Autoimmune heparin‐induced thrombocytopenia

Summary

Autoimmune heparin‐induced thrombocytopenia (aHIT) indicates the presence in patients of anti‐platelet factor 4 (PF4)–polyanion antibodies that are able to activate platelets strongly even in the absence of heparin (heparin‐independent platelet activation). Nevertheless, as seen with serum obtained from patients with otherwise typical heparin‐induced thrombocytopenia (HIT), serum‐induced platelet activation is inhibited at high heparin concentrations (10–100 IU mL^?1 heparin). Furthermore, upon serial dilution, aHIT serum will usually show heparin‐dependent platelet activation. Clinical syndromes associated with aHIT include: delayed‐onset HIT, persisting HIT, spontaneous HIT syndrome, fondaparinux‐associated HIT, heparin ‘flush’‐induced HIT, and severe HIT (platelet count of < 20 × 10⁹ L^?1) with associated disseminated intravascular coagulation (DIC). Recent studies have implicated anti‐PF4 antibodies that are able to bridge two PF4 tetramers even in the absence of heparin, probably facilitated by non‐heparin platelet‐associated polyanions (chondroitin sulfate and polyphosphates); nascent PF4–aHIT‐IgG complexes recruit additional heparin‐dependent HIT antibodies, leading to the formation of large multimolecular immune complexes and marked platelet activation. aHIT can persist for several weeks, and serial fibrin, D‐dimer, and fibrinogen levels, rather than the platelet count, may be helpful for monitoring treatment response. Although standard anticoagulant therapy for HIT ought to be effective, published experience indicates frequent failure of activated partial thromboplastin time (APTT)‐adjusted anticoagulants (argatroban, bivalirudin), probably because of underdosing in the setting of HIT‐associated DIC, known as ‘APTT confounding’. Thus, non‐APTT‐adjusted therapies with drugs such as danaparoid and fondaparinux, or even direct oral anticoagulants, such as rivaroxaban or apixaban, are suggested therapies, especially for long‐term management of persisting HIT. In addition, emerging data indicate that high‐dose intravenous immunoglobulin can interrupt HIT antibody‐induced platelet activation, leading to rapid platelet count recovery.

     

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.     

Heparin‐induced thrombocytopenia – therapeutic concentrations of danaparoid,unlike fondaparinux and direct thrombin inhibitors,inhibit formation of platelet factor 4–heparin complexes

Summary. Background: Treatment of heparin‐induced thrombocytopenia (HIT), a disorder in which anti‐platelet factor 4 (PF4)–heparin antibodies cause platelet activation and hypercoagulability, requires alternative (non‐heparin) anticoagulation. Treatment options include direct thrombin inhibitors [lepirudin and argatroban (approved), and bivalirudin], danaparoid (approved) (mixture of anticoagulant glycosaminoglycans), or fondaparinux (synthetic heparin‐mimicking pentasaccharide). PF4–heparin complexes form at optimal stoichiometric ratios. Objectives: To compare the effects of these various non‐heparin anticoagulants in disrupting the formation of PF4–heparin complexes, and PF4‐containing immune complexes. Patients/methods: Sera were obtained from patients with serologically confirmed HIT. The effects of the alternative anticoagulants on PF4 and PF4–heparin complex interactions with platelets, as well as HIT antibody binding and platelet activation, were investigated. Results: Danaparoid at very low concentrations increased PF4 binding to platelets. In therapeutic concentrations, however, it decreased PF4 binding to platelets (P = 0.0004), displaced PF4–heparin complexes from platelets (P = 0.0033) and PF4 from the surface of a PF4‐transfected HEK‐293 EBNA cell line expressing the PF4 receptor CXCR3‐B (P = 0.0408), reduced PF4–heparin complex size (P = 0.025), inhibited HIT antibody binding to PF4–heparin complexes (P = 0.001), and prevented platelet activation by HIT antibodies (P = 0.046). Although fondaparinux also interfered with PF4 binding to platelets, HIT antibody binding to PF4–heparin complexes, and activation of platelets by HIT antibodies, these effects occurred only at supratherapeutic concentrations. The direct thrombin inhibitors had no effect at any concentrations. Conclusions: Danaparoid uniquely interferes with the pathogenesis of HIT by disrupting PF4‐containing immune complexes at therapeutic dose concentrations. It is possible that these effects contribute to its therapeutic efficacy.     

