fibrin and Factor-XIII-Deficiency

Factor XIII (FXIII) is the final factor in the coagulation cascade. It converts soluble fibrin monomers into a stable fibrin clot, prevents premature degradation of fibrin, participates in wound healing, and helps prevent the loss of the endothelial barrier function. FXIII deficiency is believed to be rare, and this may explain why clinicians do not routinely take it into consideration. Congenital FXIII deficiency is a rare disease with a reported prevalence of 1 per million. However, the prevalence of acquired FXIII deficiency is much higher. Acquired forms have been described in patients with decreased hepatic or bone marrow synthesis, overconsumption and increased degradation by autoantibodies. This review offers guidance on how to suspect and diagnose FXIII deficiency in both the preoperative consultation and different surgical settings. We also analyze current scientific evidence in order to clarify when and why this clinical situation should be suspected, and how it may be treated.

Topics: Blood Coagulation; Blood Loss, Surgical; Factor XIII; Factor XIII Deficiency; Fibrin; Humans

Coagulation factor XIII (FXIII), a plasma transglutaminase, is best known as the final enzyme in the coagulation cascade, where it is responsible for cross-linking of fibrin. However, a growing body of evidence has demonstrated that FXIII targets a wide range of additional substrates that have important roles in health and disease. These include antifibrinolytic proteins, with cross-linking of α2-antiplasmin to fibrin, and potentially fibrinogen, being the principal mechanism(s) whereby plasmin-mediated clot degradation is minimised. FXIII also acts on endothelial cell VEGFR-2 and αvβ3 integrin, which ultimately leads to downregulation of the antiangiogenic protein thrombospondin-1, promoting angiogenesis and neovascularisation. Under infectious disease conditions, FXIII cross-links bacterial surface proteins to fibrinogen, resulting in immobilisation and killing, while during wound healing, FXIII induces cross-linking of the provisional matrix. The latter process has been shown to influence the interaction of leukocytes with the provisional extracellular matrix and promote wound healing. Through these actions, there are good rationales for evaluating the therapeutic potential of FXIII in diseases in which tissue repair is dysregulated or perturbed, including systemic sclerosis (scleroderma), invasive bacterial infections, and tissue repair, for instance healing of venous leg ulcers or myocardial injuries. Adequate levels of FXIII are also required in patients undergoing surgery to prevent or treat perioperative bleeding, and its augmentation in patients with/at risk for perioperative bleeding may also have potential clinical benefit. While there are preclinical and/or clinical data to support the use of FXIII in a range of settings, further clinical evaluation in these underexplored applications is warranted.

Topics: Angiogenesis Inducing Agents; Animals; Bacterial Infections; Blood Coagulation; Blood Loss, Surgical; Coagulants; Factor XIII; Factor XIII Deficiency; Factor XIIIa; Fibrin; Humans; Neovascularization, Physiologic; Postoperative Hemorrhage; Scleroderma, Systemic; Signal Transduction; Substrate Specificity; Thrombospondin 1; Wound Healing

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

Topics: Coagulants; Factor VIII; Factor XIII; Factor XIII Deficiency; Fibrin; Fibrinogen; Humans; Protein Conformation; Protein Stability; Recombinant Proteins

Coagulation factor XIII (FXIII) is a protein that promotes fibrin stabilization by forming multiple covalent cross-links between fibrin monomers. Beside congenital FXIII deficiency, due to FXIII gene mutations, severe acquired FXIII deficiency has been described in association with autoantibodies against coagulation FXIII. These inhibitors, which occurs very rarely but may cause life-threatening bleeding complications, may arise spontaneously or in association with autoimmune and lymphoproliferative disorders or medications. The management of patients with acquired FXIII inhibitors is very demanding and treatment regimens must be focused on eradication of the inhibitor and to increase the plasma FXIII levels. In this systematic review, we analyse all the published case-reports on anti-FXIII autoantibodies focusing on the clinical features and treatment modalities of this acquired hemorrhagic condition.

Topics: Autoantibodies; Autoimmune Diseases; Blood Coagulation Factor Inhibitors; Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Lymphoproliferative Disorders

Acquired factor XIII (FXIII) deficiency, arising from an autoantibody against factor XIII, is a rare bleeding disorder. This autoimmune disorder most commonly occurs in the elderly. Patients who develop such acquired FXIII inhibitors may present with catastrophic bleeding events and are hard to be diagnosed with the normal general coagulation tests. Though the disease is relatively rare, it is known to cause significant mortality. In this article we briefly describe a patient who presented with extensive bleeding and a normal activated partial thromboplastin time and prothrombin time (PT), but had an acquired inhibitor to FXIII; her primary disease was systemic lupus erythematosus (SLE). Also, we will focus on the clinical features, treatment modalities, fibrin structure and epitope identification for acquired factor XIII inhibitor with a review of the literature.

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Factor Inhibitors; Epitopes; Factor VIII; Factor XIII Deficiency; Female; Fibrin; Hemorrhage; Hemorrhagic Disorders; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic

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.

Topics: Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Polymorphism, Genetic; Substrate Specificity

The most powerful instrument to establish the presence or absence of a coagulation disorder is the history of the patient. In addition, screening laboratory tests (consisting of the platelet count, bleeding time and global clotting assays, such as the prothrombin time and the activated partial thromboplastin time) may be helpful to support the diagnosis. In two patients, a 21-year-old man and a 10-year-old girl, with a marked history of enhanced bleeding normal screening laboratory tests were found. The male patient had a congenital alpha 2-antiplasmin deficiency and the girl had a homozygous deficiency of factor XIII. Some defects in the coagulation system (such as defects in fibrin network formation and fibrinolysis, but also mild Von Willebrand disease) are indeed not detected by screening laboratory tests. In patients with a strong suspicion of a coagulation disorder such defects should be specifically tested for.

