Hemostatic Factors Research Articles

Thrombotic Disorders in the Newborn.

The coagulation and thrombotic systems of an infant are fundamentally different from those of adults and older children. Hemostatic factors have inherently lower circulation levels in infants and are also affected prenatally by conditions of pregnancy. The unique physiology of neonates can contribute to a procoagulant state, which can result in a high level of morbidity and mortality. This review outlines the epidemiology, clinical characteristics, diagnosis and management, and etiologies of congenital and acquired forms of thrombotic disorders, with a discussion of the evaluation for hypercoagulation.

Disorders of Coagulation in the Newborn.

The coagulation system in newborns varies from that of children and adults, with many circulating hemostatic factors being lower in the newborn. Infants are also susceptible to diseases and conditions in the pregnant person affecting their coagulation system, which can make it difficult to rapidly identify the cause behind coagulopathy in a neonate. Coagulation disorders can result in high levels of infant morbidity and mortality, which makes early diagnosis and prompt treatment critical. This review outlines the clinical characteristics, diagnosis and management, epidemiology, and etiologies of both common and uncommon congenital and acquired forms of neonatal coagulopathy.

Markers of coagulation and early coronary stent thrombosis

Abstract Background Acute stent thrombosis is a rare but deleterious event after percutaneous coronary intervention (PCI). Hemostatic factors such as D-Dimer, fibrinogen, and platelet count have emerged as potential indicators of increased thrombotic risk. However, data regarding the association with early stent thrombosis (ST) is sparse. Purpose The aim of this study was to investigate whether markers of coagulation are associated with increased risk of early (< 30 days after PCI) ST. Methods Within a prospective single-center registry, we retrospectively analyzed the association between pre-procedural platelet count, plasma levels of fibrinogen and D-Dimer with the occurrence of early ST within 30 days after PCI. Results We included 10,714 consecutive patients who underwent percutaneous coronary intervention (PCI) with implantation of drug-eluting stents (DES). Pre-procedural measurements of platelet count, fibrinogen and D-Dimer was available in 6,337, 6,155 and 956 patients, respectively. The number of definite early ST within 30 days was 58 (0.92 %). Pre-procedural platelet count (p<0.05) and plasma levels of fibrinogen (p<0.05) were significantly higher in patients with early ST as compared to patients without ST. Whereas D-Dimer was not associated with early ST, patients in the fifth quintile of platelet count had a significant increased risk for early ST (HR 2.43; 95% CI 1.43 - 4.14; p=0.001) as compared to patients in the lower four quintiles and patients in the fifth quintile of fibrinogen had a significant increased risk for early ST (HR 1.86; 95% CI 1.07 – 3.26; p<0.05) as compared to patients in the lower four quintiles. These associations were independent of clinical risk factors, the presence of acute coronary syndromes and the number of stents. Conclusions Pre-procedural platelet count and plasma levels of fibrinogen are associated with the risk of early ST in patients after implantation of DES. Device-level risk factors like stent-type or size and procedure-level risk factors like peri-interventional medication and complications during stent apposition are associated with ST. Platelet count and plasma levels of fibrinogen may be additional patient-level risk factors that have to be taken in account in the development of future personalized strategies to prevent these rare but deleterious complications.

12509 Identification Of Novel Exercise Training-induced Circulating Proteins: Hemostatic, Apoptotic, And Key Neuronal Factors

