Technology-based approaches toward a better understanding of neuro-coagulation in brain homeostasis

Blood coagulation factors can enter the brain under pathological conditions that affect the blood–brain interface. Besides their contribution to pathological brain states, such as neural hyperexcitability, neurodegeneration, and scar formation, coagulation factors have been linked to several physiological brain functions. It is for example well established that the coagulation factor thrombin modulates synaptic plasticity; it affects neural excitability and induces epileptic seizures via activation of protease-activated receptors in the brain. However, major limitations of current experimental and clinical approaches have prevented us from obtaining a profound mechanistic understanding of “neuro-coagulation” in health and disease. Here, we present how novel human relevant models, i.e., Organ-on-Chips equipped with advanced sensors, can help overcoming some of the limitations in the field, thus providing a perspective toward a better understanding of neuro-coagulation in brain homeostasis.

Microfluidic Simulation and Optimization of Blood Coagulation Factors and Anticoagulants in Polymethyl Methacrylate Microchannels

Blood coagulation is a critical and complex reaction that involves various chemical substances, such as prothrombin, fibrinogen, and fibrin. The process can be divided into three main steps, namely the formation of the prothrombin activator, conversion of prothrombin to thrombin, and conversion of fibrinogen to fibrin. In this study, an ANSYS simulation is carried out to determine the prothrombin time (PT) of blood, the chemical changes that occur during coagulation and the anticoagulation factor. The addition of deionized water to the microchannels before the addition of blood and reagents results in a two-phase flow. The evaluation of this two-phase flow is necessary, and dynamic simulations are required to determine the PT. The chemical rate constant and order of the chemical reaction are derived from the actual prothrombin time. Moreover, the genetic algorithms in PYTHON and ANSYS are used to estimate chemical reaction parameters for a 20 s PT. The blood and anticoagulant exhibit increased dynamic behavior in the microchannel. In addition, particles are added to the microchannel and the dynamic mesh method is used to simulate the flow behaviors of the red and white blood cells in the microchannel. The PTs for different volumes of blood are also reported.

Impact of Polyethylene Glycol Functionalization of Graphene Oxide on Anticoagulation and Haemolytic Properties of Human Blood

Graphene oxide (GO) is one of the most explored nanomaterials in recent years. It has numerous biomedical applications as a nanomaterial including drug and gene delivery, contrast imaging, cancer treatment, etc. Since most of these applications need intravenous administration of graphene oxide and derivatives, the evaluation of their haemocompatibility is an essential preliminary step for any of the developed GO applications. Plentiful data show that functionalization of graphene oxide nanoparticles with polyethylene glycol (PEG) increases biocompatibility, thus allowing PEGylated GO to elicit less dramatic blood cell responses than their pristine counterparts. Therefore, in this work, we PEGylated graphene oxide nanoparticles and evaluated the effects of their PEGylation on the structure and function of human blood components, especially on the morphology and the haemolytic potential of red blood cells (RBCs). Further, we studied the effect of PEGylation on some blood coagulation factors, including plasma fibrinogen as well as on the activated partial thromboplastin (aPTT), prothrombin time (PT) and platelet aggregation. Our findings provide important information on the mechanisms through which PEGylation increases GO compatibility with human blood cells. These data are crucial for the molecular design and biomedical applications of PEGylated graphene oxide nanomaterials in the future.

Changes in the blood coagulation system that determine postoperative complications in patients with non-tumor mechanical jaundice

