title: Thrombus formation and platelet-vessel wall interaction in the nephrotic syndrome under flow conditions.
abstract: Increased in vitro platelet aggregability and hypercoagulability are generally held to be main determinants in the prethrombotic state in nephrosis. In vivo, however, thrombotic events depend on the dynamic interaction of flowing blood with the vessel wall. The present study confirms that aggregability of platelets of nephrotic patients is significantly increased by mere stirring or by exogenous stimuli as adenosine diphosphate and arachidonic acid. Moreover, the nephrotic patients have high von Willebrand factor and decreased red blood cell deformability, which normally increase platelet-vessel wall interaction. However, perfusion studies under well-defined flow conditions, in which anticoagulated nephrotic blood was exposed to deendothelialized human umbilical artery segments and sprayed collagen, showed normal platelet adhesion and only a modest increase in the deposition of platelet aggregates. This suggests that some factor counteracts platelet-vessel wall interaction under flow conditions in the nephrotic syndrome. When tissue factor associated with endothelial extracellular matrix (ECM) was allowed to generate thrombin, perfusions with nephrotic blood over this ECM resulted in a strong increase in fibrin generation. The capacity of patient blood to form increased amounts of fibrin appeared strongly correlated with the level of hyperfibrinogenemia. Platelet adhesion as well as aggregation in these experiments was even decreased below control values. This suggests that fibrin coverage may block the direct contact between blood platelets and matrix. We therefore also studied the isolated effect of high fibrinogen on platelet-vessel wall interaction by increasing fibrinogen concentrations in normal blood. Modulation of fibrinogen concentrations in normal blood could mimic all the observations in nephrotic blood: platelet aggregation in suspension increased with increasing concentrations of fibrinogen, while platelet adhesion and aggregate formation under flow conditions decreased. In perfusions over tissue factor-rich matrix, fibrin deposition increased. Therefore, our observations indicate that nephrotic hyperaggregability in suspension is not associated with increased platelet vessel wall-interaction under flow conditions. The latter is probably counteracted by high levels of fibrinogen. Our observations further suggest that hyperfibrinogenemia may be a major thrombotic risk factor in nephrosis by inducing more fibrin depositions.
authors.affiliation: Department of Nephrology, University Hospital Utrecht, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Zwaginga
authors.forename: H A
authors.initials: HA
authors.lastname: Koomans
authors.forename: J J
authors.initials: JJ
authors.lastname: Sixma
authors.forename: T J
authors.initials: TJ
authors.lastname: Rabelink
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000805:Angiotensin III / Q000097:blood; D016718:Arachidonic Acid / Q000494:pharmacology; D001706:Biopsy; D001779:Blood Coagulation Factors / Q000378:metabolism*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D003094:Collagen / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000648:ultrastructure; D004907:Erythrocyte Deformability; D005109:Extracellular Matrix / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005337:Fibrin / Q000032:analysis / Q000378:metabolism; D005340:Fibrinogen / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000473:pathology; D008297:Male; D008855:Microscopy, Electron, Scanning; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D009404:Nephrotic Syndrome / Q000097:blood* / Q000473:pathology / Q000503:physiopathology*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D013927:Thrombosis / Q000473:pathology* / Q000503:physiopathology; D014469:Umbilical Arteries / Q000502:physiology
chemical_list: D001779:Blood Coagulation Factors; D000805:Angiotensin III; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D005337:Fibrin; D005340:Fibrinogen; D003094:Collagen