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PubMed1993

Packaging zinc, fibrinogen, and factor XIII in platelet alpha-granules.

Zinc(II) accumulated by platelets has profound effects on platelet activity. This study is focused on the distribution of Zn(II) between human platelet subcellular compartments. After incubation with 86Rb+ and platelet lysis, the organelles were separated by sucrose density gradient centrifugation. Fibrinogen served as a marker for alpha-granules. 86Rb+ and factor XIII served as markers for the cytoplasmic fractions. Zn(II) was found to be distributed between the cytoplasm and the alpha-granules, with variations between different individual units. The total platelet Zn concentration and its relative subcellular distribution were dependent on its extracellular level. Incubation of platelets with 100 microM Zn(II) resulted in a twofold increase of its level in the cytoplasm and by one order of magnitude in the alpha-granules. In addition to the anticipated factor XIII activity in the cytoplasmic pool fraction, we found thrombin-inducible factor XIII activity within the alpha-granules. Immunoblotting confirmed the presence of both the a and b subunits of plasma factor XIII (a2b2 form) in the alpha-granules. As fibrinogen is not synthesized in the platelet, we propose that by virtue of their mutual binding, fibrinogen, Zn(II) and plasma factor XIII-a2b2 are simultaneously taken up into the alpha-granules by endocytosis, presumably through the vehicle of the GPIIb/IIIa fibrinogen receptor. A rationale for co-packaging these components within the alpha-granules is that Zn(II) inhibits factor XIII activity and thereby prevents the premature cross-linking of the concentrated fibrinogen prior to platelet activation and secretion. By contrast, cytoplasmic Zn(II) may increase platelet responsiveness to agonists due to its interaction with cytoplasmic modulators of platelet activity.

Blood Platelets↗
PubMed1980

Structural features of glutamine substrates for human plasma factor XIIIa (activated blood coagulation factor XIII).

The action of human plasma factor XIIIa (thrombin-activated blood coagulation factor XIII) and guinea pig liver transglutaminase on purified caseins, fibrin, the derivatized gamma chain of fibrin, and a number of synthetic glutamine peptides, and peptide derivatives is reported. There are wide variations in the properties of the individual proteins and peptides as substrates for amine incorporation by the two transglutaminases. beta-Casein and several of its derivatives are excellent substrates for factor XIIIa. However, beta-casein is a relatively poor substrate for the liver enzyme. The primary site of amine incorporation by factor XIIIa in beta-casein was identified as glutamine 167. This was accomplished by labeling with fluorescent amine followed by proteolytic digestion and identification of labeled peptides. An 11-residue peptide and a 15-residue peptide, each containing 1 glutamine residue and each modeled after the primary site of amine incorporation in beta-casein, were prepared. A 13-residue peptide modeled after the primary crosslinking site in fibrin gamma chain was also prepared. Each of these polypeptides proved to be an efficient substrate for factor XIIIa and displayed significantly better substrate properties than a number of small glutamine peptide derivatives that are good substrates for liver transglutaminase.

Amino Acid Sequence↗
PubMed2002

[Factor XIII in man: a review].

Activated by calcium and thrombin, factor XIII (FXIIIa) cross-links fibrin, thus increasing the stability of the fibrin clot. Furthermore, the hemostatic and reparative function of factor XIIIa is mediated by cross-linking other proteins like alpha(2)-plasmin-inhibitor, fibronectin, and collagen. The FXIII Val34Leu polymorphism plays a role in athero- and thrombogenesis. FXIII deficiency is an autosomal recessive disorder. The most common symptom is the bleeding tendency of the umbilical cord some days after birth. The diagnosis is confirmed by a solubility clot test in urea (5 mol/l) and then differentiated with an incorporation assay and immuno-electrophoresis. The bleeding tendency typically becomes obvious when FXIIIa activity is <1-2%. Severe bleeding episodes, however, may even occur with FXIIIa activities of 30-50%, especially in heterozygous persons. The sometimes life-threatening bleeding tendency of the inherited FXIII deficiency can be treated with FXIII concentrates. Acquired FXIII deficiency occurs in several internal diseases and after major surgery. The clinical significance is not completely clear. Moreover, FXIII is applied locally as a component of fibrin glues.

