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PubMed1982

An investigation into the role of coagulation factor XIII in ADP-induced aggregation and fibrinogen binding with rabbit platelets.

Because there was a possibility that activated factor XIII (factor XIIIa) might stabilize a platelet-fibrinogen aggregate through its crosslinking action, we have isolated plasma factor XIII, activated it, and studied the effect of factor XIIIa at a concentration of 3.3 micrograms/ml on aggregation and 125I-fibrinogen binding of rabbit platelets stimulated with 9 microM ADP. Factor XIIIa did not cause aggregation in the absence of ADP, nor did it enhance ADP-induced aggregation or substantially stabilize the platelet aggregate. The presence of factor XIIIa did not affect the amount of fibrinogen bound to platelets immediately after stimulation with ADP, but it appeared to cause a slow specific binding of 125I-fibrinogen to platelets whether or not they were stimulated with ADP. This binding, which was not inhibited by prostaglandin E1, did not lead to aggregation and was accompanied by crosslinking of fibrinogen through its A alpha and gamma chains, either to other fibrinogen molecules or to a platelet protein or proteins.

Adenosine Diphosphate↗
PubMed1995

Stimulated monocytes release factor XIII subunit A and fibronectin in vitro.

Factor XIII catalyses the formation of covalent bonds between several proteins involved in wound healing. Subunit A of factor XIII has been found inside and on the surface of monocytes and macrophages. In our study we investigated the ability of cultured monocytes to release factor XIII A subunit and its substrate-fibronectin. Human monocytes were cultured for up to 36 hours with lipopolysaccharide (LPS) from Escherichia coli. In supernatants of LPS stimulated monocytes we found 22 +/- 4 nM/ml and 40 +/- 6 nM/ml of factor XIII subunit A after 24 and 36 hours of incubation respectively. We also observed an increase of fibronectin concentration in supernatants of stimulated monocytes. The obtained results suggest that activated monocytes might be a source of factor XIII and fibronectin, which are critical for tissue repair processes.

Cells, Cultured↗
PubMed1996

Gene defects in congenital factor XIII deficiency.

The knowledge of the molecular basis of factor XIII deficiency has improved significantly in recent years. Almost 20 different mutations have been described in the gene coding for the factor A-subunit and 3 mutations in the gene coding for the B-subunit. Half of the mutations in the factor XIIIa A-subunit gene are nonsense mutations that result in premature termination of translation. Three of them are frameshift mutations that are caused by minor deletions. Two of them are splicing mutations and 3 are stop mutations that are caused by single nucleotide substitutions. Ten of the mutations are missense mutations caused by nucleotide transitions leading to amino acid substitutions. In the factor XIII B-subunit gene, the 3 mutations are an amino acid substitution, a splicing mutation, and a trinucleotide insertion. These mutations explain the disease in the two families reported to have XIII B-subunit deficiency. In factor XIII A-subunit deficiency, the genetic defects have been characterized so far only in a minority of cases. In most of the reports of factor XIII A-subunit mutations, each family carries its own mutation/mutations. However, in some populations such as Finns and Arabs some enrichment of specific mutations has occurred. Some international migration of a few mutations has also been noted. The structural and functional effects of the mutations have been analyzed by studying the expression of the factor XIII subunits on mRNA and protein levels in vivo or in vitro, and by utilizing the three-dimensional model of crystallized factor XIII A-subunit in modeling of the missense mutations.

Arabs↗
PubMed1985

A contribution to the pathology of acquired plasma factor XIII deficiency.

The biologic activity of Factor XIII was measured in four groups of patients: 20 with liver cirrhosis, ten with acute DIC, 30 with acute leukemia with DIC, and 20 with acute leukemia without DIC. In all groups, the plasma Factor XIII transamidating activity was reduced, but this deficiency was more evident in patients with DIC alone or with leukemia and DIC. The immunologic determination of the a and b subunits of Factor XIII was also performed. Both subunits were below the normal range in the groups of patients studied, except for subunit b, which was normal in patients with leukemia without coagulopathy. Acute DIC patients showed an equally reduced level of both subunits, whereas in patients with leukemia, even in the presence of a complicating coagulopathy, a lesser decrease of subunit b than subunit a was found. Both subunits were equally reduced in patients with cirrhosis, suggesting an impaired synthesis of these proteins. In conclusion, our findings do not support the use of Factor XIII subunit measurements in distinguishing between thrombin- or protease-mediated consumption coagulopathy, and they seem to suggest that the deficiency pattern of the subunits is not accounted for by a simple pathogenetic mechanism.