Topics: Adult; alpha-2-Antiplasmin; Antifibrinolytic Agents; Blood Coagulation Tests; Child; Diagnosis, Differential; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Fibrinolysis; Hemorrhagic Disorders; Humans; Male; Medical History Taking; Tranexamic Acid

Factor XIII is a proenzyme for a plasma transglutaminase. Factor XIII in plasma is a tetramer (A2B2) held together by noncovalent bonds, and the A subunit contains the active site. Recently, the three-dimensional structure of the A subunit has been determined by x-ray crystallography. To understand the structure-function relationships of the factor XIII molecule and its clinical implications in factor XIII deficiency, we characterized its genetic defects and closely examined its gene products, including mRNA and protein levels. A variety of missense and nonsense mutations (Arg260-Cys, Tyr283-Cys, Gly562-Arg) and deletions/insertions with or without out-of-frame shift/premature termination and splicing abnormalities (4-bp deletion with 464Stop, T insertion at the exon IV/intron D boundary with exon IV-skipping, 20-bp deletion at the exon I/intron A boundary) has been identified in cases demonstrating A subunit deficiency. In some cases, the A subunit mRNA levels were severely reduced. Their molecular and cellular bases have also been explored by expression experiments in mammalian cells and by molecular modeling. In most cases, impaired folding and/or conformational changes of the mutant A subunits lead to both intra- and extracellular instability, which is responsible for the A subunit deficiency in the patients.

Topics: alpha-2-Antiplasmin; Amino Acid Sequence; Amino Acid Substitution; Binding Sites; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 6; DNA Mutational Analysis; Enzyme Activation; Factor XIII Deficiency; Fibrin; Humans; Models, Molecular; Molecular Sequence Data; Point Mutation; Protein Conformation; RNA, Messenger; Sequence Deletion; Structure-Activity Relationship; Thrombin; Transglutaminases

Congenital factor XIII deficiency is a rare disease, but has provided valuable information on the physiological role of factor XIII and the benefit of factor XIII replacement therapy. It could be shown that not only homozygous patients but also heterozygotes are at risk for bleeding complications. Acquired factor XIII deficiency, however, is much more common, and preliminary studies suggest a lack of factor XIII to be an important feature of various diseases. In acute states and severe hemorrhages, replacement therapy with factor XIII concentrates is recommended. Recent progress in assay methods and future clinical studies should help to evaluate the therapeutic potential of factor XIII.

Topics: Autoantibodies; Autoimmune Diseases; Epitopes; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Fracture Healing; Hemorrhage; Humans; Isoantibodies; Isoniazid; Male; Pregnancy; Pregnancy Complications, Hematologic; Wound Healing

Factor XIII (XIII), an enzyme found in plasma (present as a pro-enzyme), platelets and monocytes, is essential for normal haemostasis. It may also have a role to play in the processes of wound healing and tissue repair. Inherited XIII deficiency results in a life-long, severe bleeding diathesis which, if untreated, carries a very high risk of death in early life from intracranial bleeding. XIII is a zymogen requiring thrombin and calcium for activation. In plasma, XIII has two subunits: the 'a' subunit, which is the active enzyme, and the 'b' subunit which is a carrier protein. Activated XIII modifies the structure of clot by covalently crosslinking fibrin through an epsilon (gamma-glutamyl)lysine link. It also crosslinks other proteins, including fibronectin and alpha-2-plasmin inhibitor (alpha-2PI), into the clot through the same link. Clot modified by XIII is physically stronger, relatively more resistant to fibrinolysis and may be a more suitable medium for the ingrowth of fibroblasts. Inheritance of factor XIII is autosomal recessive. The majority of patients with the inherited defect show no XIII activity and absence of 'a' subunit protein in plasma, platelets and monocytes. At the molecular level, the defect is not a major gene rearrangement or deletion, but most likely a single point mutation which may be different in each family. Because of the severity of the bleeding diathesis, prophylaxis is desirable and has been shown to be very effective as the in vivo half-life of plasma XIII is long, and low plasma levels are sufficient for haemostasis. Acquired inhibitors have been reported in only two cases with inherited XIII deficiency. Acquired XIII deficiency has been described in a variety of diseases and bleeding has been controlled by therapy with large doses of XIII in such conditions as Henoch-Schönlein purpura, various forms of colitis, erosive gastritis and some forms of leukaemia. Large dose XIII therapy has also been used in an endeavour to promote wound healing after surgery and bone union in non-healing fractures. The use of XIII in these conditions remains controversial. Very rarely a bleeding diathesis results from the development of a specific inhibitor to XIII arising de novo, often as a complication in the course of a disease or in association with long-term drug therapy. The bleeding diathesis in these patients is difficult to treat.

Topics: Amino Acid Sequence; Enzyme Activation; Factor XIII; Factor XIII Deficiency; Fibrin; Hemorrhagic Disorders; Hemostasis; Humans; Molecular Sequence Data; Protein Conformation; Wound Healing

Topics: Amino Acids; Blood Coagulation; Blood Platelets; Carbohydrates; Electrophoresis, Polyacrylamide Gel; Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Liver Diseases; Molecular Weight; Neoplasms; Placenta

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.

Topics: Adult; Blood Coagulation Disorders; Electrophoresis, Polyacrylamide Gel; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Hemorrhagic Disorders; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications, Hematologic

Topics: Animals; Blood Coagulation; Blood Protein Electrophoresis; Calcium; Enzyme Activation; Factor XII; Factor XIII; Factor XIII Deficiency; Fibrin; Fibrinogen; Fibrinolysin; Half-Life; Hemorrhage; Hemorrhagic Disorders; Hemostasis; Heparin; Humans; Molecular Weight; Rats; Sulfhydryl Compounds; Thrombin

Topics: Abortion, Spontaneous; Blood; Blood Coagulation Tests; Blood Platelets; Cerebral Hemorrhage; Ecchymosis; Factor XIII; Factor XIII Deficiency; Female; Fetal Death; Fibrin; Hematoma; Hemorrhage; Hemorrhagic Disorders; Humans; Infant, Newborn; Placenta; Pregnancy; Pregnancy Complications, Hematologic; Umbilical Cord

Topics: Abruptio Placentae; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelet Disorders; Blood Transfusion; Disseminated Intravascular Coagulation; Embolism, Amniotic Fluid; Factor XIII Deficiency; Female; Fetal Death; Fetal Diseases; Fibrin; Fibrinogen; Fibrinolysis; Hemophilia A; Humans; Liver Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Sepsis; Uterine Hemorrhage; Vitamin K

