Von Willebrand disease in the United States: perspective from the Zimmerman program.

This article will discuss the diagnosis and management of von Willebrand disease (VWD) in the United States and results from the Zimmerman Program, a national study of VWD. An algorithm is presented to show how we currently approach diagnostic testing for VWD, including the potential replacement of the ristocetin cofactor assay with a new von Willebrand factor (VWF)-GPIb binding assay. Results from the Zimmerman Program type 1 cohort are presented, including the findings that genetic defects in the VWF gene are most common with VWF levels <30 IU/dL, but bleeding symptoms were present across the entire cohort regardless of VWF level. Typical management of VWD patients is also discussed, including the use of desmopressin and VWF concentrates. Despite these advances, there remain several areas of VWD where more research is required to optimize treatment.

Prophylactic efficacy and pharmacokinetically guided dosing of a von Willebrand factor/factor VIII concentrate in adults and children with von Willebrand's disease undergoing elective surgery: a pooled and comparative analysis of data from USA and European Union clinical trials.

BACKGROUND: Surgical intervention may pose significant risk of life-threatening bleeding in patients with von Willebrand's disease; prophylactic treatment with von Willebrand factor/factor VIII concentrate is generally indicated for von Willebrand's disease characterized by moderate to severe qualitative and quantitative deficiencies of Willebrand factor to raise and maintain both Willebrand factor and FVIII at haemostatic levels for surgical prophylaxis. MATERIALS AND METHODS: Since prospective clinical data in such situations were lacking, two recent, prospective, multicentre studies evaluated the prophylactic perioperative use of the on Willebrand factor/ factor VIII concentrates, Humate-P® and Haemate P. Despite some differences in the two studies, one conducted in the USA (n =35) and one in the European Union (n =27), the designs were similar enough to allow for a limited pooled analysis of data. In both studies, preoperative loading doses and subsequent maintenance doses were calculated using individual subject-derived incremental in vivo recovery values, although von Willebrand factor:ristocetin cofactor and FVIII:coagulation activity target levels differed between the protocols. Efficacy was rated daily by the investigator as excellent, good, moderate, or poor. RESULTS: Overall haemostatic efficacy (rating of excellent/good), assessed 24 hours after the last infusion (USA) or taken as the worst rating between surgery and day 14 (EU), was achieved in 95% of the pooled population of 62 adults and children. Efficacy did not appear to be affected by dosing variations. The rate of possibly related adverse events was low (8 subjects; 13%); one of these events was considered serious (pulmonary embolism). DISCUSSION: This pooled analysis of a relatively large number of patients for a rare disease confirms the feasibility of pharmacokinetically guided dosing of von Willebrand factor/factor VIII concentrate and highlights its efficacy and safety in the prevention of excessive perioperative bleeding.

CD4+ T-cell engagement by both wild-type and variant HCV peptides modulates the conversion of viral clearing helper T cells to Tregs.

AIM: To determine whether modulation of T-cell responses by naturally occurring viral variants caused an increase in numbers of Tregs in HCV-infected patients. PATIENTS MATERIALS & METHODS: Human peripheral blood mononuclear cells, having proliferative responses to a wild-type HCV-specific CD4+ T-cell epitope, were used to quantify, via proliferative assays, flow cytometry and class II tetramers, the effects of naturally occurring viral variants arising in the immunodominant epitope. RESULTS: In combination, the wild-type and variant peptides led to enhanced suppression of an anti-HCV T-cell response. The variant had a lower avidity for the wild-type-specific CD4+ T cell. Variant-stimulated CD4+ T cells had increased Foxp3, compared with wild-type-stimulated cells. CONCLUSION: A stable viral variant from a chronic HCV subject was able to induce Tregs in multiple individuals that responded to the wild-type HCV-specific CD4+ T-cell epitope.

Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes.

Venous thromboembolism and adverse pregnancy outcomes are potential complications of pregnancy. Numerous studies have evaluated both the risk factors for and the prevention and management of these outcomes in pregnant patients. This consensus group was convened to provide concise recommendations, based on the currently available literature, regarding the use of antithrombotic therapy in pregnant patients at risk for venous thromboembolic events and adverse pregnancy outcomes.

Diagnosis and treatment of von Willebrand disease.

Von Willebrand disease (VWD) is the most common bleeding disorder; it is believed to occur in approximately 1% to 2% of the population. Mucocutaneous and surgical hemorrhage in affected individuals is caused by quantitative and qualitative defects in von Willebrand factor (VWF), a large, multimeric protein that supports platelet adhesion and aggregation in the initiation of hemostasis at the time of vascular injury and functions as a carrier protein for factor VIII in the circulation. Advances in cellular and molecular biology have led to improved understanding of the pathophysiology of the disorder and development of a classification scheme that is based on quantitative and qualitative defects. Effective treatment is dependent on an accurate diagnosis using specific assays of VWF that define the various defects.