Regulation Of Hemostasis Research Articles

Endotheliopathy is Associated with a 24-hour Fibrinolysis Phenotype Described by Low TEG Lysis and High D-Dimer after Trauma: a Secondary Analysis of the PROPPR Study.

Determine associations between biomarkers of endotheliopathy, 24-hour fibrinolysis phenotypes and clinical outcomes after trauma. The vascular endothelium is a critical regulator of hemostasis and organ function. The relationship between markers of endotheliopathy and fibrinolysis following trauma has not been evaluated. We performed a secondary analysis of prospectively collected biomarker data in the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized controlled trial. We stratified subjects by 24-hour thromboelastography (TEG) percent clot lysis (LY30) and plasma D-dimer (DD) levels and evaluated differences in endotheliopathy biomarkers and clinical outcomes between subjects with one of four 24-hour fibrinolysis phenotypes: LY30 0.9-2.9% (LY30norm), LY30 >2.9% (LY30high), LY30 <0.9% and low DD (LY30low+DDlow), and LY30 <0.9% and high DD (LY30low+DDhigh). The analysis included 168 subjects with LY30norm, 32 with LY30high, 147 with LY30low+DDlow and 124 with LY30low+DDhigh. LY30low+DDhigh subjects had greater injury severity and a higher incidence of severe head injury, multiorgan failure (MOF), and mortality than the other phenotypes. All endotheliopathy biomarkers were significantly higher in the LY30low+DDhigh phenotype. Adjusting for injury severity, mechanism and head trauma, 24-hour angiopoietin-2 and soluble thrombomodulin were independently associated with the LY30low+DDhigh phenotype. Both endothelial biomarkers were discriminating for MOF. Subjects with thrombomodulin level >9.5 ng/mL and angiopoietin-2 level >3.6 ng/mL accounted for 64% of subjects who developed MOF. In a multicenter trauma cohort, subjects with a fibrinolysis phenotype characterized by low TEG lysis and elevated DD 24 hours after injury have significantly worse endotheliopathy and clinical outcomes. Our findings support mechanistic evaluations of the role of the endothelium in fibrinolysis dysregulation that may drive late-stage organ injury.

Preparations from Various Organs of Sea Buckthorn (Elaeagnus rhamnoides (L.) A. Nelson) as Important Regulators of Hemostasis and Their Role in the Treatment and Prevention of Cardiovascular Diseases.

Numerous studies on the chemical composition of various organs of sea buckthorn (Elaeagnus rhamnoides (L.) A. Nelson) have found the plant to be a rich source of vitamins, phenolic compounds, amino acids, fatty acids, and micro- and macro-elements. Furthermore, other studies on preparations from various organs have found them to have significant anti-cancer, anti-ulcer, and hepatoprotective properties, as well as various antibacterial and antiviral activities. This paper reviews the current literature concerning the effect of different sea buckthorn preparations, i.e., extracts and fractions with various chemical contents, on hemostasis, and their positive role in the treatment and prevention of cardiovascular diseases. It also sheds new light on the mechanisms involved in their action on hemostasis both in vivo and in vitro. For these studies, biological materials, including blood platelets, plasma, and blood, were isolated from healthy subjects and those with cardiovascular risk factors. In addition, it describes the cardioprotective potential of commercial products from different organs of sea buckthorn.

Prognostic criteria to assess the efficacy of the combined use of a low-frequency electrostatic field and transcranial magnetic therapy

The paper analyzes the dynamics of indicators characterizing the state of various functional body systems in patients with metabolic syndrome with the combined use of transcranial magnetic therapy and low-frequency electrostatic field in order to identify the main predictors of effectiveness. It was found that with such exposure, against the background of a significant increase in clinical efficacy, the degree of variation of dynamic changes increases, which is due to the difference in the initial condition of patients. It was revealed that the most pronounced therapeutic effect is observed in patients with preserved reserve and adaptive capabilities in the system of hemostasis, lipid peroxidation, micro-circulatory system and insulin regulation of glucose metabolism.

