a quarter of patients have a positive ELISA of unclear significance. Once HIT is diagnosed, the high risk of thrombosis necessitates empiric anticoagulation with an antithrombin such as argatroban or lepirudin, or the heparinoid danaparoid. Additional agents under further study include the antithrombin bivalirudin and the pentasaccharide fondaparinux. Future issues in HIT include increasing awareness for HIT, improving the specificity of HIT testing and the development of new anticoagulants for HIT that will enable out-patient management.     

肝素诱导的血小板减少症的临床研究

目的 观察应用肝素治疗患者肝素诱导的血小板减少症(HIT)发病情况,探索血小板计数监测HIT的可行性及HIT抗体检测对HIT诊断的意义.方法 对在血管外科应用普通肝素(UFH)治疗的145例患者进行临床观察,于应用UFH治疗前及治疗后进行血小板计数、HIT抗体ELISA检测及肝素诱导的血小板聚集试验(HIPA)等实验室检测.结果 145例患者中血小板减少40例(27.6%),HIT抗体阳性59例(40.7%),HIPA阳性26例(17.9%),诊断HIT 24例(16.5%),其中发生HIT并血栓形成综合征(HITTS)5例(发病率3.4%,占HIT患者的20.8%).多数HIT患者(15例,62.5%)血小板减少与HIT抗体阳性、HIPA阳性同时发生.24例HIT患者的血小板计数均在停用UFH后3～6 d恢复到正常或达到用UFH前水平.结论 通过动态监测血小板计数、联合HIT抗体ELISA法检测及HIPA,可以早期诊断HIT,及时停用UFH,换用抗凝剂,HITTS的发生率有望进一步下降,减少致残、死亡的发生.

Abstract：

Objective To observe the incidence of heparin-induced thrombocytopenia (HIT) in patients received unfractionated heparin ( UFH ) treatment, and explore the feasibility of monitoring HIT by platelet counts, as well as the significance of HIT-antibody test in HIT diagnosis. Methods 145 patients received UFH treatment in Vascular Surgery Department were studied. Before and after the UFH treatment,platelet counts, HIT-antibody ELISA test and heparin-induced platelet aggregation (HIPA) were tested.Results Among the 145 patients, thrombocytopenia occurred in 40 ( 27.6% ) cases, HIT-antibody ELISA test positive in 59(40.7% ) cases, HIPA test positive in 26( 17.9% ) cases. The HIT was diagnosed in 24 (16.5%) cases, and heparin-induced thrombocytopenia and thrombosis (HITTS) occurred in 5( 3.4% in all cases, and 20.8% in HIT patients). In HIT patients, 15 patients (62.5%) were thrombocytopenia, HITantibody positive and HIPA test positive. Platelet counts in all of the 24 patients recovered to normal or level before UFH treatment in 3 -6 days after heparin withdrawal therapy. Conclusion HIT can be early diagnosed by monitoring platelet counts, HIT-antibody ELISA test and HIPA test. Withdrawal of heparin therapy in time and use of alternative anticoagulant, HITTS rate might be expected to decline further.     

Heparin‐induced thrombocytopenia complicating extracorporeal membrane oxygenation support: Review of the literature and alternative anticoagulants

Heparin‐induced thrombocytopenia (HIT) is a life‐threatening prothrombotic, immune‐mediated complication of unfractionated heparin and low molecular weight heparin therapy. HIT is characterized by moderate thrombocytopenia 5‐10 days after initial heparin exposure, detection of platelet‐activating anti‐platelet factor 4/heparin antibodies and an increased risk of venous and arterial thrombosis. Extracorporeal membrane oxygenation (ECMO) is a form of mechanical circulatory support used in critically ill patients with respiratory or cardiac failure. Systemic anticoagulation is used to alleviate the thrombotic complications that may occur when blood is exposed to artificial surfaces within the ECMO circuit. Therefore, when HIT complicates patients on ECMO support, it is associated with a high thrombotic morbidity and mortality. The risk for HIT correlates with the accumulative dosage of heparin exposure. In ECMO patients receiving continuous infusion of heparin for circuit patency, the risk for HIT is not neglected and must be thought of in the differential diagnosis of the appropriate clinical and laboratory circumstances. The following article reviews the current knowledge in HIT complicating ECMO patients and the alternative anticoagulation options in the presence of HIT.     

