Research: Selective Platelet Activaiton.

 

Platelets in Haemostasis and Thrombosis.

Platelets are anuclear 3 - 4 μm cell fragments. They circulate in the blood in the resting (inactive, quiescent) state. They become activated, e.g., at the site of the wound, but also at atherosclerotic plaques.

Activation entails a number of changes: exposure of phosphatidyl serine (PS) , secretion of granules and the appearance of the granule markers CD62P and CD63 on the platelet surface, change in the conformation of GPIIb/IIIa.
Activated platelets aggregate, adhere to the wound site, and catalyze clotting cascade reactions that culminate in the production of thrombin (the catalyst is PS).

Thrombin activates fibrinogen that polymerizes into fibrin, forming a clot, which seals the wound and stops the bleeding.
Platelet activation at the site of atherosclerotic plaques leads to thrombus formation (thrombosis), vessel occlusion, heart attacks, and strokes.

 

Other Functions of Platelets


Recently, multitude of new functions of platelets have been discovered.[Leslie M. 2010, Science328, 562] They play an important role in wound healing, inflammation, other aspects of the innate immune responses as well as adaptive immune response, angiogenesis, cancer metastasis, etc. 

In combination with their haemostatic functions, this means that they also play a key role in rejection or integration of artificial implants. 

Presumably, different stimuli trigger different responses in platelets, leading to different functions.

 

Platelets appear to be the "Swiss army knife" of host defense reactions.

What are the characteristics of platelet response selectivity? How do different stimuli trigger different responses? Can we exploit it to achieve specific, desired response?

The idea, that platelet responses to different stimuli are different is very attractive for the design of new haemocompatible materials and better antiplatelet therapies.

In my group, we study the process of platelet activation, both by biomaterials (in the context of biocompatibility) and by natural agonists (in the context of physiological coagulation and wound healing as well as pathological thrombosis).
We also develop new methods for detecting differences in platelets activated by different stimuli.

Our goal is to understand the underlying molecular mechanisms and to apply this knowledge towards the design of new materials, diagnostic assays, and therapeutic options.

 
 

Selective platelet activation by surfaces.

The figure above shows that platelet activation profiles on the surface of a popular biomaterial, TiO2, depend on whether Ca2+ is present or not.

In solution, activated platelets can be distinguished from the resting platelets by flow cytometry (left). For platelets adhering at surfaces, the same can be done by fluorecence microscopy (right). In both cases, platelets are labeled with antibodies against the various markers. 

Resting platelets do not express PS, CD62P, or CD63. Activated platelets in solution, platelets adsorbed on glass, or on TiO2 in the presence of Ca2+, express all these markers. Platelets adsorbed on TiO2 in the absence of Ca2+ do not express CD62P.

Selectivity of platelet activation is a topic of considerable current interest due to the possible applications in implant integration, thrombosis and bleeding therapies, and drug delivery protocols. 

References:
Gupta and Reviakine, Biointerphases 2012.
S. Gupta  Selective Activation of Platelets by Surfaces and Soluble Agonists. Ph.D. thesis,  March 21st, 2014.

 

A new assay to differentiate between platelets activated by different agonists.

 Coming soon!