Autoantibody-mediated disruption of the epidermal growth factor system during implantation and pregnancy.

Factor XIII and cardiovascular disease: biomarker, culprit or victim in acute myocardial infarction outcomes?

Linking factor XIII activity to all-cause mortality after myocardial infarction: the overlooked role of serum albumin

BackgroundPlasma coagulation factor XIII (OMIM#134570 (F13A1) and 134580(F13B), synthesized in haematopoietic cells (FXIII-A) and hepatocytes (FXIII-B); stabilizes and protects fibrin clots against fibrinolytic breakdown, ensuring haemostasis. Inherited FXIII deficiency is a rare inherited autosomal recessive bleeding disorder affecting 1–3 million people globally and demonstrating strong consanguinity contributing to high incidence of cases in Pakistan. Patients manifesting severe illness are homozygotes or compound heterozygotes.AimsThis study aims to estimate phenotypic traits, genetic alterations, and carrier rates in families with known genetic abnormalities in individuals with Factor XIII deficiency.MethodsThis cross-sectional study was approved by Advanced Studies Research Board and Ethical Review Committee of LUMHS, Jamshoro and conducted in concordance with Declaration of Helsinki 2000 in collaboration at the Biochemistry Department of LUMHS and Haematology Department, Baqai medical university, Karachi. Written informed consent obtained from all participants included in the study. Pedigree was constructed. Direct DNA sequencing performed via big dye terminator by using selective exon as per previously identified mutations in the patients of their families. FXIII confirmed with clot solubility testing and Elisa performed for Assay antigen detection for FXIII. Pathogenicity scoring done by using different software.ResultsAll the families had a history of consanguineous marriages and history of bleeding. From the six families, four families show same mutation in patient i.e. IVS11 (+ 1) G > A while two families showed c.2045G > A mutation in their homozygous patient.ConclusionThe results of this study highlight how crucial it is to combine biochemical, clinical, and statistical approaches to increase the precision of diagnoses, improve patient treatment, and make genetic counselling easier for families who are at risk.

The goal of the present study was to compare the volumetric three-dimensional growth of traumatic intracerebral hemorrhage (tICH) in patients with and without abnormal coagulation and question the necessity to perform repeated CT scans in all those patients. We retrospectively analysed CT-Scans from 50 patients with traumatic ICH. Abnormal coagulation was defined by the results of standard coagulation tests at admission including Factor XIII. The three-dimensional size of the hemorrhage was measured at admission, within 48 hours and 2 weeks. Growth of the ICH was detected in 56 % of the patients. In the group with normal coagulation out of 30 patients, growth could only be detected in 10 (33.34 %) whereas in the abnormal coagulation group increased ICH volume occurred in 18 of 20 patients (90 %). The mean growth was 3.46 ml [95 % CI: +/- 2.99 ml] and varied from 0,1 ml [95 % CI: +/- 1.57] in the normal coagulation group to 8.52 ml [95 % CI: +/- 6.67 ml] in the coagulation disorder group. This study demonstrates the need to perform repeated CT scans in patients with coagulation disorders since patients with tICH and coagulation abnormalities are likely to experience substantial growth of the hemorrhage.

