The Challenge of Detecting Heparin-induced Thrombocytopenia (HIT) in a Developing Country: A Systematic Review.

Prospective evaluation of the '4Ts' score and particle gel immunoassay specific to heparin/PF4 for the diagnosis of heparin-induced thrombocytopenia.

Immunoassays are not created equal.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder that occurs following the administration of heparin and is caused by antibodies to platelet factor 4 and heparin. Diagnosis of HIT is essential to guide treatment strategies using non-heparin anticoagulants and to avoid unwanted and potential fatal thromboembolic complications. This consensus statement, formulated by members of the Thrombosis and Haemostasis Society of Australia and New Zealand, provides an update on HIT pathogenesis and guidance on the diagnosis and management of patients with suspected or confirmed HIT. A 4Ts score is recommended for all patients with suspected HIT prior to laboratory testing. Further laboratory testing with a screening immunoassay or confirmatory functional assay is not recommended in individuals with a low 4Ts score. However, if there are missing or unreliable clinical data, then laboratory testing should be performed. A positive functional assay result confirms the diagnosis of HIT and should be performed to confirm a positive immunoassay result. Heparin exposure must be ceased in patients with suspected or confirmed HIT and initial treatment with a non-heparin alternative instituted. Non-heparin anticoagulants (danaparoid, argatroban, fondaparinux and bivalirudin) used to treat HIT should be given in therapeutic rather than prophylactic doses. Direct oral anticoagulants may be used in place of warfarin after patients with HIT have responded to alternative parenteral anticoagulants with platelet count recovery. These are the first Australasian recommendations for diagnosis and management of HIT, with a focus on locally available diagnostic assays and therapeutic options. The importance of examining both clinical and laboratory data in considering a diagnosis of HIT cannot be overstated.

The letter by de Cooman and Devreese is interesting as these authors have evaluated the clinical pre-test 4T's score combined with the STic Expert® HIT (Diagnostica Stago, Asnières sur Seine, France) in a retrospective cohort of 153 patients to exclude the diagnosis of heparin-induced thrombocytopenia (HIT). The authors compared their data to those we recently published (Leroux et al, 2014), and found a false negative result using this rapid nano-particle flow immunoassay in one patient. Briefly, the pre-test probability of HIT evaluated with the 4Ts score system in this patient was low (score = 3), and the STic Expert® HIT was negative, suggesting that HIT was unlikely. However, an IgG-specific immunoassay (Asserachrom® HPIA IgG, Diagnostica Stago) was positive, although a relatively low optical density (OD) value (0·725, cut-off = 0·251) was measured. Finally, the investigators confirmed the diagnosis of HIT in this patient based on the results of a flow cytometric CD62p functional assay, and concluded that caution was appropriate when the STic Expert® HIT was used with the possibility of false negative results. Several points about the methods that were applied, which may limit the clinical impact of this study, have to be discussed. First, the performances of STic Expert® HIT were evaluated retrospectively by testing frozen plasma samples collected over an 8-year period. However, this rapid assay is a screening test primarily designed for testing fresh plasma or serum in emergency conditions, and the evaluation of frozen samples has therefore not been recommended. Also, the definite diagnosis of HIT used by De Cooman and Devreese was based on the detection of platelet activation by a flow cytometric method that has been mainly used in few laboratories and remains to be validated prospectively in a large cohort of patients, compared with a validated and highly sensitive/specific functional assay, such as the serotonin release assay (SRA). In addition, the authors did not define the percentage of positive CD62p (p-selectin; SELP) platelets measured with their assay in the presence of patient plasma and heparin, and this result could be critical due to the apparent low level of anti-platelet factor 4 (PF4) antibodies detected by Asserachrom® HPIA IgG. Recently, we also recorded a false negative result with the STic Expert® HIT used on a fresh plasma sample, associated with a low OD value (0·77) measured by a PF4-specific enzyme immunoassay (EIA) (HAT® 45, Genetic Testing Institute Diagnostics, Waukesha, WI, USA). However, the pre-test probability of HIT was high in our patient (4T score = 7) and the SRA was strongly positive (maximum release 66%). We therefore agree that in practice, clinicians and biologists have to be very careful regarding the diagnosis and management of HIT given that most assays or scoring systems exhibit a negative predictive value not equal to 100%. The clinical features used to calculate clinical scores, such as the 4Ts or the HIT Expert Probability score (Cuker et al, 2010) have to be rigorously recorded. Furthermore, the interpretation of HIT laboratory tests has to take into account the clinical history, the OD value measured with EIA (as recently outlined by Cuker, 2014) and the extent of heparin-dependent platelet activation measured with functional assays. As recommended by the Platelet Immunology Working Group on HIT for the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (Warkentin et al, 2011), ‘the diagnosis of HIT requires a clinical scenario in which HIT is judged to be the most plausible diagnosis, generally meeting at least an intermediate probability for HIT (judged by a clinical scoring system), plus either a strong positive EIA-IgG or, preferably, a positive test for platelet-activating antibodies’. However, an improvement in the standardization of HIT immunoassays allowing a more precise quantification of pathogenic IgG antibodies to modified PF4 would be very helpful for the diagnosis of HIT in suspected patients.

