Factor XIII Research Articles

Structural properties of newly 4,7-dihydroxycoumarin derivatives as potential inhibitors of XIIa, Xa, IIa factors of coagulation

Some coumarin derivatives show notable anticoagulant properties through their ability to interrupt the enzymatic function of vitamin K epoxide reductase. The current challenge lies in the development of novel derivatives that are more efficient and less harmful, specifically targeting the direct inhibition of coagulation factors. This study examined the direct inhibitory potential of two recently synthesized coumarin derivatives, 3-(1-(3-hydroxy-4-methoxyphenyl)-amino)-ethyldiene)-2,4-dioxochroman-7-yl acetate (A-3OH) and 3-(1-(4-hydroxy-3-methoxyphenyl)-amino)-ethyldiene)-2,4-dioxochroman-7-yl acetate (A-4OH), according to coagulation factors IIa, Xa, and XIIa. Accurately defining the structural properties of compounds is of great importance for a comprehensive understanding of the biological activity of pharmaceutical agents. In regard, this study aimed to analyze the structural (Potential Energy Surface (PES)), spectroscopic (FT-IR, NMR, and UV–Vis), and electronic properties (Quantum Theory of Atoms in Molecules (QTAIM)) of two newly synthesized compounds. These properties are determined using a combination of experimental and theoretical methods (B3LYP-D3BJ/6–311++G(d,p) level of theory). The investigated compounds deviate from planarity based on the results of structural properties. The results of QTAIM analysis show the presence of partially covalent hydrogen bonds and closed-shell van der Waals interactions that stabilize the examined compounds. Based on the large correlation coefficient (R) and low mean absolute error (MAE) of the spectroscopic data showed that the applied level of theory effectively replicated the experimental finding. The results from the molecular docking study suggest that both compounds demonstrate similar inhibitory effects on IIa when compared to the standard inhibitor dabigatran (DAB). The efficacy of A-3OH in inhibiting Xa is similar to that of conventional inhibitors apixaban (API), and rivaroxaban (RIV). The observed inhibitory effect of both compounds on coagulation factor XIIa was more potent than that of the conventional co-crystallized inhibitor. The results of this study add to the understanding of the structure-activity relationship of coumarin derivatives and provide possibilities for enhancing anticoagulant therapy and clinical outcomes for coagulation-related illnesses. The findings lay a foundation for further in vitro and in vivo investigations into the anticoagulant activities of the compounds, contributing to their potential pharmaceutical application.

Discovery of potential plasma protein biomarkers for ventricular fibrillation due to first ST-elevation myocardial infarction via proteomics

Abstract Background Although most sudden cardiac deaths are a consequence of ventricular fibrillation (VF) subsequent to myocardial infarction, the underlying biological mechanisms of VF in the setting of ischemia are largely unknown. We used an unbiased mass-spectrometry (MS)-based proteomic approach to improve our understanding of the molecular VF mechanisms. Purpose We aimed to identify and characterize proteins that are associated with VF during first ST-elevation myocardial infarction (STEMI). Methods We included 230 participants from a Danish ongoing case-control study on patients with first STEMI with VF (case, n=110) and without VF (control, n=120) before guided catheter insertion for primary percutaneous coronary intervention. Using MS-based proteomics on plasma samples collected within 24h of symptom onset, we investigated the plasma proteome. After quality control, one patient was excluded and the difference in the quantitative proteome composition between cases and controls were analysed using t-tests, and further corrected for multiple comparison using the Benjamini-Hochberg procedure (q-value). Cardiac enzymes and anterior infarct location were used in a subset as a proxy for large myocardial damage. Results In 229 STEMI patients (72% men, median age 62 years (interquartile range (IQR): 54-70)), a total of 401 unique proteins were identified with a median of 257 proteins (IQR: 244-281) quantified per patient. A total of 26 proteins were associated with VF, these proteins were involved in several biological processes. The most frequent processes were blood coagulation, hemostasis and immunity. After correcting for multiple testing, two up-regulated proteins remained significantly associated with VF, actin beta-like 2 (ACTBL2, FC 2.25, p<0.001, q=0.023) and coagulation factor XIII-A (F13A1, FC 1.48, p<0.001, q=0.023). The most up-regulated protein was ACTBL2, and the second most up-regulated protein was actin alpha 2 (ACTA2, FC 1.72, p=0.001, q=0.073). None of the three proteins were correlated with cardiac enzymes or anterior infarct location. Conclusion VF due to first STEMI was significantly associated with two up-regulated proteins (ACTBL2 and F13A1). None of these proteins were correlated with infarct size which could reflect novel underlying molecular VF mechanisms.