Topics: Amino Acids; Animals; Blood Coagulation; Blood Platelets; Chemical Phenomena; Chemistry; Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Enzyme Precursors; Factor XIII; Factor XIII Deficiency; Fibrin; Fibrinogen; Fibrinolysis; Glutamine; Guinea Pigs; Humans; Liver; Macromolecular Substances; Molecular Weight; Peptides; Sodium Dodecyl Sulfate; Solubility; Transferases

Topics: Amines; Animals; Binding Sites; Binding, Competitive; Blood Coagulation; Calcium; Centrifugation, Density Gradient; Chemical Phenomena; Chemistry; Chromatography, DEAE-Cellulose; Elasticity; Enzyme Activation; Enzyme Precursors; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Glutamine; Humans; Infant, Newborn; Peptides; Pregnancy; Structure-Activity Relationship; Thrombin; Transferases

Topics: Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Transglutaminases

 Coagulation factor XIII (FXIII) is a proenzyme of plasma transglutaminase. It comprises two catalytic A subunits (FXIII-A) and two carrier B subunits (FXIII-B). We previously reported that alloantibodies against FXIII-B could promote FXIII clearance in a patient with congenital FXIII-B deficiency who had received infusions of plasma-derived human FXIII (A.  We aimed to investigate whether anti-FXIII-B antibodies affect the catalytic function of FXIII..  FXIII activation and fibrin crosslinking were examined in the presence of patient plasma, isolated patient IgG, or rat anti-FXIII-B monoclonal antibodies..  Alloantibody levels were increased by repeated infusions of plasma-derived A.  Anti-FXIII-B antibodies binding to the A

Topics: Animals; Antibodies, Monoclonal; Factor XIII; Factor XIII Deficiency; Factor XIIIa; Fibrin; Humans; Isoantibodies; Peptides; Rats

Factor XIII (FXIII) cross-links fibrin, completing blood coagulation. Congenital FXIII deficiency is managed with plasma-derived FXIII (pdFXIII) or recombinant FXIII (rFXIII) concentrates.. As the mechanisms protecting patients with low FXIII levels (<5IU/dL) from spontaneous bleeds remain unknown we assessed the interplay between thrombin generation (TG), fibrin formation and clot kinetics before and after FXIII administration in three patients with FXIII deficiency.. Patients received initially rFXIII (35IU/kg, A-subunit) following with pdFXIII at 1250IU or 2500IU (12-30IU/kg) monthly. TG (CAT), thromboelastometry (ROTEM), prothrombin fragments F1+2, fibrinogen and FXIII activity (FXIII:C) were measured at baseline and one-hour recovery.. FXIII was at the target level of 20±6IU/dL at the 4-week trough. rFXIII corrected FXIII to 98±15 and high-dose pdFXIII to a level of 90±6, whereas low-dose/half dose pdFXIII reached 45±4IU/dL. Although fibrinogen (Clauss Method) was normal, coagulation in FIBTEM was impaired, which FXIII administration tended to correct. CAT implied 1.6- to 1.9-fold enhanced TG, which FXIII administration normalized. Inhibition of fibrin polymerization by Gly-Pro-Arg-Pro peptide mimicked FXIII deficiency in CAT by enhancing TG both in control and FXIII recovery plasma. Antithrombin, α2-macroblobulin-thrombin complex and prothrombin were normal, whereas F1+2 were elevated compatible with in vivo TG.. FXIII deficiency impairs fibrinogen function and fibrin formation simultaneously enhancing TG on the poorly polymerizing fibrin strands, when fibrin's antithrombin I -like function is absent. Our study suggests an inverse link between low FXIII levels and enhanced TG modifying structure-function relationship of fibrin to support hemostasis.

Topics: Coagulants; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Hemostasis; Humans; Male; Middle Aged; Recombinant Proteins; Thrombin

Factor XIII (FXIII) cross-links fibrin upon activation by thrombin. Activation involves cleavage at residue 37 by thrombin, releasing an activation peptide. A common polymorphism (valine to leucine variant at residue 34, V34L), located in the activation peptide, has been associated with increased activation rates and paradoxically a protective effect in cardiovascular disease. There is, currently, no data available on the effects of V34L from in vivo models of thrombosis. We examined the effect of FXIII V34L on clot formation and cross-linking in vivo.. We generated a panel of full-length recombinant human FXIII-A2 variants with amino acid substitutions in the activation peptide to investigate the effect of these variants on activation rate, and we used wild-type, V34L, and alanine to glycine variant at residue 33 variants to study the effects of varying FXIII activation rate on thrombus formation in a murine model of FeCl3 injury. FXIII activation assay showed that residues 29, 30, 33, and 34 play a critical role in thrombin interaction. Full-length recombinant human FXIII-A2 V34L has significant effects on clot formation, structure, and lysis in vitro, using turbidity assay. This variant influenced fibrin cross-linking but not size of the thrombus in vivo.. Mutations in the activation peptide of full-length recombinant FXIII regulate activation rates by thrombin, and V34L influences in vivo thrombus formation by increased cross-linking of the clot.

Topics: Amino Acid Substitution; Animals; Blood Coagulation; Blood Coagulation Tests; Disease Models, Animal; Factor XIII Deficiency; Factor XIIIa; Fibrin; Genotype; Humans; Male; Mice, 129 Strain; Mice, Inbred CBA; Mice, Knockout; Mutation; Phenotype; Recombinant Proteins; Thrombin; Time Factors; Venous Thrombosis

Phylogenetically conserved serine protease cascades play an important role in invertebrate and vertebrate immunity. The mammalian coagulation system can be traced back some 400 million years and shares homology with ancestral serine proteinase cascades that are involved in, for example, Toll receptor signaling in insects and release of antimicrobial peptides during hemolymph clotting. In the present study, we show that the induction of coagulation by bacteria leads to immobilization and killing of Streptococcus pyogenes bacteria inside the clot. The entrapment is mediated via cross-linking of bacteria to fibrin fibers by the action of coagulation factor XIII (fXIII), an evolutionarily conserved transglutaminase. In a streptococcal skin infection model, fXIII(-/-) mice developed severe signs of pathologic inflammation at the local site of infection, and fXIII treatment of wild-type animals dampened bacterial dissemination during early infection. Bacterial killing and cross-linking to fibrin networks was also detected in tissue biopsies from patients with streptococcal necrotizing fasciitis, supporting the concept that coagulation is part of the early innate immune system.