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.”     

The utility of pre-test clinical scoring for clinical diagnosis of heparin-induced thrombocytopenia in cardiac surgery patients of a tertiary care centre in north India

Background: Heparin‐induced thrombocytopenia (HIT) should be diagnosed clinically as well as by laboratory assays for timely recognition, prevention and management of complications. Objective: To evaluate the clinical utility of pre‐test clinical scoring system in combination with two immunoassays for the diagnosis of HIT in cardiac surgery patients. Materials and methods: A total of 100 consecutive patients undergoing cardiac surgery were studied. Pre‐test clinical scoring was carried out in patients with thrombocytopenia and further tested by two immunoassays, i.e. Heparin platelet factor 4 (H‐PF4) enzyme‐linked immunosorbent assay (ELISA) and particle gel immunoassay (PaGIA). Results: Of the 100 patients studied, 42 patients developed thrombocytopenia post‐operatively. On pre‐test clinical scoring, low T‐score was observed in 6 patients, intermediate in 28 and high score in 8 patients, whereas 19 patients (45·2%) were positive by H‐PF4 ELISA and 10 (23·8%) by PaGIA for H‐PF4 antibody. The difference in the incidence of clinically significant HIT antibodies in the three categories was statistically significant. A good correlation was also observed with ELISA optical density, T‐scoring and PaGIA. Conclusions: Pre‐test clinical scoring correlates well with the development of H‐PF4 antibodies which are incriminated in the causation of thrombotic complications in patients with HIT. We also propose a protocol for diagnosing patients with clinical suspicion of HIT using pre‐test clinical scoring and immunoassay.     

Heparin‐induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests

Summary. Background: Laboratory confirmation of heparin‐induced thrombocytopenia (HIT) is based on detection of heparin‐dependent platelet‐activating antibodies. Platelet factor 4 (PF4)/heparin enzyme‐immunoassays (EIA) are a widely available surrogate for platelet‐activating antibodies. Objective: Defining the optical density (OD) reactivity profiles of a PF4/heparin EIA in reference subject and patient populations and the correlation of the EIA results (expressed in OD units) with the prevalence of platelet‐activating antibodies. Patients/methods: Using quantile regression we determined the 97.5th percentile of PF4/heparin‐immunoglobulin G (IgG) EIA reactivities in non‐heparin‐treated individuals [blood donors (n = 935)] and patients before heparin therapy (n = 1207). In patients with suspected HIT, we compared the correlation of EIA‐IgG reactivities (Greifswald laboratory; n = 2821) and the heparin‐induced platelet activation assay (HIPA) with the correlation of reactivities of another EIA‐IgG (McMaster laboratory; n = 1956) with the serotonin‐release assay (SRA). Results: PF4/heparin‐IgG EIA OD reactivities had a lower OD 97.5th percentile in blood donors compared with patient groups before heparin treatment (P < 0.001). The percentage of sera testing positive in the functional assays strongly correlated with PF4/heparin‐IgG EIA OD reactivities in both laboratories with very similar results (correlation coefficient > 0.9) when normalized OD ranges (maximum OD divided by 10) were used instead of absolute OD values. Conclusions: Results of PF4/heparin‐IgG EIA should not be reported as only positive or negative as there is no single acceptable cut‐off value. Instead, reporting PF4/heparin‐IgG EIA OD results in ranges allows for risk‐stratified prediction for presence of platelet‐activating antibodies. Use of normalized OD ranges permits a standardized approach for inter‐laboratory comparisons.     

