Prospective Evaluation of Heparin-Induced Thrombocytopenia Expert Probability and 4T Scores in Chinese Patients with Suspected Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is a prothrombotic and potentially fatal complication of heparin treatment, caused by anti-platelet factor 4 (anti-PF4)/heparin antibodies of the immunoglobulin G (IgG) class. It affects approximately 0.1% to 5% of patients receiving unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Given the widespread use of heparin in clinical practice, HIT remains a critical differential diagnosis for patients presenting with thrombocytopenia and heparin exposure. However, diagnosing HIT is challenging, particularly in complex and critically ill patients. Physicians often need to make urgent clinical decisions while awaiting the results of anti-PF4/heparin antibody tests. Functional assays, considered the gold standard for HIT diagnosis, are time-consuming, technically complex, and expensive. Immunoassays, while more accessible, often have high sensitivity but low specificity, leading to overdiagnosis. In many developing countries, including China, neither screening immunoassays nor specific functional tests are widely available, underscoring the importance of pre-test scoring systems to guide clinical decision-making.
The 4T score and the HIT expert probability (HEP) score are the two principal scoring systems used for HIT diagnosis. The 4T score includes four variables: thrombocytopenia, timing of platelet fall, thrombosis, and other causes of thrombocytopenia. It classifies patients into low, intermediate, or high risk of HIT. The HEP score, introduced in 2010, comprises eight clinical and biological criteria with corresponding positive and negative points. Both scores have high sensitivity and are effective in ruling out HIT in low-risk individuals. However, the reliability of the HEP score compared to the 4T score remains uncertain. Previous studies evaluating these scoring systems were conducted retrospectively by hematologists and clinicians with expertise in HIT diagnosis, which may not reflect real-life clinical practice. This study aimed to prospectively validate the diagnostic performance of the HEP score compared to the 4T score in a heterogeneous patient population in China and to evaluate the inter-rater reliability of the 4T score in a clinical setting.
The study was conducted at Peking Union Medical College Hospital, a tertiary hospital in Beijing, China. It included 89 HIT-suspected patients between May 2016 and July 2018. The inclusion criteria were the use of UFH or LMWH and the presence of thrombocytopenia or a platelet count fall. Patients with repeated tests, lost samples, or chronic hemodialysis were excluded due to the high risk of developing asymptomatic anti-PF4/heparin antibodies. Three hematologists independently assessed the HEP and 4T scores for each patient, and a consensus was reached through discussion. Additionally, residents who were responsible for HIT-suspected patients but lacked intentional training were asked to complete the 4T score using a structured questionnaire. The IgG-specific anti-PF4/heparin antibody was detected using an enzyme-linked immunosorbent assay (ELISA) kit, with a cutoff value of 0.4 optical density (OD) units.
Of the 89 patients included in the study, 22 (24.7%) tested positive for anti-PF4/heparin antibodies. The median age of HIT-positive patients was significantly higher than that of HIT-negative patients (64.5 vs. 54.0 years), and HIT-positive patients were more likely to develop thrombosis. The median 4T and HEP scores were significantly higher in HIT-positive patients compared to HIT-negative patients (5 vs. 3 for the 4T score, and 7 vs. 2 for the HEP score). The correlation between the antibody titer and the HEP score (r = 0.392) was similar to that between the antibody titer and the 4T score (r = 0.444). Receiver operating characteristic (ROC) curve analysis showed no significant difference in the diagnostic performance of the two scoring models, with an area under the curve (AUC) of 0.778 for the HEP score and 0.741 for the 4T score.
The inter-observer agreement of the 4T score between residents and hematologists was evaluated using the intraclass correlation coefficient (ICC). Only 72 of the 89 questionnaires (80.9%) were completed by residents, and less than half of these (43.1%) included the four individual item scores that make up the 4T score. The AUC of the 4T score assessed by residents was significantly lower than that assessed by hematologists (0.657 vs. 0.780). The ICC for the total 4T score between residents and hematologists was 0.49, indicating fair inter-observer agreement. Among the four individual items of the 4T score, “existence of other causes of thrombocytopenia” and “timing of thrombocytopenia” had lower ICCs (0.36 and 0.57, respectively), while “magnitude of thrombocytopenia” and “presence of thrombosis” had excellent ICCs (0.79 and 0.80, respectively).
The study concluded that the HEP score does not outperform the 4T score in predicting HIT in Chinese patients. The inter-observer agreement of the 4T score in a real-life clinical setting was fair, but the completion rate was unsatisfactory. This highlights the need for continuing education for physicians to improve the use of pre-test probability scores before ordering anti-PF4/heparin antibody tests in HIT-suspected patients. The findings also underscore the importance of clear definitions for the individual items of the 4T score, particularly “existence of other causes of thrombocytopenia” and “timing of thrombocytopenia,” to enhance reliability.
In summary, while the HEP score offers a more extensive definition of assessment criteria compared to the 4T score, it does not provide a significant advantage in diagnostic performance. The 4T score remains a practical and effective pre-test scoring system for HIT, but its application in clinical practice requires improvement. Physicians should be better trained to use these scoring systems to avoid unnecessary laboratory assays and reduce the risk of overdiagnosis. Future studies with larger sample sizes and more diverse patient populations are needed to further validate these findings and explore the diagnostic performance of these scoring models in different clinical settings.
doi.org/10.1097/CM9.0000000000000261
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