Restoring platelet balance to treat antiphospholipid syndrome

Antiphospholipid syndrome, or APS, is an autoimmune clotting disorder that is caused by abnormal “antiphospholipid antibodies” in the blood.

A diagnosis of APS comes with a significantly increased risk of blood clots, for example, stroke and deep vein thrombosis.

APS is also well known for its obstetrical complications that can impact the mother and child during pregnancy, childbirth and postpartum.

Despite its status as an autoimmune condition, APS is still treated primarily with blood-thinning medications like warfarin, which bring with them a significantly increased risk of bleeding.

A research study led by Naveen Kumar Somanathapura Kumarswamy, Ph.D., a research assistant professor of rheumatology at University of Michigan Health has uncovered new findings that may eventually help improve the care of patients living with APS.

The research published in Blood Advances found that enhancing a natural pathway within small blood-clotting cells called platelets has the potential to eventually change how patients are treated.

Platelet activation can occur within seconds, which is critical to the body’s ability to rapidly halt bleeding.

Platelets, therefore, have finely tuned signaling pathways that keep them quiet one moment and allow for activation the next.

SEE ALSO: Could targeting metabolism treat blood clots in antiphospholipid syndrome?

“That balance appears to be lost in APS, where platelets inappropriately shed a surface enzyme called CD73, which we found was critical for maintaining platelets in their resting state,” said Kumarswamy.

Beyond profiling fresh platelets isolated from the blood of patients with APS, the team also found that exposing healthy platelets to antiphospholipid antibodies caused changes similar to those appreciated in patients.

CD73 was lost, and with it, a chemical that it produces called adenosine, which normally surrounds platelets with an anti-clotting halo.

SEE ALSO: Inside antiphospholipid syndrome: a patient's personal health journey 

The team identified several promising agents for restoring platelet balance, some of which are already FDA-approved for other indications. One example is cilostazol, a medication currently prescribed to improve blood flow in the lower legs in certain people.

“This remains a really important topic, as the need to take lifelong blood thinners has a negative impact on the quality of life of many patients. We must find better treatments for these individuals.”

Going forward, the research team will continue to focus on identifying new ways to restore this protective platelet pathway, either by increasing adenosine production or finding a safe way to compensate for its decrease.

“Unlike current therapies that increase bleeding risk, we hope to find strategies that will reduce harmful clotting while keeping the hemostatic system (which addresses bleeding) relatively intact. Sometimes the answer is to block bad pathways, but here, we think it is actually about restoring the good.”

Additional authors: Thalia Newman, Bruna Fonseca, Srilakshmi Yalavarthi, Mariane Flores Nascimento, Kaitlyn Sabb, Katarina Kmetova, Emily Chong, Kavya Sugur, Caroline Ranger, Megan Tompkins, Cyrus Sarosh, Jacqueline Madison, Ajay Tambralli, Jordan Schaefer, Michael Holinstat, Yu Zuo, and Jason Knight from the University of Michigan, Ann Arbor, Michigan

Funding/disclosures: This work was supported by NIH grant R01HL134846 to JSK. NSK was supported by a grant from the Arthritis National Research Foundation. BMF was supported by the São Paulo Research Foundation (FAPESP), Brazil. Process number 2022/06868-1. AT was supported by a grant from the Rheumatology Research Foundation.  YZ was supported by NIH grant K08AR080205.

Michigan Research Core(s): Platelet Pharmacology and Physiology Core

Paper cited: “A Disrupted Adenosinergic Axis Facilitates Platelet Activation in APS: Exploring a Novel Therapeutic Target,” Blood Advances.

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