The OBJECTIVE was to study the features of changes in the blood coagulation system that contribute to the development of postoperative complications in patients depending on the stage of non-tumor mechanical jaundice at admission.METHODS AND MATERIALS. A total of 537 patients with mechanical jaundice were examined and changes in the blood coagulation system were analyzed. Vascular-platelet hemostasis was characterized by the following tests: capillary resistance, the number of desquamated endothelial cells, the number of blood platelets. Plasma hemostasis was analyzed using activated partial thromboplastin time, plasma soluble fibrin level, thrombin time, prothrombin ratio, prothrombin index, and fibrinogen blood level. Then, XIIa-dependent fibrinolysis in the blood and the level of the fibrin D-dimer in the blood plasma were determined.RESULTS. It was found that in the first stage of mechanical jaundice, with cholestasis, there were no changes in blood coagulation system that go beyond the normal limits. In the second stage, during cytolysis of hepatocytes, hyperbilirubinemia and hypertransaminasemia contribute to the activation of platelet first, and then plasma hemostasis. In the third stage (cholangitis), the death of endotheliocytes increases and there is a deficiency of blood coagulation factors due to their consumption and increased fibrinolysis.CONCLUSION. In the stage of cholestasis in patients with non-tumors mechanical jaundice, the parameters of the coagulation system remain within the reference values. In the stage of cytolysis, as endotheliotoxicosis increases, platelet and plasma hemostasis begins to activate, which can lead to thrombosis and thromboembolism in vital organs. In the stage of cholangitis, further activation of plasma hemostasis causes hemorrhagic syndrome. The occurrence of the described disorders in blood coagulation system with the progression of MJ dictates the need to monitor the changes in the blood coagulation system and their correction for the prevention of intra-and postoperative complications.

Mechanisms of action of new oral coagulants

The article provides a brief description of drugs in the class of direct oral anticoagulants. The mechanisms of the therapeutic effect and the ways of excretion of drugs-inhibitors of blood coagulation factors Xa and IIa are considered. It was shown that all of them are characterized by high selectivity to the active centers of target molecules, successfully affect the coagulation cascade and have a quick therapeutic effect. A comparative analysis of drugs of the class of direct oral anticoagulants showed that rivaroxaban, apixaban, edoxaban, betrixaban (inhibitors of FXa) and dabigatran (inhibitor of factor IIa) do not have significant advantages over each other in terms of mechanism and speed of action. A comparison of the main characteristics of direct oral anticoagulants and the indirect anticoagulant warfarin is presented. It is shown that, first of all, the advantage of the former is associated with an immediate pharmacological response. The decision to prescribe this drug requires consideration of risk factors for the patient, such as age, the presence of chronic diseases of the gastrointestinal tract, liver and kidneys. The article presents the most frequent complications of anticoagulant therapy, as well as the mechanisms of action of specific and universal antidotes indicated for use in patients with life-threatening bleeding or in need of urgent surgery when using direct oral anticoagulants. However, such neutralizing agents have not yet found widespread use due to their high cost and low availability. Nevertheless, the emergence of direct anticoagulants on the market has undoubtedly led to significant progress in the treatment of thrombotic and cardiovascular diseases (1 table, bibliography: 28 refs).

Procoagulant and Antimicrobial Effects of Chitosan in Wound Healing

Chitosan, a polysaccharide derived from chitin, has excellent wound healing properties, including intrinsic antimicrobial and hemostatic activities. This study investigated the effectiveness of chitosan dressing and compared it with that of regular gauze dressing in controlling clinically surgical bleeding wounds and profiled the community structure of the microbiota affected by these treatments. The dressings were evaluated based on biocompatibility, blood coagulation factors in rat, as well as antimicrobial and procoagulant activities, and the microbial phylogenetic profile in patients with abdominal surgical wounds. The chitosan dressing exhibited a uniformly fibrous morphology with a large surface area and good biocompatibility. Compared to regular gauze dressing, the chitosan dressing accelerated platelet aggregation, indicated by the lower ratio of prothrombin time and activated partial thromboplastin time, and had outstanding blood absorption ability. Adenosine triphosphate assay results revealed that the chitosan dressing inhibited bacterial growth up to 8 d post-surgery. Moreover, 16S rRNA-based sequencing revealed that the chitosan dressing effectively protected the wound from microbial infection and promoted the growth of probiotic microbes, thereby improving skin immunity and promoting wound healing. Our findings suggest that chitosan dressing is an effective antimicrobial and procoagulant and promotes wound repair by providing a suitable environment for beneficial microbiota.