Abstract 15197: Differential Impact of Factor XII, Factor XI and Prekallikrein Deficiency on Thrombosis: A Pro-Thrombotic Vascular Action of Bradykinin

Objective: Factor XII (FXII) initiates the plasma contact system that triggers the intrinsic coagulation pathway and the kallikrein-kinin pathway via factor XI (FXI) and plasma prekallikrein (PK), respectively. The importance of the contact system for thrombosis sparing hemostasis is well established, however a comprehensive head-to-head comparison of the three proteases in arterial thrombosis is missing. Approach and Results: We produced mice deficient in FXII ( F12 -/- ), FXI ( F11 -/- ) and PK ( Klkb1 -/- ) and compared them in two distinct thrombosis models. While all (100%) of WT mice formed occlusive thrombi upon 30% ferric chloride challenge, carotid artery occlusion was reduced to 0, 4.8, 27.3 % in F12 -/- , F11 -/- and Klkb1 -/- mice (n=14-22), respectively. Upon photochemical-induced cremaster arteriolar thrombosis, occlusion time (s) prolonged to 226.1±60.4, 123.8±32.0 and 87.8±25.3 (mean±SEM, n=10-15) respectively in F12 -/- , F11 -/- and Klkb1 -/- mice, largely exceeding WT levels (38.3±12.1). A discordance was observed between in vivo thrombotic effects of the proteases and their roles for ex vivo coagulation, which ranked FXII≈FXI>PK as assayed by thromboelastography and activated partial thromboplastin time. Activation of FXII promoted thrombosis in WT and Klkb1 -/- mice, and impressively, it also accelerated thrombosis in F11 -/- mice, increasing activated PK activity and plasma bradykinin formation. Infusion of bradykinin and blockade of degradation of endogenous bradykinin increased platelet-endothelium adhesion and promoted thrombotic occlusions, which involved bradykinin mediated endothelial cell-release of platelet activating factor, rather than direct activation of platelets by bradykinin. Conclusion: FXII, FXI and PK differentially mediate experimental thrombosis in vivo and FXII/FXI appear as superior targets for thrombosis as compared to PK. PK- bradykinin axis activated by FXII contributes to thrombosis in vivo .

Coagulation Factor XII ( F12) Haploinsufficiency Is Protective Against Venous Thromboembolism in 415,921 Individuals

