INTRAPERITONEAL COAGULATION AND FIBRINOLYSIS DURING INFLAMMATION - IN-VIVO AND IN-VITRO OBSERVATIONS

We used continuous peritoneal dialysis (CAPD) as a model to study intr aperitoneal fibrin turnover during peritonitis. Activation markers of coagulation and fibrinolysis including prothrombin fragment F1+2 (F1+2 ), thrombin-antithrombin III complex (TAT), fibrin monomer (FM), and f ibrin degradation products (FbDP) were measured in the peritoneal dial ysis effluents from 23 CAPD patients, In the dialysate of patients who had not suffered from peritonitis during the last 6 months (n=18) we found remarkably high levels of F1+2, TAT and FM concomitant with a hi gh concentration of FbDP, indicating a high rate of intraperitoneal fi brin turnover. The balance between peritoneal generation and degradati on of fibrin was disturbed in untreated patients with acute peritoniti s (n=5), who had significantly higher levels of coagulation markers an d a higher ratio between FM and FbDP. To evaluate the role of mesothel ial cells (MC) in the high peritoneal fibrin turnover, we investigated the expression of tissue-type plasminogen activator (t-PA), urokinase -type plasminogen activator (u-PA), plasminogen activator inhibitor ty pe-1 (PAI-1) and tissue factor (TF) in cultured human peritoneal MC un der basal conditions and after exposition to tumor necrosis factor alp ha (TNF alpha), interleukin-1 alpha (IL-1 alpha) or bacterial lipopoly saccharide (LPS). The exposure of MC to TNF alpha, or to a lesser exte nt, IL-1 alpha or LPS, reduced their fibrinolytic activity by decreasi ng t-PA production and increasing PAI-1 synthesis. Furthermore the add ition of TNF alpha resulted in an activation of the coagulation cascad e by the expression of TF. We found that the isoflavone compound genis tein (25 mu g/ml) prevented the TNF alpha-induced expression of PAI-1 and TF, while also slightly counteracting the decrease in t-PA synthes is. The protein kinase C inhibitor, Ro 31-8220 (3 mu M), only moderate ly opposed the TNF alpha-induced changes in t-PA and PAI-1 synthesis, but completely prevented the induction of TF mRNA. In summary our in v itro findings explain the disbalance between intraperitoneal coagulati on and fibrinolyis during peritonitis in vivo. To restore the balance between fibrinolysis and coagulation under inflammatory conditions att empts to interfere with the TNF alpha signalling pathway could be a ne w therapeutic approach.