Activated Coagulation Factor Research Articles

Coagulation abnormalities following brown recluse spider (Loxosceles reclusa) envenomation: A description of 2 cases and review of the literature.

Hemostatic abnormalities, including disseminated intravascular coagulation (DIC), are often cited as a common finding in patients following Loxosceles spider envenomation (ie, loxoscelism). The prevalence and severity of coagulopathy, however, particularly following L reclusa (ie, brown recluse) envenomation, is not well described. This study aimed to characterize coagulation laboratory parameters and coagulopathy in patients following L reclusa envenomation. We evaluated the coagulation laboratory parameters (eg, prothrombin time, partial thromboplastin time, coagulation factor activity levels, lupus anticoagulant [LA] testing) of 2 patients seen at our institution following brown recluse spider envenomation. We also comprehensively reviewed the literature for all reported cases of brown recluse spider envenomation and assessed patient demographics, clinical presentations, coagulation laboratory parameters, and outcomes. We identified 2 patients with loxoscelism (1 cutaneous only, 1 systemic with hemolysis) with prolonged partial thromboplastin times but with normal clotting factor levels following envenomation. Literature review identified 263 patients: 12 patients had at least 1 prolonged clotting time, 31 reported a platelet count below 150× 109/L, and there was clinical concern for DIC in 12 cases. The odds of death were statisticallysignificantly higher in patients with clinical concern for DIC than in cases without concern for DIC or coagulopathy (odds ratio, 82.9 [95% CI, 12.6-433.8]; P < .001). Following brown recluse spider envenomation, hemostatic perturbations are infrequent and clinical coagulopathy is uncommon, but the odds of death following a brown recluse spider bite are statisticallysignificantly greater if DIC develops, even when compared to individuals with hemolysis without DIC.

Efficient production of recombinant human FVII in CHO cells using the piggyBac transposon system.

As an important coagulation factor, activated coagulation factor VII (FVIIa) is mainly used to treat the bleeding of hemophilia patients who have developed inhibitory antibodies against FVIII and FIX conventional treatment. Recombinant human factor VII (rhFVII) produced in mammalian cell lines have been developed as the most important resource of FVIIa. However, cell lines express rhFVII protein derived from an exogenous expression vector at a lower level than most other proteins. In the current study, we have shown efficient rhFVII production in CHO cell lines using piggyBac (PB) transposon system. rhFVII is successfully expressed in fed-batch culture of CHO cells, and the expression of rhFVII up to 100 mg/L. Moreover, the purified secreted rhFVII was determined by SDS-PAGE and Western Blot. The coagulation activity was determined by the chromogenic Activity ELISA kit. In conclusion, this study has demonstrated that the piggyBac transposon system can be used for an efficient production of recombinant FVII.

KNG1 mutations (c.618 T > G and c.1165C > T) cause disruption of the Cys206-Cys218 disulfide bond and truncation of the D5 domain leading to hereditary high molecular weight kininogen deficiency.

High molecular weight kininogen (HMWK), encoded by the kininogen-1 (KNG1) gene, is a multifunctional glycoprotein closely associated with the initiation of blood coagulation, tumor growth, and other pathological processes. We conducted a study on the clinical phenotype, genetic mutations, and molecular pathogenesis of a female patient with uterine leiomyosarcoma, who presented with HMWK deficiency and an isolated prolonged activated partial thromboplastin time (APTT). Clinical phenotyping was conducted through APTT mixing studies, quantitative assessments of intrinsic coagulation factor activities, antigen levels of HMWK, and thromboelastography. Genetic analysis revealed a novel mutation within the KNG1 gene. Subsequent bioinformatics analysis focused on the evolutionary conservation of regions flanking codons 618 and 1165 of the KNG1 gene, with an aim of predicting the mutation's functional impact. Clinical phenotypic analysis indicated a severe deficiency of HMWK antigen levels in the patient, with levels below 1.0 % of normal. Genetic sequencing identified two mutation sites in the KNG1 gene: a novel missense mutation in exon 5, c.618 T > G (p.Cys206Trp), which leads to disruption of the disulfide bond between Cys206 and Cys218, and a known nonsense mutation in exon 10, c.1165C > T (p.Arg389X), resulting in truncation of the D5 domain in the HMWK protein and reducing its quantity. These two mutations collectively impact the activation of HMWK within the coagulation system. The compound heterozygous mutations, c.618 T > G (p.Cys206Trp) and c.1165C > T (p.Arg389X), result in a loss of HMWK function, leading to a deficiency in the kinin system and consequently a significant prolongation of the APTT. These findings advance understanding of coagulation factor deficiencies and inform diagnostic and therapeutic approaches for HMWK deficiency, potentially enhancing clinical management strategies.