Background: Coagulation factor XII (FXII) has drawn significant attention as a potential drug target due to the observation that severe congenital deficiency in FXII is not associated with bleeding, while deletion or inhibition of FXII in pre-clinical models consistently protects against thrombosis. However, the contribution of FXII to thrombosis in humans remains controversial, with early reports suggesting that FXII deficiency may even be associated with an increased risk of venous thromboembolism (VTE). Meanwhile, epidemiologic studies of FXII deficiency have yielded conflicting results and are fraught with methodological challenges in part because FXII-deficient patients have no known phenotype and do not typically present to medical attention. To overcome these limitations, we performed the first large-scale analysis of differential thrombotic risk associated with germline loss of function in the gene encoding FXII ( F12) across over 400,000 individuals. Aims: To determine the impact of rare F12 loss-of-function variants on the risk of VTE in a large-scale whole exome sequencing dataset. Methods: The UK Biobank (UKBB) is a population-scale registry dataset containing paired clinical and genomics data for nearly 500,000 individuals. We identified individuals in the UKBB with rare (MAF <1%) variants in F12 that were predicted in silico to result in altered protein function. Qualifying variants included missense variants with an in silico functional impact score of ≥0.9 and high-confidence loss-of-function (HCLOF) variants such as frameshift, nonsense, and essential splice site mutations. We used Firth's logistic regression to assess the association between qualifying F12 variants in a single-gene collapsing analysis and the risk of VTE after adjusting for age, sex, and ancestry as well as several known contributory factors. Differences in the levels of 1,472 plasma proteins between carriers and non-carriers of qualifying F12 variants were evaluated in a subset of 48,892 UKBB participants using the Olink Explore 1536 proteomics platform. Results: Data from 415,921 UKBB participants were included in our analysis. In total, 1,598 individuals carried qualifying variants in F12, of which 99.8% were heterozygous. The presence of rare, function-altering variants in F12 was significantly associated with protection against VTE (OR=0.74, 95% CI: 0.55-0.97, P=0.029) ( Figure 1). This finding remained unchanged when we restricted the analysis to HCLOF variants (OR=0.74, 95% CI: 0.55-0.97, P=0.031). Further, we replicated several known risk factors for VTE, including female sex (P=0.0015), older age (P<1 x 10 -16), higher BMI (P<1 x 10 -16), non-O blood group (P<1 x 10 -16), higher CRP (P<1 x 10 -16), and a history of smoking (P<1 x 10 -16), suggesting that clinical annotation for the dataset is reliable. As expected, the presence of F12 variants was not associated with increased risk of hemorrhage (OR=0.90, P=0.44). Because FXII is also involved in pathways of innate immunity, we interrogated the relationship between carriage of rare F12 variants and sepsis and found no increased risk (OR=0.95, P=0.73). Next, we compared the circulating plasma levels of 1,472 proteins between participants with and without qualifying F12 variants ( Figure 2). We determined that plasma concentrations of three proteins are significantly elevated in participants with a variant F12 allele. Of these, heme binding protein 1 (HEBP1) levels demonstrated the most striking difference (fold-change=7.08, P=1.439 x 10 -43). However, germline loss-of-function variants in the HEBP1 gene are not associated with decreased risk of VTE (OR=1.109, P=0.88), suggesting that HEPB1 levels are regulated by FXII and do not directly influence VTE risk. Conclusions: Operating at the level of germline genetics, our data are the first to demonstrate that FXII loss-of-function is protective against VTE in humans. Because F12 variant carriers in the UKBB dataset predominantly possess only a single defective allele, it is possible that larger effect sizes would be observed among homozygous or compound heterozygous individuals. Additionally, F12 loss-of-function does not appear to increase the risk of hemorrhage or severe infection. Our findings suggest that therapeutic blockade of FXII in humans is likely to be safe and effective.

Analysis of Laboratory Parameters before the Occurrence of Hepatic Sinusoidal Obstruction Syndrome in Pediatric Patients after Hematopoietic Stem Cell Transplantation