Acute Disease↗
PubMed2000

Bleeding risk and reproductive capacity among patients with factor XIII deficiency: a case presentation and review of the literature.

Factor XIII deficiency is an uncommon, inherited bleeding disorder that usually manifests in infancy or early childhood, involving both boys and girls. We present the case of a woman who had experienced two previous intracranial bleeding events, and was treated before and during her current pregnancy with factor XIII concentrate. Her pregnancy was successful, and she experienced an uncomplicated vaginal delivery. To better understand the issues surrounding bleeding, reproductive capacity, and management of factor XIII deficiency during pregnancy, we conducted a systematic literature review using MEDLINE from 1966 to December 1998. We also examined the bibliographic references from all articles, and included all cases, case reports, or case series of patients with factor XIII deficiency. We retrieved data on 117 patients from 37 articles, the majority of which had type II deficiency. Among untreated patients with type II factor XIII deficiency, the literature suggests an elevated mortality rate due to uncontrolled bleeding and intracranial hemorrhage. Because of its high degree of efficacy, the evidence supports the use of life long prophylactic therapy with at least monthly infusions of factor XIII concentrate, including during pregnancy. The opinion that women with type II factor XIII deficiency have inevitable recurrent abortions, or that men are sterile, is not well substantiated. No data were found on whether treatment alters male reproductive capacity. A policy of universal factor XIII replacement, starting in childhood, will likely enable more patients to attain reproductive status. The development of an international data registry would optimally address both bleeding risk and reproductive capacity among patients with factor XIII deficiency.

Adult↗
PubMed1989

Inherited factor XIII deficiency.

A new observation of inherited factor XIII deficiency is described. The patient had presented in the past with an umbilical haemorrhage, a cerebral haemorrhage, multiple haematomas with delayed onset after minimal trauma, and episodes of spontaneous haemarthrosis. The biological diagnosis was made at the age of 7 years. The child had undetectable transamidating activity and factor XIII a chains, while the level of b chains was reduced. The values observed in the parents were intermediate between those of the patient and those of normal plasma. Heated factor VIII concentrates were found to contain only low amounts of factor XIII, and were thus unsuitable for the prophylactic therapy of this rare disease. The patient was successfully treated with monthly injections of a factor XIII concentrate.

Blood Coagulation Factors↗
PubMed1995

Biosynthesis of plasma factor XIII: evidence for transcription and translation in hepatoma cells.

Factor XIIIa belongs to a family of ubiquitous transglutaminases, which catalyze formation of covalent bonds between the epsilon-amino group of specific lysines and the gamma-carboxyl group of glutamines. Factor XIII is synthesized as a zymogen and after activation, it participates in both the coagulation and fibrinolytic mechanisms. Most transglutaminases are intracellular, but factor XIII is both intracellular and extracellular. the biosynthesis of extracellular (plasma) factor XIII, with the structure of a noncovalent heterotetramer, A2B2, is complex. Here, evidence is presented from PCR analysis and Northern blotting that mRNAs for both A and B subunits are present in the liver. The distribution of mRNA, specific for factor XIII subunits, in various human tissues was also analyzed. Among the tissues examined, the only signal for B subunit was found in the liver. For subunit A, the signal was observed in placenta, liver, kidney, lung, skeletal muscle and heart with varying intensities; in brain or pancreas there was no signal. With an immunoperoxidase method, factor XIII A subunit was identified in the PLC/PRF/5 cell line. By ELISA and reverse immunoblotting, with antibodies specific for the A-B complex, it was also shown that these cells produce and secrete factor XIII. From all of these results, we conclude that the liver is a source of plasma factor XIII, and that the complex A2B2 is secreted from these cells.

Base Sequence↗
PubMed1977

Factor XIII deficiency in BALB/c mice with plasmacytoma.

These studies examined the fate of Factor XIII (fibrin-stabilizing factor) in mice with plasmacytoma (MOPC-300, MOPC-384, MOPC-467, and J-558). Plasma Factor XIII levels in these mice decreased progressively with tumor expansion. No plasma inhibitors of Factor XIII activity could be detected. Factor XIII was found on plasmacytoma cell membranes and in the cytoplasm of the malignant cells by immunofluorescence. The inverse relationship between tumor load and plasma Factor XIII levels suggested that the fibrin-stabilizing factor was absorbed by the malignant cells.

Animals↗
PubMed1986

Amino acid sequence of the b subunit of human factor XIII, a protein composed of ten repetitive segments.

