Publications by authors named "Veronica H Flood"

44 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

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

Screening for von Willebrand disease does not impact posttonsillectomy bleeding in a low-risk population.

Pediatr Blood Cancer 2021 Dec 4;68(12):e29371. Epub 2021 Oct 4.

Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Background: Bleeding is an important complication in children following tonsillectomy. Screening with coagulation tests prior to procedure is common to assess bleeding risk in the perioperative period, although ASH/ASPHO Choosing Wisely guidelines recommend against routine PT/PTT testing. Our aim was to compare von Willebrand factor antigen (VWF:Ag) and activity levels among patients with postoperative bleeding following tonsillectomy to evaluate for potential risk for bleeding.

Procedure: Eligible subjects were aged 0-18 without significant personal or family history of major bleeding. Postoperative bleeding diaries were collected and symptoms measured using a postoperative bleeding score. Plasma VWF levels were drawn at time of anesthesia administration.

Results: Postoperative bleeding occurred in 248 cases out of 1399 total subjects. Median VWF:Ag was 86 in patients with postoperative bleeding scores of 1-2, 86 for scores 3-4, 84 for scores 5-6, and 83 for scores >6, with no significant difference among groups (p = .98). Additionally, no difference was observed for subjects with multiple days of postoperative bleeding as compared to those with only 1 day of postoperative bleeding. Finally, no difference in VWF:Ag was observed for subjects whose first reported bleed occurred early in the postoperative course compared to those whose first reported bleed occurred later. VWF:Ag does not correlate with severity of bleeding, time of onset of first bleeding event, or recurrence of bleeding in healthy children with no personal or family history of bleeding who have postoperative bleeding following tonsillectomy.

Conclusions: This data does not support routine von Willebrand disease screening prior to tonsillectomy.
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http://dx.doi.org/10.1002/pbc.29371DOI Listing
December 2021

Von Willebrand Disease: Current Status of Diagnosis and Management.

Hematol Oncol Clin North Am 2021 Dec 13;35(6):1085-1101. Epub 2021 Aug 13.

Department of Pediatrics, Medical College of Wisconsin and Versiti Blood Research Institute, Milwaukee, WI, USA; Comprehensive Center for Bleeding Disorders, 8739 Watertown Plank Road, PO Box 2178, Milwaukee, WI 53201-2178, USA. Electronic address:

Von Willebrand disease (VWD) is a common bleeding disorder, affecting male and female individuals equally, that often manifests in mucosal bleeding. VWD can be secondary to a quantitative (Type 1 and Type 3) or qualitative (Type 2) defects in Von Willebrand factor (VWF). Initial testing includes VWF antigen, as well as a platelet binding assay to differentiate between qualitative and quantitative defects. Further subtyping requires additional testing and is needed to ensure appropriate treatment. Desmopressin, antifibrinolytics, hormonal treatments for heavy menstrual bleeding, and VWF concentrates are commonly used in the treatment of VWD.
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http://dx.doi.org/10.1016/j.hoc.2021.07.004DOI Listing
December 2021

Fibronectin binding to von Willebrand factor occurs via the A1 domain.

Res Pract Thromb Haemost 2021 Jun 5;5(5):e12534. Epub 2021 Jun 5.

Department of Pediatrics Division of Hematology/Oncology Medical College of Wisconsin Milwaukee WI USA.

Background: Collagen interactions with von Willebrand factor (VWF) perform an important role in initiation of hemostasis.

Objectives: We hypothesized that in addition to collagen, other extracellular matrix (ECM) proteins such as fibronectin can bind VWF.

Methods: Fibronectin-VWF interactions were measured by ELISA using both plasma-derived and recombinant VWF-containing variants in specific domains. Inhibition was measured by antibody competition using antibodies directed against both VWF and fibronectin. Binding affinities were measured by the Octet Biosensor for fibronectin and collagen IV.

Results: Fibronectin was able to bind both plasma-derived and recombinant wild-type VWF. This interaction was inhibited by both anti-VWF antibodies and collagen types III and IV. Several VWF A1 domain variants in the region of the collagen IV binding site also demonstrated absent fibronectin binding, as did variants with defects in high-molecular-weight multimers. Binding affinity testing showed fibronectin has a strong affinity for VWF, in a range similar to that of collagen IV. Fibronectin binds VWF via a restricted region of the A1 domain. This interaction requires high-molecular-weight multimers and is similar to that seen with vascular collagens.

