von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges.
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.
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.
The panel agreed on 11 recommendations.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ABO incompatible (ABOi) kidney transplantation is an important modality to facilitate living donor transplant for incompatible pairs. To date, reports of the outcomes from this practice in the United ...States have been limited to single-center studies.
Using the Scientific Registry of Transplant Recipients, we identified 738 patients who underwent live-donor ABOi kidney transplantation between January 1, 1995, and March 31, 2010. These were compared with matched controls that underwent ABO compatible live-donor kidney transplantation. Subgroup analyses among ABOi recipients were performed according to donor blood type, recipient blood type, and transplant center ABOi volume.
When compared with ABO compatible-matched controls, long-term patient survival of ABOi recipients was not significantly different between the cohorts (P=0.2). However, graft loss was significantly higher, particularly in the first 14 days posttransplant (subhazard ratio, 2.34; 95% confidence interval, 1.43-3.84; P=0.001), with little to no difference beyond day 14 (subhazard ratio, 1.28; 95% confidence interval, 0.99-1.54; P=0.058). In subgroup analyses among ABOi recipients, no differences in survival were seen by donor blood type, recipient blood type, or transplant center ABOi volume.
These results support the use and dissemination of ABOi transplantation when a compatible live donor is not available, but caution that the highest period of risk is immediately posttransplant.
A normal hemostatic response to vascular injury requires both factor VIII (FVIII) and von Willebrand factor (VWF). In plasma, VWF and FVIII normally circulate as a noncovalent complex, and each has a ...critical function in the maintenance of hemostasis. Furthermore, the interaction between VWF and FVIII plays a crucial role in FVIII function, immunogenicity, and clearance, with VWF essentially serving as a chaperone for FVIII. Several novel recombinant FVIII (rFVIII) therapies for hemophilia A have been in clinical development, which aim to increase the half-life of FVIII (∼12 hours) and reduce dosing frequency by utilizing bioengineering techniques including PEGylation, Fc fusion, and single-chain design. However, these approaches have achieved only moderate increases in half-life of 1.5- to 2-fold compared with marketed FVIII products. Clearance of PEGylated rFVIII, rFVIIIFc, and rVIII-SingleChain is still regulated to a large extent by interaction with VWF. Therefore, the half-life of VWF (∼15 hours) appears to be the limiting factor that has confounded attempts to extend the half-life of rFVIII. A greater understanding of the interaction between FVIII and VWF is required to drive novel bioengineering strategies for products that either prolong the survival of VWF or limit VWF-mediated clearance of FVIII.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The field of desensitization and incompatible transplantation has made great gains over the past decade. There are now several options and effective therapies for many patients who face antibody ...barriers. Kidney paired donation (KPD) and desensitization have traditionally been considered competing strategies and patients have been offered one or the other without regard for the probability of a successful outcome. It is now possible to predict which donor/recipient phenotypes will benefit from each of these modalities. KPD should be favored among patients with immunologic phenotypes that are likely to match without prolonged waiting times. However, as many as 50% of patients with incompatible donors will fail to find a match in a KPD pool and many of these patients could be desensitized to their donor. Positive crossmatch and ABO incompatible transplantation has been accomplished in selective cases without the need for heavy immunosuppression or B‐cell ablative therapy. Patients who are both difficult‐to‐match due to broad sensitization and hard‐to‐desensitize because of strong donor reactivity can often be successfully transplanted through a combination of desensitization and KPD. Using these various modalities it is estimated that most patients with incompatible live donors can undergo successful renal transplantation.
This article reviews the options available for crossing HLA and ABO incompatible barriers and the donor/recipient phenotypes that benefit from these modalities. See editorial by Gebel and Halloran on page 443.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The cellular source of coagulation factor VIII (FVIII) remains controversial. Like many coagulation proteins, FVIII is produced in the liver, and FVIII synthesis has long been associated with ...hepatocytes. But extrahepatic synthesis also occurs, and mounting evidence suggests that hepatocytes are not responsible for FVIII production. To determine the tissue that synthesizes FVIII, we developed a Cre/lox-dependent conditional knockout (KO) model in which exons 17 and 18 of the murine factor VIII gene (F8) are flanked by loxPsites, or floxed (F8F). In cells expressing Cre-recombinase, the floxed sequence is deleted, resulting in F8F→KOgene inactivation. When F8Fmice were crossed with various tissue-specific Cre strains, we found that hepatocyte-specific F8-KO mice are indistinguishable from controls, whereas efficient endothelial-KO models display a severe hemophilic phenotype with no detectable plasma FVIII activity. A hematopoietic Cre model was more equivocal, so experimental bone marrow transplantation was used to examine hematopoietic FVIII synthesis. FVIIInullmice that received bone marrow transplants from wild-type donors were still devoid of plasma FVIII activity after hematopoietic donor cell engraftment. Our results indicate that endothelial cells are the predominant, and possibly exclusive, source of plasma FVIII.