Dengue and COVID-19 are viral diseases characterized by coagulopathies, with Dengue associated with fibrinolysis and COVID-19 with prothrombotic events. Furthermore, cross-reactivity between anti-SARS-CoV-2 and anti-DENV antibodies may confer protective immunity or exacerbate disease severity. Our investigation explored the impact of prior COVID-19 exposure on the immunopathogenesis of Dengue, focusing on hemostatic parameters. We quantified nitrites, procoagulant, anticoagulant, and fibrinolytic mediators in the plasma of Dengue patients before and after the COVID-19 pandemic. We also evaluated the influence of plasma from dengue patients on platelet activation in vitro using platelets from healthy donors exposed to DENV-2. Hemorrhagic manifestations were more frequent in pre-COVID-19 Dengue, while nitrite levels were elevated in post-COVID-19 Dengue patients, particularly among those without hemorrhagic signs. Among procoagulant factors, tissue factor (TF) levels were increased in post-COVID-19 Dengue, whereas Factor XIII was higher in pre-COVID-19 Dengue. In contrast, antithrombin (an anticoagulant) and plasminogen (a profibrinolytic factor) were more elevated in pre-COVID-19 Dengue than in post-COVID-19 cases. In vitro, DENV-2-infected platelets exposed to plasma of Dengue patients before and after COVID-19 showed decreased nitrite production in relation to DENV-2 alone. These findings suggest that prior COVID-19 exposure may influence hemostatic responses in Dengue, potentially modulating disease pathophysiology and opening new avenues for research and therapeutic strategies.

Lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, is well-known for its role in triggering inflammation via innate immune receptors. However, evidence suggests that LPS can influence coagulation, in part through activation of the contact pathway. Recent studies from our group and others demonstrate that the supramolecular organization and physicochemical properties of LPS-such as aggregate size, surface charge, and chemotype-critically determine the ability of LPS to activate coagulation factor XII (FXII). While monomeric LPS can modulate FXII activity, only aggregated forms of LPS (e.g., micelles) function as a procoagulant surface, initiating contact activation. This review synthesizes current knowledge on LPS structural heterogeneity and explores how the biophysical properties of LPS govern supramolecular assembly in aqueous environments, ultimately dictating interactions with the contact activation pathway. We further discuss the possible mechanisms by which LPS-driven FXII activation contributes to thromboinflammatory disorders, including disseminated intravascular coagulation and sepsis-associated vascular leakage. Finally, we highlight novel therapeutic strategies-from FXIIa inhibitors to molecules that disrupt LPS supramolecular structures-as potential interventions to mitigate coagulation-driven pathology during bacterial infections. These insights not only reflect our growing understanding of infection-associated thrombosis but may also pave the way for targeted therapies in sepsis and other thromboinflammatory conditions.

Postpartum haemorrhage (PPH) remains a leading cause of maternal mortality. The 2022 Trinational Guidelines recommend the early detection of PPH and standardised haemostatic management, including the systematic administration of tranexamic acid, targeted correction of fibrinogen and substitution with factor XIII. The transfusion strategy should be sequential and individualised. Among mechanical interventions, intrauterine vacuum tamponade has emerged as an effective alternative to invasive procedures by enhancing myometrial contraction. Chitin-based haemostatic dressings are easy to use and remain effective even in the presence of coagulopathy. However, their efficacy still requires confirmation in controlled clinical trials.

Monocytes contribute to the initiation and propagation of venous thrombosis. Little is known about the roles monocytes play in arterial thrombosis, the cause of stroke and myocardial infarction. We investigated how CCR2 (chemokine receptor 2) knockout (-/-)-mediated monocyte deficiency affects platelet function, blood coagulation, thrombus volume, and thrombolytic susceptibility in 666 male mice with FeCl3-mediated carotid arterial thrombosis, including 365 C57BL/6 wild type (WT) mice, 295 CCR2-/- mice, and 6 CX3CR1-GFP (CX3C chemokine receptor 1-green fluorescent protein) mice. Intravital microscopy and flow cytometry showed that both neutrophils and monocytes were recruited to the acute arterial thrombus, as observed 30 minutes postthrombosis. Platelet function tests demonstrated platelet aggregation to be lower in the whole blood of CCR2-/- mice (versus C57BL/6 WT mice) but not in their leukocyte-free platelet-rich plasma, suggesting this platelet dysfunction is cell-mediated. Flow cytometry experiments revealed lower numbers of monocyte-platelet aggregates in the blood of CCR2-/- mice, compared with C57BL/6 WT mice. Blood levels of FXIII (factor XIII) and monocyte levels of FXIII-A were increased after carotid thrombosis in C57BL/6 WT mice but not CCR2-/- mice. Further, in vivo micro-computed tomography-based thrombus imaging using fibrin-targeted gold nanoparticles and histology showed that CCR2-/- mice had smaller thrombi (0.112±0.002 mm3, n=22) than C57BL/6 WT mice (0.125±0.007 mm3, n=27; P<0.01), with increased porosity and reduced fibrin cross-linking. Moreover, tPA (tissue-type plasminogen activator) mediated thrombus volume reduction progressed up to ≈1 hour faster during the initial 3-hour period in CCR2-/- mice and CCR2-siRNA-treated mice, compared with C57BL/6 WT mice. In addition, clopidogrel reduced baseline thrombus volume more, but CCR2-/- better facilitated tPA-mediated thrombolysis. CCR2 antagonism decreases platelet aggregation and reduces FXIII (factor XIII) levels in blood and monocytes, thus driving arterial thrombosis towards the generation of a relatively small, porous, more lysable clot.

