СУЧАСНІ АСПЕКТИ РОЗВИТКУ КОАГУЛОПАТІЇ У ПАЦІЄНТІВ ПРИ COVID‑19 ІНФЕКЦІЇ: ОГЛЯД ЛІТЕРАТУРИ

This review summarizes current knowledge about coagulation disorders associated with COVID-19 infection. Despite a significant amount of research, it is currently unclear whether COVID-19 is the direct cause of coagulopathic disorders or they occur as the infectious process progresses. Different authors have proposed several pathogenetic mechanisms for the development of coagulopathy in this disease. However, the most important is the release of a large number of cytokines that provoke interstitial inflammation, endothelial damage and activation of coagulation, in the pathogenesis of which the tissue factor plays a key role. Hyperinflammatory reactions lead to tissue damage, disruption of the endothelial barrier and uncontrolled activation of coagulation. In the lungs and, possibly, in other organs, under the influence of the virus, local damage to the vascular endothelium occurs, which leads to angiopathy, activation and aggregation of platelets with the formation of blood clots and concomitant consumption of platelets. Systemic hypercoagulation and hyperfibrinogenemia significantly increase the likelihood of large vessel thrombosis and thromboembolic complications, which are detected in 20–30% of patients in the intensive care units. Along with an increase in the level of cytokines in the blood, their content also increases in the lungs and in the bronchoalveolar lavage fluid. Cytokine storm leads to systemic intravascular coagulation, multiple organ failure and death. The review also provides the rationale for the principles of managing patients with coagulopathy based on the known mechanisms of unique disorders inherent in COVID-19. It has been shown that the problem of the pathogenesis of the development of blood clotting disorders in COVID-19 infection remains relevant.

Ultrastructural Study of Platelet Behavior and Interrelationship in Sprouting and Intussusceptive Angiogenesis during Arterial Intimal Thickening Formation

Platelets in atherosclerosis, bypass stenosis, and restenosis have been extensively assessed. However, a sequential ultrastructural study of platelets in angiogenesis during the early phases of these lesions has received less attention. Our objective was the study of platelets in angiogenesis and vessel regression during intimal thickening (IT) formation, a precursor process of these occlusive vascular diseases. For this purpose, we used an experimental model of rat occluded arteries and procedures for ultrastructural observation. The results show (a) the absence of platelet adhesion in the de-endothelialized occluded arterial segment isolated from the circulation, (b) that intraarterial myriad platelets contributed from neovessels originated by sprouting angiogenesis from the periarterial microvasculature, (c) the association of platelets with blood components (fibrin, neutrophils, macrophages, and eosinophils) and non-polarized endothelial cells (ECs) forming aggregates (spheroids) in the arterial lumen, (d) the establishment of peg-and-socket junctions between platelets and polarized Ecs during intussusceptive angiogenesis originated from the EC aggregates, with the initial formation of IT, and (e) the aggregation of platelets in regressing neovessels (‘transitory paracrine organoid’) and IT increases. In conclusion, in sprouting and intussusceptive angiogenesis and vessel regression during IT formation, we contribute sequential ultrastructural findings on platelet behavior and relationships, which can be the basis for further studies using other procedures.

Clot Retraction: Cellular Mechanisms and Inhibitors, Measuring Methods, and Clinical Implications