Heparin-induced thrombocytopenia

Heparin is widely used for the prevention and treatment of thrombotic and particularly cardiovascular disorders. Unfortunately, 0.5 to 3.0% of patients given heparin develop an immune reaction, commonly termed Type II heparin-induced thrombocytopenia (HIT). This is characterized by a moderate thrombocytopenia and in some patients, a venous or arterial thrombosis. This frequently leads to disastrous sequelae, such as limb amputation and death. The pathophysiological basis of this serious adverse drug reaction is the production of an immunoglobulin G antibody that reacts with an antigenic complex consisting of heparin and platelet factor 4. A significant risk factor for the development of HIT is recent surgery, and the frequency of developing an antiheparin–platelet factor 4 or HIT antibody is particularly high in cardiac surgery patients, although surprisingly, only a few of these patients actually develop the clinical syndrome of HIT. This review will discuss the frequency, pathophysiology, clinical features, diagnosis and management of HIT.     

Heparin-induced thrombocytopenia: how to manage it, how to avoid it

Heparin therapy has two potential adverse effects: bleeding and heparin-induced thrombocytopenia (HIT). There are two types of HIT: type I is more common but less severe; type II occurs less frequently but involves severe thrombocytopenia and a high risk for thrombotic events. Treatment involves discontinuing heparin, allowing the platelet count to return to normal, and treating any thrombosis. Lepirudin (Refludan) is the only agent currently approved for the treatment of HIT-related thrombosis, but other agents may have a role in combination therapy. Prevention includes using low molecular weight heparin instead of unfractionated heparin and limiting unfractionated heparin therapy to less than 5 days.     

Heparin-induced thrombocytopenia

Summary.  Heparin-induced thrombocytopenia (HIT) is not only a common but also a potentially serious drug adverse effect. Unlike other drug-induced thrombocytopenias, HIT does not usually cause bleeding, but instead causes thrombosis. Thrombosis in HIT can lead to limb gangrene (requiring leg amputation) or even death. HIT is mediated by an antibody that recognizes an epitope on the platelet factor 4 (PF4)–heparin complex. The antibody–PF4–heparin complex binds to FcγRII receptors on the platelet surface and cross-links the receptors. This induces intense platelet activation and platelet aggregation, and simultaneously activates blood-coagulation pathways. These changes are probably the basis of the thrombotic events in HIT. Diagnosis of HIT should be made mainly on clinical criteria but should be confirmed whenever possible by laboratory tests, particularly in patients with comorbid conditions, in whom the diagnosis of HIT cannot be made with certainty without testing. The tests for HIT antibodies are either immunoassays (e.g. ELISA), or functional tests, (e.g. ¹⁴C-serotonin release assay). Once a clinical diagnosis of HIT is made, heparin should be ceased immediately and treatment with an alternative anticoagulant (such as danaparoid, r-hirudin or argatroban) commenced. This should continue for at least 5 days unless the diagnosis of HIT is subsequently proven to be incorrect. Warfarin should also be commenced when the patient is clinically stable and thrombosis is under control. There should be an overlap of a few days between warfarin and the alternative anticoagulant therapy.     

Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need?

Heparin-induced thrombocytopenia (HIT) is usually caused by platelet-activating antibodies of immunoglobulin G class that recognize platelet factor-4 (PF4) bound to heparin or certain other polyanions. Commercial enzyme immunoassays (EIAs) for PF4/polyanion-reactive antibodies detect two immunoglobulin classes (IgA and IgM) besides IgG. To investigate whether the additional detection of these antibody classes improves or worsens assay operating characteristics, we compared the sensitivity and specificity of EIAs that detect these 3 immunoglobulin classes individually with that of a commercial EIA (Genetic Testing Institute, GTI), as well as a platelet-activation assay, the serotonin-release assay (SRA). We compared the operating characteristics of these 5 assays by evaluating 448 patients, in 14 of whom clinical HIT developed, who received either unfractionated or low molecular weight heparin in prospective studies that included systematic platelet-count monitoring and serologic evaluation for anti-PF4/polyanion antibodies. We found that the SRA and IgG and commercial EIAs had similar high sensitivity for HIT; however, diagnostic specificity (for unfractionated and low molecular weight heparin, respectively) varied considerably, as follows: SRA (95.1%, 97.2%) > IgG EIA (89.0%, 93.7%) > GTI EIA (74.2%, 87.6%). Additional detection of IgA and IgM antibodies by the GTI EIA worsened test specificity by detecting numerous nonpathogenic antibodies. Moreover, the frequency and magnitude of IgA and IgM antibody formation in non-HIT immune responses did not differ from that exhibited by patients in whom clinical HIT developed. We conclude that an EIA that detects anti-PF4/polyanion antibodies of only the IgG class has greater diagnostic usefulness in revealing clinical HIT than does an assay that also detects IgA and IgM class antibodies.     