Conclusions: Therefore, VWF would appear to be the common factor linking platelet adhesion to various ECM proteins and facilitating hemostasis under conditions of ECM exposure.
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http://dx.doi.org/10.1002/rth2.12534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178691PMC
June 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

Laboratory variability in the diagnosis of type 2 VWD variants.

J Thromb Haemost 2021 01 10;19(1):131-138. Epub 2020 Nov 10.

Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.

Essentials Patients with von Willebrand disease were enrolled in our study. Type 2 VWD diagnoses were based on original test results. Repeat evaluation resulted in many patients receiving a different type 2 diagnosis. Some genetic variants were particularly likely to move type 2 subcategories. ABSTRACT: Introduction Type 2 von Willebrand disease (VWD) refers to patients with a qualitative defect in von Willebrand factor. Accurate diagnosis of type 2 VWD subtypes can be challenging. Aim of the study To compare the historical diagnosis of type 2 VWD with current laboratory testing. Methods Subjects were enrolled in the Zimmerman Program either because of a preexisting diagnosis of VWD (retrospective cohort) or from evaluation for bleeding symptoms or suspected VWD (prospective cohort). Original diagnosis was assigned by the local center and central diagnosis was based on central laboratory testing. Results Two hundred and seventeen index cases in the retrospective cohort and 35 subjects in the prospective cohort carried a local diagnosis of type 2 VWD (29% and 6% of enrolled index cases, respectively). In the retrospective cohort, the diagnosis was confirmed in 66% of cases with a preexisting diagnosis of 2A, 77% 2B, 54% 2M, and 72% 2N. In the prospective cohort, 31% were confirmed 2A, 60% 2B, 23% 2M, and 100% 2N. Several genetic variants were repeatedly implicated in subjects with changed diagnosis: p.M1304R, p.R1315C, p.R1374C, and p.R1374H. Conclusions Both the prospective and retrospective cohorts demonstrated consistent variation in subjects whose diagnosis changed between 2A, 2B, and 2M. The importance of accurately diagnosing type 2 VWD may be most significant in the 2B subtype given potential concerns with the use of desmopressin in type 2B VWD. Some genetic variants appear in multiple types of VWD, making specific diagnoses challenging.
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http://dx.doi.org/10.1111/jth.15129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790985PMC
January 2021

von Willebrand factor variant D1472H has no effect in mice with humanized VWF-platelet interactions.

Blood Adv 2020 09;4(17):4065-4068

Division of Hematology/Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

The von Willebrand factor ristocetin cofactor activity assay (VWF:RCo) is used for diagnosis of von Willebrand disease (VWD) because of its ability to evaluate VWF binding to platelets. VWF sequence variant p.D1472H is associated with lower VWF:RCo levels in the absence of associated bleeding symptoms, indicating the VWF:RCo may not be accurate for characterizing VWF function in individuals with this variant. Thus, this study aimed to determine the implications of the variant on VWF functioning in vivo. Mice were engineered with humanized wild-type (WT*) VWF A1/A2 and VWF with the p.D1472H (1472H) variant along with humanized platelet GPIbα and bred to homozygosity. VWF antigen and VWF binding to GPIbα were measured using enzyme-linked immunosorbent assay. Gel electrophoresis was used for VWF multimer analysis. Tail bleeding assays were performed at a 3-mm defined length. Normal VWF multimers were preserved in both WT* and 1472H mice. VWF expression was normal in the WT* and 1472H mice, and VWF binding to GPIbα did not statistically differ between the groups. Additionally, tail bleeding times were similar for WT* and 1472H mice. These results show the p.D1472H variant does not impair hemostasis in mice, and support the conclusion that p.D1472H is a normal variant in humans.
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http://dx.doi.org/10.1182/bloodadvances.2020002629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479953PMC
September 2020

A rat model of severe VWD by elimination of the VWF gene using CRISPR/Cas9.

Res Pract Thromb Haemost 2020 Jan 29;4(1):64-71. Epub 2019 Dec 29.

Department of Pediatrics Division of Hematology/Oncology Medical College of Wisconsin Milwaukee WI USA.

Background: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, caused by quantitative and qualitative changes in von Willebrand factor (VWF). The biology of VWD, studied in canine, porcine, and murine models, differ in species-specific biology of VWF and the amenability to experimental manipulations such as phlebotomy. The factor VIII (FVIII) levels in these models are higher than in humans with type 3 VWD, suggesting functional differences between FVIII and VWF.ObjectivesTo develop a VWF knock out (VWF) rat by excision of all 52 exons of the VWF locus.

