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PubMed1988

Clinical experience with a pasteurised human plasma concentrate in factor XIII deficiency.

A three-day-old infant presented with umbilical haemorrhage. Factor XIII deficiency was diagnosed. When one month old she commenced prophylactic injections of pasteurised factor XIII concentrate of human plasma origin. During two and a half years treatment there were no haemorrhagic episodes and factor XIII concentrate was well tolerated. Satisfactory post infusion factor XIII levels were achieved. Three transient elevations of aspartate transaminase occurred, the cause of which has not been established. There was no evidence of transmission of hepatitis or H.I.V. infection. A brother, born one year later, is also affected and commenced prophylactic therapy with the same factor XIII concentrate. Experience in these two infants suggests the product is efficacious.

Aspartate Aminotransferases↗

PubMed2006

Clinical and prognostic role of plasma coagulation factor XIII activity for bleeding disorders and 6-year survival in patients with chronic liver disease.

BACKGROUND/AIMS: Alterations of plasma coagulation factor XIII may contribute to bleeding disorders in patients with liver cirrhosis. As standard clotting tests such as prothrombin time or activated thromboplastin time (aPTT) cannot detect factor XIII deficiency, this may often be overlooked in clinical practice. We aimed to define factor XIII's clinical and prognostic role in chronic liver disease. PATIENTS AND METHODS: Factor XIII activities were assessed among various other parameters in 111 patients with chronic liver diseases during evaluation for liver transplantation in a prospective study. RESULTS: Unlike coagulation factors II, V or VII, factor XIII activity was maintained in the majority of patients with liver cirrhosis. However, although rarely, factor XIII deficiencies (<50%) occurred, especially in Child C cirrhosis. Factor XIII levels correlated with liver's biosynthetic capacity (cholinesterase activity, albumin, total protein) as well as with platelet count, global coagulation tests and other single coagulation factors. Patients reporting a current systemic bleeding tendency at study entry had significantly reduced factor XIII. In a 6-year follow-up, patients with factor XIII<50% had a significantly increased risk of severe upper gastrointestinal bleed, and reduced factor XIII (<50%, 50-75% vs. normal) was associated with increased mortality. CONCLUSIONS: Factor XIII deficiency is rare in patients with liver cirrhosis, but is associated with a clinical bleeding tendency and an unfavorable prognosis for future hemorrhages and survival.

Adolescent↗

PubMed2004

Expression of functional human coagulation factor XIII A-domain in plant cell suspensions and whole plants.

Coagulation factor XIII, a zymogen present in blood as a tetramer (A2B2) of A- and B-domains, is one of the components of many "wound sealants" which are proposed for use or currently in use as effective hemostatic agents, sealants, and tissue adhesives in surgery. After activation by alpha-thrombin cleavage, coagulation factor XIII A-domain, a transglutaminase, is formed and catalyzes the covalent cross-linking of the alpha- and gamma-chains of linear fibrin to form homopolymers, which can quickly stop bleeding. We have successfully expressed the A-domain of factor XIII in both plant cell cultures and whole plants. Transgenic plant cell culture allows a rapid method for testing production feasibility while expression in whole plants demonstrates an economic production system for recombinant human plasma-based proteins. The expressed factor XIII A-domain had a similar size as that of human plasma-derived factor XIII. Crude plant extract containing recombinant factor XIII A-domain showed transglutaminase activity with monodansylcadaverine and casein as substrates and cross-linking activity in the presence of linear fibrin. The expression of factor XIII A-domain was not affected by plant leaf position.

Factor XIII↗

PubMed1992

Marked and prolonged depression of factor XIII after esophageal resection.

Anastomotic leakage is one of the most common complications of esophagectomy and, since Factor XIII is required for normal wound healing, we investigated the temporal changes in plasma Factor XIII following esophagectomy and hepatectomy. A control group of patients undergoing other abdominal operations was also studied. Factor XIII activity was determined before surgery and on postoperative days (POD) 1, 3, 7 and 14. The plasma levels of acute phase protein were also measured. The plasma Factor XIII activity decreased significantly in both the hepatectomy and control groups until POD 7, reaching the lowest level on POD 3. In contrast, the esophagectomy group showed significant decreases in Factor XIII levels throughout the postoperative study period, with a nadir with an average activity of 56 per cent on POD 7. Preoperative transferrin levels had a positive correlation with Factor XIII levels measured on POD 3 and there was also a positive significant correlation between Factor XIII activity and alpha 2-macroglobulin levels on POD 3. These results suggest that there is a marked and prolonged depression of plasma Factor XIII activity following esophagectomy which may be attributed to accelerated tissue demands, inadequate synthesis or increased degradation. Moreover, the severe and sustained decrease in Factor XIII activity may be related to poor wound healing after esophagectomy.

