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In the days following a burn injury, major burn patients (MBP) present a multifactorial coagulation disorder known as acute burn-induced coagulopathy. Several studies have investigated coagulation in MBPs; however, Factor XIII (FXIII), which converts fibrin monomers into a stable clot and promotes wound healing, has not yet been studied. To determine the kinetics of FXIII and other coagulation factors and cofactors in MBPs in order to clarify coagulopathy in these patients and its potential relationship with surgical bleeding. Prospective observational pilot study of the kinetics of FXIII and other coagulation factors and cofactors in MBPs during the first 30 days of burn injury. FXIII levels show a significant decline of 75.10% in the interval between the burn injury and surgery, and a decline of 87.70% in the 24 h following surgery. Patients undergo surgery with a median antigenic FXIII of 32%. Plasma levels of most factors decrease significantly 24 h after the burn injury. MBPs experience a significant decrease in plasma levels of FXIII from the time of admission up to 24 h after surgery. Abnormally low levels were observed at the time of surgery that could not be detected by other coagulation tests. The decrease in most factors at 24 h seems to be associated with dilution due to intensive fluid resuscitation. [Display omitted] • MBPs experienced a significant decrease in FXIII levels from the time of admission up to 24 h after surgery. • Abnormal low levels of FXIII could not be detected by other coagulation tests. • FXIII deficiency could be partly responsible for massive intraoperative bleeding in MBPs. • Most of the factors studied showed a decrease at 24 h suggesting a fluid resuscitation-driven dilution mechanism. • Normal ROTEM parameters in the early stages could be due to a compensated dilution of procoagulant and anticoagulant factors. [ABSTRACT FROM AUTHOR]

Sepsis is a common and critical condition encountered in clinical practice that can lead to multi-organ dysfunction. Sepsis-induced coagulopathy (SIC) significantly affects patient outcomes. However, the precise mechanisms remain unclear, making the identification of effective prognostic and therapeutic targets imperative. The analysis of transcriptome data from the whole blood of sepsis patients, facilitated the identification of key genes implicated in coagulation. Then we developed a prognostic model and a nomogram to predict patient survival. Consensus clustering classified sepsis patients into three subgroups for comparative analysis of immune function and immune cell infiltration. Single-cell sequencing elucidated alterations in intercellular communication between platelets and immune cells in sepsis, as well as the role of the coagulation-related gene FYN. Real-time quantitative PCR determined the mRNA levels of critical coagulation genes in septic rats' blood. Finally, administration of a FYN agonist to septic rats was observed for its effects on coagulation functions and survival. This study identified four pivotal genes—CFD, FYN, ITGAM, and VSIG4—as significant predictors of survival in patients with sepsis. Among them, CFD, FYN, and ITGAM were underexpressed, while VSIG4 was upregulated in patients with sepsis. Moreover, a nomogram that incorporates the coagulation-related genes (CoRGs) risk score with clinical features of patients accurately predicted survival probabilities. Subgroup analysis of CoRGs expression delineated three molecular sepsis subtypes, each with distinct prognoses and immune profiles. Single-cell sequencing shed light on heightened communication between platelets and monocytes, T cells, and plasmacytoid dendritic cells, alongside reduced interactions with neutrophils in sepsis. The collagen signaling pathway was found to be essential in this dynamic. FYN may affect platelet function by modulating factors such as ELF1, PTCRA, and RASGRP2. The administration of the FYN agonist can effectively improve coagulation dysfunction and survival in septic rats. The research identifies CoRGs as crucial prognostic markers for sepsis, highlighting the FYN gene's central role in coagulation disorders associated with the condition and suggesting novel therapeutic intervention strategies. [Display omitted] • Found four key genes for sepsis prognosis linked to coagulation. • Created sepsis survival nomogram combining gene scores and clinical data. • Unveiled three sepsis subtypes with unique prognoses and immune traits. • Showed potential of FYN agonist in treating sepsis-induced coagulopathy. [ABSTRACT FROM AUTHOR]

Animal venoms are a rich and complex source of components, including peptides (such as neurotoxins, anionic peptides and hypotensins), lipids, proteins (such as proteases, hyaluronidases and phospholipases) and inorganic compounds, which affect all biological systems of the envenoming victim. Their action may result in a wide range of clinical manifestations, including tachy/bradycardia, hyper/hypotension, disorders in blood coagulation, pain, edema, inflammation, fever, muscle paralysis, coma and even death. Scorpions are one of the most studied venomous animals in the world and interesting bioactive molecules have been isolated and identified from their venoms over the years. Tityus spp. are among the scorpions with high number of accidents reported in the Americas, especially in Brazil. Their venoms have demonstrated interesting results in the search for novel agents with antimicrobial, anti-viral, anti-parasitic, hypotensive, immunomodulation, anti-insect, antitumor and/or antinociceptive activities. Furthermore, other recent activities still under investigation include drug delivery action, design of anti-epileptic drugs, investigation of sodium channel function, treatment of erectile disfunction and priapism, improvement of scorpion antivenom and chelating molecules activity. In this scenario, this paper focuses on reviewing advances on Tityus venom components mainly through the modern omics technologies as well as addressing potential therapeutic agents from their venoms and highlighting this abundant source of pharmacologically active molecules with biotechnological application. [Display omitted] • Tityus venoms are still underexploited sources of pharmacological agents. • Only few Tityus venom sequences (of ∼3000 available at databases) have been studied in depth. • T. serrulatus venom is the most studied venom among the Tityus venoms. • Many Tityus toxins are versatile toxins presenting a broad spectrum potential. • Some Tityus venom components whose function is still unknown include the PAPE and anionic peptides. [ABSTRACT FROM AUTHOR]

Coagulation disorders frequently complicate the clinical course of acute myeloid leukemia (AML) patients. This study examined the frequency and prognostic significance, with regards of early mortality, of the presence of overt disseminated intravascular coagulation (DIC) at AML diagnosis and its correlation with clinical and biological characteristics. A retrospective analysis of 351 newly diagnosed non-promyelocytic AML patients was conducted, utilizing the 2018 ISTH DIC-Score criteria to evaluate the presence of overt DIC at AML onset. The study cohort had a median age of 65 years with a predominance of male gender (59 %). Overt DIC was present in 21 % of cases and was associated with advanced age, comorbidities, poor performance status, hyperleukocytosis, LDH levels, NPM1 mutations, expression of CD33 and CD4, and lack of expression of CD34. With a median follow-up of 72 months (3–147 months), the 6-year overall survival (OS) was 17.4 %, with patients having overt DIC showing significantly poorer outcomes (7.2 % compared to 20.3 % of those without DIC, p < 0.001). Patients with overt DIC showed markedly high early mortality rates at 30 (42.5 % vs 8 %), 60 (49.3 % vs 16.9 %), and 120 days (64.4 % vs 25.6 %) from disease onset. In multivariate analysis overt DIC retained its independent prognostic value for early mortality. In conclusion, the prevalence and clinical relevance of DIC in non-promyelocytic AML is not negligible, underlining its potential as an unfavorable prognostic marker. In newly diagnosed patients with AML, early recognition and measure to counteract coagulation disturbances might help mitigate the elevated mortality risk associated with DIC. • Disseminated intravascular coagulation frequently complicates acute leukemias. • The 2018 ISTH DIC-Score criteria serve as a simple tool to diagnose disseminated intravascular coagulation in acute myeloid leukemia patients. • Acute myeloid leukemia patients with disseminated intravascular coagulation at presentation have a 14-fold increased risk of major bleeding. • Disseminated intravascular coagulation has independent prognostic value for early death. [ABSTRACT FROM AUTHOR]

Viscoelastic hemostatic assays are point-of-care devices that assess coagulation and fibrinolysis in whole blood samples. These technologies provide numeric and visual information of clot initiation, clot strength, and clot lysis under low-shear conditions, and have been used in a variety of clinical settings and subpopulations, including trauma, cardiac surgery, and obstetrics. Emerging data indicate that these devices are useful for detecting important coagulation defects during major postpartum hemorrhage (especially low plasma fibrinogen concentration [hypofibrinogenemia]) and informing clinical decision-making for blood product use. Data from observational studies suggest that, compared with traditional formulaic approaches to transfusion management, targeted or goal-directed transfusion approaches using data from viscoelastic hemostatic assays are associated with reduced hemorrhage-related morbidity and lower blood product requirement. Viscoelastic hemostatic assays can also be used to identify and treat coagulation defects in patients with inherited or acquired coagulation disorders, such as factor XI deficiency or immune-mediated thrombocytopenia, and to assess hemostatic profiles of patients prescribed anticoagulant medications to mitigate the risk of epidural hematoma after neuraxial anesthesia and postpartum hemorrhage after delivery. [ABSTRACT FROM AUTHOR]