Topics: Animals; Blood Bactericidal Activity; Blood Coagulation; Evolution, Molecular; Factor XIII; Factor XIII Deficiency; Fasciitis, Necrotizing; Fibrin; Fibrinolysin; Humans; Inflammation; Mice; Mice, Inbred CBA; Mice, Knockout; Phylogeny; Species Specificity; Streptococcus pyogenes; Thrombin

The transglutaminase-mediated, covalent cross-linking of proteins is an essential step in tissue remodeling after injury. This process provides tissues with extra rigidity and resistance against proteolytic degradation. Plasma coagulation factor XIII (FXIII) is a transglutaminase that promotes cross-linking of the extracellular matrix (ECM) components fibrin and fibronectin to form a provisional matrix in response to tissue damage. However, the functional requirement for this FXIII-mediated cross-linked provisional matrix in adult tissue remodeling remains to be defined. Although it has been proposed that the formation FXIII-mediated fibrin-fibronectin provisional matrix is a critical step for ECM remodeling, we show in an FXIII subunit A-deficient murine model of acute liver injury that the lack of FXIII subunit A did not interfere with collagen reconstruction and resolution after liver injury. Furthermore, FXIIIA deficiency caused significantly increased hepatocyte apoptosis and a delay in hepatocyte regeneration after injury, which were accompanied by a significantly high induction of p53 expression. These findings suggest novel functions of FXIII that the FXIII-mediated covalently cross-linked matrix could promote survival signals for hepatocytes in adult tissue remodeling.

Topics: Animals; Apoptosis; Carbon Tetrachloride; Cell Adhesion; Cell Proliferation; Cell Transdifferentiation; Chemical and Drug Induced Liver Injury; Collagen; Cross-Linking Reagents; Extracellular Matrix; Factor XIII; Factor XIII Deficiency; Factor XIIIa; Fibrin; Fibrinogen; Fibroblasts; Fibronectins; Hepatic Stellate Cells; MAP Kinase Signaling System; Mice; Mice, Inbred CBA; Wound Healing

Topics: Algorithms; Autoantibodies; Biomarkers; Blood Coagulation; Blood Coagulation Tests; DNA Mutational Analysis; Electrophoresis, Polyacrylamide Gel; Factor XIII; Factor XIII Deficiency; Fibrin; Genetic Predisposition to Disease; Humans; Predictive Value of Tests

Carbon monoxide derived from carbon monoxide releasing molecules (CORMs) has been demonstrated to enhance normal plasma thrombus speed of growth and strength as well as diminish vulnerability to fibrinolysis in vitro. We tested the hypothesis that tricarbonyldichlororuthenium (II) dimer (CORM-2) would modify plasma thrombi ultrastructure as determined by electron microscopy. Normal and FXIII-deficient (<1% normal activity) plasmas were exposed to 0 or 100 micromol/l CORM-2, with coagulation initiated with tissue factor followed by a 15 min incubation at 37 degrees C prior to fixation. Transmission electron microscopy of the four conditions was conducted at 5000-60,000-fold magnification. CORM-2 markedly diminished the formation of thick diameter fibrin fibres in normal plasma and FXIII-deficient plasma. The density of thin diameter fibrin fibres did not seem to be changed by CORM-2 in normal plasma, but was increased in FXIII-deficient plasma. CORM-2 significantly modifies thrombin-mediated polymerization of fibrin. This finding may partially explain how CORM-2 exposure results in stronger thrombi resistant to fibrinolysis.

Topics: Biopolymers; Blood Coagulation; Carbon Monoxide; Drug Resistance; Factor XIII Deficiency; Fibrin; Fibrinolysis; Humans; In Vitro Techniques; Microscopy, Electron; Organometallic Compounds; Plasma; Prodrugs

Topics: Factor XIII; Factor XIII Deficiency; Female; Fibrin; Humans; Middle Aged; Paraproteinemias

Extravascular activation of the coagulation system and consequent fibrin deposition is involved in the pathomechanism of chronic bronchoalveolar inflammatory diseases. The turnover of extravascular fibrin is attenuated by its cross-linking with activated factor XIII (FXIII).. Determination of cellular and plasmatic forms of FXIII and their correlation with D-dimer level in the bronchoalveolar lavage fluid (BALF) from healthy children and from children with bronchoalveolar inflammation.. Highly sensitive immunoassays were used for the quantitation of cellular and plasma FXIII and D-dimer in the BALF of children with recurrent wheezy bronchitis and fibrosing alveolitis. BALF was investigated for FXIII-containing cells by flow cytometry.. In the BALF of controls a low amount of the cellular form of FXIII (FXIII A2) and D-dimer were measured, while plasma FXIII (FXIII A2B2) was absent. Alveolar macrophages represented the single cell population in BALF that contained FXIII. In the BALF of both patients' groups the concentration and the total amount of FXIII A2 was significantly elevated, and plasma FXIII also appeared in the BALF of most patients. The D-dimer concentration was also elevated in the patients' groups and it correlated both with plasma FXIII and neutrophil count. These findings suggest that FXIII A2 is released from activated or injured alveolar macrophages into the bronchoalveolar lining fluid and in bronchoalveolar inflammatory diseases, FXIII A2B2 also leaks out from the capillaries. By cross-linking fibrin and inhibitors of fibrinolysis to fibrin, FXIII might be a key regulator of fibrin turnover in the extravascular compartment.