Factor XIII is a plasma protein that participates in the final stages of blood coagulation. The complete amino acid sequence of the b subunit of human factor XIII was determined by a combination of cDNA cloning and amino acid sequence analysis. A lambda gt11 cDNA library prepared from human liver mRNA was screened with an affinity-purified antibody against the b subunit of human factor XIII. Nine positive clones were isolated from 2 X 10(6) phage and plaque-purified. The largest cDNA insert was sequenced and shown to contain 2180 base pairs coding for a portion of the leader sequence (19 amino acids), the mature protein (641 amino acids), a stop codon (TGA), a 3' noncoding region (187 nucleotides), and a poly(A) tail. When the b subunit of human factor XIII was digested with cyanogen bromide, nine peptides were isolated by gel filtration and reverse-phase high-performance liquid chromatography. Amino acid sequence analyses of these peptides were performed with an automated sequenator, and 299 amino acid residues were identified. These amino acid sequences were in complete agreement with the amino acid sequence predicted from the cDNA. The b subunit of factor XIII contained 10 repetitive homologous segments, each composed of about 60 amino acids and 4 half-cystine residues. Each of these repeated segments is a member of a family of repeats present in human beta 2-glycoprotein I, complement factor B, and haptoglobin alpha 1 chain. Three potential Asn-linked carbohydrate attachment sites were also identified in the b subunit of factor XIII.

Amino Acid Sequence↗
PubMed1985

Cleavage of blood coagulation factor XIII and fibrinogen by thrombin during in vitro clotting.

Thrombin cleavage of blood coagulation Factor XIII (a2b2) and fibrinogen was studied during in vitro clotting to determine the physiologic sequence of these events. First, the time course of fibrin formation and cleavage of Factor XIII was measured in platelet-rich plasma. Cleavage of fibrinogen was measured by using a radioimmunoassay for fibrinopeptide A. Conversion of trace amounts of radioiodinated a-chains of 125I-Factor XIII to thrombin-modified a-chains was measured in unreduced 10% sodium dodecyl sulfate-polyacrylamide gels. During spontaneous clotting, a similar percentage of 125I-Factor XIII and fibrinogen was cleaved at each time point. Visible gelation of polymerized fibrin monomer occurred when 24 +/- 8% of fibrinogen was cleaved and 21 +/- 6% of Factor XIII was converted to Factor XIII'. Thrombin cleavage of Factor XIII and fibrinogen was also studied in platelet-poor plasma to which thrombin was added. In order to measure Factor XIIIa activity, fibrin polymerization was completely inhibited by the addition of Gly-Pro-Arg-Pro. Factor XIIIa formation was measured by the incorporation of [3H]putrescine into casein. The concentration of added thrombin required to cleave 50% of fibrinogen and Factor XIII was 0.65 U/ml and 0.35 U/ml, respectively. The rate of cleavage of fibrinogen by thrombin was 43-fold greater than cleavage of Factor XIII. Lower Gly-Pro-Arg-Pro concentrations were used to determine the effects of incompletely inhibiting fibrin polymerization on cleavage of Factor XIII and fibrinogen. Thrombin cleavage of Factor XIII but not fibrinogen was dependent on the extent of fibrin polymerization. The more marked the degree of inhibition of fibrin polymerization, the slower the rate of Factor XIIIa formation. Thus, in platelet-rich plasma, thrombin cleavage of Factor XIII and fibrinogen are closely related events during spontaneous clotting. Furthermore, cleavage of Factor XIII during clotting is enhanced by fibrin polymerization in platelet-poor plasma.

Binding Sites↗
PubMed1998

Characterization of the reciprocal binding sites on human alpha-thrombin and factor XIII A-chain.

