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.     

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.

     

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 – 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.     

Apixaban used for the management of heparin‐induced thrombocytopenia in a 72‐year‐old woman with lung cancer

Heparin‐induced thrombocytopenia (HIT) is a serious adverse reaction to heparin treatment with a high risk of thrombosis. Heparin must be discontinued immediately and replaced with alternative anticoagulants that do not interact with HIT antibodies. In this case, a lung cancer patient, diagnosed with HIT was successfully treated with apixaban.     

The costs of heparin‐induced thrombocytopenia: a patient‐based cost of illness analysis

Summary. Background and objectives: Due to the complexity of heparin‐induced thrombocytopenia (HIT), currently available cost analyses are rough estimates. The objectives of this study were quantification of costs involved in HIT and identification of main cost drivers based on a patient‐oriented approach. Methods: Patients diagnosed with HIT (1995–2004, University‐hospital Greifswald, Germany) based on a positive functional assay (HIPA test) were retrieved from the laboratory records and scored (4T‐score) by two medical experts using the patient file. For cost of illness analysis, predefined HIT‐relevant cost parameters (medication costs, prolonged in‐hospital stay, diagnostic and therapeutic interventions, laboratory tests, blood transfusions) were retrieved from the patient files. The data were analysed by linear regression estimates with the log of costs and a gamma regression model. Mean length of stay data of non‐HIT patients were obtained from the German Federal Statistical Office, adjusted for patient characteristics, comorbidities and year of treatment. Hospital costs were provided by the controlling department. Results and conclusions: One hundred and thirty HIT cases with a 4T‐score ≥4 and a positive HIPA test were analyzed. Mean additional costs of a HIT case were 9008 €. The main cost drivers were prolonged in‐hospital stay (70.3%) and costs of alternative anticoagulants (19.7%). HIT was more costly in surgical patients compared with medical patients and in patients with thrombosis. Early start of alternative anticoagulation did not increase HIT costs despite the high medication costs indicating prevention of costly complications. An HIT cost calculator is provided, allowing online calculation of HIT costs based on local cost structures and different currencies.     

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.     

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.     

The HIT Expert Probability (HEP) Score: a novel pre‐test probability model for heparin‐induced thrombocytopenia based on broad expert opinion

Summary. Background: The diagnosis of heparin‐induced thrombocytopenia (HIT) is challenging. Over‐diagnosis and over‐treatment are common. Objectives: To develop a pre‐test clinical scoring model for HIT based on broad expert opinion that may be useful in guiding clinical decisions regarding therapy. Patients/methods: A pre‐test model, the HIT Expert Probability (HEP) Score, was constructed based on the opinions of 26 HIT experts. Fifty patients referred to a reference laboratory for HIT testing comprised the validation cohort. Two hematology trainees scored each patient using the HEP Score and a previously published clinical scoring system (4 T’s). A panel of three independent experts adjudicated the 50 patients and rendered a diagnosis of HIT likely or unlikely. All subjects underwent HIT laboratory testing with a polyspecific HIT ELISA and serotonin release assay (SRA). Results: The HEP Score exhibited significantly greater interobserver agreement [intraclass correlation coefficient: 0.88 (95% CI 0.80–0.93) vs. 0.71 (0.54–0.83)], correlation with the results of HIT laboratory testing and concordance with the diagnosis of the expert panel (area under receiver‐operating curve: 0.91 vs. 0.74, P = 0.017) than the 4 T’s. The model was 100% sensitive and 60% specific for determining the presence of HIT as defined by the expert panel and would have allowed for a 41% reduction in the number of patients receiving a direct thrombin inhibitor (DTI). Conclusion: The HEP Score is the first pre‐test clinical scoring model for HIT based on broad expert opinion, exhibited favorable operating characteristics and may permit clinicians to confidently reduce use of alternative anticoagulants. Prospective multicenter validation is warranted.     

Cutaneous dalteparin reactions associated with antibodies of heparin-induced thrombocytopenia

OBJECTIVE: To report widespread cutaneous lesions due to low-molecular-weight heparin therapy associated with heparin-induced thrombocytopenia (HIT), but without evidence of thrombocytopenia, and to review previously reported cases of skin reactions related to heparin therapy. CASE SUMMARY: A 59-year-old white man with a subtotally resected glioblastoma developed febrile neutropenia and pneumonia secondary to chemotherapy. The development of an upper extremity thrombosis, following insertion of a peripherally inserted central venous catheter, was treated with subcutaneous dalteparin. Cutaneous lesions developed distant from the site of injection. The diagnosis of HIT was confirmed despite stable platelet counts. Dalteparin therapy was discontinued immediately, and anticoagulation was maintained with warfarin. The skin lesions resolved without further complications. DISCUSSION: Numerous cases of heparin-induced cutaneous reactions have been reported. The majority of these describe a local reaction at the heparin injection site with or without associated thrombocytopenia. The case presented here is unique in that the observed skin reaction was distant to the injection site and occurred without thrombocytopenia, but with detectable heparin-dependent antibodies. CONCLUSIONS: Although a skin reaction is a rare complication of heparin therapy, it can be a clinical indicator of HIT despite normal platelet counts. Patients who develop skin lesions should have their heparin therapy discontinued and a diagnosis of HIT investigated.     