Platelets have important functions in hemostasis. Best investigated is the aggregation of platelets for primary hemostasis and their role as the surface for coagulation leading to fibrin- and clot-formation. Importantly, the function of platelets does not end with clot formation. Instead, platelets are responsible for clot retraction through the concerted action of the activated αIIbβ3 receptors on the surface of filopodia and the platelet’s contractile apparatus binding and pulling at the fibrin strands. Meanwhile, the signal transduction events leading to clot retraction have been investigated thoroughly, and several targets to inhibit clot retraction have been demonstrated. Clot retraction is a physiologically important mechanism allowing: (1) the close contact of platelets in primary hemostasis, easing platelet aggregation and intercellular communication, (2) the reduction of wound size, (3) the compaction of red blood cells to a polyhedrocyte infection-barrier, and (4) reperfusion in case of thrombosis. Several methods have been developed to measure clot retraction that have been based on either the measurement of clot volume or platelet forces. Concerning the importance of clot retraction in inborn diseases, the failure of clot retraction in Glanzmann thrombasthenia is characterized by a bleeding phenotype. Concerning acquired diseases, altered clot retraction has been demonstrated in patients with coronary heart disease, stroke, bronchial asthma, uremia, lupus erythematodes, and other diseases. However, more studies on the diagnostic and prognostic value of clot retraction with methods that have to be standardized are necessary.

Snake extract–laden hemostatic bioadhesive gel cross-linked by visible light

Bioadhesives reduce operation time and surgical complications. However, in the presence of blood, adhesion strength is often compromised. Inspired by the blood clotting activity of snake venom, we report a visible light–induced blood-resistant hemostatic adhesive (HAD) containing gelatin methacryloyl and reptilase, which is a hemocoagulase (HC) extracted from Bothrops atrox. HAD leads to the activation and aggregation of platelets and efficiently transforms fibrinogen into fibrin to achieve rapid hemostasis and seal the tissue. Blood clotting time with HAD was about 45 s compared with 5 to 6 min without HAD. HAD instantaneously achieved hemostasis on liver incision (~45 s) and cut rat tail (~34 s) and reduced blood loss by 79 and 78%, respectively. HAD is also efficient in sealing severely injured liver and abdominal aorta. HAD has great potential to bridge injured tissues by combing hemostasis with adhesives.

EDTA‑dependent pseudothrombocytopenia in child (clinical case report)

Ethylenediaminetetraacetic acid (EDTA)-dependent pseudothrombocytopenia is the phenomenon of a spurious low platelet count due to antiplatelet antibodies that cause platelet clumping in blood anticoagulated with EDTA. The aggregation of platelets in EDTA-dependent pseudothrombocytopenia is usually prevented by other anticoagulants, such as sodium citrate. EDTA-dependent pseudothrombocytopenia has never been associated with hemorrhagic diathesis or platelet dysfunction. In this article, a 2,5-year-old boy with EDTA-dependent pseudothrombocytopenia is presented because of rare presentation. We report that EDTA can induce platelet clumping, and thus spuriously low platelet counts. However, aggregation of platelets was not detected in blood samples with sodium citrate, and platelet count was normal.

FUNCTIONAL PROPERTIES OF PLATELET IN CHILDREN WITH IRRITABLE BOWEL DISEASE

The aim of the study was to evaluate platelet activation and aggregation in children with irritable bowel disease (IBD), as well as the effect of hyperbaric oxygenation on these processes. Platelet activation and aggregation in artificial shear flow were studied in 120 patients of both sexes aged 6 to 17 years with IBD. In pediatric patients with CD and UC, a significant increase in the activation and aggregation of platelets was revealed under shear flow conditions. The use of hyperbaric oxygen therapy leads to a decrease in the studied processes. It was found that IBD in children is characterized by significant changes in the functional properties of platelets (activation and aggregation processes).

Blood coagulation components in GtoPdb v.2021.2

Coagulation as a process is interpreted as a mechanism for reducing excessive blood loss through the generation of a gel-like clot local to the site of injury. The process involves the activation, adhesion (see Integrins), degranulation and aggregation of platelets, as well as proteins circulating in the plasma. The coagulation cascade involves multiple proteins being converted to more active forms from less active precursors (for example, prothrombin [Factor II] is converted to thrombin [Factor IIa]), typically through proteolysis (see Proteases). Listed here are the components of the coagulation cascade targeted by agents in current clinical usage or at an advanced level of development.

