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1
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Perez Botero J. von Willebrand disease and heavy menstrual bleeding: when and how to test. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:376-381. [PMID: 39644046 DOI: 10.1182/hematology.2024000563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
von Willebrand disease (VWD) is a common inherited bleeding disorder caused by von Willebrand factor (VWF) deficiency and is an important cause of heavy menstrual bleeding in young patients. A clinical evaluation using standardized bleeding scores helps determine when screening hemostatic testing is indicated by identifying patients with a moderate or high probability of an inherited bleeding disorder. The diagnosis of VWD is made when VWF levels are under 30 IU/dL or between 30 and 50 IU/dL when there is a positive bleeding history. Activity levels above 100 IU/dL have a high negative predictive value. Multiple factors, including stress from acute bleeding and anemia, pregnancy, and medications, can affect VWF levels, hence testing for VWD is best performed when a person's health is at its baseline level, although this is not always possible in clinical practice. Variation in assay methodologies measuring VWF activity can have a significant impact on the diagnostic evaluation, and it is important for clinicians to be familiar with the limitations of the assay used by their local or reference laboratory. Genetic testing can be useful in establishing the VWD subtype and providing accurate reproductive counseling but is not required to make a diagnosis.
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2
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Kumar V, Goode D, Worfolk LA, Rhea-McManus J, Mitsios JV, Wong ECC. Analytical and Clinical Validation of a Non-Ristocetin Based VWF Assay on 2 Automated Analyzers in a Large Reference Laboratory. J Appl Lab Med 2024; 9:926-939. [PMID: 39045843 DOI: 10.1093/jalm/jfae063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 05/10/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND Historically, von Willebrand factor (VWF) activity assays utilized ristocetin despite limitations including poor limits of detection and high imprecision. Newer VWF activity assays such as the INNOVANCE® VWF Ac assay, however, do not rely on ristocetin to measure platelet-dependent VWF function. The purpose of this study was to evaluate the analytical and clinical performance of the Siemens Healthineers INNOVANCE VWF Ac Assay on the Siemens BCS® XP and the Sysmex® CS-2500 systems in a large reference laboratory setting. METHODS Performance indicators for the INNOVANCE VWF Ac assay were the limit of quantitation (LoQ), precision, and method comparison. Method comparison studies were performed using remnant plasma patient samples from routine coagulation tests and analyzed using both the INNOVANCE VWF Ac assay and the Siemens Healthineers ristocetin-dependent BC von Willebrand Reagent. RESULTS Evaluation of the INNOVANCE VWF Ac assay on the BCS® XP and CS-2500 systems demonstrated good precision and a lower LoQ compared to the BC von Willebrand Reagent. Method comparisons support the use of the INNOVANCE VWF Ac assay on the BCS® XP and CS-2500 systems to measure platelet-dependent VWF function. The INNOVANCE VWF Ac assay was able to further assist in von Willebrand disease classification in 6/7 (86%) samples when the result was below the LoQ for the BC von Willebrand Reagent (ristocetin cofactor activity). CONCLUSIONS These data are consistent with the 2021 American Society of Hematology/International Society on Thrombosis and Haemostasis/National Hemophilia Foundation/World Federation of Hemophilia von Willebrand disease guidelines that suggest using newer assays such as the INNOVANCE VWF Ac assay in place of ristocetin cofactor activity assays.
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Affiliation(s)
- Vivek Kumar
- Quest Diagnostics, Secaucus, NJ, United States
| | - Debra Goode
- Quest Diagnostics, Secaucus, NJ, United States
| | | | | | - John V Mitsios
- Siemens Healthcare Diagnostics Inc., Tarrytown, NY, United States
| | - Edward C C Wong
- Quest Diagnostics, Secaucus, NJ, United States
- Department of Pediatrics, George Washington School of Medicine and Health Sciences, Washington, DC, United States
- Department of Pathology, George Washington School of Medicine and Health Sciences, Washington, DC, United States
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3
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Seidizadeh O, Baronciani L, Lillicrap D, Peyvandi F. Application of genetic testing for the diagnosis of von Willebrand disease. J Thromb Haemost 2024; 22:2115-2128. [PMID: 38762018 PMCID: PMC11548015 DOI: 10.1016/j.jtha.2024.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/13/2024] [Accepted: 05/08/2024] [Indexed: 05/20/2024]
Abstract
von Willebrand disease (VWD) is the most frequent inherited bleeding disorder, with an estimated symptomatic prevalence of 1 per 1000 in the general population. VWD is characterized by defects in the quantity, quality, or multimeric structure of von Willebrand factor (VWF), a glycoprotein being hemostatically essential in circulation. VWD is classified into 3 principal types: low VWF/type 1 with partial quantitative deficiency of VWF, type 3 with virtual absence of VWF, and type 2 with functional abnormalities of VWF, being classified as 2A, 2B, 2M, and 2N. A new VWD type has been officially recognized by the ISTH SSC on von Willebrand factor which has also been discussed by the joint ASH/ISTH/NHF/WFH 2021 guidelines (ie, type 1C), indicating patients with quantitative deficiency due to an enhanced VWF clearance. With the advent of next-generation sequencing technologies, the process of genetic diagnosis has substantially changed and improved accuracy. Therefore, nowadays, patients with type 3 and severe type 1 VWD can benefit from genetic testing as much as type 2 VWD. Specifically, genetic testing can be used to confirm or differentiate a VWD diagnosis, as well as to provide genetic counseling. The focus of this manuscript is to discuss the current knowledge on VWD molecular pathophysiology and the application of genetic testing for VWD diagnosis.
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Affiliation(s)
- Omid Seidizadeh
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. https://twitter.com/OmidSeidi
| | - Luciano Baronciani
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - David Lillicrap
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada. https://twitter.com/DavidLillicrap
| | - Flora Peyvandi
- Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
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Álvarez Román MT, Rivas Pollmar MI, De la Corte-Rodríguez H, Gómez-Cardero P, Rodríguez-Merchán EC, Gutiérrez-Alvariño M, García-Pérez E, Martín-Salces M, Zagrean D, Butta-Coll NV, Jiménez-Yuste V. Knee replacement surgery in a patient with acquired von Willebrand disease: a case study with recommendations for patient management. Ann Med Surg (Lond) 2024; 86:1681-1686. [PMID: 38463081 PMCID: PMC10923270 DOI: 10.1097/ms9.0000000000001690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 12/27/2023] [Indexed: 03/12/2024] Open
Abstract
Introduction and importance Acquired von Willebrand disease (AvWD) is a rare underdiagnosed bleeding disorder caused by alterations in the levels of the major blood-clotting protein von Willebrand factor (vWF). The clinical and laboratory parameters of AvWD are similar to congenital vWD, but it is found in individuals with no positive family history with no underlying genetic basis. The disease remains multifactorial and incompletely understood. Proposed mechanisms include the development of autoantibodies to vWF, absorption of high molecular weight vWF multimers that impair normal function, shear stress induced vWF cleavage and increased proteolysis.The aetiology of the disease is variable, the most common being hematoproliferation, lymophoproliferation, myeloproliferation and autoimmune and cardiovascular disorders. Consensus and protocols for AvWD patients that require major surgery are currently lacking. Patients with AvWD can experience thrombotic events during surgery as a result of therapeutic interactions with pro-thrombotic risk factors. Case presentation Here, the authors report a patient with AvWD requiring a knee prosthesis implantation due to chronic pain, limited range of motion and functional impairment. The patient had a high risk of bleeding during surgery and was at risk of thrombosis due to age and obesity. Clinical discussion Perioperative care required a collaborative approach and the management of bleeding. The patient was administered vWF concentrate Willfact lacking Factor VIII to prevent haemorrhage and to minimize the risk of thrombosis. Conclusion The treatment was effective and well-tolerated. The authors use this information to provide recommendations for AvWD patients for whom major surgery is indicated.
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Affiliation(s)
| | | | | | | | - E. Carlos Rodríguez-Merchán
- Osteoarticular Surgery Research, Hospital La Paz Institute for Health Research, IdiPAZ (La Paz University Hospital—Autonomous University of Madrid)
| | | | | | | | | | | | - Víctor Jiménez-Yuste
- Departments ofHematology
- Department of Medicine, Autonomous University of Madrid, Madrid, Spain
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5
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Mehic D, Kraemmer D, Tolios A, Bücheler J, Quehenberger P, Haslacher H, Ay C, Pabinger I, Gebhart J. The necessity of repeat testing for von Willebrand disease in adult patients with mild to moderate bleeding disorders. J Thromb Haemost 2024; 22:101-111. [PMID: 37741511 DOI: 10.1016/j.jtha.2023.09.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 08/23/2023] [Accepted: 09/13/2023] [Indexed: 09/25/2023]
Abstract
BACKGROUND In patients with mild-to-moderate bleeding disorders (MBD), von Willebrand disease (VWD) is diagnosed at von Willebrand factor (VWF) levels ≤50 IU/dL. Although VWF levels are unstable, repeated testing for VWD diagnosis is not necessarily advised in recent guidelines. OBJECTIVES To analyze the relevance of repeated VWF testing to diagnose VWD in patients with MBD. METHODS Data of 277 patients with MBD from the Vienna Bleeding Biobank with at least 2 separate assessments of VWF antigen (VWF:Ag) and activity (VWF:Act) were analyzed. RESULTS In repeated VWF measurements, 36 patients (13.0%) had "changing" VWF levels (≤/>50 IU/dL), 27 (9.7%) had persistent levels ≤50 IU/dL ("pathologic"), and 214 (77.3%) had levels >50 IU/dL ("normal"). Of the 36 changing patients, 22 (61%) were diagnosed with VWD at baseline, whereas the others only met VWD diagnostic criteria at repeated measurements. Using logistic regression, we estimated a probability of change of 26.4% (95% CI, 12.5-47.4) at baseline VWF levels of 30 IU/dL, 50.8% (95% CI, 35.6-65.8) at 50 IU/dL, 18.8% (95% CI, 12.3-27.6) at 60 IU/dL, and 1.2% (95% CI, 0.3-4.9) at 80 IU/dL. Baseline VWF was a strong predictor for changing status (Χ2 = 49.9; P < .001), while age, sex, Vicenza score, and blood type O had limited added value (Χ2 = 5.1; P = .278). Baseline VWF:Ag or VWF:Act cutoffs of 80 IU/dL had negative predictive values of 98.1% and 99.1% for changing status, respectively. CONCLUSION Our data emphasize an overlap between patients with VWD and MBD with bleeding disorder of unknown cause and underline the need for repeated VWF testing, especially in patients with VWF levels <80 IU/dL.