Introduction: Hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease of the liver, is a serious complication following hematopoietic stem cell transplantation (HSCT). Early diagnosis and treatment with defibrotide can improve patient outcome. The pathogenesis is not fully understood, but it is obvious that some laboratory parameters are already changed before the onset of SOS. The aim of our retrospective study was to detect laboratory parameters following HSCT that can predict the occurrence of SOS. Methods: We analyzed 182 children with a median age of 7.2 years who underwent allogeneic or autologous HSCT for the first time and without defibrotide prophylaxis. Our study population consisted of 126 patients who received allogeneic HSCT (69.2%) and 56 patients who underwent autologous HSCT (30.8%). The stem cell sources were peripheral blood stem cells (50.5%) or bone marrow (49.5%) and the most frequent underlying diseases were solid tumors (34.1%), genetic diseases (19.2%), acute lymphoblastic leukemia (18.1%), and acute myeloid leukemia (13.7%). The diagnosis of SOS was based on the pediatric criteria of European Society for Blood and Marrow Transplantation. We investigated the following 15 laboratory parameters after HSCT before the onset of SOS: international normalized ratio (INR), activated partial thromboplastin time (aPTT), reptilase time, factor VIII, factor XIII, von Willebrand factor (vWF), von Willebrand factor activity (vWF activity), fibrinogen, antithrombin III, protein C, protein S, D-dimer, alanine aminotransferase (ALT), bilirubin, and ferritin. The last laboratory values within one week before the onset of SOS were analyzed in the SOS patient group. In the non-SOS patient group, we investigated the parameters for four weeks after transplantation and calculated the median. We selected cut-off values for the continuous parameters based on receiver operating characteristic curves analyses and existing reference values. We performed Mann-Whitney U test, univariate and multivariate analyses to find significant ( P < .05) associations between the values of laboratory parameters and the occurrence of SOS. The probability of developing SOS was calculated using the significant independent variables. Results: The overall incidence of SOS was 14.8% at a median time of 13 days after HSCT. SOS developed in 24 of 126 allogeneic (19.1%) and in 3 of 56 autologous (5.4%) HSCT patients. Only 3 out of 27 patients (11.1%) who suffered from very severe SOS died within 100 days after HSCT. In the univariate analysis, we found significant associations between the onset of SOS and the following parameters: INR ≥ 1.3, aPTT ≥ 40 sec, reptilase time ≥ 18.3 sec, factor VIII ≤ 80%, antithrombin III ≤ 75%, protein C ≤ 48%, D-dimer ≥ 315 µg/L, bilirubin ≥ 9 µmol/L, and ferritin ≥ 3100 µg/L. In multivariate analysis, we confirmed INR ≥ 1.3 [odds ratio (OR) = 8.104, P = .006], aPTT ≥ 40 sec (OR = 10.174, P = .001), protein C ≤ 48% (OR = 5.215, P = .014), and ferritin ≥ 3100 µg/L (OR = 7.472, P = .004) as independent risk factors after HSCT before SOS. If three of the four significant cut-off values were present, the probability of developing SOS was more than 70%. The probability of SOS was 96%, if all four laboratory parameters were changed according to the cut-off values. The values of factor XIII, vWF, vWF activity, protein S, fibrinogen, and ALT were not relevant for the occurrence of SOS. Conclusions: In summary, the laboratory parameters INR, aPTT, protein C, and ferritin were very useful to predict the occurrence of SOS. These four parameters can enable earlier diagnosis and treatment leading to an improved outcome. In addition, this is the first report on a significant association between SOS and high values of INR and aPTT after HSCT before SOS.

6-(Arylaminomethyl) Isoquinolines as Enzyme Inhibitors and Their Preparation: A Patent Highlight of Factor XIIa Inhibitors.

6-(Arylaminomethyl) Isoquinolines as Enzyme Inhibitors and Their Preparation: A Patent Highlight of Factor XIIa Inhibitors.

Nerve pathology of microangiopathy and thromboinflammation in hereditary transthyretin amyloidosis.