First modern Russian plasma-derived coagulation factor VIII concentrate (Eytoplasm): Results of clinical study of pharmacokinetics, efficacy and safety

Introduction. Replacement therapy with coagulation factor VIII concentrates remains the standard of care for patients with hemophilia A. In 2023, the drug Eytoplasm, the first modern plasma-derived coagulation factor VIII concentrate developed in the Russian Federation, was authorized for medical use in the Russian Federation.Aim: to study the efficacy, safety, immunogenicity, and pharmacokinetic properties of Eytoplasm.Methods. A multicenter, prospective, open-label clinical trial was conducted in 55 patients over 12 years of age with severe hemophilia A who had previously received treatment with coagulation factor VIII concentrates (at least 150 exposure days). All patients received the drug for prophylactic treatment 2–3 times a week; the treatment duration was 6 months (at least 50 exposure days). In addition, the drug was used to treat bleeding. Ten patients underwent 10 surgical interventions (2 major and 8 minor). Pharmacokinetic parameters were determined after the first administration of the drug to patients and after 6 months of therapy.Results. Eytoplasm pharmacokinetics properties are comparable with other plasma-derived coagulation factor VIII concentrates. No bleeding was recorded in 75.9% of patients. In 92.3 % of patients, a single administration of the drug was sufficient to stop an episode of bleeding. In all participants who completed the study, the residual activity of coagulation factor VIII 48–72 hours after drug administration was at least 1 %. Positive dynamics of APTT was showed during the study. Serious adverse events, allergic reactions, thrombotic and thromboembolic complications were absent in patients. In 3 patients, 4 adverse events associated with the use of the drug were registered: 2 cases of increased serum concentration of direct bilirubin and 2 cases of headache. An inhibitor to coagulation factor VIII was not detected in any patient. In none of the patients who did not have antibodies to parvovirus B19 before the first dose of Eytoplasm, antibodies were detected after 6 months of therapy.Conclusion. Eytoplasm is an effective option for the prevention and treatment of bleeding, and during surgical interventions, including major ones, in patients with hemophilia A. The drug has a favorable safety profi le; its use was not associated with the formation of inhibitory antibodies, allergic reactions, thrombotic and thromboembolic complications.

Perioperative Management of Hemophilia A: An Uncommon Inherited Blood Disorder

Hemophilia A is a rare hematological disorder caused by an inherited X-linked factor VIII deficiency. It can be responsible for significant perioperative bleeding with fatal consequences if not diagnosed and managed correctly in the preoperative phase. We report the case of a 6-month-old infant scheduled for a cure for bilateral inguinal hernia. During the pre-anesthetic consultation, given that the child was uncircumcised and had not yet reached walking age, a blood workout was made, which revealed a prolonged aPTT with a patient/control aPTT ratio of 3.27, without hemorrhagic signs. An activity work-up of clotting factors showed less than 1% of normal levels of active clotting factor VIII. Thus, the diagnosis of a severe form of hemophilia A was made. Recombinant factor VIII was administrated in the preoperative period, with an activity factor VIII control over 60%. The surgical procedure was uneventful, with minimal intraoperative bleeding. Our case emphasizes the importance of prophylactic treatment and a proper pre-anesthetic assessment, which are essential to establish an appropriate management strategy and avoid complications, most of which are fatal.

