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PubMed1988

Characterization of the fibrin polymer structure that accelerates thrombin cleavage of plasma factor XIII.

The effect of plasmin-derived fibrin(ogen) degradation products on alpha-thrombin cleavage of plasma Factor XIII was studied to identify the fibrin polymer structure that promotes Factor XIIIa formation. Fibrin polymers derived from fibrinogen and Fragment X enhanced the rate of thrombin cleavage of plasma Factor XIII in plasma or buffered solutions. The concentrations of fibrinogen and Fragment X that promoted half-maximal rates of Factor XIIIa formation were 5 and 40 micrograms/ml, respectively. Fragments Y, D, E, D-dimer, and photooxidized fibrinogen did not enhance thrombin cleavage of Factor XIII. Although purified Fragment D1 inhibited fibrin gelation, the soluble protofibrils promoted thrombin activation of Factor XIII. Noncrosslinked fibrin fibers failed to enhance thrombin cleavage of Factor XIII. In conclusion, soluble fibrin oligomers function to promote thrombin cleavage of plasma Factor XIII during blood clotting.

Calcium↗
PubMed2000

Interaction of the factor XIII activation peptide with alpha -thrombin. Crystal structure of its enzyme-substrate analog complex.

The serine protease thrombin proteolytically activates blood coagulation factor XIII by cleavage at residue Arg(37); factor XIII in turn cross-links fibrin molecules and gives mechanical stability to the blood clot. The 2.0-A resolution x-ray crystal structure of human alpha-thrombin bound to the factor XIII-(28-37) decapeptide has been determined. This structure reveals the detailed atomic level interactions between the factor XIII activation peptide and thrombin and provides the first high resolution view of this functionally important part of the factor XIII molecule. A comparison of this structure with the crystal structure of fibrinopeptide A complexed with thrombin highlights several important determinants of thrombin substrate interaction. First, the P1 and P2 residues must be compatible with the geometry and chemistry of the S1 and S2 specificity sites in thrombin. Second, a glycine in the P5 position is necessary for the conserved substrate conformation seen in both factor XIII-(28-37) and fibrinopeptide A. Finally, the hydrophobic residues, which occupy the aryl binding site of thrombin determine the substrate conformation further away from the catalytic residues. In the case of factor XIII-(28-37), the aryl binding site is shared by hydrophobic residues P4 (Val(34)) and P9 (Val(29)). A bulkier residue in either of these sites may alter the substrate peptide conformation.

Amino Acid Sequence↗
PubMed1975

[Change in factor XIII activity in plasma during thrombocyte aggregation].

On addition to rat plasma, platelet-enriched, of active factor XIII (XIIIa), there occurred along with increase in the aggregation induced by ADP, a reduction in the activity of factor XIII in the plasma. Addition to the plasma of inactive factor XIII failed to influence either the degree of aggregation, or the change in the activity of factor XIII in the plasma in comparison with control samples. In platelet aggregation induced by thrombin, addition of factor XIII was accompanied by a marked fall of its activity in the plasma. In comparison with control, the extent of aggregation in this case decreased. The observed differences in the character of aggregation coursing in the presence of factor XIIIa when different aggregating agents (ADP and thrombin) were used were apparently due to the interaction of active factor XIII with thrombin added to the plasma in the capacity of an aggregating agent.

Adenosine Diphosphate↗
PubMed2003

[Molecular mechanisms of two novel mutations of factor XIII gene resulting in hereditary coagulation deficiency].

