Sandra L Haberichter, PhD

Sandra L  Sandra L  profile

Sandra L Haberichter, PhD

Director, Hemostasis, Senior Investigator

Hemostasis, Thrombosis and Vascular Biology

Associate Professor of Pediatrics
Medical College of Wisconsin

Contact Information
  • 414-937-6488
  • 414-937-6488
  • 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.

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

    David Jakab
    Research Technologist II

    Connie Kwas
    Senior Research Technologist

    Heather Clift, PhD
    Postdoctoral Fellow

     
    Thrombosis & Hemostasis
    We study the properties of blood that cause it to clot. Our findings help to treat diseases that cause blood clots or excessive bleeding.
     
    Join Versiti Blood Research Institute
    Versiti Blood Research Institute, located in Milwaukee, Wisconsin, includes basic and clinical researchers in a variety of blood health fields.
     
    Our Experts
    Research investigators, postdoctoral fellows and laboratory staff at Versiti Blood Research Institute and Diagnostic Laboratories.
     
    Versiti Blood Research Institute
    Versiti Blood Research Institute investigators study blood disorders like hemophilia, blood cancers like leukemia, and other blood diseases.