Publications by authors named "Paula D James"

55 Publications

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

Blood Adv 2021 Oct 21. Epub 2021 Oct 21.

McMaster University, Canada.

Von Willebrand disease, (VWD) disproportionately affects women due to potential issues with 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/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 undergoing labor and receiving neuraxial anesthesia and 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 approach. We included 1 randomized trial, 3 comparative observational studies and 10 case series. Moderate certainty evidence showed that desmopressin results in a smaller reduction of menstrual blood loss (difference in mean change from baseline, 41.6 [95% CI, 16.6 to 63.6] points in pictorial blood assessment chart score as compared to 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 TXA administration postpartum. 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 addressing research priorities will be key when updating such guidelines.
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http://dx.doi.org/10.1182/bloodadvances.2021005589DOI Listing
October 2021

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

Blood Adv 2021 Oct 15. Epub 2021 Oct 15.

Department of Health Research Methods, Evidence and Impact, McMaster University, Canada.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD undergoing surgeries is crucial to prevent bleeding complications. To systematically summarize the evidence on the management of patients with VWD undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE through October 2019 for randomized clinical trials (RCTs), comparative observational studies and case series comparing maintaining factor VIII levels or VWF levels >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and options for perioperative management of patients undergoing minor surgery. Two authors screened, abstracted data, and assessed the risk of bias. We conducted meta-analysis when possible. We evaluated the certainty of the evidence using the 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 factor VIII levels, or VWF levels > 0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74-100% 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 less bleeding complications after minor procedures compared to increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence to guide management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD undergoing surgical and invasive procedures.
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http://dx.doi.org/10.1182/bloodadvances.2021005666DOI Listing
October 2021

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.

BMJ 2021 10 14;375:n2400. Epub 2021 Oct 14.

St Michael's Hospital, University of Toronto, Toronto, ON, Canada.

Objective: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards.

Design: Randomised controlled, adaptive, open label clinical trial.

Setting: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US.

Participants: 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237).

Interventions: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death.

Main Outcome Measures: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated.

Results: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69).

Conclusions: In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial.

Trial Registration: ClinicalTrials.gov NCT04362085.
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http://dx.doi.org/10.1136/bmj.n2400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515466PMC
October 2021

Commentary: surviving sexism in bleeding disorders affecting women.

Br J Haematol 2021 Oct 7. Epub 2021 Oct 7.

Department of Medicine, Queen's University, Kingston, ON, Canada.

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http://dx.doi.org/10.1111/bjh.17881DOI Listing
October 2021

Von Willebrand Factor Levels in The Diagnosis of Von Willebrand Disease: A Systematic Review and Meta-Analysis.

Blood Adv 2021 Oct 5. Epub 2021 Oct 5.

University of Kansas Medical Center, Kansas City, Kansas, United States.

Von Willebrand Disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding symptoms. Patients with VWD can experience easy bruising, epistaxis, gastrointestinal and oral cavity bleeding, as well as heavy menstrual bleeding and bleeding after dental work, surgical procedures, and childbirth. Early diagnosis and treatment is important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cut-off values of VWF:Ag and platelet-dependent VWF activity assays in the diagnosis of VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. Two investigators screened and abstracted data. Risk of bias was assessed using QUADAS-2 and certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity and reported patient important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis, including the approach to patients with VWF levels that have normalized with age (6 studies), VWF cut-off levels for the diagnosis of Type 1 VWD (9 studies), and platelet-dependent VWF activity/VWF:Ag ratio cut-off levels for the diagnosis of Type 2 VWD (6 studies). The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD versus simply removing the disease in patients with VWF levels that have normalized with age. For the diagnosis of Type 1 VWD, in patients with VWF:Ag <0.30 IU/mL, VWF sequence variants were detected in 75-82% of patients in 2 studies, and for VWF:Ag between 0.30-0.50 IU/mL, VWF sequence variants were detected in 44-60% of patients in 3 studies. A sensitivity of 0.90 (95% CI: 0.83 to 0.94), and a specificity of 0.91 (95% CI: 0.76 to 0.97) were observed for a platelet-dependent VWF activity /VWF:Ag ratio of <0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF antigen and platelet-dependent activity are continuous variables with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio of <0.7 versus lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD.
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http://dx.doi.org/10.1182/bloodadvances.2021005430DOI Listing
October 2021

Bleeding assessment tools in the diagnosis of VWD in adults and children: a systematic review and meta-analysis of test accuracy.

Blood Adv 2021 Dec;5(23):5023-5031

Department of Internal Medicine.

Von Willebrand disease (VWD) can be associated with significant morbidity. Patients with VWD can experience bruising, mucocutaneous bleeding, and bleeding after dental and surgical procedures. Early diagnosis and treatment are important to minimize the risk of these complications. Several bleeding assessment tools (BATs) have been used to quantify bleeding symptoms as a screening tool for VWD. We systematically reviewed diagnostic test accuracy results of BATs to screen patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Risk of bias was assessed using the revised tool for the quality assessment of diagnostic accuracy studies and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 7 cohort studies that evaluated the use of BATs to screen adult and pediatric patients for VWD. The pooled estimates for sensitivity and specificity were 75% (95% confidence interval, 66-83) and 54% (29-77), respectively. Certainty of evidence varied from moderate to high. This systematic review provides accuracy estimates for validated BATs as a screening modality for VWD. A BAT is a useful initial screening test to determine who needs specific blood testing. The pretest probability of VWD (often determined by the clinical setting/patient population), along with sensitivity and specificity estimates, will influence patient management.
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http://dx.doi.org/10.1182/bloodadvances.2021004368DOI Listing
December 2021

Approach to the Patient with Bleeding.

