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

 

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Summary

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.

• References

• 1 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: 217-222.
  CrossrefPubMedGoogle Scholar
• 2 De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996; 87: 3531-3544.
  PubMedGoogle Scholar
• 3 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia. Part 1. Thromb Haemost 1996; 76: 651-662.
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-1231.
  CrossrefPubMedGoogle Scholar
• 5 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia. Part 2. Thromb Haemost 1996; 76: 824-834.
  Article in Thieme ConnectPubMedGoogle Scholar
• 6 Denson KWE, Haddon ME, Reed SV. et al. A more discriminating test for APC resistance and a possible screening test to include protein C and protein S. Thromb Res 1996; 81: 151-156.
  CrossrefPubMedGoogle Scholar
• 7 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: 562-566.
  Article in Thieme ConnectPubMedGoogle Scholar
• 8 Preda L, Simioni P, Legnani C. et al. A new global test for the evaluation of the protein C-protein S system. Blood Coagul Fibrinolysis 1996; 7: 465-469.
  CrossrefPubMedGoogle Scholar
• 9 Gable PS, Le DT, McGehee W. et al. A Protac^®-based screening test for activated protein C -resistant factor Va and other defects of the protein C anticoagulant pathway. Blood Coagul Fibrinolysis 1997; 8: 327-335.
  CrossrefPubMedGoogle Scholar
• 10 Haas FJLM, van Sterkenburg-Kamp BM, Scheepers HAMM. A protein C pathway (PCP) screening test for the detection of APC resistance and protein C or S deficiencies. Semin Thromb Hemost 1998; 24: 355-362.
  Article in Thieme ConnectPubMedGoogle Scholar
• 11 Gardiner C, Cooper PC, Makris M. et al. A nevaluation of screening tests for defects in the protein C pathway: commercial kits lack sensitivity and specificity. Blood Coagul Fibrinolysis 2002; 13: 155-163.
  CrossrefPubMedGoogle Scholar
• 12 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: 1719-1723.
  PubMedGoogle Scholar
• 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: 501-510.
  CrossrefPubMedGoogle Scholar
• 14 Gemmati D, Serino ML, Scapoli GL. A modified functional global test to measure protein C, protein S activities and the activated protein C-resistance phenotype. Thromb Res 1998; 92: 141-148.
  CrossrefPubMedGoogle Scholar
• 15 Toulon P, Perez P, Demay Y. et al. ProC Global, a new assay to evaluate the functionality of the protein C anticoagulant pathway. Preliminary results in 223 consecutive patients with a history of venous thromboembolism. Fibrinolysis Proteolysis 1998; 12: 347-352.
  CrossrefPubMedGoogle Scholar
• 16 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: 485-489.
  CrossrefPubMedGoogle Scholar
• 17 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 trial. Blood Coagul Fibrinolysis 2000; 11: 447-454.
  CrossrefPubMedGoogle Scholar
• 18 Rimmer JE, Cooper PC, Brookfield CJ. et al. Evaluation of a global assay for the investigation of the protein C anticoagulant pathway. Clin Lab Haem 2000; 22: 351-354.
  CrossrefPubMedGoogle Scholar
• 19 Toulon P, Adda R, Perez P. Sensitivity of the ProC^® Global assay for protein C pathway abnormalities. Clinical experience in 899 unselected patients with venous thromboembolism. Thromb Res 2001; 104: 93-103.
  CrossrefPubMedGoogle Scholar
• 20 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: 337-354.
  Article in Thieme ConnectPubMedGoogle Scholar
• 21 Sarig G, Aberbach I, Schliamser L. et al. Evaluation of ProC Global assay in women with a history of venous thromboembolism on hormonal therapy. Thromb Haemost 2006; 96: 578-583.
  Article in Thieme ConnectPubMedGoogle Scholar
• 22 Grand’Maison A, Bates SM, Johnston M. et al. “ProC Global”: a functional screening test that predicts recurrent venous thromboembolism. Thromb Haemost 2005; 93: 600-604.