OBJECTIVE: To investigate the mechanisms of two novel missense mutations of factor XIIIA subunit gene (Arg77-->Cys,Ser413-->Trp) in the pathogenesis of hereditary factor XIII deficiency. METHODS: Site-directed mutagenesis was conducted to obtain 2 mutant human XIII A recombinant plasmids, mut-PCI/FXIIIA. Normal wild type factor XIII A recombinant plasmid, wt-PCI/FXIIIA, and mut-PCI/FXIIIA, were transfected into cultured COS7 cells line, renal fibroid cell of African green monkey using Superfect reagent respectively, The expression levels of DNA, RNA and protein of human factor XIII, both wild type and mutant, were detected by PCR, RT-PCR and Western blotting. Pulse-chase experiment was used to look into the changing of factor XIII A in the cytoplasm. Factor XIIIA activity was assayed by Biotin-pentylamine incorporation technique. RESULTS: The mRNA levels of the two mutants in transfected cells were similar to that of the wild type factor XIIIA. But the amount of mutant factor XIIIA protein and its activity in cells decreased markedly, even disappeared. Pulse-chase experiment revealed that at the two mutants existed chase time 0.5 h and 1 h considerable amounts in cells and then disappeared rapidly later. CONCLUSION: The 2 mutations of the factor XIIIA cause the instability, degradation, and rapid disappearance of FXIIIA in cytoplasm, thus resulting in hereditary factor XIII deficiency.

Animals↗
PubMed1975

[Therapeutic action of coagulation factor XIII in scleroderma. 20 cases].

Clotting factor XIII was used in 13 patients suffering from scleroderma, 17 with generalised scleroderma and 3 with localised scleroderma. The duration of treatment varied between 15 days and 6 months. The effect was marked in 7 cases and more moderate in 5 others. It took the form of increased suppleness of the skin, improved joint mobility and, to a lesser degree, an improvement in vasomotor disturbances of the extremities. Oesophageal abnormalities on X-ray were never altered. The return to normal of alveolar-capillary diffusion seen in two cases requires futher confirmation. The action of factor XIII in scleroderma may be explicable by the formation of transamidation bonds between the alpha chains of the collagen molecule, similar to those obtained on fibrin.

Adolescent↗
PubMed1974

The calcium-induced dissociation of human plasma clotting factor XIII.

1. Large quantities of human Factor XIII were prepared from ethanol precipitates of outdated human plasma. 2. Material homogeneous after chromatography on DEAE-cellulose was further resolved into two proteins, A and B, after filtration on Sepharose 6B. 3. Protein A has a molecular weight of 350000 and a subunit structure a(2)b(2) and is activated by thrombin and calcium. Protein B is inactive and probably has a subunit structure b(2). 4. Calcium causes protein A, after thrombin cleavage, to fragment to give protein B and a protein, containing only a' subunits, which is catalytically active. The latter protein slowly forms a misty precipitate which is still active and not cross-linked covalently. This confirms the suggestion of Schwartz et al. (1971) that catalytic activity is only associated with a' subunits. 5. Iodoacetate, which inhibits the enzyme, does not inhibit dissociation and aggregation of protein A. 6. The existence of two proteins and the fragmentation are possible explanations for the wide range of molecular weights given for Factor XIII in the literature.

Animals↗
PubMed1991

[Effect of intravenous administration of coagulation factor XIII concentrate on persistent pleural air leak].

We administered coagulation factor XIII concentrate intravenously to six patients suffering from persistent air leak with no evidence of bronchopleural fistulae They are those who had either failed to be healed in response to pleurodesis, intrapleural fibrin glue injection and surgery or had not received such treatment. Their blood coagulation factor XIII activity levels were less than 70% of the standard plasma level. In four of the six patients, air leak stopped within 10 days after the treatment begun. Because factor XIII plays an important role in wound healing, reduction in the activity level can be a cause of insufficient healing of pulmonary surface fistulae and may lead to persistent air leak. In such cases, intravenous administration of factor XIII concentrate increases the activity levels and may put an end to persistent air leak.

Adolescent↗
PubMedDate not supplied

Hereditary factor XIII deficiency.