Rare bleeding disorders in children: towards a local registry

Введение. Редкие коагулопатии представляют собой гетерогенную группу наследственных заболеваний, для которых характерен количественный или качественный дефицит факторов свертывания крови. Цель исследования: проанализировать частоту встречаемости и клинические проявления редких коагулопатий у детей, определить корреляции степени тяжести клинических проявлений с активностью дефицитного фактора. Материалы и методы. На основании анализа деперсонифицированной базы данных из общего числа визитов к врачам, специализирующимся на болезнях свертывающей системы, с января 2017 г. по декабрь 2019 г. была изучена частота встречаемости редких коагулопатий. Оценивали основные локализации кровотечений и степень выраженности клинических проявлений, используя шкалу педиатрического опросника кровоточивости (англ. Pediatric Bleeding Questionnaire, PBQ). Анализ корреляции между величиной PBQ и значением активности дефицитного фактора проводили с применением метода Пирсона. Результаты. За 2017–2019 гг. в ФГБУ НМИЦ ДГОИ им. Д. Рогачева Минздрава России диагностировано 47 пациентов с редкими коагулопатиями: 14 пациентов с гипо/афибриногенемией, 21 пациент с дефицитом фактора VII, 5 пациентов с дефицитом фактора XI, 3 пациента с комбинированным дефицитом витамин К-зависимых факторов, 2 пациента с дефицитом фактора V, 1 пациент с дефицитом фактора X и 1 пациент с сочетанным дефицитом факторов V и VIII. Заключение. Распространенность той или иной редкой коагулопатии подвержена этническим особенностям населения и не всегда пропорциональна ожидаемой частоте. Требуется больше данных для установления местных особенностей распространения редких коагулопатий и выработки адекватных критериев диагностики. Background. Rare bleeding disorders are a heterogeneous group of hereditary diseases characterized by a quantitative or qualitative deficiency of blood coagulation factors. Objectives: to analyze the incidence and clinical manifestations of various rare bleeding disorders in children, to identify correlations of clinical manifestations severity with the activity of a deficient factor. Patients/Methods. According depersonalized database of the total number of visits (from January 2017 to December 2019) to doctors specializing in diseases of the coagulation system, the incidence of rare bleeding disorders was studied. The main sites of bleeding and the severity of clinical manifestations were assessed with the Pediatric Bleeding Questionnaire (PBQ) scale. Pearson method was used to analyze the correlation between the PBQ value and the deficient factor activity. Results. For years 2017–2019 at Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology 47 patients with rare bleeding disorders were diagnosed, оf these, 14 patients with hypo/afibrinogenemia, 21 patients with factor VII deficiency, 5 patients with factor XI deficiency, 3 patients with combined deficiency of vitamin K-dependent factors, 2 patients with factor V deficiency, 1 patient with factor X deficiency and 1 patient with combined factors V and VIII deficiency. Conclusions. The prevalence of one or another rare bleeding disorder is vulnerable to ethnic characteristics of the population and is not always proportional to the expected frequency. More data is required to establish the local characteristics of the spread of rare bleeding disorders and to develop adequate diagnostic criteria.

Overview of the Therapeutic Potential of Aptamers Targeting Coagulation Factors

Aptamers are single-stranded DNA or RNA sequences that bind target molecules with high specificity and affinity. Aptamers exhibit several notable advantages over protein-based therapeutics. Aptamers are non-immunogenic, easier to synthesize and modify, and can bind targets with greater affinity. Due to these benefits, aptamers are considered a promising therapeutic candidate to treat various conditions, including hematological disorders and cancer. An active area of research involves developing aptamers to target blood coagulation factors. These aptamers have the potential to treat cardiovascular diseases, blood disorders, and cancers. Although no aptamers targeting blood coagulation factors have been approved for clinical use, several aptamers have been evaluated in clinical trials and many more have demonstrated encouraging preclinical results. This review summarized our knowledge of the aptamers targeting proteins involved in coagulation, anticoagulation, fibrinolysis, their extensive applications as therapeutics and diagnostics tools, and the challenges they face for advancing to clinical use.