Robert R. Montgomery, M.D.

Senior Investigator
Blood Research Institute
BloodCenter of Wisconsin

Professor of Pediatric Hematology

Department of Pediatrics
Medical College of Wisconsin

Selected Publications
Selected Abstracts
Grant Support
Invited Lectures
Patents
Laboratory Staff
Contact Information

Research Interests
Our laboratory's primary focus is on the role of von Willebrand factor (vWF) and vW AgII, the vWF propolypeptide in intracellular processing and trafficking in endothelial cells and platelets.

The vWF protein also serves as both an inter molecular chaperone for coagulation Factor VIII (FVIII) and as the obligate extracellular carrier protein for FVIII in order to protect FVIII from proteolytic degradation.

Our laboratory is exploring techniques to incorporate these discoveries into strategy for gene therapy of hemophilia and von Willebrand disease. Molecular causes of von Willebrand disease variants result in dysfunctional vWF that fails to interact with its many ligands, its function as a carrier protein, and its normal multimerization and processing. A number of the molecular causes of these variants have been discovered in our laboratory including 2A, 2B, 2N, 2MMilwaukee, and hereditary persistence of pro-vWF. Newer variants are being discovered that are used to define intra- and extracellular function of this multifunctional glycoprotein. We are also studying the unique differences between vWF from different animal species. We have sequenced canine vWF and are employing murine sequence to study vWF in vivo and its interaction with other thrombotic and antithrombotic proteins.

The glycoprotein, GPIb, is a receptor on platelets for von Willebrand factor and its function is missing on platelets from individuals with Bernard Soulier Syndrome (BSS). Together with Dermot Kenny, MD, we are studying the various molecular causes of BSS including molecular defects of GPIba, GPIbb, GPV, and GPIX - all of which are members of the GPIb Complex. We have sequenced canine GPIb and will use the human and canine proteins to study GPIb function.

Clinical research studies include the in vivo biology of von Willebrand factor in patients with von Willebrand disease, patients with an acquired antibody to vWF, and in patients with various other pathologic states. 

Figure 1. Staining of endothelial cells for vWF (top). When the gene for FVIII is inserted into an endothelial cell (center cell of middle panel), the localization of FVIII (green) follows vWF and co-localizes in Weibel-Palade bodies using confocal laser microscopy. Yellow staining of the center cell in the lower figure demonstrates co-localization of both proteins in the same granules. In the absence of a cell storing vWF (not shown), FVIII localizes only to the cytoplasm and not stored

