Assessment of two contact activation reagents for the diagnosis of congenital factor XI deficiency

Abstract

Introduction: Congenital FXI deficiency, a coagulopathy associated with low bleeding risk but thrombotic protection, is usually diagnosed by prolonged APTT and confirmed by coagulation assays. Recent evidences suggest that FXI deficiency might be underestimated. Sensitive and reliable methods to detect FXI deficiency are required.

Aim: To examine the sensitivity of two methods and two contact activators on FXI deficiency screening.

Methods: 140 cases with FXI deficiency, 9 severe and 131 moderate, caused by 11different mutations were recruited. APTT and FXI:C were assessed in ACL-TOP 500coagulometer with silica-based (SynthASil) and ellagic acid-based (SynthAFax) reagents. F12 rs1801020 SNP was genotyped with Taqman probes.

Results: Severe FXI deficiency significantly prolonged APTT with both reagents. However, a high proportion of moderate deficiencies would not be detected using APTT, with false negatives of 22% for SynthASil and 12% for SynthAFax. False negatives results mainly corresponded to cases with qualitative deficiency (CRM+: p.Pro538Leu), which also had higher FXI coagulant activity. Using SynthASil, the common F12 rs1801020 variant, associated to low FXII levels, significantly prolonged APTT in moderate FXI deficiency subjects. FXI:C values were significantly higher with SynthAFax than with SynthASil (47.7±12.7 vs. 40.4±14.9), so SynthAFax rendered higher rate of false negatives than SynthASil (7% vs.2%).

Conclusions: Moderate FXI deficiency, particularly CRM+, might be underestimated using current diagnostic methods. The activator, FXI and FXII levels may contribute to a higher rate of false negatives using APTT. Our results suggests that the best screening method for FXI deficiency is FXI:C using silica.

Keywords: APTT; Ellagic acid; FXI deficiency; FXI:C; Silica; rs1801020.