title: Circulating and progenitor endothelial cells are abnormal in patients with different types of von Willebrand disease and correlate with markers of angiogenesis.
abstract: von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by quantitative or qualitative defects of von Willebrand factor (VWF). VWF, synthesized by endothelium and megakaryocytes (MK), circulates in plasma and is present in subendothelium and platelets. Circulating endothelial cells (CEC) and progenitor endothelial cells (EPC) have been recently proposed as markers of peripheral and bone marrow-derived angiogenesis. To evaluate the association of CEC/EPC with known inherited defects of cellular and circulating VWF, we have measured the number of CEC/EPC together with cytokines involved in angiogenesis in different VWD types. A group of 74 patients was composed by the following VWD types: VWD1 (n = 22), VWD2A (n = 9), VWD2B (n = 19), VWD2M (n = 17), and VWD3 (n = 7). Healthy individuals (n = 20) were used as controls. CEC (CD146(+) , CD31(+) , and CD45(-) ) and EPC (CD34(+) , CD133(+) , and CD45(-) ) were evaluated by flow cytometry. Circulating serum levels of VEGF, E-selectin, P-selectin, EPO, and TPO were determined by ELISA. CEC, VEGF, E-selectin, and EPO were higher and EPC lower in VWD patients than in controls (P < 0.01). Among the five groups of VWD patients and controls, a significant difference was found for CEC (one-way ANOVA: P = 0.005), EPC (P = 0.001), E-Selectin (P < 0.0001), EPO (P = 0.021), and TPO (P = 0.004): the latter was high in VWD3 patients. In VWD1, we found an inverse relationship between CEC and VWF:Ag levels (P = 0.048; R(2) = 0.19). Based on these data, CEC are increased in VWD and are associated with the high levels of cytokines involved in angiogenesis (up-regulation). EPC are decreased, suggesting down-regulation of bone marrow-derived angiogenesis in VWD.
authors.affiliation: Department of Hematology-1, Fondazione IRCCS Cà Granda Maggiore Policlinico Hospital and Università degli Studi di Milano, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gritti
authors.forename: Agostino
authors.initials: A
authors.lastname: Cortelezzi
authors.forename: Paolo
authors.initials: P
authors.lastname: Bucciarelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Rezzonico
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonati
authors.forename: Silvia
authors.initials: S
authors.lastname: La Marca
authors.forename: Ilaria
authors.initials: I
authors.lastname: Silvestris
authors.forename: Augusto B
authors.initials: AB
authors.lastname: Federici
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D002452:Cell Count; D002648:Child; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000097:blood; D019040:E-Selectin / Q000097:blood; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000453:epidemiology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*; D042442:Vascular Endothelial Growth Factors / Q000097:blood; D055815:Young Adult; D014842:von Willebrand Diseases / Q000097:blood* / Q000473:pathology* / Q000503:physiopathology
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; D019040:E-Selectin; C546936:SELE protein, human; D042442:Vascular Endothelial Growth Factors