Abstract Disclosure: A. Shalit: None. M. Vamvini: None. P. Nigro: None. L.K. Simpson: None. H. Pan: None. J.M. Dreyfuss: None. L.J. Goodyear: Grant Recipient; Self; Daiichi Sankyo. R.J. Middelbeek: None. Exercise training induces a plethora of health benefits including improved glucose homeostasis, decreased cardiovascular disease, and improved cognitive function. An emerging concept is that many of these beneficial effects of exercise are mediated through the secretion of humoral factors into the blood. Identification of these exercise-regulated factors hold promise for novel treatments for disease. Here, we performed proteomic analysis to discover novel circulating factors in response to endurance exercise training in human participants. Given that nutritional status can affect the circulating proteome, another aim was to determine if proteomic adaptations to exercise training have similar effects under both fasted and random-fed conditions. Sedentary normoglycemic participants (3M/5F, age 22-41y) performed a supervised 10-week exercise training program, which by week 4 was 4x60 min exercise at 65-70% V̇O2peak. Fasted and random-sampling morning blood draws were collected pre-training and between 24-72 hours following the final training session. Proteomic detection was by SOMAscan. Exercise training significantly improved V̇O2peak by 17% (p=0.003). Out of 1,310 detected proteins, exercise training significantly changed 293 proteins in the fasted state and 360 proteins in the random-sampling state (p<0.05). Integration showed that 172 proteins were changed under both nutritional conditions (123 upregulated and 49 downregulated). Gene Set Enrichment Analysis (GSEA) of the commonly upregulated proteins showed that training resulted in enrichment in neuronal, hemostatic, and apoptotic pathways, whereas the downregulated proteins were enriched in neuronal and extracellular matrix processes. Since neuronal pathways were identified in both up and downregulated proteins, we focused our analysis there, identifying 31 upregulated and 4 downregulated neuronally-associated proteins. Importantly, exercise training reduced levels of CDK5, a protein that is hyperactivated in neurodegeneration and Alzheimer's disease. Moreover, GSTP1, a direct inhibitor of CDK5, along with downstream proteins inhibited by CDK5 (RAC1, STUB1, 14-3-3ε/YWHAE, HSP90AA1, CFL1), were significantly increased following exercise training.In conclusion, exercise training regulates circulating factors involved in neuronal, hemostatic, apoptotic, and extracellular matrix pathways, with these effects being independent of nutritional status. Our finding of exercise training-induced decreases in multiple proteins of the CDK5 pathway, a pathway whose downregulation is associated with neuroprotection, identify CDK5 as a novel and potentially important mediator of the beneficial effects of exercise training on cognitive function. Presentation: 6/1/2024

Gelsolin controls the release of phosphatidylserine (PS)-positive microvesicles (MVs) from platelets

Upon activation by vascular injury or extracellular agonists, platelets undergo rapid change shape, a process regulated by the actin cytoskeleton and accessory proteins. Platelet shape change is accompanied by the secretion of hemostatic factors and immunomodulatory cytokines from their intracellular granules, as well as the release of microvesicles (MVs) containing pro-inflammatory cytokines and procoagulant phosphatidylserine (PS). However, the role of actin dynamics in MV generation remains unclear. In this study, we found that blocking actin polymerization with cytochalasin D attenuated the release of PS-positive MVs in human platelets stimulated by thrombin or the calcium ionophore A23187. The actin-severing protein gelsolin (Gsn) facilitates normal actin filament turnover in activated platelets. Platelets from Gsn-deficient (Gsn−/−) mice showed reduced MV release compared to platelets from control mice. These findings indicate that the proper dynamics of the actin cytoskeleton are essential for MV generation in platelets, which has implications for their pro-inflammatory and procoagulant functions.

RalB uncoupled exocyst mediates endothelial Weibel-Palade body exocytosis.

Ras-like (Ral) GTPases play essential regulatory roles in many cellular processes, including exocytosis. Cycling between GDP- and GTP-bound states, Ral GTPases function as molecular switches and regulate effectors, specifically the multi-subunit tethering complex exocyst. Here, we show that Ral isoform RalB controls regulated exocytosis of Weibel-Palade bodies (WPBs), the specialized endothelial secretory granules that store hemostatic protein von Willebrand factor. Remarkably, unlike typical small GTPase-effector interactions, RalB binds exocyst in its GDP-bound state in resting endothelium. Upon endothelial cell stimulation, exocyst is uncoupled from RalB-GTP resulting in WPB tethering and exocytosis. Furthermore, we report that PKC-dependent phosphorylation of the C-terminal hypervariable region (HVR) of RalB modulates its dynamic interaction with exocyst in endothelium. Exocyst preferentially interacts with phosphorylated RalB in resting endothelium. Dephosphorylation of RalB either by endothelial cell stimulation, or PKC inhibition, or expression of nonphosphorylatable mutant at a specific serine residue of RalB HVR, disengages exocyst and augments WPB exocytosis, resembling RalB exocyst-binding site mutant. In summary, it is the uncoupling of exocyst from RalB that mediates endothelial Weibel-Palade body exocytosis. Our data shows that Ral function may be more dynamically regulated by phosphorylation and may confer distinct functionality given high degree of homology and the shared set of effector protein between the two Ral isoforms.

