Factor XIII Activity Research Articles

Efficacy and safety of prophylactic treatment with plasma-derived factor XIII concentrate (human) in patients with congenital factor XIII deficiency.

Congenital factor XIII (FXIII) deficiency is an extremely rare, potentially life-threatening bleeding disorder. Routine prophylactic management is recommended for individuals with clinically relevant FXIII deficiency. This prospective, multicentre, open-label study evaluated the long-term efficacy and safety of prophylactic infusions of FXIII concentrate (human) 40 IU kg(-1) in patients with congenital FXIII deficiency. FXIII concentrate (human) was administered every 4 weeks for 12 months. Dosing was adjusted to maintain trough FXIII activity levels of 5-20%. Logistical and ethical constraints precluded use of a placebo control group. Annualized incidence of spontaneous bleeding was compared with historical rates; safety was assessed as a secondary objective. Forty-one patients were enrolled and completed the study. The annualized rate for spontaneous bleeding episodes requiring FXIII treatment was 0.000 episodes per patient-year (95% CI: 0.000; 0.097). The study met its primary endpoint: the upper limit of the 95% CI was substantially below the historical rate of 2.5 bleeding episodes per patient-year. Five spontaneous bleeding episodes (involving three patients; none requiring FXIII treatment) and eight trauma-related bleeding episodes (two requiring FXIII treatment) occurred. Five patients had surgery during the study, only one of whom required FXIII treatment for post-surgical bleeding. Most patients (≥ 85%) had trough FXIII activity levels ≥ 10%. No patient discontinued treatment due to an adverse event. No adverse events related to thromboembolism or viral transmission were reported. Prophylactic treatment with FXIII concentrate (human) was well tolerated and prevented spontaneous bleeding episodes that were serious enough to require treatment with FXIII-containing product. www.clinicaltrials.gov/ct2/show/NCT00885742.

Response to Comment on Ågren et al. Increased Incorporation of Antiplasmin Into the Fibrin Network in Patients With Type 1 Diabetes. Diabetes Care 2014;37:2007–2014

We thank Drs. Rijken and Uitte de Willige (1) for their comments on our article (2). Unfortunately, we did not describe the method in all details, but we are happy to give missing …

Factor XIII activity mediates red blood cell retention in venous thrombi.

Venous thrombi, fibrin- and rbc-rich clots triggered by inflammation and blood stasis, underlie devastating, and sometimes fatal, occlusive events. During intravascular fibrin deposition, rbc are thought to become passively trapped in thrombi and therefore have not been considered a modifiable thrombus component. In the present study, we determined that activity of the transglutaminase factor XIII (FXIII) is critical for rbc retention within clots and directly affects thrombus size. Compared with WT mice, mice carrying a homozygous mutation in the fibrinogen γ chain (Fibγ390-396A) had a striking 50% reduction in thrombus weight due to reduced rbc content. Fibrinogen from mice harboring the Fibγ390-396A mutation exhibited reduced binding to FXIII, and plasma from these mice exhibited delayed FXIII activation and fibrin crosslinking, indicating these residues mediate FXIII binding and activation. FXIII-deficient mice phenocopied mice carrying Fibγ390-396A and produced smaller thrombi with fewer rbc than WT mice. Importantly, FXIII-deficient human clots also exhibited reduced rbc retention. The addition of FXIII to FXIII-deficient clots increased rbc retention, while inhibition of FXIII activity in normal blood reduced rbc retention and produced smaller clots. These findings establish the FXIII-fibrinogen axis as a central determinant in venous thrombogenesis and identify FXIII as a potential therapeutic target for limiting venous thrombosis.

Functional modification of fibronectin by N-terminal FXIIIa-mediated transamidation.

A straightforward strategy is presented for the site-specific incorporation of fluorophores or reactive probes into the extracellular matrix (ECM) protein fibronectin (Fn) by using the enzyme-catalyzed transamidation by activated factor XIII. Characterization by SDS-PAGE, western blotting, absorption measurements, mass spectrometry, and stepwise photobleaching for labeling quantification at the single-molecule level showed that the labeling was efficient and restricted to the N-terminal tails. The introduction of labels did not interfere with Fn fibrillogenesis, as verified by the incorporation of fluorescently labeled Fn into ECM and manually pulled Fn fibers. Site-specific incorporation of an azide was used to create a template for bioorthogonal click chemistry reactions in a second bioconjugation step, thus offering versatile modification and application possibilities in the context of matrix biology and tissue engineering.

