Evaluation of the fibrinolytic potential on plasma: Physiological and pathological variations, and associations with cardio-vascular disease risk factors.

Early studies demonstrated that the spontaneous lysis of a clot soaked in p lasma is highly variable from individual to individual, and this could refl ect the body's fibrinolytic capacity (Gurewich V., Emmons, F., Pannell R. F ibrinolysis 2. 143-149; 1988). This observation allowed us to design an ass ay to evaluate the fibrinolytic potential on plasma with a global assay (Gl obal Fibrinolytic Capacity or GFC). Briefly, a freeze dried fibrin clot tab let (depleted of all lysine binding proteins), containing silica for mobili zing the Pro-u-PA pathway, is introduced into 200 mu l of citrated plasma, supplemented with a constant and limited amount of t-PA (this supplementati on accelerates fibrinolysis kinetics and shortens its lag phase but does no t change its regulation). Following an 1 hour incubation step at 37 degrees C, fibrinolysis is stopped with 50 mu l of an aprotinin solution. The gene rated DDimer is measured and its concentration is a direct relationship of GFC. Supplementation studies with purified factors showed that the GFC assa y is influenced by t-PA, Pro-u-PA, u-PA, PAI-1, alpha 2-AP, plasminogen, Ac tivated Protein C and Histidin-Rich-Glycoprotein. There was also a strong d ependence on factor XII concentrations (GFC was totally deficient for facto r XII concentrations < 30%). The GFC assay was studied in 685 normal indivi duals (337 males and 348 females), 303 hypercholesterolemic individuals (23 2 mates and 71 females) and 210 diabetic patients (65 NIDDM and 145 IDDM) ( Thrombocheck study). Blood was collected on fasting individuals between 9 a nd 11 a.m. GFC strongly correlated inversely with blood pressure (r=-0.22)* , glycemia (r=-0.34)*, triglycerides (r=-0.41)*, and body mass index (BMI) (r=-0.52)*. GFC was lower in males than in females*, and in sedentary peopl e as compared to sport practicers*. It decreased with age only in females. GFC correlated inversely with both PAI-1 (r=-0.58)* and t-PA:Ag (r=-0.63)*. There was no association with Lp(a). In hypercholesterolemic population, G FC was reduced* and even more in individuals with associated hypertriglycer idemia*. This decrease was dramatically enhanced in NIDDM (Non Insulin Depe ndent Diabetes Mellitus), and remained highly significant after adjustment for age, sex, BMI and triglyceride concentration*. By contrast, GFC was not reduced in IDDM (Insulin Dependent Diabetes Mellitus). The GFC assay allow s to explore easily and in a reliable manner fibrinolytic dysfunctions and to evaluate the fibrinolytic potency on plasma. Our studies also suggest th at fibrinolysis could be an important link between the presence of CVD risk factors and development of thrombotic pathology.