Comparative effects of two synthetic oligosaccharides on platelet activation induced by plasma from HIT patients

Summary.  Heparin-induced thrombocytopenia (HIT) is a serious secondary event encountered in the clinical use of heparin. HIT results from the consumption of platelets that are immunologically activated by antibodies directed against complexes formed by platelet factor 4 (PF4) and sulfated polysaccharides that activate platelet aggregation, leading to paradoxical, life-threatening thrombosis. There is strong evidence that the ability of heparin and related compounds to induce HIT is closely linked to the structure of the polysaccharide, and particularly to its negative charge and to the length of the molecule. To test this hypothesis, we synthesized two sulfated oligosaccharides: SanOrg123781, a 16-mer, presenting two terminal charged domains separated by a 7-mer neutral linker, and SR121903, a highly sulfated 17-mer. Both of them displayed strong anti-factor (F) Xa and anti-FIIa activities but their affinities for PF4 were markedly different. SR121903 displaced PF4-bound heparin, whereas SanOrg123781 did not, underlining the importance of the charge of the molecule for the interaction with PF4. Platelet studies, in the presence of HIT serum, showed that SR121903 induced the secretion of platelet-dense granules (measured by the release of serotonin) whereas SanOrg123781 did not, a result in accordance with an absence of affinity of this molecule for PF4. These results were confirmed by measurements of platelet activation by flow cytometry (measured by annexin V binding, CD62 detection and activation of the GpIIb–IIIa complexes). In conclusion, we have demonstrated the importance of the charge of the polysaccharides in the HIT-induced platelet reactions measured by diverse methods, of which some are described for this purpose for the first time.     

Rare complication of nadroparin injections: Skin necrosis and heparin‐induced thrombocytopenia syndrome

We described a rare case of nadroparin‐induced skin necrosis with thrombocytopenia. LMWH therapy is used in thrombosis prophylaxis, it is important to recognize that skin necrosis can be a part of HIT early in its course and change heparin or LMWH to non‐heparin anticoagulants such as direct thrombin III inhibitors or anti‐Xa anticoagulants.     

The Syk‐kinase inhibitor R406 impairs platelet activation and monocyte tissue factor expression triggered by heparin‐PF4 complex directed antibodies

Summary. Background: Heparin‐induced thrombocytopenia (HIT) is a rare but severe complication of heparin therapy in which immunoglobulin G (IgG) antibodies against the platelet factor 4–heparin complex activate platelets through the FcγRIIA receptor. Clustering of FcγRIIA initiates signaling cascades involving tyrosine kinases including the spleen tyrosine kinase (Syk). Moreover, besides the critical role of platelets, the expression of tissue factor (TF) by human monocytes triggered by HIT antibodies has been shown to contribute to the hypercoagulability and the thrombotic complications in HIT patients. Objectives: We investigated the effect of R406, a small molecule inhibitor of Syk developed as a potential treatment of autoimmune diseases, allergic disorders and B‐cell related hematological malignancies, on FcγRIIA‐mediated platelet activation. To further assess the potential activity of Syk inhibitors in HIT treatment, the effect of R406 was also evaluated on HIT antibodies‐induced expression of TF and procoagulant activity of monocytic cells. Results: We show that R406 is a potent inhibitor of platelet signaling and functions initiated by FcγRIIA cross‐linking by specific antibodies or by sera from HIT patients. Syk inhibition efficiently prevents FcγRIIA‐induced LAT phosphorylation and activation of phosphoinositide 3‐kinase, Akt, phospholipase Cγ2 and p38 MAP‐kinase. As a consequence, FcγRIIA‐induced platelet aggregation, granule secretion and microparticles production are strongly inhibited by R406. Moreover, the Syk inhibitor efficiently impairs the expression of TF and the procoagulant activity of human monocytes triggered by HIT antibodies. Conclusion: Syk inhibitors may be of therapeutic interest in the treatment of HIT by reducing HIT antibodies‐mediated platelet activation and monocyte procoagulant activity.     

