Von Willebrand Factor Biology 

My lab is interested in the interaction of von Willebrand factor (VWF) with platelets and with collagens in the vascular endothelium. VWF is a coagulation protein that is key in linking platelets (blood clotting cells) to the injured endothelium that lines blood vessels. Therefore, normal VWF requires the ability to interact with platelets (via platelet receptors GPIb and integrin αIIbβ3) and with vascular collagens (including types 1, 3, 4 and 6). In patients with von Willebrand disease (VWD) these interactions may be decreased or absent.

VWF and Collagen

My current R01 grant focuses on type 4 collagen and its role in VWF and platelet interactions. We have generated a mouse model with defective VWF-collagen 4 binding and are currently studying the bleeding symptoms seen in these mice. We have previously shown that defects in collagen 4 binding are not uncommon in patients with types 1 and 2M VWD, and that these may predispose to increased bleeding compared to patients with normal collagen binding. Ongoing work concerns the effect of aberrant collagen binding on VWF function, platelet function, and bleeding phenotype.

The Spectrum of Von Willebrand Disease

As a clinician, I am fascinated by the variability in bleeding experienced by patients with von Willebrand disease (VWD). I also work with Bob Montgomery on the Zimmerman Program for the Molecular and Clinical Biology of VWD. We have enrolled a large number of patients with type 1 von Willebrand disease, and from this group have demonstrated that genetic variants in VWF are most common when the VWF level is below 30%. However, bleeding symptoms are highly variable and not necessarily well correlated with VWF levels. Ongoing research concerns the correlation of genotype and phenotype with bleeding symptoms in patients with VWD, with the ultimate goal of improving diagnosis and treatment for affected patients.

• NIH/NHLBI R01: Mechanism of VWF Interactions with Type 4 Collagen; 01/01/2016 - 12/31/2020