Hematol Oncol Clin North Am 2021 Dec 15;35(6):1039-1049. Epub 2021 Sep 15.

Department of Medicine, Queen's University, Room 2015, Etherington Hall, 94 Stuart Street, Kingston, Ontario K7L 3N6, Canada. Electronic address:

Approach to the patient with bleeding begins with a thorough bleeding, medical, and family history to determine the nature of bleeding and severity of bleeding symptoms. Use of a Bleeding Assessment Tool allows the clinician to obtain a comprehensive bleeding history and ultimately determine the individual bleeding score that reflects bleeding severity and is classifiable as either normal or abnormal. In the absence of significant findings within patient history or presenting symptoms clearly pointing to a specific bleeding pathology, an approach to laboratory investigation is presented that proceeds through first-line, second-line, and third-line testing.
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http://dx.doi.org/10.1016/j.hoc.2021.07.001DOI Listing
December 2021

Heparin for Moderately Ill Patients with Covid-19.

medRxiv 2021 Jul 12. Epub 2021 Jul 12.

Background: Heparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death.

Methods: We randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat.

Results: At 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85).

Conclusions: In moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days. Trial registration numbers: NCT04362085 ; NCT04444700.
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http://dx.doi.org/10.1101/2021.07.08.21259351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282099PMC
July 2021

Vascular abnormalities in patients with von Willebrand disease: A scoping review.

J Thromb Haemost 2021 09 9;19(9):2151-2160. Epub 2021 Jul 9.

Department of Medicine, Queen's University, Kingston, ON, Canada.

Background: Qualitative or quantitative defects of von Willebrand factor (VWF) such as in von Willebrand disease (VWD) are associated with vascular abnormalities, especially in the gastrointestinal (GI) tract. However, the locations, extent, and natural history of vascular abnormalities in patients with VWD is not well understood. To summarize the existing literature on the topic, we conducted a scoping review of vascular abnormalities in patients with VWD.

Methods: We searched MEDLINE and EMBASE from inception to September 1, 2020, for studies clinically describing vascular abnormalities in VWD patients. Screening and data extraction was completed independently and in duplicate and each abnormality was documented individually.

Results: After screening, 54 studies that reported patient level data comprising 146 patients were included. Type 2A (39%) and type 3 (14.4%) were the most common VWD subtypes. The most common site of vascular malformation was the GI tract, occurring in 124 patients (84.9%), whereas 18 (12.3%) had non-GI vascular abnormalities and 4 (2.7%) had both GI and non-GI vascular abnormalities. With respect to outcomes, the clinical course was not specified in the majority (55.5%) of patients. Survey and population level data were reported in nine studies, demonstrating vascular abnormalities occurred at higher rates in VWD and that VWD patients are overrepresented among those with those abnormalities.

Conclusion: Vascular malformations in patients with VWD occur primarily in the gastrointestinal tract. Type 2A and type 3 VWD are the most common subtypes affected. The clinical treatment and natural history of these abnormalities remains understudied and further research is needed.
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http://dx.doi.org/10.1111/jth.15410DOI Listing
September 2021

ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease.

Blood Adv 2021 01;5(1):280-300

Outcomes and Implementation Research Unit, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.

Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges.

Objective: 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.

Methods: 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.

Results: The panel agreed on 11 recommendations.

Conclusions: 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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http://dx.doi.org/10.1182/bloodadvances.2020003265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805340PMC
January 2021

ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease.

Blood Adv 2021 01;5(1):301-325

Outcomes and Implementation Research Unit, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients.

Objective: These evidence-based guidelines from 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 health care professionals in their decisions about management of VWD.

Methods: ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.

Results: The panel agreed on 12 recommendations and outlined future research priorities.

Conclusions: These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting.
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http://dx.doi.org/10.1182/bloodadvances.2020003264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805326PMC
January 2021

Sexism in the management of bleeding disorders.

Res Pract Thromb Haemost 2021 Jan 13;5(1):51-54. Epub 2020 Dec 13.

Department of Medicine Queen's University Kingston ON Canada.

Sexism has been an issue in bleeding disorders for centuries. Women with bleeding disorders have been underrecognized and underdiagnosed. Those who are diagnosed often experience delays in diagnosis and feel that their symptoms are dismissed or minimized. Several factors contribute to this sexism. Historically, the clinical and research focus within the bleeding disorder community has been on men and hemophilia. Von Willebrand disease, a disease that has long been recognized as affecting women, is much more common than hemophilia, yet has significantly fewer resources devoted to it. The lack of knowledge and comfort that patients and health care providers have regarding menstruation compounds the issue, as heavy menstrual bleeding is one of the most common symptoms seen in women with bleeding disorders. Stemming from the universal stigmatization of periods, this lack of comfort and knowledge results in fewer women seeking care, fewer health care providers addressing the issue, and fewer women getting the care they deserve. Progress has been made, with many organizations dedicating resources to improving the care of these women. The road is long, and much more work is needed to ensure that women with bleeding disorders receive the care they deserve.
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http://dx.doi.org/10.1002/rth2.12468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845070PMC
January 2021

Management of elective procedures in low von Willebrand factor patients in the LoVIC study.

