Coagulation disturbances and fibronectin fragmentation in preeclampsia

De Jager, Celeste Annemarie

Coagulation disturbances and fibronectin fragmentation in preeclampsia

Thesis / Dissertation

1995

Publisher

University of Cape Town

Department

Department of Paediatrics and Child Health

Faculty

Faculty of Health Sciences

Abstract

Preeclampsia or gestational proteinuric hypertension (GPH) is a major cause of maternal death worldwide. Patients may present with hypertension and proteinuria alone or may develop progressively more severe disease, ending in a fulminant syndrome with disturbed coagulation, vascular injury and end-organ damage. The reasons for this progression are unclear and can only be reversed by termination of pregnancy. There are currently no early, generally acceptable, laboratory markers of disease severity. We have shown that patients with severe preeclampsia have significantly raised plasma levels of plasminogen activator-I, tissue plasminogen activator. fibronectin and fibrin(ogen) degradation product. The tissue plasminogen activator and fibrin(ogen) degradation product concentrations were found to progressively increase with progression of the syndrome. These findings support the hypothesis of the participation of disturbed coagulation and vascular injury processes in the aetiology of preeclampsia. The additional finding that the endothelium of umbilical cords from patients with preeclampsia was disrupted and characterised by increased deposits of fibronectin further supports of this proposal. Plasma fibronectin from patients with preeclampsia was found to be degraded, with fibronectin from plasma of patients with severe preeclampsia having larger amounts of low molecular weight fibronectin degradation products than the plasma from patients with mild preeclampsia. Comparison of the apparent molecular weights of these fibronectin degradation products, with those generated from pure fibronectin by plasmin, suggest that they may arise from the action of plasmin. These fibronectin degradation products were found to inhibit the opsonic activity of intact fibronectin and to cause an underestimation in the determination of plasma fibronectin concentration by enzyme-linked immunosorbent assay. Furthermore, plasma fibronectin degradation products and fibronectin degradation products, generated by plasmin cleavage of intact pure fibronectin, were able to disrupt endothelial monolayers in in vitro culture. This was not due to cytotoxic activity, but rather due to the generation of urokinase plasminogen activator from the endothelial cells, and subsequent urokinase plasminogen activator conversion of plasminogen to plasmin. The ability of a 29 kilodalton heparin-binding fragment to cause this disruption suggests that heparin-binding fragments may, in part, be responsible for the observed effect on endothelial cells in culture. It is tenable from the results of this study that fibronectin degradation products, generated as a result of initial endothelial damage, perpetuates further damage to the endothelium. Escape of these products into the maternal circulation may be postulated to give rise to maternal endothelial cell damage and the generalised organ failure observed in preeclampsia.

Keywords

preeclampsia

fibronectin

Reference:

Collections

PhD / Doctoral

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