Tricia Slobodianuk 
Research Technologist

Chad Skaer
Research Technologist

Refereed Journal Publications/Original Papers

• Flood, V.H., Johnson, F.L., Boshkov, L.K., Thomas, G.A., Bakke, A.C., Nugent, D.J., Nicholson, H.S., Tilford, D., Brown, M.P., Godder, K.T. Sustained Engraftment Post Bone Marrow Transplant Despite Anti-Platelet Antibodies in Glanzmann Thrombasthenia. Pediatr Blood Cancer 45(7):971-975, 2005.
• Flood, V.H., Al-Mondhiry, H.A., Farrell, D.H. The Fibrinogen Aα R16C Mutation Results in Fibrinolytic Resistance. Br J Haematol 134(2):220-226, 2006.
• Flood, V.H., Nagaswami, C., Chernysh, I.N., Al-Mondhiry, H.A., Weisel, J.W., Farrell, D.H. Incorporation of Fibrin Molecules Containing Fibrinopeptide A Alters Clot Ultrastructure and Decreases Permeability. Br J Haematol 138(1):117-124, 2007.
• Flood, V.H., Galderisi, F.C., Lowas, S.R., Kendrick, A., Boshkov, L.K. Hemorrhagic Disease of the Newborn Despite Vitamin K Prophylaxis at Birth. Pediatr Blood Cancer 50(5):1075-1077, 2008.
• Flood, V.H., Al-Mondhiry, H.A., Rein, C.M., Alexander, K.S., Lovely, R.S., Shackleton, K.M., David, L.L., Farrell, D.H. Fibrinogen Hershey IV: a Novel Dysfibrinogen with a gamma V411I Mutation in the Integrin alpha(IIb)beta(3) Binding Site. Thromb Haemost 99(6):1008-1012, 2008.
• Flood, V.H., Friedman, K.D., Gill, J.C., Morateck, P.A., Wren, J.S., Scott, J.P., Montgomery, R.R. Limitations of the Ristocetin Cofactor Assay in Measurement of VWF Function. J Thromb Haemost 7(11):1832-1839, 2009.
• Flood, V.H., Lederman, C.A., Wren, J.S., Christopherson, P.A., Friedman, K.D., Hoffmann, R.G., Montgomery, R.R. Absent Collagen Binding in a VWF A3 Domain Mutant: Utility of the VWF:CB in Diagnosis of VWD. J Thromb Haemost 8(6):1431-1433, 2010.
• Flood, V.H., Gill, J.C., Morateck, P.A., Christopherson, P.A., Friedman, K.D., Haberichter, S.L., Branchford, B.R., Hoffmann, R.G., Abshire, T.C., Di Paola, J.A., Hoots, W.K., Leissinger, C., Lusher, J.M., Ragni, M.V., Shapiro, A.D., Montgomery, R.R. Common VWF Exon 28 Polymorphisms in African Americans Affecting the VWF Activity Assay by Ristocetin Cofactor. Blood 116(2):280-286, 2010.
• Flood, V.H., Gill, J.C., Morateck, P.A., Christopherson, P.A., Friedman, K.D., Haberichter, S.L., Hoffman, R.G., Montgomery, R.R. Gain of Function GPIb ELISA Assay for VWF Activity in the Zimmerman Program for the Molecular and Clinical Biology of VWD. Blood 117(6):e67-74, 2011.
• Bellissimo, D.B., Christopherson, P.A., Flood, V.H., Gill, J.C., Friedman, K.D., Haberichter. S.L., Shapiro, A.D., Abshire, T.C., Leissinger, C., Hoots, W.K., Lusher, J.M., Ragni, M.V., Montgomery, R.R. Von Willebrand Factor Mutations and New Sequence Variations Identified in Healthy Controls are More Frequent in the African-American Population. Blood 119(9):2135-2140, 2012.
• Jacobi P.M., Gill, J.C., Flood, V.H., Jakab, D., Friedman, K.D., Haberichter, S.L. Intersection of Mechanisms of Type 2A von Willebrand Disease Through Defects in VWF Multimerization, Secretion, ADAMTS-13 Susceptibility, and Regulated Storage. Blood 119(19):4543-4553, 2012.
• Flood, V.H., Gill, J.C., Christopherson, P.A., Bellissimo, D.B., Friedman, K.D., Haberichter, S.L., Lentz, S.R., Montgomery, R.R. Critical VWF A1 Domain Residues Influence Type VI Collagen Binding. J Thromb Haemost 10(7):1417-1424, 2012.
• Flood, V.H., Gill, J.C., Christopherson, P.A., Wren, J.S., Friedman, K.D., Haberichter, S.L., Hoffmann, R.G., Montgomery, R.R. Comparison of Type I, Type III, and Type VI Collagen Binding Assays in Diagnosis of VWD. J Thromb Haemost 10(7):1425-1432, 2012.
• *Franzblau, E.B., Punzalan, R.C., Friedman, K.D., Roy, A., Bilen, O., Flood, V.H. Use of Purified Fibrinogen Concentrate for Dysfibrinogenemia and Importance of Laboratory Fibrinogen Activity Measurement. Pediatr Blood Cancer 60(3):500-502, 2013.
• Flood, V.H., Gill, J.C., Friedman, K.D., Christopherson, P.A., Jacobi, P.M., Hoffmann, R.G., Montgomery, R.R., Haberichter, S.L., and the Zimmerman Program Investigators. Collagen Binding Provides a Sensitive Screen for Variant Von Willebrand Disease. Clin Chem 59(4):684-691, 2013.
• *Larsen, D.M., Haberichter, S.L., Gill, J.C., Shapiro, A.D., Flood, V.H. Variability in Platelet and Collagen Binding Defects in Type 2M Von Willebrand Disease. Haemophilia 19(4):590-594, 2013.
• Flood, V.H., Friedman, K.D., Gill, J.C., Haberichter, S.L., Christopherson, P.A., Branchford, B.R., Hoffmann, R.G., Abshire, T.C., Dunn, A.L., Di Paola, J.A., Hoots, W.K., Brown, D.L., Leissinger, C., Lusher, J.M., Ragni, M.V., Shapiro, A.D., Montgomery, R.R. No Increase in Bleeding Identified in Type 1 VWD Subjects With D1472H Sequence Variation. Blood 121(18):3742-3744, 2013.
• *Dobrozsi, S., Flood, V.H., Panepinto J., Scott, J. P., Brandow A. Vitamin B12 Deficiency: The Great Masquerader. Pediatr Blood Cancer, 61(4):753-755, 2014.
• Flood, V.H., Schlauderaff, A.C., Haberichter, S.L., Slobodianuk, T.L., Jacobi, P.M., Bellissimo, D.B., Christopherson, P.A., Friedman, K.D., Gill, J.C., Hoffmann, R.G., Montgomery, R.R. Crucial role for the VWF A1 domain in binding to type IV collagen. Blood 125(14):2297-2304, 2015.