Factor XIII↗
PubMed2000

Prevention of suture hole bleeding using fibrin sealant: benefits of factor XIII.

BACKGROUND: Suture hole bleeding is a frequent complication in vascular surgery. The use of fibrin sealants (FSs) during surgery is reported to reduce blood loss by enhancing hemostasis. OBJECTIVES: Using a pig vascular graft model we investigated: (1) the use of FSs in vascular surgery and measured blood loss with and without the use of FSs; (2) the effect of factor XIII in FSs on hemostasis and blood loss; and (3) the effect of increasing FS incubation time on hemostasis and blood loss. MATERIALS AND METHODS: During surgery, a 3-cm incision was made in the carotid artery wall. Incisions were covered with a Gore-Tex (PTFE) patch sutured with Ethicon monofil 5/0 or 3/0. The resulting suture holes were treated according to study protocol. Study 1: Nine pigs received either FS treatment (n = 5) or no treatment (n = 4). Study 2: Twenty pigs underwent bilateral surgery; right (n = 20) and left (n = 20) patches received either FS with factor XIII (FS + FXIII) or FS depleted of factor XIII (FS - FXIII). Study 3: Bilateral surgery was carried out on 24 pigs; PFTE patches secured with Ethicon 3/0 were treated with FS and allowed to polymerize for 120 s (n = 12), 180 s (n = 12), or 240 s (n = 12) or with solid support/thrombin (n = 12). RESULTS: Study 1: Mean blood loss was significantly lower in the FS-treated group compared with untreated controls (9.2 +/- 10.6 mL vs 178.8 +/- 125.5 mL, mean +/- SD, P = 0.016). Study 2: Significantly less blood was lost in the FS + FXIII group than in the FS - FXIII group (Delta = 9.6 mL, P = 0. 02). Study 3: Blood loss was significantly higher from patches treated with solid support/thrombin compared with those treated with FS (P < 0.01). CONCLUSIONS: FSs containing factor XIII, such as Beriplast P, are effective in reducing suture hole bleeding and improving hemostasis during vascular graft procedures. The presence of factor XIII contributes to the efficacy of FSs and reduces the time to hemostasis. During vascular surgery, blood loss can be reduced significantly by the use of fibrin sealant compared with absorbable gelatin sponges coated with thrombin.

Animals↗
PubMed1978

Subunits A and S inheritance in four families with congenital factor XIII deficiency.

Previous studies of the inheritance of the two molecular subunits of fibrin stablizing factor (factor XIII) refer to isolated cases. The present work investigates the hereditary mode of transmission of subunits A and S, measured by the Laurell technique, in seven homozygotes and in 29 heterozygotes belonging to four families with factor XIII deficiency. The results indicate that the homozygotes were devoid of immunologically identifiable A subunit, whereas the heterozygotes could be identified by measuring this protein. The subunit S has been found to be decreased both in homozygous and in heterozygous patients, so that it seems that the two subunits, even if their synthesis is controlled by different genes, are genetically related. The mode of transmission of this disorder, supported by quantitative determinations of plasma subunit A, is autosomal recessive.

Factor XIII↗
PubMed1998

Possible role of coagulation factor XIII in the pathogenesis of venous leg ulcers.

BACKGROUND: Aim of this placebo-controlled clinical study was to examine the expression pattern of coagulation factor XIIIa in patients with chronic venous leg ulcers and the impact of a 10 day topical factor XIII treatment on ulcer healing, leg ulcer size and radius reduction. PATIENTS AND METHODS: 24 patients were stratified into two groups, each consisting of 12 patients, with leg ulcers > 1.000 mm2, or < 1.000 mm2. Four patients of each study group were assigned to the control group (n = 8). All leg ulcers were treated by topical application of non-adhering dressings and compression therapy. Patients of the treatment group (n = 16) were treated by additional topical treatment off factor XIII twice daily for ten days. Immunohistochemical staining of leg ulcer specimens before and after treatment (day 10) was performed in all patients. RESULTS: The immunohistochemical staining of factor XIIIa in all specimens before and after therapy showed no significant increase in the expression of factor XIIIa. Comparison of the leg ulcer size, radius and daily radius reduction in the treatment and control group showed no significant differences in values of patients with leg ulcers > 1.000 mm2. However, a decreased leg ulcer size and radius was found in patients of the treatment group with more acute leg ulcers < 1.000 mm2 in contrast to patients with larger leg ulcers (daily ulcer radius reduction from day 0-10; 0.31 mm versus 0.13 mm, p < 0.015). CONCLUSIONS: These results indicate that locally applied factor XIII promotes especially wound healing of more acute smaller venous leg ulcers. Since immunohistochemical staining of factor XIIIa showed no significant differences before and after therapy, we propose that factor XIII is inactivated rapidly after local application on venous leg ulcers.

