Could platelets block your drug’s path to success?
October 7, 2020
Platelets do far more than halt the flow of blood. So how might they interact with your drug candidate?
Platelets, or thrombocytes, are small but important blood cells (fragments) that help our bodies control bleeding. They work together with blood coagulation factors to initiate clotting. In incidents both small and large, we benefit from their actions in our everyday lives. For drug developers, however, their implications can be very large indeed – and potentially catastrophic in an inflammatory response. Platelet activation, i.e. the switching of platelets from a neutral to a prothrombotic state, can be a desirable effect. There are many drugs that target it, for example via adenosine diphosphate (ADP) or trichostatin A (TSA). If your drug is concerned with hemostasis, platelet activation is bound to be a focus of your preclinical research. Yet even if you don’t examine it from a functional perspective, it’s well worth considering from a safety perspective.
There’s reason to explore platelet activation when immune profiling any drug, including drugs unrelated to hemostasis. Intentionally or unintentionally, a drug that triggers platelet activity unfolds a dramatic chain of events. Platelets are metabolically active cellular fragments, having no nuclei but a large number of surface receptors and granules. When their surface receptors are upregulated, platelets undergo a change in appearance, acquiring an irregular shape and a massive surface area that facilitates platelet aggregation. In addition, upregulation triggers the release of granule content, which includes ADP and other molecules that activate still more platelets – thus reinforcing the reaction. It’s no wonder that undesired thrombosis can appear so suddenly. Nonetheless, thrombosis may be just one platelet-related risk to clinical subjects.
As you might be aware, platelets are involved in more than the creation of a blood clot. Part of a delicate balance between accelerating and braking thrombosis, they seldom tip the balance alone. There’s a great deal of cross-talk that goes on between platelet activation and other responses in the body. The release of platelet granule contents, for example, sets the coagulation cascade in motion. Yet it’s not a one-way street from platelet activation to thrombosis. Thrombin, which is released during coagulation, is an agonist that triggers additional platelet receptors.
By extension, still other cascade systems can become involved. The complement cascade system can be activated by the coagulation cascade system and vice versa. In this way, platelets may be activated by medical devices or nanoparticles used for drug delivery. If complement interaction with a foreign element triggers an inflammatory response, it may also trigger coagulation, in turn leading to clotting.
It’s all this cross-talk, with its feedback loops and amplification between systems, that makes platelets so relevant for any drug investigation. The risk of triggering a cascade response – whether a complement cascade, a coagulation cascade or both – must be ruled out before a drug moves to first-in-human trials. With so many enzymes and other molecules involved, there’s ample potential for platelet activation to be a part of such a reaction. In fact, research indicates that platelets have a more comprehensive role in immune system activity than originally thought. Studies show that antiplatelet medications reduce mortality from infections and sepsis by modifying platelet response to inflammation, which suggests that platelets play a central part in inflammation and immune responses. Indeed, platelets secrete a range of inflammatory mediators and are capable of interacting with almost any type of immune cell. They can cross-link to leukocytes via P-selectin, which leads among other things to the upregulating release of proinflammatory cytokines. They can adhere to monocytes and neutrophils, the latter triggering the release of chemokines. And activated platelets can express CD40L that affects B and T lymphocytes, indicating a possible link between innate and adaptive immunity.
With all this in mind, it’s not only important to consider platelet activation in non-clinical drug testing. Given the complexity of platelets’ role in the body, it’s vital to examine their activation with a physiologically relevant model. Immuneed’s platform is an excellent way of accounting for platelet, blood, and immune system intricacy. A dynamic model that mimics human blood circulation, it uses fresh blood from healthy subjects, rather than isolated cells removed from their complex environment. All blood components and cascade systems are intact, which means the many interactions and amplifications can be observed. Moreover, since blood enters the Immuneed model immediately, it doesn’t have to be pretreated with anticoagulants, as it would for analysis on a well plate.
If you’d like to know more about the Immuneed platform or its benefits in evaluating platelet activation, we’d be happy to discuss its possibilities. Reach out to us and we’d be happy to tell you more.
 Estevez and X. Du. “New Concepts and Mechanisms of Platelet Activation Signaling,” Physiology 2017; 2017:00020
 S-H. Yun, E-H. Sim, R-Y. Goh, J-I. Park, and J-Y. Han. “Platelet Activation: The Mechanisms and Potential Biomarkers,” BioMed Research International 2016; 2016:9060143
Erika is one of the co-founders of Immuneed and also one of our Scientific Advisors. She's responsible for study design in customer projects as well as the continuous development of Immuneed's technical platform. Her deep knowledge of immunology and immunotherapies is of immense value for Immuneed customers. Erika holds a PhD in immunology from Uppsala University.
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