Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin-induced thrombocytopenia

Bakchoul, Tamam; Giptner, Astrid; Najaoui, Abderrahim; Bein, Gregor; Santoso, Sentot; Sachs, Ulrich J.

doi:10.1111/j.1538-7836.2009.03465.x

Cited by 127 publications

(121 citation statements)

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“…24,25 However, simply increasing the cut-off of the OD value to improve diagnostic specificity invariably compromises the sensitivity and leads to unacceptable numbers of false-negatives. 26,27 The use of a high heparin "confirmatory" step is yet another serologic parameter that has been investigated for improving assay specificity. Because HIT antibodies show heparindependent binding, the addition of excess heparin (2-100 U/mL) competes and/or disrupts binding of HIT antibodies to pre-formed PF4/H complexes.…”

mentioning

confidence: 99%

Heparin-Induced Thrombocytopenia

Arepally¹,

Cines²

2008

Diagnostic Criteria in Autoimmune Diseases

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Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies that recognize complexes of platelet factor 4 (PF4) and heparin. HIT is frequently considered in the differential diagnosis of thrombocytopenia occurring in patients on heparin therapy. HIT is a challenging diagnosis because of routine heparin use in hospitalized patients, the common occurrence of thrombocytopenia, and high rates of anti-PF4/heparin seroconversions in patients treated with heparin. This chapter will summarize our diagnostic approach to HIT by underscoring critical elements of the clinical and laboratory evaluation. Keywordsplatelet factor 4; PF4; heparin; PF4/H complexes; HIT Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening immune complication which occurs after exposure to unfractionated heparin (UFH) or less commonly, to low-molecular weight heparins (LMWHs). 1 It is characterized by declining platelet counts beginning 5-14 days after heparin exposure occurring in isolation (isolated HIT) or concurrent with new arterial and venous thrombotic complications. 2 HIT is caused by antibodies directed against complexes formed by a platelet protein, platelet factor 4, and heparin (PF4/H). Circulating immune complexes containing IgG and PF4/H complexes bind to platelet and monocyte Fc receptors and promote cellular activation leading to procoagulant microparticle release and thrombin generation. 3,4 Historically, the challenge associated with HIT was lack of awareness of the syndrome and its pursuant complications; the challenge now is in over-diagnosis and treatment of HIT. With the widespread availability of screening immunoassays and the desire of clinicians to avoid the thrombotic consequences associated with true disease, many patients without HIT Correspondence to: Gowthami M. Arepally, arepa001@mc.duke.edu. now suffer needless morbidity due to bleeding complications from use of alternative anticoagulants. To avoid a reflexive diagnosis of HIT in the heparinized thrombocytopenic patient, clinicians must have a sound understanding of the clinical and laboratory diagnostic elements essential for a diagnosis of HIT. This paper reviews our diagnostic and management strategy in evaluating the common presentation of thrombocytopenia in a heparinized patient. NIH Public Access Diagnosing HIT: the clinical challengeHIT is a challenging clinical diagnosis. The increasing use of UFH/LMWH for thromboprophylaxis in hospitalized patients 5 coupled with the frequency of thrombocytopenia, particularly among critically ill patients, 6 results in a significant overlap of patients suspected of HIT. In a recent registry of ~1000 patients treated with thromboprophylactic dosed heparin, 19% (n = 190) met thrombocytopenia criteria compatible with a diagnosis of HIT (as defined by a platelet count < 150 × 10 9 /L or > 50% drop in platelet counts), but only 5% of patients were diagnosed with HIT. 6 This study and clinical experience suggest that other causes of thrombocytopenia, such as infection, medi...

