Activation Of Coagulation System Research Articles

Inhibition of selective factor Xa suppresses type 1 diabetes development in mice via the CXCL16 chemokine

Type 1 diabetes mellitus (T1DM) is associated with enhanced thrombosis potential. This research aims to investigate the role of coagulation system activation and CXCL16 in T1DM progression and the possible preventive effect of the selective Factor Xa inhibitor, Fondaparinux (Fond). Forty male Wistar albino mice were classified into 4 groups. Control, Fond, Streptozotocin (STZ), and Fond + STZ groups. Biochemical, hematological, and histopathological parameters, expressions of CXCL16, insulin, fibrinogen, and PAR-2, were investigated. A significant increase in blood glucose level and expressions of CXCL16, fibrinogen, and PAR-2, together with histological and nuclear changes in the pancreatic islets, was observed in STZ-treated mice, accompanied by a reduction in the serum insulin level. Fond improved the deleterious effects resulting from STZ treatment. In conclusion, coagulation system activation and CXCL16 play a critical role in the initiation of T1DM and could be used as therapeutic targets for T1DM prevention.

The value of D-dimer in the prognosis of dilated cardiomyopathy: a retrospective cohort study.

D-dimer is a biomarker of coagulation and fibrinolytic system activation in response to the hypercoagulable state of the body. The research aimed to analyze the value of D-dimer in the prognosis of patients with dilated cardiomyopathy (DCM). Patients admitted to our center for the first time with DCM were enrolled consecutively. The clinical characteristics variables were obtained from the electronic medical record system, and the prognostic information was obtained using telephone return visits and a review of repeated hospitalization records. Univariate and multivariate Cox regression was used to explore the association of D-dimer with all-cause mortality. Smooth curve fitting, threshold saturation effect analysis, and subgroup analysis were performed. Ultimately, 534 patients were included. After a follow-up of the enrolled patients, 485 patients obtained prognostic information, of which 159 died from all causes, and the main cause of death was heart failure (89/159), the sudden death accounted for about 17%. The independent positive association between D-dimer and all-cause mortality remained unchanged in both unadjusted and adjusted Cox regression models. In the fully adjusted model, each standard deviation increase in D-dimer was associated with a 14% increase in all-cause mortality (HR = 1.14; 95% CI: 1.02 ~ 1.27; P < 0.05). Curve fitting and threshold effect analysis showed an inflection point in the relationship between D-dimer and all-cause mortality (non-linear test: P = 0.03). When D-dimer was equal to 362ng/ml, HR = 1; and as the value increased, the risk of all-cause mortality increased by 34.7% for every 2-fold increase in D-dimer gradually (HR = 1.347; 95% CI: 1.069 ~ 1.697; P = 0.012). In subgroup analysis, D-dimer and BMI had a significant interaction on all-cause mortality, with a significantly increased risk of all-cause mortality in subjects with BMI ≥ 25kg/m2 (HR = 1.99; 95% CI: 1.34 ~ 2.97; P < 0.01). The ROC curve showed that D-dimer was a good predictor of all-cause mortality, and the areas under the curve at 1-, 3-, and 5-year were 0.71, 0.64, and 0.59, respectively. In addition, D-dimer improved the predictive performance of the MAGGIC heart failure score in patients with DCM. D-dimer is not only independently associated with all-cause mortality in DCM patients, but also has good predictive value, suggesting that D-dimer may be an early and useful marker for improving the management of DCM patients.

The dysfunction of complement and coagulation in diseases: the implications for the therapeutic interventions.

The complement system, comprising over 30 proteins, is integral to the immune system, and the coagulation system is critical for vascular homeostasis. The activation of the complement and coagulation systems involves an organized proteolytic cascade, and the overactivation of these systems is a central pathogenic mechanism in several diseases. This review describes the role of complement and coagulation system activation in critical illness, particularly sepsis. The complexities of sepsis reveal significant knowledge gaps that can be compared to a profound abyss, highlighting the urgent need for further investigation and exploration. It is well recognized that the inflammatory network, coagulation, and complement systems are integral mechanisms through which multiple factors contribute to increased susceptibility to infection and may result in a disordered immune response during septic events in patients. Given the overlapping pathogenic mechanisms in sepsis, immunomodulatory therapies currently under development may be particularly beneficial for patients with sepsis who have concurrent infections. Herein, we present recent findings regarding the molecular relationships between the coagulation and complement pathways in the advancement of sepsis, and propose potential intervention targets related to the crosstalk between coagulation and complement, aiming to provide more valuable treatment of sepsis.

