Plasma Coagulation Research Articles

Persistent and severe hypotension during radical transabdominal ovarian cancer surgery: A case report.

In radical surgery for ovarian cancer (OC), hypotension that is difficult to correct is usually rare unless there is significant blood loss. We recently encountered a patient who developed persistent and severe hypotension during radical transabdominal OC surgery. A patient was 52 years old with a history of hypertension and well-controlled preoperative blood pressure (BP). A total of 2000 mL of ascites was drained and blood loss was 300 mL when the operation proceeded to 5.5 hours. The patient's cardiopulmonary function and blood gas analysis showed no significant abnormalities. persistent and uncorrectable hypotension. There was no significant edema in the patient's head or face, nor did the surgeon observe noticeable edema in her intestinal walls or other organs. No oozing was seen at the surgical site. Fluid resuscitation and vasopressor administration were continued. As BP control further deteriorated, blood counts, coagulation, and biochemical electrolyte analyses revealed severe hypoalbuminemia (13.5 g/L) and coagulation dysfunction. After intravenous human serum albumin (HSA) and fresh frozen plasma therapy, her hypoalbuminemia and coagulation were gradually corrected. Based on this case, we suggest that in OC patients experiencing mild intraoperative bleeding and minimal heart rate variation but persistent refractory hypotension, hypoalbuminemia should be considered even if preoperative biochemical tests (including serum albumin levels) are normal. Confirming hypoalbuminemia warrants HSA administration to alleviate hypovolemic shock symptoms. Additionally, it is important to be cautious of potential coagulation issues with albumin use, possibly requiring plasma infusion to address coagulopathy.

Treatment of a staple-line leak after laparoscopic sleeve gastrectomy using an esophagoduodenal Niti-S Mega-stent.

A 56-year-old female with class 3 obesity, was previously submitted to laparoscopic sleeve gastrectomy (LSG) two weeks before current admission. The patient was admitted due to fever, abdominal pain and vomiting. CT revealed a 13.5cm collection between the gastric wall and left hepatic lobe. Piperacillin-Tazobactam was initiated, and percutaneous drainage of the purulent collection was performed. The upper endoscopy showed pus in the gastric lumen and a 10-mm leak at the esophago-gastric junction with contrast extravasation. Argon plasma coagulation (40W, 2L/min) was applied at the orifice margins to promote healing. After 0,038'' guidewire placement through the proximal jejunum, a Niti-S™-MEGA™ (Mega-Stent) 28x230mm (Taewoong Medical™) was deployed under fluoroscopic control. CT at 72h showed absence of leakage. Oral nutrition was started uneventfully. Ambulatory endoscopy was scheduled for eight weeks later to remove the stent, which was easily accomplished with a foreign body forceps. Granulation tissue was observed in the previous leak location and no extraluminal contrast was observed at fluoroscopic evaluation, confirming complete healing and successful endoscopic treatment. Three weeks after stent removal, the patient presented with dysphagia. Upper endoscopy revealed a short and narrowed lumen stenosis at 28cm from the incisives, which was easily manage through TTS balloon dilation. No additional complications were observed.

Complex Thrombo-Inflammatory Responses versus Outcomes of Non-COVID-19 Community-Acquired Pneumonia and COVID-19

