Michael Research
Contact
1020 Locust Street
Jefferson Alumni Hall 394
Philadelphia, PA 19107
The focus of our research is to explore the role of platelets in thrombosis, with an emphasis on exploring the interactions between platelets and other blood cells. Our research approaches include the use of de-identified clinical samples, healthy human blood donors, and genetically modified mice in various biochemical assays of cell isolation, activation, and signaling, in addition to various imaging approaches. The following is a brief summary of major ongoing projects.
Recent Projects
Platelets as Regulators of Inflammation in Immune Thrombotic Thrombocytopenia Disorders
Platelet factor 4 (PF4) is an abundant chemokine released from alpha granules of activated platelets, which has a physiological role in regulating coagulation and wound repair. Development of pathological immunoglobulin G antibodies against PF4 (anti–PF4 antibodies) form the underlying etiology of a class of prothrombotic disorders including heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT). We have recently identified that the potent proinflammatory cytokines IL-1β and IL-18, which are key products of inflammasome activation, are elevated in patients diagnosed with VITT.
Using a combination of pharmacologic interventions and genetic models, ongoing studies are investigating the influence and regulators of inflammasome activity in several models of HIT both in vitro and in vivo. This project seeks to expand our fundamental basic understanding of anti-PF4 thrombotic disorders, while exploring a novel signaling pathway as a novel targetable pathway in HIT-related thrombosis.
Funding Support: American Heart Association (24CDA1276922)
Platelet Arachidonic Acid Metabolism in Platelet Procoagulant Activity
Arachidonic acid metabolism by 12(S)- lipoxygenase (12-LOX) produces the potent inflammatory lipid mediator 12(S)-HETE. We have recently reported that 12-LOX activity is a vital contributor to promote platelet phosphatidylserine exposure and the procoagulant phenotype. In addition, 12(S)-HETE has recently been identified as a ligand for G-protein coupled receptors (GPCRs) expressed on platelets and leukocytes. Ongoing studies seek to investigate the mechanisms of 12-LOX activity to promote the platelet procoagulant phenotype and characterize the effect on neighboring blood cells.
Funding Support: W.W. Smith Charitable Trust
Platelet Activity in Pregnancy Outcome of High-risk Singletons
Our team has recently reported that a common genetic variant promoting hyper-reactivity of PAR4 (Threonine 120) is associated with an increased risk of preterm birth, in addition to placental vascular pathology. Previous reports demonstrate the hyper-reactive PAR4 variant to have resistance to aspirin utilizing in vitro studies. Ongoing studies are assessing longitudinal samples from singleton pregnancies who were considered high risk for preeclampsia based on USPSTF criteria and recommended aspirin daily. One major goal is to evaluate whether platelet activity (e.g., production or release of small regulatory miRNAs) is associated with platelet inhibition following aspirin use, and if this is associated with preeclampsia, preterm birth, or intervillous thrombosis.
Funding Support: NIH (R01 HD112076) and March of Dimes