ABO blood group is a determinant of von Willebrand factor protein levels in human pulmonary endothelial cells

ABO blood group antigens are expressed on von Willebrand factor (VWF) and glycosylation patterns influence circulating VWF levels. The aim of this study was to examine the effect of ABO blood type on tissue-associated VWF protein levels. We selected 35 formalin-fixed paraffin-embedded pulmonary tissue blocks obtained at autopsy from decedents who died from pulmonary embolism with known ABO blood groups (O, A, B and AB phenotypes), prepared tissue microarrays (TMAs) and stained TMAs with antibodies to VWF and platelet/endothelial cell adhesion marker-1 (PECAM-1) as a marker of endothelial cells. A pixel count scoring algorithm was used to quantify VWF and PECAM-1 staining intensity in pulmonary arterioles in digitised images. Compared with type O, non-O individuals have a significantly higher amount of endothelial cell-associated VWF protein expression. VWF protein levels associated with pulmonary vascular endothelial cells is influenced by ABO antigenic determinants.

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Heterogeneous Detection of A-antigen on von Willebrand Factor Derived from Platelets, Endothelial Cells and Plasma

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613123 ◽

2002 ◽

Vol 87 (06) ◽

pp. 990-996 ◽

Cited By ~ 16

Author(s):

Peter Collins ◽

Derrick Bowen ◽

Simon Brown

Keyword(s):

Endothelial Cells ◽

Blood Group ◽

Von Willebrand Factor ◽

Saphenous Vein ◽

Umbilical Vein ◽

Abo Blood Group ◽

Blood Group Antigens ◽

Exact Function ◽

Von Willebrand ◽

Willebrand Factor

SummaryThe exact function of the carbohydrate component of von Willebrand factor (VWF) is unknown. ABO blood group antigens are present as integral structures on the oligosaccharide side chains and it has long been recognised that ABO blood group is a determinant of VWF levels. The mechanism for this is not known. Using a monoclonal antibody against the A-antigen, we investigated the presence of this antigen on VWF from plasma, platelets, human umbilical vein endothelial cells (HUVEC) and saphenous vein endothelial cells. Initial studies on plasma VWF revealed that 23.5% of samples appeared to be negative for the A-antigen. This was shown to correlate with the A2 subtype of the A-antigen (p <0.01). Analysis of intracellular VWF from saphenous vein endothelial cells revealed low levels of A-antigen to be present in comparison to the corresponding plasma VWF. In contrast, VWF from platelets and HUVEC gave no detectable A-antigen. However, within 1 h of administration of DDAVP to type 1 VWD patients, there was a >2-fold increase in the A-antigen/VWF:Ag ratio for VWF in the plasma. In vitro experiments with serum N-acetlygalactosaminyltransferase failed to demonstrate any addition of A-antigen to platelet or HUVEC VWF. These data are consistent with heterogeneity in the content of A-antigen on VWF from different physiological compartments. Also, they are consistent with either a change in the A-antigen content of VWF after release from the intracellular compartment or a difference in the intracellular addition of A-antigen to VWF by endothelium from different vascular beds.

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Genetic determinants of VWF clearance and FVIII binding modify FVIII pharmacokinetics in pediatric hemophilia A patients

Blood ◽

10.1182/blood.2019000190 ◽

2019 ◽

Vol 134 (11) ◽

pp. 880-891 ◽

Cited By ~ 7

Author(s):

Laura L. Swystun ◽

Kenichi Ogiwara ◽

Orla Rawley ◽

Christine Brown ◽

Ilinca Georgescu ◽

...

Keyword(s):

Blood Group ◽

Von Willebrand Factor ◽

Half Life ◽

Hemophilia A ◽

Blood Type ◽

Abo Blood Group ◽

Genetic Determinants ◽

Group Status ◽

Von Willebrand ◽

Willebrand Factor

Abstract Factor VIII (FVIII) pharmacokinetic (PK) properties show high interpatient variability in hemophilia A patients. Although previous studies have determined that age, body mass index, von Willebrand factor antigen (VWF:Ag) levels, and ABO blood group status can influence FVIII PK, they do not account for all observed variability. In this study, we aim to describe the genetic determinants that modify the FVIII PK profile in a population of 43 pediatric hemophilia A patients. We observed that VWF:Ag and VWF propeptide (VWFpp)/VWF:Ag, but not VWFpp, were associated with FVIII half-life. VWFpp/VWF:Ag negatively correlated with FVIII half-life in patients with non-O blood type, but no correlation was observed for type O patients, suggesting that von Willebrand factor (VWF) half-life, as modified by the ABO blood group, is a strong regulator of FVIII PK. The FVIII-binding activity of VWF positively correlated with FVIII half-life, and the rare or low-frequency nonsynonymous VWF variants p.(Arg826Lys) and p.(Arg852Glu) were identified in patients with reduced VWF:FVIIIB but not VWF:Ag. Common variants at the VWF, CLEC4M, and STAB2 loci, which have been previously associated with plasma levels of VWF and FVIII, were associated with the FVIII PK profile. Together, these studies characterize the mechanistic basis by which VWF clearance and ABO glycosylation modify FVIII PK in a pediatric population. Moreover, this study is the first to identify non-VWF and non-ABO variants that modify FVIII PK in pediatric hemophilia A patients.