Introduction: The thrombo-inflammatory response and outcomes of community-acquired pneumonia (CAP) due to various organisms (non-COVID-19 CAP) versus CAP due to a single virus, SARS-CoV-2 (i.e., COVID-19) may differ. Methods: Adults hospitalized with non-COVID-19 CAP (December 1, 2021–June 15, 2023) or COVID-19 (March 2, 2020–June 15, 2023) in Canada. We compared non-COVID-19 CAP and COVID-19 baseline, thrombo-inflammatory response, and mortality. We measured plasma cytokine and coagulation factor levels in a sample of patients, did hierarchical clustering, and compared cytokine and coagulation factor levels. Results: In 2,485 patients (non-COVID-19 CAP, n = 719; COVID-19 patients, n = 2,157), non-COVID-19 CAP patients had significantly lower 28-day mortality (CAP vs. COVID-19 waves 1 and 2; 10% vs. 18% and 16%, respectively), intensive care unit admission (CAP vs. all waves; 15% vs. 39%, 37%, 33%, and 24%, respectively), invasive ventilation (CAP vs. waves 1, 2, and 3 patients; 11% vs. 25%, 20%, and 16%), vasopressor use (CAP 12% vs. 23%, 21%, and 18%), and renal replacement therapy use (CAP 3% vs. Omicron 7%). Complexity of hierarchical clustering aligned directly with mortality: COVID-19 wave 1 and 2 patients had six clusters at admission and higher mortality than non-COVID-19 CAP and Omicron that had three clusters at admission. Pooling all COVID-19 waves increased complexity with seven clusters on admission. Conclusion: Complex thrombo-inflammatory responses aligned with mortality of CAP. At a fundamental level, the human thrombo-inflammatory response to a brand new virus was “confused” whereas humans had eons of time to develop a more concise efficient thrombo-inflammatory host response to CAP.

Green Tea Epigallocatechin 3-Gallate Reduced Platelet Aggregation and Improved Anticoagulant Proteins in Patients with Transfusion-Dependent β-Thalassemia: A Randomized Placebo-Controlled Clinical Trial.

Patients with transfusion-dependent β-thalassemia (TDT) with iron overload have been linked to hypercoagulability and increased platelet (PLT) activation that causes thrombosis. Green tea extract (GTE) rich in epigallocatechin-3-gallate (EGCG) exerts iron-chelating and antithrombotic properties. The study aimed to assess the effects of GTE treatment on plasma coagulation state and PLT function in vitro and in patients with TDT. The subjects consumed a placebo or GTE tablets (50 mg and 2 × 50 mg EGCG equivalent) every day for two months. Blood was then collected from the treated patients for analyses of PLT numbers, agonist-induced PLT aggregation, and anti-coagulation proteins. In our findings indicate that the in vitro treatment of GTE (at least 1 mg EGCG equivalent) inhibited PLT aggregation in patients who were healthy and with thalassemia platelet-rich plasma (PRP), which was significant in the healthy PRP. Consistently, GTE treatment inhibited the PLT aggregation that had been ex vivo generated by collagen or ADP. In addition, consumption of GTE tablets greatly inhibited PLT aggregation and increased the plasma levels of proteins C and S, as well as the free protein S concentrations depending upon the time course, but not the GTE dosage. Moreover, plasma ferritin levels decreased in both green tea tablet groups in a time-dependent manner (p < 0.05 in the second month). In conclusion, EGCG-rich GTE diminished PLT aggregation in patients who were healthy and patients with thalassemia plasma. It also improved PLT aggregation and hypercoagulability in patients with TDT by increasing the antithrombotic activity of protein C and protein S. This would suggest an adjuvant of GTE could reduce the risk of thrombosis associated with iron overload.

One-Pot Fabrication of Highly Flexible Fluorine-Free Lubricant-Infused Poly(vinyl alcohol) Films with Superior Antifouling Properties.

In clinical settings, biofluid-contacting devices can suffer from biofouling, leading to thrombus formation and bacterial biofilm buildup, which impair device function and pose health risks. Traditional antifouling methods, including the use of hydrophilic polymers and heparin coatings, often suffer from instability and reduced bioactivity over time. Lubricant-infused surfaces (LIS) have emerged as a promising alternative due to their long-term stability and broad-spectrum repellency. However, current LIS technologies typically involve complex, multistep processes that restrict their application to surface layers, potentially compromising performance under mechanical stress. This study introduces a novel method for bulk modification of poly(vinyl alcohol) (PVA) films, creating flexible lubricant-infused PVA membranes with superior antifouling properties. These films are fabricated by cross-linking the PVA chains using n-propyltrichlorosilane (n-PTCS) and subsequent infusion with silicone oil as a lubricant. The modified PVA films significantly prevent bacterial adhesion and prolong blood and plasma clot formation. Additionally, these films exhibit enhanced mechanical properties, particularly in elasticity and flexibility compared to unmodified PVA films. The developed technique provides a straightforward method for creating flexible, super-repellent biointerfaces with the potential to prevent blood adhesion and bacterial biofilm formation, which are common complications associated with biofluid-contacting devices and medical implants.