6940 Thrombotic Events in Primary Hyperparathyroidism: Association or Coincidence?

Abstract Disclosure: I.A. Guatemala Funes: None. Z. Zavgorodneva: None. Y. EL-Soufi: None. A. Khan: None. T. Zahedi: None. F. Zhang: None. Introduction: The classical manifestations of primary hyperparathyroidism are nephrolithiasis, osteoporosis, and hypercalcemia-related symptoms, such as abdominal pain, constipation, polydipsia, and polyuria. Parathyroid crisis is a rare and life-threatening presentation of primary hyperparathyroidism characterized by calcium levels above 14-15 mg/dl and marked symptoms of hypercalcemia. Here, we describe a rare case of bilateral pulmonary embolism in a patient with severe hypercalcemia secondary to parathyroid adenoma. Case Report The patient is a 70-year-old female with a past medical history of primary hyperparathyroidism, who presented with profound fatigue, shortness of breath, polyuria and constipation. The patient denied any trauma, immobilization, or long-distance travel. On physical exam patient was confused, dehydrated, and nonhypoxic but with increased work of breathing. Initial labs showed severe hypercalcemia with calcium 19.2 mg/dL, significant elevated PTH 1113.9 pg/mL from her baseline PTH 380.8 pg/mL, normal 25 VitD, and acute kidney injury with creatinine increased from 0.9 mg/dL to 2.8 mg/dL. The calcium level in 24-hour urine collection was 323 mg/24 hours. CT chest angiogram revealed a bilateral lower lobe pulmonary embolism. The lower extremity duplex was negative for venous thrombosis. Thyroid ultrasound demonstrated suspected left parathyroid adenoma 2.1 x 2.1 x 1.4 cm. Renal ultrasound was negative for renal calculi. Following treatment with intravenous fluids, Calcitonin, and Denosumab, her calcium level improved to 10.1 mg/dL. The patient’s symptoms improved and underwent parathyroidectomy. PTH levels decreased significantly after parathyroidectomy. Pathology report confirmed parathyroid adenoma. Discussion The association between hypercalcemia and venous or arterial thrombosis has been rarely reported. Calcium participates directly in the platelet activation, platelet aggregation, and coagulation cascade. However, the true correlation between hypercalcemia and thrombosis is not well understood. It is believed that indirect factors such as vasoconstriction, dehydration, and cytotoxic effects due to hypercalcemia and the direct effects over platelet function and coagulation, may act together to induce thrombosis. Unfortunately, much of the evidence between hypercalcemia and hypercoagulability is based on case reports and our case could be one more evidence that this correlation exists. The patient’s age, absence of other risk factors of hypercoagulability, simultaneous manifestation of hypercalcemic crisis, and acute PE make hypercalcemia as a more likely pathogenetic origin of thrombus formation. Conclusion: Physicians should be cautious of the hypercalcemia-induced thrombotic events caused by dehydration and calcium-triggered vasoconstriction, clotting system activation, or platelet aggregation. Presentation: 6/3/2024

Pathogenesis of respiratory failure in COVID-19 due to coagulopathy and endothelial dysfunction

Respiratory failure is known to be the main clinical manifestation of COVID-19. However, the mechanism of its development has not been sufficiently studied. The originality of the study is that for the first time, coagulation, fibrinolysis and endothelial dysfunction indicators were studied depending on the SpO2/FiO2 index in patients with COVID-19.The aim of the work. To assess the role of impaired activity of the blood coagulation system and the development of endothelial dysfunction in patients with COVID-19 in the pathogenesis of respiratory failure.Methods. The study included 134 patients infected with SARS-CoV-2 virus having varying severity of the clinical picture. They were divided into three groups according to the SpO2/FiO2 index. We determined the number of venous blood cells and studied the level of transferrin (TF), D-dimer, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), inter-cellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in the blood serum.Results. The study revealed that the tissue factor content increased by 24 % in patients of the third group compared to the first. The PAI-1 level was high in the second group and significantly decreased in the third (p &lt; 0.001). An increase in the D-dimer level was recorded in the second and third groups. The levels of ICAM-1 and VCAM-1 molecules increased significantly in the third group of patients (p = 0.021 and p = 0.028, respectively). A moderate positive correlation was found between the SpO2/FiO2 index and the VCAM-1 level (p &lt; 0.001), a weak positive correlation with PAI-1 (p = 0.012), and a weak negative correlation with TF (p = 0.027).Conclusion. Respiratory failure in patients with COVID-19 is caused by disorders in the hemostasis and fibrinolysis systems, as evidenced by an increase in the level of tissue factor and D-dimer, “consumption” of tissue activator and plasminogen activator inhibitor. Developing endothelial dysfunction, accompanied by increased secretion of adhesion molecules, aggravates the pathogenesis of respiratory failure.