Correlation between Phenotype and Coagulation Factor Activity Level in Rare Bleeding Disorders: A Systematic Review.

Rare bleeding disorders (RBDs) represent 3 to 5% of congenital bleeding disorders and are primarily inherited in an autosomal recessive manner, with increased prevalence in consanguineous populations. Clinically, RBDs can be accompanied by mild to severe bleeding episodes, often assessed using bleeding assessment tools (BATs) such as the International Society on Thrombosis and Hemostasis (ISTH)-BAT. However, the correlation between bleeding severity and coagulation factor activity levels remains inconsistent. This systematic review investigates this relationship to enhance understanding and improve management strategies for patients with RBD. This review adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered with the International Prospective Register for Systematic Reviews (PROSPERO) (CRD42024504537). Using the PICO (Population, Intervention, Comparator, and Outcomes) framework, the study focused on RBD patients to explore the correlation between coagulation factor activity levels and bleeding severity. A comprehensive search was conducted across PubMed, Scopus, and Web of Science until April 1, 2024, with data extracted on bleeding severity, phenotype, and coagulation factor activity levels. The analysis highlights complex and often inconsistent relationships between coagulation factor levels and the severity of bleeding. In cases of fibrinogen deficiency, three out of four studies (n = 73 of 111 cases, 66%) demonstrated a moderate to strong correlation between fibrinogen levels and bleeding severity. In prothrombin deficiency, one of two studies (n = 16 of 29 cases, 55%) found a strong correlation between FII levels and bleeding severity. Four of six studies (n = 106 of 139 cases, 76%) in FV deficiency found a weak or no correlation between factor activity and bleeding severity. In combined FV and FVIII deficiency, two of three studies (n = 26 of 60 cases, 43%) found a significant correlation between factor activity and bleeding severity. In FVII deficiency, four (of nine) studies with a study population of 325 patients (65%) found a weak correlation between factor activity and severity of bleeding. Almost all studies (five of six studies, n = 114 of 118 patients, 97%) in FX deficiency revealed a strong correlation between FX levels and bleeding severity. In FXI deficiency, most studies (five of seven studies, n = 254 patients, 93%) found a weak or no correlation between factor activity and bleeding severity or symptoms. For FXIII deficiency, there was a moderate to strong correlation between FXIII activity and bleeding severity in all three studies (n = 61 patients). In conclusion, despite current controversies, this review highlights a moderate or strong correlation between factor activity and bleeding severity in fibrinogen, FX, and FXIII deficiencies, but no correlation or weak correlation for FV, FVII, and FXI deficiencies. Further prospective studies with standardized BATs on a large number of patients are needed to better understand these relationships and optimize patient management.

Preclinical characterization of XB002, an anti-tissue factor antibody-drug conjugate for the treatment of solid tumors.

Tissue factor (TF) is overexpressed in various cancers, where its expression is generally associated with poor disease outcomes. XB002 is an anti-TF antibody-drug conjugate designed to deliver a cytotoxic payload to TF-expressing tumors while minimizing adverse events related to disruption of TF function, notably bleeding. XB002 is composed of a zovodotin linker-payload conjugated to a monoclonal antibody (clone 25A3) that binds to TF with high affinity (KD = 0.86 nM). In vitro coagulation studies indicated that 25A3 did not interfere with the clotting cascade; at a 100 nM concentration, 25A3 had no effect on activation of coagulation factor X or thrombin generation. XB002 was internalized in TF-expressing cancer cell lines and displayed potent cytotoxic activity at sub-nanomolar concentrations. When evaluated in the HPAF-II xenograft model, XB002 (1.5 mg/kg, IV) given once weekly for 2 weeks induced complete regression with no tumor growth even at 5 weeks after the second dose. In murine patient-derived xenograft models, a single dose of XB002 (10 mg/kg, IV) inhibited tumor growth across multiple cancer models including bladder, cervical, gastric, head and neck squamous cell carcinoma (HNSCC), and non-small cell lung cancer. Further, complete tumor regression was observed in both the cervical and HNSCC models by 30 days post-treatment. In non-human primate models, XB002 showed exposure in the desired range and no evidence of bleeding or neutropenia. Taken together, these data demonstrate potential anti-tumor activity across a spectrum of oncology indications and strongly support its clinical development.