Sodium dehydroacetate (DHA-S), a potent antifungal and antibacterial agent, is widely used in food, feed and cosmetics. However, recent studies have shown that DHA-S could pose a risk for human and animal health. We had previously reported that DHA-S could cause coagulation disorders in rats and chicken. In the present study, we further confirmed that DHA-S induced blood coagulation via VKORC1 and VKORC1L1 in rats, and elucidated the role played by mTOR/ERK signaling. The in vivo studies demonstrated that PT, APTT, and DHA-S content and relative protein expressions in tissues rebounded after drug withdrawal. In BRL-3A cells, 1.0 mM DHA-S increased the expression levels of mTOR, p-mTOR and p-ERK and decreased the levels of VKORC1, VKORC1L1 and Vitamin K. Rapamycin significantly decreased the expression levels of p-mTOR and p-ERK, while FR180204 (p-ERK Inhibition) lead to a decrease in p-ERK level. Rapamycin and FR180202 attenuated the inhibitory effect of DHA-S on VKORC1, VKORC1L1 and vitamin K levels. In addition, DHA-S increased the expression levels of mTOR, p-mTOR and p-ERK in male and female rat livers and prolonged PT and APTT. In summary, this study indicated that DHA-S induced blood coagulation via the modulation of the mTOR/ERK pathway in rats. • The Mechanism of Blood Coagulation Induced by Sodium Dehydroacetate via the Regulation of the mTOR/ERK Pathway in Rats. • Sodium dehydroacetate induces blood coagulation disorder in rats. • Sodium dehydroacetate inhibits coagulation factor activation by inhibiting VKORC1L1 and VKORC1 expression. • mTOR/ERK pathway might play an important role in the modulation of VKORC1 and VKORC1L1 expression by DHA-S. [ABSTRACT FROM AUTHOR]

Despite having relatively high COVID-19 vaccine coverage in Vietnam, a fraction of COVID-19 patients required hospitalization due to severe symptoms. The purpose of this study was to describe the clinical, laboratory, complications, and treatment of COVID-19 patients hospitalized during the pandemic's fourth wave. Genome sequencing was performed on COVID-19 patients. Data on clinical characteristics, treatment, complications, and outcomes were consistently collected. The clinical classifications were mild (37.43%), moderate (24.2%), and severe (38.37%). Patients with co-morbidities, high fever >39 °C, hypertension, tachycardia, tachypnea, and SpO 2 <90%, had a 1.2–4 folds higher of severe progression than those with mild/moderate. Serious consequences were much more common in the severe patients than in the mild/moderate. The respiratory system of severe patients was generally documented as fine, coarse crackles, and CT scanner shown ground glass, consolidation, and opacity, with Delta variant accounting for 92.6%. Complications were common in the severe patients, including bacteria pneumonia (36.42%), ARDS (61.11%), blood clotting disorder (7.14%), infection (46.92%), and acute kidney injury (12.35%). Antiviral, antifungal, corticosteroid, anticoagulant, and ECMO regimens were utilized. Patients died mostly as a result of co-morbidities, low SpO 2 , lung injury, and complications such as bacterial + fungal pneumonia (83.9%), ARDS (83.9%), bacteremia (56.5%), injury acute renal failure (27.4%), and coagulopathy (12.9%). Severe and critical COVID-19 patients frequently have several comorbidities, multiple lung lesions along with a variety of clinical signs. Despite receiving antivirals, antibiotics, corticosteroids, anticoagulants, and even ECMO therapy, the patient encountered multiple complications, with a fatality rate of up to 38.27%. [ABSTRACT FROM AUTHOR]

Viscoelastic testing has been used in adult hematologic malignancies in conjunction with conventional coagulation tests (CCTs) to predict coagulopathies and tailor blood product replacement. However, there is a paucity of similar pediatric studies. Analyze and correlate leukemia-associated coagulopathy in newly diagnosed pediatric leukemia patients using CCT's and Rotational Thromboelastometry (ROTEM). Pediatric patients with newly diagnosed acute leukemia underwent testing with ROTEM and CCTs on days 0, 15 and 29 of induction chemotherapy. Sixty-two patients were enrolled. At presentation, 54.8 % of patients had platelets <50 K/μL, 73 % had prolonged PT, 1.6 % had fibrinogen <150 mg/dL. Fifteen patients (24.2 %) had WHO grade 1 bleeding and two patients (3 %) had WHO grade 4 bleeding. EXTEM/INTEM values at presentation (day 0) reflected hypocoagulability, however FIBTEM revealed hypercoagulability. Patients showed a progressive hypocoagulability in all ROTEM assays by day 15 (day 0 vs day 15, p < 0.001), with improvement by day 29 (day 15 vs day 29, p < 0.001). Day 0 ROTEM parameters were comparable to day 29. Fibrinogen strongly correlated with ROTEM at all three time points (p < 0.0001), along with platelet count with moderate correlations (p < 0.001). Fibrinogen and platelets appear to be the drivers of leukemia associated coagulopathy in the pediatric population, suggesting the utility of using CCTs and ROTEM in this population to better evaluate hemostatic function and guide blood product replacement. • Rotational Thromboelastometry (ROTEM) has been used to assess leukemia-associated coagulopathy in adult malignancies, with a paucity of similar studies in pediatric leukemia • Abnormal coagulation test (PT/aPTT) values in leukemia patients do not clearly predict the risk of bleeding • Pediatric leukemia patients had evidence of hypocoagulability during induction chemotherapy using ROTEM assays despite acquired hypofibrinogenemia and thrombocytopenia and a low bleeding risk in our cohort • Strategies adopting ROTEM as a point of care test along with conventional coagulation tests (CCTs) can better evaluate hemostatic function to guide non-erythrocyte hemostatic factor replacement in this patient population • Our study demonstrates the utility of CCTs and ROTEM in newly diagnosed pediatric leukemia patients, with fibrinogen and platelets as the main drivers of leukemia-associated coagulopathy. [ABSTRACT FROM AUTHOR]

People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose–response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose–response relationship with Multiple Comparison Procedure–Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62–77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5–19·1) for placebo, 16·7 (14·8–18·6) for 25 mg milvexian once daily, 16·6 (14·8–18·3) for 25 mg twice daily, 15·6 (13·9–17·5) for 50 mg twice daily, 15·4 (13·4–17·6) for 100 mg twice daily, and 15·3 (12·8–19·7) for 200 mg twice daily. No significant dose–response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91–1·05) for 25 mg once daily, 0·99 (0·87–1·11) for 25 mg twice daily, 0·93 (0·78–1·11) for 50 mg twice daily, 0·92 (0·75–1·13) for 100 mg twice daily, and 0·91 (0·72–1·26) for 200 mg twice daily. No apparent dose–response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. Bristol Myers Squibb and Janssen Research & Development. [ABSTRACT FROM AUTHOR]

Congenital coagulopathies have, throughout the history of medicine, been a focus of scientific study and of great interest as they constitute an alteration of one of the most important and conserved pathways of evolution. The first therapeutic strategies developed to address them were aimed at restoring the blood components lost during hemorrhage by administering whole blood or plasma. Later on, the use of cryoprecipitates was a significant breakthrough as it made it possible to decrease the volumes of blood infused. In the 1970′ and 80′, clotting factor concentrates became the treatment and, from the 1990's to the present day, recombinant factors –with increasingly longer half-lives– have taken over as the treatment of choice for certain coagulopathies in a seamless yet momentous transition from biological to biotechnological drugs. The beginning of this century, however, saw the emergence of new advanced (gene and cell) treatments, which are currently transforming the therapeutic landscape. The possibility to use cells and viruses as well as specific or bispecific antibodies as medicines is likely to spark a revolution in the world of pharmacology where therapies will be individualized and have long-term effects. Specifically, attention is nowadays focused on the development of gene editing strategies, chiefly those based on CRISPR/ Cas technology. Rare coagulopathies such as hemophilia A and B, or even ultra-rare ones such as factor V deficiency, could be among those deriving the greatest benefit from these new developments. • Hemostasis is a highly relevant and highly conserved pathway which may be disrupted by congenital coagulopathies. • Recombinant coagulation factors constituted the transition from biological to biotechnological drugs. • The effect of advanced therapies may persist longer than that of current treatments. • Advanced therapies and CRISPR/ Cas technologies are currently being developed to address rare coagulopathies. [ABSTRACT FROM AUTHOR]