Twelve cases of hereditary factor XIII (FX III) deficiency diagnosed over five years (1986-1990) at Christian Medical College and Hospital, Vellore are presented here. Although all the cases had a history of umbilical cord bleeding and subsequent frequent bleeding episodes, diagnosis was considerably delayed. All but two patients required transfusions for bleeding episodes. Ten patients had a history of consanguinity in parents. Clinical features and family history are described in detail here. The ease of performing the Urea solubility test and problems in it's interpretation are highlighted. The role of prophylactic transfusion is also discussed.

Adolescent↗
PubMed1996

[An investigation of a family tree with congenital deficiency in coagulation factor XIII].

In order to study the hereditary trait of a 20-year-old girl with congenital deficiency of coagulation factor XIII and her family tree, the following laboratory tests were done for the propositus and her family members: clot solubility test in 5 mol/L urea, estimation of factor XIII activity, amount of the subunits A and S of factor XIII with rocket electrophoresis. The results showed that the propositus had clinical history of bleeding in umbilical cord and its stump after birth. Her parents are not consanguineously related and have no history suggestive of hemorrhagic diathesis. The propositus has one brother and three sisters. One of her sisters died of bleeding of the umbilical cord after birth, another died at age of two, but the reason of her death is unclear and the remaining siblings are clinically healthy. The propositus had an abnormal urea clot lysis test, but the other family members had normal results. For the propositus factor XIII activity was 0%. A subunit 0% and S subunit 8.2%. Factor XIII activity of her father, her mother and her sister were 25%, 50%, 25% respectively. A subunit 52%, 58%, and 58% respectively and S subunit 66%, 68% and 66% respectively. The results showed that the propositus has a congenital deficiency in coagulation factor XIII, and her parents and sister are in fact carriers.

Adult↗
PubMed1999

The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism.

BACKGROUND: The resistance of thrombi to fibrinolysis induced by plasminogen activators remains a major impediment to the successful treatment of thrombotic diseases. This study examines the contribution of activated factor XIII (factor XIIIa) to fibrinolytic resistance in experimental pulmonary embolism. METHODS AND RESULTS: The fibrinolytic effects of specific inhibitors of factor XIIIa-mediated fibrin-fibrin cross-linking and alpha2-antiplasmin-fibrin cross-linking were measured in anesthetized ferrets with pulmonary emboli. Five experimental groups were treated with heparin (100 U/kg) and/or tissue plasminogen activator (TPA, 1 mg/kg) and the percent (mean+/-SD) lysis of emboli was determined: (1) control, normal factor XIIIa activity (14.1+/-4. 8% lysis); (2) inhibited factor XIIIa activity (42.7+/-7.4%); (3) normal factor XIIIa activity+TPA (32.3+/-7.7%); (4) inhibited factor XIIIa activity+TPA (76.0+/-11.9%); and (5) inhibited alpha2-antiplasmin-fibrin cross-linking+TPA (54.7+/-3.9%). Inhibition of factor XIIIa activity increased endogenous lysis markedly (group 1 versus 2; P<0.0001), to a level comparable to that achieved with TPA (group 2 versus 3; P<0.05). Among groups receiving TPA, selective inhibition of factor XIII-mediated alpha2-antiplasmin-fibrin cross-linking enhanced lysis (group 3 versus 5; P<0.0005). Complete inhibition of factor XIIIa also amplified lysis (group 3 versus 4; P<0.0001) and had greater effects than inhibition of alpha2-antiplasmin cross-linking alone (group 4 versus 5; P<0.0005). No significant fibrinogen degradation occurred in any group. CONCLUSIONS: Factor XIIIa-mediated fibrin-fibrin and alpha2-antiplasmin-fibrin cross-linking both caused experimental pulmonary emboli to resist endogenous and TPA-induced fibrinolysis. This suggests that factor XIIIa may play a critical role in regulating fibrinolysis in human thrombosis.

Animals↗
PubMed1988

Bleeding tendency caused by IgG inhibitor to factor XIII, treated successfully by cyclophosphamide.