Circulating s-Endoglin concentrations in non-obese patients with gestational diabetes mellitus

The aim of this study was to compare maternal concentrations of soluble Endodlin (s-Endoglin) in women with gestational diabetes (GDM) and women with normal glucose tolerance (NGT) in pregnancy. Also, the association of insulin resistance markers and s-Endoglin was investigated. Forty patients complicated by GDM and forty gestational age-matched healthy pregnant women with NGT were included in the present study. s-Endoglin level was higher in patients with GDM compared with the control group (p .01). Besides a positive correlation was found between s-Endoglin and fasting glucose (r = 0.206, p = .057), insulin (r = 0.302, p = .005), HbA1c (r = 0.376, p < .01), HOMA-IR values (r = 0.283, p = .008) in pregnant women included in the study. s-Endoglin, as an anti-angiogenic marker seemed to have a role in pathogenesis and significantly associated with insulin resistance markers in non-obese GDM, thus may play important roles in the regulation of glucose hemostasis. Impact Statement What is already known on this subject? In women with GDM, hyperglycaemia induced glycosylation products might cause oxidative stress that may be subsequently involved in the release of inflammatory mediators, inducing angiogenesis What the results of this study add? s-Endoglin has an anti-angiogenic effect and is a useful marker of endothelial injury, activation of inflammation, senescence and oxidative stress, we speculate that it may be involved in the pathogenesis of GDM. What the implications are of these findings for clinical practice and/or further research? s-Endoglin seemed to have a role in the regulation of glucose hemostasis. Further exploration of novel factors like s-endoglin in the pathogenesis of GDM, is essential and valuable to develop new therapeutic strategies for this complex disease and its complications.

Role of Endothelial Cells in Hematological Malignancies

Endothelial cells (EC) are key elements of vascularized tissues that form a single-cell layer that connects the vessels to the surrounding tissues. EC participate in the regulation of blood hemostasis, leukocyte homing, acute inflammation, wound healing, and antigen presentation. EC subpopulations are characterized by diverse structures, functions, and molecular profiles. In bone marrow, EC are part of the hematopoietic stem cell vascular and endosteal niche, where they play well-defined roles in hematopoietic stem cell functioning and maintenance, and reside surrounding sinusoids and blood vessels. In the past years, the clinical and pathophysiological roles of EC have been explored due to their contribution to neoangiogenesis and alterations in the vascular endothelium functions in hematological diseases. The present review discusses the EC contribution to pathogenesis of hematological malignancies and their potential use as therapeutic target in these diseases. Keywords: Endothelial cells, hematological malignancies, bone marrow niche, pathogenesis, angiogenesis.

Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis

Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis

Distinct Serotypes of Streptococcal M Proteins Mediate Fibrinogen-Dependent Platelet Activation and Proinflammatory Effects.

ABSTRACTSepsis is a life-threatening complication of infection that is characterized by a dysregulated inflammatory state and disturbed hemostasis. Platelets are the main regulators of hemostasis, and they also respond to inflammation. The human pathogen Streptococcus pyogenes can cause local infection that may progress to sepsis. There are more than 200 serotypes of S. pyogenes defined according to sequence variations in the M protein. The M1 serotype is among 10 serotypes that are predominant in invasive infection. M1 protein can be released from the surface and has previously been shown to generate platelet, neutrophil, and monocyte activation. The platelet-dependent proinflammatory effects of other serotypes of M protein associated with invasive infection (M3, M5, M28, M49, and M89) are now investigated using a combination of multiparameter flow cytometry, enzyme-linked immunosorbent assay (ELISA), aggregometry, and quantitative mass spectrometry. We demonstrate that only M1, M3, and M5 protein serotypes can bind fibrinogen in plasma and mediate fibrinogen- and IgG-dependent platelet activation and aggregation, release of granule proteins, upregulation of CD62P to the platelet surface, and complex formation with neutrophils and monocytes. Neutrophil and monocyte activation, determined as upregulation of surface CD11b, is also mediated by M1, M3, and M5 protein serotypes, while M28, M49, and M89 proteins failed to mediate activation of platelets or leukocytes. Collectively, our findings reveal novel aspects of the immunomodulatory role of fibrinogen acquisition and platelet activation during streptococcal infections.