Antithrombotic and Antimicrobial Potential of S-Nitroso-1-Adamantanethiol-Impregnated Extracorporeal Circuit.

This study presents the utilization of a novel, highly lipophilic nitric oxide (NO) donor molecule, S-nitroso-1-adamantanethiol (SNAT), for developing an NO-emitting polymer surface aimed at preventing thrombus formation and bacterial infection in extracorporeal circuits (ECCs). S-nitroso-1-adamantanethiol, a tertiary nitrosothiol-bearing adamantane species, was synthesized, characterized, and used to impregnate polyvinyl chloride (PVC) tubing for subsequent in vivo evaluation. The impregnation process with SNAT preserved the original mechanical strength of the PVC. In vitro assessments revealed sustained NO release from the SNAT-impregnated PVC tubing (iSNAT), surpassing or matching endothelial NO release levels for up to 42 days. The initial NO release remained stable even after 1 year of storage at -20°C. The compatibility of iSNAT with various sterilization techniques (OPA Plus, hydrogen peroxide, EtO) was tested. Acute in vivo experiments in a rabbit model demonstrated significantly reduced thrombus formation in iSNAT ECCs compared with controls, indicating the feasibility of iSNAT to mitigate coagulation system activation and potentially eliminate the need for systemic anticoagulation. Moreover, iSNAT showed substantial inhibition of microbial biofilm formation, highlighting its dual functionality. These findings underscore the promising utility of iSNAT for long-term ECC applications, offering a multifaceted approach to enhancing biocompatibility and minimizing complications.

Research progress on the role of pyroptosis in sepsis-related coagulation disorder

Sepsis is a common and severe infectious disease, and its associated coagulation dysfunction can cause disseminated intravascular coagulation (DIC) and organ failure, leading to a significant increase in mortality. Pyroptosis is a form of programmed cell death mediated by caspase-1 in the classical pathway and caspase-4/caspase-5/caspase-11 in the non-classical pathway, along with the effector molecule gasdermin (GSDM) family. Recent studies have shown that pyroptosis plays an important role in the development of coagulation disorders in sepsis. Pyroptosis leads to the formation of cytoplasmic membrane pores, cell swelling and membrane rupture, as well as the release and enhanced activity of procoagulant contents, strongly promoting the development of systemic coagulation activation and DIC in sepsis. Therefore, exploring the role and molecular mechanisms of pyroptosis in sepsis-related coagulation disorders is of great significance for the prevention and treatment of sepsis. This article provides a review of the mechanisms involved in pyroptosis and coagulation disorders in sepsis, as well as the role and mechanisms of pyroptosis in sepsis-associated coagulation disorders to provide new ideas for sepsis related research.

The Role of Platelet Activation in the Development and Metastasis of Solid Tumors

The blood coagulation system is actively involved in the development of cancer. It is known that many solid tumors express tissue factor, a “trigger” of the cascade of plasma coagulation reactions, which leads to an increased risk of cancer-associated thrombosis and venous thrombosis in cancer patients. It has also long been known that platelets - small cellular fragments that are the basis of blood clots - play a critical role in metastasis by binding to the tumor cell after it enters the blood vessel, “shielding” it from the immune system and promoting the adhesion and extravasation of the tumor cell into tissues and the formation metastasis. In addition, platelets, being mobile “storehouses” of growth factors, are actively attracted and, in some cases, consumed by the tumor, which contributes to its development and vascularization. Platelet attraction occurs both through activation of the blood coagulation system in the tumor area and through exposure of the adhesive surface by the tumor. Activated in the tumor vicinity, platelets attract and induce neutrophil activation and the formation of neutrophil extracellular traps (NETs), thereby modulating the tumor microenvironment. When activated, platelets are known to secrete a variety of growth factors that promote both tumor development and vascularization. In addition to direct interaction, platelets and tumor cells exchange mRNA, micro-RNA and other regulatory molecules through microvesicles, while platelets are containers for the spread of tumor genetic material (circulating nucleic acids) throughout the body. In this review, we consider the molecular mechanisms of platelet participation in the development and metastasis of solid tumors, and also discuss possible options for pharmacological interruption of this interaction.