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Sarig G, Lanir N, Hoffman R. et al. Protein C Global assay in the evaluation of women with idiopathic pregnancy loss. Thromb Haemost 2002; 88: 32-36.
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 Heilmann L, von Tempelhoff GF, Pollow K. ProC Global assay in the evaluation of women with history of severe preeclampsia or HELLP syndrome. Clin Appl Thromb Hemost 2002; 8: 319-324.
  CrossrefPubMedGoogle Scholar
• 25 Carter CJ. Epidemiology of venous thromboembolism. In: Hull R, and Pineo GF. Eds. Disorders of thrombosis. WB Saunders Company; Philadelphia, PA, USA: 1996. pp. 159-174.
  Google Scholar
• 26 Quincampoix JC, Le Garff M, Ritling C. et al. Modification of the ProC^® Global assay using dilution of patient plasma in factor V-depleted plasma as a screening assay for factor V Leiden mutation. Blood Coagul Fibrinolysis 2001; 12: 569-576.
  CrossrefPubMedGoogle Scholar
• 27 Gandrille S, Alhenc-Gelas M, Aiach M. A rapid screening method for the factor V Arg→Gln mutation. Blood Coagul Fibrinolysis 1995; 6: 245-248.
  CrossrefPubMedGoogle Scholar
• 28 Martinoli JL, Stocker K. Fast functional protein C assay using Protac^®*, a novel protein C activator. Thromb Res 1986; 43: 253-264.
  CrossrefPubMedGoogle Scholar
• 29 Amiral J, Grosley M, Boyer-Neumann C. et al. New direct assay for free protein S antigen using two distinct monoclonal antibodies specific for the free form. Blood Coagul Fibrinolysis 1994; 5: 179-186.
  CrossrefPubMedGoogle Scholar
• 30 Brandt JT, Triplett DA, Alving B. et al. Criteri a for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995; 74: 1185-1190.
  Article in Thieme ConnectPubMedGoogle Scholar
• 31 Koster T, Blann AD, Briët E. et al. Role of clotting factor VIII in effect of von Willebrand factor on occur-rence of deep-vein thrombosis. Lancet 1995; 345: 152-155.
  CrossrefPubMedGoogle Scholar
• 32 Rosendaal FR. High levels of factor VIII and venous thrombosis. Thromb Haemost 2000; 83: 1-2.
  Article in Thieme ConnectPubMedGoogle Scholar
• 33 Zotz RB, Gerhardt A, Scharf RE. ProC^® Global assay is an independent predictor for venous thromboembolism. Blood 1998; 92 (Suppl. 01) Abstract44a.
  PubMedGoogle Scholar
• 34 Rosendaal FR, vanden Meer FJM, Visser Th. et al. ProC^® Global screening test and the risk of thrombosis. Thromb Haemost 1999; 82 (Suppl): Abstract 731.
  PubMedGoogle Scholar
• 35 Kraaijenhagen RA, in’t Anker PS, Koopman MMW. et al. High plasma concentration of factor VIIIc is amajor risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5-9.
  Article in Thieme ConnectPubMedGoogle Scholar
• 36 O’Donnell J, Mumford AD, Manning R. et al. Elevation of FVIII: C in venous thromboembolism is persistent and independent of the acute phase. Thromb Haemost 2000; 83: 10-13.
  Article in Thieme ConnectPubMedGoogle Scholar
• 37 Henkens CMA, Bom VJJ, vander Meer. Lowered APC-sensitivity ratio related to increased factor VIII-clotting activity. Thromb Haemost 1995; 74: 1198-1199.
  Article in Thieme ConnectPubMedGoogle Scholar
• 38 Laffan MA, Manning R. The influence of factor VIII on measurement of activated protein C resistance. Blood Coagul Fibrinolysis 1996; 7: 761-765.
  CrossrefPubMedGoogle Scholar
• 39 de Visser MCH, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93: 1271-1276.
  PubMedGoogle Scholar
• 40 Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med 1999; 130: 643-650.
  CrossrefPubMedGoogle Scholar
• 41 Clark P, Walker ID. The phenomenon known as acquired activated protein C resistance. Br J Haematol 2001; 115: 767-773.
  CrossrefPubMedGoogle Scholar
• 42 Gemmati D, Serino ML, Tognazzo S. et al. The reduced sensitivity of the ProC^® Global test in protein S deficient subjects reflects are duction in the associated thrombotic risk. Blood Coagul Fibrinolysis 2001; 12: 691-697.
  CrossrefPubMedGoogle Scholar