Age Is Just a Number: Ontogenetic Conservation in Activation of Blood Clotting Factors VII, X, and XII by Caucasus Blunt-Nosed Viper (Macrovipera lebetina obtusa) Venoms.

This study examined the pathophysiological effects of venoms from neonate and adult specimens of the viperid snake Macrovipera lebetina obtusa, focusing on their ability to activate various blood clotting factors in human plasma. All venoms exhibited strong procoagulant properties. In concentration-response tests, the clotting potency of the neonate venoms fell within the range of their parents' maximum clotting velocities and areas under the curve. Intriguingly, females were more potent than males within each age group, but this requires a larger sample size to confirm. Antivenom neutralization efficacy was equipotent across age groups. The venoms potently activated Factor X (FX) robustly, consistent with previous knowledge of this genus. For the first time, the ability to activate Factors VII (FVII) and XII (FXII) was identified in this genus, with FXII exhibiting particularly strong activation. The study found no significant ontogenetic variation in procoagulant venom potency on human plasma, convergent with the Daboia genus, the other large-bodied lineage within the Palearctic viperid clade. However, the activation of FXII and FVII reveals previously undocumented pathways in the procoagulant activity of these venoms, contributing to the broader understanding of venom evolution and its clinical impacts. These findings have implications for venom biodiscovery and the development of antivenoms, highlighting the complexity of clotting factor activation beyond traditional investigations that have myopically focused upon FX and prothrombin pathways, thereby underscoring the importance of exploring additional clotting factors.

Genetic Diagnosis and Prenatal Diagnosis of a Rare FVIII Family With Haemophilia A.

It is very difficult to identify the genetic variation of haemophilia A. We examined a case report from a sizable, uncommon haemophilia family, analysing the application of DHPLC in the diagnosis of haemophilia A. The comprehensive clinical data and laboratory assessments of the proband within the family were meticulously compiled. Subsequent to this, tests were conducted to evaluate the activated partial prothrombin time (APTT) and the clotting activity of coagulation factor VIII (F VIII: C). Polymerase chain reaction (PCR) techniques were employed to identify any inversions within the F8 gene's introns 22 and 1. Thereafter, direct sequencing methodology was utilised to sequence all exons of the F8 gene. To analyse the copy number variations across all exons of the F8 gene, a multiple PCR combined with denaturing high-performance liquid chromatography (DHPLC) approach was adopted. In addition, specific pathogenic mutations predisposing to progenitor cell disorders were screened in family members. The APTT of the proband was 60 s. F VIII: C is < 1%. It was found that the progenitor F8 gene exon 14 had a 226 bp insertion sequence, which was of unknown origin and was a pathogenic mutation. The analysis combined with this family situation is consistent with the expectation. The mutation was used as the detection target to complete the prenatal diagnosis. The pathogenic mutation found in this family is a rare large fragment insertion mutation. It is necessary to combine multiple experimental methods to improve the success rate of genetic diagnosis of haemophilia A.

Validation of current commercially-available devices to thaw pooled, solvent/detergent-treated human plasma.