J Thromb Haemost 2021 03 24;19(3):701-710. Epub 2021 Jan 24.

National Coagulation Centre, St James's Hospital, Dublin, Ireland.

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.
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http://dx.doi.org/10.1111/jth.15220DOI Listing
March 2021

Women and bleeding disorders: diagnostic challenges.

Authors:
Paula D James

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):547-552

Queen's University, Kingston, ON, Canada.

Women with bleeding disorders suffer from multiple bleeding symptoms, including easy bruising, epistaxis, bleeding from minor wounds and the oral cavity, and bleeding after dental work or surgery. However, women with bleeding disorders especially suffer from gynecologic and obstetrical bleeding. These symptoms often are not recognized as abnormal, and many women are left undiagnosed and without access to appropriate medical care. Additional challenges to diagnosing women with bleeding disorders include lack of access to appropriate laboratory testing and issues around disease classification and nomenclature. Efforts have been undertaken to address these challenges, including the development and validation of bleeding assessment tools and strategies to clarify diagnostic thresholds and algorithms for von Willebrand disease (VWD) and platelet function disorders. Efforts to improve communication with the nomenclature used for hemophilia carriers are also underway.
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http://dx.doi.org/10.1182/hematology.2020000140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727580PMC
December 2020

Endothelial Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling.

Arterioscler Thromb Vasc Biol 2020 11 1;40(11):2605-2618. Epub 2020 Oct 1.

Department of Surgery (M.L.O.), Queen's University, Kingston, Canada.

Objective: Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in -the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact of loss on the antiproliferative actions of BMP9 has yet to be assessed. Approach and Results: BMP9 suppressed proliferation in blood outgrowth endothelial cells from healthy control subjects but increased proliferation in blood outgrowth endothelial cells from pulmonary arterial hypertension patients with mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediated silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditional knockout mice (). BMP9-induced proliferation was not attributable to altered metabolic activity or elevated TGFβ (transforming growth factor beta) signaling but was linked to the prolonged induction of the canonical BMP target in the context of loss. In vivo, daily BMP9 administration to neonatal mice impaired both retinal and lung vascular patterning in control mice () but had no measurable effect on mice bearing a heterozygous endothelial deletion () and caused excessive angiogenesis in both vascular beds for mice.

Conclusions: loss reverses the endothelial response to BMP9, causing enhanced proliferation. This finding has potential implications for the proposed translation of BMP9 as a treatment for pulmonary arterial hypertension and suggests the need for focused patient selection in clinical trials.
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http://dx.doi.org/10.1161/ATVBAHA.119.313357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571847PMC
November 2020

Illustrated State-of-the-Art Capsules of the ISTH 2020 Congress.

Res Pract Thromb Haemost 2020 Jul 12;4(5):680-713. Epub 2020 Jul 12.

Department of Cell and Developmental Biology Perelman School of Medicine University of Pennsylvania Philadelphia PA USA.

The 2020 Congress of the International Society of Thrombosis and Haemostasis (ISTH) was held virtually July 12-15, 2019, due to the coronavirus disease 2019 pandemic. The congress convenes annually to discuss clinical and basic topics in hemostasis and thrombosis. Each year, the program includes State of Art (SOA) lectures given by prominent scientists. Presenters are asked to create Illustrated Capsules of their talks, which are concise illustrations with minimal explanatory text. Capsules cover major themes of the presentation, and these undergo formal peer review for inclusion in this article. Owing to the shift to a virtual congress this year, organizers reduced the program size. There were 39 SOA lectures virtually presented, and 29 capsules (9 from talks omitted from the virtual congress) were both submitted and successful in peer review, and are included in this article. Topics include the roles of the hemostatic system in inflammation, infection, immunity, and cancer, platelet function and signaling, platelet function disorders, megakaryocyte biology, hemophilia including gene therapy, phenotype tests in hemostasis, von Willebrand factor, anticoagulant factor V, computational driven discovery, endothelium, clinical and basic aspects of thrombotic microangiopathies, fibrinolysis and thrombolysis, antithrombotics in pediatrics, direct oral anticoagulant management, and thrombosis and hemostasis in pregnancy. Capsule authors invite virtual congress attendees to refer to these capsules during the live presentations and participate on Twitter in discussion. will release 2 tweets from @RPTHJournal during each presentation, using #IllustratedReview, #CoagCapsule and #ISTH2020. Readers are also welcome to utilize capsules for teaching and ongoing education.
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http://dx.doi.org/10.1002/rth2.12368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354406PMC
July 2020

A Population-Based Cohort Study of Venous Thromboembolism Rates Following Surgery and During Adjuvant Chemotherapy in Patients With Colon Cancer.