Heparin-induced thrombocytopenia

A summary of heparin-induced thrombocytopenia (HIT) is presented. HIT is an adverse drug reaction characterized by thrombocytopenia and a high risk for venous or arterial thrombosis. The frequency of HIT ranges from 1 to 5% of patients receiving heparin with exact frequencies ranging between specific agents. Interestingly, this immune-mediated syndrome is ironically associated with thrombosis, not bleeding, with thrombin formation playing a major role. It is caused by heparin-dependent, platelet-activating antibodies that identifies a self-protein, PF4, bound to heparin that results in an antibody formation. The resulting platelet activation is associated with increased thrombin generation. Typically, the platelet count fall begins 5–10 days after starting heparin, although a rapid platelet count fall can occur in a patient who has antibodies from recent heparin use. Typical causes of HIT as well as the best diagnostic studies and treatment are discussed in this review. HIT was reviewed using a pubmed? search; google scholar? using key words: “Heparin-induced thrombocytopenia”; “heparin”, and “drug AND thrombocytopenia.”     

Prospective observational evaluation of the particle immunofiltration anti-platelet factor 4 rapid assay in MICU patients with thrombocytopenia

Introduction

Heparin-induced thrombocytopenia (HIT) results from antibodies to PF4/heparin complexes and clinical diagnosis is difficult. We evaluated the particle immunofiltration anti-platelet factor 4 (PIFA) rapid assay, in conjunction with a clinical risk score, in the diagnosis of HIT.

Methods

We performed a prospective observational study in all patients admitted to the medical intensive care unit (MICU) in a large academic medical center. Patients were screened daily for thrombocytopenia defined as either a platelet count that decreased by at least 33% or an absolute platelet count less than 150,000/μL. Patients with suspected HIT underwent PIFA and ELISA testing for anti-PF4/heparin antibodies. Available residual frozen sera were sent to a reference laboratory for serotonin release assay (SRA) testing.

Results

During the study period, 340 patients were admitted to the MICU, of which 143 patients met criteria for thrombocytopenia. Forty-three patients had no evidence of recent heparin exposure. PIFA and ELISA testing were performed on 100 patients, of which 92 had samples available for SRA analysis. PIFA results were negative in 62, positive in 28 and inconclusive in 2 patients. The 4Ts score showed low to intermediate risk in 57 of the PIFA negative patients. The ELISA results were negative in 86 and positive in 6 patients. SRA testing identified 3 patients with a positive SRA test and 89 patients with a negative result. All patients with a negative PIFA result also had a negative SRA result. In the one patient deemed to have clinical HIT, the pretest probability was high (4Ts score of 6) and the anti-PF4/heparin antibody testing revealed a positive SRA, inconclusive PIFA and a negative ELISA result.

Conclusions

While thrombocytopenia in our population is common, the prevalence of HIT is low. The combination of a low to intermediate pretest probability with a negative PIFA test can rapidly exclude the presence of platelet activating anti-PF4/heparin antibodies and, therefore, HIT as the cause of the thrombocytopenia. Since a positive PIFA result has a low positive predictive value, a positive PIFA is not diagnostic of HIT and additional evaluation is warranted.     