Despite amyloid deposition as a hallmark of hereditary transthyretin amyloidosis (ATTRv) with polyneuropathy, this pathology could not completely account for nerve degeneration. ATTRv patients frequently have vasomotor symptoms, but microangiopathy hypothesis in ATTRv was not systemically clarified. This study examined the vascular pathology of sural nerves in ATTRv patients with transthyretin (TTR) mutation of p.Ala117Ser (TTR-A97S), focusing on morphometry and patterns of molecular expression in relation to nerve degeneration. We further applied human microvascular endothelial cell (HMEC-1) culture to examine the direct effect of TTR-A97S protein on endothelial cells. In ATTRv nerves, there was characteristic microangiopathy compared to controls: increased vessel wall thickness and decreased luminal area; both were correlated with the reduction of myelinated fiber density. Among the components of vascular wall, the area of collagen IV in ATTRv nerves was larger than that of controls. This finding was validated in a cell model of HMEC-1 culture in which the expression of collagen IV was upregulated after exposure to TTR-A97S. Apoptosis contributed to the endothelial cell degeneration of microvasculatures in ATTRv endoneurium. ATTRv showed prothrombotic status with intravascular fibrin deposition, which was correlated with (1) increased tissue factor and coagulation factor XIIIA and (2) reduced tissue plasminogen activator. This cascade led to intravascular thrombin deposition, which was colocalized with upregulated p-selectin and thrombomodulin, accompanied by complement deposition and macrophages infiltration, indicating thromboinflammation in ATTRv. Microangiopathy with thromboinflammation is characteristic of advanced-stage ATTRv nerves, which provides an add-on mechanism and therapeutic target for nerve degeneration.

Reciprocal stabilization of coagulation factor XIII-A and -B subunits is a determinant of plasma FXIII concentration

AbstractTransglutaminase factor XIII (FXIII) is essential for hemostasis, wound healing, and pregnancy maintenance. Plasma FXIII is composed of A and B subunit dimers synthesized in cells of hematopoietic origin and hepatocytes, respectively. The subunits associate tightly in circulation as FXIII-A2B2. FXIII-B2 stabilizes the (pro)active site-containing FXIII-A subunits. Interestingly, people with genetic FXIII-A deficiency have decreased FXIII-B2, and therapeutic infusion of recombinant FXIII-A2 (rFXIII-A2) increases FXIII-B2, suggesting FXIII-A regulates FXIII-B secretion, production, and/or clearance. We analyzed humans and mice with genetic FXIII-A deficiency and developed a mouse model of rFXIII-A2 infusion to define mechanisms mediating plasma FXIII-B levels. Like humans with FXIII-A deficiency, mice with genetic FXIII-A deficiency had reduced circulating FXIII-B2, and infusion of FXIII-A2 increased FXIII-B2. FXIII-A-deficient mice had normal hepatic function and did not store FXIII-B in liver, indicating FXIII-A does not mediate FXIII-B secretion. Transcriptional analysis and polysome profiling indicated similar F13b levels and ribosome occupancy in FXIII-A-sufficient and -deficient mice and in FXIII-A-deficient mice infused with rFXIII-A2, indicating FXIII-A does not induce de novo FXIII-B synthesis. Unexpectedly, pharmacokinetic/pharmacodynamic modeling of FXIII-B antigen after rFXIII-A2 infusion in humans and mice suggested FXIII-A2 slows FXIII-B2 loss from plasma. Accordingly, comparison of free FXIII-B2 vs FXIII-A2-complexed FXIII-B2 (FXIII-A2B2) infused into mice revealed faster clearance of free FXIII-B2. These data show FXIII-A2 prevents FXIII-B2 loss from circulation and establish the mechanism underlying FXIII-B2 behavior in FXIII-A deficiency and during rFXIII-A2 therapy. Our findings reveal a unique, reciprocal relationship between independently synthesized subunits that mediate an essential hemostatic protein in circulation. This trial was registered at www.ClinicalTrials.com as #NCT00978380.

