Functional Property of von Willebrand Factor Under Flowing Blood

von Willebrand factor (vWF) is produced in megakaryocytes and endothelial cells, is stored in the alpha-granule of platelets and in the Weibel-Palade body of endothelial cells, and is present in plasma and vascular subendothelium. This huge protein with a unique multimeric structure plays a pivotal role in both hemostasis and pathological intravascular thrombosis, in which vWF contributes to both platelet adhesion/aggregation and blood coagulation through its multiple adhesive functions for the platelet membrane receptors, glycoprotein Ib-IX-V complex, integrin alphaIIbbeta3, heparin, various types of collagen, and coagulation factor VIII. Among various functions, the most characteristic feature of vWF is its determinant role on platelet thrombus formation under high-shear-rate conditions. Indeed, at in vivo rheological situations where platelets are flowing with high speed in the bloodstream, the only reaction that can initiate mural thrombogenesis is the interaction of vWF with platelet glycoprotein Ibalpha. The recent x-ray analysis of the crystal structure of various functional domains and functional studies of this protein under experimental flow conditions have rapidly advanced and revised our knowledge of the structure-function relationships of vWF, a key protein for hemostasis and arterial thrombosis.     

Factor VIII Procoagulant Activity, Factor VIII Related Antigen and von Willebrand Factor in Newborn Cord Blood

The mean level of factor VIII procoagulant acitivity (VIII:C) and factor VIII related antigen (VIIIR:AG) was normal in 100 newborn cord plasmas, whereas that of von Willebrand factor (VIIIR:WF) activity was slightly lower than normal. On crossed immunoelectrophoresis, 20 of 50 newborn infants had an increased anodal mobility of VIIIR:AG. When the cord plasma showing an abnormal electrophoretic pattern was mixed with normal plasma, two precipitation peaks with a broad base were found. Similar mixing experiments with the abnormal cord plasma and plasma from a patient with atypical von Willebrand's disease did not normalize the electrophoretic mobility of VIIIR:AG. Gel filtration of the cord plasma with an abnormal electrophoretic pattern of VIII:AG, showed that the three activities were all detected at the position corresponding to a molecular weight of about 800 000. The results suggest the presence of qualitative abnormalities of the factor VIII molecule in half of full-term newborn cord plasma.     

血管性血友病因子在心血管疾病中的研究进展

血管性血友病因子是一类主要由内皮细胞分泌的多聚糖蛋白,通过激活血小板,参与血栓形成。它与一系列心血管疾病如动脉粥样硬化、急性冠状动脉综合征、心房颤动等均关系密切,特异性抑制血管性血友病因子的新型抗血小板药物研发有望突破。     

Detection of the H and I Blood Group Antigens in Normal Plasma

The levels of A, H, I and i antigens were measured in the plasma of 185 normal subjects by the agglutination-inhibition method. The presence of H in the plasma was only detectable with immune anti-H. The level of H in the plasma was directly correlated with the amount on the red cells, and was affected by the donor secretor status. The plasma of group O secretors contained more H than the plasma of donors of other phenotypes. On the other hand, I and i plasma antigens were not related to the other systems studied. Unlike the Ii antigens on the red cell membrane, there was no relationship between the levels of I and i in plasma.     

假性血友病因子与冠心病

冠心病的发病机理目前还不能确知 ,但大多数观点认为 ,冠心病尤其是不稳定型心绞痛和心肌梗死的发生与血管内皮细胞受损、血栓形成有关。近年研究发现血管内皮细胞除起机械屏障作用外 ,还分泌许多重要生物活性物质 ,如前列环素 (PGI2 )、内皮衍生舒张因子 (EDRF)、假性血友病因子 (v WF) ,这些活性物质对调节血管张力、凝血纤溶功能 ,以及维持正常血压及血流动力学均有一定的保护作用。一旦内皮细胞受损 ,则可合成释放 v WF,该因子释放入血液可引起血小板粘附聚集 ,促发血栓形成。1　概述粘附蛋白是细胞粘附糖蛋白家族 ,其种类繁多 ,多…     