A case exhibiting bleeding tendency caused by an acquired inhibitor to factor XIII is reported. The patient, a hitherto healthy 87-year-old Japanese man, presented with a massive subcutaneous bleeding, leading to severe anaemia. The routine coagulation study was normal except for a decreased plasma factor XIII level, which was 3% of the control level by the dansylcadaverine incorporation assay. An inhibitor of factor XIII was demonstrated to be present in the IgG fraction of the patient's plasma; by immunoblotting this inhibitor was shown to bind specifically the a and a' subunits of factor XIII. The IgG fraction suppressed the transglutaminase activity of activated factor XIII, but did not inhibit the molecular transformation of subunit a to a' in the activation process. Massive infusion of plasma and factor XIII concentrate was effective for controlling the bleeding temporarily. In the long-term prednisolone was ineffective for suppressing the plasma inhibitor level and bleeding episodes recurred. A small daily dose (50 mg) of cyclophosphamide, however, effectively decreased the inhibitor level and controlled bleeding.

Aged↗
PubMed1986

A pasteurised concentrate of human plasma factor XIII for therapeutic use.

A therapeutic concentrate of factor XIII containing both A and B sub-units has been prepared from 300 kg pools of human plasma. The process starts from a cold-ethanol fraction from cryoprecipitate supernatant and therefore does not interfere with the recovery of other clinically valuable plasma proteins. Factor XIII is purified approximately 600-fold from plasma by precipitation with sodium citrate and by the removal of fibrinogen by brief heating. The product has been pasteurised in sorbitol solution to inactivate blood-borne viruses, ultrafiltered to remove sorbitol, adsorbed with bentonite and freeze-dried in a formulation meeting requirements for intravenous injection.

Drug Contamination↗
PubMed2002

Increased risk for postoperative hemorrhage after intracranial surgery in patients with decreased factor XIII activity: implications of a prospective study.

BACKGROUND AND PURPOSE: The functional integrity of the hemostatic system is a prerequisite for the safe performance of neurosurgical procedures. To monitor the individual coagulation capacity of each patient, standard tests are effective to detect deficiencies involving the generation of fibrin. However, fibrin clot strength depends primarily on coagulation factor XIII, which cross-links fibrin monomers and enhances clot resistance against fibrinolysis. Therefore, factor XIII is functionally involved in both the hemostatic and fibrinolytic systems. The objective of this prospective study was to determine the incidence and clinical relevance of perioperative decreased factor XIII with respect to standard coagulation parameters and the occurrence of postoperative hematoma. METHODS: In 876 patients, 910 neurosurgical procedures were performed. Prothrombin time (PT), partial thromboplastin time (PTT), platelet count, fibrinogen, and factor XIII were tested in each patient preoperatively and postoperatively. RESULTS: Postoperative intracranial hematoma (defined as requiring surgical evacuation) occurred after 39 (4.3%) of 910 surgical procedures. Patients with postoperative hematoma had significantly lower factor XIII and fibrinogen levels preoperatively and postoperatively than patients without hematoma. In patients with postoperative hematoma, PT and platelets differed significantly only postoperatively, whereas PTT was different neither preoperatively nor postoperatively. Of the 39 patients with a postoperative hematoma, 13 (33.3%) had a postoperative factor XIII <60% compared with 61 (7%) of 867 patients without hematoma (P<0.01, Fisher's exact test). The relative risk of developing a postoperative hematoma is therefore increased 6.4-fold in patients with postoperative factor XIII <60%. The risk is increased 12-fold in patients who additionally have postoperative decreased fibrinogen levels (<1.5 g/L) and 9-fold in patients with platelet count <150x10(9)/L and factor XIII <60%. CONCLUSIONS: This is the first prospective study that demonstrates the association of decreased perioperative factor XIII with an increased risk of postoperative hematoma in neurosurgical patients. The risk is further increased in those patients with low factor XIII and additional abnormalities of fibrinogen, PT, platelets, and PTT. Factor XIII testing and specific replacement, as accepted for other clotting factors, may reduce the risk of postoperative hematoma.