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.     

Intravenous immunoglobulin as an adjunct therapy in persisting heparin-induced thrombocytopenia

Heparin induced thrombocytopenia (HIT) is a serious adverse drug reaction caused by transient antibodies against platelet factor 4 (PF4)/heparin complexes, resulting in platelet activation and potentially fatal arterial and/or venous thrombosis. Most cases of HIT respond to cessation of heparin and administration of an alternative non-heparin anticoagulant, but there are cases of persisting HIT, defined as thrombocytopenia due to platelet activation/consumption for greater than seven days despite standard therapy. These patients remain at high risk for thrombotic events, which may result in limb-loss and mortality. Intravenous immunoglobulin (IVIg) has been proposed as an adjunct therapy for these refractory cases based on its ability to saturate FcγRIIa receptors on platelets, thus preventing HIT antibody binding and platelet activation. We describe 2 cases of persisting HIT (strongly positive antigen and functional assays, and persisting thrombocytopenia >7 days) with rapid clinical response to IVIg. We performed in-vitro experiments to support IVIg response. Healthy donor platelets (1?×?10e6) were treated with PF4 (3.75?μg/mL) for 20?min followed by 1-hour incubation with patients’ sera. Platelet activation with and without addition of IVIg (levels equivalent to those reached in a patient after treatment with 2?gm/Kg) was evaluated in the PF4-dependent P-selectin expression assay (PEA). A significantly decreased platelet activation was demonstrated after the addition of IVIg to both patient samples, which correlated well with the rapid clinical response that each patient experienced. Thus, our study supports the use of IVIg as an adjunct therapy for persisting HIT.     

Heparin-induced thrombocytopenia in patients requiring prolonged intensive care unit treatment after cardiopulmonary bypass

Summary.  Background:  The diagnosis of heparin-induced thrombocytopenia (HIT) is problematic in postcardiac surgery (CS) intensive care unit (ICU) patients, as there are multiple potential explanations for thrombocytopenia and the presence of anti-platelet factor 4/heparin antibodies is not highly specific for HIT. Two platelet count profiles for HIT – a 40% or greater fall in platelet count beginning on or after day 5 (pattern 1) and persisting thrombocytopenia (< 100 × 10⁹ L^–1) beyond day 7 (pattern 2) – have been described in post-CS patients. Methods and results:  We examined the platelet count profiles of 329 consecutive post-CS patients who required ICU treatment beyond 7 days. Although 70 patients (21.3%) developed thrombocytopenia (57.1% pattern 1, 42.9% pattern 2), the overall incidence of HIT was only 1.8% [6/329; 95% confidence interval (95% CI) 0.7–3.9%] in these ICU patients, with more HIT patients showing a pattern 2 than a pattern 1 platelet count decrease (four vs. two patients). Notably, pattern 2 patients with HIT also showed a new proportional fall of > 30% in platelet count between postoperative days 5 and 10. Among the remaining 2242 post-CS patients without a prolonged ICU stay, only three (0.1%; 95% CI 0.03–0.4%) developed symptomatic HIT (OR 0.07; 95% CI 0.01–0.3; P  =   0.0002 vs. ICU patients), all presenting with pattern 1. Conclusions:  Among post-CS ICU patients, a postoperative platelet count fall between days 5 and 10 increases diagnostic specificity for HIT, irrespective of whether this platelet count fall occurs after postoperative platelet count recovery (pattern 1) or is superimposed upon persisting postoperative thrombocytopenia (pattern 2). A prospective study is required in order to validate the findings of this retrospective analysis.     

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.     

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.     