Thermal Vacuum Synthesis: Physical Processes in Nanomaterial Production

The thermovacuum process offers an efficient and cost-effective method for producing nanomaterials by ensuring the continuous flow of dispersed material inside a spiral heating element. This is achieved by introducing the material into the heating element&amp;apos;s cavity along with air, forming a two-phase gas-solid particle system. The material moves upward through the heated space, where pressure gradually decreases. Experimental studies on materials like carbon, brown coal, and zirconium dioxide indicate specific conditions are necessary for the system&amp;apos;s continuous operation. One key requirement is that the mass of solid particles should not exceed 1.0 to 1.2 grams per liter of air entering the heating element. This limit ensures that nanodispersed and finely dispersed particles can move freely, avoiding collisions and allowing faster-moving particles to overtake slower ones. These particles increase in velocity and temperature as they pass through the heating element, with changes in heat capacity and particle motion contributing to wave motion and pulsed heat loads. The velocity at which the material particles travel depends on the thermal radiation from the heater walls and the energy generated by local pulse steam explosions, which create shock waves. Higher explosion energy results in increased particle velocity, greater impact angles against the heater walls, and higher environmental temperatures. These conditions lead to accelerated electron, proton, and other charged particle flows, forming plasma clots and neutrino clouds. The nanoparticles take various forms, including nanotubes, fullerenes, thin films, and crystals, reaching velocities up to a thousand kilometers per second and heating temperatures of up to 17 million degrees during pulses. This process consistently subjects the material to force, heat, deformation, and ionization, expediting the creation of nanodispersed materials with enhanced physicochemical and mechanical properties. The thermovacuum process not only improves the efficiency of thermotechnological equipment but also reduces energy consumption, production time, and costs. The research findings support its use in the continuous and effective production of high-quality nanomaterials.

Current Status and Considerations on Endoscopic Diagnosis and Treatment of Subepithelial Microlesions in the Digestive Tract

The detection rate of subepithelial lesions in the digestive tract, especially microlesions (≤ 1 cm in diameter), has significantly increased. Historically, periodic follow-up or surgical resection has been recommended by scholars. Due to the potential risk of malignancy, regular follow-up carries certain risks, while surgical resection, though effective, is highly invasive with a high risk of complications. With the rapid development of endoscopic techniques, more and more subepithelial lesions in the digestive tract have been successfully treated through endoscopic submucosal dissection and endoscopic full-thickness resection. However, these methods require a high level of skill and are associated with significant costs for surgical instruments and materials. Therefore, it is worth exploring whether a simpler and more efficient treatment can transition patients from observation to proactive treatment. A modified technique combining snare, long transparency cap, and Argon Plasma Coagulation under endoscopy has advantages over traditional methods, such as being simpler to perform, less prone to complications, and more cost-effective. This article reviews the current status and considerations of endoscopic treatment for subepithelial lesions in the digestive tract.

Clinical features and risk factors for colorectal gas explosion during digestive endoscopy and surgery: a systematic review.