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Affiliation(s)
- Dino Mehic
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria; Institute of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria. https://twitter.com/dino_mehic
| | - Daniel Kraemmer
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Alexander Tolios
- Department of Transfusion Medicine and Cell Therapy, Medical University of Vienna, Vienna, Austria
| | - Julia Bücheler
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Peter Quehenberger
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Helmuth Haslacher
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Cihan Ay
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. https://twitter.com/Cihan_Ay_MD
| | - Ingrid Pabinger
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. https://twitter.com/IngridPabinger
| | - Johanna Gebhart
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
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Pruthi RK, Smock K, Hayward CPM. Memorial notice: William L. Nichols, MD. Int J Lab Hematol 2023; 45:139-140. [PMID: 36372989 DOI: 10.1111/ijlh.13994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 11/06/2022] [Indexed: 11/16/2022]
Affiliation(s)
- Rajiv K Pruthi
- Hematology Division, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kristi Smock
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA.,ARUP Laboratories, Salt Lake City, Utah, USA
| | - Catherine P M Hayward
- Department of Pathology and Molecular Medicine, McMaster University, and the Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada.,Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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7
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Pruthi RK, Chen D. William L. Nichols, MD (1940-2022). JOURNAL OF THROMBOSIS AND HAEMOSTASIS : JTH 2023; 21:190-191. [PMID: 36695388 DOI: 10.1016/j.jtha.2022.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 10/21/2022] [Indexed: 01/09/2023]
Affiliation(s)
| | - Dong Chen
- Mayo Clinic, Rochester, Minnesota, USA
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8
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Muacevic A, Adler JR, Patel M, Houle MC, Thomas JM. A Case of Heyde's Syndrome With Subvalvular Aortic Stenosis. Cureus 2022; 14:e31723. [PMID: 36569689 PMCID: PMC9769066 DOI: 10.7759/cureus.31723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2022] [Indexed: 11/23/2022] Open
Abstract
Heyde's syndrome is a constellation of severe aortic stenosis, gastrointestinal arteriovenous malformations (AVMs), and an acquired von Willebrand type 2A coagulopathy resulting in moderate-to-severe gastrointestinal bleeding. Additional cardiac lesions have been observed to cause Heyde's syndrome including aortic regurgitation, mitral regurgitation, aortic/mitral valve prosthetic dysfunction, ventricular septal defects, hypertrophic cardiomyopathy, left ventricular assist devices, and extracorporeal life support devices. Repairing the cardiac lesion or removing the device decreases the incidence of gastrointestinal bleeding by normalizing the acquired von Willebrand coagulopathy and decreasing the amount of gastrointestinal AVMs likely to bleed. We describe a case of a 67-year-old woman found to have Heyde's syndrome arising from a subvalvular aortic membrane resulting in severe subaortic stenosis with no other significant cardiac lesion. She underwent successful resection of the membrane with septal myectomy, relieving the severe subaortic stenosis and resolving her anemia. Years later, she re-presented with severe gastrointestinal bleeding from gastrointestinal malformations. Early recognition of these cardiac lesions with gastrointestinal bleeds may help decrease the morbidity and mortality that Heyde's syndrome portends and provide evidence for early intervention.
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9
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Hollestelle MJ, Meijers JCM, Meijer P. How Do Laboratories Perform von Willebrand Disease Diagnostics and Classification of von Willebrand Disease Patients? Results from External Quality Data and an International Survey. Semin Thromb Hemost 2022. [PMID: 36063849 DOI: 10.1055/s-0042-1757137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
BACKGROUND Reduced or dysfunctional von Willebrand factor (VWF) may lead to von Willebrand disease (VWD), which is a common inherited bleeding disorder. VWD is classified into three major types: type 1 is a partial quantitative deficiency of VWF, type 3 is a complete quantitative deficiency of VWF, and type 2 consists of qualitative abnormalities of VWF. To arrive at a correct VWD diagnosis, multiple tests and a correct interpretation of these tests are needed. AIM The aim of the present study was to gain insight into the approach of laboratories toward VWD diagnosis. METHODS Data from four samples of the external quality assessment (EQA) VWF surveys of the ECAT (External Quality Control for Assays and Tests) were evaluated. Furthermore, results were analyzed of a questionnaire that was sent to hemostasis laboratories about VWD diagnostic approaches. RESULTS For most EQA samples, the majority of participants indicated the correct classification. However, 6 to 60% indicated another classification. For all samples, significant differences in VWF results were observed between the correct and incorrect classifications. The questionnaire demonstrated that the testing approach varied between the laboratories, especially for parameters that were essential for discrimination between VWD type 1 and healthy individuals, as well as the cutoff values used to discriminate VWD types 1 and 2. CONCLUSIONS Diagnosis of VWD is heterogeneous in diagnostic approach, guidelines, and cutoff values within large ranges of VWF results between laboratories. Harmonization of approaches and increased accuracy of VWF measurements may help to establish a correct diagnosis.
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Affiliation(s)
- Martine J Hollestelle
- External Quality Control for Assays and Tests (ECAT) Foundation, Voorschoten, the Netherlands
| | - Joost C M Meijers
- Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.,Department of Molecular Hematology, Sanquin Research, Amsterdam, the Netherlands
| | - Piet Meijer
- External Quality Control for Assays and Tests (ECAT) Foundation, Voorschoten, the Netherlands
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10
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Smock KJ, Gosselin RC. Preface: Laboratory Diagnostics for Thrombosis and Hemostasis Testing - Part I. Semin Thromb Hemost 2022; 48:631-633. [PMID: 36055260 DOI: 10.1055/s-0042-1755367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Affiliation(s)
- Kristi J Smock
- Department of Pathology and ARUP Laboratories, University of Utah, Salt Lake City, Utah
| | - Robert C Gosselin
- Hemostasis and Thrombosis Center, University of California, Davis Health System, Sacramento, California
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11
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Hollestelle MJ, Meijers JCM, Meijer P. How Do Laboratories Perform von Willebrand Disease Diagnostics and Classification of von Willebrand Disease Patients? Results from External Quality Data and an International Survey. Semin Thromb Hemost 2022; 48:739-749. [DOI: 10.1055/s-0042-1758163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Abstract
Background Reduced or dysfunctional von Willebrand factor (VWF) may lead to von Willebrand disease (VWD), which is a common inherited bleeding disorder. VWD is classified into three major types: type 1 is a partial quantitative deficiency of VWF, type 3 is a complete quantitative deficiency of VWF, and type 2 consists of qualitative abnormalities of VWF. To arrive at a correct VWD diagnosis, multiple tests and a correct interpretation of these tests are needed.
Aim The aim of the present study was to gain insight into the approach of laboratories toward VWD diagnosis.
Methods Data from four samples of the external quality assessment (EQA) VWF surveys of the ECAT (External Quality Control for Assays and Tests) were evaluated. Furthermore, results were analyzed of a questionnaire that was sent to hemostasis laboratories about VWD diagnostic approaches.
Results For most EQA samples, the majority of participants indicated the correct classification. However, 6 to 60% indicated another classification. For all samples, significant differences in VWF results were observed between the correct and incorrect classifications. The questionnaire demonstrated that the testing approach varied between the laboratories, especially for parameters that were essential for discrimination between VWD type 1 and healthy individuals, as well as the cutoff values used to discriminate VWD types 1 and 2.
Conclusions Diagnosis of VWD is heterogeneous in diagnostic approach, guidelines, and cutoff values within large ranges of VWF results between laboratories. Harmonization of approaches and increased accuracy of VWF measurements may help to establish a correct diagnosis.