BackgroundThe treatment of aortic valve stenosis (AVS) remains limited to aortic valve replacement (AVR). No pharmacotherapy has yet proven efficacious, and its development is challenged by sexual dimorphism. Women display extensive valve fibrosis, and men present remarkably higher valve calcification. To accelerate the development of sex-personalised therapies, deeper molecular insights are needed. Hence, we aimed to characterise AVS sexual dimorphism using proteomics.MethodsFifty surgically excised valves (50% women) were homogenised, and the proteins were quantified by LC-MS/MS. The influence of differentially expressed proteins (DEPs) in sexual dimorphism was appraised using bioinformatics. DEPs were validated using immunohistochemistry, qRT-PCR and ELISA, with 30 additional valves.ResultsWe quantified ~ 4,000 proteins and 76 DEPs between sexes. CD163, CD74, and NADPH oxidase-2 (NOX2) were more abundant in men’s valves and central in a protein-protein interaction network. Functional enrichment analysis (FEA) supported increased lipoprotein binding and macrophage activation in men’s valves, confirmed by increased CD74 + cell infiltration (immunohistochemistry). Aminopeptidase N, coagulation factor XIII, and metalloreductase STEAP4 were more abundant in men’s valves at the transcript and protein levels. FEA indicated a women-specific dysregulation of spliceosomal proteins that may dictate a pro-fibrotic phenotype, which was observed histologically. A higher glutathione peroxidase-1/NOX2 ratio (ELISA) was found in women, suggesting increased protection against oxidative stress.ConclusionsProteomics confirms sexual dimorphism in AVS. Women displayed a higher degree of fibrotic remodelling, whereas men displayed greater immune cell infiltration and were less protected from oxidation, favouring calcification. Proteomics identified putative targets for a sex-personalised AVS modulation.Graphical abstractWe studied sexual dimorphism in aortic valve stenosis following a proteomic approach. Proteins were quantified by mass spectrometry and sex differences were uncovered by differential expression, network and pathway analyses. Some targets were selected for validation by PCR, immunohistochemistry and ELISA. Collectively, our experiments support a higher propensity for men’s valves to accumulate lipoproteins, red and white blood cells, with concomitantly greater activation of macrophages, particularly CD74+. Men’s valves also show a higher propensity for oxidative stress and calcification. Women’s valves are less prone to oxidative stress (higher GPX1/NOX2) but show a greater extent of fibrosis, which might result from an alternative splicing program that translates into a significant dysregulation of focal adhesion proteins. Some graphical elements were retrieved from Flaticon (https://www.flaticon.com/).Supplementary InformationThe online version contains supplementary material available at 10.1186/s12014-025-09549-1.

