Johnson, Gerhard J., M.D.

HEMATOLOGY/ONCOLOGY

My laboratory’s activities are focused on two areas of investigation: Studies of Platelet Activation. • Abnormal platelet activation leads to clumping, known as aggregation, within blood vessels that can obstruct blood flow and result in heart attack or stroke. The formation of thromboxane A2 (TXA2) by platelets when they are activated plays an important role in heart attacks and stroke by stimulating platelet secretion that accelerates platelet aggregation. Our laboratory has studied the process by which TXA2 activates platelets. We previously demonstrated that the response of platelets to TXA2 is regulated by the biochemical state of the site on the platelet surface (receptor) to which TXA2 binds. Increased phosphorylation of the TXA2 receptor results in decreased aggregation of dog platelets in response to TXA2. Recent work in our laboratory has focused on TXA2-stimulated platelet protein phosphorylation. We have studied the potential role of p38 MAP kinase, a protein that is capable of phosphorylating other proteins and one that is prominently phosphorylated when platelets are exposed to TXA2, in the control of platelet secretion and aggregation. These studies have defined a specific pathway of p38 MAP kinase activation originating at the thrombomxane receptor. Prior studies have linked p38 MAP kinase phosphorylation to platelet shape change and aggregation, but the pathway has not been defined. Our studies are directed toward definition of this pathway and evaluation of the role of p38 MAP kinase activation in platelet secretion. Studies of Heart and Lung Damage Produced by Weight Loss Drugs. • Heart valve damage and high blood pressure in the lungs have occurred in some persons treated with fenfluramine to lose weight. The cause of these serious adverse effects of fenfluramine has not been determined but it has been postulated that elevated blood serotonin is an important contributing factor. Since serotonin is normally transported in platelets in the blood, and fenfluramine inhibits the uptake of serotonin into platelets, it is possible that the plasma levels of serotonin are elevated by fenfluramine. However, this has not previously been demonstrated. Because fenfluramine is no longer approved for human use, we have developed a dog model to study fenfluramine-induced cardio-pulmonary toxicity. These animals demonstrate impaired platelet uptake of serotonin and decreased platelet serotonin, but no evidence of platelet secretion of serotonin or chronic elevation in plasma serotonin. Therefore, these experimental observations refute a frequently cited postulated mechanism of fenfluramine toxicity.