Platelet functional responses and signalling: the molecular relationship. Part 2: receptors.

Small, non-nuclear cells, platelets, are primarily designed to form aggregates when blood vessels are damaged, stopping bleeding. To perform this function, platelets can implement several functional responses induced by various agonists and coordinated by a complex network of intracellular signaling triggered by a dozen of different receptors. This review, the second in a series, describes the known intracellular signaling pathways induced by platelet receptors in response to canonical and rare agonists. Particular focus will be on interaction points and “synergy” of platelet activation pathways and intermediate or “secondary” activation mediators that transmit a signal to functional manifestations.

Different degrees of the platelet activation in hemostasis. Upon weak stimulation, platelets pass into a weakly activated state, in which there is no clustering of platelet integrins and no significant change in the shape of platelets. This weak activation is reversible, and it corresponds to the state of platelets in the outer layers ("coat") of the thrombus. Upon stronger activation, platelet shape significantly changes. Platelets become irreversibly activated and aggregate. The secretion of platelet granules also occurs. At the maximum degree of activation, platelet mitochondria collapse, and platelets pass into a procoagulant state, exposing phosphatidylserine, which significantly accelerates blood plasma coagulation.
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#platelets#intracellular signaling#physiology

Overview of the neutralizing antibody and memory B cell response kinetics in SARS-CoV-2 convalescent and/or mRNA vaccinated individuals.

COVID-19 pandemics triggered by the SARS-CoV-2 virus have caused millions of deaths worldwide and have led to expedited developments of various effective vaccines that, if administered, could prevent and/or circumvent the infection and reduce the death toll. Since the start of the pandemics multiple research groups around the world have been involved in the analysis of immune responses of various human cohorts to the SARS-CoV-2 infection and vaccines. Now, over 1.5 years later, the scientific community has accumulated extensive data about both the development of an immune response to SARS-CoV-2 following infection, as well as its rate of fading off. Kinetic analysis of the immune response generated by vaccines is also emerging, enabling the possibility of making comparisons and predictions. In this review we will focus on the comparing B cell and antibody immune responses to the SARS-CoV-2 infection as opposed to mRNA vaccines for the SARS-CoV-2 S-protein, which have been utilized to immunize hundreds of millions of people and analyzed in multiple studies.

#B-cells#COVID-19#vaccines#immune response

A strong correlation exists between platelet consumption and platelet hyperactivation in COVID-19 patients. Pilot study of the patient cohort from CCH RAS Hospital (Troitsk).

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It is known that in COVID-19, hypercoagulation and sometimes thrombocytopenia are related to disease severity. There is also controversial data on platelet participation in COVID-19 pathology. We aimed to determine the degree of platelet hyperactivation in COVID-19 patients. Whole blood flow cytometry with Annexin-V and lactadherin staining ("PS+ platelets") was utilized. Additionally, a stochastic mathematical model of platelet production and consumption was developed. Here we demonstrated that the percentage of PS+ platelets in COVID-19 patients was twofold that of healthy donors. There was a significant correlation between the amount of PS+ platelets and the percentage of lung damage in patients. No connection was found between platelet senescence and hospital therapy or patients' chronic diseases, except for chronic lung disease. Although no thrombocytopenia was observed in patients, the observed increase in platelet size (FSC-A parameter in flow cytometry) could indicate that platelet age is decreased in patients. The developed computational model of platelet turnover confirms the possibility of intense platelet consumption without noticeable changes in platelet count. We conclude that the observed platelet hyperactivation in COVID-19 could be caused by platelet activation in circulation, leading to platelet consumption without significant thrombocytopenia.

Computational model of platelet production in the presence of COVID-19 induced thrombosis. A – Detailed scheme of the model (most sensitive reactions are highlighted in red). B – Dependence of the average platelet count (green curve and dots) and platelet size (red curve and dots) from the platelet consumption index in the model. Platelet number and size in the absence of consumption lie in the areas, highlighted by green and red rectangles correspondingly. C – Platelet size distribution in the absence (green bars) and the presence (red bars) of consumption (with consumption index set to 2). Whiskers on all plots represent SD.
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In vitro models of thrombosis and hemostasis

Abnormalities in hemostatic response are responsible for a large number of life-threatening conditions, however, despite many decades of research, today there are no reliable ways to correct hemostasis without significant risks of thrombosis or bleeding. This situation reflects a poor understanding of the key mechanisms that regulate the hemostatic response. To uncover the principles underlying the regulation of hemostasis, both experimental models and theoretical approaches are actively used. This review focuses on current in vitro models of thrombosis and hemostasis and describes key approaches and tools for studying blood coagulation outside the human/animal body. To reconstruct this process, both microfluidic technologies and approaches based on manufacturing artificial vessels using a variety of hydrogels are actively used. In vitro models of thrombosis traditionally mimic non-penetrating damage to the vessel wall and have been used for more than 30 years to uncover the key processes responsible for the formation of arterial thrombi. Models of in vitro hemostasis have been actively developed only in recent years and are focused ono crucial mechanisms governing the formation of hemostatic plugs - clots that stop bleeding upon a penetrating vascular injury. Modern in vitro models of thrombosis and hemostasis are used not only as tools for fundamental research but are also introduced into clinical practice.

Fabrication of PDMS-based flow chamber: a) A master mold is prepared using photolithography. The relief (typically made of photoresist on a silicon wafer, shown in orange) usually contains several patterns to be imprinted on PDMS; b) The relief form (master mold) is poured with the liquid mixture of PDMS base with curing agent; с-d) A part of polymerized PDMS is then сut and extracted from the mold e) inlet and outlet holes are made and the required tubings are connected. The chamber is attached onto the glass or plastic coverslip (gray) using plasma bonding or vacuum-sealing.
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#hemostasis#platelets#microfluidics#hydrogel#whole blood#in vitro models#thrombosis

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

Blood platelets are small anucleated cells whose main function is to form a plug upon vascular damage to stop bleeding. This role involves a number of functional responses induced by different agonists and coordinated by an intricate network of signal transduction pathways. Understanding this network is vital from both basic research point of view and for the purposes of drug target identification in thrombosis and hemostasis. This review series will focus on the regulation of platelet signalling, on tracking the molecular relationship between receptor activation and functional responses, and on the networking aspects of these pathways. The present paper, first one out of two, focuses on the description of platelet functional responses and of the conditions for their triggering.
Platelet functional responses within arterial thrombus.
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#hemostasis#platelet activation#platelet intracellular signaling#thrombosis#thrombus formation
Systems Biology and Systems Physiology: regulation of biological networks
The meeting is dedicated to the 75th anniversary of Fazly Ataullakhanov
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Illuminating the nature of complex systems
«Systems Biology and Physiology Reports:Issue #3»
Latest issue from September 30, 2021