Binding of Low-Molecular-Weight Canine Factor VIII Coagulant from von Willebrand Plasma to Canine Factor VIII-Related Antigen

S ummary . Plasmas having no detectable factor VIII-related antigen but moderate factor VIII coagulant were obtained from two unrelated dogs homozygous for von Willebrand's disease and with the severe clinical expression of the disease. When these plasmas were gel-filtered in a buffer at physiologic ionic strength, the factor VIII coagulant eluted in the bed volume as a single well-defined peak. Addition of protease inhibitors, including diisopropylfluorophosphate, did not change the elution pattern. Each plasma was then combined individually with plasmas from six different mutants of canine haemophilia, all of which had normal factor VIII-related antigen but no detectable factor VIII coagulant. The factor VIII coagulant elution profile of these combined plasma resembled that of normal canine plasma. Slightly over half of the recovered factor VIII coagulant coeluted in the void volume with the factor VIII-related antigen; the rest eluted as a second, distinct peak of lower molecular weight. These results demonstrated that part of the factor VIII coagulant of the von Willebrand plasmas had bound to the factor VIII-related antigen of the haemophilic plasmas. This finding supports the theory that factor VIII exists as a macromolecular complex of nonidentical components in normal citrated plasma.     

Alterations of Factor VIII von Willebrand Factor in Clinical Conditions Associated with an Increase in its Plasma Concentration

Factor VIII-related antigen (VIIIR:Ag) was consistently higher than factor-VIII procoagulant activity (VIII:C) in 57 patients with clinical conditions characterized by acute-phase reactions. Two different methods for measuring VIII:C (one- and two-stage assays) and VIIIR:Ag (electroimmunodiffusion and immunoradiometric assay) gave concordant results in the majority of cases. In 43% of plasma samples, crossed immunoelectrophoresis in agarose gel was characterized by the appearance of an additional, fast-moving precipitin peak which was immunologically identical with the major, slower-moving VIIIR:Ag peak. The fast-moving peak was detected in all the patients with clinical conditions typically associated with increased plasma proteolysis (DIC, acute pancreatitis, during thrombolytic therapy). It was present in a smaller proportion of cases with liver and renal failure and malignancies and in the post-operative period. The additional VIIIR:Ag peak is thought to be the result of in vivo factor VIII/von Willebrand factor fragmentation by proteolytic enzymes.     

Serum Blood Group Substances and ABO Haemolytic Disease

The passage of incompatible maternal anti-A and anti-B isoagglutinins across the placenta can cause haemolysis of foetal erythrocytes. This occurs almost entirely in group A or B infants born to a group O mother, but only one in five such infants shows evidence of a mild haemolytic disease. This suggests that there must be factors protecting the foetal red cells against incompatible maternal antibody. The investigation described here suggests that one such factor is the presence of blood group substances in foetal serum.
In an investigation of the amount of A-substance present in the cord blood of group A infants, significantly greater amounts were found in secretors than in non-secretors. Also, in group A secretor infants, the amounts of A substance in the cord blood of infants with group O mothers was diminished in comparison with those with group A mothers. These findings are compatible with the idea that some of the A-substance in the serum of the group A infants with O mothers had combined with maternal anti-A agglutinin and had been removed from the circulation. This supports the suggestion that blood group substances in cord serum protect the foetal erythrocytes from incompatible maternal antibodies.     

von Willebrand因子与稳定冠心病

早期大量研究揭示了von Willebrand因子的生物学特点、结构和功能,近期研究发现von Willebrand因子可能在稳定冠心病发病、剪切力机制诱导血小板聚集、血栓形成,以及药物和介入治疗(包括支架置入等)方面有重要作用。     

