This guideline, on the basis of a systematic review of the evidence on postoperative pain management, provides recommendations developed by a multidisciplinary expert panel. Safe and effective postoperative pain management should be on the basis of a plan of care tailored to the individual and the surgical procedure involved, and multimodal regimens are recommended in many situations.

Summary.  von Willebrand disease (VWD) is a bleeding disorder caused by inherited defects in the concentration, structure, or function of von Willebrand factor (VWF). VWD is classified into three primary categories. Type 1 includes partial quantitative deficiency, type 2 includes qualitative defects, and type 3 includes virtually complete deficiency of VWF. VWD type 2 is divided into four secondary categories. Type 2A includes variants with decreased platelet adhesion caused by selective deficiency of high‐molecular‐weight VWF multimers. Type 2B includes variants with increased affinity for platelet glycoprotein Ib. Type 2M includes variants with markedly defective platelet adhesion despite a relatively normal size distribution of VWF multimers. Type 2N includes variants with markedly decreased affinity for factor VIII. These six categories of VWD correlate with important clinical features and therapeutic requirements. Some VWF gene mutations, alone or in combination, have complex effects and give rise to mixed VWD phenotypes. Certain VWD types, especially type 1 and type 2A, encompass several pathophysiologic mechanisms that sometimes can be distinguished by appropriate laboratory studies. The clinical significance of this heterogeneity is under investigation, which may support further subdivision of VWD type 1 or type 2A in the future.

Summary.  von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder affecting both males and females, causing mucous membrane and skin bleeding symptoms, and bleeding with surgical or other haemostatic challenges. VWD may be disproportionately symptomatic in women of child‐bearing age. It may also occur less frequently as an acquired disorder (acquired von Willebrand syndrome). VWD is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet haemostatic function and stabilizes blood coagulation factor VIII. The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD. These evidence‐based guidelines for diagnosis and management of VWD from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel (USA) review relevant publications, summarize current understanding of VWD pathophysiology and classification, and present consensus diagnostic and management recommendations based on analysis of the literature and expert opinion. They also suggest an approach for clinical and laboratory evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased bleeding risk. This document summarizes needs for further research in VWF, VWD and bleeding disorders, including clinical research to obtain more objective information about bleeding symptoms, advancements in diagnostic and therapeutic tools, and enhancement in the education and training of clinicians and scientists in bleeding and thrombotic disorders. The NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd) has a more detailed document, a synopsis of these recommendations, and patient education information.

In order to firmly establish a normal range for von Willebrand factor antigen (vWF:Ag), we determined plasma vWF:Ag concentrations in 1,117 volunteer blood donors by quantitative immunoelectrophoresis. The presence of the ABO blood group has a significant influence on vWF:Ag values; individuals with blood group O had the lowest mean vWF:Ag level (74.8 U/dL), followed by group A (105.9 U/dL), then group B (116.9 U/dL), and finally group AB (123.3 U/dL). Multiple regression analysis revealed that age significantly correlated with vWF:Ag levels in each blood group. We then performed reverse ABO typing on stored plasma from 142 patients with the diagnosis of von Willebrand disease (vWd). Of 114 patients with type I vWd, blood group O was found in 88 (77%), group A in 21 (18%), group B in 5 (4%), and group AB in none (0%), whereas the frequency of these blood groups in the normal population is significantly different (45%, 45%, 7% and 3%, respectively) (P less than .001). Patients with type II or III vWd had ABO blood group frequencies that were not different from the expected distribution. There may be a subset of symptomatic vWd patients with decreased concentrations of structurally normal vWf (vWd, type I) on the basis of blood group O. Some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood type.

Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges. Objective: These evidence-based guidelines of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and other health care professionals in their decisions about VWD diagnosis. Methods: ASH, ISTH, NHF, and WFH established a multidisciplinary guideline panel that included 4 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Outcomes and Implementation Research Unit at the University of Kansas Medical Center (KUMC) supported the guideline-development process, including performing or updating systematic evidence reviews up to 8 January 2020. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subsequently subject to public comment. Results: The panel agreed on 11 recommendations. Conclusions: Key recommendations of these guidelines include the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs phenotypic assays for types 2B and 2N. Future critical research priorities are also identified.