Proper thawing procedures are required to preserve the quality of human fresh frozen plasma (FFP). octaplasLG (Octapharma AG, Switzerland) is a frozen solution of solvent/detergent (S/D)-treated human plasma, produced to improve pathogen safety. This study aimed to validate the S/D plasma thawing process using the latest-generation of commercially-available thawing devices and to determine S/D plasma quality after thawing. Thawing of S/D plasma units was investigated using a microwave oven (Transfusio-therm 3000) and dry tempering systems (SAHARA 4 and Plasmatherm V). Times to defrost plasma and reach 30°C product temperature, using the 37°C thawing programmes, were defined for all devices. Thawed S/D plasma units were tested against product release parameters, as well as for hemostatic capacity tested indirectly via global coagulation parameters, coagulation factors, protease inhibitors and markers of activated coagulation. The fastest thawing was observed using the microwave oven; S/D plasma units were defrosted after 2-3 min. All S/D plasma units thawed by the different devices using optimised thawing conditions were clear and free of solid and gelatinous particles, indicating no local overheating or protein denaturation. Coagulation factor and inhibitor activities and hemostatic capacity of S/D plasma were comparable when thawed by the three different devices. With each device, all product parameters were within product release specification levels after thawing. S/D plasma can be thawed using the Transfusio-therm 3000, SAHARA 4 or Plasmatherm V thawing devices using the optimised settings defined for this plasma product, with no negative influence on plasma quality.

Advances in Development of Drug Treatment for Hemophilia with Inhibitors.

Patients with hemophilia A and B who have inhibitors face limited treatment options, because replacement therapy with clotting factor VIII or IX concentrates is ineffective, particularly for patients with high-titer inhibitors. Current mainstay therapies include immune tolerance induction (through frequent injections of clotting factor VIII or IX concentrates) to eradicate inhibitors and bypassing agents (such as recombinant activated clotting factor VII and activated prothrombin complex concentrates) for the prevention and treatment of bleeding episodes. The use of these agents typically requires intravenous injections and sometimes hospitalization, which can be burdensome for patients. More recently, emicizumab, a bispecific antibody that mimics the function of activated clotting factor VIII, has demonstrated favorable efficacy for prophylaxis in patients with hemophilia A and inhibitors, representing a promising new therapeutic strategy. Ongoing research aims to discover and develop easy-to-use nonfactor agents for managing hemophilia with inhibitors. This review summarizes the current understanding of the pathophysiology of inhibitor development in hemophilia, outlines existing treatment options, and discusses advancements in novel therapeutic biologics, including a recombinant activated clotting factor VII variant (marzeptacog alfa), a new bispecific antibody (Mim8), antitissue factor pathway inhibitor antibodies (concizumab and marstacimab), and small interfering RNA targeting antithrombin (fitusiran). All of these agents are administered subcutaneously, with some offering the convenience of less frequent dosing (e.g., weekly or monthly). These potential drug candidates may provide significant benefits for the prophylaxis or treatment of bleeding disorders in patients with hemophilia and inhibitors.

Association between coagulation activity and clinical and imaging outcomes in acute ischemic stroke patients - A sub-study of the MR CLEAN NO-IV trial

BackgroundThe MR CLEAN NO-IV trial showed neither superiority nor noninferiority of endovascular treatment (EVT) alone compared to intravenous thrombolysis (IVT; Alteplase) before EVT in acute ischemic stroke (AIS) patients with large vessel occlusion of the anterior circulation. Although the treatment effect is largely attributable to EVT, IVT may affect hypercoagulability during AIS. AimsTo investigate the association between activated coagulation and final infarct volume and clinical outcomes (modified Rankin Scale 3–6 and mortality 90 days post-EVT), and whether this effect is modified by IVT administration. MethodsEnzyme-linked immunosorbent assays were used to quantify activated coagulation markers (activated coagulation factor (F) XIIa-C1 esterase inhibitor (C1inh); FXIIa-antithrombin (AT), FXIa-C1inh, FXIa-AT, FIXa-AT, FXa-AT, T-AT, FVIIa-AT) in plasma samples obtained on admission (T0), 1 h post-EVT (T1) and 24 h post-EVT (T2). Multivariable regressions were performed to investigate the associations and effect modification. ResultsIn the total cohort of 116 patients, a significant increase at T1 was seen in FIXa-AT (p = .001), FXa-AT (p < .001), T-AT (p < .001), and FVIIa-AT (p = .012), while there was a significant increase at T2 in FXIIa-C1inh (p < .001). Similar results were seen in the IVT+EVT subgroup. The EVT alone subgroup showed a significant temporary increase at T1 in FXa-AT (p < .001) and T-AT (p = .014). Neither the enzyme:inhibitor complexes nor the interaction with IVT were significantly associated with the outcome measures. ConclusionDespite temporary significant increases in enzyme:inhibitor complexes in the IVT+EVT group, but not in the EVT alone group, there were no significant associations with final infarct volume and clinical outcomes.