Colorectal gas explosion (CGE) is an exceptional but potentially fatal complication of digestive endoscopy or surgery. The role played by bowel preparations and endoscopic or surgical devices in the risk of CGE is still unclear. We conducted a systematic review of the literature to identify risk factors for CGE. We conducted a comprehensive literature search of multiple databases from inception to September 16, 2024 including all reports of CGE according to a systematic review protocol preregistered on the PROSPERO database (CRD42023455049). Additionally, we analyzed all trials that measured explosive gas levels after different bowel preparation strategies. Twenty-nine case reports, three case series, and eleven trials were included. Thirty-six cases of CGE were described, 12 surgical and 24 endoscopic. Perforation and death following CGE occurred in 81% and 14% of patients, respectively. The most common bowel preparations taken before CGE were enemas (42%) and oral preparations (31%), while 28% of patients did not undergo any bowel preparation. Bowel preparation was reported as inadequate in most CGE (solid stool in 65% and poor in 11%). The most frequent devices that triggered CGE were argon plasma coagulation during endoscopy (58%) and the electric scalpel during surgical procedures (75%). Published trials showed that adequate bowel preparation, together with endoscopic insufflation and suction, reduces intestinal levels of hydrogen and methane. CGE predominantly occurs in patients undergoing interventional procedures with inadequate bowel preparation. Achieving optimal bowel preparation, together with endoscopic aspiration, washing, and CO2 insufflation practically abolishes potentially explosive gas concentrations.

Hemocompatibility of Albumin-Modified Magnetic Nanoparticles.

Kidney failure leads to the accumulation of metabolites in the blood compartment. This build-up of metabolites has been associated with increased mortality and morbidity in these patients; thus, these metabolites are commonly called uremic toxins. The retention of some uremic toxins in the blood results from a strong interaction with serum albumin, preventing their clearance using standard hemodialysis techniques. Adsorbents are considered the next-generation technology for clearing uremic toxins from the blood, and iron oxide magnetic nanoparticles are a promising material due to a high surface area that is easily modified and the ability to remove them from blood with an external magnetic field. Plasma protein adsorption and clot formation kinetics were determined for unmodified and albumin-modified iron oxide magnetic nanoparticles. Albumin was selected because it can bind uremic toxins, and it is commonly used to passivate surfaces. Coatings were formed and characterized using transmission electron microscopy, thermogravimetric analysis, and zeta-potential analysis. Clotting kinetics, total protein assays, and immunoblots were used to analyze the effect surface modification has on protein adsorption events. Unmodified nanoparticles showed rapid clotting and more adsorbed protein compared to albumin-coated iron oxide nanoparticles. Immunoblots show that modified particles showed changes in albumin, protein C, Immunoglobulin G, transferrin, fibrinogen, α1-antitrypsin, vitronectin, plasminogen, prothrombin, and antithrombin levels compared to unmodified controls. The hemocompatibility of adsorbent materials is essential to their clinical application in clearing the blood of uremic toxins.

Cure of Congenital Purpura Fulminans via Expression of Engineered Protein C Through Neonatal Genome Editing in Mice.

PC (protein C) is a plasma anticoagulant encoded by PROC; mutation in both PROC alleles results in neonatal purpura fulminans-a fatal systemic thrombotic disorder. In the present study, we aimed to develop a genome editing treatment to cure congenital PC deficiency. We generated an engineered APC (activated PC) to insert a furin-cleaving peptide sequence between light and heavy chains. The engineered PC was expressed in the liver of mice using an adeno-associated virus vector or CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9)-mediated genome editing using an adeno-associated virus vector in vivo. The engineered PC could be released in its activated form and significantly prolonged the plasma coagulation time independent of the cofactor activity of PS (protein S) in vitro. The adeno-associated virus vector-mediated expression of the engineered PC, but not wild-type PC, prolonged coagulation time owing to the inhibition of activated coagulation FV (factor V) in a dose-dependent manner and abolished pathological thrombus formation in vivo in C57BL/6J mice. The insertion of EGFP sequence conjugated with self-cleaving peptide sequence at Alb locus via neonatal in vivo genome editing using adeno-associated virus vector resulted in the expression of EGFP in 7% of liver cells, mainly via homology-directed repair, in mice. Finally, we succeeded in improving the survival of PC-deficient mice by expressing the engineered PC via neonatal genome editing in vivo. These results suggest that the expression of engineered PC via neonatal genome editing is a potential cure for severe congenital PC deficiency.

High-dose atorvastatin and rosuvastatin reduce the levels of neutrophil extracellular trap-related proteins in coronary artery disease: association with prothrombotic state.