Heparin‐induced acute adverse reaction – case report of a patient with acute trauma and a genetic predisposition to thrombotic events: a concurrence of events

What is known and Objective: The most common complication of heparin therapy is bleeding. Allergic reactions to heparin are rare, and the mechanisms are poorly understood. We report on a case of acute systemic reaction after subcutaneous injections of a low‐molecular‐weight heparin (LMWH) in a patient with a genetic predisposition to thrombotic events and review the literature on heparin‐induced acute adverse reaction. Case summary: A 57‐year‐old diabetic, hypertriglyceridemic and hypercholesterolemic man was admitted with a fractured right malleolus sustained while driving. He was prescribed parnaparin sodium 4250 IU subcutaneously once a day. During the third injection, the patient developed widespread pain, sickness and facial rash, followed by a state of stupor (Glasgow Coma Scale 8) and was hospitalized in Neurological Unit. He was found to be a carrier of two genetic mutations (i.e. prothrombin G20210A and MTHFR mutation) associated with an increased risk of thrombotic events. Discontinuation of parnaparin and supportive care led to a sufficient recovery of the patient to be discharged 6 days after admission. What is new and Conclusion: Treatment for heparin‐related hypersensitivity reactions is largely supportive and symptomatic. Clinicians should be aware of these rare but potentially serious adverse events. Prothrombin gene mutations are quite common, and guidelines on anticoagulant therapy for affected patients are needed.     

Age‐specific differences in binding of heparin to plasma proteins

Summary. Background: Clinically significant age‐related differences in the anticoagulation effect of heparin have previously been established in vitro as well as in different clinical settings in vivo. These differences were hypothesized to be due to the age‐specific differences in binding of heparin to plasma proteins. Objectives: The aim of this project was to investigate global age‐related differences in heparin binding to plasma proteins. Patients/Methods: Heparin‐binding proteins were identified by incubating heparin‐coated magnetic beads with plasma samples from neonates, children and adults, and purifying the proteins that were bound to the beads in this reaction system. Results: These results provide the first preliminary evidence of age‐related differences in the total number and concentration of proteins bound to heparin. The results also suggest, for the first time, that there are age‐related differences of heparin binding to antithrombin and thrombin. Conclusions: The results of this study, although preliminary, support and contribute to the explanation of the mechanism of age‐related differences in the effect of heparin observed previously in vitro and in vivo.     

Non‐necrotizing heparin‐induced skin lesions and the 4T’s score

See also Schindewolf M, Kroll H, Ackermann H, Garbaraviciene J, Kaufmann R, Boehncke W‐H, Ludwig RJ, Lindhoff‐Last E. Heparin‐induced non‐necrotizing skin lesions: rarely associated with heparin‐induced thrombocytopenia. This issue, pp 1486–91.     

Early-onset and persisting thrombocytopenia in post-cardiac surgery patients is rarely due to heparin-induced thrombocytopenia, even when antibody tests are positive

See also Gruel Y, Pouplard C. Post‐operative platelet count profile: the most reliable tool for identifying patients with true heparin‐induced thrombocypenia after cardiac surgery. This issue, pp 27–29. Summary. Background: The high frequency of thrombocytopenia in post‐cardiac surgery patients makes it challenging to diagnose heparin‐induced thrombocytopenia (HIT). Two platelet count profiles are reported as indicating possible HIT in these patients: profile 1 describes a platelet count fall that begins between postoperative days 5 and 10, whereas profile 2 denotes early‐onset thrombocytopenia that persists beyond day 5. Objectives: To examine how these platelet count profiles correlate with antibody status and HIT post‐cardiac surgery. Methods: We prospectively screened 581 cardiac surgery patients for heparin‐dependent antibodies by platelet factor 4 (PF4)–heparin immunoassay and platelet‐activation test, and performed daily platelet counts (until day 10) with 30‐day follow‐up. Results: All three patients with platelet count profile 1 tested positive for platelet‐activating anti‐PF4–heparin IgG antibodies [odds ratio (OR) 521.7, 95% confidence interval (CI) 3.9–34 000, P = 0.002], and were judged to have HIT. In contrast, none of 25 patients with early‐onset and persisting thrombocytopenia (profile 2) was judged to have HIT, including five patients testing positive for platelet‐activating anti‐PF4–heparin IgG antibodies. In these patients, the frequency of heparin‐dependent antibodies did not differ from that in non‐thrombocytopenic controls, either for anti‐PF4–heparin IgG (OR 1.7, 95% CI 0.7–4.1, P = 0.31) or for platelet‐activating antibodies (OR 1.9, 95% CI 0.6–5.7, P = 0.20). Multivariate analysis revealed that type of cardiac surgery, but not HIT antibody status, predicted early‐onset and persisting thrombocytopenia. Together, these findings show that HIT was uncommon in this study population [overall frequency, 3/581 (0.5%), 95% CI 0.1–1.5%]. Conclusions: Thrombocytopenia that begins between 5 and 10 days post‐cardiac surgery is highly predictive for HIT. In contrast, early‐onset and persisting thrombocytopenia is usually caused by non‐HIT factors with coinciding heparin‐dependent antibody seroconversion.     