Translation of pathophysiological mechanisms of atrial fibrosis into new diagnostic and therapeutic approaches.

Atrial fibrosis is one of the main manifestations of atrial cardiomyopathy, an array of electrical, mechanical and structural alterations associated with atrial fibrillation (AF), stroke and heart failure. Atrial fibrosis can be both a cause and a consequence of AF and, once present, it accelerates the progression of AF. The pathophysiological mechanisms leading to atrial fibrosis are diverse and include stretch-induced activation of fibroblasts, systemic inflammatory processes, activation of coagulation factors and fibrofatty infiltrations. Importantly, atrial fibrosis can occur in different forms, such as reactive and replacement fibrosis. The diversity of atrial fibrosis mechanisms and patterns depends on sex, age and comorbidity profile, hampering the development of therapeutic strategies. In addition, the presence and severity of comorbidities often change over time, potentially causing temporal changes in the mechanisms underlying atrial fibrosis development. This Review summarizes the latest knowledge on the molecular and cellular mechanisms of atrial fibrosis, its association with comorbidities and the sex-related differences. We describe how the various patterns of atrial fibrosis translate into electrophysiological mechanisms that promote AF, and critically appraise the clinical applicability and limitations of diagnostic tools to quantify atrial fibrosis. Finally, we provide an overview of the newest therapeutic interventions under development and discuss relevant knowledge gaps related to the association between clinical manifestations and pathological mechanisms of atrial fibrosis and to the translation of this knowledge to a clinical setting.

Detection of factor Xa activity using giant magnetoresistive biosensors

BackgroundAs anticoagulants are widely used to treat patients with atrial fibrillation (AF) and other thrombotic conditions, it is necessary for physicians to determine whether the medication has been taken in emergencies. Among many anticoagulants, rivaroxaban has attracted attention due to its safety and convenience. Since rivaroxaban inhibits activated coagulation factor X (factor Xa), measuring factor Xa activity can determine the presence of rivaroxaban. ResultsWe report a magnetic biosensing platform capable of measuring the activity of factor Xa using peptide substrates conjugated with magnetic nanoparticles (MNPs). Due to the size of factor Xa, a new method of solution-phase assays was proposed for magnetic biosensing platforms to address issues with immobilized peptides on the sensors. This method was validated with factor Xa and trypsin, both of which are serine proteases. In the solution-phase assays, samples with either the enzymes of interest or no enzyme were simultaneously measured, and the activity of the enzyme was estimated using the difference between the measurements. Unlike conventional optical methods, our platform was capable of detecting the activity of factor Xa at 2 μg mL−1 with a 30 min sample incubation. SignificanceThe assay using giant magnetoresistive biosensors outperformed conventional optical techniques. This platform can facilitate the determination of the presence of rivaroxaban and assist physicians in deciding on appropriate treatments for patients.

