Alex Marki, M.D.

Elongated Neutrophil-Derived Structures (ENDS) in Sepsis

FUNDED BY: the generosity of Dick & Karna Bodman, The Miller Family, and
2019-20 Various Donors

Sepsis, a complication of bacterial infection, is the number one cause of death of hospitalized patients. One out of four septic patients does not survive the disease, resulting in 250 thousand casualties annually in the U.S. alone. Additionally, sepsis treatment requires intensive care unit admission and prolonged hospital care, thus it imposes a substantial financial burden on the health care system. The currently available diagnostic and treatment methods are not sufficient to reduce this burden.

I discovered a new type of micro-particle, so called elongated neutrophil-derived structures (ENDS), which are more than 100-fold elevated in the blood of septic patients. Neutrophils, the immune system’s EMTs, spend most of their lives racing through the bloodstream constantly on the lookout for bacteria and other foreign invaders. They roll along the walls of blood vessels by throwing out tube-like tethers to anchor themselves to avoid being swept away by blood rushing by at high speed. As they gently roll along, tether after tether is peeled loose and slung forward like a lasso to gain new leverage, slowing them down enough to exit the blood vessel at the site of infections. Sometimes, sections of these tube-like tethers detach and remain in the vessel lumen as elongated particles.

We found a unique set of surface markers that distinguish ENDS from other blood-borne particles. It allows us to analyze the blood of septic patients and healthy donors with Image Stream, an instrument that can image the surface markers of several hundred suspended micro-particles per second. During the initial study, we only had a single blood sample from each septic patient and limited access to clinical parameters or lab tests, which prevented us from evaluating the predictive value of elongated particle count in sepsis outcome.

The goal of this project is to collect sufficient data to test the predictive value of ENDS. In collaboration with Dr. Daniel Sweeney, the head of the UC San Diego Hillcrest Intensive Care Unit, we will collect blood samples from septic patients every other day during their hospital stay. We will use Image Stream to count the elongated particles and a commercially available test kit to measure the amount of established inflammatory mediators in the blood. We will compare these values to standard sepsis monitoring clinical parameters.

Six-Month Project Update

Prior to winning my SPARK Award, I discovered a new type of micro-particle, so called elongated neutrophil-derived structures (ENDS), which are significantly elevated in the blood of septic patients. The goal of my project is to collect blood samples from septic patients during their hospital stay that we can analyze to generate sufficient data to validate the predictive value of ENDS for sepsis. My hope is that this will help improve diagnosis and clinical outcomes for septic patients. My project was significantly impacted by the pandemic, as we experienced delays in getting approval to collect blood samples from UC San Diego’s Human Research Protections Program and my clinical collaborator at UC San Diego Hillcrest ICU was overloaded with treating COVID-19 patients for much of this year. We are actively working through that approval process and hope to begin collecting patient samples soon so we can execute this project. We’ve also received an extension for this project from LJI to be able to complete this project by spring 2021. In the meantime, with funding from the laboratory of Klaus Lay, I’ve conducted additional preliminary experiments with mice which further corroborated our hypothesis for this project. I am eager to proceed with these experiments using human samples so that I can fulfill my project goal of identifying a better diagnostic option for sepsis.