Traumatic bleeding and mortality in mice are intensified by iron deficiency anemia and can be rescued with tranexamic acid.

Background: Clinical evidence suggests that anemia exacerbates traumatic bleeding and worsens outcomes. Objectives: To study the influence of iron deficiency anemia on traumatic bleeding, coagulopathy, and mortality. Methods: C57BL/6J mice received an iron-deficient diet (8 weeks; ±1 mg intraperitoneal iron dextran 2 weeks before trauma). Control mice received a normal diet. Iron deficiency anemia was confirmed by hematocrit, red cell indices, and liver iron. Mice received saline or tranexamic acid (TXA; 10 mg/kg) just before liver laceration. Blood loss, coagulopathy (activated partial thromboplastin time, factor [F]II, FV, FVIII, FX, and fibrinogen), D-dimer, thrombin-antithrombin complexes, and plasmin-alpha-2-antiplasmin complexes were analyzed at 15 and 60 minutes, and a cytokine panel was performed at 60 minutes and 6 hours after trauma. Survival was monitored for 7 days. Results: Compared with nonanemic mice, anemic mice had lower hematocrit and hepatic iron content. Anemic mice experienced higher blood loss compared with nonanemic mice, which was reduced by TXA. Both groups developed traumatic coagulopathy characterized by activated partial thromboplastin time prolongation, thrombin-antithrombin complex formation, and depletion of FV, FVIII, and fibrinogen. TXA corrected the coagulopathy. However, plasmin-alpha-2-antiplasmin complex formation and D-dimers, markers of fibrinolysis, were higher in anemic mice and were not corrected by TXA. Seven-day survival was low in anemic mice, and rescued by TXA, but high in nonanemic mice without additional improvement by TXA. Among cytokines, only interleukin-6 increased, which was prevented by TXA most notably in anemic mice. Conclusion: These observations provide first and critical proof-of-principle evidence that anemia accelerates traumatic bleeding and increases mortality, which could be rescued by anemia correction (parenteral iron) or periprocedural TXA.

Prevalence and characterization of anti-VWF antibodies in a population of subjects with type 3 VWD.

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by quantitative or qualitative defects in the von Willebrand factor protein (VWF). Type 3 VWD has a severe bleeding phenotype caused by the absence of VWF where treatment usually involves replacement therapy with VWF-containing products. The immune system can react to the VWF product and form anti-VWF antibodies to neutralize or clear the VWF which can compromise efficacy of treatment or lead to anaphylaxis. Current diagnostic testing is limited to the detection of anti-VWF antibodies that neutralize VWF binding to platelets by using a ristocetin cofactor assay. We set out to develop assays to identify both neutralizing and non-neutralizing antibodies to screen, quantify, and characterize anti-VWF antibodies in samples from the Zimmerman Program, a large multicenter study of VWD subjects. We detected anti-VWF IgG or IgM antibodies in 18% of 49 unrelated type 3 VWD individuals. The antibodies ranged in concentration and consisted of 33% non-neutralizing and 67% neutralizing to factor VIII, collagen III, platelet GPIbα, and/or collagen IV binding. Of the positive type 3 VWD samples, 8/9 were IgG which were further subclassified into mostly IgG1 and IgG4 antibodies. Through a series of testing methods, we identified VWF specific antibodies in 9 unrelated type 3 VWD individuals with varying demographics, bleeding phenotypes, and genetic variants. This anti-VWF antibody testing strategy provides a useful tool to assess risk and better navigate treatment options for type 3 VWD patients.

von Willebrand disease.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The disorder is characterized by excessive mucocutaneous bleeding. The most common bleeding manifestations of this condition include nosebleeds, bruising, bleeding from minor wounds, menorrhagia or postpartum bleeding in women as well as bleeding after surgery. Other less frequent symptoms include gastrointestinal bleeding, haematomas or haemarthroses. VWD pathophysiology is complex and results from defects in von Willebrand factor (VWF) glycoprotein. Quantitative deficiencies are responsible for type 1 VWD with a partial decrease of VWF and type 3 with the complete absence of VWF. Qualitative abnormalities cause type 2 VWD, being further divided into types 2A, 2B, 2M and 2N. Although common, VWD is at risk of misdiagnosis, overdiagnosis and underdiagnosis owing to several factors, including complex diagnosis, variability of bleeding symptoms, presence of external variables (blood groups and other physiological modifiers such as exercise, thyroid hormones, oestrogens, and ageing), and lack of disease awareness among non-specialist health-care providers. Establishing the correct VWD diagnosis requires an array of specialized phenotypic assays and/or molecular genetic testing of the VWF gene. The management of bleeding includes increasing endogenous VWF levels with desmopressin or infusion of exogenous VWF concentrates (plasma-derived or recombinant). Fibrinolytic inhibitors, topical haemostatic agents and hormonal therapies are used as effective adjunctive measures.

