An abnormal ProC Global test result is associated with an increased risk of venous thromboembolism independent of test sensitivity for protein C pathway abnormalities

Abstract

The ProC Global assay is a clotting assay primarily developed to globally evaluate the functionality of the protein C (PC) pathway. It was shown to lack both sensitivity and specificity for PC pathway abnormalities, i.e. factor V Leiden mutation, PC and PS deficiency. The hypothesis that an abnormal test result could be associated with venous thromboembolism (VTE) was evaluated in a case-control study. The proportion of reduced response was significantly higher in cases than in controls [n = 71/139 (51.1%) vs. n = 28/147 (19.0%); p < 0.0001] and the same applied after exclusion of those subjects with any PC pathway abnormality [n = 53/119 (44.5%) vs. n = 25/143 (17.5%); p < 0.0001]. An abnormal ProC Global assay result was significantly associated with thrombosis both in the whole population (odds ratio [OR]=4.44, 95% confidence interval [CI]=2.61-7.53) and in those subjects without any PC pathway abnormality (OR = 3.70, 95%CI = 2.16-6.66). The ProC Global assay result was significantly lower in cases with idiopathic VTE than in those with secondary VTE (p < 0.0001). No significant difference was observed when cases were classified according to the presence or absence of recurrent episodes. Moreover, a reduced response was found to be associated with VTE both in subjects with normal or elevated factor VIII (FVIII) level. In vitro, FVIII was found to play a critical role in the ProC Global assay result as suggested by the significant trend toward decreasing response with increasing FVIII levels. In conclusion, our results suggest that an abnormal ProC Global assay result is associated with an increased risk of VTE independently of its sensitivity for PC pathway abnormalities.