• Chen, J., Hinckley, J.D., Haberichter, S.L., Jacobi, P., Montgomery, R., Flood, V.H., Wong, R., Interlandi, G., Chung, D.W., López, J.A., Di Paola J. Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease. Blood 126(2):262-269, 2015.
• Cooper, S.T, Sell, S., Nelson, L., Hawes, J., Benrud, J.A., Kohlnhofer, B.M., Bradley R. Burmeister, B.R., Flood, V.H. Von Willebrand Factor is reversibly decreased during torpor in 13-lined ground squirrels. J Comp Physiol B 186(1):131-139, 2016.
• Flood, V.H., Christopherson, P.A., Gill, J.C., Friedman, K.D., Haberichter, S.L., Bellissimo, D.B., Udani, R.A., Dasgupta, M., Hoffmann, R.G., Ragni, M.V., Shapiro, A.D., Lusher, J.M., Lentz, S.R., Abshire, T.C., Leissinger, C., Hoots, W.K., Manco-Johnson, M.J., Gruppo, R.A., Boggio, L.N., Montgomery, K.T., Goodeve, A.C., James, P.D., Lillicrap, D., Peake, I.R., and Montgomery, R.R.. Clinical and Laboratory Variability in a Cohort of Patients Diagnosed with Type 1 VWD in the United States. Blood 2016, 127(20):2481-2488, 2016.
• *Doruelo, A.L., Haberichter, S.L., Christopherson, P.A., Boggio, L.N., Gupta, S., Lentz, S.R., Shapiro, A.D., Montgomery, R.R., Flood, V.H. Clinical and Laboratory Phenotype Variability in Type 2M von Willebrand Disease.  J Thromb Haemost 15(8):1559-1566, 2017.
• Flood, V.H., Johnsen, J.M., Kochelek, C., Slobodianuk, T.L., Christopherson, P.A., Haberichter, S.L., Udani, R., Bellissimo, D.B., Friedman, K.D., Montgomery, R.R. Common VWF Sequence Variants Associated with Higher VWF and FVIII Are Less Frequent in Subjects Diagnosed with Type 1 VWD. Research and Practice in Thrombosis and Haemostasis 2(2):390-398, 2018. 
• *Alaqzam, T., Stanley, A.C., Simpson, P.M., Flood, V.H., Menon, S.  Treatment Modalities in Adolescents Who Present With Heavy Menstrual Bleeding.  Journal of Pediatric and Adolescent Gynecology 2018, in press.
• Keesler, D.A., Flood, V.H.  Current Issues in Diagnosis and Treatment of von Willebrand Disease.  Research and Practice in Thrombosis and Haemostasis, 2(1):34-41, 2018.
• Flood, V.H., Abshire, T.C., Christopherson, P.A., Friedman, K.D., Gill, J.C., Montgomery, R.R., Haberichter, S.L., the Zimmerman Program Investigators. Von Willebrand Disease in the United States: Perspective from the Zimmerman Program. Ann Blood 2018;3:7.
• Slobodianuk, T.L., Kochelek, C., Foeckler, J., Kalloway, S., Weiler, H., Flood, V.H.  Defective Collagen Binding and Increased Bleeding in a Murine Model of VWD Affecting Collagen IV Binding.  J Thromb Haemost 17(1);63-71, 2019. 
• *Garcia, J, Flood V.H., Haberichter, S.L., Fahs, S.A., Mattson, J.G., Guerts, A.M., Zogg M., Weiler, H., Shi, Q. Montgomery, R.R. A Rat Model of Severe VWD by Elimination of the VWF Gene Using CRISPR/Cas9. Res Pract Thromb Haemost, 4(1):64-71, 2020. 
• Gill, J.C., Conley, S.F., Johnson, V.P., Christopherson, P.A., Haberichter, S.L., Diaz, C.D., Strong, T.C., Zhang, J., Simpson, P., Abshire, T.C., Montgomery, R.R., Flood, V.H. Low VWF Levels in Children and Lack of Association with Bleeding in Children Undergoing Tonsillectomy. Blood Advances, 4(1):100-105, 2020.
• Kalot, M.A., Al-Khatib, M., Connell, N.T., Flood, V., Brignardello-Petersen, R., James, P., Mustafa, R.A., and the VWD Working Group. An International Survey to Inform Priorities for new Guidelines on von Willebrand disease. Haemophilia, 26(1):106-116, 2020.
• Flood, V.H., Slobodianuk, T.L., Keesler, D., Lohmeier, H.K., Fahs, S., Zhang, L., Simpson, P., Montgomery, R.R. Von Willebrand Factor Binding to Myosin Assists in Coagulation. Blood Advances, 4(1):174-180, 2020.
• *Lohmeier, H.K., Slobodianuk, T.L., Kanaji, S., Haberichter, S.L., Montgomery, R.R., Flood, V.H. Von Willebrand Factor Variant D1472H Has No Effect in Mice with Humanized VWF-Platelet Interactions. Blood Advances 4(7):4065-4068, 2020.
• *DiGiandomenico, S., Christopherson, P.A., Haberichter, S.L., Abshire, T.C., Montgomery, R.R., Flood, V.H. and the Zimmerman Program Investigators. Laboratory Variability in the Diagnosis of Type 2 Von Willebrand Disease Variants.  J Thromb Haemost 19(1):131-138, 2021.
• James, P.D., Connell, N.T., Ameer, B., Di Paola, J., Eikenboom, J., Giraud, N., Haberichter, S., Jacobs-Pratt, V., Konkle, B., McLintock, C., McRae, S., Montgomery, R.R., O’Donnell, J.S., Scappe, N., Sidonio Jr., R., Flood, V.H., Husainat, N., Kalot, M.A., Mustafa, R.M. ASH ISTH NHF WFH 2020 Guidelines on the Diagnosis of von Willebrand Disease. Blood Advances 5(1):280-300, 2021. 
• Connell, N.T. and Flood, V.H., co-first authors, Brignardello-Petersen, R., Abdul-Kadir, R., Arapshian, A., Couper, S., Grow, J.M., Kouides, P., Laffan, M., Lavin, M., Leebeek, F.W.G., O’Brien, S.H., Ozelo, M.C., Tosetto, A., Weyand, A.C., James, P.D., Kalot, M., Husainat, N., Mustafa, R.M. ASH ISTH NHF WFH 2020 Guidelines on the Management of von Willebrand Disease. Blood Advances 5(1):301-325, 2021.