LABORATORY DIAGNOSIS OF VON WILLEBRAND DISEASE

The aim of the study. To determine the frequency of Willebrand disease (VWD) in patients which turned to the SI IBPTM of the NAMS of Ukraine with hemorrhagic manifestations. Research metods. Object and research methods. The object of the study were 298 people with hemorrhagic syndrome aged from 7 months to 66 years old who have turned to the specialists of the institution since 01.01.2021, of which 198 (66,4%) came in for the first time. Coagulation hemostasis was investigated by methods that meet international standards and recommendations. Ristocetin-cofactor activity of factor Willebrand (VWF: RCo), content of the antigen VWF (VWF: AG), and coagulant activity of factor VIII (FVIII: C) were performed for the diagnosis of VWD. Results and Conclusions. VWD were found in 29 patients (9,7%) of the 298 people with hemorrhagic syndrome. VWD was revealed in 7,6% of patients from the 198 patients who were first investigate. The 15 (51,7%) VWD patients was diagnosed for the first time. In 48 (24,2%) was first diagnosed with hereditary or caused by various factors of disaggregational thrombocytopathy. Von Willebrand disease is the most common type of congenital hemostasis disorders (0,6-1,3% of the population), the type of inheritance is autosomal recessive/dominant. An algorithmic approach should be applied to diagnosis. Laboratory diagnosis consists of screening coagulological tests and three levels special tests. To establish the diagnosis, the necessary tests are determined by VWF: RCo, VWF: Ag and FVIII: C.

From Venom to Vein: Factor VII Activation as a Major Pathophysiological Target for Procoagulant Australian Elapid Snake Venoms.

Australian elapid snake venoms are uniquely procoagulant, utilizing blood clotting enzyme Factor Xa (FXa) as a toxin, which evolved as a basal trait in this clade. The subsequent recruitment of Factor Va (FVa) as a toxin occurred in the last common ancestor of taipans (Oxyuranus species) and brown snakes (Pseudonaja species). Factor II (prothrombin) activation has been stated as the primary mechanism for the lethal coagulopathy, but this hypothesis has never been tested. The additional activation of Factor VII (FVII) by Oxyuranus/Pseudonaja venoms has historically been considered as a minor, unimportant novelty. This study aimed to investigate the significance of toxic FVII activation relative to prothrombin activation by testing a wide taxonomical range of Australian elapid species with procoagulant venoms. The activation of FVII or prothrombin, with and without the Factor Va as a cofactor, was assessed, along with the structural changes involved in these processes. All procoagulant species could activate FVII, establishing this as a basal trait. In contrast, only some lineages could activate prothrombin, indicating that this is a derived trait. For species able to activate both zymogens, Factor VII was consistently more strongly activated than prothrombin. FVa was revealed as an essential cofactor for FVII activation, a mechanism previously undocumented. Species lacking FVa in their venom utilized endogenous plasma FVa to exert this activity. The ability of the human FXa:FVa complex to activate FVII was also revealed as a new feedback loop in the endogenous clotting cascade. Toxin sequence analyses identified structural changes essential for the derived trait of prothrombin activation. This study presents a paradigm shift in understanding how elapid venoms activate coagulation factors, highlighting the critical role of FVII activation in the pathophysiological effects upon the coagulation cascade produced by Australian elapid snake venoms. It also documented the novel use of Factor Va as a cofactor for FVII activation for both venom and endogenous forms of FXa. These findings are crucial for developing better antivenoms and treatments for snakebite victims and have broader implications for drug design and the treatment of coagulation disorders. The research also advances the evolutionary biology knowledge of snake venoms.

A hypothesis linking the renin-angiotensin, kallikrein-kinin systems, and disseminated coagulation in COVID-19