Abdomen↗

PubMed2003

Coagulation factor XIII and atherothrombosis. A mini-review.

Coagulation factor XIII is a transglutaminase catalysing the crosslinking of fibrin chains as well as the formation of covalent links between several extracellular matrix proteins such as fibronectin, vitronectin and collagen. By mediating the incorporation of alpha2 antiplasmin into the fibrin network, this factor also interferes with fibrinolysis. Increased plasma factor XIII activity was reported by our laboratory 30 years ago in hypertriglyceridemic subjects who also displayed increased activity of serum cholinesterase, a marker of hepatic protein synthesis, and a delayed diluted, blood clot lysis time. Recent data in the literature emphasize a relationship between insulin resistance (metabolic syndrome) and increased plasma levels of factor XIII, confirming our results. It was also reported that a faster activation of this factor related to the Val 34 leu polymorphism provides protective effect against myocardial infarction and stroke, this effect being however negated in patients with insulin resistance and high plasma levels of plasminogen activator inhibitor-1. The pathogenic role of factor XIII in atherothrombosis seems to be bivalent. On the one side, an increased activity would favor the persistence of fibrin depositions and increase plaque burden, while on the other side it would reduce plaque vulnerability and the risk of downstream embolization.

Arteriosclerosis↗

PubMedDate not supplied

Reduced levels of coagulation factor XIII in patients with advanced tumor disease.

BACKGROUND/AIMS: Coagulation factor XIII, which induces the stabilization of fibrin the final step in the coagulation cascade, has various physiological effects. Among these, its beneficial effect in gastrointestinal bleeding episodes is well known. With the exception of inflammatory bowel disease, however, few data are available about this effect, particularly with regard to its role in diffuse bleeding in tumor patients. The study was designed to carry out prospective follow-up investigations, gathering data concerning factor XIII levels in patients with advanced gastrointestinal tumors and evaluating the course of the disease as well as the incidence of bleeding. METHODOLOGY: Sixty patients (22 women, 38 men; median age: 60; range: 29-79) with advanced gastrointestinal tumors were followed-up prospectively. Factor XIII levels were measured using chromogenic substrate. The correlation between the FXIII level and the patients' survival was analyzed using the Cox model. RESULTS: Factor XIII deficiency (below 70%) was seen in only 7 patients (11.6%), 6 of whom died within a median of 1.5 months after the measurement. In all patients however, there was a significant correlation (P = 0.0133) between FXIII levels and the risk of death. Four bleeding episodes occurred in 3 patients, three times with FXIII levels being below the lower normal range. When substitution was attempted, it was only successful in 1 patient in whom the FXIII level was reduced. CONCLUSIONS: FXIII may have predictive value as a marker for the prognosis in these patients with advanced tumor disease. Bleeding episodes were rarely seen, but when they do occur they may be associated with reduced levels of FXIII, and substitution may be beneficial as an adjunct or even as the sole therapeutic intervention.

Adult↗

PubMed2000

Prothrombin G20210A, factor V Leiden, and factor XIII Val34Leu: common mutations of blood coagulation factors and deep vein thrombosis in Austria.

Mutations in the gene for prothrombin (F2 20210A) and factor V (F5 1691A, factor V Leiden) are established risk factors for deep venous thrombosis (DVT). Recently, a mutation in the gene for factor XIII (F13 100T) leading to a Valine-Leucine exchange at amino acid position 34 has been reported to be protective against DVT. To analyze the role of these mutations for DVT in Austria, we analyzed their prevalence in 154 patients with documented DVT and 308 sex- and age-matched control subjects. Allele frequencies of F2 20210A, F5 1691A, and F13 100T were 0.018, 0.039, and 0.274 among controls, and 0.045, 0.120, and 0.211 among patients, respectively. Odds ratios for DVT associated with F2 20210A, F5 1691A, and F13 100T alleles were 2.5 (95% CI: 1.1-5.7), 3.4 (95% CI: 1.9-5.8), and 0.7 (95% CI: 0.5-1.0). We conclude that F2 20210A, F5 1691A, and F13 100T are common mutations in the Austrian population. F2 20210A and F5 1691 increase the risk for DVT, whereas F13 100T is associated with a decreased risk for DVT. Routinely, analysis of these mutations may help to analyze the individual risk for DVT.

