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1774 Von Willebrand Factor (VWF) Deficiency Leads to Altered Angiogenesis in the Gastrointestinal Tract

Program: Oral and Poster Abstracts
Session: 321. Blood Coagulation and Fibrinolytic Factors: Poster II
Hematology Disease Topics & Pathways:
Diseases, Bleeding and Clotting, Animal models, Study Population, VWD
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Mario von Depka, MD, PhD1*, Katharina Kaiser, DVM1*, Carsten Detering1*, Christiane Pfarrer, DVM, Prof2*, Mahnaz Ekhlasi-Hundrieser, PhD1* and Stefanie Lehner, DVM, PhD1*

1Werlhof-Institute, Hannover, Germany
2Institute for Anatomy, University of Veterinary Medicine Hannover, Hannover, Germany

Objectives: Gastrointestinal bleeding in Von Willebrand Disease (VWD) is a challenging complication. Recently, impaired angiogenesis has been discussed as a possible pathophysiological mechanism. In vitro studies have shown that the ANG-TIE-system regulates the activation of endothelial cells (EC) to guarantee proper angiogenesis but is altered by VWF. We, therefore, investigated the impact of VWF deficiency on angiogenesis and angiogenic modifiers in the stomach in porcine VWD type 1 (T1) and type 3 (T3).

Methods: A total of 11 pigs (3 WT, 5 T1, 3 T3) were used for immunohistochemistry (IHC) and 13 pigs (6 WT, 5 T1, 2 T3) for RT PCR to investigate the distribution and expression of Ang2 and TIE1. Pigs with a heterozygous mutation in the VWF gene represent T1 and homozygous animals represent T3. Healthy pigs were used as controls (WT, n=3). Hematoxylin-eosin (HE) staining was performed to evaluate the blood vessel architecture.

Results: HE-staining showed angiodysplasia in T3 pigs. In IHC, mean expression levels of ANG2 were increased in both VWD types relative to the WT in endothelial cells, while mean expression levels of TIE1 were reduced in the same groups in vascular smooth muscle cells. In RT PCR, ANG2 and TIE1 showed the same tendencies in T1 pigs compared to the WT. Regarding the ratio of ANG2/TIE1, a shift towards ANG2 was visible in IHC in all affected pigs and in qPCR in the T1 pigs.

Discussion and Conclusions: We, for the first time, demonstrate altered angiogenesis in VWD in vivo in a large animal model. Our results indicate a shift away from TIE1, an inhibitor of EC, towards ANG2, an activator of EC in VWD type 1 and 3. This might lead to excessively upregulated angiogenesis, thus resulting in angiodysplasia and contributing to gastrointestinal bleeding as a consequence.

Disclosures: von Depka: Octapharma: Consultancy, Honoraria, Research Funding; Shire: Research Funding.

*signifies non-member of ASH