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Affiliation(s)
- Martine J. Hollestelle
- External Quality Control for Assays and Tests (ECAT) Foundation, Voorschoten, the Netherlands
| | - Joost C. M. Meijers
- Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Molecular Hematology, Sanquin Research, Amsterdam, the Netherlands
| | - Piet Meijer
- External Quality Control for Assays and Tests (ECAT) Foundation, Voorschoten, the Netherlands
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12
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Hollestelle MJ, Meijers JCM, Meijer P. How Do Laboratories Perform von Willebrand Disease Diagnostics and Classification of von Willebrand Disease Patients? Results from External Quality Data and an International Survey. Semin Thromb Hemost 2022; 48:739-749. [PMID: 36055267 DOI: 10.1055/s-0042-1754354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
BACKGROUND Reduced or dysfunctional von Willebrand factor (VWF) may lead to von Willebrand disease (VWD), which is a common inherited bleeding disorder. VWD is classified into three major types: type 1 is a partial quantitative deficiency of VWF, type 3 is a complete quantitative deficiency of VWF, and type 2 consists of qualitative abnormalities of VWF. To arrive at a correct VWD diagnosis, multiple tests and a correct interpretation of these tests are needed. AIM The aim of the present study was to gain insight into the approach of laboratories toward VWD diagnosis. METHODS Data from four samples of the external quality assessment (EQA) VWF surveys of the ECAT (External Quality Control for Assays and Tests) were evaluated. Furthermore, results were analyzed of a questionnaire that was sent to hemostasis laboratories about VWD diagnostic approaches. RESULTS For most EQA samples, the majority of participants indicated the correct classification. However, 6 to 60% indicated another classification. For all samples, significant differences in VWF results were observed between the correct and incorrect classifications. The questionnaire demonstrated that the testing approach varied between the laboratories, especially for parameters that were essential for discrimination between VWD type 1 and healthy individuals, as well as the cutoff values used to discriminate VWD types 1 and 2. CONCLUSIONS Diagnosis of VWD is heterogeneous in diagnostic approach, guidelines, and cutoff values within large ranges of VWF results between laboratories. Harmonization of approaches and increased accuracy of VWF measurements may help to establish a correct diagnosis.
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Affiliation(s)
- Martine J Hollestelle
- External Quality Control for Assays and Tests (ECAT) Foundation, Voorschoten, the Netherlands
| | - Joost C M Meijers
- Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Molecular Hematology, Sanquin Research, Amsterdam, the Netherlands
| | - Piet Meijer
- External Quality Control for Assays and Tests (ECAT) Foundation, Voorschoten, the Netherlands
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13
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Approach to the Patient with Bleeding. Hematol Oncol Clin North Am 2021; 35:1039-1049. [PMID: 34535288 DOI: 10.1016/j.hoc.2021.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
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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14
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Lourdusamy D, Mupparaju VK, Sharif NF, Ibebuogu UN. Aortic stenosis and Heyde’s syndrome: A comprehensive review. World J Clin Cases 2021; 9:7319-7329. [PMID: 34616798 PMCID: PMC8464459 DOI: 10.12998/wjcc.v9.i25.7319] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/07/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023] Open
Abstract
Heyde’s syndrome is an under reported systemic disease of gastrointestinal and cardiac manifestation in older adults. It is characterized by a triad of aortic stenosis, angiodysplasia with bleeding and acquired von Willebrand syndrome. It is characterized by proteolysis of high molecular weight multimers of von Willebrand Factor and loss of platelet mediated homeostasis. Heyde’s syndrome is a treatable condition in most cases, especially in the current era of evolution in interventional cardiology and gastroenterology. There are currently no established guidelines in the management of this condition due to paucity of high quality studies, which warrant future trials. High index of suspicion and increasing the awareness of the syndrome among the general practitioners and sub-specialists will improve the diagnostic potential of Heyde’s syndrome. Future studies may change the management aspect of Heyde's syndrome and pave a path for drawing specific guidelines and algorithms. The aim of our review article is to summarize the basic pathophysiology, diagnostics and management of Heyde’s syndrome with a special attention to Transcatheter aortic valve replacement.
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Affiliation(s)
| | | | - Navila Fahmida Sharif
- Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, United States
| | - Uzoma N Ibebuogu
- Cardiovascular Diseases, University of Tennessee Health Science Center, Memphis, TN 38163, United States
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15
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Nagarajan VD, Shenoi A, Burgess L, Radulescu VC. Spontaneous pyohaemothorax in a teenager with von Willebrand disease: a case report and review of literature. BMJ Case Rep 2021; 14:e241613. [PMID: 34404645 PMCID: PMC8372795 DOI: 10.1136/bcr-2021-241613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2021] [Indexed: 11/04/2022] Open
Abstract
An 18-year-old man with a history of type 3 von Willebrand disease (VWD) presented with a spontaneous pyohaemothorax. Type 3 VWD may present with both mucocutaneous and deep-seated bleeds, such as visceral haemorrhages, intracranial bleeds and haemarthrosis. There have been very few cases described in children of spontaneous pyohaemothorax. Management of this patient was challenging due to risks of bleeding following surgical drainage, requiring constant replacement with von Willebrand factor concentrate, while monitoring factor VIII levels to balance the risks of thrombosis.
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Affiliation(s)
- Vaishnavi Divya Nagarajan
- Pediatrics, University of Kentucky, Lexington, Kentucky, USA
- Pediatrics, University of Kentucky, Lexington, Kentucky, USA
| | - Asha Shenoi
- Pediatric Critical Care, University of Kentucky, Lexington, Kentucky, USA
| | - Lucy Burgess
- Pediatrics, University of Kentucky, Lexington, Kentucky, USA
| | - Vlad C Radulescu
- Pediatric Hematology - Oncology, University of Kentucky, Lexington, Kentucky, USA
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Ward S, O'Sullivan JM, O'Donnell JS. The Biological Significance of von Willebrand Factor O-Linked Glycosylation. Semin Thromb Hemost 2021; 47:855-861. [PMID: 34130346 DOI: 10.1055/s-0041-1726373] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Glycosylation is a key posttranslational modification, known to occur on more than half of all secreted proteins in man. As such, the role of N- and O-linked glycan structures in modulating various aspects of protein biology is an area of much research. Given their prevalence, it is perhaps unsurprising that variations in glycan structures have been demonstrated to play critical roles in modulating protein function and have been implicated in the pathophysiology of human diseases. von Willebrand factor (VWF), a plasma glycoprotein that is essential for normal hemostasis, is heavily glycosylated, containing 13 N-linked and 10 O-linked glycans. Together, these carbohydrate chains account for 20% of VWF monomeric mass, and have been shown to modulate VWF structure, function, and half-life. In this review, we focus on the specific role played by O-linked glycans in modulating VWF biology. Specifically, VWF O-linked glycans have been shown to modulate tertiary protein structure, susceptibility to ADAMTS13 proteolysis, platelet tethering, and VWF circulatory half-life.
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Affiliation(s)
- Soracha Ward
- Haemostasis Research Group, Irish Centre for Vascular Biology, School of Pharmacy and Bimolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jamie M O'Sullivan
- Haemostasis Research Group, Irish Centre for Vascular Biology, School of Pharmacy and Bimolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - James S O'Donnell
- Haemostasis Research Group, Irish Centre for Vascular Biology, School of Pharmacy and Bimolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.,National Coagulation Centre, St James's Hospital, Dublin, Ireland
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17
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Low VWF: insights into pathogenesis, diagnosis, and clinical management. Blood Adv 2021; 4:3191-3199. [PMID: 32663299 DOI: 10.1182/bloodadvances.2020002038] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 05/29/2020] [Indexed: 01/17/2023] Open
Abstract
von Willebrand disease (VWD) constitutes the most common inherited human bleeding disorder. Partial quantitative von Willebrand factor (VWF) deficiency is responsible for the majority of VWD cases. International guidelines recommend that patients with mild to moderate reductions in plasma VWF antigen (VWF:Ag) levels (typically in the range of 30-50 IU/dL) should be diagnosed with low VWF. Over the past decade, a series of large cohort studies have provided significant insights into the biological mechanisms involved in type 1 VWD (plasma VWF:Ag levels <30 IU/dL). In striking contrast, however, the pathogenesis underpinning low VWF has remained poorly understood. Consequently, low VWF patients continue to present significant clinical challenges with respect to genetic counseling, diagnosis, and management. For example, there is limited information regarding the relationship between plasma VWF:Ag levels and bleeding phenotype in subjects with low VWF. In addition, it is not clear whether patients with low VWF need treatment. For those patients with low VWF in whom treatment is deemed necessary, the optimal choice of therapy remains unknown. However, a number of recent studies have provided important novel insights into these clinical conundrums and the molecular mechanisms responsible for the reduced levels observed in low VWF patients. These emerging clinical and scientific findings are considered in this review, with particular focus on pathogenesis, diagnosis, and clinical management of low VWF.
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18
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ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021; 5:280-300. [PMID: 33570651 DOI: 10.1182/bloodadvances.2020003265] [Citation(s) in RCA: 291] [Impact Index Per Article: 72.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 10/23/2020] [Indexed: 11/20/2022] Open
Abstract
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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19
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Konkle BA, Pipe SW. Diagnosis and management of von Willebrand disease: A community-wide effort to deliver evidence-based clinical practice guidelines. Haemophilia 2021; 27:181-183. [PMID: 33565159 DOI: 10.1111/hae.14262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 11/30/2022]
Affiliation(s)
- Barbara A Konkle
- World Federation of Hemophilia, Montréal, QC, Canada.,Department of Medicine, University of Washington, Seattle, WA, USA
| | - Steven W Pipe
- National Hemophilia Foundation, New York, NY, USA.,Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI, USA
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20
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Thau A, Saffren B, Zakrzewski H, Anderst JD, Carpenter SL, Levin A. Retinal hemorrhage and bleeding disorders in children: A review. CHILD ABUSE & NEGLECT 2021; 112:104901. [PMID: 33401159 DOI: 10.1016/j.chiabu.2020.104901] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/27/2020] [Accepted: 12/16/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Retinal hemorrhages (RH) are a common manifestation of abusive head trauma (AHT) resulting from acceleration-deceleration injury with or without blunt impact. Evaluation of a child with RH requires careful consideration of these differential diagnoses. The extent to which coagulopathy alone can cause RH would be useful to understand as coagulopathy may accompany AHT. OBJECTIVE In this systematic review, we sought to identify whether coagulopathies have been reported with RH similar to those of AHT. METHODS We performed a literature search for ocular manifestations of bleeding disorders in children less than 18 years old. We included clotting factor deficiencies, vitamin K deficiency, platelet function abnormalities, thrombocytopenia, disseminated intravascular coagulation (DIC), and trauma induced coagulopathy (TIC). We included only pediatric reports of intraocular bleeding or documented eye examinations that indicated no hemorrhages. We then re-examined cases for ocular and systemic findings that could potentially mimic abuse. RESULTS Our initial search yielded 816 results. Sixty-one articles met our inclusion criteria. Of these, there were 32 children within the AHT age range (less than 5 years old) who had RH and concomitant coagulopathy. Only 5 cases might potentially be confused for abuse. Of these, no classic characteristics of RH from abuse such as retinoschisis or retinal folds were found. Systemic features were inconsistent with AHT. CONCLUSIONS The presence of coagulopathy alone does not rule out the possibility that the child has been abused. Coagulopathy alone has not been reported as an etiology of RH that are consistent with AHT, especially when other findings are present.