Factor XIII-A subunit Val34Leu polymorphism in fatal atherothrombotic ischemic stroke

Factor XIII (FXIII) is a regulator of fibrinolysis and clot firmness. Val34Leu polymorphism of its potentially active A subunit (FXIII-A) leads to faster activation of FXIII, influences clot structure and provides a moderate protection against coronary artery disease. The effect of FXIII-A Val34Leu polymorphism on the risk of atherothrombotic ischemic stroke (AIS) has been investigated in a few studies with contradictory results. In all previous studies, only patients surviving AIS were enrolled and sex-specific effects were not explored. In this retrospective multicenter cohort, we investigated the effect of FXIII-A Val34Leu polymorphism on the risk of fatal AIS in women and men. DNA isolation and genetic determinations in the case of 316 patients who died of AIS were carried out on paraffin-embedded tissue specimens. Genetic analyses for population controls, patients with history of AIS and sex-matched controls were performed on extracted genomic DNA from peripheral blood leukocytes. The prevalence of homozygous wild-type, and heterozygous genotypes, Leu34 carriers and Leu34 allele was not different significantly between the patients with fatal AIS and their respective controls. Logistic regression analysis with age as co-variant demonstrated that in women, homozygous presentation of Leu34 allele represented a more than three-fold increased risk of AIS with fatal outcome. The results demonstrate that FXIII-A Val34Leu polymorphism does not influence the occurrence of AIS, but has an effect on the severity of its outcome. This effect is sex-specific and in homozygous women, the prothrombotic/antifibrinolytic effects of FXIII-A Val34Leu polymorphism seem to prevail.

Investigation of a link between raised levels of pepsinogen in blood as a mediator of in-vitro clot lysis in acid and a cause of abnormal factor XIII screening tests

The in-vitro lysis of plasma clots in acetic acid generally indicates a Factor XIII deficiency that is confirmed by quantitative assay. However, there are two rare, poorly understood circumstances whereby clot lysis in acid occurs when factor XIII activity levels are normal: the presence of either an atypical antifactor XIII antibody, or an unknown acid-activated protease. Our centre has identified four patients with in-vitro clot lysis in acetic acid and normal FXIII levels by activity assay. Our aim was to determine whether the cause of this unusual result was an inhibitory antibody or an aspartic acid protease. In each case, we found an inhibitor that was not an IgG but showed characteristics of an acid protease, including that it was neutralized by pepstatin. The four patients had median pepsinogen I levels five-fold to 10-fold higher than the normal median of 89 μg/l. Pepsinogen II was increased by three-fold to six-fold, but from a lower baseline median of 6.5 μg/l. Cathepsin D levels were normal. Clot lysis in the acid test was observed when recombinant human pepsinogen I was added to normal plasma at similarly high concentrations as in patient samples, consistent with a role of an acid protease. Clot lysis also occurred with addition of pepsinogen II, but required four-fold to seven-fold more than in patient samples. Laboratories should be aware that a positive acid clot lysis test can be misleading if pepsinogen levels are raised and should not use this alone to diagnose FXIII deficiency.

Molecular characterization of cat factor XII gene and identification of a mutation causing factor XII deficiency in a domestic shorthair cat colony.

Coagulation factor XII (FXII) may be important in cardiovascular and inflammatory diseases. We have identified and characterized a naturally occurring mutation in the feline FXII gene that results in a mutant protein and enzymatic loss of activity. Feline intron/exon gene structure and sequence were acquired by comparing DNA sequences obtained from a fragmented Felis catus genomic sequence and the National Center for Biotechnology Information's Cross Species Megablast of multiple species' FXII gene sequences. Fourteen exons ranging in size from 57 to 222 base pairs were confirmed spanning 8 Kb on chromosome A1. The 1828-base pair feline FXII messenger RNA (mRNA) sequence contains an open reading frame that encodes a protein of 609 amino acids with high homology to human FXII protein. Total RNA and mRNA purified from liver tissue of 4 wild-type/normal and 8 FXII-deficient cats confirmed the predicted mRNA sequence and identified one important single-nucleotide polymorphism (SNP). A single base deletion in exon 11 of the FXII coding gene in our colony of cats results in deficient FXII activity. Translation of the mRNA transcript shows a frame shift at L441 (C441fsX119) resulting in a nonsense mutation and a premature stop codon with a predicted 560-amino acid protein. The mutant FXII protein is truncated in the 3' proteolytic light chain region of the C-terminus, explaining its loss of enzymatic activity. This study is the first molecular characterization of the feline FXII gene and the first identification of an FXII mutation in the domestic cat, providing insights into the origin and nature of feline FXII deficiency.