ГЕМОСТАТИЧЕСКИЕ НАРУШЕНИЯ ПРИ НЕОПУХОЛЕВОЙ МЕХАНИЧЕСКОЙ ЖЕЛТУХЕ И ХОЛАНГИТЕ В ЗАВИСИМОСТИ ОТ ТЯЖЕСТИ И ПОЛИМОРФИЗМА ГЕНА ФИБРИНОГЕНА

Background. Mechanical jaundice (MF) and cholangitis are considered to be of great significance in emergency surgery due to their complex pathogenesis, risk of complications and high mortality. Objective. To establish the severity of hemostatic disorders in association with fibrinogen gene polymorphism (FGB (G(-455)A)) in patients with non-cancerous MF and cholangitis of varying severity. Material and methods. The subjects were 25 patients with benign MF and cholangitis divided into 2 groups: group 1 (n=12) – those with a mild form of the disease; group 2 (n=13) – those with a severe form. The research methods included the assessment of endogenous intoxication, liver function as well as blood coagulation activity. Genetic analysis of the FGB (G(-455) geneA)) was performed using a polymerase chain reaction by Real–time PCR. The severity of the disease was determined using the V.D. Fedorov scale (2000). Results. The early stage of MF and cholangitis is accompanied by endotoxicosis, resulting in the damage of a number of organs and systems, in particular the liver. The latter plays an important role in changing the activity of blood coagulation system. These disorders had a strong correlation with the severity of the disease: in mild cases, the character was less pronounced and reversible, and in severe cases – persistent and severe. Hemostatic disorders recorded in the early period of the disease depend on the severity: in mild cases, hypercoagulation and normofibrinolysis are noted, and in severe cases – hypocoagulation and hypofibrinolysis. Genetic polymorphism of the fibrinogen gene FGB (G(-455)A) had a significant impact on the pathogenetic process of MF and cholangitis. Patients with the mutant genotype (A/A) of the FGB gene were found to show the greatest severity of homeostasis system violation when compared with patients with genotypes G/G and G/A – with minimal imbalance. Conclusions. Hemostatic disorders associated with polymorphism of the fibrinogen gene FGB (G(-455)A) play an important role in the pathogenesis of MF and cholangitis.

Показники коагулограми у пацієнтів із постковідним синдромом

Coagulogram indicators were studied in patients with post-covid syndrome aged 24 to 80 years of both sexes, with different vaccination status against coronavirus infection. Determination of coagulogram parameters in patients with post-covid syndrome is an integral part of the examination of these patients. The coagulogram includes a number of indicators, such as blood clotting time, the level of fibrinogen, platelets and other factors that determine the blood coagulation system. It was determined that the indicators of the hemostasis system (APTT, PT, D-dimer, fibrinogen) exceed the permissible values, which indicates a significant impact of the post-covid syndrome on this system. An increase in these indicators may indicate the activation of the blood coagulation system, which may be associated with the risk of thrombosis or inflammatory processes. The levels of biological markers in vaccinated and unvaccinated patients vary in different ranges. However, D-dimer levels in vaccinated patients are slightly lower than in unvaccinated patients. This suggests that vaccination probably alleviates the course of the disease. The results of the study provide important information for diagnosing the state of hemostasis and determining the risk of thrombotic complications in patients with post-covid syndrome. Consideration of elevated levels of C-reactive protein and coagulogram indicators can serve as important markers for clinicians when making decisions about treatment and monitoring of patients.