False-positive tests for heparin-induced thrombocytopenia in patients with antiphospholipid syndrome and systemic lupus erythematosus

Summary.  Background : Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy that can be associated with arterial or venous thrombosis and is caused by antibodies against platelet factor 4 (PF4)–heparin complex. Patients with antiphospholipid syndrome (APS) have been reported with positive tests for PF4–heparin complex antibodies by antigen assay. Whether such patients can be treated with heparin is a dilemma. Objectives : To determine the incidence and nature of the HIT immune reaction in patients with APS and/or systemic lupus erythematosus (SLE). Methods : Antibodies against PF4–heparin complex were assayed by particle gel immunoassay (PaGIA), or enzyme immunoassay (EIA) with or without an excess of heparin. EIA for PF4 alone was also performed. Functional assays for HIT, that is, heparin-induced platelet activation (HIPA) and heparin-induced platelet aggregation, were also performed. Results : In 32 of 42 patients (76.2%) with APS, APS and SLE, SLE, or SLE with antiphospholipid antibodies, EIA IgG or PaGIA for PF4–heparin complex antibodies were positive. Of these 32 samples, 26 (81.3%) tested positive for anti-PF4 antibodies. All 24 samples that were positive for PF4–heparin complex by EIA IgG were also positive for EIA IgG in the presence of heparin excess, and all were negative by the HIPA and heparin-induced platelet aggregation tests. Conclusion : A large proportion of patients with APS and/or SLE give false-positive HIT antigen test results that are presumably related to autoantibodies against PF4, which can be distinguished from true HIT antibodies by EIA for PF4–heparin complexes tested with heparin excess, and by functional assays.     

Binding of heparin‐dependent antibodies to PF4 modified by enoxaparin oligosaccharides: evaluation by surface plasmon resonance and serotonin release assay

Summary. Background: The minimal structural requirements of low‐molecular‐weight heparins that determine the risk of developing heparin‐induced thrombocytopenia (HIT) are not fully defined.Objectives: The ability of enoxaparin‐derived oligosaccharides (OS) to induce platelet activation and exposure of platelet‐factor 4 (PF4) epitopes recognized by antibodies developed in HIT was studied by surface plasmon resonance (SPR) and serotonin release assay.Results: Decasaccharides with ≥ 11 sulfate groups induced platelet activation in the presence of plasma from patients with confirmed HIT. Serotonin release of > 80% without full inhibition at 100 μg mL^?1 was achieved with decasaccharides containing 14 or 15 sulfate groups, 2 dodecasaccharides and 2 tetradecasaccharides. An SPR method was developed using purified PF4 immobilized on carboxymethylated dextran. Antibodies from all HIT samples bound to PF4/heparin in SPR assays with resonance units (RU) ratio of 109–173 with HIT plasma vs. 88–93 with control plasma. RU ratios > 100 were measured when PF4 was pre‐incubated with OS with ≥ 10 saccharide units and one octasaccharide containing 10 sulfate groups. RU ratios > 140, similar to those measured when PF4 was pre‐incubated with unfractionated heparin or enoxaparin, were obtained with purified dodeca‐ and tetradecasaccharides. RU values strongly correlated with the number of sulfate groups in the decasaccharides tested (r = 0.93, P = 0.02).Conclusions: LMWHs with fragments > 10 saccharides and a large number of sulfate groups are more likely to be associated with a higher risk of HIT. These structure‐activity relationships were independent of the ability of the OS to bind antithrombin.     

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 immunsorbent 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.     

Diagnosis and treatment of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a major side effect secondary to the administration of heparin. This syndrome is serious and potentially life threatening. This response is the result of antibodies formed against the platelet factor 4 (PF4)/heparin complex. The incidence of this immune-mediated syndrome has been estimated to be 1-3% of all patients receiving heparin therapy. The occurrence of HIT in patients requiring full anticoagulation for cardiopulmonary bypass (CPB), therefore, presents a serious challenge to the cardiac surgery team. The diagnosis of HIT should be based on both clinical and laboratory evidence. While functional assays, platelet aggregation tests, and the serotonin release assay can be used to support the diagnosis, the negative predictive value of these tests is generally less than 50%. In contrast, although non-functional antibody detection assays are more sensitive, they have a low specificity. HIT can be treated in several ways, including cessation of all heparin and giving an alternative thrombin inhibitor, platelet inhibition followed by heparin infusion, and the use of low molecular weight heparins. In this presentation, the pathology and current diagnostic tests, as well as the successful management of patients with HIT undergoing CPB at New York Presbyterian Hospital, are reviewed.     