Dis Colon Rectum 2020 03;63(3):336-345

Cancer Care and Epidemiology, Cancer Research Institute, Queen's University, Kingston, Canada.

Background: There is an elevated risk of venous thromboembolism in patients treated for colon cancer. Postoperative venous thromboembolism has been studied previously, but no large study has compared the risks during different stages of treatment.

Objective: This study aimed to quantify and compare the risks of venous thromboembolism before surgery, after surgery, during adjuvant chemotherapy, and up to 365 days after surgery among patients with resected colon cancer.

Design: This is a population-based retrospective cohort study.

Setting: This study was conducted in a single-payer, universal health care setting (Ontario) between 2002 and 2008.

Patients: A total of 6806 patients with stage I to III colon cancer treated with surgical resection were included.

Interventions: Phases of treatment were evaluated, including preoperative, in-hospital, postoperative, during adjuvant chemotherapy, and 365 days postoperatively.

Main Outcome Measures: Venous thromboembolism, as defined using diagnostic codes from administrative data sources, was the primary outcome measured.

Results: Of the 6806 patients included, 327 (5%) developed venous thromboembolism. Patients receiving adjuvant chemotherapy had a higher risk versus surgery-alone patients (6% vs 4%, p < 0.001). Of the 327 who developed venous thromboembolism, 32% (1.6% overall) were diagnosed during hospital admission and 13.5% (0.6% overall) were diagnosed between discharge and 30 days after surgery. The majority of venous thromboembolisms diagnosed in patients receiving adjuvant chemotherapy (53%, 3.1% of all patients receiving adjuvant chemotherapy) were diagnosed within 180 days of starting adjuvant chemotherapy. Venous thromboembolism was an independent risk factor for worse 5-year overall survival (HR, 1.65; 95% CI, 1.43-1.91; p < 0.001).

Limitations: This study was limited by the potential for misclassification of venous thromboembolism and unknown compliance with prophylaxis recommendations.

Conclusion: Patients who undergo treatment for stage I to III colon cancer are at considerable risk of developing venous thromboembolism. The risk is elevated in those who require adjuvant chemotherapy, and venous thromboembolism is associated with worse long-term outcomes. There may be a role of venous thromboembolism prophylaxis during all phases of treatment, including both after surgery and during adjuvant chemotherapy. See Video Abstract at http://links.lww.com/DCR/B123. UN ESTUDIO DE COHORTE POBLACIONAL DE LAS TASAS DE TROMBOEMBOLISMO VENOSO DESPUÉS DE CIRUGÍA Y DURANTE QUIMIOTERAPIA ADYUVANTE EN PACIENTES CON CÁNCER DE COLON: Existe un riesgo elevado de tromboembolismo venoso en pacientes tratados por cáncer de colon. El tromboembolismo venoso postoperatorio se ha estudiado previamente, pero ningún estudio grande ha comparado los riesgos durante las diferentes etapas del tratamiento.Cuantificar y comparar los riesgos de tromboembolismo venoso antes de la cirugía, después de la cirugía, durante quimioterapia adyuvante y hasta 365 días después de cirugía en pacientes con cáncer de colon resecado.Estudio retrospectivo de cohorte poblacional.Escenario de atención médica universal con pagador único (Ontario) entre 2002-2008.6,806 pacientes con cáncer de colon en estadio I-III tratados con resección quirúrgica.Fase de tratamiento, incluyendo preoperatorio, hospitalización, postoperatorio, durante quimioterapia adyuvante y 365 días después de la operación.Tromboembolismo venoso, tal como se define utilizando códigos de diagnóstico de fuentes de datos administrativos.Se incluyeron 6,806 pacientes, con 327 (5%) que desarrollaron tromboembolismo venoso. Los pacientes que recibieron quimioterapia adyuvante tuvieron un mayor riesgo en comparación con los pacientes con cirugía solamente (6% vs 4%, p <0.001). De los 327 que desarrollaron tromboembolismo venoso, 32% (1.6% en general) fueron diagnosticados durante el ingreso hospitalario y 13.5% (0.6% en general) fueron diagnosticados entre el alta y 30 días después de la cirugía. La mayoría de los tromboembolismos venosos diagnosticados en pacientes que recibieron quimioterapia adyuvante (53%, 3.1% de todos los pacientes con quimioterapia adyuvante) fueron diagnosticados dentro de los 180 días de comenzar la quimioterapia adyuvante. El tromboembolismo venoso fue un factor de riesgo independiente para una peor supervivencia general a 5 años (Hazard Ratio (cociente de riesgo) 1.65, IC 95% 1.43-1.91, p <0.001).Potencial de clasificación errónea del tromboembolismo venoso, cumplimiento desconocido de las recomendaciones de profilaxis.Los pacientes que se someten a tratamiento para el cáncer de colon en estadio I-III tienen un riesgo considerable de desarrollar tromboembolismo venoso. El riesgo es elevado en aquellos que requieren quimioterapia adyuvante y el tromboembolismo venoso se asocia con peores resultados a largo plazo. La profilaxis del tromboembolismo venoso puede desempeñar un papel durante todas las fases del tratamiento, incluyendo tanto el periodo posquirúrgico como durante la quimioterapia adyuvante. Consulte Video Resumen en http://links.lww.com/DCR/B123.
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March 2020

Bleeding assessment tools to predict von Willebrand disease: Utility of individual bleeding symptoms.