Adolescent↗

PubMed2003

V34I and V34A substitutions within the factor XIII activation peptide segment (28-41) affect interactions with the thrombin active site.

In the blood coagulation cascade, thrombin helps activate Factor XIII by cleaving the Factor XIII Activation Peptide at the R37-G38 peptide bond. The common polymorphism V34L yields a Factor XIII that is more easily activated than the wildtype enzyme. Peptides based on the Factor XIII (28-41) ((28)TVELQGVVPRGVNL(41)) sequence serve as an important model system for evaluating how to regulate thrombin activation of Factor XIII and subsequently fibrin clot character. Kinetic and NMR (1D proton line broadening and 2D transferred NOESY) studies have revealed that the P(4)-P(1) region of the activation peptides is critical for binding to the thrombin surface. These results have led to an interest in exploring two new mutations at the P(4) position including V34I and V34A. The V34I peptide was found to have the lowest K(m) of the peptides studied. However, unlike the V34L peptide, there are no P(4) to P(2) interactions observed in the transferred NOESY spectrum. The Leu thus promotes a bound conformation that cannot be achieved with the similar amino acid Ile. The V34A peptide exhibited a decrease in K(m) but also a substantial decrease in k(cat). With this smaller amino acid, 1D proton line broadening NMR studies indicate that further contact of the Q32 residue with the thrombin surface is now possible. From these studies, valuable kinetic and structural information is being obtained to characterize interactions between thrombin and the Factor XIII activation peptide.

Amino Acid Sequence↗

PubMed2005

Factor XIII (FXIII) and angiogenesis.

Factor XIII is a plasma transglutaminase that participates in the final stage of the coagulation cascade. Thrombin-activated FXIII (FXIIIa) catalyzes the formation of covalent cross-links between gamma-glutamyl and epsilon-lysyl residues on adjacent fibrin chains in polymerized fibrin to yield the mature clot. In addition to its role in hemostasis, FXIII is known to participate in wound healing and embryo implantation, which are processes involving angiogenesis. In this review, we discuss the role of FXIII in angiogenesis and the molecular mechanisms underlying its proangiogenic effects. The FXIII role in tissue repair and remodeling may at least in part be attributed to its pro-angiogenic activity.

Animals↗

PubMed2006

Leukemic lymphoblasts, a novel expression site of coagulation factor XIII subunit A.

Blood coagulation factor XIII (FXIII) is a protransglutaminase circulating as a tetramer formed by two types of subunits (A2B2). The intracellular dimeric form of FXIII (A2) is present in platelets, megakaryocytes, monocytes and macrophages and has been detected in mono- and megakaryocytic leukemias. The aim of our study was to investigate FXIII-A expression in newly diagnosed B cell acute lymphoblastic leukemia (ALL) samples. We examined 47 de novo ALL cases of B cell origin by triple color labeling with flow cytometry. FXIII-A was detected by a FITC conjugated monoclonal antibody combined with CD34 and CD45 staining. In selected cases FXIII-A was investigated on slides prepared from blasts and visualized with a fluorescent microscope. In addition, blasts were studied by Western blot analysis and FXIII-A was measured by a highly sensitive ELISA method. By flow cytometry 19 samples of the 47 cases were found to be FXIII-A positive. Antigen concentration was 3.11 +/- 1.19 fg/blast, while normal lymphoid precursors and mature lymphocytes from B-CLL did not contain FXIII-A. In the lysate of lymphoblasts that were positive by flow cytometry, a single band (82 kDa) corresponding to FXIII-A was detected on Western blots. Confocal laser scanning microscopic examination revealed the presence of FXIII-A in the cytoplasm of these lymphoblasts. This novel expression site of FXIII-A in leukemic lymphoblasts can be utilized as a diagnostic tool and may also gain functional significance in B-lineage ALL.

Adolescent↗

PubMed1990

[Detection of coagulation factor XIII in the vitreous body and periretinal membranes in proliferative retinal diseases].