Coagulation and fibrinolytic markers offer utility when distinguishing between benign and malignant gallbladder tumors: A cross-sectional study

BackgroundThe metabolic or proliferative abnormalities that are characteristic of tumor cells can lead to abnormal fibrinolysis or coagulation system activity, with certain tumors exhibiting hypercoagulability or existing in a fibrinolytic state. However, the utility of biomarkers of coagulation and fibrinolysis when seeking to differentiate between benign gallbladder disease and malignant gallbladder tumors remains uncertain. MethodsThis study included a total of 81 patients with benign gallbladder polyps and 94 patients with malignant gallbladder tumors. Pre-biopsy or pretreatment levels of PT, APTT, FIB, D-dimer, FDP, PLT, PIC, TAT, TM, and t-PAIC from these patients were compared using Mann-Whitney tests. The baseline data of the patients were analyzed using chi-square tests, and the diagnostic utility of these biomarkers in distinguishing between benign and malignant gallbladder lesions was evaluated using ROC curves, and Spearman correlation analysis was employed to assess the correlation between these indicators and tumor parameters. ResultsThe average age of malignant gallbladder tumor group was higher than benign gallbladder polyp group. And the base line analysis showed that there was a statistic difference in age, history of smoking, drinking, biliary tract disease, BMI of over weight between these two groups. In patients with malignant gallbladder tumors, FIB, D-dimer, FDP, PIC, TAT, TM, and t-PAIC levels were significantly elevated relative to those in patients affected by benign gallbladder polyp. The AUC for FIB, D-dimer, and FDP was 0.8469, 0.6514, 0.5950, while for PIC, TAT, TM, t-PAIC and four biomarker combined diagnosed was 0.8455, 0.6554, 0.7130, 0.6806, and 0.8859. Among these, TM was associated with the vascular invasion of tumor patients; TAT and t-PAIC were associated with neural invasion; D-dimer and FDP were related to the maximum tumor diameter; and FDP had a certain correlation with the tumor stage. ConclusionsIn gallbladder tumor patients, conventional coagulation metrics like FIB, D-dimer, and FDP, as well as newer thrombotic indicators such as PIC, TAT, TM, and t-PAIC, were obviously increased. Correlations with tumor parameters suggested their potential as biomarkers to distinguish benign from malignant gallbladder growths.

The effects of emicizumab on in vitro coagulation and fibrinolysis parameters in patients with disseminated intravascular coagulation with and without addition of anti-FVIII antibody.

Emicizumab (Emi) is used as haemostatic prophylaxis for patients with haemophilia A (PwHA). Disseminated intravascular coagulation (DIC) is a condition characterized by persistent systemic activation of coagulation, but there is yet no information on coagulation and fibrinolysis potentials in Emi-treated PwHA with DIC. To examine the effect of Emi on coagulation and fibrinolysis potentials in HA-model DIC plasmas. Plasma from a patient with sepsis-DIC (seven patients) was treated with anti-factor (F)VIII monoclonal antibody (HA-model DIC plasma) and incubated with Emi (50µg/mL). The plasma was then assessed using clot-fibrinolysis waveform analysis (CFWA). Coagulation and fibrinolysis parameters were expressed as ratios relative to normal plasma (|min1|-ratio and |FL-min1|-ratio, respectively). In case 1, coagulant potential was slightly high and fibrinolytic potential was extremely low, presenting a coagulant-dominant state (|min1|-ratio/|FL-min1|-ratio: 1.1/.38). In cases 2-5, fibrinolytic potential was not suppressed, but there were marked hypercoagulant potentials, indicating relative coagulant-dominant states. In case 6, coagulant and fibrinolytic potentials were increased but well balanced (|min1|-ratio/|FL-min1|-ratio: 1.38/1.28). In case 7, both potentials were severely deteriorated in not only CFWA but also the thrombin/plasmin generation assay. The addition of Emi into the HA-model DIC plasmas increased |min1|-ratio values in all cases, but the coagulant potentials did not exceed the initial ones (DIC plasma before treatment with anti-FVIII antibody). The presence of Emi in the HA-model DIC plasma improved coagulation potentials, but did not increase coagulation potentials beyond those of DIC plasma in non-HA states.

Role of microbiota-derived corisin in coagulation activation during SARS-CoV-2 infection