Res Pract Thromb Haemost 2020 Jan 30;4(1):92-99. Epub 2019 Oct 30.

Department of Medicine Queen's University Kingston ON Canada.

Background: Bleeding assessment is part of the diagnostic workup of von Willebrand disease (VWD). Bleeding assessment tools (BATs) have standardized obtaining this information but have been criticized because they are time consuming.

Objective: To use our legacy data to determine which questions from BATs are the strongest predictors of a VWD diagnosis.

Patients/methods: Bleeding score data from 3 different BATs were used. Patients aged <12 years were excluded. Questions on BATs relate to different bleeding symptoms, and each symptom is scored by severity. Scores for each symptom were sorted based on whether they indicated clinically significant bleeding, and nonsignificant scores were set as the reference category. Multivariable logistic regression was used to determine the symptoms that were the strongest predictors of a laboratory-confirmed VWD diagnosis.

Results: A total of 927 participants were included; 144 (16%) were patients with VWD, and 783 (84%) were healthy controls. The top 3 symptoms for which a clinically significant positive response increased the likelihood of VWD were hemarthrosis (odds ratio [OR], 19.2; 95% confidence interval [CI], 3.7-100.4), postsurgical bleeding (OR, 15.2; 95% CI, 5.9-38.9), and menorrhagia (OR, 10.3; 95% CI, 4.9-21.9). With each increase in number of bleeding symptom categories with clinically significant scores, subjects had a stepwise increase in odds of a VWD diagnosis.

Conclusions: Our results suggest that most of the bleeding symptoms on BATs are significant predictors of VWD, and there is value in assessing multiple bleeding symptoms when eliciting a bleeding history. Certain bleeding symptoms are more useful predictors than others. Future BAT revisions may consider adding a relative weighting to each symptom.
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http://dx.doi.org/10.1002/rth2.12256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971303PMC
January 2020

Bone health in symptomatic carriers of haemophilia A: a protocol for a multicentre prospective matched-cohort study.

BMJ Open 2019 12 2;9(12):e032891. Epub 2019 Dec 2.

Hematology/Oncology, St. Michael's Hospital, Toronto, Ontario, Canada

Introduction: Haemophilia A is an X linked inherited bleeding disorder, caused by a decrease in coagulation factor VIII. Persons with haemophilia experience repeated musculoskeletal bleeding, which can lead to decreased range of motion, irreversible joint damage, low bone mineral density (BMD), and are at greater risk for osteoporosis. Women heterozygous for this mutation, also known as haemophilia A carriers, can have bleeding symptoms and even experience joint bleeding evidenced by radiological soft tissue and osteochondral changes. The prevalence of low BMD as a risk factor for osteoporosis has never been evaluated in carriers of haemophilia, and given the recent findings which suggest subclinical musculoskeletal bleeding in carrier women, we hypothesise that they too are at risk of impaired bone health.

Methods And Analysis: This is a national multicentre prospective matched-cohort study to compare BMD T-scores among symptomatic haemophilia A carriers, 50 years of age or older, with age-matched and body mass index-matched non-carriers (1:1). A total of 40 symptomatic carriers and 40 matched non-carriers will be recruited from St. Michael's Hospital, Kingston General Hospital in Ontario, Canada and Foothills Medical Centre in Alberta, Canada. Multivariable linear regression models will be used to estimate the effect of haemophilia carriership on BMD T-scores, adjusting for age, body mass index and other relevant covariates.

Ethics And Dissemination: The protocol was designed and will be conducted in compliance with applicable laws, rules and regulations. Research ethics approval was obtained from St. Michael's Hospital, Foothills Medical Centre, and Kingston General Hospital. Findings will be presented at international venues such as the American Society of Haematology and the World Federation of Haemophilia World Congress. The authors of this study will seek publication in journals such as , , and .
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http://dx.doi.org/10.1136/bmjopen-2019-032891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003383PMC
December 2019

Pregnancy and delivery in women with von Willebrand disease.

Eur J Haematol 2019 Aug 31;103(2):73-79. Epub 2019 May 31.

Department of Medicine, Queen's University, Kingston, Ontario, Canada.

Given the wide heterogeneity of phenotypes and of the underlying pathophysiological mechanisms associated with the disorder, pregnancy and delivery in von Willebrand disease (VWD) represent a significant clinical challenge. The variable pattern of changes observed during pregnancy of von Willebrand factor (VWF) and factor VIII (FVIII), the protein carried by VWF, prompts a careful evaluation of pregnant women with VWD to plan the most appropriate treatment at the time of parturition. However, there are also instances during pregnancy (amniocentesis, vaginal bleeding associated with placental detachment, sudden abortion) that may require urgent hemostatic treatment to prevent bleeding. Thus, women with VWD should start pregnancy after being well characterised as to their type, subtype and treatments. Women with VWD who have VWF and FVIII basal levels >30 U/dL typically normalise these levels at the end of pregnancy and specific anti-haemorrhagic prophylaxis is seldom required. On the contrary, those with basal levels <20 U/dL usually show a lesser increase and specific treatment is required. Some women with DNA variants associated with increased clearance can be treated with desmopressin, while those unresponsive or with contra-indications to this agent need replacement therapy. For these latter women, the risk of vaginal bleeding during pregnancy may be increased and prophylaxis with VWF concentrates required. Similarly, women with type 2 VWD who maintain reduced VWF activity throughout pregnancy require replacement therapy with FVIII/VWF concentrates. Delayed postpartum bleeding may occur when replacement therapy is not continued for some days. Tranexamic acid is useful at discharge to avoid excessive lochia.
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http://dx.doi.org/10.1111/ejh.13250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604852PMC
August 2019

