This translational research seeks to increase the therapeutic index of current treatment of pulmonary embolism, or rather to develop treatments that work better with less risk than current treatments propose. The broad interest of this project is to understand how PE produces a pathophysiological complex that worsens disease and quality of life. The two main mechanisms by which it does that is by unresolved, or even progressive pulmonary hypertension, which causes right ventricular dysfunction, and the “post PE syndrome” characterized by exercise intolerance and fatigue.
Additionally, PE produces platelet activation, which increases chance of recurrent clots. To study these events, the Kline Lab developed a rat model of PE that shows persistent pulmonary hypertension. Researchers are particularly interested in understanding how soluble guanylate cyclase (sGC) activation, administered in the first weeks after PE, prevents the progression of PE to chronic thromboembolic pulmonary hypertension (CTEPH).
This lab is interested in understanding how PE causes platelet activation followed by reactive oxygen species production, apoptosis, microparticle release and increased platelet turnover. Taken together, these effects contribute to hypercoagulability and possibly recurrent clotting. Researchers harvest platelets from patients without and with PE and study them with multiple methods to test for mechanisms of activation and potential therapeutic routes to reduce their transition to a highly thrombogenic phenotype. Techniques include high fidelity respirometry to study mitochondrial oxygen consumption under different conditions, the use of thromboelastography to measure platelet function in whole blood, and under fluorescent microscopy, using fluroprobes to measure platelet calcium transients in the presence of agonists and antagonists. With this model, investigators have found that increasing sGC activity ameliorates the exaggerated response of platelets from PE.