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Affiliation(s)
- Avrey Thau
- Thomas Jefferson University, Philadelphia, PA, USA
| | - Brooke Saffren
- Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA
| | - Helena Zakrzewski
- Department of Experimental Surgery, McGill University, Montreal, QC, Canada
| | - James D Anderst
- Division of Child Adversity and Resilience, Children's Mercy Hospital, Kansas City, MO, USA
| | - Shannon L Carpenter
- Department of Hematology, Oncology, and Bone Marrow Transplantation, Children's Mercy Hospital, Kansas City, MO, USA
| | - Alex Levin
- Flaum Eye Institute and Golisano Children's Hospital, University of Rochester, New York, USA.
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21
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James PD. Women and bleeding disorders: diagnostic challenges. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2020; 2020:547-552. [PMID: 33275722 PMCID: PMC7727580 DOI: 10.1182/hematology.2020000140] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2023]
Abstract
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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22
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Gebhart J, Hofer S, Kaider A, Rejtö J, Ay C, Pabinger I. The discriminatory power of bleeding assessment tools in adult patients with a mild to moderate bleeding tendency. Eur J Intern Med 2020; 78:34-40. [PMID: 32317240 DOI: 10.1016/j.ejim.2020.04.023] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/24/2020] [Accepted: 04/06/2020] [Indexed: 01/30/2023]
Abstract
BACKGROUND Bleeding assessment tools (BATs) have been developed to quantify bleeding severity. Their ability to predict for the diagnosis of a bleeding disorder has not been thoroughly investigated. OBJECTIVES To evaluate the ability of the Vicenza BAT and the ISTH BAT to distinguish patients with an established bleeding disorder from those with bleeding of unknown cause (BUC). PATIENTS/METHODS Three-hundred fifty-nine patients (228 with BUC, 64%) from the Vienna Bleeding Biobank were assessed in this study. RESULTS The bleeding scores were similar in patients with an established diagnosis of a bleeding disorder compared to patients with BUC. Both BATs had a low sensitivity and specificity for the diagnosis of a bleeding disorder with areas under the receiver operating characteristic (ROC) curves of 0.53 (95% confidence interval 0.47-0.60) for the Vicenza BAT and 0.52 (0.46-0.59) for the ISTH BAT. In terms of specific diagnoses, both scores were most accurate in diagnosing von Willebrand disease (VWD, areas under the ROC curve; Vicenza BAT 0.67 (0.45-0.90); ISTH BAT 0.70 (0.50-0.90)). A separate evaluation of different bleeding symptoms in patients who had undergone surgery and tooth extraction revealed that postpartum bleeding and bleeding from small wounds was predictive for diagnosing a MBD in multivariable analysis. CONCLUSIONS The Vicenza- and the ISTH BAT have a low ability to distinguish patients with an established bleeding disorder from those with BUC.
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Affiliation(s)
- Johanna Gebhart
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
| | - Stefanie Hofer
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
| | - Alexandra Kaider
- Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Austria
| | - Judit Rejtö
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
| | - Cihan Ay
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
| | - Ingrid Pabinger
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
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23
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Bagaria V, Mathur P, Madan K, Kumari M, Sagar S, Gupta A, Soni KD, Bhattacharjee H, Kumar S. Predicting Outcomes After Blunt Chest Trauma-Utility of Thoracic Trauma Severity Score, Cytokines (IL-1β, IL-6, IL-8, IL-10, and TNF-α), and Biomarkers (vWF and CC-16). Indian J Surg 2020; 83:113-119. [PMID: 32837068 PMCID: PMC7275928 DOI: 10.1007/s12262-020-02407-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 05/22/2020] [Indexed: 11/18/2022] Open
Abstract
Thoracic trauma severity score (TTSS) has been used to assess severity and risk of pulmonary complications in patients with chest trauma. The role of cytokines and biomarkers in patients with chest trauma and its association with TTSS is not well elucidated. The aim of the study was to assess the cytokines (IL-1β, IL-6, IL-8, IL-10, and TNF-α) and biomarkers (vWF, CC-16) in patients of thoracic trauma and correlate it with TTSS and patient’s outcome. This was a prospective observational study. Serum and bronchoalveolar lavage fluid samples were collected from chest trauma patients. TTSS was calculated in all patients. Suitable controls for serum and bronchoalveolar lavage (BAL) sample were selected. The outcome parameters included patient discharge or death, duration of hospital, and intensive care unit (ICU) stay. Forty-three patients were included. There was no significant correlation between the measured cytokines and biomarkers and TTSS. The mean TTSS of patients who had a fatal outcome was significantly higher than the patients who recovered. Patients with a high TTSS score had a significant prolonged ICU stay. Patients with a prolonged hospital stay had lower values of CC-16. TTSS is a useful tool to predict severity of chest trauma and prolonged ICU stay. Lower levels of CC-16 in BAL fluid of chest trauma patients were associated with prolonged hospital stay suggestive of its protective role in the airway. Longer prospective studies are required to determine the role of cytokines and biomarkers in patients with thoracic trauma in predicting the patient’s outcome.
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Affiliation(s)
- Vivek Bagaria
- Department of Surgical Disciplines, All India Institute of Medical Sciences, New Delhi, India
| | - Purva Mathur
- Department of Laboratory Medicine, JPN Apex Trauma Center, All India Institute of Medical Sciences, New Delhi, India
| | - Karan Madan
- Department of Pulmonary Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Minu Kumari
- Division of Trauma Surgery & Critical Care, JPN Apex Trauma Center, All India Institute of Medical Sciences, New Delhi, India
| | - Sushma Sagar
- Division of Trauma Surgery & Critical Care, JPN Apex Trauma Center, All India Institute of Medical Sciences, New Delhi, India
| | - Amit Gupta
- Division of Trauma Surgery & Critical Care, JPN Apex Trauma Center, All India Institute of Medical Sciences, New Delhi, India
| | - Kapil Dev Soni
- Division of Trauma Surgery & Critical Care, JPN Apex Trauma Center, All India Institute of Medical Sciences, New Delhi, India
| | - Hemanga Bhattacharjee
- Department of Surgical Disciplines, All India Institute of Medical Sciences, New Delhi, India
| | - Subodh Kumar
- Division of Trauma Surgery & Critical Care, JPN Apex Trauma Center, All India Institute of Medical Sciences, New Delhi, India
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24
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Sharma R, Haberichter SL. New advances in the diagnosis of von Willebrand disease. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2019; 2019:596-600. [PMID: 31808831 PMCID: PMC6913428 DOI: 10.1182/hematology.2019000064] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
von Willebrand disease (VWD) is the most common autosomal inherited bleeding disorder, with an estimated prevalence of 1 in 1000 individuals. VWD is classified into quantitative and qualitative forms. Diagnosis of VWD is complex and requires (1) a personal history of bleeding symptoms, (2) family history of bleeding or VWD, and (3) confirmatory laboratory testing. There are certain bleeding assessment tools to objectively measure bleeding symptoms in patients that have been shown to correlate with the diagnosis as well as the severity of VWD. Laboratory diagnosis requires at least initially a measurement of von Willebrand factor (VWF) antigen levels, VWF platelet binding activity (VWF:RCo, VWF:GPIbM, and VWF:GPIbR), and factor VIII (FVIII) activity. Additional testing to confirm the specific subtype may include VWF collagen binding activity, low-dose ristocetin VWF-platelet binding, FVIII-VWF binding, VWF multimer analysis, and VWF propeptide antigen. Recent advances have been made regarding some of these assays. Molecular testing in VWD is not found to be useful in "low VWF" or most type 1 VWD cases but may be informative in patients with severe type 1 VWD, type 1C VWD, type 2 VWD, or type 3 VWD for accurate diagnosis, genetic counseling, and appropriate treatment. The diagnostic algorithm for VWD is complex, but advances continue to be made in improving VWF functional assays and diagnostic pathways.