Heparin-induced thrombocytopenia: pathogenesis and management.

A brief overview of the pathophysiology, diagnosis, and treatment of heparin-induced thrombocytopenia (HIT) is discussed. Following any exposure to unfractionated heparin or low-molecular-weight heparin (LMWH), HIT, a serious allergic drug reaction, may occur. The frequency of HIT is thought to range from 1 to 5% of patients receiving heparin. This immune-mediated syndrome is paradoxically associated with thrombosis, not bleeding, with thrombin generation playing a central role. The diagnosis of HIT is based upon clinical findings that can be confirmed with laboratory assay; however, when there is clinical suspicion of HIT, all forms of heparin therapy should be immediately discontinued and initiation of alternative anticoagulation is strongly encouraged. In the presence of HIT, the use of LMWHs or initiation of warfarin without additional effective anticoagulation is not recommended. Argatroban and lepirudin, two direct thrombin inhibitors (DTIs), are approved by the Food and Drug Administration for the management of HIT. Both agents have been studied in the treatment and prevention of thrombotic events associated with HIT. Argatroban, a univalent inhibitor of thrombin, is eliminated via the liver, while lepirudin, the first DTI approved for HIT, is a bivalent thrombin inhibitor that is cleared by the kidneys. Neither argatroban nor lepirudin demonstrates cross-reactivity with heparin-induced antibodies, and both DTIs have been associated with effective anticoagulation and platelet recovery in patients with HIT. The appropriate use of DTIs in HIT reduces the risk of thrombotic events and severe consequences associated with this serious drug reaction.

Heparin-induced thrombocytopenia (HIT) in infants is a rare disorder, and the diagnosis and management of HIT still remains challenging. Argatroban is a synthetic direct thrombin inhibitor (DTI) that is widely used for treating HIT. However, little is known about the efficacy of the activated clotting time (ACT) test in monitoring DTI treatment as an alternative to the routinely used activated partial thromboplastin time (aPTT). Between July 2013 and January 2015, four infants were diagnosed with HIT after surgical correction of congenital anomalies. In all cases, heparin was used during cardiopulmonary bypass (CPB). Diagnosis of HIT was based on the "4 Ts" pretest clinical scoring system, and platelet factor 4 (PF4) antibody was detected using enzyme-linked immunosorbent assay. Argatroban was used in treating HIT. When argatroban was infused, anticoagulation tests (aPTT, prothrombin time [PT], thrombin time [TT], and fibrinogen) were performed every 4 to 12 hours. ACT was used in addition to monitor the anticoagulation effect of argatroban. The target ACT was 1.5 to 3.0 times the baseline. ACT was measured every 2 to 4 hours and remeasured 1 hour after each dosage adjustment. Thrombocytopenia (defined as a 50% decrease in platelet count) occurred during the 3rd to 6th day postoperatively. After the diagnosis of HIT, argatroban was started immediately, and platelet counts stabilized and gradually increased. Anticoagulation effect of argatroban was successful monitored by ACT and aPTT. Poor correlation between the ACT test and aPTT test (R = 0.270, p = 0.092) was noted in one patient. ACT values increased rapidly after 3 to 7 days on argatroban treatment. In most cases, low dosage of argatroban was given ranging from 0.04 to 5.00 μg/kg/min. Argatroban may be an effective medicine in treating HIT in infants, in a reduced dosage. The great fluctuation in argatroban dosage during the course of HIT treatment necessitates close monitoring. ACT test may be reliable and convenient for monitoring HIT treatment and may contribute to positive clinical outcomes in infants. The efficacy of argatroban and the use of ACT monitoring in the management of HIT infants needs further study.