Fondaparinux treatment of acute heparin‐induced thrombocytopenia confirmed by the serotonin‐release assay: a 30‐month, 16‐patient case series

See also Greinacher A. Immunogenic but effective: the HIT‐fondaparinux brain puzzler. This issue, pp 2386–8; Goldfarb MJ, Blostein MD. Fondaparinux in acute heparin‐induced thrombocytopenia: a case series. This issue, pp 2501–3. Summary. Background: Fondaparinux is theoretically an attractive agent for the treatment of immune heparin‐induced thrombocytopenia (HIT), a prothrombotic disorder caused by platelet‐activating anti‐platelet factor 4/heparin antibodies. Although reports of the use of fondaparinux for this indication have thus far been favorable, the diagnosis of HIT in most cases was not based on definitive laboratory confirmation of heparin‐dependent, platelet‐activating antibodies. Objectives: To report thrombotic and major bleeding outcomes with fondaparinux in patients with a high likelihood of having acute HIT based on clinical features and a positive result in the confirmatory platelet serotonin‐release assay (SRA), a sensitive and specific test for platelet‐activating HIT antibodies. Methods/Patients: We reviewed consecutive eligible patients with SRA‐positive HIT (mean peak serotonin release, 91% [normal, < 20%]; mean IgG‐specific PF4/heparin enzyme immunoassay result, 2.53 optical density units [normal, < 0.45 units]) in one medical center over a 30‐month period who received fondaparinux for anticoagulation during acute HIT (platelet count, < 150 × 10⁹ L^?1). Where available, plasma samples were used to measure thrombin–antithrombin (TAT) complex levels. Results: Sixteen patients with SRA‐positive HIT received fondaparinux: 14 surgical (11 after cardiac surgery; three after vascular surgery) and two medical (acute stroke). Fifty‐six per cent of patients had HIT‐associated thrombosis at the time of diagnosis. No patient developed new, recurrent or progressive thrombosis; one patient developed a major bleed (calf hematoma). One patient judged to have irreversible tissue necrosis before receiving fondaparinux therapy ultimately required limb amputation. TAT complex levels were reduced within 24 h of starting fondaparinux, and 13 of 13 patients were successfully switched to warfarin. Conclusion: Fondaparinux shows promise for the treatment of patients with SRA‐positive acute HIT.     

肝素／血小板因子4抗体与肝素诱导的血小板减少症

肝素诱导的血小板减少症（heparin—induced thrombocytopenia，HIT）是肝素治疗引起的严重并发症，可导致血栓形成和栓塞。HIT的发病机制主要与肝素／血小板因子4抗体介导的免疫反应有关，IgG类是主要的致病抗体，能与肝素和血小板因子4结合形成复合物，引起血小板凝集和凝血反应增强，同时抗体还通过作用于血管内皮细胞和单核细胞参与HIT的形成。抗体相关的实验室检测包括功能性血小板试验和免疫学试验，临床表现结合实验室检测有助于本病的早期诊断和治疗，但是在检测方面目前尚没有理想的方法。本文就AHPF4抗体、HIT发病机制、临床实验室检测和免疫学试验检测等问题进行了综述。     

Heparin-induced thrombocytopenia: an autoimmune disorder regulated through dynamic autoantigen assembly/disassembly

Heparin‐induced thrombocytopenia (HIT) is the most common drug‐induced, antibody‐mediated cause of thrombocytopenia and thrombosis. HIT is caused by IgG antibodies that bind to epitopes on platelet factor 4 (PF4) released from activated platelets that develop when it forms complexes with heparin. Anti‐PF4/antibodies develop in over 50% of patients undergoing surgery involving cardiopulmonary bypass (CPB), an incidence 20‐fold higher than HIT. Why might this occur? Binding of HIT IgG occurs only over a narrow molar ratio of reactants, being optimal at 1 mol PF4 tetramer to 1 mol unfractionated heparin (UFH). At these ratios, PF4 and UFH form ultralarge (>670 kD) complexes that bind multiple IgG molecules/complex, are highly antigenic, and promote platelet activation. Low molecular weight heparin (LMWH), which is less antigenic, forms ultralarge complexes less efficiently and largely at supratherapeutic concentrations. In transgenic mice that vary in expression of human PF4 on their platelets, antigenic complexes form between PF4 and endogenous chondroitin sulfate. Binding of HIT IgG to platelets and induction of thrombocytopenia in vivo is proportional to PF4 expression. Heparin prolongs the duration and exacerbates the severity of the thrombocytopenia. High doses of heparin, as used in CPB, or protamine, which competes with PF4 for heparin, disrupts antigen formation and prevents thrombocytopenia induced by HIT antibody. These studies may help explain the disparity between the incidence of antibody formation and clinical disease and may help identify patients at risk for HIT (high platelet PF4). They also demonstrate that this autoimmune disease can be modulated at the level of autoantigen formation and point to rational means to intervene proximal to thrombin generation. J. Clin. Apheresis. 22:, 2007 © 2007 Wiley‐Liss, Inc.     

