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CC BY-NC-ND 4.0 · Hamostaseologie 2020; 40(04): 472-484
DOI: 10.1055/a-1223-3329
Review Article

Challenges in Detecting Clinically Relevant Heparin-Induced Thrombocytopenia Antibodies

Theodore E. Warkentin
1   Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
2   Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
3   Transfusion Medicine, Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada
4   Service of Clinical Hematology, Hamilton Health Sciences, Hamilton General Hospital, Hamilton, Ontario, Canada
5   McMaster Centre for Transfusion Research, Hamilton, Ontario, Canada
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Abstract

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated hypercoagulable state featuring high thrombosis risk and distinct pathogenesis involving immunoglobulin G-mediated platelet activation. The target of the immune response is a cationic “self” protein, platelet factor 4 (PF4), rendered antigenic by heparin. A key problem is that only a minority of anti-PF4/polyanion antibodies induced by heparin are pathogenic, i.e., capable of causing platelet activation and thereby clinical HIT. Since thrombocytopenia occurs frequently in hospitalized, heparin-treated patients, testing for “HIT antibodies” is common; thus, the problem of distinguishing between pathogenic and nonpathogenic antibodies is important. The central concept is that those antibodies that have platelet-activating properties demonstrable in vitro correlate well with pathogenicity, as shown by platelet activation tests such as the serotonin-release assay (SRA) and heparin-induced platelet activation assay. However, in most circumstances, immunoassays are used for first-line testing, and so it is important for clinicians to appreciate which immunoassay result profiles—in the appropriate clinical context—predict the presence of platelet-activating antibodies (Bayesian analysis). Clinicians with access to rapid, on-demand HIT immunoassays (e.g., particle gel immunoassay, latex immunoturbidimetric assay, chemiluminescent immunoassay) can look beyond simple dichotomous result interpretation (“negative”/“positive”) and incorporate semiquantitative interpretation, where, for example, a strong-positive immunoassay result (or even combination of two immunoassays) points to a greater probability of detecting platelet-activating antibodies, and hence supporting a diagnosis of HIT. Recent recognition of “SRA-negative HIT” has increased the importance of semiquantitative interpretation of immunoassays, given that strong immunoassay reactivity is a potential clue indicating possible HIT despite a (false) negative platelet activation assay.

Zusammenfassung

Heparin-induzierte Thrombozytopenie (HIT) ist ein Antikörper-vermittelter Zustand der Hyperkoagulierbarkeit mit hohem Thromboserisiko und ausgeprägter Pathogenese unter Beteiligung von Immunglobulin G-vermittelter Thrombozytenaktivierung. Das Ziel der Immunantwort ist ein kationisches “Selbst” - Protein, Thrombozytenfaktor 4 (PF4), welches durch Heparin antigenisiert wird. Ein Schlüsselproblem ist, dass nur eine Minderheit der durch Heparin induzierten Anti-PF4/Polyanion-Antikörper pathogen und in der Lage ist, eine Blutplättchenaktivierung und damit eine klinische HIT zu verursachen. Da Thrombozytopenie häufig bei mit Heparin behandelten Patienten im Krankenhaus auftritt, sind Tests für “HIT-Antikörper” üblich; somit ist die Unterscheidung zwischen pathogenen und nicht pathogenen Antikörper wichtig. Das zentrale Konzept ist das diejenigen Antikörper, deren plättchenaktivierende Eigenschaften in vitro nachweisbar sind, gut mit Pathogenität korrelieren, wie durch Thrombozytenaktivierungstests wie den Serotoninrelease Assay (SRA) und Heparin-induzierten Thrombozytenaktivierungsassay gezeigt. In den meisten Fällen werden jedoch unter diesen Umständen Immunoassays als First-Line-Tests verwendet, daher ist es wichtig für Ärzte einzuschätzen, welche Immunoassay-Ergebnisprofile - im entsprechenden klinischen Kontext - das Vorhandensein von Blutplättchen-aktivierenden Antikörpern vorhersagen (Bayes'sche Analyse). Kliniker mit Zugang zu schnellen HIT-Immunoassays auf Abruf (z. B. Partikelgel Immunoassay, Latex-Immunturbidimetrie-Assay, Chemilumineszenz-Immunoassay) können über die einfache dichotome Ergebnisinterpretation hinausschauen („negativ“/„positiv“) und semiquantitative Interpretation einbeziehen, bei der zum Beispiel eine stark positives Immunoassay-Ergebnis (oder sogar die Kombination von zwei Immunoassays) auf eine größere Wahrscheinlichkeit des Nachweises plättchenaktivierender Antikörper hinweist und damit die Diagnose „HIT“ unterstützt. Die jüngste Anerkennung von „SRA-negativem HIT“ hat die Bedeutung der semiquantitativen Interpretation von Immunoassays erhöht, da eine starke Immunoassay Reaktivität ein Hinweis auf eine mögliche HIT trotz eines (falsch) negativen Blutplättchen-Aktivierungsassays sein kann.

Keywords

chemiluminescent immunoassay - heparin-induced thrombocytopenia - latex immunoturbidimetric assay - serotonin-release assay

Schlüsselwörter

Chemilumineszenz-Immunoassays - Heparin-induzierte Thrombozytopenie - Latex-Immunturbidimetrie-Assay - Serotoninrelease Assay


Publication History

Received: 15 May 2020

Accepted: 20 July 2020

Article published online:
22 October 2020

© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Georg Thieme Verlag KG
Stuttgart · New York

 

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