Summary Von Willebrand disease (VWD) constitutes the most common inherited human bleeding disorder. It is associated with a mucocutaneous bleeding phenotype that can significantly impact upon quality of life. Despite its prevalence and associated morbidity, the diagnosis and subclassification of VWD continue to pose significant clinical challenges. This is in part attributable to the fact that plasma von Willebrand factor (VWF) levels vary over a wide range in the normal population, together with the multiple different physiological functions played by VWF in vivo. Over recent years, substantial progress has been achieved in elucidating the biological roles of VWF. Significant advances have also been made into defining the pathophysiological mechanisms underpinning both quantitative and qualitative VWD. In particular, several new laboratory assays have been developed that enable more precise assessment of specific aspects of VWF activity. In the present review, we discuss these recent developments in the field of VWD diagnosis, and consider how these advances can impact upon clinical diagnostic algorithms for use in routine clinical practice. In addition, we review some important recent advances pertaining to the various treatment options available for managing patients with VWD.

Background Most individuals with mild to moderate reductions in plasma von Willebrand factor (VWF) levels do not demonstrate increased bleeding. However, some patients with plasma VWF levels of 30–50 IU/dl do have a significant bleeding phenotype. Management of these “low VWF” patients, who may have significant bleeding scores >10, around times of elective procedures continues to pose a common clinical challenge because of a lack of evidence. Objective To investigate the safety and efficacy of different periprocedural management options for adult patients with low VWF. Methods Treatment and outcomes were retrospectively reviewed for 160 invasive procedures performed in 60 patients with well characterized low VWF enrolled in the previously described Low Von Willebrand factor Ireland Cohort study. Results We demonstrate that 1‐desamino‐8‐D‐arginine vasopressin is efficacious in preventing bleeding for both minor or major elective procedures in adult low VWF patients, even in those with significant bleeding histories. In addition, tranexamic acid alone is effective for low VWF patients undergoing nondental minor procedures. Importantly, age‐related increases in plasma VWF:antigen levels above 50 IU/dl were not necessarily associated with complete correction of bleeding phenotype. Procedure‐related bleeding complications were increased in low VWF patients who did not receive any hemostatic cover before their procedure. Conclusion Elective procedures in adult patients with low VWF should be managed in liaison with a comprehensive care tertiary referral center so that personalized treatment plans may be implemented before all minor or major elective procedures.

Mantle cell lymphoma (MCL) presenting in elderly, unfit patients represents a clinical challenge. Front-line 'attenuated' or low-intensity immunochemotherapy is often employed, although outcomes are relatively unexplored. We report outcomes of attenuated immunochemotherapy in 95 patients with MCL across 19 centres in the UK and Ireland considered unfit for full-dose rituximab-bendamustine or rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP). Regimens examined were rituximab-cyclophosphamide, vincristine, prednisolone (R-CVP) (n = 19), dose-attenuated R-CHOP (n = 22), dose attenuated rituximab-bendamustine (n = 24) and rituximab-chlorambucil (n = 30). The primary outcome was progressionfree survival (PFS). The secondary outcomes included overall response, overall survival (OS) and toxicity. The median (range) age was 79 (58-89) years and 50% were aged ≥80 years. The median (range) Cumulative Illness Rating Scale-Geriatric score was 6 (0-24). The median PFS for all patients was 15 months [95% confidence interval (CI) 8Á7-21Á2) and median OS was 31Á4 months (95% CI 19Á7-43Á2). By multivariable analysis (MVA), the only clinical factor associated with an inferior PFS was blastoid morphology [hazard ratio (HR) 2Á90, P = 0Á01). Notably, higher treatment intensity (R-CHOP/R-bendamustine composite) provided an independently superior PFS compared with R-CVP/R-chlorambucil (MVA HR 0Á49, P = 0Á02). Factors associated with inferior OS by MVA were Eastern Cooperative Oncology Group Performance Status (HR 2Á14, P = 0Á04), blastoid morphology (HR 4Á08, P = 0Á001) and progression of disease at <24 months status (HR 5Á68, P < 0Á001). Overall, survival after front-line dose-attenuated immunochemotherapy is unsatisfactory. Clinical trials investigating novel agents such as Bruton tyrosine kinase and Bcell lymphoma 2 inhibitors in this specific clinical setting are warranted.

Increased von Willebrand factor (VWF) clearance plays a key role in the pathogenesis of Type 1 and Type 2 von Willebrand disease (VWD). However, the pathological mechanisms involved in patients with mild to moderate reductions in plasma VWF:Ag (30-50 IU/dL range; Low VWF) remain poorly understood. In this study, we investigated the hypothesis that enhanced VWF clearance may contribute to Low VWF pathobiology. Low VWF patients were recruited to the LoVIC study following ethical approval and informed consent. Desmopressin was administered intravenously in 75 patients and blood samples drawn at baseline, 1 and 4 hour time-points. As defined by recent ASH/ISTH/NHF/WFH guidelines, 20% of our Low VWF cohort demonstrated significantly enhanced VWF clearance. Importantly from a clinical perspective, this enhanced VWF clearance was seen following desmopressin infusion, but did not affect the steady-state VWFpp/VWF:Ag ratio in most cases. This discrepancy between VWFpp/VWF:Ag ratio and desmopressin fall-off rates in patients with mild quantitative VWD may reflect alteration in VWFpp clearance kinetics. Finally, our data further demonstrate that bleeding scores are significantly lower in Low VWF patients with enhanced VWF clearance compared to those in whom reduced VWF biosynthesis represents the principle pathogenic mechanism. This trial was registered at www.clinicaltrials.gov as #NCT03167320.