IntroductionPlatelet plug formation at the site of vascular injury is initiated by von Willebrand factor (VWF) interacting with the subendothelial matrix, followed by its binding to platelet glycoprotein (GP) Ib 1,2 and subsequent platelet activation and aggregation. VWF is synthesized by endothelial cells and megakaryocytes, 3,4 and one of its main particular features is a polymer structure ranging in size from 500 000 to more than 20 million Dalton, 5 the largest forms being hemostatically the most efficient. 6 A broad range of values characterizes plasma VWF levels, which average around 10 g/mL. Acquired and inherited factors both modulate plasma VWF levels, and twin studies have demonstrated that 66% of all variations in plasma VWF are genetically determined, while 30% of them depend on ABO blood group, 7 O blood group individuals having plasma VWF levels 25% lower than non-O subjects. 8 ABO group genotyping shows that O 1 O 1 subjects have the lowest VWF levels, and non-O group individuals heterozygous for the O 1 allele have significantly lower VWF levels than AA, AB, or BB subjects. 9,10 Glycosylation accounts for 19% of VWF by weight, and ABO determinants identified on the N-linked oligosaccharide chains are part of this glycosylation process. 11,12 ABO groups are added to the N-linked glycan chains of VWF in the post-Golgi compartment of endothelial cells before VWF secretion, albeit with the variable contribution of the endothelial cells from different vascular beds. 13 The carbohydrate moiety plays an important part in VWF polymerization and function, 14 and also affects the liver-mediated clearance of VWF. In animal models, the removal of sialic acid has been shown to induce an increase in VWF clearance, 15 and the half-life of VWF is halved in mice characterized by an aberrantly glycosylated VWF (due to the absence of the enzyme ST3Gal-IV). 16 Moreover, recombinant VWF, lacking in carbohydrate, is cleared from the circulation faster than its glycosylated counterpart, 16 and posttranslational changes in VWF induced by Galgt2, aberrantly expressed in endothelial cells, lead to a 20-fold increase in VWF clearance. 17 ABO group determinants may also regulate the susceptibility of VWF to the proteolytic action of ADAMTS13, proteolysis being faster in the case of the O blood group. 18 A different susceptibility to cleavage by ADAMTS13 may thus be one of the ways in which ABO group affects VWF removal from the circulation and consequent VWF levels.Although the mechanisms behind ABO blood group and VWF levels have yet to be fully clarified, it has been clearly demonstrated that the effects are mediated by the ABO antigen structures on the N-linked oligosaccharide chains of circulating VWF, and particularly by H antigen expression. 19 Understanding these mechanisms is of clinical relevance: non-O individuals have been shown to carry a significantly greater risk of venous thromboembolism, ischemic heart disease, and peripheral vascular disease, 21-23 while the O blood group is much more common in von Willebra...

Type Vicenza variant of von Willebrand disease (VWD) is characterized by a low plasma von Willebrand factor (VWF) level and supranormal VWF multimers. Two candidate mutations, G2470A and G3864A at exons 17 and 27, respectively, of the VWF gene were recently reported to be present in this disorder. Four additional families, originating from northeast Italy, with both mutations of type Vicenza VWD are now described. Like the original type Vicenza subjects, they showed a mild bleeding tendency and a significant decrease in plasma VWF antigen level and ristocetin cofactor activity but normal platelet VWF content. Unlike the original patients, ristocetin-induced platelet aggregation was found to be normal. Larger than normal VWF multimers were also demonstrated in the plasma. Desmopressin (DDAVP) administration increased factor VIII (FVIII) and VWF plasma levels, with the appearance of even larger multimers. However, these forms, and all VWF oligomers, disappeared rapidly from the circulation. The half-life of VWF antigen release and of elimination was significantly shorter than that in healthy counterparts, so that at 4 hours after DDAVP administration, VWF antigen levels were close to baseline. Similar behavior was demonstrated by VWF ristocetin cofactor activity and FVIII. According to these findings, it is presumed that the low plasma VWF levels of type Vicenza VWD are mainly attributed to reduced survival of the VWF molecule, which, on the other hand, is normally synthesized. In addition, because normal VWF-platelet GPIb interaction was observed before or after DDAVP administration, it is proposed that type Vicenza VWD not be considered a 2M subtype. (Blood. 2002;99:180-184)

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Background:The concurrent presence of lupus anticoagulant, anticardiolipin, and anti β2-glycoprotein I antibodies (triple positive profile) identifies patients at high risk of thromboembolic events. These patients are also positive for anti-phosphatidylserine/prothrombin antibodies (tetra-positive profile).Objective: Understand which antibody among anti-β2-glycoprotein I and anti-phosphatidyl-serine/prothrombin is responsible for lupus anticoagulant activity.Patients/Methods: Affinity purified anti-β2-glycoprotein I antibodies from plasma of 14 tetra-positive patients spiked into normal pooled plasma were tested. Results and Conclusions:Anti-β2-glycoprotein I antibodies did not prolong the diluted Russell viper venom time and silica clotting time (median ratio 0.98, interquartile ratio[IQR] 0.9-1.06; and 1.0, IQR 0.91-1.03, respectively). Anticoagulant activity remained in the flow-through that was deprived of anti-β2 glycoprotein I antibodies (median ratio 1.88, IQR 1.58-2.77; and 1.75, IQR 1.17-2.9, respectively). This material was loaded on size-exclusion chromatography Sephacryl S-300 column and showed that anticoagulant activity and anti-phosphatidyl-serine/prothrombin antibodies coeluted in the same fractions. Besides, the flow through was poured into a prothrombin affinity column. Protein yield in three patients ranged from 54 to 91 μg/mL and showed strong positivity in phosphatidyl-serine/prothrombin ELISA. The affinity purified material prolonged the coagulation time of normal pooled plasma: the diluted Russell viper venom ratio in the three patients was 2.09, 1.21, and 1.35; that of silica clotting time was 2.05, 1.5, and 2.13. In conclusion, under the assay conditions used, anticoagulant activity in tetra-positive antiphospholipid syndrome patients may largely be attributable to anti-phosphatidyl-serine/prothrombin antibodies.