Administration, Topical↗
PubMed1978

The role of factor XIII in fibroblast proliferation.

Fibrin stabilizing factor, Factor XIII (F-XIII), which is a transamidating enzyme for fibrin crosslinking, is required for wound healing or fibroblast proliferation. Two know whether or not the enzyme reacts directly to the cell surface, the 3T6 fibroblasts were cultured on fibrin which is natural matrix for the proliferation. Poor-crosslinked and crosslinked fibrin plates were prepared by human plasma clotting with or without the F-XIII inhibitors. In 48 hours culture, the seeded 3 X 10(4) cells were grown to 10.2 X 10(4) on the crosslinked fibrin but only to 3.8 X 10(4) on the poor-crosslinked fibrin plate on the average. The effect of an antifibrinolytic agent, epsilon-aminocaptroic acid was also checked. Consequently, the crosslinking of fibrin seemed to be essential to provide it with favorable property as the contact surface for the growth.

Aminocaproates↗
PubMed2002

[Factor XIII and endothelial barrier function].

Activated factor XIII (FXIIIa) crosslinks fibrin monomers to a stable clot. Due to this function, FXIIIa plays a major role in hemostasis and fibrinolysis. Additionally, it is well known that FXIIIa has a special meaning in cell adhesion and migration, in generation of extracellular matrix, in tissue repair and wound healing. New experimental studies revealed a FXIIIa stabilizing endothelial barrier function. In this function, FXIIIa reduces endothelial permeability for macromolecules in cultured endothelial monolayers and prevents impending barrier failure in coronary arteries of isolated hearts. This effect is due to the cross-linking of several proteins within the extracellular matrix, especially in the interendothelial clefts.

Cell Adhesion↗
PubMed2002

Characterizing fibrin glue performance as modulated by heparin, aprotinin, and factor XIII.

We describe the performance of fibrin glue (FG) as modulated by heparin, aprotinin, or factor XIII levels. In vitro tests and a rat kidney excision model demonstrated that the hemostatic efficacy of fibrin was not modulated by aprotinin. Overlapping rat skin sections demonstrated that adhesion strength (AS) was proportional to the area of overlap as well as to fibrinogen levels. AS was not modulated by exogenous heparin or aprotinin and was independent of the endogenous factor XIII in fibrinogen. SDS-PAGE developed by Coomassie or Western blots with anti-gamma chain antibody confirmed that normal skin sections contain adequate trans-glutaminase to maximally cross-link normal, as well as XIII-depleted, fibrin. Fibrin glue (FG) sprayed onto rat skin incision wounds with a dual channel spray applicator acted in 2 phases: initially (day 1), compared to wounds stapled without or treated with only thrombin, FG significantly increased breaking strength. In the second phase of wound healing (after day 3), all groups achieved increased but equivalent breaking strength. FG containing aprotinin (to 3000 U/m; Immuno, Behringwerke, Germany) exhibited initial tissue bonding strength equivalent to fibrin without aprotinin, but histological examination showed delayed fibrinolysis and a concomitant slower regeneration of granulation tissue. Thus, our data indicated that aprotinin was not particularly beneficial to wound healing and that the endogenous factor XIII level in the fibrinogen did not contribute significantly to skin bonding. Rather, the tissue supplied adequate trans-glutaminase activity required to crosslink fibrin to itself and to the tissue.

