Diagnostic accuracy of IgG‐specific versus polyspecific enzyme‐linked immunoassays in heparin‐induced thrombocytopenia: a systematic review and meta‐analysis

Husseinzadeh, Holleh; Gimotty, Phyllis A.; Pishko, Allyson M.; Buckley, Meghan; Warkentin, Theodore E.; Cuker, Adam

doi:10.1111/jth.13692

Cited by 33 publications

(37 citation statements)

References 36 publications

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“…All patients underwent HIT laboratory testing with a polyspecific HIT antibody ELISA (PF4/H ELISA) (Immucor GTI Diagnostics Inc) and an in‐house serotonin‐release assay (SRA) . In light of the high negative predictive value of the ELISA and SRA, all patients with a negative ELISA (<0.4 optical density units) and a negative SRA were classified as not having HIT . Clinical case summaries of the remaining subjects were prepared using a standardized case report form to include detailed clinical information about the hospital course, the platelet count trend, exposure to heparin and other medications, thrombotic events, the results of the HIT antibody ELISA and SRA, and 30‐day follow‐up information.…”

Section: Methodsmentioning

confidence: 99%

“…21 In light of the high negative predictive value of the ELISA and SRA, all patients with a negative ELISA (<0.4 optical density units) and a negative SRA were classified as not having HIT. 22 Clinical case summaries of the remaining subjects were prepared using a standardized case report form to include detailed clinical information about the hospital course, the platelet count trend, exposure to heparin and other medications, thrombotic events, the results of the HIT antibody ELISA and SRA, and 30-day follow-up information. An independent adjudication panel of three experts in HIT (GA, MC, LR) reviewed the clinical case summaries and determined if patients were positive for HIT or negative for HIT as previously described.…”

Section: Definition Of Hitmentioning

confidence: 99%

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The risk of major bleeding in patients with suspected heparin‐induced thrombocytopenia

Pishko

Lefler

Gimotty

et al. 2019

Journal of Thrombosis and Haemostasis

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Background The presence of a hypercoagulable disorder such as heparin‐induced thrombocytopenia (HIT) may protect against anticoagulant‐associated bleeding. Objectives To determine the incidence of major bleeding in patients with suspected HIT. Methods We performed a retrospective analysis of 310 patients suspected of having HIT from the Hospital of the University of Pennsylvania and an affiliated community hospital. We compared the cumulative incidence of major bleeding following suspicion for HIT by ultimate HIT status (HIT+ or HIT−) and exposure to an alternative anticoagulant (Tx+ or Tx−). Secondary outcomes included the incidence of new/progressive thrombosis and 30‐day mortality. Results The incidence of major bleeding was high in the HIT+Tx+, HIT− Tx+, and HIT−Tx− groups (35.7%, 44.0%, and 37.3%, respectively). The time to first major bleeding event did not differ between groups (P = .24). Factors associated with increased risk of major bleeding included intensive care unit admission (HR 2.24, 95% CI 1.44‐3.47), platelet count < 25 × 109/L (HR 2.13, 1.10‐4.12), and renal dysfunction (HR 1.56, 1.06‐2.27); 35.7% of HIT+Tx+, 13.8% HIT−Tx+, and 9.3% of HIT−Tx− patients experienced new or progressive thrombosis. Mortality was similar among the three groups (26.2% HIT+Tx+, 34.5% HIT−Tx+, and 26.7% of HIT−Tx− [P = .34]). Conclusions Among patients with suspected HIT, major bleeding was common regardless of HIT status. Contrary to our hypothesis, HIT+ patients were not protected from major bleeding. A better understanding of bleeding risk is needed to inform management decisions in patients with suspected HIT.

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Section: Methodsmentioning

confidence: 99%

Section: Definition Of Hitmentioning

confidence: 99%

The risk of major bleeding in patients with suspected heparin‐induced thrombocytopenia

Pishko

Lefler

Gimotty

et al. 2019

Journal of Thrombosis and Haemostasis

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“…Only antibodies of IgG class are capable of activating platelets (through platelet FcγIIa receptors), yet heparin‐exposed patients often make anti‐PF4/heparin antibodies of IgA and IgM classes . Detecting nonpathogenic IgA and IgM class antibodies explains lower diagnostic specificity of so‐called “polyspecific” EIAs that detect antibodies of any of the three major immunoglobulin classes, IgG, IgA, and IgM …”

Section: Iceberg Modelmentioning

confidence: 99%

“…The major advantage of PF4‐dependent EIAs is their high sensitivity: At least 97% of patients with HIT will test positive in a solid‐phase EIA . Moreover, these assays are commercially available and can be performed by hospitals that employ EIA technology, allowing results to be obtained within a few hours (however, testing is often batched, so test results can be delayed).…”

