Rapid and Accurate Bayesian Diagnosis of Heparin-induced thrombocytopenia

Abstract

Prompt diagnostic work-up of suspected heparin-induced thrombocytopenia (HIT) is critical for guiding initial patient management. We assessed the performance of three immunoassays detecting anti-PF4/heparin-antibodies, derived a diagnostic algorithm with a short analytical turnaround-time (TAT) and prospectively validated it. Plasma samples were analysed by Zymutest-HIA-IgG, HemosIL-AcuStar-HIT-IgG and ID-H/PF4-PaGIA in retrospective (n=221) and prospective (n=305) derivation cohorts. We calculated likelihood ratios (LR) of result intervals and cut-off values with 100% negative (NPV) and positive (PPV) predictive value for a positive gold-standard functional assay (HIPA). We established a diagnostic algorithm based on the Bayesian combination of pre-test probability and LR of first- and second-line immunoassays. Cut-offs with 100% PPV for positive HIPA were >3.0 U/ml (HemosIL-AcuStar-HIT-IgG) and titre {greater than or equal to}16 (ID-H/PF4-PaGIA); cut-offs with 100% NPV were <0.13 U/ml and {less than or equal to}1, respectively. During the prospective validation of the derived algorithm (n=687), HemosIL-AcuStar-HIT-IgG was used as unique testing in 566/687 cases (82.4%) (analytical TAT 30 min). In 121/687 unresolved cases (17.6%), ID-H/PF4-PaGIA was used as second-line testing (additional TAT 30 min). The algorithm accurately predicted HIT in 51/687 (7.4%) and excluded it in 604/687 (87.9%) patients, leaving only 20/687 (2.9%) cases unresolved. Additionally, we identified 12/687 (1.7%) positive predictions not confirmed by HIPA: 10 patients with probable HIT despite negative HIPA and two possible false positive algorithm predictions. The combination of pre-test probability with first- and second-line immunoassays for anti-PF4/heparin-antibodies is accurate for ruling in or out HIT in {greater than or equal to}95% of cases within 60 minutes. This diagnostic approach improves initial management of patients with suspected HIT.

Management of the thrombotic risk associated with COVID-19: guidance for the hemostasis laboratory

“…Therefore, a systematic evaluation of clinical probability of diagnosis allows better identification of patients in whom the occurrence of this complication must be suspected, and for whom laboratory work-up for HIT antibodies is indicated. This evaluation is generally performed with the 4Ts' score, much studied [167,168] [159], despite its limitations, particularly in more complex situations such as those encountered in ICU (no consensus on the drugs responsible for thrombocytopenia, many other causes of thrombocytopenia, very high negative predictive value but not absolute (e.g. thrombosis in the absence of thrombocytopenia), insufficient data on platelet count, weak agreement in the determination of the 4th criteria (other causes of thrombocytopenia)) [166,169,170].…”

“…In patients receiving UFH, a laboratory resistance to the anticoagulant effect of heparin, arbitrarily defined by failure to reach the therapeutic target despite the administration of doses > 1.5 times usual doses, which are about 400 to 600 U/kg/24 h [ 158 , 159 ], is frequently observed in COVID-19 [ 13 , 160 ], and adds to the clinical resistance previously outlined (occurrence of thrombotic events under well-conducted drug thromboprophylaxis). The hyperinflammatory context could also explain part of this observation.…”

Challenges in Detecting Clinically Relevant Heparin-Induced Thrombocytopenia Antibodies

“…Recently, two groups 54 55 have reported results integrating clinical and laboratory parameters, in which two rapid assays were combined. Part of the rationale of dual testing is to reduce risk of false-negative tests, given the treatment implications of missing a diagnosis of HIT.…”

“…Marchetti and coworkers 54 performed real-time evaluation of two rapid immunoassays, one a first-line assay (CLIA) and the other a second-line assay (PaGIA); samples were tested later, as required, by EIA and HIPA. A novel concept was the use of extreme positive- and negative-result thresholds, e.g., a CLIA >3 U/mL suggesting approximately 100% PPV and a CLIA <0.13 U/mL indicating 0% negative predictive value (NPV); corresponding extreme PPV and NPV values for the PaGIA titer of ≥16 and ≤1 were also used.…”

“…Marchetti and coworkers 54 identified 10 patients in a population of 687 patients evaluated for HIT whose clinical picture and combination of rapid assays suggested a likely diagnosis of HIT, despite the negative (gold standard) HIPA test. In general, these patients were EIA- and PaGIA-positive, and most also tested positive in the CLIA (and even the CLIA-“negative” patients had values >0.40 U/mL, a threshold that may have 100% sensitivity for HIT antibodies 47 ).…”