Emulating Drug-Induced Thrombosis

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We recreated a side effect of a drug inside our Organ-Chip

Maintenance of the fluidity of blood within the circulatory system is an important physiological process that is tightly regulated by the endothelial cells that line the blood vessels of the human body. The term thrombosis usually refers to pathological blood clotting that can manifest clinically in relation to dysfunction of the circulatory system. As more therapeutics have been developed, it has also become apparent that some drugs can contribute to the development of thrombosis, resulting in serious adverse events.

It is difficult, however, to predict drug-induced thrombosis using current pre-clinical cell culture and animal models, due to the dynamic nature of the flow of blood in the body and the complex molecular mechanisms that regulate drug interaction with different blood components of the human circulatory system.

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Clinically-relevant Data

In a paper published in Clinical Pharmacology and Therapeutics, my colleagues and I used our Blood Vessel-Chip to test a compound, a monoclonal antibody called Hu5c8, that had been shown to cause unwanted thrombosis in humans. Hu5c8 displayed promise as a treatment for lupus, but was ultimately terminated during clinical trials due to unexpected thrombotic and cardiovascular events it caused in patients. Unfortunately, these life-threatening side effects were not discovered during preclinical testing due to a lack of human-relevant models that could predict them. Using our Blood Vessel-Chip, we detected for the first time the pro-thrombotic effects of Hu5c8 using one clinically relevant dose of this compound in combination with human blood samples, and the data we generated were consistent with previous clinical findings.

What’s perhaps even more interesting is that though previous studies have shown that thrombosis can be recreated in vitro, these results were limited to imaging data, since the formation of the clot made it impossible to obtain soluble samples. But in our recent work, we used a new chip design that enabled us to sample and analyze biomarkers from a clotted chip, allowing us to gain insight into mechanism of action of how Hu5c8 led to thrombosis.

We were able to recapitulate thrombosis, caused by a monoclonal antibody called Hu5c8, in our Organ-Chip

We were able to recapitulate thrombosis, caused by a monoclonal antibody called Hu5c8, in our Organ-Chip

Efficacy testing of anti-platelet drugs

With this chip design, we can also induce thrombosis by stimulating endothelial inflammation, or by adding blood-borne, pro-coagulant factors. This approach allows us to study the efficacy of anti-platelet drugs, and we did just that in this paper with the anti-platelet drug Eptifibatide.

This research shows how our Organs-on-Chips technology enables human-relevant studies of drug-induced thrombosis, helps us dissect the molecular mechanisms that mediate this process, and it could also be used to study the efficacy of new anti-thrombotic therapeutics.

This work was conducted with our collaborators at Janssen Research & Development, the Wyss Institute at Harvard, and the University of Twente.

— The paper, published in Clinical Pharmacology & Therapeuticscan be found here.

— Our press release about this research.