Assessment of rare bleeding disorders in adolescents with heavy menstrual bleeding.

INTRODUCTION: There are a significant number of patients with mucocutaneous bleeding, specifically heavy menstrual bleeding (HMB), who do not have a diagnosed bleeding disorder. These patients receive nontargeted interventions and may have suboptimal treatments. Functional assays, particularly for fibrinolytic and rare platelet function defects, are not robust and not readily available. AIM: We aimed to prospectively evaluate the prevalence of genetic defects associated with rare bleeding disorders and describe alterations of coagulation and fibrinolysis in a cohort of adolescents with HMB. METHODS: We performed a prospective observational cohort study of patients with HMB and unexplained bleeding. The study utilized a next generation sequencing panel and investigational global assays of coagulation and fibrinolysis. Additionally, specific functional assays were performed to help characterize novel variants that were identified. RESULTS: In 10 of the 17 patients (∼59%), genetic variants were identified on molecular testing. Thrombin generation by calibrated thromboelastography was not significantly altered in this patient population. The clot formation and lysis assay showed a trend towards increased fibrinolysis with rapid phase of decline in 23% of the patients. Further corresponding functional assays and study population are described. CONCLUSION: Our study describes a unique correlative model in a homogenous cohort of patients with HMB and unexplained bleeding which may inform future diagnostic algorithms, genotype-phenotype correlations as well as aid in specific targeted treatment approaches. Larger future studies may inform risk stratification of patients and improve health related outcomes in patients with HMB.

The common VWF variant p.Y1584C: detailed pathogenic examination of an enigmatic sequence change.

BACKGROUND: As knowledge of the human genome has advanced, so too has the recognition that interpretation of the pathogenic nature of sequence variants can be challenging. The von Willebrand factor (VWF) gene exhibits a significant degree of sequence variability, and the first VWF variant associated with type 1 von Willebrand disease (VWD), c.4751 A>G, p.Y1584C, was described in 2003. However, since that time, the pathogenic nature of this variant has remained unclear, being assigned properties ranging from a risk factor to a pathogenic variant. OBJECTIVES: To provide additional evaluation on the interpretation of pathogenicity for this common VWF variant. METHODS: Fifty-eight subjects with only the p.Y1584C variant were recruited from 2 cohort studies (the Zimmerman Program and the Canadian type 1 VWD study). Clinical and laboratory phenotypes were assessed. RESULTS: The prevalence of the p.Y1584C variant in our cohorts was 23- to 27-fold higher than that in large normal population databases. Significantly more p.Y1584C subjects had an abnormal bleeding score when compared to Y1584 individuals. In comparison with a group of 35 subjects without the p.Y1584C variant, subjects with the variant had lower mean VWF:antigen and VWF:ristocetin cofactor values and significantly higher VWF propeptide/VWF:antigen ratios suggestive of enhanced clearance. CONCLUSION: Collectively, the results of this analysis suggest that p.Y1584C is likely pathogenic, however, due to influences such as incomplete penetrance, variable expressivity, and other genetic modifiers like ABO blood group, the straightforward assignment of pathogenicity to this variant is inevitably challenging.

Von Willebrand Factor (VWF) multiplex activity assay differentiation of type 1 von Willebrand Disease (VWD) and variant VWD.

INTRODUCTION: VWD diagnosis is challenging requiring multiple VWF activity tests using many individual assays. We have developed an ELISA-based VWF Multiplex Activity Assay (VWF-MAA) to address this concern; however, the ability of the VWF-MAA to discriminate between type 1 VWD, variant VWD, and normal subjects has not been evaluated. AIM: To evaluate the VWF-MAA and its ability to differentiate between type 1 VWD, variant VWD and normal subjects in individuals undergoing an initial laboratory evaluation for bleeding. METHODS: A total of 177 plasma samples from the Zimmerman Program: Comparative Effectiveness in the Diagnosis of VWD were evaluated from 11 centres across the US and Canada. The VWF-MAA was compared to Versiti Blood Research Institute (VBRI) and Local Center (LC) assigned VWD diagnosis. RESULTS: Overall, 129/177 (72.9%) were correctly assigned as normal (non-VWD), type 1, or variant VWD compared to the VBRI assigned diagnosis. VWF-MAA assigned non-VWD accurately in 29/57 (50.9%) samples, and type 1 VWD accurately in 93/110 (84.6%) samples. Considering LC diagnosis where there was agreement with VWF-MAA and not VBRI diagnosis, type 1 VWD was accurate in 105/110 (95.5%) samples. Bland-Altman analysis demonstrated good correlation between laboratory methods. VWD, types 2A, 2B, 1C VWD were also assigned by the VWF-MAA. CONCLUSIONS: We demonstrate that the VWF-MAA has utility in differentiating type 1 VWD, variant VWD and normal subjects in individuals undergoing an initial laboratory evaluation for bleeding.