Inhibitory immune response to exogenously infused factor VIII (FVIII) is a major complication in the treatment of hemophilia A. Generation of such inhibitors has the potential to disrupt gene therapy for hemophilia A.We explore what we believe to be a novel approach to overcome this shortcoming. Human B-domain-deleted FVIII (hBDDFVIII) was expressed under the control of the platelet-specific αIIb promoter in platelets of hemophilic (FVIII null ) mice to create 2bF8 trans mice. The FVIII transgene product was stored in platelets and released at the site of platelet activation. In spite of the lack of FVIII in the plasma of 2bF8 trans mice, the bleeding phenotype of FVIII null mice was corrected. More importantly, the bleeding phenotype was corrected in the presence of high inhibitory antibody titers introduced into the mice by infusion or by spleen cell transfer from recombinant hBDDFVIII-immunized mice. Our results demonstrate that this approach to the targeted expression of FVIII in platelets has the potential to correct hemophilia A, even in the presence of inhibitory immune responses to infused FVIII. IntroductionMonogenic diseases, characterized by the loss of a specific plasma protein, are currently treated by repetitive replacement therapy and are choice candidates amenable to gene therapy. Hemophilia A, a severe congenital bleeding disorder caused by the loss of clotting factor VIII (FVIII) (1), is a prototype of such monogenic diseases. Currently, hemophilia A is treated by infusion of recombinant or plasma-derived FVIII (2). However, 25-30% of patients develop antibodies (FVIII inhibitors) that selectively inactivate the clotting activity of FVIII and negate its therapeutic efficacy (3). Hemophilia A is considered a strong candidate for gene therapy because the therapeutic window is broad and even a minimal plasma level of plasma FVIII is clinically advantageous. The development of inhibitory antibodies to the FVIII transgene product in plasma remains a significant barrier to some patient candidates. Many groups have developed various strategies for directing FVIII synthesis (4-15), although inadequacies of gene delivery and expression and inhibitor formation remain clinical problems (7,(16)(17)(18).The approach we investigated, which we believe to be novel, is based on the hypothesis that targeting the production of FVIII to a secreting cell type that acts in the immediate vicinity of sites where FVIII is needed could overcome the presence of inhibitory antibodies. Furthermore, by sequestering the FVIII, the generation of antibodies in naive individuals might be prevented or at least rendered less relevant.

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A B ST R A CT The binding of '251-von Willebrand factor to platelets stimulated by thrombin, ADP, and a combination of ADP + epinephrine (EPI) is specific, saturable, and reversible. Active platelet metabolism and divalent cations are required for binding induced by these stimuli, but not by ristocetin, suggesting the existence of different mechanisms involved in the vWF-platelet interaction. A monoclonal antibody directed against an epitope of membrane glycoprotein (GP) lb had no effect on the binding of '251-vWF to normal platelets stimulated by thrombin or a combination of ADP + EPI, but completely blocked ristocetin-induced binding. Binding induced by thrombin to GPIb-blocked platelets was specific. Moreover, thrombin-induced binding of 1251-vWF was increased, rather than decreased, in two patients with the Bernard-Soulier syndrome whose platelets lacked GPIb. Conversely, monoclonal antibodies directed against the GPIIb/IIIa complex had no effect on ristocetininduced binding of (vWF)' is a large multimeric glycoprotein that circulates in blood complexed with the Factor VIII procoagulant activity protein (1). It plays an essential role in platelet function as shown by the prolonged bleeding time in von Willebrand disease (1). Specific binding sites for vWF are induced on the platelet membrane by the antibiotic ristocetin (2), a nonphysiologic agent, as well as by thrombin (3, 4) and ADP (5). Platelet membrane glycoprotein (GP) lb is considered to function as the surface receptor for vWF (6). In the Bernard-Soulier syndrome, a congenital bleeding disorder, platelets lack GPIb (7) and the ristocetin-induced binding of vWF is decreased (8). On the other hand, in Glanzmann thrombasthenia, another congenital platelet abnormality, there is a marked decrease of the membrane GP complex Ilb/Illa but normal content of GPIb (9). The ristocetin-induced binding of vWF to thrombasthenic platelets has been reported to be normal (8). In contrast, we have recently shown that binding of vWF to thrombasthenic platelets stimulated by thrombin is severely deficient (4). Therefore, we postulated that different sites are involved in ' Abbreviations used Marguerie et al. (12). The final platelet suspensions were all in modified calcium-free Tyrode buffer, containing 137 mM NaCI, 2 mM MgCI2, 0.42 mM NaH2PO4, 11.9 mM NaHCO3, 2.9 mM KCI, 5.5 mM glucose, 10 mM Hepes, pH 7.35, and 20 mg/ml bovine serum albumin (Fraction V, CalbiochemBehring Corp., American Hoechst Corp., San Diego, CA). When experiments of serotonin release were performed, PRP was labeled before washing by incubating 20 ml with 0. (3.3,M). However, ADG-washed platelets usually gave reversible aggregation to ADP and were unresponsive to epinephrine (EPI). On the contrary, gel-filtered platelets always gave irreversible aggregation to ADP, and responded to 20 MM EPI in the presence of fibrinogen (3.3 ,M) with a typical two-wave aggregation. Contamination of plasma vWF in all washed platelet preparations was below 5 X 10' U/dl (1 dl of a normal plasma pool contains ...