Factor XIII cross-links fibrin(ogen) independent of fibrin polymerization in experimental acute liver injury.

Intravascular fibrin clot formation follows a well-ordered series of reactions catalyzed by thrombin cleavage of fibrinogen leading to fibrin polymerization and cross-linking by factor XIIIa (FXIIIa). Extravascular fibrin(ogen) deposits are observed in injured tissues; however, the mechanisms regulating fibrin(ogen) polymerization and cross-linking in this setting are unclear. The objective of this study was to determine the mechanisms of fibrin polymerization and cross-linking in acute liver injury induced by acetaminophen (APAP) overdose. Hepatic fibrin(ogen) deposition and cross-linking were measured following APAP overdose in wild-type mice, mice lacking the catalytic subunit of FXIII (FXIII-/-), and in FibAEK mice, which express mutant fibrinogen insensitive to thrombin-mediated fibrin polymer formation. Hepatic fibrin(ogen) deposition was similar in APAP-challenged wild-type and FXIII-/- mice, yet cross-linking of hepatic fibrin(ogen) was dramatically reduced (>90%) by FXIII deficiency. Surprisingly, hepatic fibrin(ogen) deposition and cross-linking were only modestly reduced in APAP-challenged FibAEK mice, suggesting that in the APAP-injured liver fibrin polymerization is not strictly required for the extravascular deposition of cross-linked fibrin(ogen). We hypothesized that the oxidative environment in the injured liver, containing high levels of reactive mediators (eg, peroxynitrite), modifies fibrin(ogen) such that fibrin polymerization is impaired without impacting FXIII-mediated cross-linking. Notably, fibrin(ogen) modified with 3-nitrotyrosine adducts was identified in the APAP-injured liver. In biochemical assays, peroxynitrite inhibited thrombin-mediated fibrin polymerization in a concentration-dependent manner without affecting fibrin(ogen) cross-linking over time. These studies depict a unique pathology wherein thrombin-catalyzed fibrin polymerization is circumvented to allow tissue deposition and FXIII-dependent fibrin(ogen) cross-linking.

Role, Laboratory Assessment and Clinical Relevance of Fibrin, Factor XIII and Endogenous Fibrinolysis in Arterial and Venous Thrombosis.

Diseases such as myocardial infarction, ischaemic stroke, peripheral vascular disease and venous thromboembolism are major contributors to morbidity and mortality. Procoagulant, anticoagulant and fibrinolytic pathways are finely regulated in healthy individuals and dysregulated procoagulant, anticoagulant and fibrinolytic pathways lead to arterial and venous thrombosis. In this review article, we discuss the (patho)physiological role and laboratory assessment of fibrin, factor XIII and endogenous fibrinolysis, which are key players in the terminal phase of the coagulation cascade and fibrinolysis. Finally, we present the most up-to-date evidence for their involvement in various disease states and assessment of cardiovascular risk.

Magnetic Resonance Imaging Reveals Distinct Roles for Tissue Transglutaminase and Factor XIII in Maternal Angiogenesis During Early Mouse Pregnancy.

OBJECTIVE: The early embryo implantation is characterized by enhanced uterine vascular permeability at the site of blastocyst attachment, followed by extracellular-matrix remodeling and angiogenesis. Two TG (transglutaminase) isoenzymes, TG2 (tissue TG) and FXIII (factor XIII), catalyze covalent cross-linking of the extracellular-matrix. However, their specific role during embryo implantation is not fully understood. Approach and Results: For mapping the distribution as well as the enzymatic activities of TG2 and FXIII towards blood-borne and resident extracellular-matrix substrates, we synthetized selective and specific low molecular weight substrate analogs for each of the isoenzymes. The implantation sites were challenged by genetically modifying the trophoblast cells in the outer layer of blastocysts, to either overexpress or deplete TG2 or FXIII, and the angiogenic response was studied by dynamic contrast-enhanced-magnetic resonance imaging. Dynamic contrast-enhanced-magnetic resonance imaging revealed a decrease in the permeability of decidual vasculature surrounding embryos in which FXIII were overexpressed in trophoblast cell. Reduction in decidual blood volume fraction was demonstrated when either FXIII or TG2 were overexpressed in embryonic trophoblast cell and was elevated when trophoblast cell was depleted of FXIII. These results were corroborated by histological analysis. CONCLUSIONS: In this study, we report on the isoenzyme-specific roles of TG2 and FXIII during the early days of mouse pregnancy and further reveal their involvement in decidual angiogenesis. Our results reveal an important magnetic resonance imaging-detectable function of embryo-derived TG2 and FXIII on regulating maternal angiogenesis during embryo implantation in mice.Visual Overview: An online visual overview is available for this article.