Thrombosis and hemorrhage in heparin-induced thrombocytopenia in seriously ill patients

Objective Heparin-induced thrombocytopenia (HIT) is the most common form of drug-induced immune-mediated thrombocytopenia. HIT may be aggravated by life-threatening arterial and venous thrombosis and, to a lesser extent, hemorrhagic complications. We investigated the incidence of thromboembolic and hemorrhagic complications in critically ill patients with the multiple organ dysfunction syndrome and HIT.Design Case-control study.Setting A 33-bed general intensive care unit in a university-affiliated teaching hospital.Patients Twenty consecutive patients with laboratory-proven HIT compared with 20 contemporary, consecutive patients without HIT.Interventions Unfractionated heparin or low-molecular-weight heparin were replaced by danaparoid sodium in patients with HIT.Measurements and results Heparin-induced thrombocytopenia was proven by a positive platelet aggregation test. The HIT group consisted of 14 males and 6 females aged 65.2±10.8 years (mean ± standard deviation) with APACHE II scores of 26.7±5.4. Thrombocytopenia less than 100×10⁹/l developed within 6.4±7.0 days. In 12 patients thrombocytopenia resolved after discontinuation of unfractionated heparin in 8.8±6.4 days. Arterial and venous thromboembolic complications occurred more frequently in HIT patients than in non-HIT patients (10/20 (50%) versus 0/20 (0%); chi-square p<0.001). Hemorrhagic complications also occurred more frequently in HIT patients than in non-HIT patients (17/20 (85%) versus 7/20 (35%); chi-square p=0.001).Conclusion In critically ill patients with HIT, the incidence of thromboembolic complications and hemorrhagic complications was remarkably high.Electronic Supplementary Material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00134-004-2334-1     

Heparin‐induced non‐necrotizing skin lesions: rarely associated with heparin‐induced thrombocytopenia

See also Warkentin TE, Linkins L‐A. Non‐necrotizing heparin‐induced skin lesions and the 4T’s score. This issue, pp 1483–. Summary. Background: Recently, there has been an increasing number of reports regarding adverse skin reactions to subcutaneous heparin administration. Case series have implied that heparin‐induced skin lesions are predominantly associated with life‐threatening heparin‐induced thrombocytopenia (HIT) in at least 22% of patients. Skin lesions, therefore, have been included in clinical scores for HIT. Objectives: To determine the association of heparin‐induced skin lesions with HIT. This would have a pivotal impact on further anticoagulatory management in patients with heparin‐induced skin lesions. Patients/Methods: In our observational cohort study, 87 consecutive patients with heparin‐induced skin lesions (85 occurring during low‐molecular‐weight heparin administration) were evaluated using a standardized internal protocol, including HIT diagnostics (heparin‐platelet factor 4‐ELISA, heparin‐induced platelet activation assay), platelet count monitoring, clinical/sonographical screening for thrombosis, skin allergy testing and, if necessary, histology. Results: None of the observed heparin‐induced skin lesions was due to HIT; all lesions were caused by delayed‐type IV‐hypersensitivity reactions (DTH) instead. Even the cutaneous reaction in one patient with concomitant HIT could be classified histologically as DTH reaction, amounting to an association of heparin‐induced skin lesions and HIT in 1.2% (1/87; 95% confidence interval, 0.00–0.06). Conclusion: Heparin‐induced skin lesions associated with use of low‐molecular‐weight heparins do not seem to be strongly associated with a systemic immunologic reaction in terms of HIT and might rather be due to DTH reactions than due to microvascular thrombosis. Hence, we propose refining existing pretest probability scores for HIT, unless underlying causes have been clarified.     

