Laboratory diagnosis of heparin‐induced thrombocytopenia

Abstract

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.

Evaluation of a rapid and automated heparin‐induced thrombocytopenia immunoassay

“…The “4T”score was introduced in 2003 and is a commonly used means of predicting the pretest likelihood of clinical HIT using a scale of 0‐8 points. If the pretest probability score falls between 0 and 3, HIT is clinically unlikely; a score of 4‐5 indicates intermediate probability, while a score of 6‐8 makes HIT diagnosis significantly more likely.…”

“…The "4T"score was introduced in 2003 25 and is a commonly used means of predicting the pretest likelihood of clinical HIT using a scale of 0-8 points. If the pretest probability score falls between 0 and 3, HIT is clinically unlikely; a score of 4 18 Therefore, reporting the quantitative values of LIA along with the positive/negative results may help clinicians better assess the posttest probability of HIT and provide the appropriate management at an earlier time.…”

A computerized scoring system to improve assessment of heparin‐induced thrombocytopenia risk

“…The 4Ts score is a widely used pretest HIT risk assessment tool that uses clinical and laboratory data to risk‐stratify patients with suspected HIT and to determine which patients warrant specific diagnostic testing . The 4Ts score incorporates: (i) the thrombocytopenia magnitude; (ii) the timing of the onset of thrombocytopenia in relation to initiation of heparin; (iii) the occurrence of subsequent thrombotic complications; and (iv) the presence/absence of other causes of thrombocytopenia.…”

“…A clinical decision support (CDS) tool that assists clinicians in recognizing that a hospitalized patient may be experiencing early manifestations of HIT and should undergo diagnostic testing and presumptive therapy for HIT would therefore be of significant benefit. The 4Ts score is a widely used pretest HIT risk assessment tool that uses clinical and laboratory data to riskstratify patients with suspected HIT and to determine which patients warrant specific diagnostic testing [8,9]. The 4Ts score incorporates: (i) the thrombocytopenia magnitude; (ii) the timing of the onset of thrombocytopenia in relation to initiation of heparin; (iii) the occurrence of subsequent thrombotic complications; and (iv) the presence/absence of other causes of thrombocytopenia.…”

Influence of Human Leukocyte Antigen (HLA) Alleles and Killer Cell Immunoglobulin‐Like Receptors (KIR) Types on Heparin‐Induced Thrombocytopenia (HIT)

“…Further complicating the use of heparin anticoagulants, prevention of HIT‐related thrombosis is currently possible only after manifestations of HIT are evident and the disease process has already begun . Clinical algorithms and laboratory tests are inadequate for evaluation of HIT risk prior to heparin administration . The inability to predict HIT thus represents a liability with heparin administration, and a priori identification of patients with a high HIT risk could make prevention of HIT possible.…”