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Von Willebrand Factor (VWF) Collagen IV Binding Defect – A Potentially Overlooked Cause for Excessive Bleeding Phenotype

M. Escobar1, N. Montanez1, J. Lemons1, K. Friedman2

1University of Texas Health and Science Center of Houston, McGovern Medical School, Gulf States Hemophilia and Thrombophilia Center, Houston, United States, 2Diagnostic Laboratories, Versiti (Blood Center of Wisconsin), Milwaukee, United States

Abstract Number: PB0930

Meeting: ISTH 2021 Congress

Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » VWF and von Willebrand Factor Disorders - Clinical Conditions

Background: Interaction of VWF with collagen at sites of vascular injury supports initial platelet tethering. Defective collagen-binding may increase the bleeding risk in type 1 VWD and is a mechanism of type 2M VWD.  The VWF A3 domain interacts with collagens I and III while the A1 interacts with collagens IV and VI.  

Aims: Describe a single Center’s experience in diagnosis of VWF collagen IV binding defect.

Methods: Retrospective record review of a 56 y/o Caucasian female with presumptive clinical diagnosis of “Ehlers Danlos Syndrome Classic type” with history of excessive bruising, heavy menstrual bleeding, and post-operative bleeding that required RBC transfusion, suggesting additional bleeding risk factors.

Results: Testing of primary, secondary and fibrinolytic system were without evidence of abnormalities. VWF antigen, platelet-binding and multimers, as well as Factor I – XIII, platelet aggregation studies, and flow cytometry for platelets and thromboelastography (ROTEM) were within normal limits. Comprehensive bleeding disorder genetic analysis (51 genes) identified heterozygosity VWF c.4196G>A (p. Arg1399His).  Subsequent VWF collagen binding profile showed decreased VWF collagen IV binding activity, with reduction of the collagen IV binding activity to VWF antigen ratio (0.58, reference interval 0.77-1.27).  VWF collagen III binding, ratio of collagen III binding to VWF antigen and VWF multimers were all normal. VWF c.4196G>A (p. Arg1399His) has been shown through expression studies to have impaired binding to collagen type IV and association with a hemostatic defect in a mouse model (Slobodianuk 2019), potentially increasing bleeding score in patients with type 1 VWD (Flood 2016).

Conclusions: The interaction of VWF with collagen is physiologically important, but is uncommonly assessed in the evaluation of patients with excessive bleeding phenotype. Different VWF domains interact with collagen I/III versus collagen IV/VI. Although isolated collagen-binding defects are rare, such evaluation should be considered in patients with unexplained bleeding, as such defects may contribute to bleeding phenotype.

To cite this abstract in AMA style:

Escobar M, Montanez N, Lemons J, Friedman K. Von Willebrand Factor (VWF) Collagen IV Binding Defect – A Potentially Overlooked Cause for Excessive Bleeding Phenotype [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/von-willebrand-factor-vwf-collagen-iv-binding-defect-a-potentially-overlooked-cause-for-excessive-bleeding-phenotype/. Accessed June 25, 2022.

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