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Sandra L Haberichter, PhD

Sandra L Haberichter, PhD

Director, Hemostasis

Associate Professor of Pediatrics
Medical College of Wisconsin

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Sandra L Haberichter, PhD

Director, Hemostasis
(414) 937-6488 Fax: 414-937-6404

  • Research Interests

    Thrombosis, Hemostatsis and Vascular Biology

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder. Von Willebrand factor (VWF) is a very large, multimeric plasma glycoprotein. These VWF multimers function to bind to exposed subendotheliium upon vessel injury and promote platelet-platelet interaction to initiate clotting. VWD is caused by decreased levels of VWF (type 1 VWD), a complete absence of VWF (type 3 VWD), or VWF that does not function properly (type 2 VWD).

    Our lab is focused on defining mechanisms causing VWD.

    Type 2A VWD comprises a subset of type 2 VWD.  Patients with type 2A VWD have only small multimers with little platelet binding function.  VWD patients recruited through the Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCB-VWD) study were phenotypically characterized and potential mutations identified in the VWF gene.  We investigated type 2A VWD variants through in vitro expression studies by assessing secretion/intracellular retention, multimerization, regulated storage, and ADAMTS13 proteolysis.  While some variants fit into the traditional group 1 (decreased secretion) or group 2 (increased proteolysis) categories, others did not clearly fall into either category.  We determined that loss of storage granule formation is associated with markedly reduced secretion.  Mutations involving cysteine residues were likely to cause abnormalities in multimer structure but not necessarily secretion.  When co-expressed with wild-type VWF, type 2A variants negatively impacted one or more mechanisms important for normal VWF processing.  Type 2A VWD appears to result from a complex intersection of mechanisms that include:

    1. intracellular retention/degredation of VWF
    2. defective multimerization
    3. loss of regulated storage
    4. increased proteolysis
       

    A second area of focus in the lab is the clearance of VWF from plasma. 

    A subset of type 1 VWD patients have very low VWF levels caused by reduced survival of plasma VWF (a 1-3 hr VWF half-life instead of the normal 8 - 14 hr).  In patients with reduced VWF survival (type 1C), only the mature VWF protein is cleared quickly, while the VWF propeptide has a normal half-life.  We can identify Type 1C patients by their increased VWFpp/VWF:Ag ratios.  In our ZPMCB-VWD study we determined that type 1C comprises approximately 15% of all type 1 VWD subjects.  We have also identified the characteristic elements of the type 1C phenotype: a markely reduced VWF:Ag, substantially reduced VWF half-life, an apparently enhanced desmopressin response, presence of a VWF gene mutation, diminished VWF multimer satellite bands, and a significantly increased VWFpp/VWF:Ag ratio.  Identifying patients with a type 1C phenotype is clinically important as DDAVP treatment will be less effective in these individuals.  Very little is known about the mechanisms that regulate the clearance of VWF under normal and disease conditions.  Our laboratory is currently investigating these mechanisms by using in vitro expression studies and murine models of VWF clearance.  

    In summary, the knowledge gained from these studies will increase our understanding of mechanisms causing VWD, and will lead to the development of more effective treatment strategies. 

  • Grant Support

    P01-HL081588, NIH/NHLBI, Molecular and Clinical Biology of VWD, Project 2: Molecular Mechanisms of VWF alteration in vitro/vivo