300 PCSK9 induces a prothrombotic response by activation of NFKB signalling pathway in mononuclear cells

Abstract Aims Strong evidence both experimental and clinical studies point out to an involvement of proprotein convertase subtilisin/kexin 9 (PCSK9), as an important player in hypercholesterolemia and atherosclerosis pathophysiology, identifying it, as a key molecule in the development of new cholesterol-lowering drugs and therapeutic target for atherosclerosis and related diseases. Emerging evidence shown that PCSK9 is straight implicated in inflammatory process where it may directly influence the activity of various cell types through NFkB activation, a key transcription factor involved in the induction of both pro-inflammatory cytokines and Tissue Factor (TF) expression, a major regulator of haemostasis and thrombosis in monocytes. Deductive reasoning makes therefore plausible to investigate a mechanistic link between circulation PCSK9 levels and TF expression, both in monocytes as well as on the surface of microparticles (MPs) generated from the same cells, with NFkB acting as the chain in the link. To investigate the involvement of NFkB signalling pathway in PCSK9-induced TF expression. Methods THP-1 cell line were stimulated with human (h) PCSK9 (5 μg/mL) or pre-incubated with BAY-117082 (BAY, 10−5M) an NFκB inhibitor, CLI-095 (3 × 10−6M), a highly TLR-4 signalling specific inhibitor and LPS-RS(5 μg/mL) a TLR-4 antagonist. TF procoagulant activity (PCA) was assessed by one-stage clotting assay using a STart Max semi-automated coagulation analyser. Concentration of TF-bearing MPs was determined using the Zymuphen MP-activity kit. Results hPCSK9 stimulated TF activity in THP-1 (PCA: from 50 ± 20 to 120 ± 20 ρg/mL, n = 10, P &amp;lt; 0.01). BAY, an NFkB inhibitor (PCA: −71 ± 23%, n = 5, P &amp;lt; 0.01) and CLI-095, a TLR-4 signalling inhibitor, (PCA: −86 ± 26%, n = 3, P &amp;lt; 0.05) and LPS-RS (PCA: −71 ± 23%, n = 5, P &amp;lt; 0.01) down-regulated PCSK9-induced TF activity completely. Furthermore THP-1stimulation with hPCSK9 causes the release of prothrombotic MPs-TF+ (MPs release from: 0.13 ± 0.07 to 0.42 ± 0.1 nM PS, n = 7, P &amp;lt; 0.05; PCA-MP+ from: 14 ± 3 to 44 ± 28 ρg/mL, n = 5, P &amp;lt; 0.05). Conclusions These data confirm the pivotal role of monocytes in the response PCSK9-induced TF-expression as well as the involvement of PCSK9 in inflammatory-thrombotic diseases through a direct stimulation of TF procoagulant activity and by the release of TF-bearing MPs. The possible mechanism of action involves recognition of PCSK9 by TLRs 2 and/or 4, on monocytes membrane surface, leading to activation of the transcription factor NFκB via an intracellular signalling cascade. Further studies will be needed to better understand the regulatory mechanisms underlying this complex set of biological responses that bind PCSK9, and coagulation events.

Whole-exome analysis of adolescents with low VWF and heavy menstrual bleeding identifies novel genetic associations

AbstractAdolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better characterize these patients genetically and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 postmenarchal patients diagnosed with low VWF levels (30-50 IU/dL) and HMB and compared them with 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar “pathogenic” variants between cases and controls, as well as performed gene burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders and an enrichment of rare ClinVar “pathogenic” variants in genes involved in anemias. The 2 most significant genes in the gene burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene burden analysis (P = 7.31 × 10−6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in the regulation of hemostasis and angiogenesis, surpassed genome-wide significance. We demonstrate that adolescents with HMB and low VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in bleeding disorders and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in patients with HMB and could partially explain the bleeding phenotype. By identifying patients with HMB who possess these variants, we may be able to improve risk stratification and patient outcomes.

Neutrophil extracellular traps: a role in inflammation and dysregulated hemostasis as well as in patients with COVID-19 and severe obstetric pathology