Neutrophil extracellular trap (NET) formation is involved in atherothrombosis. We sought to investigate whether statins affect neutrophil extracellular traps activation and release (NETosis) in coronary artery disease (CAD), and whether such changes show associations with statin‑induced additional effects. We studied 130 patients with advanced CAD before and at least 6 months after initiation of high‑dose statin therapy with rosuvastatin 40 mg/d or atorvastatin 80 mg/d. The levels of circulating citrullinated histone H3 (H3cit), myeloperoxidase (MPO), and neutrophil elastase (NE) were assessed as proteins associated with NETosis along with thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis inhibitors. Following statin therapy intensification, we observed reduced accumulation of H3cit (-30.4%), MPO (-28.1%), and NE (-25.5%; all P <0.001), all not associated with low‑density lipoprotein cholesterol (LDL‑C) lowering (-25%). However, H3cit level was lower in 50 patients (38.5%) who achieved the target LDL‑C below 1.8 mmol/l (-16.5%; P = 0.004), and in 19 patients (14.6%) with LDL‑C below 1.4 mmol/l (-25.5%; P = 0.001), as compared with the remaining individuals. The reductions in H3cit and MPO levels were associated with a 42.9% decrease in C‑reactive protein (CRP) level on high‑dose statins (R = 0.855; P <0.001 and R = 0.25; P = 0.004, respectively), along with increases in Ks and reduction in thrombin activatable fibrinolysis inhibitor (TAFI) activity, but not with CLT or thrombin generation (all |R|, 0.24-0.4; P <0.01). In multivariable analysis, changes in CRP (β = 0.771; P <0.001), TAFI activity (β = 0.125; P = 0.013), and fibrinogen level (β = 0.106; P = 0.034) were independently associated with a decrease in H3cit concentration. We showed for the first time that high‑dose statins can reduce the level of NET‑related proteins in association with anti‑inflammatory and antithrombotic actions in CAD patients.

An experimental model of endoscopic argon plasma coagulation in liquid medium

The aim of the research was to investigate the effect of argon plasma coagulation on the wall of the gastrointestinal tract in experiment. Material and methods. A method of endoscopic argon plasma coagulation in a liquid medium was developed to eliminate the shortcomings of the standard technology. Rabbits, divided into two groups, were used as experimental animals; the developed technology of argon plasma coagulation in a liquid medium was applied in the treatment group, while the standard technology of argon plasma coagulation was used in the control group. Gastroscopy, with focal application of argon plasma coagulation followed by morphological examination of the coagulation zones after 1 hour, 1 day, 3 days, and 5 days, was performed. Results. Analysis of morphological sections indicates that when using argon plasma coagulation in a liquid medium, the depth of coagulation impact on biological tissues decreases, as well as the severity of inflammatory changes, resulting in faster reparative changes. The obtained results may be of interest for further clinical-experimental research and implementation into clinical practice of modifications of endoscopic argon plasma coagulation.

Decreased Circulating Red Cell Mass Induced by Intravenous Acepromazine Administration Alters Viscoelastic and Traditional Plasma Coagulation Testing Results in Healthy Horses.

Coagulopathy is common in equine critical illness, with its early recognition being crucial for patient management and prognosis. In vitro viscoelastic (VE) hypercoagulability with decreased RCM/PCV has been demonstrated in dogs but not horses. Our objective was to evaluate the effects of acepromazine-induced (0.1 mg/kg IV) decreased RCM on VE and plasma coagulation parameters using a prospective interventional study of eight adult horses. Complete blood count (CBC), fibrinogen, prothrombin time (PT), partial thromboplastin time (PTT), packed cell volume (PCV), total solids (TS), and VCM Vet™ VE testing performed at baseline (T0), 1 h (T1), and 12 h (T2) post acepromazine administration. Splenic volume was determined ultrasonographically. The results were analyzed using one-way repeated measures ANOVA with Tukey's post hoc HSD test to determine the effect of time (sample). PCV decreased 13% points following acepromazine administration from T0 to T1 (p < 0.001), remaining decreased at T2 (p < 0.001). Splenic volume increased from T0 to T1 (p = 0.04) and was not different from baseline at T2. Maximal clot formation (MCF) increased from T0 (p = 0.03). PTT decreased from T0 to T1 and increased at T2 (p = 0.03). No other coagulation parameters were significantly altered. This study demonstrates a non-inflammatory acute model of anemia in horses that impacts VE and plasma-based testing.

