Effects of ABO Blood Group on von Willebrand Factor Biology, Primary Hemostasis

Researchers reviewed a growing base of literature that sheds light on the mechanisms through which ABO type directly influences primary hemostasis, with a focus on von Willebrand factor (VWF) in particular. Results of the review were published in Blood.

Aside from its importance in transfusion and transplantation, the ABO blood group has also been associated with aspects of many clinically relevant phenotypes, including susceptibility to severe coronavirus disease 2019, cardiovascular disease, venous thromboembolism, atherogenesis, acute coronary syndromes, and myocardial infarction.

The investigators described numerous findings on how ABO affects multiple aspects of VWF biology. During its biosynthesis, VWF undergoes complex posttranslational glycosylation in the Golgi and endoplasmic reticulum of endothelial cells and megakaryocytes. ABO(H) blood group influences structures on VWF glycans. A and B antigen loading on VWF depends upon ABO genotype. Studies have shown significantly reduced expression of these antigens in individuals with heterozygous expression (AO or BO) compared with individuals with homozygous expression (AA or BB). Furthermore, heterogeneity in the amount of ABO(H) carried on VWF produced by endothelial cells was found to vary in different vascular beds.

Plasma VWF antigen levels vary widely among populations. Multiple studies confirmed that plasma VWF levels are 20% to 30% lower in group O individuals, conferring reduced thrombotic risk, compared with nongroup O individuals, and it has been documented that group AB individuals tend to have the highest plasma VWF antigen levels. Thus, it has been suggested that ABO-specific reference ranges should be used for diagnosis of von Willebrand disease.

Modifications in VWF glycan structures with enzymes that remove A or B antigenic determinants were associated with reduced ristocetin cofactor activity. This suggests that AB antigen expression appears to make VWF less compact and more capable of platelet interaction; however, the clinical consequences of this remain unclear.

ABO blood group influences VWF proteolysis. Blood group O VWF appears to be more susceptible to proteolysis of A disintegrin and metalloproteinase with thrombospondin type-1 repeats, while differences have also been observed among the nongroup O VWFs (B > A ≥ AB). Along with other findings, this has led to the belief that blood group O individuals may be partially protected against thrombotic thrombocytopenic purpura; however, this has not been confirmed.

It remains unclear how ABO blood group influences plasma VWF to Ag levels; however, recent evidence suggests that ABO(H) blood group affects these levels via differences in the VWF clearance rates between blood groups. VWF clearance mechanisms are being actively explored, and more studies are needed to determine the effect of ABO blood group on VWF clearance.

ABO blood group determinants are also carried on the surfaces of different platelet membrane glycoproteins and glycolipids, including those that interact with VWF during platelet plug formation. Therefore, ABO blood group may directly affect primary hemostasis by influencing platelet function. Additionally, some studies have found that group O VWF has reduced ability to interact with platelets, which may be linked to reduced ability of group O platelets to interact with VWF.

“With recent advances, particularly with regards to MS glycomic analysis, exciting developments have been achieved in this clinically important field,” wrote the authors. “Given the huge morbidity and mortality that continue to be associated with thrombotic disorders, improved understanding of these glycan-mediated effects may offer the opportunity to develop novel targeted therapeutic strategies.”

Disclosures: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

Ward S, O’Sullivan J, O’Donnell JS. The relationship between ABO blood group, von Willebrand factor and primary hemostasis. Blood. Published online August 12, 2020. doi:10.1182/blood.2020005843