Sickle Cell Disease Research News: Novel Findings Show HMGB1 Protein Enhances Platelet Activation
July 11, 2024
Research from a University of Pittsburgh and UPMC Children’s Hospital of Pittsburgh team provides new mechanistic insights into the relationship between inflammation and thrombosis in sickle cell disease (SCD).
Thrombosis and inflammation are closely connected processes in SCD. Platelets are not only key players in clot formation but also play important roles in driving inflammatory processes. High-mobility group box 1 (HMGB1) is a protein involved in inflammation and is released by damaged tissues and activated immune cells. The team’s study was designed to explore how HMGB1 affects platelet activation and interactions with the P2Y12 receptor.
The study was published in the Journal of Clinical Investigation Insight in March 2024.
Deirdre Nolfi-Donegan, MD, assistant professor of Pediatrics in the Division of Pediatric Hematology/Oncology at UPMC Children’s Hospital of Pittsburgh was the study’s lead author, alongside Gowtham K. Annarapu, PhD. Also contributing to the study from the University of Pittsburgh were, Claudette St. Croix, Michael Calderon, and Cheryl A. Hillery, MD, professor of Pediatrics and clinical director of Hematology at UPMC Children’s. Sruti Shiva, PhD, professor in the Department of Pharmacology and Chemical Biology was the senior author of the investigation.
Study Overview and Summary of Findings
The primary goal of the research was to understand how HMGB1 enhances the activation of platelets through ADP, a substance that platelets release to help with clotting. By investigating this interaction, the team sought to provide new insights into potential treatments for managing complications in SCD.
Dr. Nolfi-Donegan and colleague’s study found that HMGB1 makes platelets more responsive to another molecule, adenosine diphosphate (ADP), which usually only weakly activates platelets to form clots. The mechanism of this is twofold: first, HMGB1 stimulates platelets to release ADP into the surrounding clot, and at the same time HMGB1 increases the amount of the receptor for ADP called P2Y12 on the surface of the platelets to make platelet activation easier. Both of these processes are controlled by a specific signaling pathway in the cells – the Toll-like Receptor 4 (TLR4) pathway.
In people with SCD, the research showed higher levels of HMGB1 in the blood, leading to more active platelets. When the team treated healthy platelets with blood plasma from SCD patients, the platelets took on a much more active state, similar to what happens or is observed in SCD. Removing HMGB1 from the plasma reduced this effect, which shows HMGB1's necessary role in platelet activation.
The study also confirmed these findings in a small animal model, where blocking P2Y12 reduced the activation caused by HMGB1.
These results suggest that targeting the interaction between HMGB1 and P2Y12 could help reduce blood clotting and inflammation in the context of SCD.
Since P2Y12 blockers are already used to treat other conditions, this research supports their potential use in treating SCD.
“Understanding HMGB1's role in platelet activation offers a new perspective for treating SCD,” says Dr. Nolfi-Donegan. “P2Y12 inhibitors, used for other cardiovascular conditions, might also help reduce platelet activation in SCD patients, which opens up the door for more research and clinical trials on these treatment approaches to improve patient outcomes.”
Reference
Nolfi-Donegan D, Annarapu GK, St Croix C, Calderon M, Hillery CA, Shiva S. High-Mobility Group Box 1 Increases Platelet Surface P2Y12 and Platelet Activation in Sickle Cell Disease. JCI Insight. 2024 Mar 8; 9(5): e174575.