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Affiliation(s)
- Ruchika Sharma
- Diagnostic Laboratories and Blood Research Institute, Versiti, Milwaukee, WI
- Pediatric Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; and
- Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI
| | - Sandra L Haberichter
- Diagnostic Laboratories and Blood Research Institute, Versiti, Milwaukee, WI
- Pediatric Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; and
- Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI
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25
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Itzhar-Baikian N, Boisseau P, Joly B, Veyradier A. Updated overview on von Willebrand disease: focus on the interest of genotyping. Expert Rev Hematol 2019; 12:1023-1036. [PMID: 31536379 DOI: 10.1080/17474086.2019.1670638] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Introduction: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, characterized by a quantitative or qualitative defect of von Willebrand factor (VWF), a multimeric glycoprotein crucial for primary hemostasis and coagulation. VWD pathophysiology is heterogeneous as it includes several types and subtypes which therapeutic management is different. The mainstays of VWD treatment are desmopressin and replacement therapy based on both plasma-derived concentrates and a recently developed recombinant VWF. VWD definitive diagnosis is achieved by a battery of phenotypic biologic assays and genotyping is currently performed mostly for research.Areas covered: This narrative review will firstly present a general overview on VWD epidemiology, pathophysiology, classification, clinics, phenotypic biologic diagnosis, and treatment. Secondly, a focus on VWD genotyping will be presented with specific emphasis on the evolution of its technical aspects, its applications for research dedicated to a better understanding of VWD pathophysiology and epidemiology and its interest in both a faster diagnosis and an optimal treatment of VWD.Expert opinion: Based on analysis of the literature, it can be concluded that the fast evolution of genetic techniques together with the development of innovating treatments may significantly change diagnostic flow charts for VWD and their use for specific and personalized treatment.
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Affiliation(s)
- Nathalie Itzhar-Baikian
- Service d'Hématologie biologique Hôpital Lariboisière and EA-3518 Institut de Recherche Saint Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France
| | - Pierre Boisseau
- Service de Génétique médicale, Hôpital Hôtel-Dieu, CHU de Nantes, Nantes, France
| | - Bérangère Joly
- Service d'Hématologie biologique Hôpital Lariboisière and EA-3518 Institut de Recherche Saint Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France
| | - Agnès Veyradier
- Service d'Hématologie biologique Hôpital Lariboisière and EA-3518 Institut de Recherche Saint Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France
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26
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Abstract
Heyde described aortic stenosis and gastrointestinal bleeding in the 1950s. Since then, a link with intestinal angiodysplasia and abnormalities of von Willebrand factor (VWF) has been noted. Loss of the highest-molecular-weight multimers of VWF and bleeding also have been described in subaortic stenosis in hypertrophic cardiomyopathy, in isolated mitral and aortic insufficiency, in endocarditis, in patients with prosthetic valve stenosis or regurgitation, and in patients with left ventricular assist devices (LVADs). Bleeding tends to recur with local treatment of angiodysplasias, whereas cardiac repair or removal of LVAD eliminates VWF dysfunction is curative of bleeding in the majority.
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27
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Trossaert M, Graveleau J, Thiercelin-Legrand MF, Sigaud M, Guerrero F, Neel A, Fouassier M, Sailler L, Chauveau D, Ternisien C, Huart A, Gillet B, Hamidou M, Bene MC, Voisin S. The factor VIII:C/VWF:Ag ratio as a useful tool to predict relapse in patients with acquired haemophilia A: A retrospective cohort study. Haemophilia 2019; 25:527-534. [PMID: 31050100 DOI: 10.1111/hae.13752] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 03/14/2019] [Accepted: 03/15/2019] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Acquired haemophilia A (AHA) is a rare autoimmune bleeding disorder caused by the presence of autoantibodies against coagulation factor VIII (FVIII). The mortality rate remains high. International recommendations define complete remission as undetectable inhibitor (<0.6 Bethesda Units [BU]) and normal FVIII activity (FVIII:C) that persists after immunosuppressive therapy stopped. For patients achieving remission, the risk of relapse reaches 20%. The risk factors for this relapse are not well known. AIM In this study, we examined the accuracy of the FVIII/W ratio (FVIII:C/von Willebrand Factor Antigen (VWF:Ag) ratio) to predict relapse in 64 consecutive patients with AHA. RESULTS In this cohort, all patients had a very low FVIII/W ratio at the time of diagnosis, and this value progressively increased in the first weeks of immunosuppressive treatment. In our study, 9/55 (14%) did not achieve complete remission. Twenty-seven patients were followed long enough (more than a year) to show that in the 22 patients who did not relapse, the FVIII/W ratio remained durably normalized. By contrast, in the five patients who relapsed during follow-up, we noted either no normalization of the FVIII/W ratio, or a secondary decrease to an abnormal value of <0.7 after initial normalization. In all patients who relapsed, the ratio was the first abnormal biological result to be observed, always preceding changes in the activated partial thromboplastin time (aPTT), FVIII:C and anti-FVIII reappearance. CONCLUSION These data suggest that the FVIII/W ratio could be considered a sensitive biological marker to predict recovery and/or relapse in AHA.
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Affiliation(s)
- Marc Trossaert
- Laboratoire d'hémostase, Service d'Hématologie Biologique, CHU de Nantes, France
| | | | | | - Marianne Sigaud
- Laboratoire d'hémostase, Service d'Hématologie Biologique, CHU de Nantes, France
| | | | - Antoine Neel
- Service de Médecine Interne, CHU de Nantes, France
| | - Marc Fouassier
- Laboratoire d'hémostase, Service d'Hématologie Biologique, CHU de Nantes, France
| | | | - Dominique Chauveau
- Département de Néphrologie et Transplantation d'Organes, CHU Rangueil et Université Paul Sabatier, Toulouse, France
| | - Catherine Ternisien
- Laboratoire d'hémostase, Service d'Hématologie Biologique, CHU de Nantes, France
| | - Antoine Huart
- Service de Médecine Interne, CHU de Toulouse, France
| | - Benjamin Gillet
- Laboratoire d'hémostase, Service d'Hématologie Biologique, CHU de Nantes, France
| | | | - Marie C Bene
- Laboratoire d'hémostase, Service d'Hématologie Biologique, CHU de Nantes, France
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Dunkley S, Curtin JA, Marren AJ, Heavener RP, McRae S, Curnow JL. Updated Australian consensus statement on management of inherited bleeding disorders in pregnancy. Med J Aust 2019; 210:326-332. [PMID: 30924538 PMCID: PMC6850504 DOI: 10.5694/mja2.50123] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION There have been significant advances in the understanding of the management of inherited bleeding disorders in pregnancy since the last Australian Haemophilia Centre Directors' Organisation (AHCDO) consensus statement was published in 2009. This updated consensus statement provides practical information for clinicians managing pregnant women who have, or carry a gene for, inherited bleeding disorders, and their potentially affected infants. It represents the consensus opinion of all AHCDO members; where evidence was lacking, recommendations have been based on clinical experience and consensus opinion. MAIN RECOMMENDATIONS During pregnancy and delivery, women with inherited bleeding disorders may be exposed to haemostatic challenges. Women with inherited bleeding disorders, and their potentially affected infants, need specialised care during pregnancy, delivery, and postpartum, and should be managed by a multidisciplinary team that includes at a minimum an obstetrician, anaesthetist, paediatrician or neonatologist, and haematologist. Recommendations on management of pregnancy, labour, delivery, obstetric anaesthesia and postpartum care, including reducing and treating postpartum haemorrhage, are included. The management of infants known to have or be at risk of an inherited bleeding disorder is also covered. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT Key changes in this update include the addition of a summary of the expected physiological changes in coagulation factors and phenotypic severity of bleeding disorders in pregnancy; a flow chart for the recommended clinical management during pregnancy and delivery; guidance for the use of regional anaesthetic; and prophylactic treatment recommendations including concomitant tranexamic acid.
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Affiliation(s)
- Scott Dunkley
- Institute of HaematologyRoyal Prince Alfred HospitalSydneyNSW
| | - Julie A Curtin
- The Children's Hospital at WestmeadSydneyNSW
- Australian Haemophilia Centres Directors’ OrganisationMelbourneVIC
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29
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O'Sullivan JM, Ward S, Lavin M, O'Donnell JS. von Willebrand factor clearance - biological mechanisms and clinical significance. Br J Haematol 2018; 183:185-195. [DOI: 10.1111/bjh.15565] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Jamie M. O'Sullivan
- Haemostasis Research Group; Irish Centre for Vascular Biology; Royal College of Surgeons in Ireland; Dublin Ireland
| | - Soracha Ward
- Haemostasis Research Group; Irish Centre for Vascular Biology; Royal College of Surgeons in Ireland; Dublin Ireland
| | - Michelle Lavin
- Haemostasis Research Group; Irish Centre for Vascular Biology; Royal College of Surgeons in Ireland; Dublin Ireland
- National Coagulation Centre; St James's Hospital; Dublin Ireland
| | - James S. O'Donnell
- Haemostasis Research Group; Irish Centre for Vascular Biology; Royal College of Surgeons in Ireland; Dublin Ireland
- National Coagulation Centre; St James's Hospital; Dublin Ireland
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30
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Hayward CPM. How I investigate for bleeding disorders. Int J Lab Hematol 2018; 40 Suppl 1:6-14. [PMID: 29741250 DOI: 10.1111/ijlh.12822] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 02/07/2018] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Laboratory investigations for bleeding disorders are warranted when an individual has a personal and/or family history of bleeding, and/or laboratory findings that suggest the possibility of an inherited or acquired bleeding disorder. METHODS This review summarizes author's experience with ordering and reporting on diagnostic investigations for common and rare bleeding disorders, with consideration of recent articles on diagnosing bleeding disorders. An updated strategy is presented for investigating common and rare, congenital and acquired bleeding disorders. RESULTS An investigation of a suspected bleeding disorder requires a practical strategy that considers the clinical problem to be investigated, the pretest probability of true-positive and false-positive findings, the investigations can be performed locally or in a reference laboratory and limit the number of blood samples required to establish a diagnosis. It is often advantageous to simultaneously test for von Willebrand disease and platelet function disorders, and for coagulation defects, including fibrinogen disorders. An investigation for rarer bleeding disorders, including those affecting factor XIII, α2 antiplasmin, and plasminogen activator inhibitor-1, is appropriate when faced with a severe congenital or acquired bleeding problem that cannot be explained by the initial diagnostic investigations. CONCLUSION An organized strategy for investigating bleeding disorders that consider important issues, confirms abnormal findings, encourages proper interpretation of the results, and provides a helpful framework for assessing both common and rare causes of bleeding.
