| First Author | Shida Y | Year | 2014 |
| Journal | Blood | Volume | 124 |
| Issue | 11 | Pages | 1799-807 |
| PubMed ID | 25051961 | Mgi Jnum | J:214616 |
| Mgi Id | MGI:5603480 | Doi | 10.1182/blood-2013-09-521484 |
| Citation | Shida Y, et al. (2014) Analysis of the role of von Willebrand factor, platelet glycoprotein VI-, and alpha2beta1-mediated collagen binding in thrombus formation. Blood 124(11):1799-807 |
| abstractText | Rare missense mutations in the von Willebrand factor (VWF) A3 domain that disrupt collagen binding have been found in patients with a mild bleeding phenotype. However, the analysis of these aberrant VWF-collagen interactions has been limited. Here, we have developed mouse models of collagen-binding mutants and analyzed the function of the A3 domain using comprehensive in vitro and in vivo approaches. Five loss-of-function (p.S1731T, p.W1745C, p.S1783A, p.H1786D, A3 deletion) and 1 gain-of-function (p.L1757A) variants were generated in the mouse VWF complementary DNA. The results of these various assays were consistent, although the magnitude of the effects were different: the gain-of-function (p.L1757A) variant showed consistent enhanced collagen binding whereas the loss-of-function mutants showed variable degrees of functional deficit. We further analyzed the impact of direct platelet-collagen binding by blocking glycoprotein VI (GPVI) and integrin alpha2beta1 in our ferric chloride murine thrombosis model. The inhibition of GPVI demonstrated a comparable functional defect in thrombosis formation to the VWF(-/-) mice whereas alpha2beta1 inhibition demonstrated a milder bleeding phenotype. Furthermore, a delayed and markedly reduced thrombogenic response was still evident in VWF(-/-), GPVI, and alpha2beta1 blocked animals, suggesting that alternative primary hemostatic mechanisms can partially rescue the bleeding phenotype associated with these defects. |