This article will highlight how to identify, diagnose and manage acquired bleeding disorders in pregnancy. Postpartum haemorrhage is the leading acquired bleeding disorder, but is extensively covered in multiple guidelines and within the MRCOG curriculum, so we will instead focus on platelet disorders. This is an important area to understand the investigation of and how platelet disorders can range from pre-existing conditions to those acquired only in pregnancy and related to placental dysfunction. [ABSTRACT FROM AUTHOR]

Red cell transfusion is common in paediatric practice and indicated in haemorrhagic shock, anaemia and certain inherited haematological diseases. As with other blood products there are risks associated with their administration and improper use. Extensive national and local guidance is available in the UK in order to maintain safe transfusion practice. This article summarises the rationale behind red cell transfusion and offers a practical guide to clinical decision making in the acute hospital setting. [ABSTRACT FROM AUTHOR]

Adenosine-lidocaine-magnesium (ALM) was initially designed as a cardioplegic agent and later experimentally used to treat many other conditions, including survivable hemorrhage. Experimental ALM therapy has been proved to have beneficial partial effects, such as improved coagulopathy following hemorrhage; however, its primary desired effect of improved survival following hemorrhage remains to be undisputedly confirmed. Small (rat) and large (pig) animal models have driven the preclinical investigation of ALM therapy but also accumulated conflicting results due to their anatomical, physiological, and genetic differences. Advancement in genetic engineering is expected to create better model animals to improve the human relevance of future findings on ALM therapy, preferably using pigs, which are much more similar to humans than rats. A paradigm shift from considering ALM as one medication to three different pharmacologically active drugs, adenosine, lidocaine, and magnesium (ALM), is required to understand the underlying molecular mechanisms of action. An experimental small-volume intervention with the ALM mixture, referred to as ALM, protects from coagulopathy associated with severe hemorrhage injury in both rodent and swine animal models, but unlike rats, it does not improve conclusively the hemorrhagic shock survival of pigs, which are a similar size to humans. The control of hemorrhage is primarily attributable to ALM's lidocaine via interaction with adenosinergic G protein-coupled receptor (GPCR) signaling pathways; adenosine and magnesium are secondary to it. Adenosine-lidocaine-magnesium (ALM) mixture is a cardioplegic agent that improves survivability undisputedly in rodents, but not swine, models of hemorrhagic shock. However, despite protection from comorbid coagulopathy being the one common effect reported in both models, the underlying prothrombotic mechanism for ALM has not been fully elucidated. Here, we undertook a component-based approach focusing on individual drugs in the mixture to elaborate on the protective mechanism against coagulopathy within the frames of adenosine signaling and metabolic pathways. Additionally, the translational potential of small and large animal models of hemorrhagic shock for human survival is critically appraised, owing to substantial quantitative/qualitative differences between humans and rodents, particularly regarding the genetics of G protein-coupled receptors (GPCRs) interacting with ALM's constituents. [ABSTRACT FROM AUTHOR]

Trauma-induced coagulopathy is associated with platelet dysfunction and contributes to early mortality after traumatic injury. Plasma concentrations of the damage molecule high-mobility group box-1 (HMGB-1) increase after trauma, which may contribute to platelet dysfunction. We hypothesised that inhibition of HMGB-1 with a monoclonal antibody (mAb) or with recombinant thrombomodulin (rTM) improves trauma-induced coagulopathy in a murine model of trauma and shock. Male 129S2/SvPasOrlRJ mice were anaesthetised, mechanically ventilated, and randomised into five groups: (i) ventilation control (VENT), (ii) trauma/shock (TS), (iii) TS+anti-HMGB-1 mAb (TS+AB), (iv) TS+rTM (TS+TM), and (v) TS+anti-HMGB-1 mAb+rTM (TS+COMBI). Primary outcome was rotational thromboelastometry EXTEM. Secondary outcomes included tail bleeding time, platelet count, plasma HMGB-1 concentration, and platelet activation. Trauma and shock resulted in a hypocoagulable thromboelastometry profile, increased plasma HMGB-1, and increased platelet activation markers. TS+AB was associated with improved clot firmness after 5 min compared with TS (34 [33–37] vs 32 [29–34] mm; P =0.043). TS+COMBI was associated with decreased clot formation time (98 [92–125] vs 122 [111–148] s; P =0.018) and increased alpha angle (77 [72–78] vs 69 [64–71] degrees; P =0.003) compared with TS. TS+COMBI also reduced tail bleeding time compared with TS (P =0.007). The TS+TM and TS+COMBI groups had higher platelet counts compared with TS (P =0.044 and P =0.041, respectively). Inhibition of HMGB-1 early after trauma in a mouse model improves clot formation and strength, preserves platelet count, and decreases bleeding time. [ABSTRACT FROM AUTHOR]

• 12.5–16.7 % of trauma patients showed an initial FXIII activity of <70%, which further decreased 7 days after trauma. • FXIII activity decreased from 85% at admission to 58% after 7 days. • time interval since trauma, aPTT, fibrinogen levels, Hb and lactate were associated with FXIII activity. • In-vitro administration of FXIII showed a significant dose-dependent improvement in clot stability in trauma patients. • In sTBI patients, FXIII activity showed significant differences between patients with good and poor clinical outcomes. Fibrin stabilizing factor (FXIII) plays a crucial role in blood clotting, tissue repair, and immune defense. FXIII deficiency after trauma can lead to prolonged wound healing due to persistent infections or coagulation disorders. The aim of this study was to describe the prevalence of acquired FXIII deficiency after trauma and to provide a description of the time-course changes of important coagulation parameters in relation to FXIII activity. In this context, patient characteristics, laboratory data, and treatment modalities were examined with respect to their influence on FXIII activity. Furthermore, the effects of in vitro administration of FXIII on clot firmness and outcomes in patients with severe traumatic brain injury were investigated. Two trauma cohorts (A and B) were examined prospectively in a two-center study, and another (cohort C) was examined retrospectively. In cohort A (trauma patients, n=880) routine laboratory tests were conducted, and FXIII activity was measured. In cohort B (polytrauma patients, n=26), additional clinical parameters were collected, and in-vitro FXIII administration and rotational thromboelastometry (ROTEM) analyses were performed. In cohort C (polytrauma patients with severe traumatic brain injury [sTBI], n=84), the impact of initially measured FXIII activity on clinical outcomes after sTBI was investigated using the modified Rankin Scale (mRS) at least 6 months after trauma. The prevalence of FXIII activity <70% in cohort A was 12.4%, with significant differences in age, Hb, fibrinogen, and Hct levels, platelet count, aPTT, and INR (vs. prevalence of FXIII activity >70%). Cohort B showed a decrease in FXIII activity from 85% to 58% after 7 days. FXIII deficiency correlated with time after trauma, aPTT, and fibrinogen level, lactate, and Hb levels. In-vitro administration of FXIII showed a positive influence on clot firmness due to improved maximum clot firmness (MCF in FIBTEM) and reduced maximum lysis (ML in EXTEM). Finally, a significant difference in FXIII activity between patients after sTBI with good and poor clinical outcomes was observed 6 months after trauma. We demonstrated that trauma-associated FXIII deficiency is a common coagulation disorder, with FXIII deficiency increasing further in the first 7 days after trauma, the period of early surgical care. In vitro administration of FXIII was able to demonstrate significant clot stabilizing effects. For trauma patients with sTBI, FXIII activity could serve as a prognostic parameter, as it differed significantly between patients with good and poor clinical outcomes. [ABSTRACT FROM AUTHOR]

Women with inherited bleeding disorders in pregnancy are a group of pregnant women with varied and often complex healthcare needs. The antenatal, intrapartum and postnatal care of these women and their babies may require specialist planning and support. This article outlines the key principles of care and provides a summary of the existing Royal College of Obstetricians and Gynaecologists' guidelines on the management of inherited bleeding disorders in addition to practical advice from clinical experience of looking after these women and their pregnancies. [ABSTRACT FROM AUTHOR]