Stress-Induced Hypercoagulability: Insights from Epidemiological and Mechanistic Studies, and Clinical Integration.

By integrating findings from comprehensive reviews, meta-analyses, and cutting-edge genetic studies, this article illuminates the significance of stress-induced hypercoagulability in clinical medicine. In particular, the findings from numerous prospective cohort studies indicate that stress and hemostatic factors of a hypercoagulable state are associated with increased incident risk and poor prognosis for atherosclerotic cardiovascular disease and venous thromboembolism. Mendelian randomization studies suggest that these associations are partially causal. The review synthesizes extensive research on the link between acute and chronic stress and hypercoagulability, outlining a potential pathway from stress to thrombosis risk. Consistent with the allostatic load concept, acute stress-induced hypercoagulability, initially adaptive, can turn maladaptive under chronic stress or excessive acute stress, leading to arterial or venous thrombotic events. Individuals with predisposing factors, including atherosclerosis, thrombophilia, or immobilization, may exhibit an increased risk of thrombotic disease during stress. Contextual sociodemographic characteristics, the stress experience, and coping resources additionally modulate the extent of stress-induced hypercoagulability. Research into the neuroendocrine, cellular, and molecular bases reveals how stress influences platelet activation coagulation and fibrinolysis. The activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, along with vagal withdrawal, and the effects of catecholamines, cortisol, and vasopressin, are the central mechanisms involved. Hemoconcentration, inflammation, endothelial dysfunction, and thrombopoiesis additionally contribute to stress-induced hypercoagulability. Further research is needed to prove a causal link between chronic stress and hypercoagulability. This includes exploring its implications for the prevention and management of thrombotic diseases in stressed individuals, with a focus on developing effective psychosocial and pharmacological interventions.

Characteristics of fibrin/fibrinogen degradation products in multiple sclerosis following SARS-CoV-2 infection

Background. The purpose of this study was to investigate plasma levels of fibrinogen and products of its degradation in patients with multiple sclerosis (MS) with and without a history of coronavirus disease 2019 (COVID-19). Materials and methods. We examined 97 patients with MS. Based on the presence of COVID-19, all cases were divided into two groups. MS group included 56 patients who did not suffer from COVID-19 previously. MS + COVID group consisted of 41 cases who had a laboratory-verified diagnosis of COVID-19. The group of healthy controls included 30 healthy volunteers. Spectrophotometric techniques were used to measure the concentrations of fibrinogen, D-dimer, and soluble fibrin monomer complexes (SFMCs). Size-exclusion chromatography was applied to analyze the composition of SFMC fractions. Results. We found that concentrations of fibrinogen, D-dimer, and SFMCs were remarkably increased in plasma of all MS patients compared with healthy controls. The levels of D-dimer, and SFMCs did not differ between two MS groups, while plasma fibrinogen concentration was significantly increased in MS + COVID patients compared to MS group. Moreover, the development of MS was accompanied by the changes in both quantity and quality of SFMC composition compared to that of healthy controls. Our results demonstrated accumulation of high-molecular-weight SFMCs in plasma of MS patients. Conclusions. The findings indicated that MS patients had changed hemostasis characteristics; however, more research is required to determine the connection between particular hemostatic factors, namely fibrinogen, D-dimer, and SFMCs, and the pathophysiology of MS.

Surgical Treatment of Coronary Heart Disease Against the Background of Coagulopathy of Unknown Etiology. Case Report

