Hematopoietic cells and chemokine regulation in abdominal aortic aneurysm associated thrombosis

ABSTRACT (Project Summary)
Abdominal aortic aneurysm (AAA) is defined as a ≥ 50% dilation of normal infrarenal aortic diameter
characterized by chronic inflammation and progressive medial degeneration resulting in structural failure of the
aortic wall. Untreated, AAA can progress to fatal aortic rupture which annually accounts for an estimated 167,200
deaths and 3 million disability-adjusted life years worldwide. Pharmaceuticals (statins, ACE inhibitors) against
CVDs have had limited success in AAA patients meaning that surgical intervention is the only proven treatment
option, pursued only when the risk of aneurysm rupture outweighs the risk of surgery. Traditional risk factors for
AAA incidence include increased age, Caucasian race, male sex, peripheral artery disease, coronary heart
disease, family history, and smoking. Despite higher incidence in men, women are four times more likely to
experience aortic rupture when normalized for aortic diameter, yet aneurysm investigations are largely focused
on males, creating a need for aneurysm research addressing sex as a biological variable. The formation of a
blood facing, non-resolving intraluminal thrombus (ILT) occurs in approximately 70 – 80% of AAA patients. As an
active site of thrombosis, the highly inflammatory ILT is enriched in platelet erythrocytes (RBC), neutrophils,
macrophages, and crosslinked fibrin. The current application builds on our recent publication demonstrating that
platelet activation is positively associated with aneurysm growth rate and platelets from AAA patients activate
more robustly to agonist stimulation. Additional preliminary data indicates that genes associated with platelet
activation and coagulation are significantly increased in AAA patient platelets as compared to control. As platelets
are anucleate, changes in gene expression suggests alterations to platelet progenitor megakaryocytes (MK). In
the bone marrow, mature MKs are derived from the myeloid lineage progenitors know to be influenced by
inflammation. The regulation of systemic levels of numerous chemokines is regulated by the RBC expressed
Duffy antigen receptor for chemokines (DARC/ACKR1). Due to variable evolutionary selection pressures,
individuals of African descent largely lack RBC-DARC expression and have a reported decreased incidence of
aneurysm formation, but the chemokine reservoir functionality of RBC-DARC in AAA pathogenesis remains
unknown. This proposal aims to identify three novel mechanisms of AAA pathogenesis; (1) examining the roles
of platelet hyperactivation and coagulation, (2) reprogramming of MK mediated by aneurysm associated
inflammation (3) the role of RBC-DARC chemokine reservoir activity in thrombosis and the systemic distribution
of chemokines. Successful completion of the proposed work will uncover adaptive changes in hematopoietic
progenitor populations that could lead to new therapeutic strategies for aneurysm patients while addressing gaps
in AAA patient incidence and outcomes.

Grant Number: 1K99HL181189-01
NIH Institute/Center: NIH
Principal Investigator: Tyler Benson