Venous thrombosis occurs in 1 of 1000 individuals every year. Risk factors for thrombosis from acquired causes include age, previous thrombosis, immobilization, major trauma, prolonged surgical interventions, cancer, and paralysis from spinal cord injuries. This risk may be enhanced by putative hereditary risk factors,<sup>19 Lane D.A., Mannucci P.M., Bauer K.A. , e al. Inherited thrombophilia. Part 1 Thromb Haemost 1996 ;  76 : 651

Cliccare qui per andare alla sezione Riferimenti, 20 Lane D.A., Mannucci P.M., Bauer K.A. , e al. Inherited thrombophilia. Part 2 Thromb Haemost 1996 ;  76 : 824

Cliccare qui per andare alla sezione Riferimenti</sup> such as dysfibrinogenemias, antithrombin deficiencies, and abnormalities of the protein C anticoagulant pathway. The protein C anticoagulant pathway consists of protein C, protein S, the thrombomodulin/thrombin complex, and reactions involved in the inactivation of activated factors V and VIII. Actually, the Factor V Leiden-related activated protein C (APC) resistance is the most frequent risk factor for venous thrombosis with a frequency of between 10% and 30% in white patients<sup>15 Koster T., Rosendaal F.R., De Ronde H. , e al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study Lancet 1993 ;  342 : 1503  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 16 Koster T., Blann A.D., Briët E. , e al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis Lancet 1995 ;  345 : 152  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup>; however, a highly heterogenous world distribution of this mutation has been reported.<sup>9 Emmerich J., Poirier O., Evans A. , e al. Myocardial infarction, Arg 506 to Gln mutation and activated protein C resistance Lancet 1995 ;  345 : 321  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 25 Rees D.C., Cox M., Clegg J.B. World distribution of factor V Leiden Lancet 1995 ;  346 : 1133-1134  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 34 Zöller B., Norlund L., Leksell H. , e al. High prevalence of the FVR506Q mutation causing APC resistance in a region of southern Sweden with a high incidence of venous thrombosis Thromb Res 1996 ;  83 : 475

Cliccare qui per andare alla sezione Riferimenti</sup> Abnormalities of the protein C anticoagulant pathway, including protein C and protein S deficiency,<sup>19 Lane D.A., Mannucci P.M., Bauer K.A. , e al. Inherited thrombophilia. Part 1 Thromb Haemost 1996 ;  76 : 651

Cliccare qui per andare alla sezione Riferimenti, 20 Lane D.A., Mannucci P.M., Bauer K.A. , e al. Inherited thrombophilia. Part 2 Thromb Haemost 1996 ;  76 : 824

Cliccare qui per andare alla sezione Riferimenti</sup> APC resistance,<sup>4 Dahlbäck B., Carlsson M., Svensson P.J. 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 Proc Natl Acad Sci U S A 1993 ;  90 : 1004

Cliccare qui per andare alla sezione Riferimenti</sup> and factor Va (factor V Leiden) mutations, are found in about 30% of white patients with thrombosis. This finding clearly indicates that of all patients with thrombosis who are routinely tested for protein C, protein S, APC resistance, or the factor V Leiden point mutation, 70% have a well-functioning protein C anticoagulant system. It would therefore be helpful to have a single global clot screening test that would differentiate normal protein C anticoagulant systems from dysfunctional ones. This test would be cost-effective, because specific assays would be required only in individuals found to be outside normal ranges established by the single global clot screening assay. Even if other assays have been described already,<sup>6 Denson K.W.E., Haddon M.E., Reed S.V. , e 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

Cliccare qui per andare alla sezione Riferimenti, 8 Duchemin J., Pittet J.L., Tartary M. , e al. A new assay based on thrombin generation inhibition to detect both protein C and protein S deficiencies in plasma Thromb Haemost 1994 ;  71 : 331

Cliccare qui per andare alla sezione Riferimenti, 10 Gable P.S., Le D.T., McGehee W. , e al. A Protac®-based screening test for activated protein C-resistant factor Va and other defects of the protein C anticoagulant pathway Blood Coag Fibrinolysis 1997 ;  8 : 327

Cliccare qui per andare alla sezione Riferimenti</sup> only the ProC Global assay (Dade Behring, Marburg, Germany) and the Protein C Pathway (PCP) Test assay (Gradipore, North Ryde, Australia) are commercially available so far. They are based on the ability of endogenous activated protein C, generated by the activation of protein C by a protein C activator (Protac), to prolong clotting time. The authors evaluated the sensitivity of these two assays to distinguish normal from abnormally functional protein C anticoagulant pathways by retrospectively testing frozen plasma samples from 223 thrombosis patients. Using well-defined cut-off levels, all 25 carriers of the factor V Leiden mutation, all 10 patients with a protein C deficiency, and all 5 patients with combined defects had shorter clotting times in both assays. The sensitivity for both hereditary and acquired protein S deficiency (n = 40) was below 70% using either the ProC Global assay or the PCP Test assay, indicating that these tests have poor sensitivity for dysfunctional protein S. Among the patients who had no documented abnormalities of the protein C pathway, 40.6% of patients in the ProC Global assay and less than 3.5% of patients in the PCP Test had a ratio below the cut-off levels, indicating an occult dysfunction. From an economic point of view, these dramatically different results suggest the PCP Test would have greater value as a first-step screening assay, because 40% of patients without any known abnormality of the protein C pathway tested positive in the ProC Global assay. Possible reasons for this high percentage of positive tests are discussed later.