ProC Global: A New Automated Screening Assay for the Evaluation of Total Function of the Protein C System

Abstract

Protein C (PC) pathway represents a major physiologic inhibitory mechanism regulating the coagulation cascade. A new automated functional screening assay (ProC Global) for the evaluation of the PC-system was tested to define its ability to identify patients with known inherited defects such as factor V (FV) Leiden mutation and PC and protein S (PS) deficiency. A total of 249 patients who were symptomatic or asymptomatic for previous venous thromboembolism (VTE) were evaluated, 50 of whom had FV Leiden mutation, 36 had PC deficiency, and 34 had PS deficiency. One hundred healthy subjects were also tested, as well as 40 blood donors of both sexes in whom coagulation abnormalities were not found. Results of ProC Global test were expressed as normalized ratio (NR) and values below an established cut-off level were consistent with a positive test. ProC Global was positive in all 50 patients with the FV Leiden mutation (mean NR = 0.59; range, 0.37 to 0.69). ProC Global correctly identified 32 of 36 (89%) PC defects (mean NR = 0.63; range, 0.34 to 1.21) and 25 of 34 (73.5%) PS defects (mean NR = 0.76; range, 0.5 to 1.23). Overall, 92.5% of hereditary defects of the PC system considered in this study were identified by ProC Global test. ProC Global exhibited NR above cut-off level in all 40 blood donors without coagulation defects. ProC Global is a new automated screening test with some diagnostic potential in identifying patients with defects of the PC system. However, ProC Global in its current form cannot substitute the assay of each single component of this inhibitory system in the daily screening for thrombophilia.

Keywords

ProC Global Protein C system FV Leiden Protein C Protein S.

References

Griffin JH , Evatt B. Wideman C , et al. Anticoagulant protein C pathway defective in the majority of thrombophilic patients. Blood 1993;82:1989.

Lane DA , Mannucci PM , Bauer KA , et al. Inherited thrombophilia: part 1. Thromb Haemost 1996;76:651.

Dahlback B. , Carlsson M. , Svensson PJ Familial thrombophilia due to a previously unrecognised mechanism characterised by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993;90: 1004.

Bertina RM , Koeleman Bpc , Koster T. , et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64.

Koster T. , Rasendaal RF , de Ronde H. , et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993;342:1503.

Dahlback B. The protein C anticoagulant system: inherited defects as basis for venous thrombosis. Thromb Res 1995;77:1.

Simioni P. , Prandoni P. , Lensing Awa , et al. The risk of recurrent venous thromboembolism in patients with an Arg 506 Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997;336:399.

Kraus M. , Noah M. , Fickenscher K. The PCAT a simple screening assay for assessing the functionality of the protein C anticoagulant pathway. Thromb Res 1995;79:217.

Preda L. , Simioni P. , Legnani C. , et al. A new global test for evaluation of the protein C system. Blood Coag Fibrinolysis 1996;7: 465.

10.

Robert A. , Eschwege V. , Hameg H. , et al. Anticoagulant response to Agkistrodon Contortrix Venom (ACV test): a new global test to screen for defects in the anticoagulant protein C pathway. Thromb Haemost 1996;75:562.

11.

Dati F. , Hafner G. , Erbes H. , et al. ProC Global: the first functional screening assay for the complete protein C pathway. Clin Chem 1997;43:1719.

12.

Toulon P. , Halbmeyer WM , Hafner G. , et al. Screening for abnormalities of the protein C anticoagulant pathway using the ProC Global assay. Results of a European multicenter evaluation . Blood Coagul Fibrinolysus 2000; 11:447.

13.

Ruzicka K. , Kapiotis S. , Quehenberger P. , et al. Evaluation of a new screening assay ProC Global for identification of defects in the protein C/protein S anticoagulant pathway. Thromb Res 1997;87:501.

14.

Toulon P. , Perez P. Screening for risk factors for thrombosis using a new generation of assays developed to evaluate the functionality of the protein C anticoagulant pathway . Hematol Oncol Clin North Am 2000 ;14:379.

15.

Tripodi A. , Akhavan S. Asti D. , et al. Laboratory screening of thrombophilia. Evaluation of the diagnostic efficacy of a global test to detect congenital deficiencies of the protein C anticoagulant pathway. Blood Coagul Fibrinolysis 1998;9:485.

16.

Simioni P. , Sanson BJ , Prandoni P. et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999;81:198.

17.

Cumming AM , Tait RC , Fildes S. , et al. Development of resistance to activated protein C during pregnancy . Br J Hematol 1995;90: 725.

18.

Toglia MR , Weg JG Venous thromboembolism during pregnancy. N Engl J Med 1996;335:108.

19.

Henkens Cma , Bom Vjj , Seinen AJ , et al. Sensitivity to activated protein C: influence of oral contraceptives and sex. Thromb Haemost 1995;73:402.

20.

Aznar J. , Villa P. , Espana F. , et al. Activated protein C resistance phenotype in patients with antiphospholipid antibodies. J Lab Clin Med 1997;130:202.

21.

Gemmati D. , Serino ML , Scapoli Gla. Modified functional global test to measure Protein C. Protein S activities and the activated Protein C-resistance phenotype. Thromb Res 1998;92:141.

22.

Bernardi F. , Faioni EM , Castoldi E. , et al. A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype . Blood 1997;90:1552.

23.

Kraus M. The anticoagulant potential of the protein C system in hereditary and acquired thrombophilia: pathomechanisms and new tools for assessing its clinical relevance , Semin Thromb Hemost 1998 ;24:337.