Prevalence of heparin-induced antibodies in patients with chronic renal failure undergoing hemodialysis

Heparin-induced thrombocytopenia (HIT) type II is a serious complication of heparin therapy. It presents initially as thrombocytopenia, and is associated with thrombosis in 20-50% of the cases. HIT is related to the presence of heparin-induced antibodies (HIA), which show specificity for the PF4-heparin (PF4-H) complex. The FcgammaRIIa receptor has been suggested to participate in the pathogenic mechanism of HIA. Since patients undergoing chronic hemodialysis (HD) are exposed repeatedly to heparin, we studied the prevalence of HIA and their eventual relationship with thrombocytopenia and/or thrombosis, and the possible participation of the FcgammaRIIa polymorphism. We studied 207 patients with chronic renal failure (CRF) undergoing HD. As a control we included 130 blood donors and 28 patients with CRF without HD. The HIA patients were studied with the use of a PF4-H ELISA. Additionally, in some positive cases for the previous test, a 14C- serotonin release assay (14C-SRA) was performed. The polymorphism FcgammaRIIa H/R131 was studied by polymerase chain reaction (PCR) with allele-specific primers. Thirty-seven patients (17.9%) undergoing HD presented with HIA. The majority of these antibodies were IgG, IgM, and IgA. The HIA investigated presented specificity against the PF4-H complex, but not against PF4 alone (P<0.001). Twelve out of 22 (54.5%) PF4-H antibodies were positive when tested with the 14C-SRA. The distribution of the FcgammaRIIa polymorphism in patients and healthy controls was 42.6% and 41.6% for H/H131, 41% and 48.9% for the H/R131 isoform, and 16.4% and 9.5% for the R/R131 isoform, respectively. No statistically significant difference in the FcgammaRIIa isoform distribution was found. Twenty-nine out of 156 patients (18.5%) presented thrombocytopenia, and 21/207 (12.4%) had thrombosis of the native vein arterio-venous fistula (AVF). We did not find any statistically significant between HIA and thrombocytopenia or thrombosis. An important proportion of patients with CRF undergoing HD developed HIA, but these cases were not associated with thrombocytopenia or thrombosis of AVF. The frequency of the FcgammaRIIa polymorphism did not statistically differ between HIT type II and normal controls.     

Assays for heparin-induced thrombocytopenia

Tests for the presence of heparin-dependent antibodies (heparin-Ig) have evolved in parallel with improved understanding of the pathophysiology of heparin-induced thrombocytopenia (HIT). The first group of tests relied upon platelet aggregation or activation. Among tests in this group, the serotonin release assay has been reported to demonstrate the best performance characteristics. However, this test has not been widely adopted outside a few specialized laboratories owing to its complexity and need for radioactive materials. As a result, the less sensitive and specific platelet aggregation test is more commonly used for the diagnosis of heparin-Ig. The literature suggests that test sensitivity can be improved by the use of the patient’s own platelets, platelets from selected donors known to be reactive in the assay, or washed platelets. Test specificity has been enhanced by the use of two point assays that include neutralization of the reaction by a high dose of heparin. A second group of assays have focused on detection of heparin-dependent binding of immunoglobulins to the platelet membrane. Most of these tests are hampered by the fact that platelets in patients with suspected HIT and in conditions that are in the differential diagnosis of HIT frequently express high levels of platelet-associated immunoglobulin. The most recent tests for heparin-Ig are based on the recognition that patient antibodies are directed against the heparin-PF4 complex. This has led to the development of the PF4/heparin EIA assay. Because whole platelets are not used in this assay, problems related to under-reactivity or nonspecific reactivity are avoided. In addition, the ability of the test to predict clinical complications may be improved because the test can distinguish IgM from IgG heparin-Ig. Currently the laboratory diagnosis of heparin-Ig remains inexact. The sensitivity and specificity of laboratory assays cannot be firmly established. Much like the diagnosis of the phospholipid syndrome — where use of both the cardiolipin EIA and the lupus anticoagulant test offer overlapping advantages — the combination of the heparin-PF4 EIA plus either a test of platelet activation or a heparin-dependent antibody binding assay may prove to be a more sensitive and specific approach to the diagnosis of heparin-Ig. Despite the progress that has been made in the area of laboratory diagnosis of heparin-Ig, further improvement is needed. Heparin-induced thrombocytopenia is not rare and may be associated with devastating morbidity as well as mortality. Low-molecular-weight heparins usually cross-react with heparin-Ig. Therapy with Org 10172 appears to be the most promising alternative for patients with HIT. Because the clinical diagnosis is uncertain in sick hospitalized patients, further improvements in laboratory assays for heparin-Ig allowing earlier and more accurate diagnosis of patients at risk for HIT will be welcome.     

