Project: Platelets as Biosensors and Regulators of Metabolism in Lipedema

Principal Investigator: Scott J. Cameron, MD, PhD
Cleveland Clinic Foundation
Cleveland Clinic Lerner College of Medicine
Cleveland, OH

Summary

This research explores the role of platelets in mediating inflammatory and thrombotic responses in Lipedema. Platelets are dynamic entities with wide ranging involvement in cardiovascular, inflammatory, and thrombotic conditions. Following activation, platelets release a number of small molecules that influence tissue responses. The abnormal or pathophysiologic release of these molecules contributes to adverse clinical outcomes in several diseases and may be mitigated with use of antiplatelet medications. 

Using both real-world clinical data and laboratory-based techniques, we aim to characterize the thrombotic outcomes (blood clotting, risk of heart attack, stroke, and deep vein thrombosis), roles of antiplatelet agents, and platelet phenotype and programming in patients with Lipedema.

Background

In a recent study, the platelet-specific molecule platelet factor 4 (PF4) was identified as a biomarker that was elevated in patients with Lipedema or lymphedema and could discriminate from those with disease versus not. PF4 is released from platelets upon platelet activation and plays a key role in thrombosis and tissue inflammation. These findings suggest platelets may be hyperactivated in Lipedema and platelet degranulation may drive aberrant responses promoting a poorer clinical course. Therapeutic targeting of platelet activation with antiplatelet medications may mitigate thrombotic complications and improve symptomology in Lipedema.  A major goal will be comparing patients with Lipedema with lymphedema since many clinicians often mistake one diagnosis for the other. The potential benefit of reducing thrombotic outcomes with use of antiplatelet agents has not been assessed in Lipedema. Our lab’s work and others have demonstrated that the platelet may be reprogrammed in a disease-specific manner. 

Methodology

This is a clinical and translational research study using techniques in the basic science laboratory as well as large datasets. We will assess real-world clinical data for the incidence of thrombotic outcomes in Lipedema in a large tertiary academic medical center. Further, we will perform propensity-matched analysis of antiplatelet use in patients with Lipedema to assess if antithrombotic medications protect patients from blood clots. To test the hypothesis that platelet activation and aggregation is changed in Lipedema, we will use laboratory techniques to assess the contribution of platelets and non-platelet mediators to blood clotting in patients with Lipedema and lymphedema.

 We will also use RNA sequencing to identify biochemical and metabolic programs of circulating blood platelets that may allow us to use platelets as biosensors to differentiate a diagnosis of Lipedema from lymphedema. We will finally use metabolomics and lipidomics to evaluate the cell-free plasma from patients with Lipedema and lymphedema to tease apart unique signatures that may help not only in diagnosis but also point toward a therapeutic target. The majority of the work will be conducted at the Cleveland Clinic in the section of vascular medicine under the guidance of a physician scientist specializing in cardiology and vascular medicine, though collaborative work will also take place at New York University with a physician scientist in endocrinology/metabolism.

Expected outcomes

Since adipose tissue is inflammatory, we anticipate platelets in Lipedema will be hyperactivated and therapeutic targeting of platelet activation with commercially available antiplatelet medications may both reduce thrombotic complications and positively modify the clinical course in patients with Lipedema.

Practical implementations of results

We can establish a new mechanistic paradigm in Lipedema by assessing the role of platelets in the pathobiology of disease. There are currently no known effective medical therapies for Lipedema, but our study may support the use of antiplatelet agents in mitigating thrombotic outcomes and improving disease course in Lipedema.

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