Validation of the school age self-administered pediatric bleeding questionnaire (Self-PBQ) in children aged 8-12 years.

Pediatr Blood Cancer 2019 06 22;66(6):e27709. Epub 2019 Mar 22.

Department of Pediatrics, Division of Hematology/Oncology, Children's Hospital of Eastern Ontario, Ottawa, Canada.

Background: In the pediatric population, pathologic bleeding is often challenging to identify. The pediatric bleeding questionnaire (PBQ) was developed as a screening tool for von Willebrand disease (VWD) but was designed to be self-completed by children above 12 years of age. The study objective was to determine whether a modified Self-PBQ could be completed by 8- to 12-year-old children with adult assistance.

Procedure: The initial phase involved seven children who underwent cognitive debriefing to identify problems in the questionnaire, resulting in modifications to wording and response options. In phase 2, children completed the modified Self-PBQ independently or with assistance from their parent at five Canadian treatment centers. Parents filled out the Self-PBQ separately to serve as a comparison. Bleeding scores derived from the child self-report were compared to those of the parent proxy.

Results: Twenty-nine out of 31 patient/parent pairs successfully completed the Self-PBQ. Child and parent scores demonstrated a high level of agreement with an intraclass correlation (ICC) of 0.825. In the age subgroup analysis, the ICC was 0.834 and 0.824 for the 8- to 9-year-old and 10- to 12-year-old groups, respectively. The ICC was also determined in children with type 1 VWD (ICC = 0.829) versus those with more severe bleeding disorders (ICC = 0.802). Thus, age and disease severity had no significant effect on degree of agreement.

Conclusions: Our study shows that agreement was maintained even in younger children aged 8-9 years and in children with varying bleeding phenotypes. This supports the administration of the modified Self-PBQ to 8- to 12-year-old children.
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http://dx.doi.org/10.1002/pbc.27709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643750PMC
June 2019

The endothelial lectin clearance receptor CLEC4M binds and internalizes factor VIII in a VWF-dependent and independent manner.

J Thromb Haemost 2019 04 19;17(4):681-694. Epub 2019 Mar 19.

Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.

Essentials CLEC4M is an endocytic receptor for factor FVIII. CLEC4M interacts with FVIII in a VWF-dependent and independent manner. CLEC4M binds to mannose-containing glycans on FVIII. CLEC4M internalization of FVIII involves clathrin coated pits. SUMMARY: Background von Willebrand factor (VWF) and factor VIII (FVIII) circulate in the plasma as a non-covalent complex, and the majority of FVIII is likely to be cleared by VWF-dependent pathways. Clearance of VWF-free FVIII is rapid and underlies the pathological basis of some quantitative FVIII deficiencies. The receptor pathways that regulate the clearance of VWF-bound and VWF-free FVIII are incompletely uncharacterized. The human liver-expressed endothelial lectin CLEC4M has been previously characterized as a clearance receptor for VWF, although its influence on FVIII is unknown. Objective The interaction between FVIII and CLEC4M was characterized in the presence or absence of VWF. Methods FVIII interactions with CLEC4M were evaluated by in vitro cell-based and solid phase binding assays. Interactions between FVIII and CLEC4M or liver sinusoidal endothelial cells were evaluated in vivo by immunohistochemistry. Results CLEC4M-expressing HEK 293 cells bound and internalized recombinant and plasma-derived FVIII through VWF-dependent and independent mechanisms. CLEC4M binding to recombinant FVIII was dependent on mannose-exposed N-linked glycans. CLEC4M mediated FVIII internalization via a clathrin-coated pit-dependent mechanism, resulting in transport of FVIII from early and late endosomes for catabolism by lysosomes. In vivo hepatic expression of CLEC4M after hydrodynamic liver transfer was associated with a decrease in plasma levels of endogenous murine FVIII:C in normal mice, whereas infused recombinant human FVIII was associated with sinusoidal endothelial cells in the presence or absence of VWF. Conclusions These findings suggest that CLEC4M is a novel clearance receptor that interacts with mannose-exposed glycans on FVIII in the presence or absence of VWF.
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http://dx.doi.org/10.1111/jth.14404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083068PMC
April 2019

A decreased and less sustained desmopressin response in hemophilia A carriers contributes to bleeding.

Blood Adv 2018 10;2(20):2629-2636

Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.