Abstract Background D-dimers are the terminal degradation product of fibrin cross-linked by coagulation factor XIII. Increased plasma D-dimer concentrations indicate that both thrombin generation and plasmin-mediated fibrinolysis have occurred to a greater extent than under basal conditions. The most frequent and clinically important causes of increased plasma D-dimer concentrations are thromboembolic disorders including disseminated intravascular coagulation (DIC). Typically, D-dimers are quantitated using immunologic methods such as enzyme-linked immunosorbent assays and automated immunoturbidometric tests. For all immunologic assays, the sensitivity and specificity of the antibodies employed substantially impacts the utility of the test for a given species. Dogs are the most popular companion animal in the United States, with almost 90 million animals in 65 million households. Dogs also represent an important large-animal species for pharmaceutical and comparative biomedical research. Most D-dimer assays used to test canine plasma samples involve antibodies raised against human D-dimers, but there are substantial differences in the affinity of these antibodies for canine D-dimer epitopes Methods We compared the utility of 3 commercially available D-dimer assays for measurement of D-dimer concentrations in canine plasma samples. Two assays (Helena D-dimer, Helena Biosciences and HemosIL D-dimer, Instrumentation Laboratory) employed the same antibody clone (8D3), whereas the third assay (STA Liatest D-Di, Diagnostica Stago) employed a mixture of 2 distinct antibody clones (8D2 and 2.1.16). All 3 assays were performed on the same automated assay platform (STA Compact Max, Diagnostica Stago). Tested canine plasma samples were those submitted to the Comparative Coagulation Laboratory, Animal Health Diagnostic Center, Cornell University College of Veterinary Medicine, Ithaca, NY for routine analysis of D-dimer concentrations. Incurred samples stored frozen (-80°C) with previously measured D-dimer concentrations spanning a clinically relevant range were re-analyzed using 2 additional methods. Results were compared with scatterplots, Deming regression, Spearman’s correlation coefficients and Bland-Altman plots. Results Compared to the original reference method (HemosIL D-dimer) the D-dimer concentrations quantitated using the Helena D-dimer assay were linearly associated per Deming regression (Y=0.484X–140.1, P&amp;lt;0.0001). Deming regression showed no significant association between D-dimer concentrations measured with the HemosIL D-dimer assay and the STA Liatest assay. The Spearman correlation coefficients for these comparisons were 0.872 (P&amp;lt;0.0001) and 0.418 (P=0.0337) respectively. Bland-Altman plotting suggested a mean difference of 734 ± 672 ng/mL (DDU) between the HemosIL and the Helena assays with a greater degree of positive bias at high concentrations above a clinically relevant cutoff. Conclusion The 2 assays incorporating the 8D3 monoclonal antibody yielded concordant results for measurement of canine plasma D-dimer concentrations. The third assay using a distinct combination of antibodies had disparate values. Our results indicate that anti-human D-dimer antibodies vary in reactivity, and independent verification of assay performance is required for multi-species usage.

ABSTRACTFactor XIII deficiency is a very rare bleeding disorder that can cause serious bleeding problems, especially in infants. We describe a 5‐month‐old girl who came in with a rapidly increasing head size and a bulging fontanelle. She had no fever or injury. A CT scan showed bleeding in the right side of her brain and hydrocephalus. Her factor XIII level was low, about 25%, while other clotting factors were normal. Her older brother had the same condition and unfortunately died at 9 months due to similar brain bleeding and infection. She was treated with plasma products to replace the missing factor, antibiotics, and seizure medications. After treatment, her condition improved and she was discharged with plans for close follow‐up. This case shows how factor XIII deficiency can lead to life‐threatening bleeding and hydrocephalus. Early diagnosis and treatment are crucial, and knowing the family history was important here. She will need ongoing monitoring to catch any future bleeding or complications early.

