The diagnosis of heparin-Induced thrombocytopenia (HIT) is based on the presence of a compatible clinical picture combined with laboratory evidence of heparin-dependent, platelet-activating IgG antibodies. The 4T's Score is a clinical prediction rule that determines the likelihood that a patient has HIT before laboratory testing is performed. A rapid assay (H/PF4-PaGIA, Diamed, Switzerland) uses gel centrifugation to measure binding of antibodies to antigen-coated polystyrene beads (15 min turnover time). The purpose of this study is to evaluate the clinical utility of a diagnostic strategy which combines the 4T's Score with a H/PF4-PaGIA result to guide management of patients with suspected HIT while awaiting results of the serotonin-release assay (SRA).
Prospective cohort study of 538 consecutive adult patients with suspected HIT at 4 Canadian hospitals. Physicians completed a standardized 4T's Score sheet and the H/PF4-PaGIA was performed using fresh plasma in a central lab by technologists blinded to the 4T's Score (frozen plasma was used for 85 patients due to disruptions in worldwide availability of the assay.) The SRA and an in-house IgG anti-PF4/H enzyme-immunoassay (EIA) were performed on all patients by blinded technologists. Serologically-confirmed HIT (“HIT positive”) was defined as >50% serotonin release (mean) at three reaction conditions (0.1 U/mL heparin; 0.3 U/mL heparin; enoxaparin, 0.1 U/ml), as well as inhibition (<20% release or >50% inhibition) at 100 U/mL heparin and in the presence of Fc receptor-blocking monoclonal antibody, and a positive EIA. Thrombotic events, major bleeding events, and mortality were captured at day 30.
Recommendations for management of patients while awaiting the SRA: patients with a Low 4T's Score (irrespective of H/PF4-PaGIA result) and patients with an Intermediate 4T's Score and negative H/PF4-PaGIA were to receive low-dose danaparoid or fondaparinux. Therapeutic-dose non-heparin anticoagulation was recommended for all patients with an Intermediate 4T's Score and positive H/PF4-PaGIA and for all patients with a High 4T's Score irrespective of H/PF4-PaGIA result.
The primary outcome measure was the frequency of management failures defined as a patient with serologically-confirmed HIT who had one of the following combinations of diagnostic testing (a) Low 4T's Score and negative H/PF4-PaGIA; (b) Low 4T's Score and positive H/PF4-PaGIA or (c) Intermediate 4T's Score and negative H/PF4-PaGIA.
527 patients with mean age 66.5 yr (sd 15.4) were analyzed; 11 patients with missing diagnostic testing results were excluded. Clinical outcomes of the management of patients according to the diagnostic strategy will be reported separately. Results of diagnostic accuracy of the 4T's Score and H/PF4-PaGIA compared to the SRA are provided below.
The prevalence of serologically-confirmed HIT in the study population was 6.5%. Two patients with indeterminate SRAs but IgG>1.0 were reported as HIT Positive.
A negative H/PF4-PaGIA result reduced the probability of HIT based on the 4T's Score from 2.5% to 0.7% (95% CI: 0.1-2.6%) in the Low group, from 6.1% to 0% (95% CI: 0-2.7%) in the Intermediate group and from 35.7% to 0% (95% CI: 0-14.3%) in the High group. A positive H/PF4-PaGIA result increased the probability of HIT based on the 4T's Score to 15.4% (Low 4T's), 38.5% (intermediate 4T's) and 83.3% (High 4T's).
The proportion of management failures was 1.5% (95% CI : 0.7%-3.0%). Of the 8 patients who were identified as management failures, 2 (Low 4T's) had a negative H/PF4-PaGIA. Out of 33 HIT Positive patients, 8 (24.2%) would have been missed based on a Low 4T's Score alone and 2 (6.1%) based on negative H/PF4-PaGIA alone. The combination of a Low or Intermediate 4T's Score and a negative H/PF4-PaGIA result had a negative predictive value for HIT of 99.5% (95% CI: 98.3-99.9).
The proportion of management failures was low (1.5%) and within acceptable limits (95% CI : 0.7%-3.0%). Combining the 4T's Score with the result of H/PF4-PaGIA excludes the diagnosis of HIT in the majority of patients with a Low or Intermediate probability for HIT and raises the likelihood of HIT in patients with a High probability.
Linkins: BioRad DiaMed: PaGIA assays purchased at cost for study Other. Bates:BioRad Diamed: provided assays for study at cost Other. Lee:BioRad Diamed: provided assays for study at cost Other. Warkentin:GSK: Research Funding; WL Gore: Consultancy; Immucor GTI Diagnostics: Research Funding; Paringenix: Consultancy; Pfizer Canada: Honoraria; BioRad Diamed: provided assays for study at cost, provided assays for study at cost Other.