Methods: The entire VWF gene was eliminated in Sprague-Dawley (Crl:SD) rats via CRISPR/Cas9-mediated gene editing. VWF antigen (VWF:Ag), VWF propeptide, and VWF collagen IV binding (VWF:CB4) levels were determined by ELISA assays and FVIII chromogenic activity (FVIII:C) levels by chromogenic FVIII assays. Lateral tail veins were transected to measure bleeding time. VWF rats were infused with FVIII rat platelet poor plasma (PPP) to determine response of plasma FVIII.

Results: Breeding of VWF ± rats yielded VWF offspring at normal Mendelian ratios. VWF:Ag, VWF propeptide, VWF:CB4, and FVIII:C plasma levels were undetectable in VWF rats. VWF rats bled longer and more than VWF and VWF rats when challenged. Transfusion of FVIII-deficient platelet-poor plasma induced a rapid rise in endogenous FVIII:C in VWF rats.

Conclusion: This rat model of severe VWD due to elimination of the entire VWF gene recapitulates the severe secondary deficiency of FVIII seen in human type 3 VWD and facilitates the study of VWF and FVIII and their interactions.
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http://dx.doi.org/10.1002/rth2.12280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971331PMC
January 2020

von Willebrand factor binding to myosin assists in coagulation.

Blood Adv 2020 01;4(1):174-180

Blood Research Institute, Versiti, Milwaukee, WI.

von Willebrand factor (VWF) binds to platelets and collagen as a means of facilitating coagulation at sites of injury. Recent evidence has shown that myosin can serve as a surface for thrombin generation and binds to activated factor V and factor X. We studied whether VWF can also bind myosin as a means of bringing factor VIII (FVIII) to sites of clot formation. A myosin-binding assay was developed using skeletal muscle myosin to measure VWF binding, and plasma-derived and recombinant VWF containing molecular disruptions at key VWF sites were tested. Competition assays were performed using anti-VWF antibodies. FVIII binding to myosin was measured using a chromogenic FVIII substrate. Thrombin generation was measured using a fluorogenic substrate with and without myosin. Wild-type recombinant VWF and human plasma VWF from healthy controls bound myosin, whereas plasma lacking VWF exhibited no detectable myosin binding. Binding was multimer dependent and blocked by anti-VWF A1 domain antibodies or A1 domain VWF variants. The specific residues involved in myosin binding were similar, but not identical, to those required for collagen IV binding. FVIII did not bind myosin directly, but FVIII activity was detected when VWF and FVIII were bound to myosin. Myosin enhanced thrombin generation in platelet-poor plasma, although no difference was detected with the addition of myosin to platelet-rich plasma. Myosin may help to facilitate delivery of FVIII to sites of injury and indirectly accelerate thrombin generation by providing a surface for VWF binding in the setting of trauma and myosin exposure.
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http://dx.doi.org/10.1182/bloodadvances.2019000533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960459PMC
January 2020

Low VWF levels in children and lack of association with bleeding in children undergoing tonsillectomy.

Blood Adv 2020 01;4(1):100-105

Division of Hematology/Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

von Willebrand disease is a common bleeding disorder, but diagnosis can be difficult in young children who have not had bleeding challenges. We sought to evaluate the correlation between bleeding and von Willebrand factor (VWF) levels in children undergoing surgical challenge with tonsillectomy. Children ages 0 to 18 undergoing tonsillectomy without a personal or family history of bleeding were enrolled prospectively following informed consent and institutional review board approval. VWF levels were obtained at the time of surgery. VWF antigen (VWF:Ag) and VWF activity (VWF:GPIbM) were tested via enzyme-linked immunosorbent assay. Bleeding score was calculated using the International Society of Hematology bleeding assessment tool (BAT). Surgical and postoperative bleeding were determined using questionnaires filled out by the surgeon and patient/family. A total of 1399 subjects were enrolled with evaluable data, with a median age of 5 years. The median VWF:Ag was 85 IU/dL and the median VWF:GPIbM was 100 U/dL. Median BAT for the entire population was 0, including those with postoperative bleeding. There was no difference in VWF level between those who experienced postoperative bleeding and those who did not, with median VWF:Ag 85 vs 85 (P = .89) and mean VWF:GPIbM 98 vs 100 (P = .5). Interestingly, there was a difference in VWF levels with age, with median VWF:Ag 81 for those younger than 3 years, 82 for those 3 to 6 years, 90 for those 7 to 10 years, and 100 for those 11 to 18 years. A similar trend was noted for VWF:GPIbM. Of the 2 to 6 year olds, 5% had VWF:Ag <50, which would meet criteria for low VWF, but only 1.8% had an abnormal BAT at study entry and only 2.5% bled after surgery. Only 1 subject with low VWF had an elevated postoperative BAT >2. These data suggest that low VWF levels do not correlate with bleeding in children undergoing tonsillectomy. In addition, VWF levels outside the adult normal range in young children may be more common than previously thought and do not necessarily predict surgical bleeding.
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http://dx.doi.org/10.1182/bloodadvances.2019000992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960478PMC
January 2020