The human blood coagulation factor catalyses the cross-linking of fibrin monomers at the end of the coagulation cascade. Additional functions are the coupling of fibronectin and collagen to each other and fibrin. Therefore we tried to investigate the significance of factor XIII in the development of intraocular membranes. Using gel electrophoresis and western blotting, both subunits (A and B) of factor XIII could be detected in vitreous aspirates from patients with "idiopathic" proliferative vitreoretinopathy (PVR) (n = 5), traumatic PVR (n = 5), and proliferative diabetic retinopathy (n = 5). In contrast the vitreous of five human "normal" post mortem eyes did not contain the subunits of factor XIII. Furthermore, we observed immunofluorescence staining for both subunits of factor XIII in 20 surgically obtained periretinal membranes. In early cellular as opposed to late hypocellular membranes we observed stronger labeling for both subunits of factor XIII. With double label staining techniques, the fibroblastic cells recognized by vimentin staining did not contain factor XIII. About 50% of the macrophages stained positive for the A-subunit of factor XIII. We observed no labeling for the B-subunit in macrophages. Therefore, we hypothesize that factor XIII in proliferative vitreoretinal disorders (PVR, PDR) is derived from the exudation of plasma and platelets through disrupted blood-retinal barriers.

Diabetic Retinopathy↗

PubMed1998

The effect of factor XIII on bleeding in coronary surgery.

BACKGROUND: One cause of diffuse bleeding after cardiac operations may be a low plasma concentration of Factor XIII, which is essential for coagulation, but is not covered by standard coagulation monitoring. METHODS: In a prospective pilot study, Factor XIII levels before and after extracorporeal circulation were investigated, and drain volumes and blood transfusions of a control group of 11 patients were compared with a group of 11 patients who received 2500 units Factor XIII postoperatively. RESULTS: Factor XIII fell significantly from preoperative values of 96.1% and 88.7% (control) to 55.7% and 51.8% (control) postoperatively. By administration of Factor XIII, plasma level rose significantly from 55.7% to 103.1%; in the control group the value remained low. Drain volumes on the first and second postoperative day were significantly lower in the Factor XIII group. In the control group 1.9 units of red blood cells and 1.6 units fresh frozen plasma were administered, in the Factor XIII group 0.9 and 0.6 units were necessary. CONCLUSIONS: Factor XIII influences bleeding after coronary surgery and can reduce the need for blood transfusions. In patients with prolonged diffuse bleeding, we therefore recommend substitution of Factor XIII.

Aged↗

PubMed1987

Successful pregnancy in a woman with congenital factor XIII deficiency treated with substitutive therapy. Report of a second case.

A syndrome of marked fetal wastage is associated with congenital factor XIII deficiency in adult women. A previously unreported case of a woman with factor XIII deficiency is described, in which substitutive treatment with normal plasma or placental factor XIII concentrate permitted two normal pregnancies. Factor XIII activity was maintained above 1-2% with intermittent infusion of 300 ml to 450 ml of plasma every 14 days or of 500 units of concentrate every 21 days. This case confirms the only other case so far reported in which factor XIII substitutive therapy was able to permit a normal pregnancy in a woman with factor XIII deficiency and seems to suggest factor XIII to be involved in the process of annidation.

Abortion, Spontaneous↗

PubMed1984

Localisation of factor XIII in human tissues using an immunoperoxidase technique.

An immunoperoxidase technique has been used to localise clotting factor XIII subunits A and S in human tissues. The presence of factor XIII in placenta and megakaryocytes was confirmed. Factor XIII was also found in fibroblasts, a hitherto unreported finding. Factor XIII subunits were not detected in hepatocytes, although factor XIII was found in fibroblasts in portal tracts. These findings suggest that factor XIII is not synthesised in the liver as previously thought.

Animals↗

PubMed1987

Factor XIII binds to the A alpha- and B beta- chains in the D-domain of fibrinogen: an immunoblotting study.

The binding sites in fibrinogen for Factor XIII were localized using an immunoblotting technique. Platelet Factor XIII bound to fibrinogen and to plasmin degradation products of fibrin(ogen) including Fragments: X, D1-D3, and D-dimer, but did not bind to Fragment E. Binding of Platelet Factor XIII was independent of calcium ions but could be inhibited by the presence of 0.5 M NaCl. Binding could also be inhibited by preincubating Factor XIII with a 100-fold molar excess of fibrinogen but not by 100-fold molar excess of Fragment E. Binding of Factor XIII to fibrinogen was specific, since several other proteins tested (ovalbumin, bovine serum albumin, alpha 2-macroglobulin, beta-galactosidase, fructose kinase, lactic dehydrogenase, triose phosphate isomerase, fumarase and pyruvate kinase) did not bind Factor XIII. Furthermore, binding was not observed either when Factor XIII was left out or when antiFactor XIII antiserum was substituted with nonimmune serum. When fibrinogen was reduced prior to electrophoresis, Factor XIII bound to the A alpha and B beta chains of fibrinogen and des A,B fibrinogen, the B beta-chain of Fragment X, but not the gamma-chains. Localization of the Factor XIII binding sites to the carboxy terminal segments of the A alpha and B beta chains in the Fragment D-domain of fibrinogen could have important physiological consequences.

