Accelerated thrombin times are associated with thrombotic risk
Authors: Victoria Costa, Matthew C. Canver, Rebecca M. Harris, Jacob H. Rand, Matthew B. Greenblatt
Journal: American Journal of Hematology (2020)

The thrombin time (TT) test is one of the most commonly utilized coagulation assays, and the meaning of a prolonged result is well understood. However, accelerated TT values are also commonly encountered, and, to our knowledge, their potential clinical significance has not previously been described. To generate insight into the significance of accelerated TT values and to evaluate their clinical impact, we aimed to perform a retrospective review of accelerated TTs to determine their incidence and evaluate their clinical relationship to thromboembolic disease.1-3 All TT values were obtained between 2013-2018 from an academic medical center (New York Presbyterian Hospital/Weill Cornell Medicine, New York, NY), which identified 2907 TT values derived from 2419 unique patients (ACL Top 700; Instrumentation Laboratory, Bedford, MA). We examined the distribution of TTs for normality, which demonstrated deviation from a normal distribution (P < .001). Notably, 8.1% (234/2907 derived from 226 unique patients) of TTs were accelerated, and 12.7% (370/2907 derived from 303 unique patients) were prolonged (reference range 18-27 seconds). To improve the segregation of patients with a clinical etiology for accelerated TT from patients comprising the short TT tail of the reference population, accelerated TTs were conservatively defined as one analytical SD below the low end of the reference range (ie, ≤17.2 seconds). Using this definition, 121 accelerated TT values were identified from 121 unique patients (hereafter referred to as “accelerated TT cohort”). A control cohort of patients was generated by randomly selecting 121 unique patients from those with TTs within the reference range (hereafter referred to as “reference TT cohort”). These two cohorts showed no statistical difference in age, sex, or care setting (data not shown). Patients in both cohorts were evaluated for thrombotic events during the 12 months following TT testing with exclusion of patients without any documented follow up. 11.5% (11/96) of patients with accelerated TTs were found to have thrombotic events within 12 months after testing. However, only 1.0% (1/99) of patients experienced thrombosis from the reference TT cohort after testing (odds ratio [OR] 12.7; 95% confidence interval [CI] 1.6-100.3; P = .002; Table 1). Of note, 8/11 and 1/1 patients from the accelerated and reference TT cohorts, respectively, had a documented thrombus at the time of TT testing. Stratification to only include patients with 12 months of follow up led to comparable results. There, 10 patients in the accelerated TT cohort had subsequent thrombotic events, and one patient in the reference TT cohort experienced a subsequent thrombotic event (OR 9.47; 95% CI 1.172-76.56; P = 0.012). This suggested that the results were not confounded by follow up duration. Interestingly, there was no difference between the accelerated and reference TT cohorts in the number of recent prior thrombotic events, defined as a documented thrombotic event within 30 days prior to the date, up to and at the time of TT testing (OR 2.52; 95% CI 0.7476-8.480; P = .156; Table 1). Of note, there was also no difference in the proportion of patients with any prior documented history of ≥1 thrombotic events prior to TT testing between the accelerated and reference TT cohorts (OR 1.53; 95% CI 0.7022-3.319; P = .33; Table 1). To further investigate the relationship between accelerated TT and thrombosis, we performed a univariate logistic regression analysis of TT values among the accelerated and reference TT cohorts. This demonstrated an OR of 0.6716 (95% CI 0.5020-0.8985; P = .007), which signified that a one second increase in TT was associated with a 32.84% decrease in the odds of thrombosis. However, univariate logistic regression did not identify a statistically significant relationship between thrombosis and PT, aPTT in these cohorts (data not shown). Similarly, accelerated TT values displayed no relationship to fibrinogen levels or PT, aPTT. Factor VIII level testing was only available for a small subset of patients and therefore was not included in analysis. Thus, TT is here providing information orthogonal to other routine coagulation assays. Taken together, these data suggest an association between accelerated TT and thrombosis. Additional studies will be needed to not only confirm this finding in a prospective cohort but also deconvolute whether an accelerated TT is associated with an increased risk of a future thrombotic event, or rather indicates the presence of an active thrombus or both. Additionally, the approach utilized here provides an example of how leveraging large volumes of existing laboratory data can uncover potential new significance for routine clinical testing. The authors have no conflicts of interest to declare. V. Costa and M.C. Canver collected and analyzed data and drafted the manuscript. R.M. Harris and J.H. Rand aided with data review and review of relevant quality control data. M.B. Greenblatt supervised the project.