Numerous studies have proven a close relationship between inflammatory diseases and the state of hypercoagulability. In fact, thromboembolic complications represent one of the main causes of disability and mortality in acute and chronic inflammatory diseases, cancer and obstetric complications. Despite this, the processes of hemostasis and immune responses have long been considered separately; currently, work is underway to identify the molecular basis for a relationship between such systems. It has been identified that various pro-inflammatory stimuli are capable of triggering a coagulation cascade, which in turn modulates inflammatory responses. Neutrophil extracellular traps (NETs) are the networks of histones of extracellular DNA generated by neutrophils in response to inflammatory stimuli. The hemostasis is activated against infection in order to minimize the spread of infection and, if possible, inactivate the infectious agent. Another molecular network is based on fibrin. Over the last 10 years, there has been accumulated a whole body of evidence that NETs and fibrin are able to form a united network within a thrombus, stabilizing each other. Similarities and molecular cross-reactions are also present in the processes of fibrinolysis and lysis of NETs. Both NETs and von Willebrand factor (vWF) are involved in thrombosis as well as inflammation. During the development of these conditions, a series of events occurs in the microvascular network, including endothelial activation, NETs formation, vWF secretion, adhesion, aggregation, and activation of blood cells. The activity of vWF multimers is regulated by the specific metalloproteinase ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). Studies have shown that interactions between NETs and vWF can lead to arterial and venous thrombosis and inflammation. In addition, the contents released from activated neutrophils or NETs result in decreased ADAMTS-13 activity, which can occur in both thrombotic microangiopathies and acute ischemic stroke. Recently, NETs have been envisioned as a cause of endothelial damage and immunothrombosis in COVID-19. In addition, vWF and ADAMTS-13 levels predict COVID-19 mortality. In this review, we summarize the biological characteristics and interactions of NETs, vWF, and ADAMTS-13, the effect of NETs on hemostasis regulation and discuss their role in thrombotic conditions, sepsis, COVID-19, and obstetric complications.

Thrombin Cleaves Prolactin Into a Potent 5.6-kDa Vasoinhibin: Implication for Tissue Repair.

Vasoinhibin is an endogenous prolactin (PRL) fragment with profibrinolytic, antivasopermeability, and antiangiogenic effects. The fact that blood clotting, vascular permeability, and angiogenesis are functionally linked during the wound-healing process led us to investigate whether thrombin, a major protease in tissue repair, generates vasoinhibin. Here, we have incubated human PRL with thrombin and analyzed the resulting proteolytic products by Western blot, mass spectrometry, high-performance liquid chromatography purification, recombinant production, and bioactivity. We unveil a main thrombin cleavage site at R48-G49 that rapidly (< 10 minutes) generates a 5.6-kDa fragment (residues 1-48) with full vasoinhibin activity, that is, it inhibited the proliferation, invasion, and permeability of cultured endothelial cells and promoted the lysis of a fibrin clot in plasma with a similar potency to that of a conventional 14-kDa vasoinhibin (residues 1-123). The R48-G49 cleavage site is highly conserved throughout evolution and precedes the intramolecular disulfide bond (C58-C174), thereby allowing the 5.6-kDa vasoinhibin to be released without a reduction step. Furthermore, the 5.6-kDa vasoinhibin is produced by endogenous thrombin during the clotting process. These findings uncover the smallest vasoinhibin known, add thrombin to the list of PRL-cleaving proteases generating vasoinhibin, and introduce vasoinhibin as a thrombin-activated mechanism for the regulation of hemostasis, vasopermeability, and angiogenesis in response to tissue injury.

Роль тучных клеток в репарации кожи после термической травмы при применении дермальной пленки с мелатонином

The development of novel local therapies for thermal burns (TB) and their pathogenetic rationale are a pressing challenge. Melatonin (MT) is an endogenous factor of hemostasis regulation with pleiotropic potential. The aim of this study was to assess some parameters of tissue regeneration, the functional state of mast cells and the levels of matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the experimentally induced TB treated with the original MT-enriched dermal film (DF). A second-degree burn (3.5% of the total body surface area) was modelled by exposing a patch of skin to hot water. Applications of 12 cm2 DF enriched with 5 mg/g MT were performed every day for 5 days. The following parameters were calculated: the wound area, the rate of wound epithelization, the number of MC in the wound, the intensity of degranulation, and the levels of MMP-9 and VEGF expression. Over the course of treatment, the absolute wound area shrank by 35%, its epithelization rate increased, the number of MC rose, their functional state changed, and the expression of ММР-9 and VEGF increased. A negative correlation was established between the wound area and the expression of ММР-9 and VEGF, as well as between the wound area and the degranulation coefficient. Applications of MT-enriched DF resulted in the reduction of the wound area, higher epithelization rate, an increase in the total MC count and degranulation intensity on days 5 and 10; it also led to a reduction in the total MC count and a loss in degranulation intensity on day 20 (166.87 (154.95; 178.78) un/mm2 vs. 464.84 (452.92; 476.76) un/mm2) in the group of intact animals), an increase in MMP-9 expression on day 5 (14.20 (11.30; 18.10) vs. 3.30 (2.20; 4.40) in the intact group), an increase in VEGF expression on days 5 and 10 (33.00 (30.20; 34.90) vs 25.40 (22.20; 29.30) in the intact group), and a reduction in MMP-9 expression on days 10 and 20 after thermal injury.