Evaluating factor XIII specificity for glutamine-containing substrates using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assay

Activated factor XIII (FXIIIa) catalyzes the formation of γ-glutamyl-ε-lysyl cross-links within the fibrin blood clot network. Although several cross-linking targets have been identified, the characteristic features that define FXIIIa substrate specificity are not well understood. To learn more about how FXIIIa selects its targets, a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI–TOF MS)-based assay was developed that could directly follow the consumption of a glutamine-containing substrate and the formation of a cross-linked product with glycine ethylester. This FXIIIa kinetic assay is no longer reliant on a secondary coupled reaction, on substrate labeling, or on detecting only the final deacylation portion of the transglutaminase reaction. With the MALDI–TOF MS assay, glutamine-containing peptides derived from α2-antiplasmin, Staphylococcus aureus fibronectin binding protein A, and thrombin-activatable fibrinolysis inhibitor were examined directly. Results suggest that the FXIIIa active site surface responds to changes in substrate residues following the reactive glutamine. The P−1 substrate position is sensitive to charge character, and the P−2 and P−3 substrate positions are sensitive to the broad FXIIIa substrate specificity pockets. The more distant P−8 to P−11 region serves as a secondary substrate anchoring point. New knowledge on FXIIIa specificity may be used to design better substrates or inhibitors of this transglutaminase.

Purification and partial characterization of a novel fibrinogenase from the venom of Deinagkistrodon acutus: Inhibition of platelet aggregation

A novel fibrinogenase, DAnase, was purified from the venom of Deinagkistrodon acutus by a combination of anion and cation exchange chromatography. Unlike other fibrinogenases which are usually single polypeptide chain proteins, the enzyme was a disulfide-linked dimer with an isoelectric point of 6.03 and an apparent molecular weight of 25kDa on SDS–polyacrylamide gel electrophoresis. DAnase showed α-fibrinogenase activity devoid of fibrinolytic activity. It hydrolyzed rapidly the Aα-chain of fibrinogen and followed by the Bβ-chain and did not cleave the γ-chain. It also exhibited arginine esterase activity. The fibrinogenolytic and arginine esterase activities were completely inhibited by phenylmethanesulfonyl fluoride or tris-(2-carboxyethyl)phosphine hydrochloride, but not by EDTA, indicating that DAnase is a serine protease requiring disulfide bridge(s) for its activity. The protease strongly inhibited ADP-induced platelet aggregation in human platelet-rich plasma but was lack of ADPase activity, indicating that its fibrinogenolytic activity is involved in its inhibition of ADP-induced platelet aggregation. DAnase was devoid of hemorrhagic activity and Factor XIII activation activity. DAnase may have a potential clinical application for the therapy of thrombosis disease.

The Role of the Contact Pathway in Thrombus Propagation

The continued search for the ideal antithrombotic agent that would prevent or reduce thrombus growth inside blood vessels without an effect on the essential hemostatic functions of blood, including extraluminal thrombin generation and platelet activation, has been going in new directions in the past decade. These directions include studies suggesting that activation of the intrinsic coagulation cascade through contact activation of factor XII, and the resultant thrombin generation is a pathologic event that leads to undesirable consequences. Recent animal studies of contact pathway inhibitors in experimental thrombogenesis suggest that the contact activation pathway of blood coagulation may play a pathogenic role in thrombosis, and pharmacologic inhibition of contact activation may have antithrombotic effects. Development of reasonably potent selective inhibitors of contact activation pathway components or activities now allow for the conduct of studies in various animal species, including primates. These studies have generated interesting data that now support the hypothesis that thrombogenesis in humans may also involve the pathological activation of the intrinsic coagulation cascade. Moreover, baboons, mice, and rabbits, pretreated with antibodies that selectively inhibit factor XII activation, procoagulant factor XIIa activity, or all enzymatic activities of factor XIIa show significantly reduced propensity for occlusive thrombus propagation in various models of acute thrombogenesis on vascular grafts, membrane oxygenators, and even on injured arteries. Since contact activation of blood does not play a demonstrable role in normal hemostasis, and there has been no evidence generated to date suggesting that activation of factor XII has a physiologic function, current research now supports the original concept, developed over 2 decades ago, that temporal pharmacologic inhibition of thrombin generation through the contact pathway may have therapeutic potential and could produce beneficial antithrombotic activities without hemostasis impairment.