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Affiliation(s)
- C P M Hayward
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.,Department of Medicine, McMaster University, Hamilton, ON, Canada.,Hamilton Regional Laboratory Medicine Program, Hamilton, ON, Canada
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Abstract
Von Willebrand disease (VWD) is an inherited bleeding disorder that affects up to 1% of the population. In most cases, VWD results from a mutation in the von Willebrand Factor (VWF) gene, which alters the amount and function of VWF, a key glycoprotein in both primary and secondary hemostasis. A comprehensive analysis of patients with VWD should include VWF activity, antigen levels, platelet function, and a careful bleeding history. Treatment options include antifibrinolytics, desmopressin, and VWF replacement therapy. VWF levels fluctuate due to age, stress, environmental exposures, and pharmacologic treatment. Treatment guidelines exist to treat and prevent bleeding for patients undergoing surgery and medical procedures, but often these must be reevaluated in the setting of age-related comorbidities including cardiovascular events, venous thrombosis, and malignancy. In addition, many age-related complications are associated with a secondary acquired von Willebrand syndrome (AVWS), including malignancies, hypothyroidism, cardiovascular diseases, and cardiac replacement devices. The current literature is limited by a lack of older patients in clinical trials. Larger studies are needed to determine if age-related comorbidities affect VWD patients at different frequencies than the general elderly population. There is also a significant need for registry-based studies to evaluate many age-related comorbidities in VWD patients.
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Affiliation(s)
- John Chapin
- Department of Hematology, Shire, Lexington, MA, USA,
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Owaidah T, Saleh M, Alzahrani H, Abu-Riash M, Al Zahrani A, Almadani M, Alsulaiman A, Albanyan A, Siddiqui K, Al Saleh K, Al Momen A. Prevalence of Bleeding Symptoms among Adolescents and Young Adults in the Capital City of Saudi Arabia. Adv Hematol 2018; 2018:1858241. [PMID: 29853900 PMCID: PMC5954960 DOI: 10.1155/2018/1858241] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 03/25/2018] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Bleeding disorders vary in prevalence. While some are rare, some can be common in both sexes. Most bleeding disorders manifest as chronic bleeding tendencies or as an increase in bleeding during surgical procedures or trauma. The consequences of bleeding can be as simple as iron deficiency or catastrophic, resulting in severe morbidity and mortality. Bleeding disorders typically affect both sexes except hemophilia A and B, which mainly affects males. METHOD We conducted a questionnaire-based survey among adolescents and young adults (1901 [49%] boys, 1980 [51%] girls) in Riyadh city regarding bleeding symptoms. Of these, 1849 (47.6%) responded "Yes/Positive" for at least one question about the bleeding symptoms. RESULTS The most common bleeding symptom was epistaxis (19.7% of the sample population) detected in Phase I of the study. A tandem survey was conducted among 525 adolescents who had responded "Yes/Positive" to any one of the questions inquiring about bleeding symptoms. CONCLUSION In this study, we report for the first time the prevalence of bleeding symptoms in a representative sample of Saudi adolescents and young adults.
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Affiliation(s)
- Tarek Owaidah
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- Center of Excellence in Thrombosis and Hemostasis, King Saud University, Riyadh, Saudi Arabia
| | - Mahasen Saleh
- Pediatric Hematology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Hazzah Alzahrani
- Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mahmood Abu-Riash
- Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Ali Al Zahrani
- Research Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | | | - Ayman Alsulaiman
- Research Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Abdulmajeed Albanyan
- Center of Excellence in Thrombosis and Hemostasis, King Saud University, Riyadh, Saudi Arabia
| | - Khawar Siddiqui
- Research Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Khalid Al Saleh
- Center of Excellence in Thrombosis and Hemostasis, King Saud University, Riyadh, Saudi Arabia
| | - Abdulkareem Al Momen
- Center of Excellence in Thrombosis and Hemostasis, King Saud University, Riyadh, Saudi Arabia
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33
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Gebhart J, Hofer S, Panzer S, Quehenberger P, Sunder-Plassmann R, Hoermann G, Eigenbauer E, Haslacher H, Kepa S, Kyrle PA, Eichinger S, Knöbl P, Eischer L, Mannhalter C, Ay C, Pabinger I. High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB). Haemophilia 2018; 24:405-413. [PMID: 29388750 DOI: 10.1111/hae.13422] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2017] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Data on clinical characteristics and the prevalence of underlying coagulopathies in patients with mild-to-moderate bleeding disorders (MBDs) are scarce. AIM We established the Vienna Bleeding Biobank (VIBB) to characterize and thoroughly investigate Austrian patients with MBDs. RESULTS Four hundred eighteen patients (female = 345, 82.5%) were included. A platelet function defect (PFD) was diagnosed in 26 (6.2%) and a possible PFD in 30 (7.2%) patients. Eight patients (1.9%) were diagnosed with von Willebrand disease (VWD) (type 1 n = 6; type 2 n = 2), and 29 patients had low VWF (30-50 IU/dL). Deficiencies in factor VIII, IX, XI or XIII were found in 11 (2.6%), 3 (0.7%), 3 (0.7%) and 1 patient(s), 2 patients had dysfibrinogenaemia, and further 2 had possible PFD and FXI deficiency. Probable causal mutations were detected in 8 of 11 patients with FVIII deficiency, 2 of 3 patients with FIX deficiency and 2 of 8 patients with VWD. Three hundred three patients (72.5%) had normal results in the coagulation assays and were categorized as patients with bleeding of unknown cause (BUC). The bleeding score did not differ between patients with and without established diagnosis. A diagnosis of a bleeding disorder was more frequently made in men than in women (49.3% vs 22.9%). Male sex (OR 3.55, 95% CI: 2.02-6.22; P < .001) and blood group 0 (OR 1.86, 95% CI: 1.17-2.94; P = .008) were independently associated with diagnosis of a bleeding disorder. CONCLUSION The high rate of patients with BUC despite in-depth haemostatic assessment underlines the incompleteness of available routine laboratory tests. Males with MBDs were more likely to be diagnosed with an established bleeding disorder than females.
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Affiliation(s)
- J Gebhart
- Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - S Hofer
- Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - S Panzer
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - P Quehenberger
- Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
| | - R Sunder-Plassmann
- Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
| | - G Hoermann
- Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
| | - E Eigenbauer
- IT-Systems and Communications, Medical University of Vienna, Vienna, Austria
| | - H Haslacher
- Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
| | - S Kepa
- Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - P A Kyrle
- Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - S Eichinger
- Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - P Knöbl
- Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - L Eischer
- Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - C Mannhalter
- Department of Laboratory Medicine, Division of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria
| | - C Ay
- Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
| | - I Pabinger
- Department of Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
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34
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Bhat R, Cabey W. Evaluation and Management of Congenital Bleeding Disorders. Hematol Oncol Clin North Am 2017; 31:1105-1122. [DOI: 10.1016/j.hoc.2017.08.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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35
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Topf HG, Weiss D, Lischetzki G, Strasser E, Rascher W, Rauh M. Evaluation of a modified thromboelastography assay for the screening of von Willebrand disease. Thromb Haemost 2017; 105:1091-9. [DOI: 10.1160/th10-12-0782] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2010] [Accepted: 03/05/2011] [Indexed: 01/15/2023]
Abstract
SummaryThromboelastography (TEG) has been shown to be a valuable point-of-care device for the rapid diagnosis of various bleeding disorders. However, TEG has thus far not been used for the screening for von Willebrand disease (VWD). We evaluated the performance of a modified TEG assay for the laboratory screening of VWD. Three hundred twenty-eight patients (148 male, 180 female, median age 8.4 years, range 0.1 – 72.7 years) were included in the study. The diagnosis and classification of patients was based on personal and familial case history, von Willebrand factor antigen, ristocetin cofactor levels, collagen binding assay, factor VIII coagulant activity and multimer analysis. The ratio of clot strength after preincubation with ristocetin, and without ristocetin, represents the component of clot strength that is formed by cross-linked fibrin fibres and is dependent on the agglutinated platelet fraction. The decrease of the maximum amplitude is a function of the ristocetin concentration and provides a diagnostic parameter able to differentiate between healthy individuals and patients having VWD. Based on a preliminary cut-off value of 25% for the area under the curve (AUC) ratio, the sensitivity varied from 53% to 100% for the different VWD patient groups. The test is suitable for use as a screening test using whole blood and has the additional benefit of being suitable as a point of care test. It appears also useful for monitoring responses to desmopressin (DDAVP) and infusion therapy.
