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OBJECTIVES Acquired von Willebrand syndrome, characterized by the reduction in von Willebrand factor (vWF) large multimers, has recently been considered as one of the causes of gastrointestinal bleeding (GIB). It remains unclear whether its haematological severity is linked with susceptibility to bleeding because the definition of the haematological severity of acquired von Willebrand syndrome has not been precisely determined. This study sought to establish a quantitative methodology to assess the haematological severity of acquired von Willebrand syndrome and to define the threshold for occurrence of GIB in patients implanted with left ventricular assist devices (LVADs). METHODS In total, 41 patients treated with continuous-flow LVAD implanted between 2011 and 2017 at Tohoku University Hospital were investigated. vWF large multimers were quantitatively evaluated using the 'vWF large multimer index' defined as the ratio of a large multimer proportion in total vWF derived from a patient to that from a normal control. Using this index, the amount of vWF large multimers was expressed as a percentage of its normal control value obtained with a simultaneous analysis of each time measurement. RESULTS Twelve (29%) patients developed GIB events during follow-up periods (median 591 days) after an LVAD implantation. The vWF large multimer index in patients with GIB was significantly lower than that in those without GIB (25.0 ± 10.3% vs 37.5 ± 17.8%, P  = 0.008). Most importantly, all patients experiencing GIB exhibited a vWF large multimer index below 40%. CONCLUSIONS Patients with GIB exhibited a more severe loss of vWF large multimers. The vWF large multimer index may dictate the risk of GIB after an LVAD implantation. Clinical trial registration number UMIN000018135. [ABSTRACT FROM AUTHOR]

Introduction: Acquired von Willebrand syndrome (aVWS), characterized by reduction in von Willebrand factor (vWF) large multimers, have recently been considered as a principal mechanism responsible for bleedings in patients with left ventricular assist device (LVAD). The hematological severity of aVWS varies from case to case even if the identical device is implanted. Hypothesis: We hypothesized that the diversity in hematological severity of aVWS is due to individual variability in vWF fragility in response to incremental shear stress. Methods: Whole blood samples derived from 20 healthy people were sheared at 20,000 to 40,000 s-1 using a custom-made shear stressor that can generate LVAD compatible shear stress. The amount of vWF large multimers was evaluated with our original vWF large multimer index. Results: Significant inverse correlation was observed between the level of vWF large multimer index and LVAD-compatible magnitude of shear stress exhibiting 64.7, 51.6, 31.8, 24.7 and 17.1% (median) of index at 20,000, 25,000, 30,000, 35,000, and 40,000 s-1 of shear stress, respectively. Furthermore, the values of vWF large multimer index were compatible with those derived from clinical implantable LVAD patients (median; 28.9%). With regard to the decrease patterns of vWF large multimer index corresponding to shear stress in each subject, they showed various changes remarkably (Fig). We found that the degradation patterns of the index can be characterized with three parameters, that is, the magnitude of initial drop; degree of reduction in the index at 20,000 s-1, ΔIndex; difference between the indices at 20,000 s-1 and 40,000 s-1, and Degradation slope; slope with a linear regression model. Conclusions: Significant individual variability in vWF fragility can be demonstrated quantitatively. The combined use of the novel high shear-loading device and quantitative evaluation of vWF large multimer may enable us to predict a bleeding risk by taking blood sample from each patient prior to LVAD implantation. [ABSTRACT FROM AUTHOR]

UVA1 induces the formation of 8-hydroxy-2′-deoxyguanosines (8-OH-dGs) and cyclobutane pyrimidine dimers (CPDs) in the cellular genome. However, the relative contribution of each type of damage to the in vivo genotoxicity of UVA1 has not been clarified. We irradiated living mouse skin with 364-nm UVA1 laser light and analyzed the DNA damage formation and mutation induction in the epidermis and dermis. Although dose-dependent increases were observed for both 8-OH-dG and CPD, the mutation induction in the skin was found to result specifically from the CPD formation, based on the induced mutation spectra in the skin genome: the dominance of C → T transition at a dipyrimidine site. Moreover, these UV-specific mutations occurred preferentially at the 5′-TCG-3′ sequence, suggesting that CpG methylation and photosensitization-mediated triplet energy transfer to thymine contribute to the CPD-mediated UVA1 genotoxicity. Thus, it is the CPD formation, not the oxidative stress, that effectively brings about the genotoxicity in normal skin after UVA1 exposure. We also found differences in the responses to the UVA1 genotoxicity between the epidermis and the dermis: the mutation induction after UVA1 irradiation was suppressed in the dermis at all levels of irradiance examined, whereas it leveled off from a certain high irradiance in the epidermis.Journal of Investigative Dermatology (2008) 128, 2289–2296; doi:10.1038/jid.2008.61; published online 20 March 2008 [ABSTRACT FROM AUTHOR]