Serotonin release assay (SRA)-negative HIT, a newly recognized entity: Implications for diagnosis and management

Pandya, Komal; Johnson, Eric; Davis, George A.; Padmanabhan, Anand

doi:10.1016/j.thromres.2018.10.022

Cited by 21 publications

(22 citation statements)

References 9 publications

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“…A further impetus for our study was our recent identification of a patient with SRA‐negative HIT (see results section, Index case of SRA‐negative HIT). Our strategy was to use this patient cohort that was systematically evaluated for a diagnosis of HIT, and where residual blood samples permitted evaluation for subthreshold levels of platelet‐activating antibodies …”

Section: Discussionmentioning

confidence: 99%

“…In contrast, other investigators, using another PF4‐enhanced assay (also performed without heparin), called the PF4‐dependent, P‐selectin expression assay (PEA), have reported that a large proportion of clinically‐suspected HIT patients who test SRA‐negative are PEA‐positive . These investigators suggested that “SRA‐negative HIT” is a relatively common condition, with the SRA, as performed in their laboratory, missing approximately 50% of patients with HIT …”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serotonin‐release assay‐negative heparin‐induced thrombocytopenia

et al. 2019

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“…Vayne et al reported an SRA‐negative patient strongly suspected to have HIT; by adding PF4 (10 μg/mL) to their conventional SRA (performed at 0, 0.1, 0.5, and 10 U/mL heparin), these authors obtained a positive test result. Pandya and colleagues reported 2 patients with clinical courses consistent with HIT, and who tested EIA‐IgG positive but SRA negative; both patients tested positive in the PEA. More work is needed to determine how often SRA‐negative HIT occurs and to what extent this phenomenon reflects differences in SRA performance among laboratories or rather reflect fundamental nuances in HIT pathogenesis.…”

Section: Platelet Activation Assaysmentioning

confidence: 99%

Laboratory diagnosis of heparin‐induced thrombocytopenia

Warkentin

2019

Int J Lab Hematology

114

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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“…We report using the combined strategy of high‐dose IVIG plus cangrelor (ultra‐short‐acting antiplatelet agent) for a patient with subacute HIT type A who required urgent cardiac reoperation for HIT‐associated intracardiac thrombosis. Despite such severe HIT‐associated complications, our patient had serotonin‐release assay (SRA)‐negative HIT 9‐11 . We therefore used a modified SRA to demonstrate inhibition of platelet‐activating HIT antibodies in this patient.…”

Section: Introductionmentioning

confidence: 99%

High‐dose IVIG plus cangrelor platelet “anesthesia” during urgent heparin‐CPB in a patient with recent SRA‐negative HIT‐thrombosis with persisting platelet‐activating antibodies

Koster

Nazy

Birschmann

et al. 2020

Research and Practice in Thrombosis and Haemostasis

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In a high‐risk patient with subacute heparin‐induced thrombocytopenia (HIT) type A (platelet count recovery following acute HIT but with persisting platelet‐activating antibodies), in whom urgent cardiac surgery was required, a key clinical question arose: could intraoperative heparin be given safely with “platelet anesthesia” provided with high‐dose intravenous immunoglobulin (IVIG) plus cangrelor (ultra‐short‐acting antiplatelet agent)? This approach proved successful, without unexpected postoperative thrombocytopenia or thromboembolism. In vitro studies confirmed that both IVIG and cangrelor contributed to perioperative inhibition of HIT antibody‐induced platelet activation. Interestingly, despite the patient testing strongly positive in 4 HIT immunoassays (latex immunoturbidimetric assay and 3 enzyme‐immunoassays), the serotonin‐release assay (SRA) was consistently negative. Nevertheless, platelet‐activating HIT antibodies were detectable using modified (platelet factor 4–enhanced) SRA. Our protocol of heparin rechallenge following IVIG/cangrelor provides both intraoperative and early postoperative inhibition of HIT antibody‐induced platelet activation and is applicable to patients with circulating functional HIT antibodies requiring urgent heart surgery, including those with “SRA‐negative HIT.”

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Serotonin release assay (SRA)-negative HIT, a newly recognized entity: Implications for diagnosis and management

Cited by 21 publications

References 9 publications

Serotonin‐release assay‐negative heparin‐induced thrombocytopenia

Serotonin‐release assay‐negative heparin‐induced thrombocytopenia

Laboratory diagnosis of heparin‐induced thrombocytopenia

High‐dose IVIG plus cangrelor platelet “anesthesia” during urgent heparin‐CPB in a patient with recent SRA‐negative HIT‐thrombosis with persisting platelet‐activating antibodies

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