Animals↗
PubMed2003

A case of giant expanding cephalhematoma: does the administration of blood coagulation factor XIII reverse symptoms?

BACKGROUND: The mechanism of continuous massive hemorrhage into the subperiosteal space in children without coagulation defects is unknown. We report a case of giant expanding cephalhematoma reversed by the administration of blood coagulation factor XIII concentrate. METHOD: The patient was an 8-year-old boy with a history of minor head trauma who developed a giant expanding cephalhematoma with intraorbital extension. The laboratory data showed severe anemia, but a routine blood coagulation test showed no abnormalities except for a low factor XIII level. RESULT: The administration of factor XIII concentrate completely reversed the symptoms in 2 weeks. CONCLUSION: We speculate that one of the possible mechanisms of cephalhematoma expansion without blood coagulation defects might be acquired factor XIII deficiency from severe hemorrhage in a hematoma.

Bone Diseases↗
PubMed2006

Development and evaluation of a modified colorimetric solid-phase microassay for measuring the activity of cellular and plasma (Factor XIII) transglutaminases.

Plasma TG (transglutaminase) [FXIII (Factor XIII)] stabilizes fibrin and plays an essential role in haemostasis. In the present paper, we report a simple colorimetric assay for measuring FXIII activity. The advantage of this approach, compared with all the other solid-phase assays described so far for measuring TG activity, is that the first substrate, namely the synthetic dipeptide, N-benzyloxycarbonyl-L-Gln-L-Gly, is coupled covalently by its C-terminus with amine-substituted polystyrene plates. Covalent coupling eliminates the problem of desorption of proteins such as casein and N,N'-dimethylcasein (first substrates) when 'blocking' buffers containing proteins, e.g. BSA, are employed, or when samples of plasma or cell homogenates are used. The principle of the assay itself is based on the incorporation of the well-known second substrate, 5-(biotinamido)pentylamine, into the gamma-carboxamide of glutamine in the immobilized dipeptide. The amount of biotinylated amine bound to the plate, as measured by the phosphatase activity of Extravidin phosphatase attached to the biotin moiety, is directly proportional to the TG activity. The method shows strong correlation (r = 0.96) with the radiometric assay for FXIII activity. For plasma samples, a linear response was obtained in the range 0-1.33 i.u. (international unit)/ml, versus the Behring standard. In a preliminary clinical investigation, the method was applied to normal and pathological plasma samples from patients with liver failure and disseminated intravascular coagulation. In the isolation of TG from guinea-pig liver, it was used to measure enzyme activity after each purification step. This method is rapid, sensitive and can easily be applied to routine clinical analyses and to specific research problems.

Animals↗
PubMed1980

An electrophoretic and quantitative analysis of coagulation factor XIII in normal and deficient subjects.

Previous electrophoretic studies of the A and B subunits of factor XIII have revealed considerably genetic heterogeneity. The present work investigates the electrophoretic forms and quantitates the A and B subunits in a family with inherited factor XIII deficiency. The data indicate that the deficiency in this family is due to a null allele at the locus controlling the A subunit. All family members were found to have decreased levels of B subunit. The data also indicate that there is no difference in thrombin activated transamidase activity between normal individuals with the three commonly occurring electrophoretic phenotypes of the A subunit.

Alleles↗
PubMed2006

A novel assay for factor XIII based on cross-linking of synthetic peptides: analysis of different substrates.

A novel assay for factor XIII is described that utilizes exclusively small synthetic peptides as substrates for the cross-linking reaction catalyzed by activated factor XIII (FXIIIa). The acyl donor substrate (selection peptide) is immobilized on a microplate via biotin while the acyl acceptor substrate (detection peptide) is labeled with the fluorochrome Oregon green to allow sensitive detection without the need for secondary enzyme systems for signal amplification. Starting with an amino acid sequence from the fibrin gamma-chain (GQQHHLGGAKQAGDV) as a prototype peptide, the influence of amino acid exchanges were investigated with respect to their impact on the FXIIIa-catalyzed reaction. It was found that FXIIIa readily accepts a broad range of substrate peptides, with a proline neighboring the essential lysine having the most detrimental effect. The assay appears to be valuable for the molecular characterization of factor XIII and may be used for a deeper investigation into the substrate requirements of this final enzyme of wound repair, and eventually also for the characterization of other transglutaminases.