Efficacy of emicizumab in a pediatric patient with type 3 von Willebrand disease and alloantibodies.

Blood Adv 2019 09;3(18):2748-2750

Division of Hematology and Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, MI.

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http://dx.doi.org/10.1182/bloodadvances.2019000656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759735PMC
September 2019

The role of genetics in the pathogenesis and diagnosis of type 1 Von Willebrand disease.

Curr Opin Hematol 2019 09;26(5):331-335

Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin.

Purpose Of Review: Von Willebrand disease (VWD) is a common bleeding disorder, but diagnosis of VWD is challenging, particularly with type 1 VWD. Although most clinicians use specific tests of von Willebrand factor (VWF) activity to classify patients with VWD, genetic testing for VWF defects is another potential method of diagnosis.

Recent Findings: Studies of patients with type 1 VWD report consistently that many, but not all, study participants have VWF gene defects. Certain populations, including those with VWF levels less than 30 IU/dl and those with clearance defects, are more likely to have a VWF sequence variant. In addition, a number of loci outside the VWF gene have been shown to affect VWF levels, including ABO, CLEC4M, STXBP5, and STAB2.

Summary: Genetic defects in VWF are common, but not all defects lead to disease. Type 1 VWD in particular does not always have an associated VWF sequence variant. New data stemming from genome-wide association studies on modifier genes suggest that the etiology of type 1 VWD is multifactorial.
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http://dx.doi.org/10.1097/MOH.0000000000000524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727843PMC
September 2019

Von Willebrand disease in the United States: perspective from the Zimmerman program.

Ann Blood 2018 Jan 26;3. Epub 2018 Jan 26.

Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI, USA.

This article will discuss the diagnosis and management of von Willebrand disease (VWD) in the United States and results from the Zimmerman Program, a national study of VWD. An algorithm is presented to show how we currently approach diagnostic testing for VWD, including the potential replacement of the ristocetin cofactor assay with a new von Willebrand factor (VWF)-GPIb binding assay. Results from the Zimmerman Program type 1 cohort are presented, including the findings that genetic defects in the gene are most common with VWF levels <30 IU/dL, but bleeding symptoms were present across the entire cohort regardless of VWF level. Typical management of VWD patients is also discussed, including the use of desmopressin and VWF concentrates. Despite these advances, there remain several areas of VWD where more research is required to optimize treatment.
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http://dx.doi.org/10.21037/aob.2017.12.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100783PMC
January 2018

Common sequence variants associated with higher VWF and FVIII are less frequent in subjects diagnosed with type 1 VWD.

Res Pract Thromb Haemost 2018 Apr 23;2(2):390-398. Epub 2018 Jan 23.

Department of Pediatrics Division of Hematology/Oncology Medical College of Wisconsin Milwaukee WI USA.

Background: Genetic variation in the gene is associated with von Willebrand factor (VWF) and factor VIII (FVIII) levels in healthy individuals.

Objectives: We hypothesized that sequence variants associated with higher VWF or FVIII could impact the diagnosis of type 1 von Willebrand disease (VWD).

Methods: We examined VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF propeptide (VWFpp), and FVIII levels along with gene sequencing in 256 healthy control and 97 type 1 VWD subjects as part of a cross-sectional study.

Results: We found several VWF sequence variants ( c.2880G>A and c.2365A>G(;)c.2385T>C, found in linkage disequilibrium) associated with higher VWF and FVIII levels in healthy controls (<.001 for both variants). In addition, these variants were significantly more common in controls than in subjects diagnosed with type 1 VWD and VWF:Ag <30 (<.005). The decreased variant frequencies in type 1 VWD was not seen in other VWD types. VWF:Ag, VWF:RCo, and FVIII were not statistically different in type 1 VWD subjects who had these variants compared to type 1 VWD patients without them. There was no difference in ABO blood group, VWF propeptide levels (excluding subjects with known VWF clearance defects), or bleeding score using the ISTH bleeding assessment tool.

