Investigators will use the funds to do specialized genetic tests of von Willebrand function and create a repository of patient samples.
Versiti has been on the cutting edge of blood research for more than 70 years. One of its primary research topics is von Willebrand disease (VWD), the most common bleeding disorder, which affects up to 1% of the total population. Patients with von Willebrand disease often experience repetitive nosebleeds, bruising and abnormal bleeding from cuts. There are many varieties of the disease, and Versiti Blood Research Institute (BRI) investigators have long been industry leaders in this research. In fact, investigators at the BRI first discovered the 2M version of von Willebrand disease, and later found that DNA causes several types of VWD:
- 2A: This version is abnormal because it is assembled incorrectly. The long chains of proteins and amino acids are either not made correctly or are unduly susceptible to enzymatic degradation, rendering von Willebrand factor (VWF) ineffective.2
- 2B: The von Willebrand protein abnormally binds too much to platelets, resulting in low platelet counts and low VWF.1
- 2M: 2M was discovered at the BRI. The long chain of proteins is present and the amount in the blood is normal, but it does not stick to platelets and collagen, causing bleeding symptoms.3-8
- 2N: 2N VWD was discovered at the BRI, but because of changes in naming conventions, it wasn’t credited to Versiti. It was rediscovered in Normandy 10 years after investigators at the BRI identified it.9-11
Recently, Senior Investigator Robert Montgomery, MD, was awarded a $13 million program project grant from the National Institutes of Health (NIH) to study a group of patients with von Willebrand disease. In about one third of patients, it’s difficult to figure out what causes VWD. This grant will enable Dr. Montgomery and his team to perform gene sequencing and specialized tests of von Willebrand factor function, helping investigators better understand what affects and causes the disorder.
This program project consists of 20 clinical centers across the country and around the world that will diagnose their own von Willebrand patients, then send patient samples to Versiti Blood Research Institute and Versiti Diagnostic Labs’ hemostasis laboratory for testing and creation of a repository of samples to study over time. Every two years, centers will send follow-up samples from the same patient groups, so that investigators can track these patients’ progression. The BRI will conduct four of these projects: two in Dr. Montgomery’s lab will study the different varieties of VWD, while BRI Director of Hemostasis Sandra Haberichter, PhD, and an investigator in Dublin, Ireland, will study the role of sugars in von Willebrand disease and how carbohydrates may play a role in varying levels of VWF.
As the only NIH-funded program project with a large clinical study, the BRI and its affiliate organizations stand to greatly contribute to von Willebrand disease research, giving new hope to patients who suffer from the blood disorder.
About the expert: Robert Montgomery, MD, is a senior investigator at Versiti Blood Research Institute and Professor of Pediatric Hematology in the Department of Pediatrics at the Medical College of Wisconsin.
- Kroner PA, Kluessendorf ML, Scott JP, Montgomery RR. Expressed full-length von Willebrand factor containing missense mutations linked to type IIB von Willebrand disease shows enhanced binding to platelets. Blood 1992;79(8):2048-2055.
- Ginsburg D, Konkle BA, Gill JC, Montgomery RR, Bockenstedt PL, Johnson TA, Yang AY. Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA. Proc.Natl.Acad.Sci.U.S.A 1989;86(10):3723-3727.
- Mancuso DJ, Kroner PA, Christopherson PA, Vokac EA, Gill JC, Montgomery RR. Type 2M:Milwaukee-1 von Willebrand disease: an in-frame deletion in the Cys509-Cys695 loop of the von Willebrand factor A1 domain causes deficient binding of von Willebrand factor to platelets. Blood 1996;88(7):2559-2568.
- Flood VH, Lederman CA, Wren JS, Christopherson PA, Friedman KD, Hoffmann RG, Montgomery RR. Absent collagen binding in a VWF A3 domain mutant: utility of the VWF:CB in diagnosis of VWD. J.Thromb.Haemost. 2010;8(6):1431-1433. (PMCID: PMC3892206).
- Flood VH, Haberichter SL, Friedman KD, Lentz SR, Gill JC, Montgomery RR. VWF binding to Types I, III, or VI collagen in the ZPMCB-VWD with identification of subjects with selective reduced VWF:CB. Blood 2010;116235a.
- Flood VH, Gill JC, Morateck PA, Christopherson PA, Friedman KD, Haberichter SL, Branchford BR, Hoffmann RG, Abshire TC, Di Paola JA, Hoots WK, Leissinger C, Lusher JM, Ragni MV, Shapiro AD, Montgomery RR. Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor. Blood 2010;116(2):280-286. (PMCID: PMC2910611).
- Flood VH, Friedman KD, Gill JC, Morateck PA, Wren JS, Scott JP, Montgomery RR. Limitations of the ristocetin cofactor assay in measurement of von Willebrand factor function. J.Thromb.Haemost. 2009;7(11):1832-1839.
- Flood VH, Morateck P, Christopherson P, Gill JC, Friedman KD, Montgomery RR. Functional Assays for the Discrimination of Type 2 VWD Variants. J Thromb Haemost 2009(ISTH Abstract):
- Montgomery RR, Hathaway WE, Johnson J, Jacobson L, Muntean W. A variant of von Willebrand's disease with abnormal expression of factor VIII procoagulant activity. Blood 1982;60(1):201-207.
- Kroner PA, Foster PA, Fahs SA, Montgomery RR. The defective interaction between von Willebrand factor and factor VIII in a patient with type 1 von Willebrand disease is caused by substitution of Arg19 and His54 in mature von Willebrand factor. Blood 1996;87(3):1013-1021.
- Kroner PA, Friedman KD, Fahs SA, Scott JP, Montgomery RR. Abnormal binding of factor VIII is linked with the substitution of glutamine for arginine 91 in von Willebrand factor in a variant form of von Willebrand disease. J Biol.Chem. 1991;266(29):19146-19149.