Solution- and solid-phase techniques were used to probe Factor XIII A-chain-alpha-thrombin interactions. Alpha-thrombin activated Factor XIII more efficiently (Km = 0.83 +/- 0.08 x 10(-7) M; V/K = 14.90 +/- 3.20 x 10(-3) min(-1)) than beta-thrombin (Km = 6.14 +/- 1.26 x 10(-7) M; V/K = 3.30 +/- 1.00 x 10(-3) min(-1)) or gamma-thrombin (Km = 6.25 +/- 1.15 x 10(-7) M; V/K = 3.00 +/- 0.80 x 10(-3) min(-1)). Immobilized FPR-alpha-thrombin bound plasma Factor XIII (Kd = 0.17 +/- 0.04 x 10(-7) M) > Factor XIIIa (Kd = 0.69 +/- 0.18 x 10(-7) M) > liver transglutaminase (Kd = 4.73 +/- 1.01 x 10(-7) M) > Factor XIII A-chain (Kd = 49.00 +/- 9.40 x 10(-7) M). FPR-alpha-thrombin and alpha-thrombin also bound immobilized Factor XIII A-chain with affinities inversely related to protease activity: maximal binding at 1.36 x 10(-7) M and 13.6 x 10(-7) M, respectively. Plasma Factor XIII, transglutaminase, and dithiothreitol competitively inhibited Factor XIII A-chain binding to FPR-alpha-thrombin: IC50 = 1.0 x 10(-7) M, 3.0 x 10(-6) M and 1.52 x 10(-4) M, respectively. Transglutaminase also inhibited Factor XIII binding to alpha-thrombin (IC50 = 2.0 x 10(-6) M). Thrombin-binding site was localized to G38-M731 fragment of Factor XIII A-chain, probably within homologous regions (N72-A493) of transglutaminase. R320-E579 of alpha-thrombin was Factor XIII A-chain binding site. Intra-B-chain disulfides in alpha-thrombin were essential for binding but not catalytic H363 or residues R382-N394 and R443-G475. These studies propose a structural basis for Factor XIII activation, provide a regulatory mechanism for Factor XIIIa generation, and could eventually help in the development of new structure-based inhibitors of thrombin and Factor XIIIa.

Animals↗
PubMed1975

[Blood coagulation factor XIII and fibrin stabilization (author's transl)].

Coagulation factor XIII (fibrin stabilizing factor, FSF) is detectable in plasma, platelets, placenta and various tissues. In the activated form FSF has the enzymatic properties of a transglutaminase and is capable of stabilizing fibrin by inducing covalent bondings between fibrin monomers. In patients with congenital factor XIII deficiency or acquired immune inhibitors of fibrin stabilization a severe bleeding tendency is evident. There is not yet enough information available concerning the significance of reduced FSF-activity as cofactor in hemorrhagic diathesis and wound healing disturbances in various disease states. There are some indications from experimental studies that there might be an influence of FSF on tumor growth and metastasis as well as arteriosclerosis. The quantitation of the enzyme by radiological and immunological techniques yield reproducible results. Fibrin in its stabilized or non stabilized form can be discriminated in polyacrylamide gel electrophoresis after reduction of fibrin clots.

Adult↗
PubMed2006

[Congenital factor XIII deficiency in the south of Tunisia].

Factor XIII deficiency is a rare autosomal recessive congenital disorder of haemostasis characterised by a plasmatic factor XIII level less than 1% in homozygote and bleeding as of the youth. We report a study about ten patients with congenital factor XIII deficiency from seven south-Tunisian families, there are seven females. Umbilical bleeding was common and only two patients had intracranial bleeding. The standard screening tests are normal. Factor XIII activity was less than 1% in all patients. A sub-unit A deficit was detected for the ten patients. Out hemorrhagic context, five patients receive regular prophylactic transfusion with fresh frozen plasma.

Factor XIII Deficiency↗
PubMed1994

Optimisation of a new continuous UV assay for the determination of blood coagulation factor XIII activity in human plasma.

The new photometric assay described by Fickenscher et al. (Thromb. Haemostas. 65 (1991) 535-540) for the determination of factor XIII facilitates the diagnosis of factor XIII deficiency. In spite of easy handling, this test should be used critically. Patients with hyperfibrinogenaemia showed factor XIII activities of less than 20%, whereas with an optimized assay we found normal factor XIII values. Also, the use of a fixed period of incubation for the analysis is questionable, because the period of constant reaction rate occurs earlier and is shorter with high factor XIII activities and later and longer with low factor XIII activities. A linear relation between factor XIII activity and signal only exists up to 80% of activity. In some plasma samples from patients with hyperfibrinogenaemia the factor XIII determination actually shows decreased values for factor XIII. During the reaction, a fibrin clot is formed. The resulting turbidity simulates an increase in absorbance so that NADH consumption is apparently decreased. In six patients with hyperfibrinogenaemia (8.1-9.4 g/l), a factor XIII activity of 26 U/l or less was determined. Using 50 microliters instead of 100 microliters sample volume, 50% (3/6) of the patients showed a normal factor XIII activities (80-96 U/l), whereas 50% (3/6) values of 6-15 U/l were found. In our modified assay we measured normal factor XIII activities (72-151 U/l) in all 6 patients. The procedure is optimized by reducing the sample volume from 100 microliters to 50 microliters.(ABSTRACT TRUNCATED AT 250 WORDS)

Factor XIII↗
PubMed1987

Localization of the gene for coagulation factor XIII a-chain to chromosome 6 and identification of sites of synthesis.

