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We describe here the mechanism of platelet adhesion to immobilized von Willebrand factor (VWF) and subsequent formation of platelet-derived microparticles mediated by glycoprotein Ib␣ (GPIb␣) under high shear stress. As visualized in whole blood perfused in a flow chamber, platelet attachment to VWF involved one or few membrane areas of 0.05 to 0.1 m 2 that formed discrete adhesion points (DAPs) capable of resisting force in excess of 160 pN. Under the influence of hydrodynamic drag, membrane tethers developed between the moving platelet body and DAPs firmly adherent to immobilized VWF. Continued stretching eventually caused the separation of many such tethers, leaving on the surface tubeshaped or spherical microparticles with a diameter as low as 50 to 100 nm. Adhesion receptors (GPIb␣, ␣IIb␤3) and phosphatidylserine were expressed on the surface of these microparticles, which were procoagulant. Shearing platelet-rich plasma at the rate of 10 000 s ؊1 in a cone-and-plate viscosimeter increased microparticle counts up to 55-fold above baseline. Blocking the GPIb-VWF interaction abolished microparticle generation in both experimental conditions. Thus, a biomechanical process mediated by GPIb␣-VWF bonds in rapidly flowing blood may not only initiate platelet arrest onto reactive vascular surfaces but also generate procoagulant microparticles that further enhance thrombus formation. IntroductionThe integrity of the vessel wall is key for the normal circulation of blood and is constantly surveyed by platelets. 1 In arterial flow, platelets are positioned at high density near the endothelial-cell layer, while erythrocytes are lifted away from it through a hemodynamic process called axial migration. 2,3 When damage to the vascular surface occurs, von Willebrand factor (VWF) binds rapidly to exposed subendothelial structures 4,5 and enables platelet arrest from fast-flowing blood through the interaction of its A1 domain (VWFA1) with the platelet glycoprotein Ib␣ (GPIb␣) receptor. 6 The VWFA1-GPIb␣ bond has a short half-life and by itself cannot provide irreversible adhesion. Consequently, the torque imposed by flowing blood causes platelets to translocate over immobilized VWF until receptors such as glycoprotein VI or integrin ␣IIb␤3 engage their respective ligands and mediate permanent adhesion, spreading, and aggregation. 7 Under the effect of shear stress, platelet-derived microparticles (PMPs) can be generated in blood through a process that was reported to be dependent on the VWF-GPIb␣ interaction by some investigators 8 but not others. 9 Owing to their ability to bind coagulation factors, and the exposure on their surface of phosphatidylserine 9 as well as adhesion receptors 10 and possibly tissue factor, 11,12 PMPs have been suggested to play a role in blood clotting and thrombus formation. 13 Lacking so far, however, is a direct visualization and explanation of how shear stress can induce the generation of microparticles from platelets and how this may be linked to the subsequent development of thrombi. Becaus...

The European Study on the Clinical Outcomes and Resource Utilization associated with Haemophilia Care was designed to compare various health outcomes associated with on-demand and prophylactic factor substitution methods in European haemophilia patients. While the primary objective of this research is to conduct an economic analysis, an important component of this study is to evaluate quality-of-life differences that may exist between patients who utilize these two styles of therapy. Quality-of-life research has emerged as a primary measure of health outcomes because it allows the augmentation of traditional clinical indicators of health with data gathered from the patient's perspective. A total of 1033 haemophilia patients from 16 European haemophilia treatment centres were enrolled in this study. The SF-36, a multidimensional quality-of-life instrument, was administered to all participants. This instrument measures eight health-related quality-of-life dimensions: physical functioning, physical role limitations, bodily pain, general health, vitality, social functioning, emotional role limitations, and mental health. All haemophilia subjects enrolled in the study scored significantly lower than the population normative means in the three physical dimensions and in the general health dimension. HIV-negative haemophiliac subjects differed significantly by factor substitution type in a multivariate analysis examining all eight health dimensions. Univariate analyses testing each dimension separately indicated that patients treated prophylactically reported significantly less bodily pain, better general health, and scored significantly higher in the physical functioning, mental health, and social functioning dimensions. While these results suggest that health-related quality-of-life may be better for haemophilia patients treated prophylactically, future prospective studies that gather periodic quality-of-life data over time should be conducted.

Summary. Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long-term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality-of-life assessment instruments, and cost-benefit analyses.

Summary. As the management of haemophilia is complex, it is essential that those with the disorder should have ready access to a range of services provided by a multidisciplinary team of specialists. This document sets out the principles of comprehensive haemophilia care in Europe. Within each country there should be a national organization which oversees the provision of specialist Comprehensive Care Centres that provide the entire spectrum of clinical and laboratory services. Depending upon the size and geographical distribution of the population, a network of smaller haemophilia centres may also be necessary. There should be arrangements for the supply of safe clotting factor concentrates which can also be used in home treatment and prophylaxis programmes. A national register of patients is recommended along with collection of treatment statistics. As comprehensive haemophilia care is multidisciplinary by nature, the need for education and research programmes for all staff members is emphasized: Members of the Interdisciplinary Working Group not represented in the list of authors are mentioned in Section 4 of this document.