CIB1 Regulates Hemostasis through Integrin Outside-in Signaling

On circulating platelets, integrin αIIbβ3, the fibrinogen receptor, is in a low affinity state unable to bind soluble ligands. Agonist-dependent inside-out signaling is necessary for activation of the integrin αIIbβ3 in order to bind ligands such as fibrinogen (Fg). Ligand binding induces a cascade of signaling that culminates in platelet aggregation, leading to hemostatic plug formation and clot retraction. Although it is well known that signaling through integrin αIIbβ3 is necessary, the mechanism of clot retraction is not well understood. Previously, we have identified a calcium- and integrin-binding protein 1 (CIB1) that specifically interacts with integrin αIIbβ3. One study implicated CIB1 as an endogenous inhibitor of integrin αIIbβ3 activation, while another study suggested CIB1 to be an activator of inside-out signaling. Using a novel technique to inhibit interaction of CIB1 with integrin in vivo, we have shown that CIB1 regulates outside-in signaling through integrin αIIbβ3. Definitive proof for the role of CIB1 in platelets remained absent, however. Here, using Cib1 null platelets, we show for the first time that CIB1 is a key regulator of hemostasis. Genetic ablation of CIB1 had no effect on agonist-induced platelet aggregation, excluding the role for CIB1 in inside-out signaling. However, deletion of the Cib1 gene significantly increased mouse bleeding times. More than 50% of the mice also showed a rebleeding phenotype, suggesting a defect in clot stability. Incomplete and significantly delayed clot retraction was observed in Cib1 null platelets compared to wildtype littermates. The absence of CIB1 also affects the ability of platelets to spread on immobilized Fg. Platelet adhesion and subsequent filopodia formation was not affected by the absence of CIB1. Platelet spreading can be restored by addition of exogenous ADP, suggesting that the defect is not in the ability of the platelet to spread. These in vivo and in vitro results clearly show that CIB1 regulates hemostasis by supporting transition of platelets from filopodial stage to fully spread morphology during outside-in signaling through integrin αIIbβ3.

Biochemical and Pharmacological Differentiation of APC and Recombinant Thrombomodulin with Reference to the Effect on the Hemostatic and Fibrinolytic Processes

Introduction:Both thrombomodulin and activated protein C play an important role in the regulation of hemostasis. Recombinant versions of both the thrombomodulin (rTM) and activated protein C (rAPC) have been developed for clinical applications. Marked differences in their biochemical and pharmacological profiles exist. Such differences in their effects may be due to target sites and other interactions and may have therapeutic and safety implications.Aim:The aim of this study is to investigate the biochemical and pharmacological differences between a clinically developed rTM (ART-123, Asahi Kasei Pharma, Tokyo, Japan) and a plasma derived APC (Haematologic Technologies, Burlington, VT, USA).Materials and Methods:The anticoagulant profile of both agents was investigated in native whole blood using the ACT, TEG and global anticoagulant profile using PT and APTT assays at a concentration range of 0-10 ug/ml. The global anticoagulant profile in plasma based systems in terms of PT and APTT was also investigated. The effect of both of these agents was studied in the antiprotease (Xa and IIa) inhibitory assays and thrombin generation inhibition methods. A modified TEG system was used to study the modulation of tissue plasminogen activator mediated fibrinolysis by these agents.Results:In the ACT assays APC produced a much stronger anticoagulant effect in a concentration range of 0-10 ug/ml with a doubling time at 3 ug/ml, whereas rTM produced marginal effects on this parameter. The TEG profile of APC exhibited much stronger anticoagulant effects in comparison to rTM. At 3 ug/mL, APC produces much longer prolongation of the R and K time parameters in comparison to rTM. APC also facilitated tPA-mediated fibrinolysis in contrast to rTM. In the anti-IIa assays, rTM produced concentration dependent inhibition of thrombin and no inhibition of factor Xa. APC did not have any effect on either Factor Xa or IIa. In the thrombin generation assays, APC produced a stronger inhibition of thrombin generation (IC50=0.4 ug/mL) whereas rTM was relatively weaker (IC50 = 1.2 ug/mL). In the APTT assay APC produced a much stronger anticoagulant effect whereas rTM produced relatively weaker effects. Both agents did not produce any modification of agonist induced platelet aggregation. In terms of anticoagulant potency the APC exhibited 70 + 6 USP U/mg whereas the rTM was much weaker < 10 USP U/mg.Conclusions:These studies demonstrate that APC is a much stronger anticoagulant in comparison to rTM. In addition both agents produced different modulation of fibrinolytic and hemostatic processes. These observations suggest that in clinical indications such as DIC, these agents may have differential safety/efficacy implications. DisclosuresTanaka:Asahi Kasei Pharma America Corporation: Employment. Tsuruta:Asahi Kasei Pharma America Corporation: Employment.