*first author a trainee.

Books, Chapters & Reviews

• Flood, V.H. Blueprints Q&A Step 2: Pediatrics. Blackwell Science; Malden, MA, 2002, contributor.
• Flood, V.H. Blueprints Q&A Step 3: Pediatrics. Blackwell Science; Malden, MA, 2002, contributor.
• Flood, V.H., Montgomery, R.R. Von Willebrand Disease: Biological Diagnosis. Textbook of Hemophilia, 2nd edition. Lee, C., Berntorp, E., Hoots, K., eds. Wiley-Blackwell; Oxford, UK, 2010. Revised chapter for 3rd edition submitted December 2012.
• Flood, V.H., Recht, M. Autoimmune Hemolytic Anemia. Textbook of Clinical Pediatrics, 2nd edition. Elzouki, A.Y., ed. Springer; New York, NY, 2011.
• Punzalan, R.C., Flood, V.H. Developmental Hemostasis. Textbook of Clinical Pediatrics, 2nd edition. Elzouki, A.Y., ed. Springer; New York, NY, 2011.
• Flood, V.H., Gill, J.C., Friedman, K.D., Bellissimo, D.B., Haberichter, S.L., Montgomery, R.R. Von Willebrand Disease in the United States: A Perspective from Wisconsin. Semin Thromb Hemost, 37(5):528-534, 2011.
• Berntorp, E., Fuchs, B., Makris, M., Montgomery R., Flood, V., O’Donnell, J.S., Federici, A.B., Lillicrap, D., James, P., Budde, U., Morfini, M., Petrini, P., Austin, S., Kannicht, C., Jiménez-Yuste, V., Lee, C. Third Åland Islands Conference on von Willebrand Disease, 26-28 September 2012: Meeting Report. Haemophilia, 19(Suppl 3): 1-18, 2013.
• Flood, V.H. Perils, Problems, and Progress in Laboratory Diagnosis of Von Willebrand Disease. Semin Thromb Hemost, 40(1):41-48, 2014.
• Flood, V.H., Montgomery, R.R. Von Willebrand Disease: Biological Diagnosis. Textbook of Hemophilia, 3rd edition. Lee, C., Berntorp, E., Hoots, K., eds. Wiley-Blackwell; Oxford, UK, 2014. (Revision of chapter from previous edition.)
• Flood, V.H. New Insights into Genotype and Phenotype of von Willebrand Disease. Hematology Am Soc Hematol Educ Program, 2014(1):531-535, 2014.
• *Roberts, J.C., Flood, V.H. Laboratory Diagnosis of von Willebrand Disease. International Journal of Laboratory Hematology, 37(Suppl 1): 11-17, 2015.
• Di Paola, J., Montgomery, R.R., Gill, J.C., Flood, V.H. Hemophilia and von Willebrand Disease. Nathan and Oski’s Hematology and Oncology of Infancy and Childhood, 8th edition. Orkin, S.H., Fisher, D.E., Ginsburg, D., Look, A.T., Lux, S.E., Nathan, D.G., eds. Elsevier; Philadelphia, PA, 2015.
• Flood, V.H., Scott, J.P. Von Willebrand Disease. Nelson Textbook of Pediatrics, 20th edition. Kleigman, R., Stanton, B., St. Geme III, J. Schor, N., eds. Elsevier; Philadelphia, PA, 2016.
• Flood, V.H. Platelet-Derived VWF in the Stroke Spotlight. Blood 126(14):1640-1641, 2015.
   

*first author a trainee.