Section: Pf4‐dependent Immunoassaysmentioning

confidence: 99%

“…For example, the frequency of a positive SRA is less than 5% if the EIA is only weakly positive (0.40 to 0.99 optical density [OD] units), whereas the probability of a positive SRA exceeds 90% if the OD is > 2.00 units . Diagnostic specificity is enhanced if an IgG‐specific EIA is performed (although a lower cutoff of 0.40 units is suggested when interpreting IgG‐specific EIAs) …”

Section: Pf4‐dependent Immunoassaysmentioning

confidence: 99%

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Laboratory diagnosis of heparin‐induced thrombocytopenia

Warkentin

2019

Int J Lab Hematology

113

160

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Heparin‐induced thrombocytopenia (HIT) is a clinical‐pathological disorder; thus, laboratory testing for the pathogenic platelet‐activating antiplatelet factor 4 (PF4)/heparin antibodies is central for diagnosis. The “iceberg” model summarizes the inter‐relationship between platelet activation assays and PF4‐dependent immunoassays, with platelet‐activating antibodies comprising a subset of anti‐PF4/heparin antibodies. The platelet serotonin‐release assay (SRA), performed by reference laboratories, has high sensitivity and specificity for HIT (~95% each), and is especially suited for detecting highly pathogenic HIT sera containing both heparin‐dependent and heparin‐independent platelet‐activating antibodies; this latter subgroup of antibodies explains “autoimmune HIT” disorders (delayed‐onset, persisting, spontaneous, heparin “flush,” fondaparinux‐associated). Recently, SRA‐negative HIT has become recognized, in which serum from some HIT patients contains subthreshold levels of platelet‐activating antibodies (by SRA) that become detectable using a PF4‐enhanced platelet activation assay. Unusual immunologic features of HIT include early antibody detectability (at onset of platelet count fall) and antibody transience (seroreversion). Widely available PF4‐dependent enzyme immunoassays (EIAs) have high sensitivity but poor specificity for HIT, although specificity is enhanced with IgG‐specific EIAs and strong positive results; unfortunately, EIA results are usually not available in real time. Automated rapid immunoassays, such as the chemiluminescence immunoassay (CLIA) and latex immunoturbidimetric assay (LIA), facilitate real‐time laboratory diagnosis. Recently available likelihood ratio (LR) data for positive (LR+) and negative (LR−) test results allow clinicians to adjust their pretest probabilities for HIT, using Bayesian analysis, into real‐time posttest probabilities that are dramatically increased (test positive) or decreased (test negative). Moreover, (semi‐)quantitative CLIA‐ and LIA‐positive results (weak, moderate, strong positive) can further refine the posttest probability of HIT.

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Serotonin‐release assay‐negative heparin‐induced thrombocytopenia

et al. 2019

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Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Pathogenic HIT antibodies can be detected by the serotonin-release assay (SRA), a platelet activation test. We have regarded the SRA performed in our medical community ("McMaster" SRA) as having high sensitivity and specificity. Recently, the concept of "SRAnegative HIT" has been proposed for enzyme-immunoassay (EIA)-positive/SRAnegative patients with a HIT-compatible clinical picture, who test positive in a PF4-enhanced platelet activation assay. After identifying an index case of SRAnegative HIT, we estimated the frequency of this condition by performing the "PF4-SRA" (modified SRA using high concentrations of added PF4 rather than heparin) in EIA-positive patients from a cohort study evaluating clinical and laboratory diagnosis of HIT. We defined SRA-negative HIT as patients meeting three criteria: clinical picture compatible with HIT (4Ts ≥ 4 points); EIA-positive (≥1.00 units); and PF4-SRA-positive. Among 430 patients, 35 were EIA-positive/SRA-positive and 27 were EIA-positive/SRA-negative. Among these 27 SRA-negative patients, three were found to have subthreshold levels of platelet-activating antibodies by PF4-SRA, of whom one met clinical criteria for SRA-negative HIT. Thus, based on identifying one patient with SRA-negative HIT within a cohort study that found 35 SRA-positive HIT patients, we estimate the sensitivity of the McMaster SRA for diagnosis of HIT to be 35/36 (97.2%; 95% CI, 85.8-99.9%). Although the McMaster SRA is highly sensitive for HIT, occasional SRA-negative but EIA-positive patients strongly suspected of having HIT can have this diagnosis supported by a PF4-enhanced activation assay such as the PF4-SRA.

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Diagnostic accuracy of IgG‐specific versus polyspecific enzyme‐linked immunoassays in heparin‐induced thrombocytopenia: a systematic review and meta‐analysis

Cited by 33 publications

References 36 publications

The risk of major bleeding in patients with suspected heparin‐induced thrombocytopenia

The risk of major bleeding in patients with suspected heparin‐induced thrombocytopenia

Laboratory diagnosis of heparin‐induced thrombocytopenia

Serotonin‐release assay‐negative heparin‐induced thrombocytopenia

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