•Endothelial cells are the predominant (and possibly exclusive) source of coagulation factor VIII.•Hepatocytes do not contribute to plasma FVIII production.
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With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more ...common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.
Approximately 35% of patients with type 1 von Willebrand disease (VWD) do not have a known pathogenic variant in the von Willebrand factor (VWF) gene. We aimed to understand the impact of VWF coding ...variants on VWD risk and VWF antigen (VWF:Ag) levels, studying 527 patients with low VWF and VWD and 210 healthy controls. VWF sequencing was performed and VWF:Ag levels assayed. A combined annotation-dependent depletion (CADD) score >20 was used as a predicted pathogenicity measure. The number of rare nonsynonymous VWF variants significantly predicted VWF:Ag levels (P = 1.62 × 10−21). There was an association between average number of rare nonsynonymous VWF variants with VWD type 1 (P = 2.4 × 10−13) and low VWF (P = 1.6 × 10−27) compared with healthy subjects: type 1 subjects possessed on average >2 times as many rare variants as those with low VWF and 8 times as many as healthy subjects. The number of rare nonsynonymous variants significantly predicts VWF:Ag levels even after controlling for presence of a variant with a CADD score >20 or a known pathogenic variant in VWF (P = 2.7 × 10−14). The number of rare nonsynonymous variants in VWF as well as the presence of a variant with CADD >20 are both significantly associated with VWF levels. The association with rare nonsynonymous variants holds even when controlling for known pathogenic variants, suggesting that additional variants, in VWF or elsewhere, are associated with VWF:Ag levels. Patients with higher VWF:Ag levels with fewer rare nonsynonymous VWF gene variants could benefit from next-generation sequencing to find the cause of their bleeding.
•The number of rare nonsynonymous VWF variants is significantly associated with VWF:Ag levels, regardless of VWD type.•VWF sequence alone will not reveal the cause of VWD in a majority of patients with higher VWF:Ag levels.
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A tendency to simplify complex systems Montgomery, Robert A.; Moll, Remington J.; Say-Sallaz, Elise ...
Biological conservation,
20/May , Volume:
233
Journal Article
Peer reviewed
Predation is a fundamental force exerting strong selective pressure on prey populations. Predators not only kill prey, triggering lethal effects, but also hunt prey which can induce risk effects. ...Foundational research has documented the importance of risk effects in predator-prey systems of arthropods, fish, birds, and rodents, among others. Risk effects research in carnivore-ungulate systems has expanded in the last 20 years. Presently, the degree to which this research mirrors the complexity of carnivore-ungulate trophic systems has been questioned. We synthesized this literature to quantify the tendency of risk effects research in carnivore-ungulate systems to be multispecies in design. Among the 170 studies that we reviewed, we found that on average just 1.26 (range = 1 to 5) carnivore species and 1.60 (range = 1 to 11) ungulate species were considered per study. Furthermore, 63% (n = 107 of 170) of the studies featured single predator - single prey research designs. These results contrast with the fact that all but one of the 82 carnivore-ungulate systems used this literature had multiple species of carnivores and/or ungulates. Thus, we detected a tendency to simplify complex systems. We relate these observations to the role of simplicity as: i) an underlying value of science (i.e., Occam's razor), ii) a cornerstone of predator-prey theory (e.g., Lotka-Volterra equations), and iii) part of the origins of risk effects research (i.e., experimental systems). Finally, we ground our discussion in the implications of this research for the conservation of carnivores and ungulates in the dynamic 21st century.
•Predators not only kill prey, triggering lethal effects, but also hunt prey which can induce risk effects•The degree to which this research mirrors the complexity of carnivore-ungulate trophic systems has been questioned•We quantified the tendency of risk effects research in carnivore-ungulate systems to be multispecies in design•We found that on average just 1.26 carnivore species and 1.60 ungulate species were considered per study•Thus, we detected a tendency to simplify complex systems in carnivore-ungulate risk effects research
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma ...VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.
In this issue of Blood, O'Regan et al have extended our understanding of von Willebrand factor (VWF) in the pathogenesis of malaria. According to the World Health Organization ...(http://www.who.int/gho/malaria/en/), malaria affects 3.2 billion people in 97 countries with 198 million cases having occurred in 2013, and of those, 584 000 died. Ninety percent of those deaths in 2013 were children under the age of 5. The most devastating form of the disease is cerebral malaria, which occurs most frequently in young children. Although blood coagulation changes such as disseminated intravascular coagulation have been recognized since the 1970s, recent studies have focused on markers of these hemostatic changes as being most prevalent in cerebral malaria caused by Plasmodium falciparum. Cerebral malaria is more lethal in children than adults. Exchange transfusion has been used as an aggressive adjunct therapy for this condition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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