Exploring the structural similarity yet functional distinction between coagulation factor XIII-B and complement factor H sushi domains.

Coagulation factor XIII (FXIII) covalently crosslinks pre-formed fibrin clots preventing their premature fibrinolysis. In plasma, FXIII circulates as a zymogenic heterotetramer composed of catalytic FXIII-A subunits, and carrier/regulatory FXIII-B subunits. FXIII-A is a well characterized component of this complex, and has been associated with several pleiotropic roles outside coagulation as well. In comparison only protective/regulatory roles towards the FXIII-A subunit have been identified for FXIII-B. Strong homology between FXIII-B and complement regulator Complement factor H suggests a putative role of FXIII-B in complement activation. In the current study we have analyzed the similarities and yet functional divergence of these two proteins using in silico sequence alignment and structural analysis. We have evaluated complement activation post reconstitution of FXIII components into FXIII deficient and CFH deficient plasma. We have also transiently expressed FXIII-B in SH-SY5Y cell lines and evaluated its effect on the endogenous complement activation. Our investigations show no effect of FXIII-B subunit on the rate of complement activation. Therefore we conclude that at a physiological level, FXIII-B subunit plays no role in the complement system, although a vestigial function in altered pathological states might still exist.

Factor XIII in plasma, but not in platelets, mediates red blood cell retention in clots and venous thrombus size in mice.

The transglutaminase factor XIII (FXIII) stabilizes clots against mechanical and biochemical disruption and is essential for hemostasis. In vitro and in vivo models of venous thrombosis demonstrate that FXIII mediates clot size by promoting red blood cell (RBC) retention. However, the key source of FXIII and whether FXIII activity can be reduced to suppress thrombosis without imposing deleterious hemostatic consequences are 2 critical unresolved questions. FXIII is present in multiple compartments, including plasma (FXIIIplasma) as a heterotetramer of A2 and B2 subunits and platelets (FXIIIplt) as an A2 homodimer. We determined the role of the FXIII compartment and level in clot contraction, composition, and size in vitro and using in vivo models of hemostasis and venous thrombosis. Reducing overall FXIII levels decreased whole blood clot weight but did not alter thrombin generation or contraction of platelet-rich plasma clots. In reconstituted platelet-rich plasma and whole blood clot contraction assays, FXIIIplasma, but not FXIIIplt, produced high-molecular-weight fibrin crosslinks, promoted RBC retention, and increased clot weights. Genetically imposed reduction of FXIII delayed FXIII activation and fibrin crosslinking, suggesting FXIII levels mediate the kinetics of FXIII activation and activity and that the timing of these processes is a critical determinant of RBC retention during clot formation and contraction. A 50% reduction in FXIIIplasma produced significantly smaller venous thrombi but did not increase bleeding in tail transection or saphenous vein puncture models in vivo. Collectively, these findings suggest that partial FXIII reduction may be a therapeutic strategy for reducing venous thrombosis.

Advances of Coagulation Factor XIII.

OBJECTIVE: To provide a comprehensive literature review on roles of coagulation factor XIII (FXIII) in coagulation, wound healing, neoplasm, bone metabolism, and pregnancy. DATA SOURCES: All articles in PubMed with key words "Coagulation factor XIII", "wound", "leukemia", "tumor", "bone," and "pregnancy" with published date from 2001 to 2016 were included in the study. Frequently cited publications before 2000 were also included. STUDY SELECTION: We reviewed the role of FXIII in biologic processes as documented in clinical, animal, and in vitro studies. RESULTS: FXIII, a member of the transglutaminase (TG) family, plays key roles in various biological processes. Besides its well-known function in coagulation, the cross-linking of small molecules catalyzed by FXIII has been found in studies to help promote wound healing, improve bone metabolism, and prevent miscarriages. The study has also shown that FXIII concentration level differs in the blood of patients with leukemia and solid tumors and offers promises as a diagnostic indicator. CONCLUSIONS: FXIII has many more biologic functions besides being known as coagulation factor. The TG activity of FXIII contributes to several processes, including wound healing, bone extracellular matrix stabilization, and the interaction between embryo and decidua of uterus. Further research is needed to elucidate the link between FXIII and leukemia and solid tumors.