Plasma and platelet von Willebrand factor defects in uremia

PURPOSE: Several mechanisms have been proposed to explain the prolonged bleeding times and clinical bleeding in chronic renal failure. Recent evidence has implicated an abnormality in the structure or function of the von Willebrand factor or in its interaction with uremic platelets. We investigated this factor in 11 patients with chronic renal failure. PATIENTS AND METHODS: Blood samples for cell counts, chemistries, and coagulation studies were obtained from 11 patients with chronic renal failure and prolonged bleeding times. Concentrations of von Willebrand factor antigen and ristocetin cofactor activity were determined in plasma and platelets. Multimeric analysis of von Willebrand factor in plasma and platelets was conducted. In eight cases, the platelets of uremic patients were purified, and the thrombin- and ristocetin-induced binding of normal von Willebrand factor to these platelets was examined. RESULTS: The mean plasma von Willebrand factor antigen and activity (ristocetin cofactor assay) were elevated 2.77 mu/ml and 1.88 mu/ml, respectively (normal, 1.01 mu/ml and 1.07 mu/ml, respectively). The ratio of activity to antigen in uremic plasma was 0.67 (normal, 1.05). The mean platelet von Willebrand factor antigen and activity in the uremic patients was decreased (0.26 and 0.50 mu/10(9) platelets, respectively) compared with normal patients (0.46 and 0.93 mu/10(9) platelets, respectively). The oligomeric structure of the uremic plasma von Willebrand factor lacked the largest multimers. Collection of the blood for analysis in several protease inhibitors and/or EDTA did not change the multimeric structure. The von Willebrand factor multimeric structure of platelets from uremic patients was normal. The ristocetin-induced platelet aggregation of the uremic platelet-rich plasma was decreased compared with normal plasma samples. Thrombin and ristocetin-induced binding of normal von Willebrand factor to uremic patients' platelets was indistinguishable from the binding to normal platelets. CONCLUSION: These data suggest that the uremic platelet-binding sites for von Willebrand factor are intact and that the defect in ristocetin-induced platelet aggregation is most likely plasmatic in nature. At least one plasmatic defect was the observed reduction or absence of the largest plasma von Willebrand factor multimer in uremic patients. The platelet von Willebrand content was significantly decreased. These defects may play a role in the prolonged bleeding time and the clinical bleeding observed in patients with uremia.     

Ultracentrifugal Analysis of Factor VIII and von Willebrand Factor in Therapeutic Preparations

Plasma and therapeutic preparations of factor VIII (1 recombinant factor VIII and two monoclonally purified plasma-derived factor VIII preparations, Kogenate, and AHF-M and Monoclate, respectively) were centrifuged in a sucrose density gradient, and the fractions were analyzed for factor VIII and von Willebrand factor (vWF). The residual vWF in the monoclonally purified factor VIII preparations sediments more slowly than the vWF of plasma. In the absence of added vWF, the factor VIII in all preparations sediments more slowly than plasma factor VIII. These same preparations of factor VIII added to hemophilic plasma as a source of vWF sediment differently. The addition of either recombinant factor VIII or AHF-M results in sedimentation of the factor VIII with the plasma vFW and in a position indistinguishable from factor VIII in plasma. In contrast, when Monoclate is added to hemophilic plasma in vitro, the factor VIII sediments more slowly than the vWF of the hemophilic plasma. However, 5 min after the infusion of Monoclate into a patient with hemophilia A, the factor VIII sediments with the plasma vWF. These results indicate that the addition of recombinant factor VIII and AHF-M results in random binding to all vWF multimers of plasma, while there is little exchange between the added factor VIII in Monoclate and the plasma vWF in vitro. In contrast, when the Monoclate is infused, there is rapid binding of factor VIII to the plasma vWF. This is presumably due to tight binding of the factor VIII to the vWF in Monoclate, whereas the factor VIII in Kogenate and AHF-M, containing no or very low amounts of vWF, are free to bind to plasma vWF. In vivo there are other conditions, as yet uninvestigated, which allow for the binding of factor VIII to vWF.     