Dynamics of Factor XIII Levels After Open Heart Surgery for Congenital Heart Defects: Do Cyanotic and Acyanotic Patients Differ?

Cardiopulmonary bypass (CPB) reduces coagulation factor levels through hemodilution and consumption. Differences in CPB-induced alterations of factor XIII (FXIII) levels in children with cyanotic and acyanotic congenital heart defects (CHDs) are not well characterized. FXIII activity (determined by Berichrom assay), prothrombin index, activated partial thromboplastin time, and fibrinogen were measured before open heart surgery with CPB and 5 days postoperatively for children older than 3 years with acyanotic (n = 30) and cyanotic (n = 30) CHDs. The preoperative FXIII levels did not differ significantly among the children of the compared groups. The cyanotic patients showed a significantly longer duration of CPB (111.4 ± 45.8 vs 71.5 ± 33.6 min; p = 0.026) and aortic cross-clamp (68.0 ± 27.1 vs 45.4 ± 31.4 min; p = 0.034). The drop in FXIII levels after termination of CPB was more profound for the children with cyanotic CHDs (87.1 ± 13.4 to 49.1 ± 13.2 vs 81.5 ± 12.6 to 58.6 ± 11.1 %, respectively; p = 0.018). The cyanotc patients also were restored to their baseline FXIII levels later than the children with acyanotic CHDs (at 48 vs 24 h). The post-CPB dynamics of the majority of the other coagulation parameters in the compared groups of patients were similar. The cyanotic patients experienced significantly greater postoperative blood loss than the acyanotic patients (12.6 ± 4.9 vs 5.0 ± 2.1 mL/kg; p < 0.001) and were transfused with larger volumes of red blood cells (10.4 ± 6.5 vs 4.2 ± 2.5 mL/kg; p = 0.007). The decrease in FXIII levels after CPB is more profound and lasts longer in children with cyanotic CHDs than in acyanotic patients. The rational strategy of postoperative FXIII replacement therapy for these categories of patients needs to be determined.

Construction of a scoring system for predicting the risk of severe gastrointestinal involvement in Henoch-Schönlein Purpura.

ObjectiveTo evaluate the parameters associated with significant gastrointestinal (GI) involvement in Henoch-Schönlein Purpura (HSP), and construct a scoring system for the identification of patients at high risk of gross blood in stools.Study designData for HSP patients hospitalized at each of seven institutes were retrospectively analyzed. Patients were divided into four groups according to the consequent severity of GI involvement. Identification of laboratory parameters at the time of admission were then used to differentiate the groups, and a scoring system to predict gross intestinal bleeding was constructed. Prognostic efficiency, correlation with the subsequent duration of abdominal pain, and association with manifestations excluding abdominal pain were also analyzed.ResultsAn analysis of variance (ANOVA) test showed significant intergroup differences in white blood cell (WBC) count, neutrophil count, serum albumin, potassium, plasma D-dimer and coagulation factor XIII activity. A scoring system consisting of these parameters showed a good prognostic value for gross intestinal bleeding in a receiver operating characteristic (ROC) analysis, and a cut-off value of 4 points showed a sensitivity of 90.0% and specificity of 80.6%. The score was also correlated with the duration of abdominal pain after admission. A significantly higher score (s) was observed in patients presenting with nephritis, although the predictive value was poor.ConclusionA scoring system consisting of generally available parameters was of use in predicting severe GI involvement in HSP patients. Although further study is needed, initial therapy in accordance with disease activity may be taken into consideration using this scoring system.

Hageman Factor C46T Promoter Gene Polymorphism in Patients with Hypercortisolism

Glucocorticoids are a group of hormones with a particularly significant effect on hemostasis. In hypercortisolemic patients increased concentrations of II, VIII, and von Willebrand factors were reported. Considerably fewer studies were concerned with factor XII (FXII). There are reports of decreased FXII concentrations in both venous and arterial thrombosis patients. Also, it was determined that FXII C46T promoter gene polymorphism leads to changes of its concentration. The aim of the study was to determine the C46T polymorphism of FXII promoter gene in hypercortisolemic patients. Thirty hypercortisolemic patients were enrolled in the study. Twenty-nine healthy individuals served as controls. Genomic DNA was isolated from peripheral blood leukocytes. To analyse the polymorphism, PCR products were digested by Hga I at 37°C for 23 h, subjected to 2% agarose gel, and stained with ethidium bromide. In all subjects FXII activity was determined using a clot-based method. All statistical calculations were performed using STATA 12.0 software. A p-value lower than 0.05 was considered statistically significant. Prevalence of FXII C46T polymorphism did not differ significantly between hypercortisolemic patients and controls. No correlation was found between FXII activity and its gene promoter polymorphism in the hypercortisolemic group; however, a clear trend was recorded toward higher FXII activities in 46C homozygotes, and lower in 46T homozygotes. Mean FXII activities did not differ significantly between hypercortisolemic patients and the control group. It seems that in hypercortisolemic patients no significant disorders are present concerning FXII concentrations due to the C46T polymorphism of its gene promoter.