Selected Publications

• Kroner PA, Foster PA, Fahs SA, Montgomery RR: The Defective Interaction Between von Willebrand Factor and Factor VIII in a Patient with type 1 vWD is caused by Substitution of Arg19 and His54 in mature von Willebrand Factor. Blood 87:1013-1021, 1996.
• Menache D, Aronson LD, Darr F, Montgomery RR, and the Cooperative Study Group (Inc. Gill JC): Pharmacokinetics of von Willebrand factor and factor VIIIC in patients with severe von Willebrand disease (type 3 vWD): Estimation of the rate of factor VIIIC synthesis. Br Jr Hematol 94:740-745, 1996.
• 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 88:2559-2568, 1996.
• Herrmann M, Hartleib J, Kehrel B, Montgomery RR, Sixma JJ, Peters G: Interaction of von Willebrand factor with Staphylococcus aureus. J Infect Dis 984-991, 1997.
• Kenny D, Newman PJ, Morateck PA, and Montgomery RR: A dinucleotide deletion in glycoprotein Iba results in defective membrane anchoring and circulating soluble glycoprotein Iba in a novel form of Bernard-Soulier syndrome. Blood 90:2626-2633, 1997.
• Hillery CA, Mancuso DJ, Sadler JE, Ponder JW, Jozwiak ML, Christopherson PA, Gill JC, Scott JP, Montgomery RR: Type 2M von Willebrand disease: F606I and I662F mutations in the glycoprotein Ib binding domain selectively impair ristocetin- but not botrocetin-mediated binding of von Willebrand factor to platelets. Blood 91:1572-81, 1998.
• Rosenberg JB, Foster PA, Kaufman RF, Vokac EA, Kroner PA, Montgomery RR: Intracellular trafficking of factor VIII to von Willebrand factor storage granules. J Clin Invest, 101:613-24, 1998.
• Kenny D, Jonsson OG, Morateck PA, Montgomery RR: Naturally occurring mutations in glycoprotein Iba that result in defective ligand binding and synthesis of a truncated protein. Blood 92:175-183, 1998.
• Hessner, JM, Luhm RA, Pearson SL, Endean DJ, Friedman KD, Montgomery, RR: Prevalence of prothrombin G20210A, Factor V G1691A (Leiden), and methylenetetrahydrofolate reductase (MTHFT) C677T in seven different populations determined by multiplex allele-specific PCR. Thromb Haemost 81:733-38, 1999.
• Hessner MJ, Dinauer DM, Luhm RA, Endres JL, Montgomery RR, Friedman KD: Contribution of the glycoprotein Ia 807TT, thylene tetrahydrofolate reductase 677TT and prothrombin 20210GA genotypes to prothrombotic risk among factor V 1691GA (Leiden) carriers. Br.J.Haematol. 106: 237-239, 1999
• Kenny D, Morateck PA, Fahs SA, Warliter DC, Montgomery RR: Cloning and expression of canine glycoprotein 1ba. Thromb Haemost 82:1327-33, 1999.
• Kenny D, Morateck PA, Gill JC, Montgomery RR: The critical interaction of glycoprotein (GP) IB-beta with GPIX-a genetic cause of Bernard-Soulier syndrome. Blood 93: 2968-2975, 1999.
• White II GC, Montgomery RR: Chapter 114: Clinical Aspects of and Therapy for von Willebrand Disease. In: Hematology: Basic Principles and Practice, 3rd Edition. Editors, R. Hoffman, EJ Benz Jr, SJ Shattil, B Furie, HJ Cohen, LE Silberstein, P McGlave. Churchill Livingstone, Philadelphia, pp. 1946-1958, 1999.
• Montgomery RR, Scott JP: Section 7. Hemorrhagic and Thrombotic Diseases, Chapters 481-490. In: Nelson's Textbook of Pediatrics 16th Edition. Editors, Behrman RE, Kliegman RM. pp. 1504-1524, 1999.
• Montgomery RR: Interactions between von Willebrand factor and factor VIII: Where did they first meet? J Pediatr Hematol Oncol 22:269-275,2000.
• Punzalan RC, Hillery CA, Montgomery RR, Scott JP, Gill JC: Low molecular weight heparin (enoxaparin) in thrombotic disease in children and adolescents. J Pediatr Hematol Oncol. 22:137-142, 2000.
• Montgomery RR: von Willebrand Disease. In: Disorders of Hemostasis and Thrombosis. A Clinical Guide. Editors, WE Hathaway and SH Goodnight, Jr. 2001.
• Montgomery RR: Chapter 7. Structure and Function of von Willebrand Factor. In: Hemostasis and Thrombosis, Basic Principles and Clinical Practice. Editors, R Colman, J Hirsh, V Marder, A Clowes, J George, 2001.
• Rosenberg JB, Haberichter SL, Jozwiak MA, Vokac EA, Kroner PA, Fahs SA, Kawai Y, Montgomery RR.
• The role of the D1 domain of the von Willebrand factor propeptide in multimerization of VWF. Blood 100:1699-706, 2002.
• Kenny D, Morateck PA, Montgomery RR: The cysteine knot of platelet glycoprotein lb beta (GPlb beta) is critical for the interaction of GPlb beta with GPIX. Blood 99:4428-33, 2002.
• Haberichter SL, Jozwiak MA, Rosenberg JB, Christopherson PA, Montgomery RR: The von Willebrand factor propeptide, VWFpp, trafficks an unrelated protein to storage. Arterioscler Thromb Vasc Biol 22:921-926, 2002.
• Wilcox DA, Shi Q, Nurden P, Haberichter SL, Rosenberg JB, Johnson BD, Nurden AT, White GC 2nd, Montgomery RR:Induction of megakaryocytes to synthesize and store a releasable pool of human factor VIII.J Thromb Haemost 12:2477-89, 2003.
• Shi Q, Wilcox DA, Fahs SA, Kroner PA, Montgomery RR: Expression of human factor VIII under control of the platelet-specific alphaIIb promoter in megakaryocytic cell line as well as storage together with VWF. Mol Genet Metab 79:25-33, 2003.
• Haberichter SL, Jacobi P, Montgomery RR:Critical independent regions in the VWF propeptide and mature VWF that enable normal VWF storage.Blood 101:1384-91, 2003.

