Platelet functional responses and signalling: the molecular relationship. Part 1: responses.

aiming to stop bleeding upon vascular injury. Blood platelets play a critical role in this response. They actually have a number of critical roles in human physiology, which include formation of the hemostatic plug upon injury

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, tissue growth and regeneration

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. In order to perform these urgent functions when and where it is needed, platelets rely on their huge network of receptors and signal transduction pathways.

The functional responses of platelets to stimulation are numerous

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(Fig. 1), and the number of positive and negative stimuli to be processed by the cellular signalling networks in order to make correct decisions is likewise not small

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. As a result, the network of platelet signal transduction that is initiated by at least ten major receptors, goes through multiple interconnected pathways and ends up with various responses of different degree might appear quite terrifying (Fig. 2).

Figure 1. Scheme of the main platelet functional responses to activation (all of them could be blocked by inhibition)

Scheme of the relationship between platelet-activating agents (thrombin, ADP, collagen, thromboxane A2, vWF, podoplanin and adrenalin) and platelet functional responses (shape change depicted by filopodia formation, adhesion and aggregation depicted by integrin activation, granule secretion and thromboxane A2 synthesis).

Figure 2. Scheme of the relationship between platelet-activating agents (thrombin, ADP, collagen, thromboxane A2, vWF, podoplanin and adrenalin) and platelet functional responses (shape change depicted by filopodia formation, adhesion and aggregation depicted by integrin activation, granule secretion and thromboxane A2 synthesis).

When these pathways are reviewed and discussed, they are usually analyzed not as a network but rather as a simpler cause-and-effect chain. For example: activator X stimulates receptor Y leading to an increase of a secondary messenger Z that mediates further downstream events, including responses “1”, “2”, and “3”. The interplay of different receptors that could work cooperatively or downregulate each other is often overlooked. Interestingly, in other fields like immunology, terms like "co-activator" or "co-receptor" have already became accepted

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. Likewise, transformation of the signal along the signalling pathway, different dose-dependence for different responses to the same agonist caused by it, principles of signal encoding and de-coding are rarely discussed even beyond the platelet field

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, and almost never for platelets.

Another not usually discussed point in platelet receptor-response relationship is the mechanosensitivity of these cells, whose whole life is spent in fast streams of blood. There is enough evidence that platelets can “sense” the shear rate of the blood stream and even turbulence of the flow

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. However, this question will be discussed in the next part of this review, as here our goal is to address issues of responses rather than receptors. We shall highlight the main principles of platelet signal processing and decision-making, with the focus not on the description of signalling pathways but rather on the attempt to characterize how they work together to achieve different sets of physiologically relevant responses depending on the situation.

Functional responses and their immediate causes

Here we shall mostly focus on the platelet responses relevant to hemostasis, because they are believed to be more comprehensively studied. The minimal set of main platelet functions implemented in response to injury usually includes integrin α_IIbβ₃ activation

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, dense granule release

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, alpha-granule release

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, thromboxane A2 synthesis, shape change, procoagulant activity

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, and contraction

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(Fig. 1). The initial adhesion to von Willebrand factor mediated by glycoprotein Ib is not included among them because it does not require platelet activation

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. It should be noted that these functions are probably not equally important, or rather not all of them were reliably shown to contribute to hemostatis.

Integrin activation.

Integrin activation is probably the one response believed to be the most vitally important as demonstrated by severe bleeding in their deficiency, Glanzmann's thrombasthenia

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. Platelets have about 100000 integrin α_IIbβ₃ molecules per cell that are capable to radically increase their affinity to von Willebrand factor and fibrinogen thus directly mediating aggregate formation

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. All platelet agonists, including biomechanical platelet activation via the vWf-glycoprotein Ib axis, are believed to cause integrin activation to some degree

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. This response is gradual, probably with the intermediate activation states

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. The immediate cause of the integrin transition between the states is formation of a large cytoskeleton-associated complex of proteins at the cytosolic side of the plasmatic membrane. The critical structural role in this complex is played by proteins talin-1

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and kindlin-3

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, while the signal transduction switch triggering its formation is believed to be small soluble cytosolic GTPase, Rap1-GTP

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. In addition to α_IIbβ₃, platelets have a number of other integrins specific to collagen, fibronectin, laminin and other molecules; their significance is less certain, while the activation mechanisms appear to be similar

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Dense granule release.

Dense (or delta-, δ-) granules are platelet-specific organelles released upon stimulation

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. They contain mostly low-molecular-weight compounds, the major of them being ADP able to activate other platelets

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and will be discussed in the next part of this Review. The essential signal transduction switch mediating these processes is believed to be various isoforms of protein kinase C

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Alpha granule release.

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intracellular vesicles released upon activation, which have specific cargo composed mostly of proteins including fibrinogen, von Willebrand factor, factor V, C1 inhibitor, growth factors, and other molecules

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. Membranes of alpha-granules have additional integrins and P-selectin. Some of the studies suggest that contact-pathway-activating components of platelets are associated with alpha granules, and not dense granules

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Conclusions

Some of the platelet responses are critical for platelet plug formation (integrins, dense granules, thromboxane A2), while others are involved in blood coagulation (procoagulant activity, alpha-granules); yet other responses while being important have less clearly defined area of applicability, such as contraction and shape change.

These responses are spatiotemporally organized: they occur at different stages in different parts of the thrombi (Fig. 3). Integrin activation of different degree is responsible for forming the whole body of the thrombus, both the dense parts of highly activated platelets and loosely activated external regions; dense granule release is vital for the activation of platelets distal from the damaged region; alpha-granules and procoagulant surfaces are vital for fibrin formation and thrombus solidification.

In order to achieve this, platelet activation responses form a hierarchy of strength: some of them are induced by all or most agonists (alpha granule release, weak integrin activation), while others require potent stimulation (procoagulant activity), with all shades of gray in-between. Some of the responses are gradual meaning that the response is gradually increased within a wide range of activation conditions (dense granules), while others are trigger-like meaning that they either completely implemented or not at all (alpha granules).

The in-depth analysis of the signalling pathways interaction, encoding and decoding of information, which give rise to these properties, are considered in the next part of this review. As a post-note it is worth mentioning that the computational biology approach

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Mathematical Techniques for Understanding Platelet Regulation and the Development of New Pharmacological Approaches. In: Gibbins JM, Mahaut-Smith M, editors. Platelets and Megakaryocytes 

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Interspecies differences in protein expression do not impact the spatiotemporal regulation of glycoprotein VI mediated activation.

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Control of Platelet CLEC-2-Mediated Activation by Receptor Clustering and Tyrosine Kinase Signaling.

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greatly facilitates our understanding of the platelet receptor-function relationship.

Figure 3. Platelet functional responses within arterial thrombus.

Author Contributions: A.N.S. drew the figures, wrote the text and edited the paper; M.G.S. drew the figures; M.A.P. supervised the project, wrote the text and edited the paper. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest: The authors declare no conflict of interest

Funding: The study was supported by Russian Science Foundation (Grant 21-74-20087).

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