Coronary heart disease (CHD) is one of the most common cardiovascular diseases and one of the leading causes of death in the world. Diet is the first step in the prevention of CHD. Vegetarians have significantly lower risk of death from CHD, but also have changes in the hemostasis system due to a deficiency of blood clotting factors. Cardiosurgical intervention for patients with hemostatic disorders should be performed in specialized centers with the necessary support.
 Case description. A 73-year-old patient G. was hospitalized to the National Amosov Institute of Cardiovascular Surgery with angina pectoris, weakness and edema. From the past medical history it is known that the patient has been following a diet with complete exclusion of meat and dairy products for 20 years, rarely eats fish; in addition, he smoked for 20 years at a young age. After coronary angiography, the patient developed bleeding from the oral cavity of unknown origin, which resolved on its own. According to the examination, the patient was found to have a multivessel lesion of the coronary arteries, and cardiosurgical intervention was indicated: coronary bypass surgery. At a case conference with cardiovascular surgeons, anesthesiologist and cardiologist, a decision was made to perform salvage cardiac surgery. The predicted mortality risk was 7.0% by the EuroSCORE II. The early postoperative period was complicated by bleeding with subsequent revision of the pericardium to identify the source of bleeding. Coagulopathy of unknown origin was suspected. Replacement hemostatic therapy was started, which included massive blood transfusions. The pace and level of exudation significantly decreased, the operation was completed. After surgical interventions and hemotransfusions, thromboelastography was performed and plasma hypercoagulation was detected. The patient was discharged for continued cardiopulmonary rehabilitation, and outpatient treatment was prescribed.
 Conclusions. This case report describes successful treatment of multivessel coronary artery disease by bypass grafting in a vegetarian patient with a coagulation disorder. Studies of the effects of a vegetarian diet on the hemostatic system indicate that vegetarians may have lower concentrations of hemostatic factors and that thrombin time is also prolonged due to the nutritional guidance provided by this diet. In addition, timely detection of a deficiency of blood coagulation factors in the plasma of a patient with such history can facilitate the diagnosis of the hemostasis system.

The Influence of Hyperthyroidism on the Coagulation and on the Risk of Thrombosis.

Introduction: Apart from the well-known fact that hyperthyroidism induces multiple prothrombotic disorders, there is no consensus in clinical practice as to the impact of hyperthyroidism on the risk of thrombosis. The aim of this study was to examine the various hemostatic and immunologic parameters in patients with hyperthyroidism. Methods: Our study consists of a total of 200 patients comprised of 64 hyperthyroid patients, 68 hypothyroid patients, and 68 euthyroid controls. Patient thyroid status was determined with standard tests. Detailed hemostatic parameters and cardiolipin antibodies of each patient were determined. Results: The values of factor VIII (FVIII), the Von Willebrand factor (vWF), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and anticardiolipin antibodies of the IgM class were significantly higher in the hyperthyroid patients than in the hypothyroid patients and euthyroid controls. The rate of thromboembolic manifestations was much higher in hyperthyroid patients (6.25%) than in hypo-thyroid patients (2.9%) and euthyroid controls (1.4%). Among hyperthyroid patients with an FVIII value of ≥1.50 U/mL, thrombosis was recorded in 8.3%, while in hyperthyroid patients with FVIII value ≤ 1.50 U/mL the occurrence of thrombosis was not recorded. The incidence of atrial fibrillation (AF) was significantly higher (8.3%) in the hyperthyroid patients compared to the hypothyroid patients (1.5%) and euthyroid controls (0%). Conclusions: High levels of FVIII, vWF, fibrinogen, PAI-1, and anticardiolipin antibodies along with other hemostatic factors contribute to the presence of a hypercoaguable state in patients with hyperthyroidism. The risk of occurrence of thrombotic complications is especially pronounced in patients with a level of FVIII exceeding 150% and positive anticardiolipin antibodies of the IgM class. Patients with AF are at particularly high risk of thrombotic complications due to a hyperthyroid prothrombotic milieu.

Is the Habitual Dietary Intake of Foods of Plant or Animal Origin Associated with Circulating Hemostatic Factors?-Results of the Population-Based KORA-Fit Study.

Blood coagulation is a complex physiological process critical for maintaining hemostasis, and disruptions in this system can lead to various health complications. Since the effects of specific food groups on a series of circulating coagulation parameters in the population are not well established, this study examines such associations in the population-based KORA-Fit study. A total of 595 subjects (263 men and 332 women) born between 1945 and 1964 and living in the study region of Augsburg were included in the study. Habitual food intake was estimated based on a combination of repeated 24-h food lists (24HFLs) and a food frequency questionnaire (FFQ). Antithrombin III, D-dimers, factor VIII, fibrinogen, protein C, protein S, aPTT, Quick value and INR were measured in citrate plasma. Multivariable linear regression models were applied to investigate associations between the consumption of specific foods of plant or animal origin and hemostatic factors. We found that the consumption of plant-based food groups, including green leafy vegetables (rich in vitamin K1), were hardly associated with coagulation parameters. Surprisingly, a high consumption of dairy products and especially butter were associated with higher D-dimer concentrations. These findings need further evaluation in prospective studies.

