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Intraperitoneal coagulation and fibrinolysis during inflammation: In vivo and in vitro observations

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Author: Sitter, T. · Gödde, M. · Spannagl, M. · Fricke, H. · Kooistra, T.
Type:article
Date:1996
Institution: Gaubius Instituut TNO
Source:Fibrinolysis, SUPPL. 2, 10, 99-104
Identifier: 233523
Keywords: Biology · 2 [1 (3 amidinothiopropyl) 1h indol 3 yl] 3 (1 methyl 1h indol 3 yl)maleimide · genistein · interleukin 1alpha · lipopolysaccharide · plasminogen activator inhibitor 1 · tissue plasminogen activator · tumor necrosis factor alpha · adult · blood clotting · clinical article · conference paper · continuous ambulatory peritoneal dialysis · female · fibrinolysis · human · male · peritonitis · priority journal

Abstract

We used continuous peritoneal dialysis (CAPD) as a model to study intraperitoneal 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 fibrin degradation products (FbDP) were measured in the peritoneal dialysis 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 high concentration of FbDP, indicating a high rate of intraperitoneal fibrin turnover. The balance between peritoneal generation and degradation of fibrin was disturbed in untreated patients with acute peritonitis (n = 5), who had significantly higher levels of coagulation markers and a higher ratio between FM and FbDP. To evaluate the role of mesothelial 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 type-1 (PAI-1) and tissue factor (TF) in cultured human peritoneal MC under basal conditions and after exposition to tumor necrosis factor α (TNFα), interleukin-1α (IL-1α) or bacterial lipopolysaccharide (LPS). The exposure of MC to TNFα, or to a lesser extent, IL-1α or LPS, reduced their fibrinolytic activity by decreasing t-PA production and increasing PAI-1 synthesis. Furthermore the addition of TNFα resulted in an activation of the coagulation cascade by the expression of TF. We found that the isoflavone compound genistein (25 μg/ml) prevented the TNFα-induced expression of PAI-1 and TF, while also slightly counteracting the decrease in t-PA synthesis. The protein kinase C inhibitor, Ro 31-8220 (3μM), only moderately opposed the TNFα-induced changes in t-PA and PAI-1 synthesis, but completely prevented the induction of TF mRNA. In summary our in vitro findings explain the disbalance between intraperitoneal coagulation and fibrinolyis during peritonitis in vivo. To restore the balance between fibrinolysis and coagulation under inflammatory conditions attempts to interfere with the TNFα signalling pathway could be a new therapeutic approach.