Factor VIII-Mediated Global Hemostasis in the Absence of von Willebrand Factor

Although the efficacy of recombinant factor VIII (rFVIII) in the treatment of type 3 von Willebrand disease (VWD) has been reported, the mechanisms by which FVIII concentrates devoid of von Willebrand factor (VWF) induce improvements in hemostasis are poorly understood. To address the role of FVIII or intrinsic coagulation in the absence of VWF, we performed a hemostatic analysis. Blood samples were obtained before and after the administration of rFVIII to 2 patients with type 3 VWD. A rotating thromboelastometry assay was performed to examine global interactions in hemostasis. Studies of thrombin-and shear-induced platelet aggregation were also conducted to elucidate the effect on platelet activation. Furthermore, we assessed the rise in the thrombin-induced intracellular concentration of free calcium [Ca2+]i. Addition of rFVIII to preinfusion blood in vitro corrected thromboelastometric parameters and thrombin-induced aggregation. In ex vivo studies, thromboelastometry analysis showed that rFVIII shortened the onset and progression of the coagulation process. Furthermore, rFVIII corrected low shear-induced and thrombin-induced platelet aggregation in platelet-rich plasma. In addition, rFVIII improved thrombin-induced [Ca2+]i flux in washed platelets. Our observations suggested that FVIII is incorporated into platelets to activate them, as well as to act directly in intrinsic coagulation in the absence of VWF. FVIII may play a critical role even in the absence of VWF.     

A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor

ABO blood groups greatly influence circulating von Willebrand factor (VWF) levels, and O group subjects have lower VWF values. In this study, we investigated whether ABO groups affect VWF survival by monitoring the post-DDAVP (1-desamino-8-d arginine vasopressin) time courses of VWF antigen (VWF:Ag), VWF collagen binding (VWF:CB), and factor VIII (FVIII) in 47 healthy subjects (28 O and 19 non-O blood groups). The elimination half-life (T1/2el) of VWF was found significantly shorter in O than in non-O subjects (10.0+/-0.8 hours vs 25.5+/-5.3 hours, respectively; P<.01), as was the T1/2el of VWF:CB (7.9+/-0.5 hours vs 20.9+/-4.5 hours; P<.01). A direct linear correlation was found between basal VWF:Ag and T1/2el, subjects with higher VWF levels having longer-surviving VWF. ABO blood groups appeared to strongly influence VWF clearance, but not its synthesis or release from endothelial cells. The VWF propeptide to VWF:Ag ratio, useful for predicting an increased VWF clearance, was found significantly higher in O than in non-O individuals (1.6+/-0.1 vs 1.2+/-0.5, P<.001), with values that correlated inversely with T1/2el (P<.001). Based on these findings, we conclude that the lower VWF values in O group individuals is attributable to a shorter VWF survival and circulating VWF values are strongly influenced by its half-life.     

Lack of Association Between Asthma and ABO Blood Group

ABO is the most important blood group system in transfusion and transplantation practices. Glycosyltransferases are controlled by the ABO system which is helpful in building oligosaccharide structures on the cell surface of erythrocytes and vascular endothelium and in the exocrine secretion system, including the respiratory tract. We analyzed the ABO blood group of 200 children and adults with asthma as well as that of 2000 healthy subjects as controls. The most common blood group among the patients and controls was “O” (43.5% and 43.6%, respectively), followed by B, A, and AB. In the distribution of different blood groups, nonsignificant difference between patients and controls was observed (p = 0.931). We conclude that ABO blood group status has a nonsignificant association with asthma among the population of Mysore, Karnataka, South India.     

von Willebrand因子与蛛网膜下腔出血后脑血管痉挛

脑血管痉挛是蛛网膜下腔出血后的并发症之一,也是蛛网膜下腔出血患者残疾和死亡的重要原因,其发病机制至今尚不明确,目前有关血管内皮细胞功能的研究较多.von Willebrand因子(vWF)是反映血管内皮细胞功能的特异标志物,文章就vWF在脑血管痉挛中的作用做了综述.