Characterization of copy-number variants in a large cohort of patients with von Willebrand disease reveals a relationship between disrupted regions and disease type.

Background: Genetic analysis for von Willebrand disease (VWD) commonly utilizes DNA sequencing to identify variants in the von Willebrand factor (VWF) gene; however, this technique cannot always detect copy-number variants (CNVs). Additional mapping of CNVs in patients with VWD is needed. Objectives: This study aimed to characterize CNVs in a large sample of VWF mutation-negative VWD patients. Methods: To determine the role of CNVs in VWD, a VWF high-resolution comparative genomic hybridization array was custom-designed to avoid multiple sequence variations, repeated sequences, and the VWF pseudogene. This was performed on 204 mutation-negative subjects for whom clinical variables were also available. Results: Among the 204 patients, 7 unique CNVs were found, with a total of 24 CNVs (12%). Of the 7 unique CNVs, 1 was novel, 1 was found in a VWF database, and 5 were previously reported. All patients with type 1C VWD and a CNV had the same exon 33 and 34 in-frame deletion. Certain clinical variables were also significantly different between those with and without CNVs. Conclusion: The in-frame deletion in patients with type 1C VWD exactly matches the D4N module of the D4 domain, a region where mutations and deletions are known to affect clearance. We observed significantly higher VWF-to-ristocetin cofactor levels in patients with type 1C VWD and a CNV than in patients without a CNV, suggesting a relationship between CNVs and the increased clearance observed in patients with type 1C VWD. Glycoprotein IbM activity was significantly lower in patients with type 1 VWD and a CNV than in patients without a CNV, suggesting that platelet binding is more affected by CNVs than single base pair mutations. This work elucidates some of the underlying genetic mechanisms of CNVs in these patients.

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for mucocutaneous bleeding disorders.

BACKGROUND: Excessive or abnormal mucocutaneous bleeding (MCB) may impact all aspects of the physical and psychosocial wellbeing of those who live with it (PWMCB). The evidence base for the optimal diagnosis and management of disorders such as inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD), Ehlers-Danlos syndromes (EDS), and von Willebrand disease (VWD) remains thin with enormous potential for targeted research. RESEARCH DESIGN AND METHODS: National Hemophilia Foundation and American Thrombosis and Hemostasis Network initiated the development of a National Research Blueprint for Inherited Bleeding Disorders with extensive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. They recruited multidisciplinary expert working groups (WG) to distill community-identified priorities into concrete research questions and score their feasibility, impact, and risk. RESULTS: WG2 detailed 38 high priority research questions concerning the biology of MCB, VWD, inherited qualitative platelet function defects, HDS/EDS, HHT, bleeding disorder of unknown cause, novel therapeutics, and aging. CONCLUSIONS: Improving our understanding of the basic biology of MCB, large cohort longitudinal natural history studies, collaboration, and creative approaches to novel therapeutics will be important in maximizing the benefit of future research for the entire MCB community.

More people experience mucocutaneous bleeding (MCB), affecting tissues like skin and gums, than have hemophilia A or B. MCB is not understood as well as hemophilia. Common types of MCB include nosebleeds, bleeding gums, heavy menstrual bleeding, and digestive tract bleeding. Mucocutaneous inherited bleeding disorders include inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS), von Willebrand Disease (VWD), and others. Diagnosing and treating MCB is complicated and sometimes medical providers dismiss the bleeding that patients report when they cannot find a medical explanation for it. Many people with mucocutaneous bleeding (PWMCB) do not receive the care they need; for example, women with VWD live with symptoms for, on average, 16 years before they are diagnosed in the US. This struggle to obtain care has important negative impacts on patients' physical and psychological health and their quality-of-life. The National Hemophilia Foundation (NHF), a large US bleeding disorders patient advocacy organization, set out to develop a National Research Blueprint for Inherited Bleeding Disorders focused on community priorities. They brought together a group of patients, providers, and researchers with MCB expertise to identify the research that would most improve the lives of PWMCB through targeted and accessible diagnostics and therapies. We report in this paper that research is needed to better understand the biology of MCB and to define the mechanisms of disease in these disorders. We also describe high priority research questions for each of the main disorders, novel therapeutics, and aging.