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36
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Strauss E, Mazzeffi M, Williams B, Key N, Tanaka K. Perioperative management of rare coagulation factor deficiency states in cardiac surgery. Br J Anaesth 2017; 119:354-368. [DOI: 10.1093/bja/aex198] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2017] [Indexed: 01/21/2023] Open
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37
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Ettel M, Nardi MA, McVoy L. Validation of automated latex von Willebrand factor activity assay in a new prospective study including post-treatment patient samples. Int J Lab Hematol 2017; 39:286-292. [PMID: 28120508 DOI: 10.1111/ijlh.12622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 12/06/2016] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Von Willebrand disease (VWD) is the most prevalent inherited bleeding disorder. Diagnosis requires measurement of VWF-platelet binding function, for which VWF ristocetin cofactor activity (VWF:RCo) is the reference method. Recently, an automated latex particle-enhanced immunoturbidimetric von Willebrand factor activity assay (VWF:Ab) has been validated showing superior characteristics. We further validate VWF:Ab in a prospective study including post-treatment patient samples. METHODS A total of 1151 samples were collected from patients tested for VWD, including 119 samples from patients treated with desmopressin or VWF replacement product. All samples were tested for VWF:Ab and VWF:RCo, and the methods were compared using linear regression. Imprecision, linearity and lower detection limit were determined for both assays. RESULTS VWF:Ab showed improved precision compared to VWF:RCo. Linear regression of VWF:Ab and VWF:RCo across all samples exhibited good agreement (R2 = 0.89) with statistical significance (P < 0.001) and bias of -8.7. Concordance was high in classifying samples as normal or abnormal. Analysis of treated samples showed excellent agreement (R2 = 0.91) with statistical significance (P < 0.001) and bias of -4.3. CONCLUSIONS Our analysis validates the VWF:Ab assay in a prospective study of a large cohort of patient samples and extends these results to post-treatment patient samples.
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Affiliation(s)
- M Ettel
- Department of Pathology, New York University School of Medicine, New York, NY, USA
| | - M A Nardi
- Department of Pathology, New York University School of Medicine, New York, NY, USA.,Department of Pediatrics, New York University School of Medicine, New York, NY, USA
| | - L McVoy
- Department of Pathology, New York University School of Medicine, New York, NY, USA
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A genetically-engineered von Willebrand disease type 2B mouse model displays defects in hemostasis and inflammation. Sci Rep 2016; 6:26306. [PMID: 27212476 PMCID: PMC4876317 DOI: 10.1038/srep26306] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 04/25/2016] [Indexed: 12/27/2022] Open
Abstract
von Willebrand disease (VWD)-type 2B is characterized by gain-of-function mutations in the von Willebrand factor (VWF) A1-domain, leading to increased affinity for its platelet-receptor, glycoprotein Ibα. We engineered the first knock-in (KI) murine model for VWD-type 2B by introducing the p.V1316M mutation in murine VWF. Homozygous KI-mice replicated human VWD-type 2B with macrothrombocytopenia (platelet counts reduced by 55%, platelet volume increased by 44%), circulating platelet-aggregates and a severe bleeding tendency. Also, vessel occlusion was deficient in the FeCl3-induced thrombosis model. Platelet aggregation induced by thrombin or collagen was defective for KI-mice at all doses. KI-mice manifested a loss of high molecular weight multimers and increased multimer degradation. In a model of VWF-string formation, the number of platelets/string and string-lifetime were surprisingly enhanced in KI-mice, suggesting that proteolysis of VWF/p.V1316M is differentially regulated in the circulation versus the endothelial surface. Furthermore, we observed increased leukocyte recruitment during an inflammatory response induced by the reverse passive Arthus reaction. This points to an active role of VWF/p.V1316M in the exfiltration of leukocytes under inflammatory conditions. In conclusion, our genetically-engineered VWD-type 2B mice represent an original model to study the consequences of spontaneous VWF-platelet interactions and the physiopathology of this human disease.
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Livesey K, Yealy DM, Li J, Moore CG, Ragni MV. Von Willebrand disease in the emergency department. Haemophilia 2016; 22:263-267. [DOI: 10.1111/hae.12841] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2015] [Indexed: 12/20/2022]
Abstract
SummaryBackgroundThe emergency department (ED) is often the first medical contact point for von Willebrand disease (VWD) patients experiencing acute conditions, notably bleeding. However, knowledge of VWD disease types and management options by ED providers is uncertain.AimTo determine the scope of VWD bleeding and treatment in the ED.MethodsWe evaluated medical record data in an IRB‐approved study from 922 notes accounting for 385 ER visits by 183 VWD patients from a single large institution's emergency department.ResultsOver half the ED visits were for an active or suspected bleed, the majority of which were associated with trauma, surgery, epistaxis, gastrointestinal bleeding or gynaecologic bleeding. By treatment, only 25% of all bleeds, including 77.8% of those with menorrhagia and 50.0% of those with epistaxis, received DDAVP or von Willebrand factor concentrate (VWF). The likelihood of receiving treatment was related to referral source, with the highest rates of treatment in patients referred by a haematologist.ConclusionsThese data suggest more patient and physician education are needed in managing patients with VWD, preferably at the time of diagnosis, including confirmation of the diagnosis, response to DDAVP testing, indication for DDAVP testing and formulation of a plan for suspected or actual bleeding.
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Affiliation(s)
- K. Livesey
- Division Hematology/Oncology Department of Medicine University of Pittsburgh Medical Center Pittsburgh PA USA
| | - D. M. Yealy
- Department of Emergency Medicine University of Pittsburgh Medical Center Pittsburgh PA USA
| | - J. Li
- Department of Healthy Policy and Management Graduate School of Public Health Pittsburgh Pittsburgh PA USA
| | - C. G. Moore
- Department of Biostatistics Carolinas Healthcare System Charlotte NC USA
| | - M. V. Ragni
- Division Hematology/Oncology Department of Medicine University of Pittsburgh Medical Center Pittsburgh PA USA
- Hemophilia Center of Western PA Pittsburgh PA USA
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40
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Maxillary pseudotumor as initial manifestation of von Willebrand disease, type 2: report of a rare case and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol 2016. [DOI: 10.1016/j.oooo.2015.05.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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41
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Budde U, Scheppenheim S, Dittmer R. Treatment of the acquired von Willebrand syndrome. Expert Rev Hematol 2015; 8:799-818. [DOI: 10.1586/17474086.2015.1060854] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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Misfolding of vWF to pathologically disordered conformations impacts the severity of von Willebrand disease. Biophys J 2015; 107:1185-1195. [PMID: 25185554 DOI: 10.1016/j.bpj.2014.07.026] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Revised: 07/03/2014] [Accepted: 07/09/2014] [Indexed: 12/11/2022] Open
Abstract
The primary hemostatic von Willebrand factor (vWF) functions to sequester platelets from rheological blood flow and mediates their adhesion to damaged subendothelium at sites of vascular injury. We have surveyed the effect of 16 disease-causing mutations identified in patients diagnosed with the bleeding diathesis disorder, von Willebrand disease (vWD), on the structure and rheology of vWF A1 domain adhesiveness to the platelet GPIbα receptor. These mutations have a dynamic phenotypical range of bleeding from lack of platelet adhesion to severe thrombocytopenia. Using new rheological tools in combination with classical thermodynamic, biophysical, and spectroscopic metrics, we establish a high propensity of the A1 domain to misfold to pathological molten globule conformations that differentially alter the strength of platelet adhesion under shear flow. Rheodynamic analysis establishes a quantitative rank order between shear-rate-dependent platelet-translocation pause times that linearly correlate with clinically reported measures of patient platelet counts and the severity of thrombocytopenia. These results suggest that specific secondary structure elements remaining in these pathological conformations of the A1 domain regulate GPIbα binding and the strength of vWF-platelet interactions, which affects the vWD functional phenotype and the severity of thrombocytopenia.
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43
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Neff AT. Current controversies in the diagnosis and management of von Willebrand disease. Ther Adv Hematol 2015; 6:209-16. [PMID: 26288715 DOI: 10.1177/2040620715587879] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Von Willebrand disease (VWD) is the most common inherited bleeding disorder in the world. The spectrum of VWD spans quantitative and qualitative deficiencies of von Willebrand factor (VWF), a platelet adhesive protein. It manifests primarily as mucocutaneous bleeding, but severely affected patients may suffer soft tissue bleeding and hemarthroses. There is disagreement in the multiple guidelines published regarding diagnosis, especially of type 1 VWD, which also remains the most opaque with respect to molecular characterization. Treatment with desmopressin (DDAVP) is most effective in type 1 VWD, but regimens are not standardized. It is not clear which type 2 VWD patients with qualitative deficiencies can be treated with DDAVP and which ones should receive VWF concentrates. No guidelines stipulate which patients might benefit from prophylactic VWF infusions and how they should be dosed. These are some current controversies in VWD that are discussed in this review.