Topics: Adolescent; Bronchi; Bronchitis; Bronchoalveolar Lavage Fluid; Capillaries; Child; Child, Preschool; Enzyme-Linked Immunosorbent Assay; Factor XIII; Factor XIII Deficiency; Factor XIIIa; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Flow Cytometry; Humans; Infant; Inflammation; Macrophages; Male; Neutrophils; Pulmonary Alveoli; Time Factors

The impact of clot stability affecting the vasculopathy and tissue necrosis in Shwartzman reaction was investigated using plasma Factor XIII A2-depleted rabbit (FXIII-DR). Plasma Factor XIIIA2 (FXIIIA2) was depleted by infusion of the mono-specific goat anti-rabbit FXIIIA2 IgG. Generalized Shwartzman reaction (GSR) was induced by priming and challenged by i.v. injection of LPS and local Shwartzman reaction (LSR) was primed by intradermal injection of LPS and challenged by i.v. injection of LPS. Histological examination of the GSR animals showed, extensive thrombi accumulation in renal tubules and bilateral cortical necrosis of kidney in 8 out of 10 rabbits but none in the FXIII-DR. Fibrinogen levels were elevated to 3 approximately 4 fold at 24 h and lowered at 48 h whereas a steady rise was seen in the FXIII-DR. FDP levels in GSR animals were significantly elevated at 24 h and further increased at 48 h but only slightly elevated in the FXIII-DR. Examination of the LSR tissues after 48 h showed an acute onset of progressive cutaneous vascular thrombosis, purpura, and secondary hemorrhagic necrosis whereas neither fibrin deposit nor necrosis of tissue were detected in FXIII-DR despite of an early edema formation. Fibrinogen levels were also increased two fold at 24 h but returned to basal levels at 48 h in control LSR animals but not affected at all in FXIII-DR. These results suggest that during the severe inflammatory conditions such as sepsis, the fibrinolytic system is functionally sufficient to dissipate the pathogenic accumulation of disseminated intravascular clots and exudated fibrin clots if those clots were prevented from getting crosslinked in plasma.

Topics: Animals; Antibodies, Monoclonal; Disease Models, Animal; Disseminated Intravascular Coagulation; Factor XIII; Factor XIII Deficiency; Fibrin; Fibrinogen; Kidney; Kidney Diseases; Lipopolysaccharides; Necrosis; Plasminogen; Rabbits; Sepsis; Shwartzman Phenomenon; Skin; Skin Diseases

Without a prior history of hemorrhagic disease, a 62-year-old man suffered recurrent episodes of bleeding. Solubility of the patient's clot in 5 mol/L urea indicated a problem with fibrin stabilization. The transamidase activity potential of factor XIII, measured by the incorporation of radioactive putrescine into N,N-dimethylcasein as test substrate, was 62% of control, close to the normal range of values. Examination of the patient's clot from recalcified plasma by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that essentially none of the alpha chains and only about two thirds of the gamma chains of fibrin became cross-linked under conditions where both were fully cross-linked in the controls. An antibody to factor XIII was isolated which, although recognizing the recombinant rA2 subunits, as well as the virgin A2B2 plasma ensemble, showed a 100-fold greater affinity for the thrombin-activated rA2' and A2'B2 forms of the zymogen, suggesting that the latter would be its main target during coagulation. Furthermore, the patient's IgG has an ability, never seen before, for inducing an enzymatically active configuration in the thrombin-activated zymogen in the absence of Ca2+.

Topics: Antigen-Antibody Reactions; Autoantibodies; Autoimmune Diseases; Enzyme Precursors; Factor XIII Deficiency; Fibrin; Humans; Immunoglobulin G; Male; Middle Aged; Protein Conformation; Recombinant Fusion Proteins; Solubility; Thrombin; Transglutaminases; Urea

Factor XIII (FXIII) is of high importance in the regulation of fibrinolysis. It crosslinks alpha 2-antiplasmin (alpha 2AP) and fibrin and by this way protects fibrin from the prompt elimination by plasmin. Although FXIII of platelets has been implicated in this protective mechanism, the role of platelets and platelet FXIII in the crosslinking process is far from being elucidated. As demonstrated by SDS PAGE and by immunoblotting for alpha 2AP, intact normal platelets resuspended in FXIII-free plasma or FXIII-free fibrinogen solution catalyzed the crosslinking of fibrin chains and also the crosslinking of alpha 2AP to fibrin alpha-chains. With FXIII-deficient platelets no crosslinking reaction could be observed indicating that the crosslinking with normal platelets was, indeed, due to platelet FXIII and not to another, putative platelet transglutaminase. However, the crosslinking of alpha 2AP to fibrin induced by the FXIII of intact platelets resuspended in FXIII-free plasma was considerably less extensive than the crosslinking carried out by the FXIII of normal plasma in the presence of FXIII-free platelets. Furthermore, the replacement of FXIII-free platelets by normal platelets in normal FXIII-containing plasma resulted in little, if any, difference in the crosslinking process. When crosslinking was induced by highly purified plasma FXIII the presence of intact FXIII-free platelets significantly accelerated the formation of alpha-chain polymers as well as the incorporation of alpha 2AP-fibrin alpha-chain hetero-dimer into these polymers. The results indicate that, in physiological conditions, platelet FXIII plays only a minor role in the crosslinking of alpha 2AP and fibrin; however, platelets, independently of their FXIII content, promote the crosslinking reaction by providing a catalytic surface on which the formation of highly crosslinked fibrin polymers is accelerated.

Topics: alpha-2-Antiplasmin; Blood Platelets; Factor XIII; Factor XIII Deficiency; Fibrin; Fibrinolysis; Humans; Immunoblotting; Macromolecular Substances

The photometric method of Fickenscher et al. for the determination of factor XIII (FXIII) activity has been used in the study of 35 patients with severe chronic hepatopathy, in comparison with 25 normal subjects. The FXIII proteic fractions a and b were determined by quantitative immuno-electrophoresis after Laurell. The plasmatic FXIII activity, as well as the proteic fractions a and b, were significantly reduced in hepatopatic patients, in comparison to controls, and proportional to the prolongation of prothrombin times. Ratios between functional and immunological levels of FXIII in hepatopatics were similar to those observed in controls. These results confirm the involvement of fibrin stabilization deficiency in the coagulation defect of severe chronic hepatopathies. The correlations between functional and antigenic values are in agreement with the hepatic origin of FXIII. The method of Fickenscher has been proved to be rapid and simple, and it may be useful in the routine study of hepatopathies, for a better knowledge of the role of FXIII deficiency in the complex coagulopathy of liver diseases, as well as of other acquired FXIII deficiencies.