There is a growing body of evidence for a prothrombotic tendency in patients with primary biliary cholangitis (PBC). The aim of the study was to evaluate coagulation disorders in patients with early stage PBC compared to healthy controls and evaluation of their relationship with clinical data, with particular emphasis on minimal hepatic encephalopathy (MHE). Fifty-one participants (PBC group – 38 patients, all patients but one Child-Pugh A; control group – 13 healthy controls) were included in our prospective, single center study. We assessed the plasma levels of sGPV, plasma procoagulant phospholipids (PPL) and rotational thromboelastometry (ROTEM) profiles in all study participants. Porto-systemic encephalopathy syndrome test was used to assess MHE. The sGPV levels were higher in the PBC group compared to the controls: 36.07 ​± ​11.32 ​ng/mL vs 27.04 ​± ​11.72 ​ng/mL, p ​= ​0.031. The PPL level was lower in the PBC group compared to controls resulting in increased clotting time in a factor Xa-based coagulation assay: 54.65 (47.83–58.83) sec. vs 45.90 (43.3–50.5) sec., p ​= ​0.0065. PPL levels were correlated with platelet count (rho ​= ​−0.46, p ​= ​0.001). ROTEM parameters did not differ significantly between groups. Coagulation parameters did not differ significantly between patients with and without MHE. We have showed increased levels of sGPV - a plasma marker of platelet activation by thrombin in patients with early stage PBC compared to healthy controls. We found no relationship between the coagulation disorders and the occurrence of MHE. The PPL level was lower in the PBC group. [ABSTRACT FROM AUTHOR]

Thrombophilia is a group of inherited or acquired coagulation disorders that have been associated with reproductive failure. However, there are still no clear recommendations on whether its inclusion in the initial study of the infertile couple or patients with recurrent implantation failure is necessary. In this discussion paper, based on a SWOT (strengths, weaknesses, opportunities, threats) analysis, the different aspects of the repercussions of thrombophilia screening and treatment in reproduction are evaluated. To avoid possible subjectivity in the analysis and results of this study, researchers followed Oxford criteria for the evaluation of evidence. The results from the evaluation of the reviewed bibliography seem to indicate that, pending new evidence, it would be advisable not to include thrombophilia screening in the initial baseline study of the infertile couple. There is no evidence to support a clear association between thrombophilia and implantation failure or infertility. Thrombophilia testing in this setting may increase cost, with minimal potential benefit and lead to inappropriate use of anticoagulants with possible deleterious adverse effects. Future well-designed studies are needed to assess the possible benefit of anticoagulant therapy in infertile thrombophilic patients with implantation failure. [ABSTRACT FROM AUTHOR]

Trauma induced coagulopathy (TIC) is common after severe trauma, increasing transfusion requirements and mortality among patients. TIC has several phenotypes, with primary hyperfibrinolysis being among the most lethal. We aimed to investigate the contribution of hypercoagulation, hemodilution, and fibrinolytic activation to the hyperfibrinolytic phenotype of TIC, by examining fibrin formation in a plasma-based model of TIC. We hypothesized that instabilities arising from TIC will be due primarily to increased fibrinolytic activation rather than hemodilution or tissue factor (TF) induced hypercoagulation. The influence of TF, hemodilution, fibrinogen consumption, tissue plasminogen activator (tPA), and the antifibrinolytic tranexamic acid (TXA) on plasma clot formation and structure were examined using rheometry, optical properties, and confocal microscopy. These were then compared to plasma samples from trauma patients at risk of developing TIC. Combining TF-induced clot formation, 15 % hemodilution, fibrinogen consumption, and tPA-induced fibrinolysis, the clot characteristics and hyperfibrinolysis were consistent with primary hyperfibrinolysis. TF primarily increased fibrin polymerization rates and reduced fiber length. Hemodilution decreased clot optical density but had no significant effect on mechanical clot stiffness. TPA addition induced primary clot lysis as observed mechanically and optically. TXA restored mechanical clot formation but did not restore clot structure to control levels. Patients at risk of TIC showed increased clot formation, and lysis like that of our simulated model. This simulated TIC plasma model demonstrated that fibrinolytic activation is a primary driver of instability during TIC and that clot mechanics can be restored, but clot structure remains altered with TXA treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to retrospectively analyze Thrombelastography (TEG) data of severe burn patients to provide a clinical basis for timely diagnosis and treatment of coagulation dysfunction.Methods: The present study comprised burn patients with full thickness TBSA ≥ 60%. The patients included in the study were admitted to the Third Affiliated Hospital of Inner Mongolia Medical University between March 2019 and March 2022 and died within 10 days. Patient demographic and clinical data, including abbreviated burn severity index (ABSI) score, full thickness and overall total surface burn area (TBSA), injury cause, International Society on Thrombosis and Hemostasis (ISTH) score, were retrieved from the electronic medical record system. TEG data (including ACT, K, α, MA and LY30), platelet count (PLT), mean platelet volume (MPV) and platelet distribution width (PDW) data were obtained from the records of included patients for analysis.Results: A total of 9 patients were enrolled. The average burn area was 90.0% TBSA and the full-thickness TBSA was 72.0%. The results showed that α, MA and PLT count values were significantly lower relative to those at obtained throughout admission period (all p < 0.05). PDW and MPV were significantly higher compared with the values at admission (all p < 0.05). ACT time was significantly longer from day 2 after severe burn compared with the ACT time at admission (all p < 0.05). LY30 value from day 3 after severe burn was significantly higher compared with the value at admission (p < 0.05). One patient was diagnosed with diffuse intravascular coagulation (DIC) on admission, whereas eight patients were diagnosed with DIC on the day of death.Conclusion: Coagulation dysfunction after severe burn is mainly characterized by procoagulant disorders and hyperfibrinolysis, which can be timely detected by TEG. Coagulation after severe burn exhibits a gradual aggravation, and can lead to death of patients. [ABSTRACT FROM AUTHOR]

Various studies have reported discordant results on the magnitude and direction of burn-induced coagulopathy (BIC), which has recently been associated with multiple organ dysfunction syndrome (MODS) and death. The increased mechanistic understanding of BIC is due, in part, to novel assays that have expanded the armamentarium beyond traditional tests like PT and aPTT. Still, BIC is a dynamic process, and the progression is difficult to define in the thermally-injured. To this end, we aimed to enhance the understanding of burn-induced coagulation abnormalities by employing functional assessments of platelet aggregation, viscoelastic kinetics, and thrombin generation in an extensive burn model in swine. Anesthetized Yorkshire pigs sustained 40% total body surface area (TBSA) full-thickness contact burns and recovered in metabolic cages. Blood was collected at baseline (BL), as well as 6, 24, and 48 h after injury. A significant effect of burn (P < 0.0001) was seen on platelets, with mild thrombocytopenia apparent at 24 h. While slight decreases in aPTT were not significant, rotational thromboelastometry (ROTEM) analysis revealed hypercoagulation 6 and 24 h after burn by a decreased clotting time. Maximum clot firmness increased after burn, but was not statistically significant until 48 h. Hypercoagulation was not supported by platelet aggregation, as the response to ADP was greatly and persistently diminished, and the response to collagen was unchanged. Endogenous thrombin potential was significantly reduced at 6 and 24 h after burn (P < 0.0001), and also correlated with a number of ROTEM parameters and collagen-induced platelet aggregation. In contrast, PT was not correlated with other measured parameters. Taken together, novel coagulation parameters may be more sensitive than PT in characterizing coagulopathy in the setting of burns. The data presented herein makes initial strides to report the natural history of several of these variables over time in a large animal model of extensive burns, indicating early hypercoagulability followed by hypocoagulation. Future work will elucidate the effects of standard of care. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF), also known as fulminant hepatitis, coagulation disorders, and worsening mental status. It has a poor prognosis and high mortality rate. Among these, the top 10 upregulated genes included GKA-DPA1, IGLL5, PLA2G7, CCL5, IGLJ, GUSBP11, RHOBT1, IGLL3P, CCL18, and ADRBK2. On the other hand, the top 10 downregulated genes were SLC6A1, PID1, AVPR1A, PP1R1A, ST3GAL6, TPST, ERO1LB, SLCO4C1, and KLF15. Furthermore, the DEGs were found to be enriched in processes related to LIAO metastasis and creighton endocrine therapy resistance. To explore the interactions among the DEGs, we constructed a PPI network. This network revealed 16 hub genes that play crucial roles in ALF pathogenesis. Within this network, hsa-mir-375 and hsa-mir-650 were identified as central nodes, indicating their potential importance in ALF. By identifying and analyzing the transcriptional-level ceRNA network, we have provided valuable insights into the etiology of ALF. [ABSTRACT FROM AUTHOR]