Free factor XIII activation peptide (fAP-FXIII) is a regulator of factor XIII activity via factor XIII-B.

In a factor XIIIa (FXIIIa) generation assay with recombinant FXIII-A2 (rFXIII-A2 ) free FXIII activation peptide (fAP-FXII) prolonged the time to peak (TTP) but did not affect the area under the curve (AUC) or concentration at peak (CP). Addition of recombinant factorXIII-B2 (rFXIII-B2 ) restored the characteristics of the FXIIIa generation parameters (AUC, TTP and CP) to those observed for plasma FXIII (FXIII-A2 B2 ). FXIII-A2 B2 reconstituted from rFXIII-A2 and rFXIII-B2 showed a similar effect on AUC, TTP and CP in the presence of fAP-FXII as observed for plasma FXIII-A2 B2 , indicating a role for FXIII-B in this observation. An effect of fAP-FXIII on thrombin, the proteolytic activator of FXIII, was excluded by thrombin generation assays and clotting experiments. In a purified system, fAP-FXIII did not interfere with the FXIIIa activity development of thrombin-cleaved rFXIII-A2 (rFXIII-A2 ') also excluding direct inhibition of FXIIIa. However, FXIIIa activity development of FXIII-A2 'B2 was inhibited in a concentration-dependent manner by fAP-FXIII, indicating that an interaction between AP-FXIII and FXIII-B2 contributes to the overall stability of FXIII-A2 'B2 . In addition to its well-known role, FXIII-B also contributes to FXIII-A2 B2 stability or dissociation depending on fAP-FXIII and calcium concentrations.

Transglutaminase factor XIII promotes arthritis through mechanisms linked to inflammation and bone erosion.

Rheumatoid arthritis is a chronic inflammatory disease characterized by synovial hyperplasia, inflammatory cell infiltration, irreversible cartilage and bone destruction, and exuberant coagulation system activity within joint tissue. Here, we demonstrate that the coagulation transglutaminase, factor XIII (fXIII), drives arthritis pathogenesis by promoting local inflammatory and tissue degradative and remodeling events. All pathological features of collagen-induced arthritis (CIA) were significantly reduced in fXIII-deficient mice. However, the most striking difference in outcome was the preservation of cartilage and bone in fXIIIA(-/-) mice concurrent with reduced osteoclast numbers and activity. The local expression of osteoclast effectors receptor activator of nuclear factor-κB ligand (RANKL) and tartrate resistant acid phosphatase were significantly diminished in CIA-challenged and even unchallenged fXIIIA(-/-) mice relative to wild-type animals, but were similar in wild-type and fibrinogen-deficient mice. Impaired osteoclast formation in fXIIIA(-/-) mice was not due to an inherent deficiency of monocyte precursors, but it was linked to reduced RANKL-driven osteoclast formation. Furthermore, treatment of mice with the pan-transglutaminase inhibitor cystamine resulted in significantly diminished CIA pathology and local markers of osteoclastogenesis. Thus, eliminating fXIIIA limits inflammatory arthritis and protects from cartilage and bone destruction in part through mechanisms linked to reduced RANKL-mediated osteoclastogenesis. In summary, therapeutic strategies targeting fXIII activity may prove beneficial in limiting arthropathies and other degenerative bone diseases.

Fibrinogen and factor XIII at the intersection of coagulation, fibrinolysis and inflammation.

Fibrinogen and factor XIII are two essential proteins that are involved directly in fibrin gel formation as the final step of a sequence of reactions triggered by a procoagulant stimulus. Haemostasis is the most obvious function of the resulting fibrin clot. Different variables affect the conversion of fibrinogen to fibrin as well as the mode of fibrin polymerisation and fibrin crosslinking, hereby, critically influencing the architecture of the resulting fibrin network and consequently determining its mechanical strength and resistance against fibrinolysis. Due to fibrinogen's structure with a multitude of domains and binding motifs the fibrin gel allows for complex interactions with other coagulation factors, with profibrinolytic as well as antifibrinolyic proteins, with complement factors and with various cellular receptors. These interactions enable the fibrin network to control its own further state (i. e. expansion or degradation), to influence innate immunity, and to function as a scaffold for cell migration processes. During the whole process of fibrin gel formation biologically active peptides and protein fragments are released that additionally influence cellular processes via chemotaxis or by modulating cell-cell interactions. Thus, it is not surprising that fibrinogen and factor XIII in addition to their haemostatic function influence innate immunity as well as cell-mediated reactions like wound healing, response to tissue injury or inflammatory processes. The present review summarises current knowledge of fibrinogen's and factor XIII's function in coagulation and fibrinolysis giving special emphasis on their relation to inflammation control.