Topics: Adult; Aged; Chronic Disease; Evaluation Studies as Topic; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Humans; Immunoelectrophoresis; Liver Diseases; Male; Middle Aged; Photometry; Prothrombin Time

We report a new case of severe bleeding diathesis due to an acquired inhibitor of fibrin crosslinking. The patient, an 80-year-old woman, was admitted to the hospital for a massive subcutaneous hematoma, with severe anemia requiring red cell transfusion; a subsequent retroperitoneal hematoma developed 2 weeks later. Coagulation studies were normal except for a thromboelastographic pattern suggestive of FXIII deficiency. Clot solubility test was abnormal even after 1:1 mix with normal plasma. Immunochemical studies confirmed the presence of a monoclonal IgG lambda inhibitor directed against FXIII activity (type II FXIII inhibitor). The patient IgG fraction selectively inhibited FXIII transamidating activity but did not inhibit the thrombin-mediated activation of FXIII. The patient was treated with high doses of FXIII concentrate to overcome the inhibitor and immunosuppressive therapy with cyclophosphamide and discharged in good conditions. High doses of commercially available FXIII appear to be a safe and effective method of controlling acute episodes of bleeding in patients with acquired FXIII deficiency.

Topics: Aged; Aged, 80 and over; Cyclophosphamide; Drug Therapy, Combination; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Hematoma; Humans; Immunoglobulin G

Pericapillary fibrin cuffs are probably involved in the pathogenesis of venous leg ulcers. Factor XIII (Fibrin stabilizing factor) is of importance in wound healing. Its activity, which may affect ulceration, was found to be significantly reduced in the blood of venous leg ulcer patients and in post-phlebitic patients, compared with healthy controls.

Topics: Chronic Disease; Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Leg Ulcer; Postphlebitic Syndrome; Varicose Ulcer; Wound Healing

The physiologic function of the monocyte transglutaminases is not known. In this study, we detected Factor XIII A-subunit antigen and "tissue" transglutaminase antigen in human monocytes by polyacrylamide gel electrophoresis and immunoblotting techniques. Flow cytometric analysis demonstrated that 27% and 49% of the total Factor XIII antigen in monocytes and human peritoneal macrophages, respectively, are expressed on the surface of the cells. Monocytes maintained in culture for 8 days had a 4-fold increase in Factor XIIIa activity and a 3.2-fold increase in the amount of Factor XIII antigen/mg cell protein. However, there was no increase in the "tissue" transglutaminase activity or antigen levels in cultured monocytes. In addition, we identified a Factor XIII deficient individual who does not express Factor XIII activity or antigen in plasma, platelets, monocytes, lymphocytes or erythrocytes. Intact monocytes from normal donors were able to cross-link fibrin formed in the plasma from the Factor XIII deficient individual. This suggests that transglutaminase activity expressed by peripheral blood monocytes may play a physiologic role in cross-linking fibrin during blood clotting or inflammation.

Topics: Antigens, Surface; Blood Platelets; Cells, Cultured; Electrophoresis, Polyacrylamide Gel; Erythrocytes; Factor XIII Deficiency; Fibrin; Humans; Immunoblotting; Lymphocytes; Macrophages; Monocytes; Transglutaminases

Fibrinogen, the major structural precursor of blood clots, was deglycosylated by peptide-N-(N-acetyl-beta-glucosaminyl)asparagine amidase without denaturation of the polypeptide chains. Deglycosylated fibrinogen behaved normally in clinical coagulation assays, although it is less soluble than normal fibrinogen. However, the turbidity of clots formed from deglycosylated fibrinogen always rose faster and higher than that of clots from normal fibrinogen. Scanning and transmission electron microscopy demonstrated that fibrin made from clots of deglycosylated fibrinogen consisted of thicker, less-branched fiber bundles in a more porous network. Moreover, the degree of lateral aggregation was directly related to clot turbidity and inversely related to branching. Deglycosylation promoted turbidity development, lateral aggregation, and porosity of clots under all conditions tested. All other steps in the coagulation pathways appeared to be unaffected by the absence of carbohydrate. These results suggest that carbohydrate constitutively affects the behavior of deglycosylated fibrinogens by 1) contributing a repulsive force that promotes fibrinogen solubility and limits fibrin assembly and 2) sensitizing fibrin to conditions that influence assembly and clot structure.

Topics: Factor XII; Factor XIII Deficiency; Fibrin; Fibrinogen; Glycosylation; Humans; Kinetics; Macromolecular Substances; Microscopy, Electron; Microscopy, Electron, Scanning; Models, Molecular; Thrombin

Sudden increase of viscosity in former times indicated the start of coagulation. Yet its measurement destroyed the structure of coagulum. By the precursor method of thrombelastography the author 1944 found elasticity to be the essential physiological property of coagulum. In the production of elastic fibrin structure its early phase is the most efficient in this respect. The speed of prime structure formation is extremely fast in presence of enough phospholipid as well as of plasma factor XIII. Even high amounts of thrombin cannot replace one or both of these substances indispensable to grow rapidly a perfect fibrin web. This phase yet does not become effective if it is not accompanied by the orbital micro-flow of the new orbitometry method. Its shear is comparable to that in a coronary artery. The special resonance effect of the method in combination with the early phase of fibrin production is generating some kind of a physiological feed back: increasing fibrin will strengthen shear stress as long as less platelets are entangled which will reduce the elastic flexibility of fibrin web. Some kind of a "coagulation spin effect" in optimal combination of shear stress, phospholipid and factorXIII, will extremely fast originate a firm fibrin structure, a mechanism which may be of significance for a fast occlusion of arterial stenoses.

Topics: Blood Coagulation; Blood Platelet Disorders; Elasticity; Equipment and Supplies; Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Immune Sera; Macromolecular Substances; Methods; Phospholipids

In 16 patients affected with acute leukemia (7 patients with acute lymphatic leukemia and 9 patients with acute myeloid leukemia) the resonance thrombogramme was recorded during cytostatic induction therapy, coagulation factor XIII (subunit XIII-A, XIII-S) and further hemostasiological parameters were determined. Subunit XIII-A was lowered to 36%, subunit XIII-S to 65% and the fibrin formation time of the resonance thrombogramme was extended to 9 minutes. There exists a negative correlation between component XIII-A and fibrin formation time r = -0.48 (p less than 0.01). The influence exerted by diminishing factor XIII and fibrin(ogen) splitting products on the fibrin formation time was investigated in in-vitro tests. A diminution of factor XIII below 10% will extend the fibrin formation time to about 10 minutes, an increase of fibrin(ogen) splitting products to 100 micrograms/ml to about 3 minutes.