Comorbidity↗
PubMed1979

An acquired inhibitor to factor XIII A case report.

An elderly woman presented with a postoperative bleeding problem, and a presumptive diagnosis of factor XIII (fibrin-stablilizing factor) deficiency was made. However, on further testing, an inhibitor to factor XIII was detected. She was on isoniazid (INH) therapy at the time. INH has been implicated in other patients who have developed inhibitors to factor XIII, and it was felt that this was the reason for this patient developing the inhibitor. The patient subsequently died from a cerebral haemorrhage, a well-described complication of factor XIII deficiency.

Aged↗
PubMed1987

Platelet factor XIII is activated by calpain.

The action of calpain (EC 3.4.22.17; Ca2+-dependent cysteine proteinase) on platelet factor XIII has been studied. Calpain I activated platelet factor XIII up to 76% of the maximum level observed with thrombin. Activation was accompanied by the limited proteolysis of the a subunit of platelet factor XIII to produce a 76 kDa fragment which was comparable to the proteolytic product by thrombin. Activation of platelet factor XIII by calpain was inhibited by EDTA, leupeptin, and endogenous calpain-specific inhibitor calpastatin. These findings suggest that calpain is responsible for the intracellular activation of platelet factor XIII.

Blood Platelets↗
PubMed1987

Factor XIIIa formation promoted by complexing of alpha-thrombin, fibrin, and plasma factor XIII.

Fibrin polymers (des A,B fibrinogen) reduced the concentration of alpha-thrombin required for 50% activation of plasma factor XIII (a2b2 tetramer) by approximately 100-fold. In the presence of fibrin, the amount of gamma-thrombin required for activation was not affected. Catalytically inactive i-Pr2P- and D-Phe-Pro-Arg-CH2-alpha-thrombin were found to inhibit over 95% of the activation by alpha-thrombin in the presence of fibrin. Unlike plasma factor XIII, the concentration of alpha-thrombin required for 50% activation of platelet factor XIII (a2 dimer) was lower, and the activation was not enhanced by fibrin. However, when the a2 platelet factor XIII was incubated with purified b-chains, the alpha- and gamma-thrombin concentrations required for activation increased tenfold and reached levels similar to those required for activation of the plasma factor XIII. When fibrin was present, the alpha-thrombin concentrations needed for activation of the a2b2 complexes were reduced, and the presence of fibrin had no effect on gamma-thrombin cleavage of the a2b2 complexes. Therefore, the b-chains must inhibit a-chain cleavage by alpha-thrombin in the absence of fibrin. These results imply that the formation of a cocomplex involving alpha-thrombin, fibrin, and plasma factor XIII causes some conformational change in plasma factor XIII such that the b-chains no longer inhibit cleavage of the a-chains.

Factor XIII↗
PubMed1984

[Factor XIII in the treatment of postoperative refractory wound-healing disorders. Results of a controlled study].

The efficacy of factor-XIII concentrate in the improvement of postoperative wound healing disorders (suture dehiscences, fistulae) was examined in 61 patients. In an open, randomised, and controlled trial the results (decrease of wound area, signs of inflammation, wound secretion, drainage volume, contrast x-ray films, and colour photos) were evaluated twice: open judgement by the clinicians themselves and blind judgement by an independent evaluation committee. The blind evaluation of the clinical data showed relevant general improvement in the patient groups treated with factor-XIII concentrate: 61.9% (dosage: 750 IU factor XIII for 3 days) and 76.2% (dosage: 1500 IU factor XIII for 3 days) as compared to 10.5% in the control group without factor XIII substitution. The differences were significant (Mann-Whitney-U-Test, p less than or equal to 0.001). These results would suggest substituting factor XIII activity in plasma above 70% of normal value in case of wound healing disorders.

Adult↗