Selected Abstracts

• Montgomery RR, Rosenberg JB, Jozwiak MA, Nelson CA, Haberichter SL: Genetic targeting of proteins to regulated storage in vascular endothelial cells. Pediatric Research 45(Suppl): ,1999.
• Rosenberg JB, Greengard J, Montgomery RR: Creation of a releasable storage pool of factor VIII by retroviral transduction of human endothelial cells. Accepted for Plenary Session and received a Presidential Award, August 1999. Thrombosis and Haemostasis Abstract Book, abstract 2159, 1999.
• Visentin GP, Scheidt MJ, Aster RH, Montgomery RR, Gill JC: Formation of antibodies reactive with PF4:heparin complexes by children exposed to heparin. Blood 94 (Suppl 1): 16a, 1999.
• Haberichter SL, Fahs SA, Rosenberg JB, Montgomery RR: Von Willebrand factor (vWF) storage and multimerization - two independent intracellular processes dissected by canine/human chimeras. Blood 94 (Suppl 1): 447a, 999.
• Wilcox DA, Rosenberg JB, White II GC, Montgomery RR: Factor VIII (FVIII) trafficks to megakaryocyte a-granules following retroviral transduction of human CD34+ cells. Blood 94 (Suppl 1): 442a, 1999.
• Montgomery RR, Jozwiak MA, Hutter JJ, Endres JL, Foster PA, Friedman KD: A homozygous variant of von Willebrand Factor (vWF) that fails to C-terminal dimerize resulting in loss of vWF multimers larger than dimer. Blood 94 (Suppl 1): 443a, 1999.
• Raife TJ, Atkinson BS, Montgomery RR, Friedman KD: von Willebrand factor proteolytic activity: correlation with clinical parameters in 94 adult thrombotic thrombocytopenic purpura/hemolytic uremic syndrome patients. Blood 94 (Suppl 1): 16a, 1999.

Grant Support

• RO1 HL33721, NIH, "Structure and Function of vW AgII," (1999-2008).
• P01 HL81588, NIH, "Molecular and Clinical Biology of VWD" (2005-2010)
• PO1 HL44612, NIH, "Molecular and Cellular Mechanisms in Transfusion Medicine,"
• Project 5, “Molecular & Cellular Consequences of vWf Alteration” (1995-2005)

 Invited Lectures

• "Laboratory Diagnosis of von Willebrand Disease", International Society of Laboratory Hematology, Banf, Canada.
• "von Willebrand Disease", Canadian Society of Hematology, Toronto, Canada.

 Patents

“Synthetic and Recombinant Substrates for the Detection of the von Willebrand Factor-Cleaving Protease.” filed 2001

Back Row: Crystal Perry, Pam Christopherson, Bob Montgomery, Scot Fahs, Jeff Wren, Guowei Zhang, Erin Kuether; Middle Row: Rashmi Sood, Carissa Schubert, Patti Morateck, Sandy Ingram, Paula Jacobi, Ann Leeder; Front Row: Anthony Lee, Mary Jozwiak, Sandy Haberichter, Qizhen Shi, Veronica Flood

Laboratory Staff

Employment Opportunities
If opportunities are available, they will be listed on the Employment page.

Contact Information
Phone: (414) 937-6318
Fax: (414) 937-6284
E-mail: bob.montgomery@bcw.edu