Annexin A2 in Fibrinolysis, Inflammation and Fibrosis.

As a cell surface tissue plasminogen activator (tPA)-plasminogen receptor, the annexin A2 (A2) complex facilitates plasmin generation on the endothelial cell surface, and is an established regulator of hemostasis. Whereas A2 is overexpressed in hemorrhagic disease such as acute promyelocytic leukemia, its underexpression or impairment may result in thrombosis, as in antiphospholipid syndrome, venous thromboembolism, or atherosclerosis. Within immune response cells, A2 orchestrates membrane repair, vesicle fusion, and cytoskeletal organization, thus playing a critical role in inflammatory response and tissue injury. Dysregulation of A2 is evident in multiple human disorders, and may contribute to the pathogenesis of various inflammatory disorders. The fibrinolytic system, moreover, is central to wound healing through its ability to remodel the provisional matrix and promote angiogenesis. A2 dysfunction may also promote tissue fibrogenesis and end-organ fibrosis.

ОСОБЕННОСТИ АНАМНЕЗА И ЛАБОРАТОРНЫХ ПАРАМЕТРОВ ДЕТЕЙ С ПАТОЛОГИЕЙ ТРОМБОЦИТОВ

The aim of the study is to identify the features of the anamnesis and laboratory characteristics of children and adolescents with platelet pathology. Materials and methods of research: the features of medical history and laboratory characteristics of children and adolescents aged 1 to 17 years with platelet pathology (thrombocytopenia and thrombocytopathy) were studied based on the analysis of 112 medical records of inpatients. Study design: retrospective, single-center, solid, non-randomized, uncontrolled. Results: when comparing parameters of the indicated nosological groups, a higher viral load was revealed in children with thrombocytopenia (level of antibodies to the herpesvirus group was statistically significantly higher in children with thrombocytopenia than with thrombocytopathy: for HSV1,2 and VEB – p&lt;0,001, CMV – p=0,008). According to hemostasiogram, APTT was statistically significantly higher in the thrombocytopathy group (29,56±2,18 s versus 28,44±1,62 s respectively, p=0,0011), the prothrombin time was higher in thrombocytopenia (12,37±0,72 s and 12,03±0,48 s, respectively, p=0,014). The activity of von Willebrand factor is statistically significantly higher in thrombocytopenia compared with thrombocytopathy (123,78±36,35% versus 79,73±35,21%, respectively, p&lt;0,001). A positive correlation between the relative number of platelets and leukocytes (Rs=0,40, p&lt;0,001) has been established in the group of children with thrombocytopathy. Conclusion: the differences and dependencies identified indicate the inclusion of compensatory mechanisms of hemostasis regulation and immune protection in platelet pathology, which is more pronounced with decrease in their number.

Proteolytic enzyme and adiponectin receptors as potential targets for COVID-19 therapy

The coronavirus disease 2019 (COVID-19) pandemic requires not only the creation of vaccines to prevent the spread of the disease, but also the development of novel drugs aimed at reducing viral load, suppressing an excessive immune response and preventing the severe complications such as lung fibrosis and acute respiratory distress syndrome. One of the promising targets for studying the development of pneumonia, systemic inflammation and disseminated intravascular coagulation in COVID-19 is the plasminogen activator system. In patients with a severe disease course, impaired activity or expression of plasminogen activators significantly increases the blood level of D-dimer and fibrinogen, as well as correlates with intravascular coagulation and thrombus formation. The second promising target for studying the pathogenesis of COVID-19 is the adiponectin/T-cadherin system: adiponectin is able to reduce the content of pro-inflammatory cytokines, the increase of which is characteristic of COVID-19, and stimulate the production of an anti-inflammatory cytokine interleukin-10. The review describes the role of plasminogen and T-cadherin activators in their possible participation in the development of pulmonary fibrosis in COVID-19 and hemostasis regulation, as well as cardio- and vasculoprotective function of adiponectin and its receptor, T-cadherin.

