title: A novel interpretation of the role of von Willebrand factor in thrombotic microangiopathies based on platelet adhesion studies at high shear rate flow.
abstract: Clinical manifestations of thrombotic microangiopathies (TMA) are secondary to platelet aggregation and thrombotic occlusion of the microvasculature of the affected organs. Abnormalities in von Willebrand factor (vWF) in these patients were considered instrumental in promoting the process leading to microvascular thrombosis. We evaluated the capacity of plasma in these patients to induce adhesion of normal platelets and thrombus formation under conditions of controlled fluid shear stress. We also studied vWF multimeric distribution to establish whether abnormalities of this glycoprotein correlate with platelet adhesion and thrombus formation. Plasma from patients in the acute phase and remission showed the same capacity to induce platelet adhesion and thrombus formation at a low level of shear rate (600 sec(-1)) as plasma from control subjects. At a high shear rate (1,500 sec(-1)), platelet adhesion and thrombus dimensions were significantly increased (P: < 0.05) by plasma from patients with TMA compared with controls. The capacity to enhance thrombus formation at high shear stress was present during the acute phase and disease remission and did not correlate with the presence of unusually large vWF multimers. Increased thrombus formation with patient plasma is completely normalized by blocking the interaction of vWF with the platelet receptors, glycoprotein (GP)Ib and GPIIb-IIIa, suggesting that the phenomenon is completely mediated by vWF. Our results suggest the possibility of an intrinsically altered vWF molecule in these patients that is probably more effective than normal vWF in mediating platelet adhesion and thrombus formation.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Division of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Galbusera
authors.forename: A
authors.initials: A
authors.lastname: Remuzzi
authors.forename: A
authors.initials: A
authors.lastname: Benigni
authors.forename: C
authors.initials: C
authors.lastname: Rossi
authors.forename: G
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002648:Child; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000097:blood*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008833:Microcirculation / Q000502:physiology; D010973:Platelet Adhesiveness / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood*; D012008:Recurrence; D012044:Regression Analysis; D012075:Remission, Spontaneous; D014841:von Willebrand Factor / Q000502:physiology*
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014841:von Willebrand Factor