Trauma-induced coagulopathy (TIC) refers to an abnormal coagulation process, an imbalance between coagulation and fibrinolysis due to several pathological factors, such as haemorrhage and tissue injury. Platelet activation and subsequent clot formation are associated with mitochondrial activity, suggesting a possible role for mitochondria in TIC. Comprehensive studies of mitochondrial dysfunction in platelets from severe trauma patients have not yet been performed. In this prospective case-control study, patients with severe trauma (ISS≥16) had venous blood samples taken at arrival to the Emergency Unit of a Level 1 Trauma Centre. Mitochondrial functional measurements (Oxygraph-2k, Oroboros) were performed to determine oxygen consumption in different respiratory states, the H 2 O 2 production and extramitochondrial Ca2+ movements. In addition, standard laboratory and coagulation tests, viscoelastometry (ClotPro) and aggregometry (Multiplate) were performed. Measurements data were compared with age and sex matched healthy control patients. Severe trauma patients (n = 113) with a median age of 38 years (IQR, 20–51), a median ISS of 28 (IQR, 20–48) met our inclusion criteria. Oxidative phosphorylation in platelet mitochondria from severe trauma patients significantly decreased compared to controls (34.7 ± 8.8 pmol/s/mL vs. 48.0 ± 19.7 pmol/s/mL). The mitochondrial H 2 O 2 production significantly increased and greater endogenous Ca2+ release was found in the polytrauma group. Consistent with these results, clotting time (CT) increased while maximum clot firmness (MCF) decreased with the EX-test and FIB-test in severe trauma samples. Multiplate aggregometry showed significantly decreased ADP-test (38 ± 12 AUC vs. 112 ± 14 AUC) and ASPI test (78 ± 22 AUC vs. 84 ± 28 AUC) also tended to decrease in mitochondria of polytrauma patients as compared with controls. Significant strong correlation has been demonstrated between mitochondrial OxPhos and MCF while it was negatively correlated with ISS (R2=0.448, P˂0.05), INR, CT and lactate level of patients. The present study revealed that severe trauma is associated with platelet mitochondrial dysfunction resulting in reduced ATP synthesis and impaired extramitochondrial Ca2+ movement. These factors are required for platelet activation, recruitment and clot stability likely thus, platelet mitochondrial dysfunction contributes to the development of TIC. [ABSTRACT FROM AUTHOR]

Plasma proteins involved in coagulation and fibrinolysis are essential to hemostasis. Consequently, their circulating levels and functionality are critical in bleeding and thrombosis development. Well-established laboratory tests to assess these are available; however, said tests do not allow high multiplicity, require large volumes of plasma and are often costly. A novel technology to quantify plasma proteins is quantitative protein mass spectrometry (QPMS). Aided by stable isotope-labeled internal standards a large number of proteins can be quantified in one single analytical run requiring <30 μL of plasma. This provides an opportunity to improve insight in the etiology and prognosis of bleeding and thrombotic disorders, in which the balance between different proteins plays a crucial role. This manuscript aims to give an overview of the QPMS potential applications in thrombosis and hemostasis research (quantifying the 38 proteins assigned to coagulation and fibrinolysis by the KEGG database), but also to explore the potential and hurdles if designed for clinical practice. Advantages and limitations of QPMS are described and strategies for improved analysis are proposed, using as an example the test requirements for antithrombin. Application of this technology in the future could represent a step towards individualized patient care. • Well-established laboratory tests are available for coagulation and fibrinolysis. • Unmet clinical needs for test development exist for undiagnosed bleeding disorders and venous thrombosis risk stratification. • Quantitative targeted proteomics (QPMS) might address these needs through multiplex proteins quantitation. • Application of QPMS in the future could represent a step towards individualized patient care. [ABSTRACT FROM AUTHOR]

In Taiwan, Trimeresurus stejnegeri stejnegeri (Stejneger's Bamboo pitviper) is responsible for more than half of all venomous snakebites annually. This species often causes local envenoming characterized by tissue swelling and pain, occasional local ecchymosis, bullae and blister formation, and lymphangitis and lymphadenitis. The pathophysiology and treatment of potentially life-threatening coagulopathy and defibrinogenation induced by T. s. stejnegeri systemic envenoming have not been specifically addressed. Here, we describe the case of a man who was bitten by T. s. stejnegeri on his right first toe, which later developed into swelling above the ankle. It was found that there was severe hypofibrinogenemia, prolonged prothrombin time, and reduced activities of factors V and XI, plasminogen, and α2-antiplasmin. Even though a favorable outcome was achieved after repeatedly administering specific antivenom, fresh frozen plasma, and cryoprecipitate, probably low effectiveness of antivenom against the coagulopathy and prodigious amounts of replacement products were observed. To control coagulopathy early and avoid the needless replacement of coagulation factor, which are associated with inherent adverse reactions, more frequent serial blood assessment (e.g., every 6 h) and higher initial antivenom doses may be helpful. Knowledge of the specific coagulation factor deficiencies may improve our understanding of the relationship between hemotoxins and the resulting envenoming syndromes in this snakebite. [Display omitted] • Defibrinogenation and coagulopathy caused by Trimeresurus stejnegeri bite have uncommonly been reported. • We observed hypofibrinogenemia and reduced activities of factors V and XI, plasminogen, and α2-antiplasmin after the bite. • A repeated administration of a specific antivenom and blood component replacement was performed to treat the patient. • Frequent blood assessments and large initial antivenom doses may help achieve early control of coagulopathy. • Coagulation factors and fibrinogen levels should be included to better evaluate consumptive coagulopathy. [ABSTRACT FROM AUTHOR]

Background: The reversal of anticoagulant or antiplatelet medications is a priority in the management of patients with severe injury with the goal of minimizing further bleeding without thrombotic complications. There are few studies, however, evaluating the dosing of reversal agents in the setting of trauma specific to patients with extreme obesity. Nevertheless, clinicians must still make decisions, balancing concerns of ongoing bleeding with excessive thrombosis.Objectives: We describe the literature pertaining to dosing of medications used for the reversal of both drug-induced and trauma-related coagulopathy with the intent of providing a framework for clinicians to make dosing decisions in this challenging population.Discussion: Obesity is known to impact both the volume of distribution and the clearance of medications, but these changes are not usually linear with size nor are they uniform across drugs. Current strategies for dosing reversal agents in obesity include a capped dose (e.g., prothrombin complex concentrates), fixed dosages (e.g., andexanet alfa, idarucizumab, and tranexamic acid), and weight-based dosing (e.g., desmopressin). Extreme obesity, however, was not highly prevalent in the studies that have validated these dosing strategies. In fact, many of the clinical studies fail to report the average weight of the patients included.Conclusion: Future studies should make efforts to increase reporting of patients with obesity included in clinical trials along with results stratified by weight class. In the meantime, doses listed in product labels should be used. Desmopressin should be dosed using either ideal body weight or a dose-capping strategy. [ABSTRACT FROM AUTHOR]

Background: Coagulopathy in cardiac surgery is frequently associated with acquired hypofibrinogenaemia, which can be treated with either purified fibrinogen concentrate (FC) or cryoprecipitate. Because the latter is not purified and therefore contains additional coagulation factors, it is thought to be more effective for treatment of coagulopathy that occurs after prolonged cardiopulmonary bypass (CPB). We examined the impact of CPB duration on the efficacy of the two therapies in cardiac surgery.Methods: This was a post hoc analysis of the Fibrinogen Replenishment in Surgery (FIBRES) RCT comparing FC (4 g) to cryoprecipitate (10 U) in adult patients undergoing cardiac surgery and experiencing bleeding with acquired hypofibrinogenaemia (n=735). The primary outcome was allogeneic blood products transfused within 24 h after CPB. Subjects were stratified by CPB duration (≤120, 121-180, and >180 min). The interaction of treatment assignment with CPB duration was tested.Results: Subjects with longer CPB duration experienced more bleeding and transfusion. With CPB time ≤120 min (FC, n=134; cryoprecipitate, n=146), the ratio of least-squares means between the FC and cryoprecipitate groups for total allogeneic blood products at 24 h was 0.90 (one-sided 97.5% confidence interval [CI]: 0.00-1.12); P=0.004. For subjects with CPB time 121-180 min, it was 1.00 ([one-sided 97.5% CI: 0.00-1.22]; P=0.03], and for CPB time >180 min it was 0.91 ([one-sided 97.5% CI: 0.00-1.12]; P=0.005). Results were similar for all secondary outcomes, with no interaction between treatment and CPB duration for all outcomes.Conclusions: The haemostatic efficacy of FC was non-inferior to cryoprecipitate irrespective of CPB duration in cardiac surgery.Clinical Trial Registration: NCT03037424. [ABSTRACT FROM AUTHOR]

