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Von Willebrand Factor Contributes to Alternative Complement Pathway Activation, Microangiopathy, and Renal Dysfunction in Murine Thromboinflammation

P. Jacobi1,2, S. Sartain1,2

1Baylor College of Medicine, Houston, United States, 2Texas Children's Hospital, Houston, United States

Abstract Number: OC 66.3

Meeting: ISTH 2021 Congress

Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Non HUS/TTP Microangiopathies

Background: Thrombosis in the setting of inflammation, or thromboinflammation, complicates a variety of medical disorders. Microvascular thromboinflammation can be devastating, associated with microangiopathy, endothelial injury, and end-organ damage. The alternative complement pathway (AP) is overactivated in several disorders of microvascular thromboinflammation, but little is known about the mechanisms of AP activation. In vitro, it has been demonstrated that von Willebrand factor (VWF) serves as a surface for AP activation on inflammatory cytokine-stimulated endothelial cells.

Aims: To assess in vivo in murine thromboinflammation VWF-mediated AP activation and initiation of microangiopathy and renal injury.

Methods: To provoke thromboinflammation, wild-type (WT) and VWF-/- C57BL/6J mice were injected intraperitoneally with 5 mg/kg of inflammatory endotoxin lipopolysaccharide (LPS). Twenty-four hours after injection of LPS or saline (control), markers of thromboinflammation (glomerular fibrin, tumor necrosis factor [TNF]), microangiopathy (lactate dehydrogenase [LDH], platelet count, hemoglobin), renal dysfunction (creatinine), and AP activation (complement factor Ba [Ba] levels) were measured and analyzed using an unpaired t-test.

Results: LPS-injected WT mice, compared to saline-injected mice, demonstrated increased glomerular fibrin deposition and significantly higher TNF, higher LDH, lower platelet count, lower hemoglobin, higher creatinine, and higher Ba levels (Fig.1). LPS-injected VWF-/- mice, compared to LPS-injected WT mice, demonstrated significantly lower LDH, higher platelet counts, higher hemoglobin, lower creatinine, and lower Ba levels (Fig.2).

Markers of Murine Thromboinflammation, Microangiopathy, Renal Dysfunction, and AP Activation.

Markers of Microangiopathy, Renal Dysfunction, and AP Activation in WT and VWF-/- Mice with Provoked Thromboinflammation. 

Conclusions: In this study, we showed for the first time that in addition to inducing thromboinflammation, LPS injection caused AP activation in WT mice. Our data also suggested VWF contributed to AP activation (with subsequent microangiopathy and renal dysfunction) in vivo, as LPS-injected VWF-/- mice that do not produce VWF had lower Ba levels than WT mice. These data help better our understanding of the relationship between VWF and the AP, and may lead to development of therapeutics that inhibit VWF-complement interaction to curb AP activation, microangiopathy, and renal dysfunction in thromboinflammation.

To cite this abstract in AMA style:

Jacobi P, Sartain S. Von Willebrand Factor Contributes to Alternative Complement Pathway Activation, Microangiopathy, and Renal Dysfunction in Murine Thromboinflammation [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/von-willebrand-factor-contributes-to-alternative-complement-pathway-activation-microangiopathy-and-renal-dysfunction-in-murine-thromboinflammation/. Accessed June 25, 2022.

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