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ABO Blood Group Antigens on Human Plasma von Willebrand Factor After ABO-Mismatched Bone Marrow Transplantation

Blood ◽

10.1182/blood.v94.8.2895.420a03_2895_2900 ◽

1999 ◽

Vol 94 (8) ◽

pp. 2895-2900 ◽

Cited By ~ 41

Author(s):

Taei Matsui ◽

Taketo Shimoyama ◽

Masanori Matsumoto ◽

Yoshihiro Fujimura ◽

Yoshinobu Takemoto ◽

...

Keyword(s):

Bone Marrow ◽

Endothelial Cells ◽

Stem Cell ◽

Bone Marrow Transplantation ◽

Stem Cell Transplantation ◽

Blood Group ◽

Abo Blood Group ◽

Blood Group Antigens ◽

Von Willebrand ◽

Willebrand Factor

von Willebrand factor (vWF) is synthesized exclusively by endothelial cells and megakaryocytes, and stored in the intracellular granules or constitutively secreted into plasma. ABO blood group antigens are covalently associated with asparagine-linked sugar chains of plasma vWF. The effect of ABO-mismatched bone marrow transplantation (BMT) or blood stem cell transplantation (BSCT) on the expression of ABO blood group antigens on the vWF was examined to obtain information on the origin of these antigens. In ABO-mismatched (HLA-matched) groups, 8 cases of BMT and 4 cases of BSCT were examined. In all cases, the ABO blood groups on red blood cells were gradually converted to the donor’s type within 80 to 90 days after the transplantation. The blood group antigens on the vWF were consistent with the recipient’s blood group for the period monitored by enzyme-linked immunosorbent assay (ELISA). When vWF was isolated from normal platelets and examined for the blood group antigens using ELISA or immunoblotting, it showed few antigens. However, vWF extracted from veins expressed blood group antigens. These findings indicate that platelet (megakaryocyte)-derived vWF does not contain blood group antigens and that these antigens may be specifically associated with vWF synthesized in endothelial cells and secreted into plasma. Furthermore, it is possible that the persistence of the recipient’s blood group antigens on plasma glycoproteins such as vWF, independent of the donor-derived erythrocytes, after ABO-mismatched stem cell transplantation, may influence the immunological system in the production of anti-blood group antibodies resulting in the establishment of immunological tolerance in the recipient plasma.

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Blood group alters platelet binding kinetics to von Willebrand factor and consequently platelet function

Blood ◽

10.1182/blood-2018-06-855528 ◽

2019 ◽

Vol 133 (12) ◽

pp. 1371-1377 ◽

Cited By ~ 14

Author(s):

Eimear Dunne ◽

Qin M. Qi ◽

Eric S. Shaqfeh ◽

Jamie M. O’Sullivan ◽

Ingmar Schoen ◽

...

Keyword(s):

Myocardial Infarction ◽

Blood Group ◽

Platelet Function ◽

Von Willebrand Factor ◽

Critical Role ◽

Blood Type ◽

Blood Group Antigens ◽

Interaction Modeling ◽

Von Willebrand ◽

Willebrand Factor

Abstract Blood type O is associated with a lower risk of myocardial infarction. Platelets play a critical role in myocardial infarction. It is not known whether the expression of blood group antigens on platelet proteins alters platelet function; we hypothesized that platelet function would be different between donors with blood type O and those with non-O. To address this hypothesis, we perfused blood from healthy type O donors (n = 33) or non-O donors (n = 54) over pooled plasma derived von Willebrand factor (VWF) protein and purified blood type–specific VWF at arterial shear and measured platelet translocation dynamics. We demonstrate for the first time that type O platelets travel farther at greater speeds before forming stable bonds with VWF. To further characterize these findings, we used a novel analytical model of platelet interaction. Modeling revealed that the kinetics for GPIb/VWF binding rate are significantly lower for type O compared with non-O platelets. Our results demonstrate that platelets from type O donors interact less with VWF at arterial shear than non-O platelets. Our results suggest a potential mechanism for the reduced risk of myocardial infarction associated with blood type O.