Immune mechanisms in heparin-induced thrombocytopenia: no evidence for immunoglobulin M anti-idiotype antibodies

BACKGROUND: Heparin-induced thrombocytopenia (HIT), which is caused by platelet (PLT)-activating immunoglobulin (Ig)G antibodies against platelet factor 4 (PF4)/heparin complexes, differs from other immune responses seen in immunohematology: IgG antibodies are formed as early as 5 days even without previous heparin exposure; antibodies are remarkably transient (<100 days); HIT is more frequent in postsurgery patients compared with medical patients despite administering the same type and dose of heparin; and increasing evidence implicates autoantibody-like reactivity of anti-PF4/heparin antibodies. We hypothesized that these unusual features could be caused by loss of regulatory anti-idiotype IgM antibodies due to disturbance (e.g., by surgery) of an idiotype–anti-idiotype network.
STUDY DESIGN AND METHODS: Sera were obtained prospectively before heparin administration and during the immunization phase of HIT and also from patients with previous HIT after waning of antibodies to nondetectable levels. To detect inhibitory IgM anti-idiotype antibodies, we performed serum coincubation experiments and IgG purification by protein G and size filtration to exclude coprecipitating IgM. Sera (n = 3) containing known anti-PF4/heparin IgG or IgM antibodies and normal sera (n = 20) were processed as controls.
RESULTS: Fifteen preimmune response sera (seroconverting in the PF4/heparin-IgG enzyme-linked immunosorbent assay only [n = 4] or additionally in a PLT activation assay [n = 5] or in both assays plus thrombosis [n = 6]) and four sera of previously immunized patients were included. Neither did the neat sera inhibit binding of anti-PF4/heparin antibodies nor did the purified IgG fractions show enhanced binding to PF4/heparin complexes.
CONCLUSION: The atypical immunologic features of HIT do not appear to be caused by disruption of an idiotype (IgG)–anti-idiotype (IgM) network.     

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.     

Pseudo-pulmonary embolism as a sign of acute heparin-induced thrombocytopenia in hemodialysis patients: safety of resuming heparin after disappearance of HIT antibodies

Heparin-induced thrombocytopenia (HIT) is a syndrome caused by platelet-activating antibodies that recognize complexes of platelet factor 4 (PF4) and heparin. Thrombocytopenia is the most common clinical feature of HIT. HIT can be considered as a hypercoagulable state, with a high risk of thrombosis. Another feature of HIT is an acute systemic reaction that characteristically begins 5-30 min after receiving an intravenous bolus of unfractionated heparin, such as is commonly given for hemodialysis (HD). Here we present 4 patients who developed acute HIT at or near the start of their chronic HD. All patients were anticoagulated with the low-molecular-weight heparin, nadroparin, for HD. Three of our patients underwent surgery approximately 1-2 weeks before developing HIT. All patients presented with an acute systemic reaction during HD. All patients were treated and further dialyzed with lepirudin. Under this treatment we observed a quick recovery of the platelet count, and patients remained symptom-free. Antibodies against the PF4-heparin complex were detected with a combination of a 'quick test' and an enzyme-linked immunosorbent assay test. The likelihood of having HIT previous to the detection of antibodies was estimated with the pre-test probability score criteria. The tests for PF4-heparin antibodies remained positive for an average of 165 days. Three patients underwent a rechallenge with nadroparin after disappearance of the HIT antibodies in their serum. All 3 remained symptomless when they were further hemodialyzed on nadroparin. Our observations indicate that nadroparin can be successfully reintroduced for HD anticoagulation once the patient's HIT antibodies have disappeared.     

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.     

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.