Factor XIII, the clotting factor essential for covalent stabilization of the fibrin clot, is a heterodimer consisting of a2 and b2 subunits, with catalytic function residing in the a-chain. In order to address questions regarding sites of synthesis and chromosomal localization of the Factor XIII a-chain, cDNA was cloned from a lambda gt11 human placental cDNA library. Nucleotide and amino acid sequences were determined from the cDNA. Amino acid sequencing of purified platelet Factor XIII a-chains confirmed the authenticity of the lambda gt11 clone. The gene for Factor XIII a-chain was mapped uniquely to chromosome 6. Northern blot analysis of human placental and U937 (monocytelike) cell poly (A)+ mRNA showed a single approximately 4.0-kb message for the Factor XIII a-chain. These results provide conclusive evidence that the a-chain is synthesized by placenta and monocyte cell lines.

Amino Acid Sequence↗
PubMed1995

Generation and mechanism of action of a potent inhibitor of factor XIII function.

Although known to play a critical role in thrombosis, the precise role of factor XIII in other processes like wound healing and gestation remains to be elucidated. Because a specific, potent inhibitor could help define the function of factor XIII in these processes, or determine the potential benefits of factor XIII suppression in thrombotic disease, we have derived and characterized a monoclonal antibody inhibitor of factor XIII activation. This immunoinhibitor, 9C11, reacts specifically with both plasma and platelet forms of factor XIII. When added to human plasma, either as whole immunoglobulin or as Fab fragments, 9C11 completely prevented thrombin-activated factor XIII activity with small molecular weight substrates like 14C-putrescine. In addition, when clotted with plasma, 9C11 ablated the gamma chain crosslinking of fibrin catalyzed by factor XIII and markedly accelerated the fibrinolysis of plasma clots by urokinase. Studies of the mechanism of action showed that 9C11 inhibited the cleavage and activation of factor XIII by thrombin, but did not affect the catalytic function of previously activated factor XIII. Although it inhibited thrombin activation, experiments indicated that it bound comparably to both factor XIII zymogen and the thrombin-cleaved zymogen, and did not bind to the thrombin cleavage site of the molecule. Taken together these experiments indicated that 9C11 acted as an inhibitor of the thrombin cleavage and activation of the factor XIII A-subunit. Its potency and specificity make it a useful agent for studying thrombin-activatable factor XIII function in biological systems.

Animals↗
PubMed1988

Intracranial hemorrhage in congenital deficiency of factor XIII.

We describe a male infant with congenital deficiency of coagulation Factor XIII who presented in the immediate postnatal period with umbilical stump bleeding and suffered a severe intracranial hemorrhage at 2 months of age. Factor XIII, also known as "fibrin-stabilizing factor," is a transpeptidase that produces strong covalent bonds between soluble fibrin monomers formed during coagulation. Presumptive diagnosis of Factor XIII deficiency was made with a clot solubility screening test, and confirmation was accomplished by demonstrating the absence of cross-linked fibrin chains by electrophoresis. This patient had received replacement therapy for 2 years, initially with intravenous fresh frozen plasma, and recently with Fibrogammin (Hoechst-Roussel Pharmaceuticals), a European Factor XIII concentrate soon to be available in the United States. Factor XIII deficiency is associated with a high incidence of life-threatening complications, notably intracranial hemorrhage. In light of the long half-life of this factor and the relatively low risk associated with new Factor XIII concentrates, such as Fibrogammin, prophylactic life-long replacement therapy should be considered for patients with severe Factor XIII deficiency.

Cerebral Hemorrhage↗
PubMed1976

Coagulation factor XIII concentration in sickle-cell disease.

Plasma factor XIII was assayed serially for a 1 1/2 to 2 year period in four patients with sickle-cell disease (SSD), during which several episodes of SSD crisis were observed. During crisis-free periods, plasma factor XIII concentration was lower than in normal subjects. With crisis onset, there was usually a concomitant fall in platelets and in plasma factor XIII soon after followed by a rise in fibrinogen concentration and platelet count. Following crisis resolution there was an increase in plasma factor XIII concentration peaking 3 weeks after crisis onset and occurring at the time of subsidence of thrombocytosis. It is suggested that the observed changes in plasma factor XIII concentration in SSD patients support the hypothesis that in the early stage of SSD crisis, fibrin deposition and/or thrombosis significantly enhance the role of sickled erythrocytes in producing vascular occlusion and/or organ infarction.

Adult↗