The cause of hemophilia A carrier bleeding is not well established. Desmopressin (DDAVP), used clinically to treat or prevent bleeding, can also be used as a medical stress surrogate. This study's objective was to compare the response to DDAVP in hemophilia A carriers with that in normal control patients. Bleeding was assessed by the International Society on Thrombosis and Hemostasis Bleeding Assessment Tool (ISTH-BAT). DDAVP (0.3 μg/kg) was administered either IV or subcutaneously (SC), and blood was drawn at baseline and 1, 2, and 4 hours postadministration. Blood was assessed for factor VIII (FVIII) level, von Willebrand factor (VWF) antigen (VWF:Ag), VWF activity (VWF:RCo or VWF:GPIbM), thromboelastography (TEG), and thrombin generation assay (TGA) at all points, and for VWF propeptide (VWFpp):Ag ratio and ABO blood type at baseline. Carriers were older than control patients (median age, 34 and 21 years, respectively; = .003) and had higher ISTH-BAT bleeding scores (median bleeding score, 8 and 0, respectively; = .001). Carriers had a significantly reduced FVIII response to DDAVP compared with control patients ( ≤ .0001). When only carriers with normal baseline FVIII levels (n = 10) were included, carriers maintained a reduced FVIII response ( ≤ .0001). Furthermore, participants with abnormal bleeding scores had a significantly lower FVIII response to DDAVP compared with those with normal bleeding scores ( = .036). Hemophilia A carriers have a lower and less sustained FVIII response to DDAVP, suggesting an impaired ability to respond to hemostatic stress, which contributes to bleeding.
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http://dx.doi.org/10.1182/bloodadvances.2018023713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199650PMC
October 2018

Idiopathic pulmonary arterial hypertension - a unrecognized cause of high-shear high-flow haemostatic defects (otherwise referred to as acquired von Willebrand syndrome) in children.

Br J Haematol 2018 10 23;183(2):267-275. Epub 2018 Aug 23.

Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.

Acquired von Willebrand syndrome (AVWS) is reported in high-flow high-shear congenital cardiac disorders. We hypothesized that the narrowed pulmonary vasculature in idiopathic pulmonary arterial hypertension (IPAH) may induce AVWS. We conducted a cross-sectional evaluation of children with IPAH. Patients with bleeding symptoms and/or laboratory abnormalities (thrombocytopenia, anomalies in coagulation screening tests) were tested in-depth for haemostatic defects. Fourteen children were followed with IPAH of which 8 were eligible. Four children exhibited abnormal bleeding scores (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool: 3-5). All 8 patients showed very prolonged platelet function analyser (PFA)-100 closure times. Six children demonstrated either mild thrombocytopenia or low-normal von Willebrand factor (VWF) antigen (VWF:Ag) or VWF activity [mean (range), in iu/dl: VWF:Ag: 70 (61-91); VWF activity: 57 (34-70)]. Average VWF collagen binding capacity (VWF:CB) was 64 iu/dl (range: 53-123 iu/dl), with low-normal VWF activity/VWF:Ag or VWF:CB/VWF:Ag ratios occurring in five patients. All children had normal multimers distribution patterns. One patient underwent a lung transplantation, with normalization of haemostatic abnormalities post-surgery. Overall, 8 out of 14 children with IPAH had mild to moderate bleeding symptoms and/or laboratory abnormalities in keeping with AVWS. Normalization of the haemostatic defects following lung transplantation and lack of family history of bleeding attests to the acquired nature of their defects.
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http://dx.doi.org/10.1111/bjh.15530DOI Listing
October 2018

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity.

J Clin Invest 2018 08 20;128(9):4057-4073. Epub 2018 Aug 20.

Department of Pathology and Molecular Medicine and.

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.
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http://dx.doi.org/10.1172/JCI96400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118640PMC
August 2018

Spinal Anesthesia in 2 Consecutive Cesarean Deliveries in a Parturient With Type 3 von Willebrand Disease: A Case Report.

A A Pract 2019 Feb;12(3):79-81

From the Departments of Anesthesia and Perioperative Medicine.

Type 3 von Willebrand disease is a rare and severe inherited bleeding disorder that carries an elevated risk for epidural and spinal hematoma as well as pregnancy-associated complications. Neuraxial anesthesia in these patients is controversial but may be considered if the parturient has received appropriate factor replacement. We present the case of a woman with type 3 von Willebrand disease and a severe bleeding history that underwent successful spinal anesthesia during successive cesarean deliveries. Our case highlights the importance of early multidisciplinary consultation and advance planning in the care of these rare events.
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http://dx.doi.org/10.1213/XAA.0000000000000854DOI Listing
February 2019

Significant gynecological bleeding in women with low von Willebrand factor levels.

Blood Adv 2018 07;2(14):1784-1791

National Coagulation Centre, St. James's Hospital, Dublin, Ireland.