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Affiliation(s)
- Anne T Neff
- Department of Hematology/Medical Oncology, Cleveland Clinic, 9500 Euclid Ave Desk R35 Cleveland, OH, USA
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44
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Deforest M, Grabell J, Albert S, Young J, Tuttle A, Hopman WM, James PD. Generation and optimization of the self-administered bleeding assessment tool and its validation as a screening test for von Willebrand disease. Haemophilia 2015; 21:e384-8. [PMID: 26179127 DOI: 10.1111/hae.12747] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2015] [Indexed: 11/29/2022]
Abstract
INTRODUCTION/AIM Our aim was to generate, optimize and validate a self-administered bleeding assessment tool (self-BAT) for von Willebrand disease (VWD). METHODS In Phase 1, medical terminology in the expert-administered International Society on Thrombosis and Haemostasis (ISTH)-BAT was converted into a Grade 4 reading level to produce the first version of the Self-BAT which was then optimized to ensure agreement with the ISTH-BAT. In Phase 2, the normal range of bleeding scores (BSs) was determined and test-retest reliability analysed. In Phase 3, the optimized Self-BAT was tested as a screening tool for first time referrals to the Haematology clinic. RESULTS Bleeding score from the final optimized version of the Self-BAT showed an excellent intra-class correlation coefficient (ICC) of 0.87 with ISTH-BAT BS in Phase 1. In Phase 2, the normal range of BSs for the optimized Self-BAT was determined to be 0 to +5 for females and 0 to +3 for males and excellent test-retest reliability was shown (ICC = 0.95). In Phase 3, we showed that a positive Self-BAT BS (≥6 for females, ≥4 for males) has a sensitivity of 78%, specificity of 23%, positive predictive value (PPV) of 0.15 and negative predictive value (NPV) of 0.86 for VWD; these figures improved when just the females were analysed; sensitivity of 100%, specificity of 21%, PPV = 0.17 and NPV = 1.0. CONCLUSION We show an optimized Self-BAT can generate comparable BS to the expert-administered ISTH-BAT and is a reliable, effective screening tool to incorporate into the assessment of individuals, particularly women, referred for a possible bleeding disorder.
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Affiliation(s)
- M Deforest
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
| | - J Grabell
- Department of Medicine, Queen's University, Kingston, ON, Canada
| | - S Albert
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
| | - J Young
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
| | - A Tuttle
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
| | - W M Hopman
- Clinical Research Centre, Kingston General Hospital, Queen's University, Kingston, ON, Canada.,Department of Public Health Sciences, Queen's University, Kingston, ON, Canada
| | - P D James
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.,Department of Medicine, Queen's University, Kingston, ON, Canada
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Costa-Pinto J, Pérez-Rodríguez A, del C Goméz-del-Castillo M, Lourés E, Rodríguez-Trillo A, Batlle J, López-Fernández MF. Diagnosis of inherited von Willebrand disease: comparison of two methodologies and analysis of the discrepancies. Haemophilia 2015; 20:559-67. [PMID: 25077350 DOI: 10.1111/hae.12380] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Diagnostics of von Willebrand disease (VWD) includes assessment of factor VIII (FVIII) coagulant activity, von Willebrand factor (VWF) antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo), and more specific tests as multimeric and genetic analyses are necessary for the correct VWD classification. The ACL AcuStar analyzer introduces chemiluminescence (CL) technology in detection of VWD with automated VWF:Ag and VWF:RCo assays. Compare VWF:Ag-ELISA and VWF:RCo by aggregometry conventional assays with new CL VWF:Ag-IL and VWF:RCo-IL assays, investigate the ability to make accurate VWD diagnosis and concordance with multimeric and genetic analyses. 146 patients with congenital VWD (51 Type 1; 34 Type 2A; 16 Type 2B; 31 Type 2M; 5 Type 2N; 9 Type 3) and 30 healthy normal subjects were included. A comparison was made between CL and conventional methods. Diagnostic evaluation included: VWF:RCo/VWF:Ag ratio, multimeric distribution (sodium dodecyl sulfate [SDS]-agarose gel) of VWF and genetic analysis in 110 of 146 patients. CL and conventional methods revealed good correlation. Kappa test agreement diagnosis was >0.8. CL diagnostic sensitivity was 100% and specificity 97%. Multimeric and genetic analysis were of help in clarifying 13 discrepancies of diagnosis between methods, of which six discrepancies were explained by lack of conventional methods′ sensibility. CL methodology can detect VWD and discriminate between type 1, 3 and variant forms and offers an automated, faster, sensitive and less cumbersome method when compared to conventional assays, in particular VWF:RCo by aggregometry. In some cases, even with all phenotype and genetic analyses, discrepancies exist in the classification of VWD.
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de Maistre E, Volot F, Mourey G, Aho LS, Ternisien C, Briquel ME, Bertrand MA, Tardy B, Frotscher B, Nguyen P, Dumont L, Vandroux D, Hézard N, Trossaërt M. Performance of two new automated assays for measuring von Willebrand activity: HemosIL AcuStar and Innovance. Thromb Haemost 2014; 112:825-30. [PMID: 25103956 DOI: 10.1160/th14-02-0108] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 04/30/2014] [Indexed: 11/05/2022]
Abstract
The ristocetin cofactor activity assay (VWF:RCo) is the reference method for assessing von Willebrand factor (VWF) activity but remains difficult to perform, and the coefficient of variation of the method is high (about 20-30%). This study evaluated and compared the performance for measuring the VWF activity of two newly commercialised assays [VWF:Ac Innovance (VWF:Ac) and VWF:RCo Acustar (VWF:RCo Acu)] with the reference VWF:RCo aggregation in 123 pathological plasma samples. The correlation and concordance between both new tests (VWF:RCo-Acu and VWF:Ac) and the reference VWF:RCo were good. The results of the VWF activity to VWF antigen ratio were also comparable whatever the method for the classification of VWF deficiency in all patients. Our results showed that both new tests could replace the "gold standard" VWF:RCo in aggregometry with several benefits: they are fully automated, easier and faster to perform, better adapted to emergency situations if necessary.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Marc Trossaërt
- Dr. Marc Trossaërt, Centre Régional de Traitement de l'Hémophilie, 1 Place Alexis RICORDEAU, Centre Hospitalier Universitaire, 44093 Nantes Cedex 1, France, Tel.: +33 2 40 08 74 68, Fax: +33 2 40 08 42 59, E-mail:
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48
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Qiao SK, Ren HY, Ren JH, Guo XN. Compound heterozygous hemophilia A in a female patient and the identification of a novel missense mutation, p.Met1093Ile. Mol Med Rep 2013; 9:466-70. [PMID: 24317041 PMCID: PMC3896510 DOI: 10.3892/mmr.2013.1841] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 11/25/2013] [Indexed: 11/23/2022] Open
Abstract
Hemophilia A (HA) in females is rare. Female HA cases are often misdiagnosed as acquired HA (AHA) or as von Willebrand disease type 2N (vWD-2N). Here, we report the case of a 37-year-old female HA patient with a moderate factor VIII (FVIII) deficiency. The patient had no personal or family history of bleeding disorders, but presented with heavy uterine bleeding following surgery to remove an intrauterine device. IgG inhibitory antibodies against FVIII were undetected. A compound heterozygote mutation of the FVIII gene (F8) was found in this patient. The p.Val502Asp mutation, which has been reported previously, affects A2 domain function. A novel missense point mutation, p.Met1093Ile, was identified in the B domain. The compound heterozygote mutations in F8, p.Val502Asp and p.Met1093Ile, caused HA in this female patient, with a moderate phenotype.
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Affiliation(s)
- Shu-Kai Qiao
- Department of Hematology, Peking University First Hospital, Beijing 100034, P.R. China
| | - Han-Yun Ren
- Department of Hematology, Peking University First Hospital, Beijing 100034, P.R. China
| | - Jin-Hai Ren
- Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
| | - Xiao-Nan Guo
- Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China
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Affiliation(s)
- Jecko Thachil
- Department of Haematology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom
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Stuijver DJF, Piantanida E, van Zaane B, Galli L, Romualdi E, Tanda ML, Meijers JCM, Büller HR, Gerdes VEA, Squizzato A. Acquired von Willebrand syndrome in patients with overt hypothyroidism: a prospective cohort study. Haemophilia 2013; 20:326-32. [DOI: 10.1111/hae.12275] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2013] [Indexed: 11/29/2022]
Affiliation(s)
- D. J. F. Stuijver
- Department of Internal Medicine; Slotervaart Hospital; Amsterdam The Netherlands
- Department of Vascular Medicine; Academic Medical Centre; Amsterdam The Netherlands
| | - E. Piantanida
- Endocrinology Unit; Department of Clinical and Experimental Medicine; University of Insubria; Varese Italy
| | - B. van Zaane
- Department of Internal Medicine; Slotervaart Hospital; Amsterdam The Netherlands
- Department of Vascular Medicine; Academic Medical Centre; Amsterdam The Netherlands
| | - L. Galli
- Department of Clinical and Experimental Medicine; Research Center on Thromboembolic Disorders and Antithrombotic Therapies; University of Insubria; Varese Italy
| | - E. Romualdi
- Department of Clinical and Experimental Medicine; Research Center on Thromboembolic Disorders and Antithrombotic Therapies; University of Insubria; Varese Italy
| | - M. L. Tanda
- Endocrinology Unit; Department of Clinical and Experimental Medicine; University of Insubria; Varese Italy
| | - J. C. M. Meijers
- Department of Vascular Medicine; Academic Medical Centre; Amsterdam The Netherlands
- Department of Experimental Vascular Medicine; Academic Medical Centre; Amsterdam The Netherlands
| | - H. R. Büller
- Department of Vascular Medicine; Academic Medical Centre; Amsterdam The Netherlands
| | - V. E. A. Gerdes
- Department of Internal Medicine; Slotervaart Hospital; Amsterdam The Netherlands
- Department of Vascular Medicine; Academic Medical Centre; Amsterdam The Netherlands
| | - A. Squizzato
- Department of Clinical and Experimental Medicine; Research Center on Thromboembolic Disorders and Antithrombotic Therapies; University of Insubria; Varese Italy
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