  • Lab

    David Jakab
    Research Technologist II

    Connie Kwas
    Senior Research Technologist

  • Publications
    • Haberichter, S.L., Fahs, S.A., and Montgomery,R.R. Von Willebrand (VWF) storage and multimerization – two independent intracellular processes, Blood, 96, 1808 (2000)
    • Haberichter, S.L., Jozwiak, M.A., Rosenberg, J.B., Christopherson, P.A., Montgomery, R.R. The von Willebrand factor propeptide, VWFpp, trafficks an unrelated protein to storage, Arterioscler Thromb Vasc Biol., 22, 921-926 (2002)
    • Haberichter, S.L., Jacobi, P., and Montgomery, R.R. Critical independent regions in the VWF propeptide and mature VWF that enable normal VWF storage, Blood, 101, 1384-1391 (2003)
    • Wilcox, D.A., Shi, Q., Nurden, P., Haberichter, S.L., Rosenberg, J.B., Johnson, B.D., Nurden, A.T., White II, G.C., Montgomery, R.R.  Induction of megakaryocytes to synthesize and store a releasable pool of human factor VIII.  Journal of Thrombosis and Haemostasis, 1, 2477-2489 (2003) 
    • Haberichter, S.L., Merricks, E.P., Fahs, S., Christopherson, P., Nichols, T.C., Montgomery, R.R., Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells, Blood, 105, 145-152 (2005) 
    • Haberichter, S.L., Shi, Q., Montgomery, R.R.  The biology of von Willebrand factor and factor VIII-Regulated Release.  Haematologica Reports, 1, 9-14 (2005)
    • Haberichter, S.L., Shi, Q., Montgomery, R.R., The Regulated Release of VWF and FVIII and the Biologic Implications, Pediatric Blood and Cancer, 46, 547 – 553 (2006) 
    • Michaux, G., Abbitt, K.B., Collinson, L.M., Haberichter, S.L., Norman, K.E., Cutler,  D.F.  The unique shape of endothelial Weibel-Palade bodies is necessary for the physiological function of von Willebrand factor.  Dev. Cell, 10, 223-232 (2006)
    • Haberichter, S.L., Balistreri, M., Christopherson, P., Morateck, P., Gavazova, S., Bellissimo, D.B., Manco-Johnson, M.J., Gill, J.C., Montgomery, R.R., Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease VWD with decreased VWF survival, Blood, 108: 3344 – 3351 (2006) 
    • Haberichter, S.L. , Castaman, G., Peake, I., Goodeve, A., Rodeghiero, F., Federici, A., Batlle, J., Meyer, D., Mazurier, C., Goudemand, J., Eikenboom J., Schneppenheim, R., Budde, U., Ingerslev, J., Vorlova, Z., Habart, D., Holmberg, L., Lethagen, S., Pasi, J., Hill, F., Montgomery, R.R. Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD (MCMDM-1VWD), Blood, 111; 4979 – 4985 (2008)
    • Haberichter, S.L, Allmann, A.M., Jozwiak, M.A., Montgomery, R.R., Gill, J.C., Genetic Alteration of the D2 Domain Abolishes von Willebrand Factor Multimerization and Trafficking to Storage, Journal of Thrombosis and Haemostasis, 7, 641 – 50 (2009)
    • Haberichter, S.L., Budde, U., Drewke, E., Obser, T., Wermes, C., Schneppenheim, R., The Mutation N528S In the von Willebrand Factor (VWF) Propeptide Causes Defective Multimerization and Storage of VWF, Blood, 115, 4580 - 87 (2010)
    • Flood, V.H., Gill, J.C., Morateck, P.A., Christopherson, P.A., Friedman, K.D., Haberichter, S.L, Branchford, B.R., Hoffman, R.G., Abshire, T.C., DiPaola, 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, 280-86(2010) 
    • Castaman, G., Giacomelli, S.H., Jacobi, P., Obser, T., Budde, U., Rodeghiero, F., Haberichter, S.L., Schneppenheim, R. Homozygous Type 2N R854W von Willebrand Factor Is Poorly Secreted And Causes a Severe von Willebrand Disease Phenotype, Journal of Thrombosis and Haemostasis, 8; 2011–6 (2010)
    • Flood, V.H., Gill, J.C., Morateck, P.A., Christopherson, P.A., Friedman, K.D., Haberichter, S.L., Hoffmann, 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, e67-74 (2011)
    • Pruss, C.M., Golder, M., Bryant, A., Burnett, E., Sponagle, K., Hegadorn, C., Haberichter, S.L., Lillicrap, D., Mouse Models Of The Common, Recurring Type 1 Von Willebrand Disease Mutations Y1584C and R1205H, Blood, 117; 4358-66 (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 (in press, 2012)