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ABO blood group also influences the von Willebrand factor (VWF) antigen level in heterozygous carriers of VWF null alleles, type 2N mutation Arg854Gln, and the missense mutation Cys2362Phe

Blood ◽

10.1182/blood-2002-04-1168 ◽

2002 ◽

Vol 100 (5) ◽

pp. 1927-1928 ◽

Cited By ~ 14

Author(s):

Giancarlo Castaman ◽

Jeroen C. J. Eikenboom

Keyword(s):

Missense Mutation ◽

Blood Group ◽

Von Willebrand Factor ◽

Null Alleles ◽

Abo Blood Group ◽

Antigen Level ◽

Heterozygous Carriers ◽

Von Willebrand ◽

Willebrand Factor

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PERTURBATION OF CULTURED ENDOTHELIAL CELLS ALTERS CELLULAR VON WILLEBRAND FACTOR DISTRIBUTION

10.1055/s-0038-1642912 ◽

1987 ◽

Author(s):

J H Reinders ◽

C L Verweii ◽

J A V Mourlk ◽

Ph G de Groot

Keyword(s):

Extracellular Matrix ◽

Endothelial Cells ◽

Endothelial Cell ◽

Von Willebrand Factor ◽

Phorbol Esters ◽

Term Treatment ◽

Cellular Distribution ◽

Long Term Treatment ◽

Von Willebrand ◽

Willebrand Factor

Endothelial cells, cultured from human umbilical veins, synthesize von Willebrand Factor (vWF), that is stored by the cells in Weibel-Palade bodies, secreted into the medium and incorporated into the extracellular matrix underneath the cells. We have studied the influence of perturbation by phorbol esters and thrombin on the cellular distribution of vWF. Short-term (< 1 hour) treatment of endothelial cells with phorbol ester PMA or thrombin resulted in the release of cellular stored vWF. Long-term treatment with perturbants evoked a distinct change in the endothelial cell distribution of vWF, evident 24 to 48 hours after exposure. While the contents of the vWF storage vesicles were gradually restored within 48 hours, enhanced amounts of vWF were secreted into the medium. However, PMA did not increase the endothelial cell contents of mRNA encoding for vWF. The number as well as the size of vWF storage granules in the cells increased after exposure to perturbants. The perturbed cells responded to stimuli in releasing stored vWF, the amounts secreted were even greater than those in control cells. The extracellular matrix lost its vWF contents as the result of PMA or thrombin treatment, by blocking deposition of vWF in the matrix, not by enhancing degradation of matrix vWF. In perfusion experiments, the adhesion of washed platelets onto the isolated matrix of perturbed cells was considerable less than that in controls. Addition of vWF to the perfusate overcame this impairment. Thus, perturbation of endothelial cells changes the cellular distribution of vWF.Supported in part by ZWO grants 13-30-31 and 13-90-91 and Netherlands Heart Foundation grant 28.004.

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ABO Blood Group Genotype and Plasma von Willebrand Factor in Normal Individuals

Vox Sanguinis ◽

10.1159/000462939 ◽

1995 ◽

Vol 68 (4) ◽

pp. 236-240 ◽

Cited By ~ 6

Author(s):

Masayuki Shima ◽

Yoshihiro Fujimura ◽

Takayuki Nishiyama ◽

Tomomi Tsujiuchi ◽

Nobuhiro Narita ◽

...

Keyword(s):

Blood Group ◽

Von Willebrand Factor ◽

Abo Blood Group ◽

Normal Individuals ◽

Von Willebrand ◽

Willebrand Factor

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Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum

Blood ◽

10.1182/blood.v81.3.683.683 ◽

1993 ◽

Vol 81 (3) ◽

pp. 683-689 ◽

Cited By ~ 88

Author(s):

SR Lentz ◽

JE Sadler

Keyword(s):

Endothelial Cells ◽

Endoplasmic Reticulum ◽

Endothelial Cell ◽

Von Willebrand Factor ◽

Protein Transport ◽

Cell Protein ◽

Carboxyl Terminal ◽

Insulinoma Cells ◽

Von Willebrand ◽

Willebrand Factor

Abstract Intracellular protein transport in endothelial cells is selectively inhibited by homocysteine, a thiol amino acid associated with both thrombosis and atherosclerosis. In a previous study, homocysteine decreased cell surface expression of the surface transmembrane glycoprotein thrombomodulin without decreasing secretion of another endothelial cell protein, plasminogen activator inhibitor-1. To define further the effects of homocysteine on protein transport, we examined the processing and secretion of the multimeric glycoprotein von Willebrand factor (vWF) in human umbilical vein endothelial cells. Incubation with 2 mmol/L homocysteine resulted in complete loss of vWF multimers and prevented asparagine-linked oligosaccharide maturation, propeptide cleavage, and secretion; these effects are consistent with impaired exit from the endoplasmic reticulum (ER). Dimerization was only partially inhibited, suggesting that homocysteine causes retention of provWF in the ER without preventing dimer formation. In pulse-chase incubations, intracellular provWF was degraded before exiting the ER in homocysteine-treated cells. Homocysteine also inhibited the processing and secretion of a carboxyl-terminal truncation mutant of human provWF expressed in rat insulinoma cells, indicating that retention in the endoplasmic reticulum can be mediated by regions of provWF apart from the carboxyl-terminal 20-Kd segment. These results suggest that retention of secretory proteins in the ER is regulated by redox mechanisms and imply that the intracellular transport of multiple endothelial cell proteins may be altered in patients with homocystinuria.

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