Recurrent arteriovenous fistula thrombosis: The role of genetic mutations and hyperhomocysteinemia – a clinical case

Thrombophilia denotes an increased predisposition to the formation of blood clots within blood vessels, stemming from genetic or acquired abnormalities in the hemostasis system. The challenge of establishing durable vascular access for hemodialysis in patients is compounded by various detrimental factors affecting the vascular wall, with vascular wall remodeling and hemostasis system disruptions being paramount among them. This clinical case report outlines our findings in a rare instance of recurrent thrombosis in an arteriovenous fistula.
 The objective of this study is to present a clinical case involving repeated arteriovenous fistula thrombosis in a patient with chronic kidney disease, exacerbated by a confluence of hyperhomocysteinemia and mutations in hemostasis-related genes: F13A1 (103G>T) (heterozygous carrier of blood coagulation factor XIII), FGB-fibrinogen (455G>A) (heterozygous carrier of coagulation factor I), and Serpin1 (PAI-1) (675 5G>4G) (homozygous carrier of tissue plasminogen activator antagonist). Additionally, we aim to illustrate the diagnostic exploration for coagulopathy causes in cases of chronic recurrent thrombosis, emphasizing the importance of utilizing modern genetic tests for diagnosing thrombophilias and urging healthcare professionals to consider these advanced diagnostic possibilities.

Prevalence of FXII-Deficiency and Its Relevance to Monitoring Anticoagulation in Adults Receiving Extracorporeal Membrane Oxygenation.

During extracorporeal membrane oxygenation (ECMO) blood is exposed to artificial surfaces, resulting in contact activation of the intrinsic coagulation pathway initiated by coagulation factor XII (FXII). Little is known about the prevalence of acquired FXII-deficiency, especially during ECMO. The primary outcome was the prevalence of acquired FXII-deficiency (FXII activity <60%) during ECMO. Secondary outcomes included differences in hemorrhagic/thromboembolic complications, doses of unfractionated heparin administered, and time points of anticoagulation within target ranges between patients with and without FXII-deficiency. Of 193 adults receiving ECMO therapy between 2013 and 2021, FXII testing was performed in 64 (33%) patients. Of these, 89% ( n = 57) had an acquired FXII-deficiency. Median complication-free intervals were not different between patients with and without acquired FXII-deficiency (bleeding: 28 days [6-145] vs. 12 days [11-not available], p = 0.85; thromboembolism: 16 days [8-54] vs. 13 days [3-15], p = 0.053). Patients with acquired FXII-deficiency received less heparin (16,554 IU/day vs. 25,839 IU/day; p = 0.009) and were less likely to be within aPTT-target ranges (23.1% [14.3%-36.4%] vs. 37.8% [33.7%-58.3%], p = 0.005). Acquired FXII-deficiency is common during ECMO and may affect monitoring of anticoagulation. The impact of FXII-activity on complications needs to be determined in future studies.

Heterozygosity in factor XIII genes and the manifestation of mild inherited factor XIII deficiency

BackgroundThe characterization of inherited mild factor XIII deficiency is more imprecise than its rare, inherited severe forms. It is known that heterozygosity at FXIII genetic loci results in mild FXIII deficiency, characterized by circulating FXIII activity levels ranging from 20% to 60%. There exists a gap in information on 1) how genetic heterozygosity renders clinical bleeding manifestations among these individuals and 2) the reversal of unexplained bleeding upon FXIII administration in mild FXIII-deficient individuals. ObjectivesTo assess the prevalence and burden of mild FXIII deficiency among the apparently healthy German-Caucasian population and correlate it with genetic heterozygosity at FXIII and fibrinogen gene loci. MethodsPeripheral blood was collected from 752 donors selected from the general population with essentially no bleeding complications to ensure asymptomatic predisposition. These were assessed for FXIII and fibrinogen activity, and FXIII and fibrinogen genes were resequenced using next-generation sequencing. For comparison, a retrospective analysis was performed on a cohort of mild inherited FXIII deficiency patients referred to us. ResultsThe prevalence of mild FXIII deficiency was high (∼0.8%) among the screened German-Caucasian population compared with its rare-severe forms. Although no new heterozygous missense variants were found, certain combinations were relatively dominant/prevalent among the mild FXIII-deficient individuals. ConclusionThis extensive, population-based quasi-experimental approach revealed that the burden of heterozygosity in FXIII and fibrinogen gene loci causes the clinical manifestation of inherited mild FXIII deficiency, resulting in ‘’unexplained bleeding’’ upon provocation.