Topics: Adult; Aged; Blood Coagulation Tests; Factor XIII; Factor XIII Deficiency; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Middle Aged

After fibrin polymerization, activated Factor XIII catalyzes the formation of intermolecular cross-links between gamma-chain pairs and also among two or more alpha-chains to form polymers. In this report we characterize the size and heterogeneity of alpha-chain polymers, establish the role of high concentrations of Factor XIII in determining the extent and rate of alpha-polymer formation, and also provide evidence that the Factor XIII required can be provided by platelets. Fibrin prepared from purified fibrinogen or platelet-deficient plasma contained a series of cross-linked alpha-chain polymers with Mr from 140,000 to 770,000 with a mean Mr difference of 32,000 consistent with a staggered, overlapping addition of monomers to the growing alpha-polymer chain. In plasma containing no platelets, alpha-polymer formation was incomplete with residual alpha-monomer remaining, but higher platelet counts facilitated more rapid cross-linking into larger polymers. Purified Factor XIII was equally effective as platelets in facilitating cross-linking. We conclude that cross-linked alpha-polymer chains are heterogeneous in size reaching a molecular weight of several million and that high concentrations of Factor XIII as provided by platelets are required for maximum cross-linking.

Topics: Blood Platelets; Electrophoresis, Polyacrylamide Gel; Factor XIII; Factor XIII Deficiency; Fibrin; Fibrinogen; Humans; Macromolecular Substances; Molecular Weight; Platelet Count; Polymers

In vitro and in vivo formed fibrin clots were investigated by SDS-PAA gel electrophoresis in regard to the amount and distribution of fibrin subunits. It was found that with decreasing factor XIII levels fewer and shorter alpha-polymers were formed in vitro and more so in the exterior than in the core of a clot. Inversely the concentrations of residual alpha-chains rose. These structural changes already began at factor XIII levels of 50%. gamma-dimer formation was not influenced. Nearly all in vivo thrombi, either arterial or venous, consisted of a normal distribution of subunits, but alpha-polymerization was more extensive in the core than in the exterior parts. A significant impairment of alpha polymerization was found in extravasal clots, but not in thrombi formed during anticoagulant therapy.

Topics: Blood Coagulation; Factor XIII Deficiency; Fibrin; Fibrinogen; Humans; Macromolecular Substances; Microscopy, Electron

In spontaneous fibrinolysis of an alpha 2-plasmin inhibitor-deficient plasma clot or tissue-type plasminogen activator-induced fibrinolysis in a purified system without alpha 2-plasmin inhibitor, the lysis was faster when factor XIII-mediated crosslinking of fibrin to fibrin did not occur. During the initial period, the binding of plasminogen to fibrin steadily increased with incubation time. The initial level and subsequent increase of the binding, which may be critical for the subsequent development of fibrinolysis, were more remarkable when fibrin was not crosslinked. The amount of glu- or lys-plasminogen bound to noncrosslinked fibrin was around 4 or 1.5 times larger than the amount of the respective plasminogen bound to crosslinked fibrin. Plasmin was also found to be bound to noncrosslinked fibrin twice as much as the amount bound to crosslinked fibrin. Structural changes induced by crosslinking of fibrin alpha-chain may reduce either the affinity or the number of available complementary sites to lysine binding sites of plasmin(ogen), thereby decreasing the binding of plasmin(ogen) to fibrin. These results suggest that an increased affinity of noncrosslinked fibrin for plasmin(ogen) is contributory to the accelerated fibrinolysis observed in factor XIII deficiency, in addition to an absence of crosslinking of alpha 2-plasmin inhibitor to fibrin.

Topics: Enzyme Activation; Factor XIII Deficiency; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Plasminogen

The contribution of fibrin stabilization to clot strength, measured as the static elastic modulus, was evaluated in human plasma by two independent procedures. In the first approach, amine inhibitors of fibrin stabilization were examined for their effects on the rigidity of normal plasma clots. It is a unique property of these inhibitors that they do not interfere with the reversible aggregation of fibrin molecules, i.e., do not delay clotting time, but selectively prevent only the formation of gamma-glutamyl-epsilon-lysine protein-to-protein linkages. Though the compounds tested were of different chemical structures and potencies, a fivefold reduction in clot strength was obtained in each instance. This value of 20% of normal seems to correspond to the rigidity of the Factor XIII-deficient plasma clot because, as demonstrated by the second approach, when a plasma specimen that genetically lacked the fibrin stabilizing factor was supplemented by the addition of measured amounts of the purified zymogen, a fivefold increase in clot strength could be achieved. The described procedure of evaluating Factor XIII in terms of correcting the elastic modulus of a deficient plasma clot is considered an important assay for the functional competence of purified preparations of the zymogen for the purpose of therapeutic application.

Topics: Aminoacetonitrile; Blood Coagulation; Cadaverine; Dose-Response Relationship, Drug; Elasticity; Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Hydroxylamine; Hydroxylamines

Topics: Adolescent; Factor XIII Deficiency; Female; Fibrin; Gingival Hemorrhage; Humans; Oral Hemorrhage; Tooth Extraction; Wound Healing

Topics: Adult; Afibrinogenemia; Aged; Animals; Carcinoma; Factor XIII Deficiency; Fibrin; Humans; Middle Aged; Neoplasms; Neoplasms, Experimental; Rats; Sulfhydryl Compounds

The role of Factor XIII in clot retraction was studied using the plasma from Factor XIII-deficient patients. Time course experiments revealed no significant difference in clot retraction between a plasma deficient in Factor XIII and one to which purified Factor XIII had been added. Using Factor XIII-free fibrinogen and Factor XIII-deficient platelets, it is shown that there is no significant difference in clot retraction with or without added Factor XIII.