BackgroundCoagulopathy is a major cause of morbidity and mortality in COVID-19 patients. Hypercoagulability in COVID-19 results in deep vein thrombosis, thromboembolic complications, and diffuse intravascular coagulation. Microbiome dysbiosis influences the clinical course of COVID-19. However, the role of dysbiosis in COVID-19-associated coagulopathy is not fully understood. ObjectivesThe present study tested the hypothesis that the microbiota-derived proapoptotic corisin is involved in the coagulation system activation during SARS-CoV-2 infection. MethodsThis cross-sectional study included 47 consecutive patients who consulted for symptoms of COVID-19. A mouse acute lung injury model was used to recapitulate the clinical findings. A549 alveolar epithelial, THP-1, and human umbilical vein endothelial cells were used to evaluate procoagulant and anticoagulant activity of corisin. ResultsCOVID-19 patients showed significantly high circulating levels of corisin, thrombin-antithrombin complex, D-dimer, tumor necrosis factor-α, and monocyte-chemoattractant protein-1 with reduced levels of free protein S compared with healthy subjects. The levels of thrombin-antithrombin complex, D-dimer, and corisin were significantly correlated. A monoclonal anticorisin-neutralizing antibody significantly inhibited the inflammatory response and coagulation system activation in a SARS-CoV-2 spike protein-associated acute lung injury mouse model, and the levels of corisin and thrombin-antithrombin complex were significantly correlated. In an in vitro experiment, corisin increased the tissue factor activity and decreased the anticoagulant activity of thrombomodulin in epithelial, endothelial, and monocytic cells. ConclusionThe microbiota-derived corisin is significantly increased and correlated with activation of the coagulation system during SARS-CoV-2 infection, and corisin may directly increase the procoagulant activity in epithelial, endothelial, and monocytic cells.

Aggressive Vaccine-Induced Immune Thrombocytopenia and Thrombosis in a Young Woman with a Past Mild SARS-CoV-2 Infection

Vaccine- induced immune thrombocytopenia and thrombosis (VITT) is a rare adverse event occurring after immunization with adenoviral vector-based vaccines against SARS-CoV-2. This life-threatening condition is characterized by thrombocytopenia, systemic activation of coagulation, and anti-platelet factor 4 antibodies, often resulting in extensive venous thrombosis. Arterial thrombosis is less common and mainly affects the aorta, peripheral arteries, heart, and brain. Several cases of ischemic stroke have been reported in VITT patients, frequently being associated with large vessel occlusion (LVO). Here, we present a case of aggressive VITT in a 46-year-old woman with a past mild SARS-CoV-2 infection, who was admitted with a left-middle cerebral artery (MCA) territory stroke and thrombocytopenia eight days after her first dose of the ChAdOx1 nCoV-19 vaccine. The patient developed a diffuse arterial thrombosis with concomitant thrombotic events in the intrahepatic portal branches. The patient’s clinical condition worsened rapidly due to a significant enlargement of the ischemic cerebral lesion in the left hemisphere, cerebral herniation, and incipient hydrocephalus requiring decompressive neurosurgery with an unfavorable outcome. Our observations may be indicative of a stroke variant in VITT and highlight the diverse clinical manifestations of the syndrome.

The Inhibition of Serine Proteases by Serpins Is Augmented by Negatively Charged Heparin: A Concise Review of Some Clinically Relevant Interactions.

Serine proteases are members of a large family of hydrolytic enzymes in which a particular serine residue in the active site performs an essential role as a nucleophile, which is required for their proteolytic cleavage function. The array of functions performed by serine proteases is vast and includes, among others, the following: (i) the ability to fight infections; (ii) the activation of blood coagulation or blood clot lysis systems; (iii) the activation of digestive enzymes; and (iv) reproduction. Serine protease activity is highly regulated by multiple families of protease inhibitors, known collectively as the SERine Protease INhibitor (SERPIN). The serpins use a conformational change mechanism to inhibit proteases in an irreversible way. The unusual conformational change required for serpin function provides an elegant opportunity for allosteric regulation by the binding of cofactors, of which the most well-studied is heparin. The goal of this review is to discuss some of the clinically relevant serine protease-serpin interactions that may be enhanced by heparin or other negatively charged polysaccharides. The paired serine protease-serpin in the framework of heparin that we review includes the following: thrombin-antithrombin III, plasmin-anti-plasmin, C1 esterase/kallikrein-C1 esterase inhibitor, and furin/TMPRSS2 (serine protease Transmembrane Protease 2)-alpha-1-antitrypsin, with the latter in the context of COVID-19 and prostate cancer.

Cardiovascular Manifestations in Inflammatory Bowel Disease.