A next generation FVIII mimetic bispecific antibody, Mim8, the impact on non-factor VIII related haemostasis assays.

Mim8 is a next generation bispecific antibody developed for the treatment of haemophilia A (HA). Mim8 has an increased potency compared to first generation molecules. The impact on Mim8 on non-FVIII measuring haemostasis assays was assessed in plasma containing Mim8. Congenital severe HA plasma was spiked with increasing concentrations of Mim8 (0-20μg/mL). 28 routine and specialist haemostasis assays were used to measure activities. These included tests for prothrombin time (PT), fibrinogen, thrombin, D-dimer, anti-Xa, heparin induced thrombocytopenia (HIT), clotting factors II-XII, factor XIII, von Willebrand factor (VWF), thrombophilia and DRVVT. Less than 10 % difference was calculated between plasma without Mim8 and plasma spiked to 15μg/mL Mim8 in all assays except thrombin time (-10.5%), APTT-based factor IX, XI and XII, Werfen VWF:RCo (10.6%) and Siemens LA1 (-26.4%) and LA2 (-16.9%). At the expected therapeutic steady state levels of Mim8 (5-8μg/mL), less than 10% difference was calculated for thrombin time and Werfen VWF:RCo. APTT-based assays of FIX, XI and XII are significantly elevated in the presence of Mim8 and should not be performed. A chromogenic FIX assay could be used to accurately measure FIX activity in the presence of Mim8. There was some interference in the DRVVT method we used so local assessment of other DRVVT methods is advised. Differences in all other tests would not be predicted to affect patient management.

Discovery of plasma proteins associated with ventricular fibrillation during first ST-elevation myocardial infarction via proteomics.

The underlying biological mechanisms of ventricular fibrillation (VF) during acute myocardial infarction are largely unknown. To our knowledge, this is the first proteomic study for this trait, with the aim to identify and characterize proteins that are associated with VF during first ST-elevation myocardial infarction (STEMI). We included 230 participants from a Danish ongoing case-control study on patients with first STEMI with VF (case, n = 110) and without VF (control, n = 120) before guided catheter insertion for primary percutaneous coronary intervention. The plasma proteome was investigated using mass spectrometry-based proteomics on plasma samples collected within 24 h of symptom onset, and one patient was excluded in quality control. In 229 STEMI patients {72% men, median age 62 years [interquartile range (IQR): 54-70]}, a median of 257 proteins (IQR: 244-281) were quantified per patient. A total of 26 proteins were associated with VF; these proteins were involved in several biological processes including blood coagulation, haemostasis, and immunity. After correcting for multiple testing, two up-regulated proteins remained significantly associated with VF, actin beta-like 2 [ACTBL2, fold change (FC) 2.25, P < 0.001, q = 0.023], and coagulation factor XIII-A (F13A1, FC 1.48, P < 0.001, q = 0.023). None of the proteins were correlated with anterior infarct location. Ventricular fibrillation due to first STEMI was significantly associated with two up-regulated proteins (ACTBL2 and F13A1), suggesting that they may represent novel underlying molecular VF mechanisms. Further research is needed to determine whether these proteins are predictive biomarkers or acute phase response proteins to VF during acute ischaemia.

Combined Omics Approaches Reveal Distinct Mechanisms of Resistance and/or Susceptibility in Sugar Beet Double Haploid Genotypes at Early Stages of Beet Curly Top Virus Infection.