A systematic evaluation of laboratory testing for drug‐induced immune thrombocytopenia

Summary. Background: Drug‐induced immune thrombocytopenia (DITP) can be confirmed by the demonstration of drug‐dependent platelet antibodies in vitro; however, laboratory testing is not readily accessible and test methods are not standardized. Objective: To identify drugs with the strongest evidence for causing DITP based on clinical and laboratory criteria. Patients/Methods:  We developed a grading system to evaluate the quality of DITP laboratory testing. The ‘DITP criteria’ were: (i) Drug (or metabolite) was required for the reaction in vitro; (ii) Immunoglobulin binding was demonstrated; (iii) Two or more laboratories obtained positive results; and (iv) Platelets were the target of immunoglobulin binding. Laboratory diagnosis of DITP was considered definite when all criteria were met and probable when positive results were reported by only one laboratory. Two authors applied the DITP criteria to published reports of each drug identified by systematic review. Discrepancies were independently adjudicated. Results: Of 153 drugs that were clinically implicated in thrombocytopenic reactions, 72 (47%) were associated with positive laboratory testing. Of those, 16 drugs met criteria for a definite laboratory diagnosis of DITP and thus had the highest probability of causing DITP. Definite drugs were: quinine, quinidine, trimethoprim/sulfamethoxazole, vancomycin, penicillin, rifampin, carbamazepine, ceftriaxone, ibuprofen, mirtazapine, oxaliplatin and suramin; the glycoprotein IIbIIIa inhibitors abciximab, tirofiban and eptifibatide; and heparin.Conclusions: We identified drugs with the strongest evidence for an association with immune thrombocytopenia. This list may be helpful for ranking potential causes of thrombocytopenia in a given patient.     

Anti‐PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non‐drug risk factors and evidence for a stoichiometry‐based model of immunization

Summary. Background: Heparin‐induced thrombocytopenia is an antibody‐mediated disorder exhibiting variable frequency in different clinical settings. Antibodies recognize PF4/heparin complexes formed at optimal stoichiometric molar ratios. Objective: To identify clinical factors influencing risk of anti‐PF4/heparin immunization. Patients/methods: We performed observational studies and exploratory analyses of the frequency of anti‐PF4/heparin antibody formation in 6324 patients who received enoxaparin or fondaparinux in four randomized controlled trials of postorthopedic surgery thromboprophylaxis. Variables included surgery type (knee vs. hip), timing of first anticoagulant dose (pre‐ vs. postsurgery), circumstances of surgery (elective vs. hip fracture), anticoagulant (enoxaparin vs. fondaparinux) and body‐mass index (BMI). We applied a stoichiometry‐based model that predicts immunization risk based on expected differences in PF4/anticoagulant ratios in different settings, and specifically used this model to predict the effect of increasing BMI quartiles upon relative risk (RR) of immunization for fondaparinux vs. enoxaparin. Results: Anti‐PF4/heparin immunization was more frequent after knee vs. hip surgery (particularly for enoxaparin), and when enoxaparin was given post‐ rather than pre‐elective surgery; however, the opposite occurred with hip fracture surgery, that is, antibody formation was more frequent when enoxaparin or fondaparinux was given presurgery. The RR of immunization for fondaparinux vs. enoxaparin decreased significantly for increasing BMI quartiles, an effect predominantly because of increasing immunization with enoxaparin at increasing BMI quartiles. Conclusions: Several non‐drug factors – including type and circumstances of surgery, timing of first anticoagulant dose and BMI – influence risk of anti‐PF4/heparin antibody formation, consistent with a stoichiometry‐based immunization model of PF4 and anticoagulant ratios occurring during the early peri‐operative period.     

Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT

Summary. Background: Early‐onset hypertensive disorders (HD) of pregnancy and small‐for‐gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk. Objectives: Adding low‐molecular‐weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early‐onset HD (pre‐eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies. Patients/methods: In a multicenter randomized control trial (RCT), 139 women included were < 12 weeks gestation. Inclusion criteria: previous delivery < 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected. Intervention: either daily LMWH (dalteparin, 5000 IU weight‐adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone. Main outcome measures: Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age. Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention‐to‐treat. Results: Low‐molecular‐weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects. Trial Registration: http://www.isrctn.org ) (isrctn87325378). Conclusions: Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.