Altered fibrin clot properties and elevated von Willebrand Factors level are associated with progression to permanent atrial fibrillation during follow-up: a cohort study

Abstract Introduction Little is known about association of prothrombotic markers and atrial fibrillation (AF) progression to permanent arrythmia (PerAF). Formation of denser and poorly lysable fibrin clots have been observed in AF including patients with sinus rhythm in association with stroke and bleeding risk. We investigated whether altered fibrin clot properties and other prothrombotic state markers may contribute to AF transition to PerAF. Methods In the cohort study, in 226 anticoagulated AF patients (median age 69 years, median CHA2DS2-VASc of 3)with paroxysmal (n=83, 36.7%) or persistent (n=143, 63.3%) arrythmia we assessed at baseline plasma clot permeability (Ks), lysis time (CLT), and fibrinolysis involved proteins, including plasminogen activator inhibitor type 1 (PAI-1) along with von Willebrand factor (vWF) antigen. We recorded patients with PerAF during a median follow-up of 58 months. Results PerAF was documented in 62 (27.4%, 5.7%/year) subjects. These patients were older, with larger prevalence of heart failure (HF), higher body mass index by 9.6%, more often presented persistent AF and had longer history of arrythmia by 60%. We observed by 25.7% longer CLT and similar Ks, compared with the remainders, along with higher levels of vWF by 29% and PAI-1 by 21.3%. By multivariable analysis CLT, vWF and HF were independently associated with PerAF (R2=0.697, P&amp;lt;0.001). A cut-off CLT value of ≥105 min had a sensitivity of 88.7% and specificity of 78.7% in prediction of PerAF (area under curve 0.892, 95% confidence interval 0.848-0.935, P&amp;lt;0.001). Conclusion Impaired global fibrinolysis and elevated vWF levels are independently associated with faster progression to PerAF despite anticoagulation.Figure1

The high-dose statin treatment reduces neutrophil extracellular traps formation in patients with coronary artery disease

Abstract Background Neutrophil extracellular traps formation (NETosis) is currently considered as an important mediator in atherosclerosis and atherothrombosis. However, the impact of high-dose statin treatment, as potent cholesterol-lowering agents with pleiotropic effects, on NETosis in coronary artery disease (CAD) has been poorly described. Purpose We sought to assess whether in CAD patients the recommended statin treatment intensification is associated with changes in NETs-related markers and if such changes can alter fibrin clot properties. Methods 130 patients with advanced CAD, who did not achieve the target low-density lipoprotein cholesterol (LDL-C) were included. Before and at least 6 months after initiation of high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) citrullinated histone H3 (H3cit), myeloperoxidase (MPO) and neutrophil elastase (NE) as markers associated with NETosis were assessed in relation to C-reactive protein (CRP), thrombin generation, plasma clot permeability (Ks), clot lysis time (CLT), and fibrinolysis proteins. Results At baseline, NETosis did not differ depending on gender and cardiovascular risk factors but H3cit correlated with MPO (R=0.543, P&amp;lt;0.001) and CRP (R=0.540, P&amp;lt;0.001). All NETosis markers were inversely correlated with Ks. Median LDL-C reduction by 25% (P&amp;lt;0.001) on high-dose statin treatment was independent from H3cit reduction by 30.4%, MPO by 28.1%, and NE by 25.5% (in all P&amp;lt;0.001, Figure 1). The ΔH3cit and ΔMPO, but not ΔNE were associated with ΔCRP (R=0.855, P&amp;lt;0.001; R=0.250, P=0.004, respectively), Δthrombin activatable fibrinolysis inhibitor (TAFI) (R=0.385, P&amp;lt;0.001; R=0.245, P=0.005), and inversely with ΔKs (R=-0.315, P&amp;lt;0.001; R=-0.395, P=0.001). In multivariable analysis the H3cit decrease was independently associated with ΔCRP (β=0.771, P&amp;lt;0.001), ΔTAFI (β=0.125, P=0.013) and Δfibrinogen (β=0.106, P=0.034) but not with ΔLDL-C. Conclusions As has been shown for the first time high-dose statin treatment reduces levels of NETs-related markers, regardless of lipid-lowering effect in CAD patients.