Topics: Clot Retraction; Electrophoresis, Polyacrylamide Gel; Factor XIII; Factor XIII Deficiency; Fibrin; Fibrinogen; Humans; Platelet Count; Thrombin

Homozygous patients with factor XIII deficiency are devoid of immunologically identifiable A protein, the active enzymatic component. Quantitative studies of transamidase activity of the factor are available in only a few cases, and the fibrin cross-linking pattern is not well known. The present paper deals with the quantitative estimation of factor XIII transamidase activity (dansylcadaverine system), factor XIII molecular subunits, and the corresponding fibrin cross-linking pattern in seven homozygous patients with factor XIII deficiency. The results indicate that transamidase activity was present in all patients, and the range was 0.5-1.7%. The pattern of fibrin stabiisation showed an absence of cross-linking in two patients, the presence of gamma-gamma-dimers (traces) in four, and gamma-gamma-dimers plus incomplete alpha-polymers (traces) in one patient. In conclusion, the homozygous patients reported here were not completely devoid of functioning factor XIII.

Topics: Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Protein Binding; Thrombin

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Transfusion; Calcium; Disseminated Intravascular Coagulation; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Fibrinogen; Half-Life; Hemorrhage; Humans; Leukemia; Liver Diseases; Male; Plasma; Pregnancy; Thrombin; Time Factors

It has been demonstrated that activated factor XIII may catalyze the formation of covalent cross-links between fibrin and collagen. This is shown by the disappearance of the gamma-gamma dimer band in PAA-SDS gel electrophoresis when fibrinogen is clotted in presence of collagen, factor XIII and Ca ions, and by the binding of labeled fibrinogen. This reaction may explain the outstanding physiological importance of factor XIII.

Topics: Collagen; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Hemostasis; Humans; Pregnancy; Thrombin; Wound Healing

Topics: Binding Sites; Blood Transfusion; Chemical Phenomena; Chemistry; Factor XIII; Factor XIII Deficiency; Fibrin; Humans

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.

Topics: Acetates; Adult; Blood Coagulation Disorders; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Humans; Peptide Hydrolases; Solubility; Wound Healing

Topics: Afibrinogenemia; Factor XIII Deficiency; Female; Fibrin; Humans; Male

The effect of fibrinogen concentration, Factor XIII deficiency, and Factor XIII inhibition, utilizing hydroxylamine, on the formation of clot structure in vitro was studied in human platelet-free plasma systems. Rheological and biochemical techniques were employed to relate changes in clot elasticity and viscosity to clot structure formation following recalcification of citrate anticoagulated samples. Classical theories of linear viscoelasticity for swollen crosslinked materials were shown to give an excellent estimate of the number of covalent crosslinks per fibrin monomer, which is directly attainable from rheological data. SDS gel electrophoresis was utilized to show qualitatively that decreases in maximum clot elasticity, at constant fibrinogen concentration, are directly related to a decrease in Factor XIII-mediated intermolecular crosslinking. The use of the technique to investigate both kinetic and equilibrium crosslinking (or structure formation) abnormalities in plasma systems is discussed.

Topics: Blood Coagulation; Blood Viscosity; Elasticity; Factor XII; Factor XIII Deficiency; Fibrin; Fibrinogen; Humans; Hydroxylamines; In Vitro Techniques; Rheology

Topics: Autoantibodies; Enzyme Precursors; Factor XIII; Factor XIII Deficiency; Fibrin; Humans; Immune Tolerance; Isoniazid; Peptide Fragments; Solubility; Thrombin

Topics: Adolescent; Adult; Aged; Blood Cell Count; Blood Platelets; Blood Protein Electrophoresis; Electrophoresis, Polyacrylamide Gel; Factor XIII Deficiency; Female; Fibrin; Fibrinogen; Hematocrit; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Thrombelastography

Topics: Blood Coagulation Tests; Factor XIII Deficiency; Fibrin; Fibrinogen; Humans; Methods; Prothrombin Time; Urea

Topics: Ammonia; Blood Cell Count; Blood Coagulation; Blood Platelets; Blood Proteins; Factor XIII; Factor XIII Deficiency; Fibrin; Fibrinolysin; Fibrinolysis; gamma-Globulins; Humans; Hypergammaglobulinemia; Immune Sera; Methods; Putrescine; Solubility; Streptokinase; Thrombocytopenia; Thrombophlebitis; Time Factors

Topics: Blood Coagulation; Consanguinity; Factor XIII Deficiency; Female; Fibrin; Genotype; Humans; Male; Phenotype; Sex Chromosomes; Sex Factors

Topics: Amino Acid Sequence; Amino Acids; Animals; Biological Evolution; Blood Coagulation; Blood Coagulation Factors; Blood Platelets; Contraceptives, Oral; Enzyme Activation; Enzyme Precursors; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Fibrinogen; Glutamine; Humans; Neoplasms, Experimental; Peptides; Pregnancy; Thrombin; Thrombosis; Transferases

Topics: Blood Coagulation; Blood Platelets; Cadaverine; Child; Cross Reactions; Dansyl Compounds; Enzyme Activation; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Glutamine; Hematoma; Hemorrhage; Heterozygote; Humans; Immunodiffusion; Immunoelectrophoresis; Male; Polymorphism, Genetic; Pregnancy; Transferases; Umbilical Cord

Topics: Ammonium Sulfate; Blood Coagulation; Blood Platelets; Chromatography, DEAE-Cellulose; Drug Stability; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Fibrinogen; Glutamine; Humans; Hydrogen-Ion Concentration; Immunodiffusion; Male; Microscopy, Electron; Multienzyme Complexes; Peptides; Protein Conformation; Transferases

Topics: Alkylation; Animals; Blood Coagulation; Blood Platelets; Chemical Phenomena; Chemistry; Electrophoresis, Polyacrylamide Gel; Factor XIII; Factor XIII Deficiency; Female; Fibrin; Fibrinogen; Glutamine; Haplorhini; Humans; Hydrogen-Ion Concentration; Lysine; Macaca; Peptides; Plasma; Protein Conformation; Sodium Dodecyl Sulfate; Solubility; Species Specificity; Trypsin

Topics: Chronic Disease; Factor XIII Deficiency; Fibrin; Humans; Kidney Diseases