Use of plasma exchange in patients with heparin-induced thrombocytopenia: a report of two cases and a review of the literature

Heparin-induced thrombocytopenia (HIT), which is characterized by thrombocytopenia and potentially serious thromboses, may develop in patients exposed to heparin anticoagulation. HIT is caused by antibodies to the heparin/platelet factor 4 (PF4) complex. Management of HIT involves discontinuation of heparin and anticoagulation with a nonheparin alternative such as a direct thrombin inhibitor (DTI). This poses a challenge in the management of patients who need to undergo cardiopulmonary bypass surgery (CPB), because CPB requires anticoagulation with heparin and standardized protocols for use of DTIs are not widely available. We report two patients with HIT who underwent successful CPB with heparin anticoagulation following plasma exchange (PE) to reduce heparin/PF4 antibody titers. Case 1 is a 46-year-old male with cardiac amyloidosis who needed urgent placement of a left ventricular assist device. Case 2 is a 34-year-old woman with acute myocarditis who needed placement of a biventricular assist device. Both patients had positive enzyme-linked immunosorbent assay assays for heparin/PF4 antibodies and clinical evidence of HIT before PE. Following PE and subsequent CPB, neither patient had clinical or laboratory evidence of HIT. The literature regarding the use of PE for the treatment of complications of HIT and as prophylaxis before CPB is reviewed.     

Lepirudin for therapeutic use in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) type II is an antibody mediated severe adverse event to heparin with a paradoxical decrease of platelet count and an increased risk for thromboembolic complications. The antibodies are directed against a neoepitop of platelet factor 4 after its binding to heparin. The incidence of HIT type II is lower with low-molecular-weight heparin compared to unfractionated heparin and lower in not operated patients compared to those after major surgery. In patients with HIT type II alternative anticoagulation has to be performed immediately due to the high thrombogenicity of the antibodies. The recombinant hirudin lepirudin (Refludan) is the anticoagulant drug of choice. A long-term anticoagulation has to be performed depending on the concomitant risk factors, intravenous administration followed by subcutaneous lepirudin overlapping with vitamin K antagonists.     

Heparin-induced thrombocytopenia (an overview)

Heparin induced thrombocytopenia is a serious side effect of a drug that is widely used in clinical practice. All patients exposed to heparin, administered by any route or at any dose, are at varying risk of developing HIT and its potentially devastating thrombotic complications. There are two clinical forms of HIT, type I and type II. Type I HIT, is a non-immunologic response, while type II HIT is an immunologic response to heparin therapy. Type I HIT is not associated with an increased risk of thrombosis and is characterized by reversible thrombocytopenia. Type II HIT occurs in approximately 1 to 3% of patients receiving unfractionated heparin. Type II HIT is more severe because of the increased risk of thrombotic events. Venous and arterial thromboembolic complications may lead to amputation, stroke, myocardial infarction, and death.     

Activation of platelets by heparin-induced thrombocytopenia antibodies in the serotonin release assay is not dependent on the presence of heparin

The serotonin release assay (SRA) tests for antibodies responsible for heparin-induced thrombocytopenia (HIT). By definition, SRA-positive antibodies cause platelet serotonin release in vitro, in the presence of low concentrations of heparin, but not with excess heparin. Many SRA-positive sera activate platelets in the presence of saline without drug, either as a result of residual heparin in the specimen, or because of intrinsic features of the HIT antibodies. The present experiments show that neither exhaustive heparinase treatment, nor chromatographic removal of heparin abrogates the spontaneous platelet activation caused by these HIT antibodies. This is the first study to systematically demonstrate that in vitro activity of HIT antibodies can be independent of heparin. In addition, T-gel chromatography demonstrated differences among fractions of enzyme-linked-immunosorbent assay (ELISA)-positive HIT antibodies within individual specimens. Certain ELISA-positive fractions had SRA activity while others did not, and the SRA activity was not proportional to HIT antibody ELISA titer. These data suggest that antibodies formed as a result of heparin treatment are heterogeneous, and that some can contribute to the pathogenesis of HIT even when heparin is no longer present.