Coagulation Factor XIIIa Substrates in Human Plasma: IDENTIFICATION AND INCORPORATION INTO THE CLOT

Coagulation factor XIII (FXIII) is a transglutaminase with a well defined role in the final stages of blood coagulation. Active FXIII (FXIIIa) catalyzes the formation of ε-(γ-glutamyl)lysine isopeptide bonds between specific Gln and Lys residues. The primary physiological outcome of this catalytic activity is stabilization of the fibrin clot during coagulation. The stabilization is achieved through the introduction of cross-links between fibrin monomers and through cross-linking of proteins with anti-fibrinolytic activity to fibrin. FXIIIa additionally cross-links several proteins with other functionalities to the clot. Cross-linking of proteins to the clot is generally believed to modify clot characteristics such as proteolytic susceptibility and hereby affect the outcome of tissue damage. In the present study, we use a proteomic approach in combination with transglutaminase-specific labeling to identify FXIIIa plasma protein substrates and their reactive residues. The results revealed a total of 147 FXIIIa substrates, of which 132 have not previously been described. We confirm that 48 of the FXIIIa substrates were indeed incorporated into the insoluble fibrin clot during the coagulation of plasma. The identified substrates are involved in, among other activities, complement activation, coagulation, inflammatory and immune responses, and extracellular matrix organization.

Factor XIII: Congenital Deficiency Factor XIII, Acquired Deficiency, Factor XIII A-Subunit, and Factor XIII B-Subunit

Factor XIII (FXIII) is a transglutaminase consisting of 2 catalytic A subunits and 2 noncatalytic B subunits in plasma. The noncatalytic B subunits protect the catalytic A subunits from clearance. Congenital FXIII deficiency may manifest as a lifelong bleeding tendency, abnormal wound healing, and recurrent miscarriage. Acquired FXIII deficiency, with significant reductions in FXIII levels, has been reported in several medical conditions. The routine screening tests for coagulopathies-prothrombin time, activated partial thromboplastin time, and thrombin time-do not show abnormalities in cases of FXIII deficiency. A quantitative, functional, FXIII activity assay that detects all forms of FXIII deficiency should be used as a first-line screening test. Treatment consists of recombinant FXIII or FXIII concentrate. If these are unavailable, then fresh-frozen plasma and cryoprecipitates may be used. Factor XIII has a long half-life; therefore, the patients can lead near-normal lives with regular replacements. Patients with acquired FXIII deficiency with inhibitors need immunosuppressive therapy in addition to factor replacements.

The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis

Factor XIII is a 320 kDa tetramer, comprising two enzymatic A-subunits and two carrier B-subunits (FXIII A₂ B₂). Activated FXIII (FXIIIa) catalyses the formation of ε-(γ-glutamyl)lysyl covalent bonds between γ-γ, γ-α and α-α chains of adjacent fibrin molecules and also cross-links the major plasmin inhibitor, α2-antiplasmin, to fibrin. We investigated the role of FXIII cross-linking of fibrin directly in clot morphology and its functional effect on clot formation and lysis, in the absence of α2-antiplasmin. Our data show that the presence of FXIII during clot formation results in fibrin clots that have a significant 2.1-fold reduction in pore size, as determined by the Darcy constant, Ks, and formed thinner fibers (74.7 ± 1.5 nm) and higher density of fibers compared with those without FXIII (86.0 ± 1.7 nm, P < 0.001), as determined by scanning electron microscopy. Additionally, fibrinolysis showed a significant increase in the time to lysis for clots formed in the presence of FXIII in both static and flow systems. These data demonstrate that independent of α2-antiplasmin, FXIII activity plays a role in increasing the stability of the fibrin clot by altering its structure and increasing the resistance to fibrinolysis.