Inflammatory bowel disease is a group of long-term systemic inflammatory disorders affecting the gastrointestinal tract, including Crohn's disease and ulcerative colitis, which may be associated with an increased risk of developing extraintestinal manifestations, including cardiovascular disease, thereby decreasing the quality of life. Pathophysiological changes associated with inflammatory bowel disease include alterations of the microbiome, endotoxemia, and changes to glucose and lipid metabolism. Inflammatory bowel disease patients have higher carotid intima-media thickness, lower flow-mediated dilatation, and increased carotid-femoral pulse wave velocity, which are markers of elevated cardiovascular risk. In addition, inflammatory bowel disease patients are at an increased risk for developing venous and arterial thrombotic events due to a hypercoagulable state caused by thrombocytosis and coagulation system activation. To reduce the risk of developing cardiovascular disease, lifestyle modifications, such as smoking cessation, dietary changes, and increased physical activity alongside management with appropriate medication, should be considered. This research paper examines how inflammatory bowel disease can influence the risk of cardiovascular complications and the involvement of drug therapy. Methods: PubMed was searched using keywords, such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, cardiovascular disease, pericarditis, thromboembolism, and many more. Relevant literature up to March 2023 has been examined and summarized, which consisted of data from various clinical trials, meta-analyses, retrospective/prospective cohort studies, and current guidelines.

Clinical guidelines for disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is defined as systemic intravascular coagulation activity that has been acquired in the presence of various underlying diseases and is outside local or compensatory control, and is a fatal condition. Although the pathogenesis, diagnosis, and treatment of DIC are well known in Japan, each clinician has a different understanding of DIC, which makes it difficult to standardize diagnosis and treatment. Even at the international level, perception of DIC varies widely. This makes it difficult for residents and novice clinicians to standardize routine care for DIC. To meet the demands of the times, my colleagues and I are currently working on a globally unprecedented project to develop guidelines for the treatment of DIC for each underlying disease (tentative title). This article will also review the status of past guidelines from inside and outside Japan.

Damage-associated cellular markers in the clinical and pathogenic profile of vaccine-induced immune thrombotic thrombocytopenia

BackgroundAdenoviral vector-based COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) is rare but carries significant risks of mortality and long-term morbidity. The underlying pathophysiology of severe disease is still not fully understood. The objectives were to explore the pathophysiological profile and examine for clinically informative biomarkers in patients with severe VITT. MethodsTwenty-two hospitalized patients with VITT, 9 pre- and 21 post-ChAdOx1 vaccine controls, were recruited across England, United Kingdom. Admission blood samples were analyzed for cytokine profiles, cell death markers (lactate dehydrogenase and circulating histones), neutrophil extracellular traps, and coagulation parameters. Tissue specimens from deceased patients were analyzed. ResultsThere were strong immune responses characterized by significant elevations in proinflammatory cytokines and T helper 1 and 2 cell activation in patients with VITT. Markers of systemic endothelial activation and coagulation activation in both circulation and organ sections were also significantly elevated. About 70% (n = 15/22) of patients met the International Society for Thrombosis and Haemostasis criteria for disseminated intravascular coagulation despite negligible changes in the prothrombin time. The increased neutrophil extracellular trap formation, in conjunction with marked lymphopenia, elevated lactate dehydrogenase, and circulating histone levels, indicates systemic immune cell injury or death. Both lymphopenia and circulating histone levels independently predicted 28-day mortality in patients with VITT. ConclusionThe coupling of systemic cell damage and death with strong immune-inflammatory and coagulant responses are pathophysiologically dominant and clinically relevant in severe VITT.

Perioperative hemorheological status of oncological patients with primary knee replacement

Introduction. Endoprosthesis of large joints is associated with high risk of venous thromboembolism. Researchers focus on biochemical characteristics of homeostasis, blood clotting in particular, as the main reason for abnormal blood flow. At the same time, biophysical condition of homeostasis, namely decreased blood fluidity, is rarely considered. Study of rheological behavior of blood after primary oncological endoprosthesis of large joints in patients can potentially affect the selection of perioperative thromboprophylaxis and patient rehabilitation approach.Aim. To study the indicators of the hemorheological status of patients with tumours of long bones in the preand postoperative periods of primary oncological knee replacement.Materials and methods. The study included 36 patients (26 men and 10 women, mean age 46 years) without cardiovascular diseases and pathology of the veins of the lower limb admitted to the Russian Scientific Center of Roentgen Radiology for oncological endoprosthesis of the knee joint. All patients were prescribed: an antiplatelet agent (acetylsalicylic acid) and an anticoagulant (enoxaparin sodium 40 mg daily). Distal resection of the femur (on average 14 cm) was performed in 28 patients, and proximal resection of the tibia (on average 12 cm) in 8 patients, followed by knee replacement. Before the operation, on the 1st and 6th days after the operation, the hemorheological status and the state of the hemostasis system were evaluated in all patients. To determine the reference values, 24 healthy people were examined, comparable in gender and age. Statistical analysis using Statistica 10.0.Results. During the preoperative examination, integral assessment showed the differences in the severity of hemorheological disorders between patients, and two groups were identified: Group 1 – 21 (61 %) patients whose hemorheological disorders were classified as severity degree I, and Group 2 – 14 (39 %) patients with severity degree II d. On day 1 after the surgery, both patient groups showed negative dynamics: hemorheological disorders in group 1 worsened from grade I to II d., and in group 2 to III d. (critical) (p &lt;0.05). On day 6, the parameters did not change significantly in all patients. Similar dynamic changes were observed in the haemostasis system.Conclusion. Activation of the blood coagulation system and deterioration of hemorheology occurred after surgery during administration of anticoagulant and antiplatelet therapy. None of the patients had venous thromboembolic complications, however the risk of their development remained high. A differential model describing hemorheological status can be useful for selection of thromboprophylaxis and rehabilitation methods which include physical factors that improve the hemorheological profile: low-frequency magnetic and/or laser therapy in patients.