Viperid snakebite envenoming is often characterized by a venom-induced consumption coagulopathy due to the procoagulant effect of venom components, resulting in the alteration of clotting laboratory tests. There is a growing trend to use rotational thromboelastometry in the assessment of clotting disturbances in a variety of pathologies, although its use in experimental models of envenoming has been limited. An in vivo murine model was implemented to assess the coagulopathy induced by three Central American viperid venoms which have different mechanisms of action on clotting factors, i.e., Bothrops asper , Crotalus simus and Bothriechis lateralis. Venom was injected by the intravenous route and blood samples were collected at 1, 3, 5 and 24 h after envenoming. Coagulopathy was assessed by standard clotting tests and by routine rotational thromboelastometric parameters. In addition, the changes in platelet number were followed. B. asper and C. simus venoms induced coagulopathy and thrombocytopenia 1 h after injection, followed by a slow recovery at 3, 5 and 24 h, although the majority of clotting parameters were still significantly affected by 3 and 5 h, and were corrected by 24 h. In general, a similar time-course of alterations was observed for standard clotting tests and most rotational thromboelastomeric assays. However, some thromboelastometric parameters, especially those related to Fibtem, showed more drastic alterations than standard tests and remained altered even at 24 h in some cases. This is likely related to the low fibrinogen concentration observed at most time intervals. B. lateralis venom did not induce a consumption coagulopathy, although it caused a marked thrombocytopenia. [Display omitted] • Bothrops asper and Crotalus simus venoms induced coagulopathy judged by standard tests and rotational thromboelastometry. • Venom of Bothriechis lateralis did not induce coagulopathy in mice. • The three venoms induced thrombocytopenia. • In most time intervals, similar alterations were detected by both types of tests. • Rotational thromboelastometric parameters were altered at times when standard clotting tests had recovered. [ABSTRACT FROM AUTHOR]

Background: Reversal of antithrombotic agents and treatment of life-threatening bleeding episodes from coagulopathies can be a stressful scenario for clinicians, especially when the selection of treatment options should occur quickly. Understanding the options available for these agents requires emergency physicians to be familiar with the current data surrounding new therapies and dosing strategies for the treatment of bleeding from reversible and nonreversible antithrombotics and coagulopathic conditions.Objective: To provide quick resource guides for the reversal of major or life-threatening bleeding caused by antithrombotic agents or in the setting of coagulopathies.Methods: A literature search for articles published through September 2021 related to antithrombotic reversal and treatment of acute bleeding from coagulopathies was conducted using the PubMed clinical database. Selected articles were used to generate 5 guidance tables in this clinical review.Discussion: Four guidance tables for how to treat major or life-threatening bleeding from antithrombotic agents and 1 table for how to manage life-threatening bleeding for coagulopathies are presented as a quick reference tool for the emergency physician. Additional information on upcoming reversal agents and possible treatment options are provided herein.Conclusions: In this clinical review, a series of 5 tables were created to provide quick and comprehensive guidance for the emergency physician when treating major or life-threatening bleeding caused by antithrombotic agents or coagulopathies. © 2022 Elsevier Inc. [ABSTRACT FROM AUTHOR]

The pathophysiology after polytrauma represents a complex network of interactions. While it was thought for a long time that the direct and indirect effects of hypoperfusion are most relevant due to the endothelial permeability changes, it was discovered that the innate immune response to trauma is equally important in modifying the organ response. Recent multi center studies provided a "genetic storm" theory, according to which certain neutrophil changes are activated at the time of injury. However, a second hit phenomenon can be induced by activation of certain molecules by direct organ injury, or pathogens (damage associated molecular patterns, DAMPS - pathogen associated molecular patterns, PAMPS). The interactions between the four pathogenetic cycles (of shock, coagulopathy, temperature loss and soft tissue injuries) and cross-talk between coagulation and inflammation have also been identified as important modifiers of the clinical status. In a similar fashion, overzealous surgeries and their associated soft tissue injury and blood loss can induce secondary worsening of the patient condition. Therefore, staged surgeries in certain indications represent an important alternative, to allow for performing a "safe definitive surgery" strategy for major fractures. The current review summarizes all these situations in a detailed fashion. [ABSTRACT FROM AUTHOR]

Rattlesnake envenomation may lead to a multitude of clinical effects, including a late onset hemorrhage. Laboratory values such as platelets and fibrinogen are commonly used to assess the risk of developing a life-threatening bleed. To date, no specific threshold has been identified that links a lab value to the risk of bleeding. This has led to widespread practice variability among clinicians managing snake bites. In assessing risk for patients, we apply the concept that the more abnormal the lab values are, the higher the risk probably is. Late onset coagulopathies pose a unique clinical challenge because they indicate the potential risk for a life-threatening hemorrhage, yet they have been identified after hospital discharge. There are currently two antivenom (AV) products on the US market to treat rattlesnake envenomations, a Fab product, CroFab® (BTG, UK) and a F (ab') 2 product, Anavip® (Bioclon, Mexico). This study intended to characterize the incidence and severity of late coagulopathies reported to a Regional Poison Center (RPC) and hypothesized that late coagulopathies occur at rates higher than previously reported in the literature. Additionally, we sought to compare rates of late coagulopathy between Fab and F (ab') 2 AV. The investigators performed an in-depth review of all suspected snakebite envenomations from 2018 to 2020 that presented to an Arizona healthcare facility in the RPC's catchment area between January 2018 through December of 2020. Patients were excluded from analysis if they did not receive any antivenom, had an incomplete medical record with the APDIC, were diagnosed as something other than a rattlesnake bite or had a known medical history that clouded the diagnosis or assessment of a rattlesnake envenomation. In total, 522 records were reviewed of which 283 patients met the inclusion criteria. There were 149 patients who received Fab AV and 134 who received F (ab') 2. No significant baseline or demographic differences existed between the groups. 95 of the 283 patients developed a late onset coagulopathy. 39% of the late onset coagulopathies were delayed, 32% were recurrent and 29% were persistent. When comparing the two different AV products, delayed or recurrent coagulopathies occurred in 36% of Fab AV- and 10% of F (ab') 2 treated patients. Persistent coagulopathies occurred in 17% of Fab AV- and 8% of F (ab') 2 treated patients. Interestingly, there were zero cases of late hypofibrinogenemia in any of the 134 F (ab') 2 treated patients compared to 26% of all Fab treated ones. The average onset of late coagulopathy post-bite was 8 days for Fab AV and 7 for F (ab') 2. The results from this study suggest the total rate of late onset coagulopathies may be underestimated. Additionally, our results suggest the potential that F (ab') 2 AV may be associated with fewer late onset coagulopathies, especially late onset hypofibrinogenemia. [Display omitted] • Two antivenoms available for rattlesnake envenomation in US, Fab and F(ab')2. • F(ab')2 antivenom significantly reduces chance of late coagulopathies. • Late coagulopathies occur with either antivenom on average 7–8 days post-envenomation. • No patient treated with F(ab')2 antivenom developed a late hypofibrinogenemia. [ABSTRACT FROM AUTHOR]

Severe Lonomia caterpillar envenoming is an increasing hazard in South America. It can trigger severe coagulation disorders that can progress to systemic complications and death. We report the first documented case of severe Lonomia caterpillar envenoming in Guyana. It was managed using antivenom provided by the Brazilian Ministry of Health as part of humanitarian support. This case describes a successful international collaboration driving a favorable outcome for the envenomed patient. [Display omitted] • Lonomism is an increasing hazard in South America. • Lonomia obliqua and Lonomia achelous are the most involved species. • Antivenom is the key treatment of Lonomism. • Antivenom can be obtained through an international cooperation process. [ABSTRACT FROM AUTHOR]

Severe inflammation and oxidative stress are characteristics of sepsis-associated kidney injury with high morbidity and mortality. Eriocitrin (ERI) has shown promise in suppressing sepsis-associated kidney injury and LPS-induced periodontal disease, however, its efficacy in alleviating SAKI remains unexplored. This study aimed to investigate the therapeutic potential of ERI on SAKI through in vivo and in vitro experiments, elucidating its underlying mechanism. The therapeutic effects of ERI against SAKI were evaluated by survival rate, changes of serum creatinine (Scr) and blood urea nitrogen (BUN) and statistic of renal histological score in a Cecal ligation and puncture (CLP)-induced septic mice. Impactions about anti-coagulation, anti-inflammation, anti-oxidative stress and improvement of mitochondrial damage and mitochondrial morphology were further assayed. In vitro, HUVECs upon stimulation of LPS with or without different dosage of ERI, followed by evaluating changes in inflammation, mitochondrial dynamic equilibrium and signaling pathways. ERI demonstrated ameliorative effects on SAKI by attenuating inflammation, oxidative stress and coagulation evidenced by the improved survival rate, alleviated kidney histological injury, declined BUN and Scr in serum and diminished levels of inflammation cytokines, and coagulation factors. Mechanistically, ERI suppressed DRP1-regulated mitochondrial fission and promoted OPA1-modulated mitochondrial fusion by activating Nrf2 in septic mice and LPS-stimulated HUVECs, which maintained mitochondrial dynamic equilibrium, improved mitochondrial morphology, assured integrity of mitochondrial function, decreased oxidative stress, impeded overwhelming inflammation, and thus, played a pivotal role in ERI's protection against SAKI. Our data confirmed the therapeutic potential of ERI in mitigating SAKI，suggesting its viability as a pharmacological agent in clinic settings. • ERI markedly improved survival rate of septic mice, mitigated sepsis-induced acute kidney injury. • ERI suppressed coagulation disorder. • ERI down-regulated inflammation and ROS associated with the integrity of mitochondrial function. • ERI maintained mitochondrial dynamic equilibrium through inhibiting mitochondrial fission and promoting fusionby Nrf2. [ABSTRACT FROM AUTHOR]

