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

SummaryThe 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.