Binding Sites↗

PubMed2002

Factor XIII polymorphisms and venous thromboembolism.

OBJECTIVE: To review the relationship between factor XIII polymorphisms and venous thromboembolism. METHODS: Review of the medical literature using computerized databases and secondary sources identified through reviews of bibliographies. DATA SYNTHESIS: Plasma factor XIII is the precursor of a transglutaminase that cross-links fibrin, thereby altering its properties, including resistance to fibrinolysis. It is, therefore, biologically plausible that alterations in factor XIII activity could affect thrombosis risk. There are 4 common polymorphic forms of factor XIII that differ among ethnic groups. The Val34Leu polymorphism results in an amino acid change near the thrombin cleavage site that may alter the rate of activation. Several case-control studies have investigated the relation of the Val34Leu polymorphism to venous thromboembolism. Some have shown a potentially protective effect of this polymorphism, but the association is not consistent. CONCLUSION: Evidence is conflicting regarding the association of the factor XIII Val34Leu polymorphism with risk of venous thromboembolism, and further studies are needed before screening for this polymorphism can be recommended for evaluation of thrombophilia.

Blood Coagulation Tests↗

PubMed1988

B protein of factor XIII: differentiation between free B and complexed B.

Plasma factor XIII is a complex of A and B proteins noncovalently linked in a tetramer, A2B2, Enzyme-linked immunosorbent assays (ELISA) were developed to measure the separate factor XIII proteins and the complex. All of the A protein in plasma is in the zymogen complex. The B assay measures the total amount of B protein in plasma (both free B and complexed B). This was confirmed by nondenaturing gel electrophoresis and immunoblotting, which showed two bands for B in plasma with this antibody. Two assays were developed to measure A2B2 complex specifically. One assay used a monoclonal antibody to B to bind antigen and measured B protein in the zymogen complex only and hence the concentration of the complex. The specificity of this antibody was also shown by immunoblotting. In the second assay, the capture antibody was to B and the tag antibody was to A. These two assays gave identical results for the concentration of A2B2 (0.07 mumol/L, 21.6 micrograms/mL in normal plasma). Thus, for the first time, differentiation and quantitation of free B and complexed B in plasma was possible. The assays were used to measure factor XIII proteins in plasma from normal controls, homozygous-deficient factor XIII patients, and their heterozygous relatives. The normal concentration of A in plasma is 0.13 to 0.16 mumol/L (approximately 11 micrograms/mL), all of which is in A2B2. The total B concentration is 0.26 to 0.28 mumol/L (approximately 21 micrograms/mL), half of which is complexed. The free B concentration is 0.13 mumol/L (approximately 10 micrograms/mL). Homozygous-deficient patients have essentially no A protein, but their free B concentration is 0.11 mumol/L. Heterozygotes have decreased A2B2, but their free B is 0.11 mumol/L. These results indicate that the concentration of free B is remarkably constant and does not depend on the concentration of A2 or A2B2.

Antibodies, Monoclonal↗

PubMed1976

Bleeding disorder with abnormal wound healing, acid-soluble clots and normal factor XIII.

An unusual bleeding disorder clinically resembling factor XIII deficiency is presented. The only detectable coagulation abnormality was rapid clot dissolution in 1% monochloroacetic acid. This abnormality was ascribed to the sustained increase of a pepsin-like plasma protease which is activated at low pH. Asystematic search for similar phenomena revealed that massive blood transfusion may also enhance plasma-clot solubility in acid, possibly by release of a red cell protease. We conclude that the acid clot solubility test is not a specific indicator of factor XIII deficiency, but this simple assay is recommended for further studies of acid plasma protease activity. The diagnostic relevance and pathophysiologic importance of increased pepsin-like activity in plasma remain to be elucidated.

Acetates↗