Thomas Wilson Meade. 21 January 1936—24 October 2022

Tom Meade made outstanding contributions to our understanding of the role of the haemostatic (clotting) system in the causation of cardiovascular disease by combining epidemiological approaches with rigorous standardization of laboratory methods. As director of the MRC Epidemiology and Medical Care Unit (EMCU) at Northwick Park Hospital he led major prospective studies to investigate the relationship between a range of haemostatic factors and cardiovascular disease outcomes. He also led several major randomized trials of interventions to reduce cardiovascular risk, notably the Thrombosis Prevention Trial. The EMCU also undertook several landmark studies on common and often neglected conditions to improve knowledge of the burden of ill health (for example from incontinence) and effective interventions, including for low back pain and stroke rehabilitation. In his later career he also set up and led a series of large case–control studies among myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism cases, together with their matched controls using a primary care database, showing elevated risks of both arterial and venous thrombosis following respiratory infections. He had many major scientific leadership roles, including playing a significant role in guiding the UK Biobank at its inception and chairing the steering committee of the Heart Protection Study Collaborative Group.

РОЛЬ ГЕНЕТИЧЕСКИХ ПОЛИМОРФИЗМОВ ФАКТОРОВ ГЕМОСТАЗА В ПАТОГЕНЕЗЕ И ПРОГНОЗЕ СЕПСИСА (ОБЗОР)

Sepsis is a typical form of pathology, which is based on the body's reaction in the form of generalized inflammation to an infection of various nature, leading to acute multiple organ dysfunction. In sepsis, endothelial dysfunction, platelet adhesion and aggregation, hypercoagulation, hypocoagulation occur, microthrombogenesis, disturbances in the anticoagulant and fibrinolytic systems increase. Only a few studies have assessed the relationship of single nucleotide polymorphisms (SNPs) of hemostatic factors in the prognosis of sepsis: VWF, EPCR, SELP, SELE, ITGA2, ITGA2b, ITGB3, GP1BA, FGG, FGA, FII, FV, FVII, THBD, PAI-1. The disparity of the SNP results highlights the need for larger-scale studies within the framework of a personalized approach to complement the theoretical basis of the pathogenesis of sepsis, as well as to obtain new laboratory tools to improve prognostic scales, the formation of a mathematical model depending on the outcome of sepsis.

Role of factor XIII in ischemic stroke: a key molecule promoting thrombus stabilization and resistance to lysis

BackgroundActive coagulation factor XIII (FXIII) catalyzing crosslinking of fibrin and other hemostatic factors plays a key role in clot stability and lysis. ObjectivesTo evaluate the effect of FXIII inhibition in a mouse model of ischemic stroke (IS) and the role of activated FXIII (FXIIIa) in clot formation and lysis in patients with IS. MethodsA ferric chloride IS murine model was performed before and after administration of a FXIIIa inhibitor (FXIIIinh). Thromboelastometry in human and mice blood was used to evaluate thrombus stiffness and lysis with FXIIIinh. FXIIIa-dependent fibrin crosslinking and lysis with fibrinolytic drugs (tissue plasminogen activator and tenecteplase) were studied on fibrin plates and on thrombi and clotted plasma of patients with IS. Finally, circulating and thrombus FXIIIa were measured in 85 patients with IS. ResultsFXIIIinh administration before stroke induction reduced infarct size, α2-antiplasmin (α2AP) crosslinking, and local microthrombosis, improving motor coordination and fibrinolysis without intracranial bleeds (24 hours). Interestingly, FXIII blockade after stroke also reduced brain damage and neurologic deficit. Thromboelastometry in human/mice blood with FXIIIinh showed delayed clot formation, reduced clot firmness, and shortened tissue plasminogen activator lysis time. FXIIIa fibrin crosslinking increased fibrin density and lysis resistance, which increased further after α2AP addition. FXIIIinh enhanced ex vivo lysis in stroke thrombi and fibrin plates. In patients with IS, thrombus FXIII and α2AP were associated with inflammatory and hemostatic components, and plasma FXIIIa correlated with thrombus α2AP and fibrin. ConclusionOur results suggest a key role of FXIIIa in thrombus stabilization, α2AP crosslinking, and lysis resistance, with a protective effect of FXIIIinh in an IS experimental model.

Glucagon-Like Peptide-1 (GLP-1) during Ramadan: Narrative Review of the Published Literature.