Background: Short bowel syndrome (SBS) refers to a malabsorptive state caused by extensive resection of the intestinal tract that leads to chronic diarrhea, electrolyte disturbances, and malnutrition. Although relatively uncommon, patients with SBS can present to the emergency department with more serious complications that are potentially life-threatening. Among these complications, coagulopathy secondary to SBS is an underrecognized condition.Case Report: We present a case of severe coagulopathy secondary to vitamin K deficiency in SBS. The patient presented with unexplained coagulopathy and spontaneous bleeding in multiple organs. With a review of surgical history and detailed clinical evaluation, SBS complicated with vitamin K deficiency was diagnosed, and the patient was treated successfully. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: When a patient with a history of repeated intestinal surgery presents with diarrhea, malnutrition, or electrolyte abnormalities, emergency physicians should suspect SBS. Among complications of SBS, vitamin K deficiency is a rare but serious cause of unexplained coagulopathy presenting to the emergency department. Understanding the pathophysiology of SBS facilitates early identification of complications and improves patient outcomes. [ABSTRACT FROM AUTHOR]

Severe COVID-19 patients frequently present thrombotic complications which commonly lead to multiorgan failure and increase the risk of death. Severe SARS-CoV-2 infection induces the cytokine storm and is often associated with coagulation dysfunction. D -dimer, a hallmark of venous thromboembolism (VTE), is observed at a higher level in the majority of hospitalized COVID-19 patients. The precise molecular mechanism of the disproportionate effect of SARS-CoV-2 infection on the coagulation system is largely undefined. SARS-CoV-2 –induced endotheliopathy and, induction of cytokines and growth factors (GFs) most likely play important roles in platelet activation, coagulopathy, and VTE. Generally, viral infections lead to systemic inflammation and induction of numerous cytokines and GFs and many of them are reported to be associated with increased VTE. Most importantly, platelets play key thromboinflammatory roles linking coagulation to immune mediators in a variety of infections including response to viral infection. Since the pathomechanism of coagulopathy and VTE in COVID-19 is largely undefined, herein we highlight the association of dysregulated inflammatory cytokines and GFs with thrombotic complications and coagulopathy in COVID-19. [Display omitted] • There is association between a cytokine storm and coagulation dysfunction in reported viral pandemics including COVID-19. • An increased TF expression on different cells and decreased TFPI likely contribute to the coagulation dysfunction. • Platelet activation markers P-selecin and sCD40L along with growth factors play important roles in COVID-19 pathogenesis. • The pattern of coagulation pathway in COVID-19 appears to be different than the traditional coagulation pathway. [ABSTRACT FROM AUTHOR]

Introduction: Uncontrolled bleeding is the primary cause of death in complex liver trauma and perihepatic packing is regularly utilized for hemorrhage control. The purpose of this study was to investigate the effectiveness of a novel inflatable device (the airbag) for perihepatic packing using a validated liver injury damage control model in swine.Material and Methods: The image of the human liver was digitally isolated within an abdominal computerized tomography scan to produce a silicone model of the liver to mold the airbag. Two medical grade polyurethane sheets were thermal bonded to the configuration of the liver avoiding compression of the hepatic pedicle, hepatic veins, and the suprahepatic vena cava after inflation. Yorkshire pigs (n = 22) underwent controlled hemorrhagic shock (35% of the total blood volume), hypothermia, and fluid resuscitation to reproduce the indications for damage control surgery (coagulopathy, hypothermia, and acidosis) prior to a liver injury. A 3 × 10 cm rectangular segment of the left middle lobe of the liver was removed to create the injury. Subsequently, the animals were randomized into 4 groups for liver damage control (240 min), Sponge Pack (n = 6), Pressurized Airbag (n = 6), Vacuum Airbag (n = 6), and Uncontrolled (n = 4). Animals were monitored throughout the experiment and blood samples obtained.Results: Perihepatic packing with the pressurized airbag led to significantly higher mean arterial pressure during the liver damage control phase compared to sponge pack and vacuum airbag 52 mmHg (SD 2.3), 44.9 mmHg (SD 2.1), and 32 mmHg (SD 2.3), respectively (p < 0.0001), ejection fraction was also higher in that group. Hepatic hemorrhage was significantly lower in the pressurized airbag group compared to sponge pack, vacuum airbag, and uncontrolled groups; respectively 225 ml (SD 160), 611 ml (SD 123), 991 ml (SD 385), 1162 ml (SD 137) (p < 0001). Rebleeding after perihepatic packing removal was also significantly lower in the pressurized airbag group; respectively 32 ml (SD 47), 630 ml (SD 185), 513 ml (SD 303), (p = 0.0004). Intra-abdominal pressure remained similar to baseline, 1.9 mmHg (SD 1), (p = 0.297). Histopathology showed less necrosis at the border of the liver injury site with the pressurized airbag.Conclusion: The pressurized airbag was significantly more effective at controlling hepatic hemorrhage and improving hemodynamics than the traditional sponge pack technique. Rebleeding after perihepatic packing removal was negligible with the pressurized airbag and it did not provoke hepatic injury. [ABSTRACT FROM AUTHOR]

• Factor XI deficiency in plasma was not correlated with clinical bleeding phenotype. • With 1 pM of tissue factor, a non-significant decrease of TGA was observed in FXI deficiency bleeders. • During pregnancy, a normalization of thrombin generation was observed in FXI deficiency. Factor XI (FXI) deficiency is characterized by a lack of correlation between FXI plasma levels and the occurrence of hemorrhagic events. The main objective of our study was to determine whether thrombin generation assay (TGA) could be used to assess the hemorrhagic phenotype of patients with FXI deficiency. All patients had confirmed laboratory measurement of FXI < 50% in two plasma samples. Relevant bleeding history was evaluated by a senior physician. TGA was performed with Calibrated Automated Thrombography, in platelet poor plasma, from patients and healthy controls. The assay was performed with PPP low reagent (1 pM of human tissue factor). Seventy-six patients with FXI deficiency were included between 2011 and 2020. Among them, eight patients had severe deficiency (FXI < 15%). Mean age was 34 years [range: 9–77]. Endogenous thrombin potential (ETP) was significantly lower in patients with FXI deficiency and bleeding (573 nM·min [225–1214]) or no bleeding (732 nM·min [222–1435]), compared to healthy controls (1184 nM·min [933–1518]). No difference was observed for ETP and peak between patients with FXI deficiency and bleeding and patients with FXI deficiency and no bleeding. No difference was observed for ETP (923 nM·min [377–1497] vs 1063 nM·min [252–2529]), peak (82 nM [28–154] vs 131 nM [20–330]) or velocity (13.7 nM/min [3.6–29.6] vs 26.5 nM/min [2.5–90]) in women with (n = 4) and without history (n = 17) of post-partum bleeding. No difference of thrombin generation was observed in pregnant women with FXI deficiency (ETP: 1395 nM·min [351–2529]; peak: 154 nM [26–330]; velocity: 29.6 nM/min [4.1–90.0]), compared to healthy controls and a control group of healthy pregnant women. In conclusion, under our experimental condition, a non-significant decrease of thrombin generation was observed in plasma samples of patients with FXI deficiency and bleeding. Our results suggest an increase of coagulation parameters during pregnancy in women with FXI deficiency. A larger sample size or other experimental conditions are required to evaluate the use of TGA in FXI deficiency. [ABSTRACT FROM AUTHOR]