Conclusions: These data suggest that certain sequence variants associated with elevated FVIII and VWF levels may protect against reduced VWF levels. These findings were independent of other pathogenic sequence variants in , suggesting a possible independent effect of c.2880G>A and c.2365A>G(;)c.2385T>C on VWF levels.
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http://dx.doi.org/10.1002/rth2.12077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974909PMC
April 2018

Current issues in diagnosis and treatment of von Willebrand disease.

Res Pract Thromb Haemost 2018 Jan 12;2(1):34-41. Epub 2017 Dec 12.

Department of Pediatrics Division of Hematology/Oncology Medical College of Wisconsin Milwaukee WI USA.

Clinically, von Willebrand disease (VWD) presents as mucosal bleeding caused by a decreased quantity or quality of von Willebrand factor (VWF). Diagnosis of VWD requires careful consideration of patient specific factors, bleeding symptoms, and laboratory results. Patients with borderline low VWF levels remain challenging, given that low VWF is not necessarily a guarantee of bleeding, but is present in many patients with symptoms, and treatment of low VWF may improve bleeding. Laboratory diagnosis of VWD is complex and no single test can determine the presence or absence of functional VWF. Historically, VWF binding to platelet GPIbα was measured by the ristocetin cofactor assay (VWF:RCo); a new assay using platelet GPIbα in the absence of ristocetin (VWF:GPIbM) is gradually replacing the VWF:RCo due to improved accuracy in diagnosis. VWF binding to collagen is a separate function, and requires specific testing to determine if a collagen binding defect is present. Regardless of these laboratory complexities, clinicians can empirically treat VWD to alleviate bleeding symptoms by raising VWF levels through desmopressin or VWF concentrate. Recombinant VWF is now available, but clinicians may need to add an initial dose of FVIII when treating emergency bleeds.
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http://dx.doi.org/10.1002/rth2.12064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974913PMC
January 2018

Treatment Modalities in Adolescents Who Present with Heavy Menstrual Bleeding.

J Pediatr Adolesc Gynecol 2018 Oct 8;31(5):451-458. Epub 2018 Mar 8.

Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Study Objective: On this study we sought to determine the relationship of bleeding disorders to iron deficiency anemia. Additionally, this study was undertaken to examine all current treatment modalities used in a menorrhagia clinic with respect to heavy menstrual bleeding management to identify the most effective options for menstrual management in the setting of an underlying bleeding disorder. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We performed a retrospective chart review of adolescents younger than 21 years with heavy menstrual bleeding attending a multidisciplinary hematology-adolescent gynecology clinic. Information including demographic characteristics, bleeding diathesis, hematologic parameters, treatment, and the diagnosis was extracted from each chart. Subjects were grouped into 2 categories on the basis of the diagnosis of a bleeding disorder. Hemoglobin level, iron deficiency anemia, and need for transfusion were compared between a bleeding disorder and no bleeding disorder group. Subjects were grouped into categories depending on hormonal modality and treatment success of the groups were compared.

Results: Seventy-three subjects were tested for a bleeding disorder. Of the subjects who completed testing, 34 (46%) were diagnosed with a bleeding disorder. Thirty-nine subjects (54%) had heavy menstrual bleeding because of other causes. There was no significant difference in hemoglobin between those with and without a bleeding disorder. Iron deficiency anemia was significantly higher in subjects without a bleeding disorder. In a comparison of hormone therapy success, the levonorgestrel intrauterine device (89%, 8 out of 9 subjects) had the highest rate of menstrual suppression followed by norethindrone acetate 5-10 mg/d (83%, 5 out of 6 subjects), and the transdermal patch (80%, 4 out of 5 subjects). All subjects using tranexamic acid as well as hormonal therapy had 100% achievement of menstrual suppression.

Conclusion: A high frequency of bleeding disorders was found in those tested. Subjects with a bleeding disorder were less likely to present with severe anemia requiring blood transfusion and less likely to have iron deficiency anemia. Although combined oral contraceptives were commonly used clinically for menstrual suppression, they were not found to be the most effective option.
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http://dx.doi.org/10.1016/j.jpag.2018.02.130DOI Listing
October 2018

Advances in the diagnosis and treatment of Von Willebrand disease.