Beyond the guidelines: how we approach challenging scenarios in the diagnosis and management of von Willebrand disease.

Although von Willebrand disease (VWD) is the most common inherited bleeding disorder, its diagnosis and management are often challenging. Clinical practice guidelines, developed through systematic review of the medical literature and considering the best available evidence, provide guidance for common clinical scenarios. However, in the clinical setting, patients often present with characteristics and nuances that may fall outside the realm of available evidence and guidelines, and hence, shared decision-making will be essential in the evaluation and management of these patients. The challenges in the diagnosis of VWD are mainly attributable to the heterogeneity of the disorder, limitations of laboratory assays, and the significant impact of various physiologic processes on von Willebrand factor. The impact of physiologic normalization of von Willebrand factor, which may occur in various settings such as pregnancy, inflammation, or aging, remains uncertain, as is the optimal management in these scenarios. Multidisciplinary and individualized care, based on evolving evidence supported by clinicians, patients, caregivers, and stakeholders, will be needed to ensure the highest quality care for those who live with VWD.

Ristocetin dependent cofactor activity in von Willebrand disease diagnosis: Limitations of relying on a single measure.

Background: Von Willebrand disease (VWD) is a common inherited bleeding disorder, however the diagnosis can be complicated by a subjective bleeding history and issues with some current von Willebrand factor (VWF) laboratory assays. Objectives: In the Zimmerman Program, we sought to determine how often a type 1 diagnosis was based on a single low VWF ristocetin cofactor (VWF:RCo) level resulting from the common genetic variant p.D1472H or an isolated assay issue, if that low value was corroborated by the VWF glycoprotein-IbM (VWF:GPIbM) assay, and if retesting confirmed original levels. Methods: New patients being evaluated for bleeding were consented. Analysis included VWF sequencing, bleeding scores, and comparisons of local VWF antigen (VWF:Ag) and VWF:RCo to central VWF:Ag and VWF:GPIbM. Results: A total of 18% of VWD subjects had a low local VWF:RCo, but normal VWF:Ag and normal central testing including VWF:GPIbM. Seventy percent of the low VWF:RCo cohort had no pathogenic VWF variants; however, 33% carried p.D1472H. Low VWF:RCo subjects with follow-up local testing within 2 years showed those with p.D1472H continued to have low VWF:RCo and VWF:RCo/VWF:Ag ratio with normal VWF:GPIbM. Subjects without p.D1472H had an increase mean VWF:RCo, resulting in 59% with normal levels on repeat testing. Conclusions: The diagnosis of VWD based on a single low VWF:RCo but normal VWF:Ag, was often attributed to p.D1472H or variability in VWF:RCo that was eliminated with VWF:GPIbM. Our study suggests that using VWF:RCo alone for diagnostic purposes may be insufficient while repeat VWF:RCo or VWF:GPIbM testing can be valuable in establishing a VWD diagnosis.

Longitudinal bleeding assessment in von Willebrand disease utilizing an interim bleeding score.

BACKGROUND: Assessment of bleeding phenotype is critically important in the diagnosis of von Willebrand disease (VWD). Despite advances in bleeding assessment tools (BATs), standardized tools to evaluate bleeding following diagnosis (interim bleeding) are lacking. OBJECTIVES: We assessed the clinical utility of an interim bleeding protocol in a multicenter, international study involving patients with VWD. METHODS: The enrolment ISTH BAT formed the original bleeding score (0 BS). At follow-up, the International Society on Thrombosis and Haemostasis BAT was repeated but included only interval bleeding (Interim BS, 1 BS). Both scores were annualized (0 BS/yr, 1 BS/yr). BS were analyzed by VWD subtype, plasma VWF level, sex, and age. RESULTS: Interim BS discriminated by subtype, with significantly increased 0 BS and 1 BS in patients with type 3 VWD. In patients with type 1 VWD, a positive or negative 0 BS did not predict future bleeding, with similar 1 BS/yr (median 1.0 vs. 0.7, p = .2). Despite significantly higher 0 BS in females with type 1 VWD than males (median 7 vs. 5, p = .0012), 1 BS were not significantly different (median 4 vs. 4, p = .16). While 0 BS were lower in children than adults with type 1 VWD, interim BS were similar (median 5 vs. 3, p = .5; 1BS/yr, median 1 vs. 0.8, p = .7). Interestingly, in those with plasma von Willebrand factor:ristocetin cofactor levels >50 IU/dl, interim BS rates were similar to those 30-50 IU/dl (1 BS/yr 0.8 vs. 1.3, p = .5). CONCLUSION: This study provides both a new approach to longitudinal bleeding assessment and insights into the evolution of bleeding in VWD.

Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program.

BACKGROUND: Type 3 von Willebrand Disease (VWD) is a rare and severe form of VWD characterized by the absence of von Willebrand factor (VWF). OBJECTIVES: As part of the Zimmerman Program, we sought to explore the molecular pathogenesis, correlate bleeding phenotype and severity, and determine the inheritance pattern found in type 3 VWD families. PATIENTS/METHODS: 62 index cases with a pre-existing diagnosis of type 3 VWD were analyzed. Central testing included FVIII, VWF:Ag, VWF:RCo, and VWFpp. Bleeding symptoms were quantified using the ISTH bleeding score. Genetic analysis included VWF sequencing, comparative genomic hybridization and predictive computational programs. RESULTS: 75% of subjects (46) had central testing confirming type 3, while 25% were re-classified as type 1-Severe or type 1C. Candidate VWF variants were found in all subjects with 93% of expected alleles identified. The majority were null alleles including frameshift, nonsense, splice site, and large deletions, while 13% were missense variants. Additional studies on 119 family members, including 69 obligate carriers, revealed a wide range of heterogeneity in VWF levels and bleeding scores, even amongst those with the same variant. Co-dominant inheritance was present in 51% of families and recessive in 21%, however 28% were ambiguous. CONCLUSION: This report represents a large cohort of VWD families in the U.S. with extensive phenotypic and genotypic data. While co-dominant inheritance was seen in approximately 50% of families, this study highlights the complexity of VWF genetics due to the heterogeneity found in both VWF levels and bleeding tendencies amongst families with type 3 VWD.

Outcomes of long-term von Willebrand factor prophylaxis use in von Willebrand disease: A systematic literature review.

BACKGROUND: Von Willebrand Disease (VWD) is a common inherited bleeding disorder. Patients with VWD suffering from severe bleeding may benefit from the use of secondary long-term prophylaxis. AIM: Systematically summarize the evidence on the clinical outcomes of secondary long-term prophylaxis in patients with VWD and severe recurrent bleedings. METHODS: We searched Medline and EMBASE through October 2019 for relevant randomized clinical trials (RCTs) and comparative observational studies (OS) assessing the effects of secondary long-term prophylaxis in patients with VWD. We used Cochrane Risk of Bias (RoB) tool and the RoB for Non-Randomized Studies of interventions (ROBINS-I) tool to assess the quality of the included studies. We conducted random-effects meta-analyses and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: We included 12 studies. Evidence from one placebo controlled RCT suggested that VWD prophylaxis as compared to no prophylaxis reduced the rate of bleeding episodes (Rate ratio [RR], .24; 95% confidence interval [CI], .17-.35; low certainty evidence), and of epistaxis (RR, .38; 95%CI, .21-.67; moderate certainty evidence), and may increase serious adverse events RR 2.73 (95%CI .12-59.57; low certainty). Evidence from four before-and-after studies in which researchers reported comparative data suggested that VWD prophylaxis reduced the rate of bleeding (RR .34; 95%CI, .25-.46; very low certainty evidence). CONCLUSION: VWD prophylaxis treatment seems to reduce the risk of spontaneous bleeding, epistaxis, and hospitalizations. More RCTs should be conducted to increase the certainty in these benefits.