Sugar beet is susceptible to Beet curly top virus (BCTV), which significantly reduces yield and sugar production in the semi-arid growing regions worldwide. Sources of genetic resistance to BCTV is limited and control depends upon insecticide seed treatments with neonicotinoids. Through double haploid production and genetic selection, BCTV resistant breeding lines have been developed. Using BCTV resistant (R) [KDH13; Line 13 and KDH4-9; Line 4] and susceptible (S) [KDH19-17; Line 19] lines, beet leafhopper mediated natural infection, mRNA/sRNA sequencing, and metabolite analyses, potential mechanisms of resistance against the virus and vector were identified. At early infection stages (2- and 6-days post inoculation), examples of differentially expressed genes highly up-regulated in the 'R' lines (vs. 'S') included EL10Ac5g10437 (inhibitor of trypsin and hageman factor), EL10Ac6g14635 (jasmonate-induced protein), EL10Ac3g06016 (ribosome related), EL10Ac2g02812 (probable prolyl 4-hydroxylase 10), etc. Pathway enrichment analysis showed differentially expressed genes were predominantly involved with peroxisome, amino acids metabolism, fatty acid degradation, amino/nucleotide sugar metabolism, etc. Metabolite analysis revealed significantly higher amounts of specific isoflavonoid O-glycosides, flavonoid 8-C glycosides, triterpenoid, and iridoid-O-glycosides in the leaves of the 'R' lines (vs. 'S'). These data suggest that a combination of transcriptional regulation and production of putative antiviral metabolites might contribute to BCTV resistance. In addition, genome divergence among BCTV strains differentially affects the production of small non-coding RNAs (sncRNAs) and small peptides which may potentially affect pathogenicity and disease symptom development.

Factors affecting progressive facial swelling immediately after orthognathic surgery: A retrospective cohort study

The aim of this study was to identify clinical factors associated with progressive facial swelling after orthognathic surgery. Patients diagnosed with jaw deformities and undergoing orthognathic surgery were retrospectively evaluated, and those with surgical site infection, Le Fort I osteotomy, or genioplasty only were excluded. Facial swelling volume was calculated by comparing facial volume preoperatively and three days postoperatively using 3D images and image analysis software (VECTRA H2). FXIII was measured within three days after surgery in only patients with unexplained postoperative bleeding or hematoma. The correlation between facial swelling volume and clinical factors was statistically analyzed. Facial swelling volume was examined in 78 patients. Univariate analysis showed a significant difference between facial swelling volume (mean = 41.6 cm3) and operation time (mean = 209.3 min, r = 0.283, p = 0.012), ΔHb level (mean = 1.18 g/dL, r = 0.235, p = 0.039), as well as decreased factor XIII activity (mean = 75.3%, p = 0.012). Multivariate analysis showed a significant difference between facial swelling volume and FXIII deficiency (standard error = 6.44, p = 0.031).Progressive facial swelling immediately after orthognathic surgery may be due to factor XIII deficiency.

LB 01.3 Factor XIII 24-Hour Trajectory Analysis in Severely Injured Patients: Post-hoc Analysis of the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Study

LB 01.3 Factor XIII 24-Hour Trajectory Analysis in Severely Injured Patients: Post-hoc Analysis of the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) Study

PB0234 Comprehensive Evaluation of Coagulation and Fibrinolysis Parameters in Patients with Congenital Factor XIII Deficiency in Pakistan: Case Control Study

PB0234 Comprehensive Evaluation of Coagulation and Fibrinolysis Parameters in Patients with Congenital Factor XIII Deficiency in Pakistan: Case Control Study

OC 28.5 Exploring Interdomain Interactions Mediated by the Factor XIII Activation Peptide

OC 28.5 Exploring Interdomain Interactions Mediated by the Factor XIII Activation Peptide

PB0574 Severe Bleeding in an Acquired Factor XIII Deficiency in an Otherwise Healthy Patient

PB0574 Severe Bleeding in an Acquired Factor XIII Deficiency in an Otherwise Healthy Patient

PB1200 Evaluation of the Association of Factor XIII at Hospital Arrival and Outcomes in a Cohort of Severely Injured Patients

PB1200 Evaluation of the Association of Factor XIII at Hospital Arrival and Outcomes in a Cohort of Severely Injured Patients