Association between Hereditary Angioedema and Venous Thromboembolism in a Large Population-Based Case-Control Study

Introduction: Hereditary Angioedema (HAE) is a rare congenital disorder primarily caused by mutations in the SERPING1 gene that results in C1 inhibitor (C1INH) deficiency or dysfunction. C1INH is a multifunctional serine protease inhibitor that functions as a major endogenous negative regulator of the kallikrein-kinin, contact pathway of coagulation and complement systems. HAE typically presents with episodes of unpredictable subcutaneous and submucosal swelling. However, HAE patients also have evidence of systemic activation of coagulation including elevated plasma prothrombin fragments, thrombin antithrombin complexes and D-dimers. Further, patients with HAE have recently been reported to have an increased risk of venous thromboembolism (VTE). Methods: To evaluate the risk of VTE in patients with HAE we conducted a large population-based case-control study leveraging data from the United Kingdom Clinical Practice Research Datalink (CPRD). The CPRD Aurum dataset used here maintains anonymized electronic medical records of over 40 million individuals from over 1600 primary care practices in the United Kingdom. SNOMED CT medical codes were used to identify a cohort of 2,198 patients diagnosed with HAE between 1992 and 2022 in the CPRD Aurum dataset with a matched (age, gender, family practice, and index date for HAE) cohort of 4,376 controls selected. VTE events including deep vein thrombosis (DVT) and pulmonary embolism in the HAE case and control cohorts were identified using SNOMED CT medical codes. The Cox proportional hazards model was used to determine hazard ratios (HR) for VTE events in HAE cases versus controls adjusting for covariates age, sex, body mass index, blood pressure, smoking status and a number of co-morbidities specifically; neoplasm, type 2 diabetes, ischemic heart disease, chronic obstructive pulmonary disease, chronic kidney disease, autoimmune disorders and depression. Results: A greater proportion of the HAE cases were female (62%) with a mean age at HAE diagnosis of 37 years. The median follow-up period for both cases and controls was 17 years (interquartile range (IQR):8-28 years). The overall incidence of VTE in HAE cases was 1.1/1000 patient years versus 0.6/1000 patient years in the control cohort. In unadjusted analyses HAE was associated with a significantly increased risk of VTE (HR 1.70, 95% CI 1.37-2.22, P&amp;lt;0.0001). Importantly, in adjusted analyses HAE remained significantly associated with an increased risk of VTE (HR 1.44, 95% CI 1.12-1.83, P=0.004, Figure 1). Of note, this association is similar in magnitude to that previously reported for heterozygous carriers of FV Leiden, the prothrombin gene mutation and high confidence loss of function mutations in Protein C and Protein S in comparable population-based case-control studies. In adjusted sub-analyses HAE was associated with a significantly increased risk of DVT (HR: 1.42, 95% CI 1.09-1.87, P=0.01) with a trend towards an increased risk of PE (HR 1.37, 95% CI 0.84-2.27, P=0.2). Conclusions: The results of this population-based case-control study, roughly an order of magnitude larger in size than prior reports, demonstrate that HAE is associated with a significantly increased risk of VTE similar to that reported for common hereditary thrombophilias. These findings reinforce the important role of endogenous C1INH as a negative regulator of prothrombotic processes involved in VTE in the setting of HAE.