Designing 1,2,3‐Triazole Derivatives for Targeted Inhibition of Proteolytic and Coagulant Activities in Bothrops Jararaca and Bothrops neuwiedi Snake Venoms

AbstractSnakebites inflict significant injuries on humans and animals, posing a severe global public health challenge due to high mortality and morbidity rates. This study presents results against the venoms of Bothrops jararaca and Bothrops neuwiedi using sixteen synthetic hybrid molecules containing thiophene and triazoles, designated as 6a–h and 7a–h. The compounds were assessed for their ability to inhibit proteolytic and plasma coagulant activities induced by the snake venoms, and their toxicity was analyzed. Most derivatives demonstrated nontoxicity through in silico analysis with the Osiris Property Explorer tool and in vitro cytotoxic hemocompatibility on red blood cells. Notably, only derivative 6e exhibited toxicity to erythrocytes, while 6b, 6d, 7c, and 7f displayed mutagenic, tumorigenic, or adverse effects on the reproductive system. Derivatives 6a, 6c–h, 7c–e, 7g, or 7h effectively inhibited the coagulating activity of B. jararaca venom, while 6a–b, 6d–e, 6h, or 7a–f inhibited coagulation induced by B. neuwiedi venom. All derivatives demonstrated inhibition of the proteolytic activity caused by B. jararaca venom, and derivatives 6a–d and 7e–f inhibited the activity of B. neuwiedi venom. Consequently, these derivatives exhibited varying degrees of efficacy in countering two crucial toxic effects of B. jararaca or B. neuwiedi venoms, suggesting their potential as antivenoms against both species.

Cryo-EM structure of the human native plasma coagulation factor XIII complex

AbstractThe structure of human coagulation factor XIII (FXIII), a heterotetrameric plasma protransglutaminase that covalently cross-links preformed fibrin polymers, remains elusive until today. The heterotetrameric complex is composed of 2 catalytic FXIII-A and 2 protective FXIII-B subunits. Structural etiology underlying FXIII deficiency has so far been derived from crystallographic structures, all of which are currently available for the FXIII-A2 homodimer only. Here, we present the cryogenic electron microscopy structure of a native, human plasma–derived FXIII-A2B2 complex at 2.4 Å resolution. The structure provides detailed information on FXIII subunit interacting interfaces as the 2 subunits interact strongly in plasma. The native FXIII-A2B2 complex reveals a pseudosymmetric heterotetramer of 2 FXIII-B monomers intercalating with a symmetric FXIII-A2 dimer forming a “crown”-like assembly. The symmetry axes of the A2 and B2 homodimers are twisted relative to each other such that Sushi domain 1 interacts with the catalytic core of the A subunit, and Sushi domain 2 with the symmetry related A′ subunit, and vice versa. We also report 4 novel mutations in the F13A1 gene encoding the FXIII-A subunit from a cohort of patients with severe FXIII deficiency. Our structure reveals the etiological basis of homozygous and heterozygous pathogenic mutations and explains the conditional dominant negative effects of heterozygous mutations. This atomistic description of complex interfaces is consistent with previous biochemical data and shows a congruence between the structural biochemistry of the FXIII complex and the clinical features of FXIII deficiency.

Efficacy and Safety of Rivaroxaban, Apixaban, and Edoxaban for Nonvalvular Atrial Fibrillation Based on Blood Coagulation Activity and Drug Plasma Concentration: SETtsu and North Osaka Multicenter Direct Oral AntiCoagulant (SET DOAC) Registry.