Ramadan fasting, a religious practice observed by Muslims worldwide, involves abstaining from eating, drinking, smoking, and using oral medications from dawn to dusk during the ninth lunar month. Studies have demonstrated that fasting during Ramadan has been shown to increase HDL cholesterol, leptin, adiponectin, and insulin sensitivity, as well as lower several hemostatic risk factors for cardiovascular diseases. Additionally, it may result in a drop in blood sugar levels, especially in diabetics who are also on blood sugar-lowering medicine. Hypoglycemia, characterized by low blood sugar levels, could also result from fasting during Ramadan. The GLP-1 (glucagon-like peptide-1) hormone plays a significant role in regulating glucose metabolism and insulin secretion, and Ramadan fasting can affect its production and release in the gut. Research contributes to our understanding of the utilization of GL-1 medications during Ramadan among patients, broadening therapy alternatives and offering insightful information for well-informed decision-making. Therefore, this narrative review aims to explore the current evidence that studies the safety and efficacy of GLP-1 agonists during Ramadan for nondiabetic and diabetic patients to ensure healthy fasting during Ramadan.

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

BackgroundThrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient’s prognosis. ObjectivesTo investigate the association between genetically determined natural hemostatic factors’ levels and increased risk of HT after r-tPA treatment. MethodsUsing data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. ResultsLocal correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10−11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10−10; rs1421067 (CHD9), P = 1.81 × 10−14; and rs34780449, near ROBO1 gene, P = 1.64 × 10−8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10−14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [−0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05). ConclusionWe identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.

A stochastic multicompartment model of hemostasis and oxygenation during trauma resuscitation as a platform for in silico trials of transfusion

Abstract Uncontrolled hemorrhage accounts for up to 40% of trauma related mortality, and approximately 30% of trauma related deaths occur in the hospital within the first 1-4 hours of injury. The Advanced Trauma Life Support (ATLS) guidelines still recommend initial resuscitation with crystalloid fluid as an integral part of maintaining or restoring hemodynamic stability, but are starting to recognize the role of early resuscitation with blood products in patients with evidence of Class III and IV hemorrhage, in line with recent clinical trial and observational data. Although there is a growing body of evidence that early transfusion with blood products may be associated with improved survival compared with crystalloid infusion, the optimal transfusion strategy still remains unclear and is being actively investigated in clinical trials. In silico models of resuscitation offer a means to evaluate the effectiveness and safety of resuscitation protocols, including effects on body fluid compartment volumes, tissue oxygenation, and hemostatic factors. Here we describe our work extending earlier deterministic models of trauma resuscitation to incorporate hemodynamic, hemostatic, resuscitation, biomarker, and tissue-oxygenation domains into a single comprehensive model. Additionally, this model expands upon previous deterministic models to create a stochastic computational model of hemostatic resuscitation that accounts for variations in blood component composition and temporal features of transfusion therapy. Using this stochastic model, an in silico trial was piloted to compare conventional component therapy, i.e. red cell, platelet and plasma components, to cold-stored whole blood using the following starting assumptions: patient weight of 81.3±21.8 kg, hematocrit of 41.8±4.3%, initial bleeding rate between 50 and 150 mL/min, systolic blood pressure of 125±18 mmHg, fibrinogen of 293±88 mg/dL, international normalized ratio of 1.0±0.1 and platelet count of 239±62x109/L, with blood component and whole blood constituent distributions based on laboratory quality control data. This in silico trial demonstrated that resuscitation with whole blood was associated with a 28-minute reduction in the time spent in the critical window defined by platelet count <50x109/L, INR≥2, hemoglobin <9 g/dL and fibrinogen <150 mg/dL compared with conventional component resuscitation over the course of a 4 hour simulation (p<0.001 based on median regression). We demonstrate how stochastic models of hemostatic resuscitation can be used to perform in silico trials of resuscitation strategies. Our work can guide inclusion and exclusion criteria for future clinical trials and facilitate identification of patient subgroups most likely to benefit from certain resuscitation strategies. This work was partially funded by the AABB Foundation (formerly the National Blood Foundation).

OC 03.3 Effect of Intravenous tPA Treatment on Hemostatic Factors in Relationto Outcome in Acute Ischemic Stroke Patients Undergoing Thrombectomy

OC 03.3 Effect of Intravenous tPA Treatment on Hemostatic Factors in Relationto Outcome in Acute Ischemic Stroke Patients Undergoing Thrombectomy

Midlife Hemostasis Measures, 20-Year Cognitive Decline, and Incident Dementia.