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confidence: 99%

Heparin-Induced Thrombocytopenia

Arepally¹,

Cines²

2008

Diagnostic Criteria in Autoimmune Diseases

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“…This method has been applied to the detection of a broad spectrum of antibodies ranging from those against Helicobacter pylori 7 to markers in rheumatoid arthritis, 8,9 lupus 10 and heparin-induced thrombosis. 11 Other related fluorescent marker approaches include, for example, immunoprecipitation assays and recombinant immunofluorescence assays for detection of antibodies to aquaporin-4 in patients with neuromyelitis optica. 12,13 Increasingly, these sensing techniques are being developed as antigen-bound micro-arrays in which large numbers of antigens are anchored to a substrate to show good sensitivity and low detection limit due to a high fluorescence signal, or a combination of antigens are bound providing a multiparametric sensor for a range of antibodies.…”

Section: Introductionmentioning

confidence: 99%

Application of Functionalized Lanthanide-Based Nanoparticles for the Detection of Okadaic Acid-Specific Immunoglobulin G

Stipić

Pletikapić²,

Jakšić

et al. 2015

J. Phys. Chem. B

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Marine biotoxins are widespread in the environment and impact on human health via contaminated shellfish, causing diarrhetic, amnesic, paralytic or neurotoxic poisoning. In spite of this methods for determining if poisoning has occurred are limited. We show the development of a simple and sensitive luminescence resonance energy transfer (LRET) -based concept which allows the detection of anti-okadaic acid rabbit polyclonal IgG (mouse monoclonal IgG1) using functionalized lanthanide-based nanoparticles. Upon UV excitation, the functionalized nanoparticles were shown to undergo LRET with fluorophore-labeled anti-okadaic acid antibodies which had been captured and bound by okadaic acid-decorated nanoparticles. The linear dependence of fluorescence emission intensity with antigen-antibody binding events was recorded in the nanomolar to micromolar range, while essentially no LRET signal was detected in the absence of antibody. These results may find applications in new, cheap and robust sensors for detecting not only immune responses to biotoxins but to a wide range of biomolecules based on antigen-antibody recognition systems. Further, as the system is based on solution chemistry it may be sufficiently simple and versatile to be applied at point-of-care.

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“…The specificity was higher for the IgG-specific EIA (89% versus 81%), and could be further increased by increasing the OD cutoff at the expense of sensitivity, as would be anticipated. The authors found that a cutoff OD of 0.65 reflected the optimal compromise between sensitivity and specificity (sensitivity 97.1% and specificity 92.4%) [42]. This cutoff cannot be universally applied, however, as OD thresholds vary between laboratories.…”

Section: Laboratory Detection Of Hit Antibodiesmentioning

confidence: 99%

“…In the aforementioned study by Bakchoul et al [42], the authors included PaGIA in their evaluation of different antigen binding assays. The PaGIA had a PPV of 36.6%, compared with 28% for Poly-EIA and 40.6% for IgG-specific EIA.…”

Section: Laboratory Detection Of Hit Antibodiesmentioning

confidence: 99%

Heparin‐induced thrombocytopenia: Current status and diagnostic challenges

Otis

Zehnder

2010

American J Hematol

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Heparin‐induced thrombocytopenia (HIT) is a fairly common and potentially catastrophic complication of heparin therapy. Diagnosing HIT remains a challenge, as the patients at risk often have other reasons for thrombocytopenia and/or thrombosis. HIT is considered a clinicopathologic disorder whose diagnosis is generally made on the basis of both clinical criteria and the presence of “HIT antibodies” in the patient's serum or plasma. There are two basic laboratory approaches to detect HIT antibodies. The immunoassays detect antibodies based on their binding properties, whereas the functional assays detect antibodies based on their platelet‐activating properties. Prompt and accurate diagnosis of HIT is imperative, as overdiagnosis exposes patients to alternative anticoagulants and their associated bleeding risks, whereas under‐ or delayed diagnosis leaves patients vulnerable to the thromboembolic sequelae of HIT, which can be life threatening. A critical interpretation of laboratory results by the clinician is an essential component of diagnosing HIT. This requires a keen understanding of the current concepts in the pathophysiologic mechanisms of the disease, and the application of these concepts when interpreting the results of both the functional and immunoassays. Equally important is an awareness of the strengths and weaknesses, as well as the current lack of standardization and proficiency testing, of these assays. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.

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Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin-induced thrombocytopenia

Abstract: Our observation indicates that an IgG-ELISA provides the best diagnostic information of all antigen-binding assays.

Cited by 127 publications

References 29 publications

Heparin-Induced Thrombocytopenia

Heparin-Induced Thrombocytopenia

Application of Functionalized Lanthanide-Based Nanoparticles for the Detection of Okadaic Acid-Specific Immunoglobulin G

Heparin‐induced thrombocytopenia: Current status and diagnostic challenges

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