Background: The therapeutic effects of oral anticoagulant drugs for nonvalvular atrial fibrillation (NVAF) suggest that the three factor Xa (FXa) inhibitors may have distinct safety profiles, though this is not yet fully conclusive. This study investigated the current dosing of rivaroxaban, apixaban, and edoxaban by monitoring drug plasma concentration (PC) and coagulation activity from the viewpoint of the safety. Methods and results: This multicenter clinical study monitored the drug PC and two coagulation biomarkers (fibrinogen and fibrin monomer complex [FMC]) at peak and trough timing in 268 outpatients taking rivaroxaban (n = 72), apixaban (n = 71), and edoxaban (n = 125) for NVAF. Doses were adjusted based on the dose-adjustment criteria of each drug. Referencing our previous study, peak drug PC remained below the cut-off level for predicting bleeding events except in eight patients (rivaroxaban, n = 3; apixaban, n = 2; edoxaban, n = 3) in whom bleeding events occurred. Among them, two (one each on rivaroxaban and edoxaban) had a peak drug PC below the cut-off level. Drug PCs widely varied from peak to trough, whereas FMC levels, reflecting thrombin activity, remained within the normal range (<6.1 µg/mL) regardless of PC variations. These results indicated that the anticoagulant effects of these drugs persisted throughout the day regardless of the drug PC levels, dosage, and dosing frequency. Regarding the change over time in peak PC, the elevation over time developed more in rivaroxaban (29/57; 50.9%, p < 0.05) than in edoxaban (32/101; 31.7%), and rivaroxaban tended to accumulate more than edoxaban. Conclusions: Although drug PC levels of once-daily FXa inhibitors widely varied from peak to trough, FMC levels were maintained within the normal range without daily variations. Rivaroxaban also tended to accumulate over time. The results indicate the low risk of thrombotic events with once-daily FXa inhibitors and its correspondence to the twice-daily regimen.

Cellular fate of a plant virus immunotherapy candidate

Cowpea mosaic virus (CPMV) is a plant virus that is currently being developed for intratumoral immunotherapy. CPMV relieves the immune system from tumor-induced immunosuppression; reprograms the tumor microenvironment to an activated state whereby the treated and distant tumors are recognized and eradicated. Toward translational studies, we investigated the safety of CPMV, specifically addressing whether pathogenicity would be induced in mammalian cells. We show that murine macrophage immune cells recognize CPMV; however, there is no indication of de novo viral protein synthesis or RNA replication. Furthermore, we show that CPMV does not induce hemolysis, platelet aggregation and plasma coagulation amongst other assays in human blood and immune cells. Taken together, we anticipate that these results will reinforce the development of CPMV as an immunotherapeutic platform.

Procoagulant platelet activation promotes venous thrombosis

AbstractPlatelets are key players in cardiovascular disease, and platelet aggregation represents a central pharmacologic target, particularly in secondary prevention. However, inhibition of adenosine diphosphate and thromboxane signaling has low efficacy in preventing venous thromboembolism, necessitating the inhibition of the plasmatic coagulation cascade in this disease entity. Anticoagulation carries a significantly higher risk of bleeding complications, highlighting the need of alternative therapeutic approaches. We hypothesized that procoagulant activation (PA) of platelets promotes venous thrombus formation and that targeting PA could alleviate venous thrombosis. Here, we found elevated levels of procoagulant platelets in the circulation and in thrombi of patients with deep vein thrombosis (DVT) and pulmonary embolism, and in mice developing DVT following inferior vena cava stenosis. Furthermore, we detected PA of recruited platelets within murine venous thrombi and human pulmonary emboli. Mice with platelet-specific deficiency in central pathways of PA—cyclophilin D and transmembrane protein 16F—were more resistant toward low flow–induced venous thrombosis. Finally, we found that a clinically approved carbonic anhydrase inhibitor, methazolamide, reduced platelet procoagulant activity and alleviated murine thrombus formation without affecting trauma-associated hemostasis. These findings identify an essential role of platelet procoagulant function in venous thrombosis and delineate novel pharmacologic strategies targeting platelets in the prevention of venous thromboembolism.