Blood concentrations of hemostatic factors affect thrombosis and bleeding diathesis and may contribute to cognitive impairment through modifiable vascular pathologies. Whether hemostasis, assessed in middle age, is associated with late-life cognitive impairment remains largely unknown in a community-dwelling population. Using data from 14,128 participants with cognitive function measurements in 1990-1992 from the Atherosclerosis Risk in Communities study, we assessed the associations of hemostasis measures with 20-year changes in cognitive performance and incident dementia. Activated partial thromboplastin time (aPTT) and level of fibrinogen, von Willebrand factor (VWF), factor VIII, factor VII, factor XI, d-dimer, and soluble thrombomodulin were measured in 1987-1989 or 1993-1995. Hemostasis measures were categorized into quintiles, with the lowest quintile indicating low coagulability. Cognitive performance was characterized using a combined z-score from 3 tests (that is, delayed word recall test [DWRT], digit symbol substitution [DSST], and word fluency test [WFT]), assessed in 1990-1992, 1996-1998, and 2011-2013. Dementia was determined either from in-person evaluations or using dementia surveillance through 2017. Mixed-effects models and Cox proportional hazards models were used to assess cognitive trajectories and risk of dementia, respectively. Among 12,765 participants with hemostasis measures in 1987-1989, who were aged 47-70 years at the first cognitive assessment, we observed significant trends of shorter aPTT (p for trend <0.001; difference in 20-year cognitive decline for fifth vs first quintile [Q5 vs Q1]: -0.104 [95% CI -0.160 to -0.048]) and higher levels of factor VII (p < 0.002; Q5 vs Q1: -0.085 [-0.142, -0.028]) and factor VIII (p = 0.033; Q4 vs Q1: -0.055 [-0.111, -0.000]) with greater 20-year cognitive declines. The associations with the decline in DSST were stronger than those with the decline in WFT or DWRT. Consistently, shorter aPTT and higher factor VIII levels were associated with higher dementia risk with HRs for Q5 vs Q1 of 1.23 (95% CI 1.07 to 1.42) and 1.17 (1.01-1.36), respectively, and p for trend of 0.008 and 0.024, respectively. Overall, our study found consistent trend associations of aPTT and factor VIII measured in midlife with cognitive decline and incident dementia over 20 years, likely driven by vascular pathologies.

Cow haemostasis and resistance of calves under hypoxia conditions

Intensification of the livestock industry is impossible without effective animal reproduction. The solution to this problem is possible only if a viable offspring is obtained, and their body resistance and safety are increased, which determines the research relevance. In this regard, determining the influence of the haemostasis system and blood properties of cows on the growth and development of the foetus, and subsequently on the resistance of newborn calves, depending on the condition at birth, determined the research aim. The conditions of foetal growth and development were found to be related to the activity of haemostatic factors and blood properties of cows. Hemocoagulation factors were active in animals that gave birth to calves in a state of hypoxia. The prothrombin time was 1.63, 1.40, 1.23 and 1.40 times lower, and the prothrombin haemostasis index was 1.53, 1.52, 1.35 and 1.46 times lower, respectively than in cows that gave birth to functionally active calves (p&lt;0.01). The thrombin time of haemostasis, partially activated thrombin time and fibrinogen content in cows of the experimental groups were higher than in animals of the control group. The blood viscosity of cows in the control group was lower (p&lt;0.01), and the blood coagulation of cows in the experimental groups was faster (p&lt;0.05). The increase in coagulation properties of the blood of cows that gave birth to calves in a state of hypoxia occurred against the background of a decrease in the activity of the fibrinolytic system (p&lt;0.05) and retraction of the blood clot. All this reduced the growth and development of the embryo and foetus. The placental ligamentous connection of foetuses born with signs of hypoxia was significantly greater than that of functionally active calves. The intensity and size of embryo growth were higher in the group of functionally active calves (p&lt;0.05). The activity of leukocyte defence factors, and, accordingly, the resistance of the organism of functionally active calves at birth was higher. The percentage of activated leukocytes in the blood of calves was practically the same, and the microbial count was higher in calves of the control group (p&lt;0.05). The results obtained in the course of the research can be implemented in the process of obtaining and rearing calves, and offered to all livestock farms in Ukraine