    • Jacobi, P.M., Gill, J.C., Flood, V.H., Friedman, K.D., Haberichter, S.L., Intersection of Mechanisms of Type 2A Von Willebrand Disease Through Defects In Von Willebrand Factor Multimerization, Secretion, ADAMTS-13 Susceptibility, And Regulated Storage, Blood, 119(19): 4543-4553 (2012) 
    • Castaman, G., Giacomelli, S.H., Jacobi, P.M., Obser, T., Budde, U., Rodeghiero, F., Schneppenheim, R., Haberichter, S.L., Reduced von Willebrand Factor Secretion is Associated With Loss of Weibel-Palade Body Formation, Journal of Thrombosis and Haemostasis, 10; 940-950 (2012)
    • Hubbard, A.R., Hammill, M., Eikenboom, H.C., Montgomery, R.R., Mertens, K., and Haberichter, S.L, on behalf of the SSC Sub-Committee on von Willebrand Factor of ISTH.  Standardization of von Willebrand factor propeptide: value assignment to the WHO 6th IS Factor VIII/von Willebrand factor, plasma (07/316).  Journal of Thrombosis and Haemostasis; 10: 959-60 (2012) 
    • Flood, V.H., Gill, J.C., Christopherson, P.A., Wren, J.S., Friedman, K.D., Haberichter, S.L., Hoffman, R.G., Montgomery, R.R.  Comparison of Type I, Type III, and Type VI collagen binding assays in the diagnosis of VWD.  Journal of Thrombosis and Haemostasis, 10(7): 1425-1432 (2012)
    • Kanaji, S., Fahs, S.A., Shi, Q., Haberichter, S.L., Montgomery, R.R.  Contribution of platelet versus endothelial VWF to Platelet Adhesion and Hemostasis, Journal of Thrombosis and Haemostasis, 10(8): 1646-1652 (2012)
    • Flood, V.H., Gill, J.C., Christopherson, P.A., Larsen, D.M., Friedman, K.D., Haberichter, S.L., Lentz, S., Montgomery, R.R.  Critical VWF A1 Domain residues influence type VI collagen binding.  Journal of Thrombosis and Haemostasis, 10(7):1417-1424 (2012)
    • Huang, J., Haberichter, S.L.,  Sadler, J.E.  The B subunits of Shiga-like toxins induce regulated VWF secretion in a phospolipase D1-dependent manner.  Blood, 120(5): 1143-1149 (2012)
    • Flood, V.H., Gill, J.C., Friedman, K.D., Christopherson, P.A., Jacobi, P.M., Hoffman, R.G., Montgomery, R.R., Haberichter, S.L.  Collagen binding provides a sensitive screen for variant von Willebrand Disease.  Clinical Chemistry, 59(4): 684-691 (2013)
    • Flood, V., Friedman, K., Gill, J., Haberichter, S.L., Chistopherson, P., Branchford, B., Hoffman, R., Abshire, T., Dunn, A., Di Paola, J., Hoots, W., Brown, D., Leissinger, C., Lusher, J., Ragni, M., Shapiro, A., Montgomery, R.  No increase in bleeding identified in Type I VWD subjects with D1472H sequence variation.  Blood, 121(18): 3742-3744 (2013)
    • Skipwith, C., Haberichter, S.L.,  Gehrand, A., Zheng, X.L.  Comprised proteolytic cleavage of type 2N von Willebrand factor variants by ADAMTS13 in the presence of factor FVIII, Thromb Haemost, 110(1): 202-204 (2013)
    • Muia, J., Gao, W., Haberichter, S.L., Dolatshahi, L., Zhu, J., Westfield, L.A., Friedman, K.D., Sadler, J.E.  An optimized fluorogenic ADAMTS13 assay with increased sensitivity for the investigation of patients with thrombotic thrombocytopenic purpura.  Journal of Thrombosis and Haemostasis,  11(8): 1511-1518 (2013)
    • Du, L.M., Nurden, P., Nurden, A.T., Nichols, T.C., Bellinger, D.A., Jensen, E.S., Haberichter, S.L., Merricks, W., Raymer, R.A., Fang, J., Koukouritaki, S.B., Jacobi, P.M., Hawkins, T.B., Cornetta, K., Shi, Q., Wilcox, D.A.  Platelet targeted gene therapy with human factor VIII estabilshes haemostasis in dogs with haemophilia A. Nature Communications, 4:2773 (2013)
    • Rusu, L., Andreeva, A., Visintine, D.J., Kim, K., Vogel, S.M., Stojanovic-Terpo, A., Chernaya, O., Liu, G., Bakhshi, F.R., Haberichter, S.L., Iwanari, H., Kusano-Arai, O., Suzuki, N., Hamakubo, T., Kozasa T., Cho, J., Du, X., Minshall, R.D.  G protein-dependent basal and evoked endothelial cell vWF secretion.  Blood, 123(3): 442-450 (2014)
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