Hematology Am Soc Hematol Educ Program 2017 12;2017(1):379-384

Pediatric Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet diagnosis and management remain challenging. Development and use of bleeding assessment tools allows for improved stratification of which patients may require further assessment and which patients are most likely to require treatment of their VWD. New options for laboratory assessment of von Willebrand factor (VWF) activity include a new platelet-binding assay, the VWF:GPIbM, which is subject to less variability than the ristocetin cofactor activity assay, and collagen-binding assays that provide insight into a different function of VWF. Genetic testing may be helpful in some cases where a type 2 VWD variant is suspected but is usually not helpful in type 1 VWD. Finally, treatment options for VWD are reviewed, including the use of recombinant VWF. Despite these advances, still more work is required to improve diagnosis, treatment, and quality of life for affected patients.
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http://dx.doi.org/10.1182/asheducation-2017.1.379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142610PMC
December 2017

Advances in the diagnosis and treatment of Von Willebrand disease.

Blood 2017 11;130(22):2386-2391

Pediatric Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, yet diagnosis and management remain challenging. Development and use of bleeding assessment tools allows for improved stratification of which patients may require further assessment and which patients are most likely to require treatment of their VWD. New options for laboratory assessment of von Willebrand factor (VWF) activity include a new platelet-binding assay, the VWF:GPIbM, which is subject to less variability than the ristocetin cofactor activity assay, and collagen-binding assays that provide insight into a different function of VWF. Genetic testing may be helpful in some cases where a type 2 VWD variant is suspected but is usually not helpful in type 1 VWD. Finally, treatment options for VWD are reviewed, including the use of recombinant VWF. Despite these advances, still more work is required to improve diagnosis, treatment, and quality of life for affected patients.
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http://dx.doi.org/10.1182/blood-2017-05-782029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709787PMC
November 2017

What have we learned from large population studies of von Willebrand disease?

Hematology Am Soc Hematol Educ Program 2016 Dec;2016(1):670-677

Blood Research Institute, BloodCenter of Wisconsin and Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

Von Willebrand factor (VWF) is a critical regulator of hemostatic processes, including collagen binding, platelet adhesion, and platelet aggregation. It also serves as a carrier protein to normalize plasma factor VIII synthesis, release, and survival. While VWF protein measurements by immunoassay are reasonably comparable between institutions, the measurement of VWF ristocetin cofactor activity (VWF:RCo) has significant variability. Other tests of VWF function, including collagen binding or platelet glycoprotein IIb-IIIa binding, are not universally available, yet these functional defects may cause major bleeding even with normal VWF antigen (VWF:Ag) and VWF:RCo assays. This results in both the overdiagnosis and underdiagnosis of VWD. Newer assays of VWF function (using recombinant glycoprotein Ib rather than whole platelets) have been developed that may improve interlaboratory variability. Some of these tests are not uniformly available and may not be licensed in the United States. Large longitudinal studies of VWF in von Willebrand disease (VWD) patients are not available. Patients are sometimes diagnosed with a single diagnostic VWF panel. Plasma VWF levels increase with age, but it is not clear if this results in less bleeding or whether different normal ranges should be used to identify age-related decreases in VWF. In order to quantitatively compare bleeding symptoms in VWD patients and normal individuals, recent studies in the European Union, Canada, United Kingdom, Holland, and the United States have used semiquantitative bleeding assessment tools (BATs). Even with careful centralized testing, including functional assays of VWF, addition of a BAT does not solve all of the problems with VWD diagnosis. No matter where the line is drawn for diagnosis of VWD, VWF is still a continuous variable. Thus, VWD can be a severe hemorrhagic disease requiring frequent treatment or a mild condition that may not be clinically relevant. As will be discussed by Dr. Goodeve in her presentation, genetics has helped us to diagnose type 2 functional variants of VWD but has not been helpful for the many patients who are at the interface of normal and low VWF and carry the possible diagnosis of type 1 VWD. The hematologist's management of patients with reduced levels of VWF still requires both the art and science of clinical medicine.
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http://dx.doi.org/10.1182/asheducation-2016.1.670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518316PMC
December 2016

Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States.

Blood 2016 05 9;127(20):2481-8. Epub 2016 Feb 9.

