Evan Sadler.jpg

J. Evan Sadler, MD, PhD

Department of Medicine
Hematology Division
Department of Biochemistry & Molecular Biophysics


  • 314-362-9029 (tel)
  • 314-454-3012 (fax)
  • Room 10027 Clinical Sciences Research Building (office)
  • Room 10034 Clinical Sciences Research Building (lab)
  • Hematology Division
    Campus Box 8125
    Washington University Medical School
    660 South Euclid Avenue
    St. Louis, MO 63110


My laboratory studies the pathophysiology of hemorrhage and thrombosis, focusing on the mechanisms that promote and inhibit platelet adhesion. Von Willebrand factor (VWF) is a multimeric protein that mediates platelet adhesion to sites of vascular injury and stabilizes blood coagulation factor VIII; these interactions are essential for hemostasis. Von Willebrand disease (VWD) is caused by deficiency of VWF, and is the most common inherited bleeding disorder. Endothelial cells assemble VWF multimers into ordered tubules within storage organelles called Weibel-Palade bodies, and tubular packing is necessary for the secretion of VWF filaments that can bind connective tissie and recruit platelets to sites of vascular injury. Specific domains of VWF interact with platelet receptor proteins, and binding is regulated allosterically. We are investigating the processes of VWF multimer assembly, self-organization into helical tubules, and regulated secretion. We have recently discovered that Shiga toxin, a cause of epidemic food borne illness, can induce VWF secretion from endothelial cells. A single VWF molecule can be enormous, up to 4 micrometers in length. VWF assembly into large multimers is required to prevent bleeding and, conversely, the proteolytic cleavage of VWF multimers is required to prevent thrombosis. We are studying a metalloprotease with a complex multidomain structure, ADAMTS13, which participates in the feedback inhibition of VWF function by cleaving a Tyr-Met bond in the center of the VWF subunit. Interestingly, VWF cleavage by ADAMTS13 is regulated by tensile stress, so that VWF only becomes susceptible when it is stretched at the site of a growing platelet thrombus. We recently discovered that ADAMTS13 is allosterically activated upon binding its substrate, VWF. We are characterizing the extensive multidomain interactions between ADAMTS13 and VWF that are responsible for this remarkable process. Congenital or acquired deficiency of ADAMTS13 causes life-threatening microvascular thrombosis (thrombotic thrombocytopenic purpura), and we also are conducting clinical trials to assess the use of ADAMTS13 assays and immediate immunosuppressive therapy for patients with thrombotic thrombocyotpenic purpura.


vWF assembly

Model for the assembly, tubular packing, and secretion of VWF multimers

(A and B) In the ER, proVWF subunits dimerize through disulfide bonds between C-terminal CK domains (small gray spheres). The propeptide consists of domains D1 ("1," yellow) and D2 ("2," orange) and is linked to D'D3 of the mature subunit ("3," blue) by a furin cleavage site (green). Two potential orientations of the propeptide are distinguished by whether homodimer contacts involve domain D1 (A) or D2 (B). In either case, pH-dependent interactions bring two D′D3 domains together and facilitate intersubunit disulfide bond formation.
(C) The propeptide (yellow) and dimeric D′D3 domains (blue) pack into a helix surrounded by the C-terminal remainder of the VWF subunits (gray).
(D) Secretion exposes the tubules to blood at pH 7.4, which destabilizes the contacts between propeptide and D′D3 domains and allows extension of the multimer.

From: Huang RH, Wang Y, Roth R, Yu X, Purvis AR, Heuser JE, Egelman EH, Sadler JE
Assembly of Weibel-Palade body-like tubules from N-terminal domains of von Willebrand factor.
Proc Natl Acad Sci U S A 2008 Jan 15;105(2):482-7