Cross-Linking Reagents↗
PubMed1983

Influences of clotting factors (thrombin, factor XIII) and of fibronectin on the growth of tumor cells and leukemic cells in vitro.

Thrombin, factor XIII and fibronectin were incubated with cultures of mouse sarcoma cells, human cervix carcinoma cells (HeLa cells) and cells of an acute lymphoblastic leukemia. Thrombin induced a significant increase of 3H-thymidine uptake into cells with a 1,5- to 2-fold increase of cell count. The cells of an acute lymphoblastic leukemia showed a similar response to the influence of thrombin. Factor XIII in tumor cells merely induced an increase of 3H-thymidine uptake, the cell count remained constant. The cells of an acute lymphoblastic leukemia showed under the influence of factor XIII a significant increase of cell count and thymidine uptake. HeLa cell growth was optimal at low fibronectin concentrations. Fibronectin concentrations of 1 mg/ml to 3 mg/ml inhibited HeLa and mouse sarcoma cell growth.

Animals↗
PubMed1977

Factor XIII and fracture healing. An experimental study.

The effect of exogenous factor XIII on fracture healing has been tested. It could be shown that after administration of the fibrin stabilizing factor, the concentration of fibrin fibres in the fracture haematoma increases. The resistance against breaking is thus enhanced in treated animals as compared to untreated controls, mainly during the early phases of fracture healing. X-ray diagnosis demonstrated an enhanced healing process of the treated fractures. The accelerated fracture healing by factor XIII adminstration could also be substantiated through histological examinations.

Animals↗
PubMed1986

Plasma factor XIII and some other haemostasis parameters in patients with diabetic angiopathy.

Since intravascular and endoparietal fibrin deposition is thought to be involved in the development of atherosclerosis, we measured factor XIII activity and its subunit 'a' and 'b' concentrations against a background of other haemostasis parameters in diabetics with angiopathy and in 2 control groups (healthy subjects and diabetics without vascular complications). Diabetics with angiopathy revealed a significant increase of factor XIII activity as well as its subunit concentrations. They also had significantly elevated anti-thrombin III, alpha 2 macroglobulin, alpha 1 antitrypsin, C1 inhibitor, fibrinogen, FDP concentrations and prolongation of euglobulin lysis time. The highest factor XIII levels were found in diabetics with renal failure. We suppose that increased factor XIII level and other observed changes of haemostasis in patients with diabetic angiopathy might promote intravascular and endoparietal fibrin deposition and contribute to the development of atherosclerotic complications of diabetes.

Adult↗
PubMed1990

Effects of blood coagulation factor XIII on the development of experimental cerebral aneurysms in rats.

Pathological and experimental studies have shown that cerebral aneurysms develop in part as a result of injury to the blood vessel wall. One of the peculiar aspects of aneurysm development is a defective proliferative or healing response to such injury. To examine this phenomenon, blood coagulation Factor XIII, which is known to enhance the healing process of wounds in general, was given to rats to induce experimental cerebral aneurysms. The rats were subjected to ligation of one common carotid artery and induction of hypertension, and were fed beta-aminoproprionitrile. Two weeks thereafter, Factor XIII was injected intravenously daily for 5 days (10 U/100 gm body weight/day). Twelve days after the start of Factor XIII injections, the rats were sacrificed and examined under light and electron microscopy. In seven of 12 bifurcations which developed small aneurysms, prominent intimal thickening was observed in the aneurysm lumen. In the most advanced cases, the aneurysm lumen was completely filled with proliferated smooth-muscle cells and collagen. In five of nine bifurcations that showed no aneurysm development, apparent intimal thickening was found at the site where aneurysms might be expected to grow. In the group of rats studied for induction of cerebral aneurysms but not given Factor XIII, none of 11 bifurcations with or without aneurysms showed such intimal thickening. The results indicated that the proliferative response at the sites of aneurysm development was modified by exogenous Factor XIII.

Animals↗