To summarize new information on frequency of heparin-induced thrombocytopenia (HIT) in patients treated in intensive care units (ICU), developments in the interpretation of assays for detecting anti-PF4/heparin antibodies, and treatment of HIT patients. All data on the frequency of laboratory-confirmed HIT in ICU patients were included; for laboratory testing of HIT and treatment of patients, this review focuses on recent data that became available in 2005 and 2006. HIT is a potentially life-threatening adverse effect of heparin treatment caused by platelet-activating antibodies of immunoglobulin G class usually recognizing complexes of platelet factor 4 and heparin. HIT is more often caused by unfractionated heparin than low-molecular-weight heparin and is more common in postsurgical than in medical patients. In the ICU setting, HIT is uncommon (0.3-0.5%), whereas thrombocytopenia from other causes is very common (30-50%). For laboratory diagnosis of HIT antibodies, both antigen assays and functional (platelet activation) assays are available. Both tests are very sensitive (high negative predictive value) but specificity is problematic, especially for the antigen assays, which also detect nonpathogenic immunoglobulin M and immunoglobulin A class antibodies. Detection of immunoglobulin M or immunoglobulin A antibodies could potentially lead to adverse events such as bleeding if a false diagnosis of HIT prompts replacement of heparin by an alternative anticoagulant. For treatment of HIT, three alternative anticoagulants are approved: the direct thrombin inhibitors, lepirudin and argatroban, and the heparinoid, danaparoid (not approved in the United States). Recent data indicate that the approved dosing regimens of the direct thrombin inhibitors are too high, especially in ICU patients. HIT affects <1% of ICU patients even though 30-50% develop thrombocytopenia. The choice of the optimal alternative anticoagulant depends on patient characteristics. Many ICU patients require lower doses of alternative anticoagulant than those recommended by the manufacturer.

Antibodies to Heparin–Platelet Factor 4 Complex: Pathogenesis, Epidemiology, and Management of Heparin-Induced Thrombocytopenia in Hemodialysis

Heparin-induced thrombocytopenia (HIT) is a drug-mediated, prothrombotic disorder caused by immunization against platelet factor 4 (PF4) after complex formation with heparin or other polyanions. After their binding to PF4/heparin complexes on the platelet surface, HIT antibodies are capable of intravascular platelet activation by cross-linking Fcγ receptor IIA leading to a platelet count decrease and/or thrombosis. Diagnosis of HIT is often difficult. This, and the low specificity of the commercially available immunoassays, leads currently to substantial overdiagnosis of HIT. Timing of onset, the moderate nature of thrombocytopenia, and the common concurrence of thrombosis are very important factors, which help to differentiate HIT from other potential causes of thrombocytopenia. A combination of a clinical pretest scoring system and laboratory investigation is usually necessary to diagnose HIT. Although HIT is considered to be a rare complication of heparin treatment, the very high number of hospital inpatients, and increasingly also hospital outpatients receiving heparin, still result in a considerable number of patients developing HIT. If HIT occurs, potentially devastating complications such as life-threatening thrombosis make it one of the most serious adverse drug reactions. If HIT is strongly suspected, all heparin must be stopped and an alternative nonheparin anticoagulant started at a therapeutic dose to prevent thromboembolic complications. However, the nonheparin alternative anticoagulants bear a considerable bleeding risk, especially if given to patients with thrombocytopenia due to other reasons than HIT. While established drugs for HIT are disappearing from the market (lepirudin, danaparoid), bivalirudin, fondaparinux and potentially the new anticoagulants such as dabigatran, rivaroxaban and apixaban provide new treatment options.

Heparin-induced thrombocytopenia (HIT) occurs following an immune reaction to the administration of heparin, which results in increased platelet activation and thrombocytopenia, and lead to arterial and venous thrombosis in untreated cases. It may be considered as an idiosyncratic, drug-induced reaction in which heparin injections result in the formation of complexes with platelet factor 4 (PF4), triggering an antibody-mediated reaction in certain individuals. Low platelet count in this instance is secondary to platelet aggregation and can lead to thrombotic complications by vascular occlusion and other mechanisms. Early recognition of this complication is essential to prevent life- and limb-threatening thrombosis. Therefore, it is important that intensive care physicians who administer heparin in different forms are aware of this potential adverse event and follow a regular plan in monitoring the platelet count while the patient is on heparin. In a patient whose platelet count falls while on heparin, when no other diagnostic possibilities can easily explain it, immediate withdrawal of any form of heparin and commencement of an alternative anticoagulant is necessary until the diagnosis of HIT is confirmed or excluded. At the same time, it is important that over-diagnosis of HIT is not made to avoid unwanted bleeding complications from the alternative anticoagulants. This review outlines the pathophysiology, diagnosis and management of HIT with a focus on the intensive care setting.

Intraoperative Thrombosis From a Heparin-Containing Irrigation Solution in a Patient With Heparin-Induced Thrombocytopenia

Outcomes of IVC Filter Use in Heparin-Induced Thrombocytopenia: A Retrospective Study

Heparin induced thrombocytopenia antibodies in Covid-19.

The Use of the Pre-Test Clinical Score (4T's) Alone Does Not Detect All Diagnoses of Heparin-Induced Thrombocytopenia in the Critically Ill.