Division of Hematology/Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI; Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI;

von Willebrand disease (VWD) is the most common inherited bleeding disorder, and type 1 VWD is the most common VWD variant. Despite its frequency, diagnosis of type 1 VWD remains the subject of debate. In order to study the spectrum of type 1 VWD in the United States, the Zimmerman Program enrolled 482 subjects with a previous diagnosis of type 1 VWD without stringent laboratory diagnostic criteria. von Willebrand factor (VWF) laboratory testing and full-length VWF gene sequencing was performed for all index cases and healthy control subjects in a central laboratory. Bleeding phenotype was characterized using the International Society on Thrombosis and Haemostasis bleeding assessment tool. At study entry, 64% of subjects had VWF antigen (VWF:Ag) or VWF ristocetin cofactor activity below the lower limit of normal, whereas 36% had normal VWF levels. VWF sequence variations were most frequent in subjects with VWF:Ag <30 IU/dL (82%), whereas subjects with type 1 VWD and VWF:Ag ≥30 IU/dL had an intermediate frequency of variants (44%). Subjects whose VWF testing was normal at study entry had a similar rate of sequence variations as the healthy controls (14%). All subjects with severe type 1 VWD and VWF:Ag ≤5 IU/dL had an abnormal bleeding score (BS), but otherwise BS did not correlate with VWF:Ag. Subjects with a historical diagnosis of type 1 VWD had similar rates of abnormal BS compared with subjects with low VWF levels at study entry. Type 1 VWD in the United States is highly variable, and bleeding symptoms are frequent in this population.
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http://dx.doi.org/10.1182/blood-2015-10-673681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874228PMC
May 2016

Von Willebrand factor is reversibly decreased during torpor in 13-lined ground squirrels.

J Comp Physiol B 2016 Jan;186(1):131-9

During torpor in a hibernating mammal, decreased blood flow increases the risk of blood clots such as deep vein thrombi (DVT). In other animal models platelets, neutrophils, monocytes and von Willebrand factor (VWF) have been found in DVT. Previous research has shown that hibernating mammals decrease their levels of platelets and clotting factors VIII (FVIII) and IX (FIX), increasing both bleeding time and activated partial thromboplastin time. In this study, FVIII, FIX and VWF activities and mRNA levels were measured in torpid and non-hibernating ground squirrels (Ictidomys tridecemlineatus). Here, we show that VWF high molecular weight multimers, collagen-binding activity, lung mRNA and promoter activity decrease during torpor. The VWF multimers reappear in plasma within 2 h of arousal in the spring. Similarly, FIX activity and liver mRNA both dropped threefold during torpor. In contrast, FVIII liver mRNA levels increased twofold while its activity dropped threefold, consistent with a post-transcriptional decrease in FVIII stability in the plasma due to decreased VWF levels. Finally, both neutrophils and monocytes are decreased eightfold during torpor which could slow the formation of DVT. In addition to providing insight in how blood clotting can be regulated to allow mammals to survive in extreme environments, hibernating ground squirrels provide an interesting model for studying.
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http://dx.doi.org/10.1007/s00360-015-0941-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838567PMC
January 2016

Platelet-derived VWF in the stroke spotlight.

Authors:
Veronica H Flood

Blood 2015 Oct;126(14):1640-1

MEDICAL COLLEGE OF WISCONSIN.

In this issue of Blood, Verhenne et al present data showing the role of platelet-derived von Willebrand factor (VWF) in mediating ischemic stroke injury using a murine model. They created mice with either endothelial VWF or platelet-derived VWF and examined each phenotype for bleeding and thrombosis. Their intriguing findings were that mice lacking platelet-derived VWF, but with adequate endothelial VWF stores, demonstrated normal hemostasis in a tail bleeding model and normal carotid artery thrombosis. Mice with only platelet-derived VWF had defective hemostasis and defective carotid artery thrombosis, but experienced significant cerebral infarction using a stroke model with middle cerebral artery occlusion (see figure). In contrast, minimal infarcts were seen for VWF-deficient mice. These data suggest that platelet-derived VWF plays a specific role in stroke pathology.
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http://dx.doi.org/10.1182/blood-2015-08-661439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591789PMC
October 2015

Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease.

Blood 2015 Jul 27;126(2):262-9. Epub 2015 May 27.

