Comparison of three activated protein C resistance tests in the risk assessment of venous thrombosis in non-carriers of the factor V Leiden mutation

Summary Activated protein C resistance (APCR), measured using the original assay described by Dahlbäck, is a risk factor for venous thrombosis independent of the factor V Leiden (FVL) mutation. This assay is based on the activated partial thromboplastin time (APTT) after plasma exposure to activated protein C (APC).As this assay was sensitive to numerous interferences, new assays have been developed for FVL screening. The objectives of the study were to investigate the association of second generation assays for APCR with venous thrombosis in FVL non-carriers. One hundred ninety-seven subjects with a history of venous thrombosis and 211 controls were explored using 3 APCR assays, the original APTT-based assay (test A), an APTT-based assay with factorV depleted plasma pre-dilution (test B) and a direct factorX activation-based assay with the same pre-dilution (test C).We found that subjects with results in the lowest quartile of the APTT-based assays are at increased risk, compared to those in the highest quartile (test A Odds Ratio = 6.39; 95%CI 3.23–12.63; test B OR=2.72; 95%CI 1.50–4.94). There was no significant risk increase associated with test C results. After adjusting for FVIII levels, the ORs of tests A and B were similar (test A OR=3.22; 95%CI 1.47–7.08; test B OR=3.10; 95%CI 1.54–6.21). In conclusion, APTT-based assays, but not direct factor X activation-based assays, effectively detect the risk for venous thrombosis independent of FVL. Pre-dilution in factor V depleted plasma is an effective way to directly assess the risk independent of FVIII levels.

[1]  F. Rosendaal,et al.  Determinants of the APTT‐ and ETP‐based APC sensitivity tests , 2005, Journal of thrombosis and haemostasis : JTH.

[2]  P. Wells,et al.  Elevated factor VIII is a risk factor for idiopathic venous thromboembolism in Canada – is it necessary to define a new upper reference range for factor VIII? , 2005, Thrombosis and Haemostasis.

[3]  Jeffrey S. Ginsberg,et al.  "ProC Global": A functional screening test that predicts recurrent venous thromboembolism , 2005, Thrombosis and Haemostasis.

[4]  D. Girelli,et al.  Impaired APC cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations. , 2004, Blood.

[5]  J. Goudemand,et al.  Reassessment of von Willebrand factor (VWF), VWF propeptide, factor VIII:C and plasminogen activator inhibitors 1 and 2 during normal pregnancy , 2003, British journal of haematology.

[6]  B. Dahlbäck,et al.  Molecular basis of quantitative factor V deficiency associated with factor V R2 haplotype. , 2002, Blood.

[7]  A. Folsom,et al.  A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. , 2002, Blood.

[8]  B. Polack,et al.  Preanalytical Recommendations of the ‘Groupe d’Etude sur l’Hémostase et la Thrombose’ (GEHT) for Venous Blood Testing in Hemostasis Laboratories , 2001, Pathophysiology of Haemostasis and Thrombosis.

[9]  R. Bertina,et al.  Elevated Factor VIII Levels and the Risk of Thrombosis , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[10]  L. Almasy,et al.  Genetic determinants of hemostasis phenotypes in Spanish families. , 2000, Circulation.

[11]  A. Tosetto,et al.  Activated Protein C Resistance and Factor V Leiden Mutation Are Independent Risk Factors for Venous Thromboembolism , 1999, Annals of Internal Medicine.

[12]  F. Rosendaal,et al.  A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. , 1999, Blood.

[13]  P. Mannucci,et al.  Screening for the FV: Q506 Mutation – Evaluation of Thirteen Plasma-based Methods for their Diagnostic Efficacy in Comparison with DNA Analysis , 1997, Thrombosis and Haemostasis.

[14]  B. Dahlbäck,et al.  Evaluation of Original and Modified APC-Resistance Tests in Unselected Outpatients with Clinically Suspected Thrombosis and in Healthy Controls , 1997, Thrombosis and Haemostasis.

[15]  J. van der Meer,et al.  Lowered APC-Sensitivity Ratio Related to Increased Factor VIII-Clotting Activity , 1995, Thrombosis and Haemostasis.

[16]  D. Girelli,et al.  Resistance to activated protein C in healthy women taking oral contraceptives , 1995, British journal of haematology.

[17]  A. Cumming,et al.  Development of resistance to activated protein C during pregnancy , 1995, British journal of haematology.

[18]  K. Radtke,et al.  Acquired Activated Protein C-Resistance in Patients with Lupus Anticoagulants , 1995, Thrombosis and Haemostasis.

[19]  R. Bertina,et al.  Laboratory Diagnosis of APC-Resistance: A Critical Evaluation of the Test and the Development of Diagnostic Criteria , 1994, Thrombosis and Haemostasis.

[20]  B. Dahlbäck,et al.  Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa. , 1994, The Journal of biological chemistry.

[21]  Pieter H. Reitsma,et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C , 1994, Nature.

[22]  F. Rosendaal,et al.  Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study , 1993, The Lancet.

[23]  B. Dahlbäck,et al.  Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[24]  L. Almasy,et al.  A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility. , 2003, Blood.

[25]  E. Favaloro,et al.  A 9‐year retrospective assessment of laboratory testing for activated protein C resistance: evolution of a novel approach to thrombophilia investigations , 2002, Pathology.

[26]  E. Favaloro,et al.  Functional activated protein C resistance assays: correlation with factor V DNA analysis is better with RVVT-than APTT-based assays. , 1999, British journal of biomedical science.