Soluble Glycoprotein VI Predicts Abdominal Aortic Aneurysm Growth Rate and is a Novel Therapeutic Target

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (JAQ1) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist. Human AAA tissue was obtained from four patients (4 males) aged 65 ± 7.7 years (mean ± SD; range 45 to 71 years) undergoing open aneurysm repair (between 2015 and 2018) at the University of Rochester Medical Center in Rochester, NY under an approved University of Rochester Cardiovascular Tissue Bank Internal Review Board Application (RSRB 00036669). The patient criteria for open surgical repair were defined as AAA diameter exceeding 55 mm for males, AAA diameters between 50 and 55 mm for females, rapidly expanding aortic diameters (≥ 5 mm in 6 months with a minimum diameter of 40 mm), or symptoms attributable to AAA and AAA rupture. Mural thrombi (easily separated from the aortic wall) were collected during surgery, along with residual aortic wall fragments, and were immediately flash frozen until RNA extraction. Control tissue was procured from the infrarenal aortas of 5 males aged 58 ± 6.6 years (mean ± SD; range 42 to 65 years) cause of death deemed non-aortic causes. Tissues were collected within 24 hours of death and flash frozen for analysis. To identify what genes were enriched within the ILT as a part of the overall AAA, comparisons between the transcriptome of thrombi and surroding aortic tissue was performed.