Novel perspectives on redox signaling in red blood cells and platelets in cardiovascular disease

The fundamental physiology of circulating red blood cells (RBCs) and platelets involving regulation of oxygen transport and hemostasis, respectively, are well-described in the literature. Their abundance in the circulation and their interaction with the vascular wall and each other have attracted the attention of other putative physiological and pathophysiological effects of these cells. RBCs and platelets are both important regulators of redox balance harboring powerful pro-oxidant and anti-oxidant (enzymatic and non-enzymatic) capacities. They are also involved in the regulation of vascular tone mainly via export of nitric oxide bioactivity and adenosine triphosphate. Of further importance are emerging observations that these cells undergo functional alterations when exposed to risk factors for cardiovascular disease and during developed cardiometabolic diseases. Under these conditions, the RBCs and platelets contribute to increased oxidative stress by their formation of reactive species including superoxide anion radical, hydrogen peroxide and peroxynitrite. These alterations trigger key changes in the vascular wall characterized by enhanced oxidative stress, reduced nitric oxide bioavailability and endothelial dysfunction. Additional pathophysiological effects are triggered in the heart resulting in increased susceptibility to ischemia-reperfusion injury with impairment in cardiac function. Pharmacological interventions aiming at restoring circulating cell function has been shown to exert marked beneficial effects on cardiovascular function. In this review, we summarize the current knowledge of RBC and platelet biology with special focus on redox biology, their roles in the development of cardiovascular disease and potential therapeutic strategies targeting RBC and platelet dysfunction. Finally, the complex and scarcely understood interaction between RBCs and platelets is discussed.

Bilateral vocal fold paralysis after COVID-19 infection. Another neuro-invasive manifestation? Case series

The agent that causes the coronavirus disease (COVID-19), associated with the severe acute respiratory syndrome (SARS-CoV-2), produces a spectrum of symptoms that mainly affect the respiratory system, the central nervous system (CNS), the regulation of hemostasis and the immune system.&#x0D; Bilateral vocal fold paralysis (BVFP) is a condition of unknown incidence among infected patients, either because it is short-lived or because of the difficulty in establishing a direct cause to the virus.&#x0D; Viral infection has been described in the literature as a cause of BVFP and there is the suspicion that a proportion of the idiopathic cases are due to undiagnosed viral infections.&#x0D; Although the neurotropic mechanisms for SARS-CoV-2 remain unclear, there is strong evidence to ensure its neuroinvasive potential.&#x0D; The most frequent etiologies of BVFP are trauma, neoplasm, and neurological, but a viral origin should not be ruled out. Causality between COVID-19 and BVFP is plausible and will require further study in the short and long term.

Till Death Do Us Part-The Multifaceted Role of Platelets in Liver Diseases.

Platelets are tightly connected with the liver, as both their production and their clearance are mediated by the liver. Platelets, in return, participate in a variety of liver diseases, ranging from non-alcoholic fatty liver diseases, (viral) hepatitis, liver fibrosis and hepatocellular carcinoma to liver regeneration. Due to their versatile functions, which include (1) regulation of hemostasis, (2) fine-tuning of immune responses and (3) release of growth factors and cellular mediators, platelets quickly adapt to environmental changes and modulate disease development, leading to different layers of complexity. Depending on the (patho)physiological context, platelets exert both beneficial and detrimental functions. Understanding the precise mechanisms through which platelet function is regulated at different stages of liver diseases and how platelets interact with various resident and non-resident liver cells helps to draw a clear picture of platelet-related therapeutic interventions. Therefore, this review summarizes the current knowledge on platelets in acute and chronic liver diseases and aims to shed light on how the smallest cells in the circulatory system account for changes in the (patho)physiology of the second largest organ in the human body.