FXIII: mechanisms of action in the treatment of hemophilia A

Hemophilia is characterized by abnormal thrombin generation and impaired clot stability. FXIII promotes clot stability and may be a useful adjunct treatment for hemophilia. This study examined the clot stabilizing effects and safety of supra-physiological FXIII and explored the mechanisms via which FXIII exerts its effects in hemophilia A. The effects of FXIII on clot formation and stability were examined using a thromboelastometry assay and blood samples collected from six patients with severe hemophilia A. The effect of FXIII on clot formation was also assessed using a murine model. The mechanisms of FXIII action in hemophilia A were explored by measuring thrombin generation, rates of FXIII activation and effects on clot permeability, pore size and fibrin fiber diameter. This study demonstrates that supra-physiological concentrations of FXIII stabilize clots in blood from patients with hemophilia by improving resistance to t-Pa-induced fibrinolysis even at low concentrations of FVIII (FVIII< 0.1 IU mL⁻¹, P < 0.05, anova). Addition of FXIII stoichiometrically up-regulates its activation, correcting the fibrin clot structure, reducing clot permeability and facilitating thrombin generation; FXIII significantly shortens ttPeak and lagtime (P < 0.05) in FVIII-deficient plasma, providing a novel explanation for its positive effects on clot stability and structure. The murine model indicates that supra-physiological FXIII is tolerated and does not significantly alter time to clot formation. The effects of FXIII on clot stability and physical clot structure are seen at low concentrations of FVIII, indicating that FXIII could be a useful treatment in a variety of clinical scenarios.

Enhanced lysis and accelerated establishment of viscoelastic properties of fibrin clots are associated with pulmonary embolism

The factors that contribute to pulmonary embolism (PE), a potentially fatal complication of deep vein thrombosis (DVT), remain poorly understood. Whereas fibrin clot structure and functional properties have been implicated in the pathology of venous thromboembolism and the risk for cardiovascular complications, their significance in PE remains uncertain. Therefore, we systematically compared and quantified clot formation and lysis time, plasminogen levels, viscoelastic properties, activated factor XIII cross-linking, and fibrin clot structure in isolated DVT and PE subjects. Clots made from plasma of PE subjects showed faster clot lysis times with no differences in lag time, rate of clot formation, or maximum absorbance of turbidity compared with DVT. Differences in lysis times were not due to alterations in plasminogen levels. Compared with DVT, clots derived from PE subjects showed accelerated establishment of viscoelastic properties, documented by a decrease in lag time and an increase in the rate of viscoelastic property formation. The rate and extent of fibrin cross-linking by activated factor XIII were similar between clots from DVT and PE subjects. Electron microscopy revealed that plasma fibrin clots from PE subjects exhibited lower fiber density compared with those from DVT subjects. These data suggest that clot structure and functional properties differ between DVT and PE subjects and provide insights into mechanisms that may regulate embolization.

Anticoagulant effects of statins and their clinical implications

There is evidence indicating that statins (3-hydroxy-methylglutaryl coenzyme A reductase inhibitors) may produce several cholesterol-independent antithrombotic effects. In this review, we provide an update on the current understanding of the interactions between statins and blood coagulation and their potential relevance to the prevention of venous thromboembolism (VTE). Anticoagulant properties of statins reported in experimental and clinical studies involve decreased tissue factor expression resulting in reduced thrombin generation and attenuation of pro-coagulant reactions catalysed by thrombin, such as fibrinogen cleavage, factor V and factor XIII activation, as well as enhanced endothelial thrombomodulin expression, resulting in increased protein C activation and factor Va inactivation. Observational studies and one randomized trial have shown reduced VTE risk in subjects receiving statins, although their findings still generate much controversy and suggest that the most potent statin rosuvastatin exerts the largest effect.

Controlled assembly of peptide-functionalized gold nanoparticles for label-free detection of blood coagulation Factor XIII activity

A highly sensitive label-free assay for the determination of blood coagulation Factor XIII activity is demonstrated through the controlled assembly of peptide-functionalized gold nanoparticles (AuNPs). Activated Factor XIII catalyzes the formation of covalent crosslinking between peptide chains through ε-(γ-glutamyl)-lysine bonds leading to the aggregation of the AuNPs and consequently a red-shift of the localized surface plasmon resonance. The selective engineering of nanoscale order over AuNP crosslinking via the formation of isopeptide bonds provides a new approach toward the design of nanoassemblies with precise control on the molecular level. The colorimetric assay reported here provides direct qualitative and quantitative analysis of Factor XIII activity with a limit of detection of 0.01 U mL(-1).