Excessive bleeding due to coagulation disorders is a well-known complication in cardiovascular surgery. Traditionally, standard coagulation tests have been used for their management, and more recently, viscoelastic tests have gained ground. These are performed using a different methodology and provide information on clot initiation, firmness, and lysis. Viscoelastic tests can diagnose coagulation factor deficiencies, the presence of heparin and protamine, fibrinogen, fibrin or Factor XIII deficiencies, platelet deficiency, and hyperfibrinolysis. The correlation between them and standard coagulation tests is strong only in a few assays, and they have limitations in detecting the absence of coagulation general preconditions, platelet aggregation deficiency, von Willebrand factor deficiency, the effect of fractionated heparin, the effect of direct anti-Factor Xa anticoagulants and low and moderate intensity local or systemic fibrinolysis. To facilitate the treatment of patients with excessive bleeding, algorithms guided by viscoelastic testing have been designed.

Tissue transglutaminase drives fibrin β-chain cross-linking: a novel fibrin modification observed in trauma patients.

Introduction to a review series on the structural underpinnings of hemostatic plugs and thrombotic occlusions.

ABSTRACTBackground and AimsNeutrophil extracellular traps (NETs) are part of the body's innate immune response. In animal models, NETs aggravated liver injury and promoted disease progression/portal hypertension by the formation of (micro)thrombi leading to parenchymal extinction.This study aimed to investigate NETosis in patients with clinically stable advanced chronic liver disease (ACLD).MethodsWe evaluated stable ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement in whom an extensive panel of laboratory tests related to coagulation and NET biomarkers was assessed in plasma. Hepatic decompensation/liver‐related death (LRD) as well as the development of ACLF/LRD were the outcomes of interest.Results194 patients (70 compensated/124 decompensated; mean Child‐Turcotte‐Pugh score (CTP): 7 ± 2 points; mean HVPG: 17 ± 6 mmHg) were included.Compared to healthy controls (n = 29), levels of cell‐free DNA (cf‐DNA) were higher (0.88 [IQR 0.84–0.93] vs. 0.94 [IQR 0.88–1.03] μg/mL; p = 0.001) in ACLD, whereas myeloperoxidase‐DNA (MPO‐DNA) values were similar (0.32 [IQR 0.17–0.54] vs. 0.39 [IQR 0.18–0.76] AU; p = 0.400).Factor XIII activity levels, soluble P‐selectin, and cf‐DNA but not MPO‐DNA levels were linked to HD/LRD and/or ACLF/LRD in univariable analysis. However, none of these tests were associated with the aforementioned outcomes after adjusting for established prognostic indicators.ConclusionPatients with stable ACLD showed increased cf‐DNA levels (i.e., NETosis, but also apoptosis/necrosis). However, MPO‐DNA as a NETosis‐specific marker was comparable to healthy controls. NETosis does not appear to drive disease progression in clinically stable ACLD as it was not linked to endpoints, thereby questioning whether findings obtained in animal models are translatable to humans.

The Proteomic Profiling of Circulating Extracellular Vesicles of Western Diet and Chemical-Induced Murine MASH Model.

Factor XIII deficiency is an extremely rare bleeding disorder with a prevalence of 1 in 2–3 millions. This deficiency is characterized by severe bleeding manifestations: life-threatening bleeding, including recurrent bleeding into the central nervous system. Here, we report 16 cases of factor XIII deficiency in children who were under our observation at the beginning of 2025. The use of factor XIII concentrate is a global standard for the treatment of patients with factor XIII deficiency. Since 2023, children with confirmed hereditary factor XIII deficiency have been receiving this concentrate with the help of the Circle of Kindness Foundation. By the time of publication, 9 out of 12 children who had been prescribed treatment with factor XIII concentrate started to receive it. All the patients receiving this therapy do not have spontaneous bleeding. In this article, we describe clinical and phenotypical features as well as bleeding manifestations in the patients with factor XIII deficiency and present our experience with factor XIII concentrate therapy. Ethical approval was not required since the study involved the use of anonymized retrospective data obtained during routine clinical practice.

The kallikrein kinin system alters neuroretinal and visual responses in mice.

Increased contact system activity three months after starting combined oral contraceptives.