The role of gaseous mediators (CO, NO and H2S) in the regulation of blood circulation: analysis of the participation of blood cell microrheology

Among the signaling molecules involved in the regulation of intra- and intercellular systems in various types of cells, a special place is occupied by gaseous compounds – gasotransmitters (GTs). Currently, the most studied are three molecules: nitrogen oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S). For them, the enzymatic systems of intracellular synthesis and degradation have been determined, the physiological effect has been proved, and the intracellular mechanisms have been determined. Changes in the work of these mechanisms under the influence of GTs causes the development of physiological and/or pathophysiological reactions. These GTs are involved in the regulation of various organs and systems of the human body under normal and pathological conditions, including the structure and function of the circulatory system. In this article, special attention is paid to the influence of all three GTs and their donors on the vascular and hemorheological aspect of the work of blood circulation, and especially on an underdeveloped problem – the microrheology of erythrocytes. It has been shown that all three GTs, along with the well-known vasodilating effect, reduce the adhesion and aggregation of platelets and leukocytes, as well as moderately stimulate the deformability of erythrocytes and strongly inhibit their aggregation. The performed analysis of the data indicates that, along with the specific signaling cascades for each GT, the use of a common signaling pathway associated with soluble guanylate cyclase and NO synthase was also revealed in microrheological responses. The intersection of signaling pathways triggered by NO, CO and H2S on common effectors, as well as their interaction with each other (cross-talk), can determine the final, resulting functional response of the cell.

Updated Role of Neuropeptide Y in Nicotine-Induced Endothelial Dysfunction and Atherosclerosis

Cardiovascular disease is the leading cause of death worldwide. Endothelial dysfunction of the arterial vasculature plays a pivotal role in cardiovascular pathogenesis. Nicotine-induced endothelial dysfunction substantially contributes to the development of arteriosclerotic cardiovascular disease. Nicotine promotes oxidative inflammation, thrombosis, pathological angiogenesis, and vasoconstriction, and induces insulin resistance. However, the exact mechanism through which nicotine induces endothelial dysfunction remains unclear. Neuropeptide Y (NPY) is widely distributed in the central nervous system and peripheral tissues, and it participates in the pathogenesis of atherosclerosis by regulating vasoconstriction, energy metabolism, local plaque inflammatory response, activation and aggregation of platelets, and stress and anxiety-related emotion. Nicotine can increase the expression of NPY, suggesting that NPY is involved in nicotine-induced endothelial dysfunction. Herein, we present an updated review of the possible mechanisms of nicotine-induced atherosclerosis, with a focus on endothelial cell dysfunction associated with nicotine and NPY.

Resveratrol inhibits Ca2+ signals and aggregation of platelets

Background Resveratrol has been shown to inhibit platelet aggregation. However, the mechanism for this action of resveratrol remains to be clarified. The purpose of this study was to elucidate the Ca2+-related mechanism for the inhibitory action of resveratrol on platelet aggregation. Methods Ca2+ entry and subsequent aggregation of human platelets induced by different stimulants including thrombin, thapsigargin, and 1-oleoyl-2-acetylglycerol (OAG) were measured by the fluorescence method and light transmittance method, respectively. Each stimulant was added to a nominally Ca2+-free medium containing platelets, and then CaCl2 was added to the medium to induce Ca2+ influx into platelets. Results Thapsigargin-induced Ca2+ entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 6.25 μM or higher concentrations, while OAG-induced Ca2+ entry and subsequent platelet aggregation were not affected by resveratrol at concentrations up to 50 μM. In the nominally Ca2+-free medium, thrombin induced a small transient increase in intracellular Ca2+ concentrations, which was attenuated in the presence of resveratrol at 12.5 μM or higher concentrations. Thrombin-induced Ca2+ entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 12.5 μM or higher concentrations. Conclusions The results suggest that resveratrol inhibits thrombin-induced platelet aggregation through decreasing Ca2+ release from its stores and inhibiting store-operated Ca2+ influx into platelets.