The activation of coagulation, inflammation and other pathways is the basic response of the host to infection in sepsis, but this response also causes damage to the host. Brain-derived extracellular vesicles (BDEVs) have been reported to cause a hypercoagulable state that can rapidly develop into consumptive coagulopathy, which is consistent with the pathophysiological process of sepsis-induced coagulopathy. However, the role of BDEVs in sepsis-induced coagulopathy remains unclear. Male Sprague-Dawley (SD) rats were used for sepsis modeling using cecal ligation puncture (CLP). Flow cytometry was used to measure the levels of circulating BDEVs. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of plasminogen activator inhibitor type 1 (PAI-1), thrombin-antithrombin (TAT), D-dimer, fibrinogen(Fib), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and IL-6. Nanoparticle tracking analysis (NTA) and Transmission electron microscopy (TEM) were used to identify BDEVs. Western blot (WB) was used to determine the expression of glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), bax, bcl-2 and cleaved caspase-3. Hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining were performed to detect tissue injury. Survival was monitored over the course of 168 h. We found that a large number of BDEVs were released into the circulating blood in septic rats. Moreover, we observed that BDEVs injection activated the systemic coagulation reaction and induced lung, liver and kidney inflammation and apoptosis(P <.05). Compared with BDEVs from sham-operated rats, BDEVs from septic rats exacerbated this process(P <.05). This finding suggests that inhibiting BDEVs may yield therapeutic benefits in the treatment of sepsis-induced coagulopathy. • Brain-derived extracellular vesicles were released into blood in septic rats. • Brain-derived extracellular vesicles induced coagulopathy and tissue damage. • Brain-derived microvesicles from septic rats aggravated coagulopathy and organ injury. [ABSTRACT FROM AUTHOR]

Background: Patients with severe burns often show systemic coagulation changes in the early stage and even develop extensive coagulopathy. Previous studies have confirmed that soluble TREM-like transcript-1 (sTLT-1) mediates a novel mechanism of haemostasis and thrombosis in inflammatory vascular injury. At present, the role of sTLT-1 in patients with severe burns is not well known.Objective: To investigate the early association between sTLT-1 levels and markers of burn severity, coagulation disorders, endothelial permeability, shock and prognosis in patients with severe burns.Methods: A prospective, observational study was conducted with 60 severe burn patients (divided into a death group and a survival group according to 30-day prognosis) admitted to our hospital. Twenty-eight healthy volunteers were recruited as the control group. Blood components at 48 h after burn were analysed for sTLT-1 and biomarkers reflecting platelet activation, shock, endothelial glycocalyx damage, capillary leakage, haemostasis, fibrinolytic activity, natural anticoagulation and blood cells. We compared the three groups, analysed the correlation between sTLT-1 and biomarkers, and investigated the predictive value of sTLT-1 for 30-day prognosis.Result: Compared with the surviving patients, the patients who died had a lower degree of platelet activation [lower sTLT-1, platelet factor 4 (PF-4) and platelet counts] and a higher degree of burn [higher abbreviated burn severity index score (ABSI score)], shock (higher lactate), endothelial glycocalyx damage [higher syndecan-1 and soluble thrombomodulin (sTM)] and capillary leakage [higher resuscitation fluid (0-48 h), lower albumin] as well as decreased haemostasis [higher activated partial prothrombin time (APTT), lower fibrinogen and thrombin-antithrombin III complex (TAT)], increased fibrinolytic activity [higher D-dimer and tissue-type plasminogen activator (tPA)] and decreased natural anticoagulation [lower protein C (PC) and protein S (PS)]. Higher D-dimer (P = 0.013) and lower PF-4 (P = 0.001) were significantly independently associated with lower sTLT-1. Low circulating sTLT-1 (a unit is 50 pg/mL) (odds ratio [OR] 2.08 [95% CI 1.11-3.92], P = 0.022) was an independent predictor of increased 30-day mortality.Conclusion: Low sTLT-1 levels at 48 h after burn in patients with severe burns is associated with increased coagulation disorders. Low circulating sTLT-1 levels were an independent predictor of increased 30-day mortality. [ABSTRACT FROM AUTHOR]

Viscoelastic assay has been used in liver transplantation since 1985 and shown to be beneficial in detecting coagulopathy and to guide transfusion. The objective of this study was to review and evaluate the current uses of viscoelastic assay among US liver transplantation programs. Anesthesia program directors at all 137 liver transplantation centers in the United States were contacted via email and asked to complete a 21-item survey. The primary outcome measure was the percentage of viscoelastic assay used in the perioperative management of liver transplantation. Secondary outcome measures were institutional demographics, physician training level, and device demographics. Sixty-one of 137 (46%) centers responded. Liver transplantations were performed in the university setting at 48 of the 61 centers (77%), with a modal value of 11 to 50 liver transplantations a year and 74% in adult patients only. Most of the institutions (n = 57, 92%) had access to either rotational thromboelastometry or thrombelastography during liver transplantation. Most centers (n = 54; 87%) also used viscoelastic monitoring routinely (>60% of the time), including 42 (67.7%) that always used viscoelastic assay intraoperatively during liver transplantation. Thirty-five centers (59%) used it preoperatively, and 51 (84%) used it postoperatively. Most viscoelastic assay users (68%) learned how to use it through self-education and 10.5% learned during their fellowship or from a superuser or colleagues. Currently, viscoelastic monitoring is widely available and routinely used in most US liver transplantation centers regardless of university or private practice setting, but training in it is limited. Only 21.1% of respondents reported that they received any type of official training in viscoelastic assay interpretation. [ABSTRACT FROM AUTHOR]

Snakebite accidents are a public health problem that affects the whole world, causing thousands of deaths and amputations each year. In Brazil, snakebite envenomations are caused mostly by snakes from the Bothrops genus. The local symptoms are characterized by pain, swelling, ecchymosis, and hemorrhages. Systemic disturbances can lead to necrosis and amputations. The present treatment consists of intravenous administration of bothropic antivenom, which is capable of reversing most of the systemic symptoms, while presenting limitations to treat the local effects, such as hemorrhage and to neutralize the snake venom serine protease (SVSP). In this context, we aimed to evaluate the activity of selective serine protease inhibitors (pepC and pepB) in combination with the bothropic antivenom in vivo. Further, we assessed their possible synergistic effect in the treatment of coagulopathy and hemorrhage induced by Bothrops jararaca venom. For this, we evaluated the in vivo activity in mouse models of local hemorrhage and a series of in vitro hemostasis assays. Our results showed that pepC and pepB, when combinated with the antivenom, increase its protective activity in vivo and decrease the hemostatic disturbances in vitro with high selectivity, possibly by inhibiting botropic proteases. These data suggest that the addition of serine protease inhibitor to the antivenom can improve its overall potential. [Display omitted] • Peptides inhibitors associated with bothropic antivenom improve the neutralization of local hemorrhage. • Fibrinogen consumption and coagulopathy decreased using bothropic antivenom associated to selective peptides inhibitors. • Venom serine protease inhibitors do not affect the human coagulation cascade. [ABSTRACT FROM AUTHOR]

Arterial pseudoaneurysm formation after transradial cardiac catheterization is a rare post-procedural complication occurring in less than 0.1% of radial arterial access. While the data on the management of femoral pseudoaneurysms is extensive, few studies have evaluated how these techniques apply for small vessel arterial pseudoaneurysms. We present the case of an octogenarian man with a radial artery pseudoaneurysm after transradial coronary intervention that failed initial compression therapy, and surgical intervention was avoided by applying continuous compression therapy with a TR Band® radial compression device. [ABSTRACT FROM AUTHOR]

Background: The presence of acute coagulopathy and its effect on prognosis in burn patients are unclear. No studies are extant verifying early coagulopathy before fluid administration in burn patients. The current study focused on arrival coagulopathy before volume resuscitation was begun in earnest.Methods: Data from 137 burn patients transported directly to the hospital without fluid administration from January 2006 to December 2019 were analyzed retrospectively.Results: The non-survival group had significantly increased age, total burn surface area (TBSA) burned, various scoring systems, prothrombin time-international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), the presence of coagulopathy, and lactate levels compared to the survival group. In the logistic regression analysis, the incidence of coagulopathy was independently associated with mortality. The coagulopathy group had significant increases in TBSA burned, various scoring systems, PT-INR, APTT, lactate levels, and the mortality than the noncoagulopathy group. The prognostic burn index (PBI) was significantly correlated with PT-INR and APTT. We also found a significant correlation between the serum lactate and the PT-INR, APTT, and PBI.Conclusions: Acute coagulopathy of burn patients might be present on arrival to the hospital before fluid replacement which is an independent risk factor for in-hospital mortality. [ABSTRACT FROM AUTHOR]