In this article we present a hypothesis based on the relationship between four physiological systems: the renin-angiotensin system (RAS), the kallikrein-kinin system (KKS), the arachidonic acid (AA) cascade, and platelet aggregation/coagulation − in the context of COVID-19. The central point of our proposition relies on ACE2 levels, which reduce following SARS-CoV-2 entry in the cell. The following cascade of events. Triggered by this reduction, involves the increase in Ang II levels and its consequent binding to AT1-R, initiating the release of pro-inflammatory cytokines such as TNF-α, IL-1, IL-10, and IL-12. These pro-inflammatory cytokines activate immune cells, including mast cells, which release heparin, thus activating Coagulation factor XII and increasing pre-kallikrein (PK) production. Consequently, there is an increase in bradykinin (BK) levels. BK, via its receptor BKB2-R, induces Ca2 + release increasing secreted phospholipase A2 (sPLA2) levels. Concomitantly, both the imbalance in Ang II/AT1-R and BK/BKB2-R signaling contribute to sPLA2 activation, inducing the release of arachidonic acid (AA) from cell membrane phospholipids, by cyclooxygenase-2 (COX-2) cleavage to produce prostaglandin G2 (PGG2), and later prostaglandin H2 (PGH2). At least, PGH2 is converted to thromboxane A2 (TXA2), which is involved in the platelet aggregation process. Platelet aggregation further increases TXA2 levels, initiating a positive feedback loop leading to further platelet activation and clot formation. Ultimately, this cascade of events may contribute to the development of a pre-thrombotic state and increase the risk of mortality, in COVID-19. We believe that this integrated approach could provide a deeper understanding of the underlying mechanisms of COVID-19 and guide future therapeutic strategies.

Modulating Coagulation via Bioinspired Mesoporous Calcium-Decorated Silica Nanoparticles for Efficient Fibrin Clot Formation.

Blood clotting is vital for preventing bleeding after an injury. Hemostasis is a complex cascade involving numerous plasma proteins. Uncontrolled bleeding leads to mortality. The presence of Ca (calcium) activates and promotes the different phases in the coagulation cascade. Even nonbiological surfaces such as silicates may activate coagulation factor XII (FXII). This causes the clotting of the blood. The exceptional hemostatic ability of the mesoporous calcium-decorated silica nanoparticles (MCSNs) is achieved by stimulating the factors needed to form fibrin mesh, a durable clot, thereby establishing hemostasis. This may be used as a hemostatic agent during an accident surgical procedure and other bleeding-related trauma conditions. This study investigates the mechanistic activation of the coagulation cascade by MCSN through blood coagulation index, clotting time, and coagulation activation studies like PT and aPTT. Our finding demonstrates that MCSN induces platelet adhesion and RBC aggregation and activates thrombin generation through distinct pathways.

The Interaction of Complement and Intrinsic Coagulation System: A Comparative Study between COVID-19 and Bacterial Sepsis Patients.

Background/Objectives: Through the past several years, a constant interaction has been implicated between complement and coagulation cascades. SARS-CoV-2 infection and bacterial sepsis are potent activators of both cascades. This study aims to compare the extent of complement and intrinsic coagulation pathway activation (and the interplay between them) among patients with COVID-19 and bacterial sepsis. Methods: Serum and plasma samples were collected from 25 ICU patients (11 patients with COVID-19 and 14 patients with bacterial sepsis) at two time points (on admission and either on improvement or deterioration). The activities of coagulation factors XI and XII and complement factors C3a and C5a were measured at both time points. Results: The activities of factors XI and XII were increased in both groups of patients and at both time points. However, there were no statistically significant differences between SARS-CoV-2 and bacterial sepsis patients. On the other hand, both C3a and C5a were significantly higher in the COVID-19 group on admission. This correlation was preserved on reassessment. Conclusions: Complement activation seems to be more enhanced in COVID-19 than bacterial sepsis. However, the lack of statistical significance in factors XI and XII indicates t the presence of additional pathways for complement activation in SARS-CoV-2 infection.

Coagulation factor XII contributes to renin activation, heart failure progression, and mortality.

Symptomatic heart failure (sHF) with cardiac dysfunction, edema, and mortality are driven by overactivation of the renin-angiotensin-aldosterone system (RAAS). Renin is widely recognized as a key initiator of RAAS function, yet the mechanisms that activate renin remain a mystery. We discovered that activated coagulation factor XII generates active renin in the circulation and is directly linked to pathological activation of the systemic RAAS, development of sHF, and increased mortality. These findings suggest a new paradigm for therapeutically modulating the RAAS in sHF and other pathological conditions.