Gynecological bleeding is frequently reported in women with von Willebrand disease (VWD). Low von Willebrand factor (VWF) may be associated with significant bleeding phenotype despite only mild plasma VWF reductions. The contribution of gynecological bleeding to this phenotype has yet to be described. The optimal clinical bleeding assessment tool (BAT) to evaluate bleeding remains unclear. Using a standardized approach to phenotypic assessment, we evaluated gynecological bleeding and directly compared the Condensed Molecular and Clinical Markers for the Diagnosis and Management of type 1 VWD (Condensed MCMDM-1 VWD) and International Society on Thrombosis and Haemostasis (ISTH) BAT scores in 120 women enrolled in the Low von Willebrand in Ireland Cohort study. Heavy menstrual bleeding (HMB) was reported in 89% of female participants; 45.8% developed iron deficiency. Using identical data, Condensed MCMDM-1 VWD menorrhagia domain scores were significantly lower than ISTH BAT scores (2 vs 3; < .0001), the discrepant results related to 40% of women not seeking medical consultation for HMB, reducing the sensitivity of the Condensed score. For those who reported HMB to physicians, the low VWF diagnosis was not expedited (age at diagnosis 34.2 vs 33.4 years in women failing to present; = .7). Postpartum hemorrhage (PPH) was self-reported in 63.5% of parous women (n = 74); 21.6% required transfusion, critical care, radiological, or surgical intervention. Our data demonstrate that gynecological bleeding is frequently reported in women with low VWF; despite pregnancy-related increases in plasma VWF levels, these women may experience PPH. Defining the optimal management approach for these patients requires further research. This trial was registered at www.clinicaltrials.gov as #NCT03167320.
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http://dx.doi.org/10.1182/bloodadvances.2018017418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058240PMC
July 2018

Identifying Children with HEreditary Coagulation disorders (iCHEC): a protocol for a prospective cohort study.

BMJ Open 2018 05 3;8(5):e020686. Epub 2018 May 3.

Pediatric Hematology, Academic Medical Center - Emma Children's Hospital, Amsterdam, The Netherlands.

Introduction: It is challenging to obtain a reliable bleeding history in children who are referred for a suspected inherited bleeding disorder. Bleeding symptoms may be subtle as children face fewer haemostatic challenges compared with adults. In order to standardise bleeding histories, questionnaires have been developed, called bleeding assessment tools (BATs). Although it has been shown that high bleeding scores are associated with the presence of a mucocutaneous bleeding disorder, these BATs lack sensitivity, efficiency and flexibility in the paediatric setting. We developed a new BAT (the iCHEC (identifying Children with HEreditary Coagulation disorders) BAT) to improve on these characteristics. We aim to evaluate the diagnostic accuracy of the iCHEC BAT as a screening tool for children who are suspected for having a bleeding disorder.

Methods And Analysis: This is a prospective cohort study. Children (age 0-18 years) suspected for a bleeding disorder who present at tertiary haematology clinics, and/or their parents/guardians, will be asked to complete the iCHEC BAT. Sensitivity was increased by inclusion of paediatric-specific bleeding symptoms and novel qualitative questions per bleeding symptom. Efficiency was improved by developing a self-administered (online) version of the questionnaire. Flexibility for changes in the bleeding phenotype of developing children was improved by including questions that define when the bleeding symptoms occurred in the past. The diagnostic accuracy of the specific bleeding items will be evaluated by receiver operator characteristic curves, using classification based on the results from laboratory assessment as the reference standard. Analysis of the discriminative power of individual bleeding symptoms will be assessed.

Ethics And Dissemination: The study has been approved by the medical ethics committees of all participating centres in the Netherlands, Canada and the UK. All paediatric subjects and/or their parents/guardians will provide written informed consent. Study results will be submitted for publication in peer-reviewed journals.
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http://dx.doi.org/10.1136/bmjopen-2017-020686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942417PMC
May 2018

Severity and Features of Epistaxis in Children with a Mucocutaneous Bleeding Disorder.

J Pediatr 2018 02 1;193:183-189.e2. Epub 2017 Dec 1.

Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada; Departments of Laboratory Medicine & Pathobiology and Biochemistry, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objective: To use standardized bleeding questionnaires to compare the severity and patterns of epistaxis in children with a mucocutaneous bleeding disorder and control children.

Study Design: The epistaxis sections of the Pediatric Bleeding Questionnaire (PBQ) administered to pediatric patients with von Willebrand disease or a platelet function disorder and healthy control children were reviewed. Scores and features of epistaxis (frequency, duration, onset, site, seasonal correlation, and need for medical/surgical intervention) were recorded. A PBQ epistaxis score ≥2 was defined as clinically significant. The Katsanis epistaxis scoring system was administered to eligible patients, ie, with ≥5 episodes of epistaxis per year.

Results: PBQ epistaxis scores were obtained for 66 patients, median age 12 years (range 0.6-18.3 years), and 56 control children. The median PBQ epistaxis score in patients was 2 vs 0 in control children (P <.0001). All of the features of epistaxis, except spontaneous onset, occurred in a significantly greater proportion of patients than control children with epistaxis. A total of 50% of the patients were graded as having severe epistaxis by the Katsanis epistaxis scoring system, and 30 of these (91%) had a clinically significant PBQ epistaxis score.

Conclusion: Standardized bleeding questionnaires are useful in the assessment of epistaxis severity and pattern and may help to distinguish children with and without a mucocutaneous bleeding disorder.
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http://dx.doi.org/10.1016/j.jpeds.2017.09.082DOI Listing
February 2018
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