Laboratory assays of VWF activity and use of desmopressin trials in the diagnosis of VWD: a systematic review and meta-analysis.

von Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of any von Willebrand factor (VWF) activity assay in the diagnosis and classification of patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and the certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity. The review included 77 studies that evaluated the use of newer tests of VWF platelet binding activity (VWF:GPIbR, VWF:GPIbM) and VWF:RCo for the diagnosis of VWD (13 studies), VWF propeptide to VWF:Ag ratio, and desmopressin trial for the diagnosis of type 1C VWD (5 studies), VWF multimer analysis and VWF:CB/VWF:Ag ratio for the classification of type 2 VWD (11 studies), genetic testing and ristocetin-induced platelet aggregation to diagnose type 2B VWD (14 studies), genetic testing and FVIII:VWF binding to diagnose type 2N VWD (17 studies). Based on available diagnostic test accuracy, there appear to be comparable test accuracy results between newer tests of platelet binding activity of VWF function and VWF:RCo. The findings of these reviews support VWF multimer analysis or VWF:CB/VWF:Ag to diagnose type 2 VWD. The desmopressin trial test with 1- and 4-hour postinfusion blood work is the test of choice to confirm increased VWF clearance in patients with suspected VWD type 1C. Additionally, genetic testing is most useful in diagnosing type 2B VWD and has a role in the diagnostic algorithm of suspected type 2N VWD.

von Willebrand factor levels in the diagnosis of von Willebrand disease: a systematic review and meta-analysis.

von Willebrand disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cutoff values of von Willebrand factor antigen (VWF:Ag) and platelet-dependent von Willebrand factor (VWF) activity assays in the diagnosis of VWD. We searched Cochrane Central Register for Controlled Trials, MEDLINE, and Embase databases for eligible studies. We pooled estimates of sensitivity and specificity and reported patient-important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis. The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD vs removing the disease diagnosis in patients with VWF levels that have normalized with age. For the diagnosis of type 1 VWD, VWF sequence variants were detected in 75% to 82% of patients with VWF:Ag < 0.30 IU/mL and in 44% to 60% of patients with VWF:Ag between 0.30 and 0.50 IU/mL. A sensitivity of 0.90 (95% confidence interval [CI], 0.83-0.94) and a specificity of 0.91 (95% CI, 0.76-0.97) were observed for a platelet-dependent VWF activity/VWF:Ag ratio < 0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF:Ag and platelet-dependent activity are continuous variables that are associated with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio < 0.7 vs lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD.

Surgical management of patients with von Willebrand disease: summary of 2 systematic reviews of the literature.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD who are undergoing surgeries is crucial to prevent bleeding complications. We systematically summarized the evidence on the management of patients with VWD who are undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE from inception through October 2019 for randomized clinical trials (RCTs), comparative observational studies, and case series that compared maintaining factor VIII (FVIII) levels or von Willebrand factor (VWF) levels at >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and those with options for perioperative management of patients undergoing minor surgery. Two authors screened and abstracted data and assessed the risk of bias. We conducted meta-analyses when possible. We evaluated the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We included 7 case series for major surgeries and 2 RCTs and 12 case series for minor surgeries. Very-low-certainty evidence showed that maintaining FVIII levels or VWF levels of >0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74% to 100% of major surgeries. Low- to very-low-certainty evidence showed that prescribing tranexamic acid and increasing VWF levels to 0.50 IU/mL resulted in fewer bleeding complications after minor procedures compared with increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence for guiding management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD who are undergoing surgical and invasive procedures.

Gynecologic and obstetric management of women with von Willebrand disease: summary of 3 systematic reviews of the literature.

von Willebrand disease (VWD) disproportionately affects women because of the potential for heavy menstrual bleeding (HMB), delivery complications, and postpartum hemorrhage (PPH). To systematically synthesize the evidence regarding first-line management of HMB, treatment of women requiring or desiring neuraxial analgesia, and management of PPH. We searched Medline and EMBASE through October 2019 for randomized trials, comparative observational studies, and case series comparing the effects of desmopressin, hormonal therapy, and tranexamic acid (TxA) on HMB; comparing different von Willebrand factor (VWF) levels in women with VWD who were undergoing labor and receiving neuraxial anesthesia; and measuring the effects of TxA on PPH. We conducted duplicate study selection, data abstraction, and appraisal of risk of bias. Whenever possible, we conducted meta-analyses. We assessed the quality of the evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We included 1 randomized trial, 3 comparative observational studies, and 10 case series. Moderate-certainty evidence showed that desmopressin resulted in a smaller reduction of menstrual blood loss (difference in mean change from baseline, 41.6 [95% confidence interval, 16.6-63.6] points in a pictorial blood assessment chart score) as compared with TxA. There was very-low-certainty evidence about how first-line treatments compare against each other, the effects of different VWF levels in women receiving neuraxial anesthesia, and the effects of postpartum administration of TxA. Most of the evidence relevant to the gynecologic and obstetric management of women with VWD addressed by most guidelines is very low quality. Future studies that address research priorities will be key when updating such guidelines.