Department of Pediatrics and Human Genetics and Genomics Program, University of Colorado, Anschutz Medical Campus, Aurora, CO;

Von Willebrand disease (VWD) is an inherited bleeding disorder characterized by incomplete penetrance and variable expressivity. We evaluated a 24-member pedigree with VWD type 2 caused by a T>G mutation at position 3911 that predicts a methionine to arginine (M1304R) change in the platelet-binding A1 domain of von Willebrand factor (VWF). This mutation manifests as an autosomal-dominant trait, with clinical and biochemical phenotypic variability among affected individuals, including differences in bleeding tendency and VWF quantity, activity, and multimer pattern. Sequencing of all VWF coding regions in 3 affected individuals did not identify additional mutations. When expressed in heterologous cells, M1304R was secreted in lower quantities, failed to drive formation of storage granules, and was defective in multimerization and platelet binding. When cotransfected in equal quantities with the wild-type complementary DNA, the mutant complementary DNA depressed VWF secretion, although multimerization was only mildly affected. A llama nanobody (AU/VWFa-11) that detects the mutant A1 domain demonstrated highly variable binding to VWF from different affected members, indicating that the VWF contained different percentages of mutant monomers in different individuals. Thus, the observed variability in VWD phenotypes could in part be determined by the extent of mutant monomer incorporation in the final multimer structure of plasma VWF.
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http://dx.doi.org/10.1182/blood-2014-11-613935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497966PMC
July 2015

New insights into genotype and phenotype of VWD.

Authors:
Veronica H Flood

Hematology Am Soc Hematol Educ Program 2014 Dec 18;2014(1):531-5. Epub 2014 Nov 18.

Division of Pediatric Hematology/Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

Recent advances in VWD research have improved our understanding of the genotype and phenotype of VWD. The VWF gene is highly polymorphic, with a large number of sequence variations reported in healthy individuals. This can lead to some difficulty when attempting to discern genotype-phenotype correlations because sequence variations may not represent disease. In type 1 VWD, mutations can be found throughout the VWF gene, but likely pathogenic sequence variations are found in only ∼2/3 of type 1 VWD patients. Sequence variations in type 2 VWD are located in the region corresponding to the defect in the VWF protein found in each type 2 variant. In type 3 VWD, sequence variations are not confined to a specific region of the VWF gene and also include large deletions that may not be picked up using conventional sequencing techniques. Use of genetic testing may be most helpful in diagnosis of type 2 VWD, in which a larger number of known, well characterized mutations are present and demonstration of one of these may help to confirm the diagnosis. Bleeding symptoms in general are more severe with decreasing VWF levels and more severe in type 2 and type 3 VWD compared with type 1 VWD. Prediction of phenotype for an individual patient, however, is still difficult, and the addition of genetic data will be most helpful in ascertaining the correct diagnosis for VWD patients.
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http://dx.doi.org/10.1182/asheducation-2014.1.531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696506PMC
December 2014

Crucial role for the VWF A1 domain in binding to type IV collagen.

Blood 2015 Apr 6;125(14):2297-304. Epub 2015 Feb 6.

Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; and.

Von Willebrand factor (VWF) contains binding sites for platelets and for vascular collagens to facilitate clot formation at sites of injury. Although previous work has shown that VWF can bind type IV collagen (collagen 4), little characterization of this interaction has been performed. We examined the binding of VWF to collagen 4 in vitro and extended this characterization to a murine model of defective VWF-collagen 4 interactions. The interactions of VWF and collagen 4 were further studied using plasma samples from a large study of both healthy controls and subjects with different types of von Willebrand disease (VWD). Our results show that collagen 4 appears to bind VWF exclusively via the VWF A1 domain, and that specific sequence variations identified through VWF patient samples and through site-directed mutagenesis in the VWF A1 domain can decrease or abrogate this interaction. In addition, VWF-dependent platelet binding to collagen 4 under flow conditions requires an intact VWF A1 domain. We observed that decreased binding to collagen 4 was associated with select VWF A1 domain sequence variations in type 1 and type 2M VWD. This suggests an additional mechanism through which VWF variants may alter hemostasis.
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http://dx.doi.org/10.1182/blood-2014-11-610824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383803PMC
April 2015

Perils, problems, and progress in laboratory diagnosis of von Willebrand disease.

Authors:
Veronica H Flood

Semin Thromb Hemost 2014 Feb 12;40(1):41-8. Epub 2013 Dec 12.

Division of Pediatric Hematology/Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.

Diagnosis of von Willebrand disease (VWD) merits consideration of personal and family history of bleeding symptoms along with confirmatory laboratory testing. As the latter yields quantifiable results, overreliance on a laboratory diagnosis may occur. However, existing tests for VWD contain potential sources for error. Both intrinsic and extrinsic factors affecting these assays can contribute to either falsely normal or falsely abnormal results. This article will discuss the present available assays as well as new developments in diagnostic testing. A clear understanding of the limitations of VWD testing is helpful for ensuring the correct diagnosis of affected patients.
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http://dx.doi.org/10.1055/s-0033-1363166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987108PMC
February 2014
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