The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis.

BACKGROUND: Factor XIII is a 320 kDa tetramer, comprising two enzymatic A-subunits and two carrier B-subunits (FXIII A2 B2). Activated FXIII (FXIIIa) catalyses the formation of ε-(γ-glutamyl)lysyl covalent bonds between γ-γ, γ-α and α-α chains of adjacent fibrin molecules and also cross-links the major plasmin inhibitor, α2-antiplasmin, to fibrin. OBJECTIVES: We investigated the role of FXIII cross-linking of fibrin directly in clot morphology and its functional effect on clot formation and lysis, in the absence of α2-antiplasmin. RESULTS AND CONCLUSIONS: Our data show that the presence of FXIII during clot formation results in fibrin clots that have a significant 2.1-fold reduction in pore size, as determined by the Darcy constant, Ks, and formed thinner fibers (74.7 ± 1.5 nm) and higher density of fibers compared with those without FXIII (86.0 ± 1.7 nm, P < 0.001), as determined by scanning electron microscopy. Additionally, fibrinolysis showed a significant increase in the time to lysis for clots formed in the presence of FXIII in both static and flow systems. These data demonstrate that independent of α2-antiplasmin, FXIII activity plays a role in increasing the stability of the fibrin clot by altering its structure and increasing the resistance to fibrinolysis.

Tissue-regenerating functions of coagulation factor XIII.

The protransglutaminase factor XIII (FXIII) has recently attracted attention within the field of tissue regeneration, as it has been found that FXIII significantly influences wound healing by exerting a multitude of functions. It supports hemostasis by enhancing platelet adhesion to damaged endothelium, and by its cross-linking activity it stabilizes the formed fibrin clot. Furthermore, FXIII limits bacterial dissemination from the wound and incorporates macromolecules of importance for cellular infiltration, supporting cell migration and survival. FXIII-mediated complex formation of the vascular endothelial growth factor receptor 2 and αV ß3 integrin is important for angiogenesis, supporting the formation of granulation tissue. Chronic inflammatory conditions involving bleeding and activation of the coagulation cascade have been shown to lead to reduced FXIII levels in plasma. Of particular importance for this review is the fact that patients suffering from inflammatory bowel disease (IBD) have reduced FXIII antigen levels and activity. Furthermore, these patients show impaired mucosal healing, which supports the inflammatory state of the disease. This review summarizes the role of FXIII in the healing of wounds, and briefly summarizes the previous use of FXIII in clinical settings. Moreover, it addresses the potential role for FXIII as a therapeutic agent in the healing of persistent wounds during chronic conditions, with an emphasis on IBD.

Biology of Factor XIII and clinical manifestations of Factor XIII deficiency.

Factor XIII (FXIII) is activated by thrombin to form a transglutaminase (FXIIIa) that stabilizes clot formation by the cross-linking of fibrin monomers and antifibrinolytic proteins. Although rare, FXIII deficiency is characterized by variable bleeding manifestations depending on the magnitude of the deficiency. A congenital FXIII deficiency with levels less than 1% can be detected in children who present with prolonged bleeding from the umbilical stump as well as protracted bleeding after trauma. An acquired FXIII deficiency may occur in a number of diseases or clinical situations where FXIII levels and/or its activity are decreased. Patients may also develop a relative deficiency in FXIII as a result of hemorrhage or dilutional changes from transfusions during surgery or trauma and are at increased risk for postoperative bleeding. Genetic studies have identified a wide range of mutations that affect the activity of the FXIII protein but in lieu of molecular genetic analyses, FXIII deficiency can be identified by specific diagnostic assays that measure either the transglutaminase activity of the protein or the levels of the protein and its individual subunits. Replacement therapy has also been shown to increase FXIII levels and reduce bleeding symptoms in patients with congenital FXIII deficiency. This review presents recent findings on the biology of FXIII and the clinical manifestations observed among patients with congenital and acquired FXIII deficiencies.

Critical role of factor XIII in the initial stages of carbon tetrachloride-induced adult liver remodeling.

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.

Hemorrhagic acquired factor XIII (13) deficiency and acquired hemorrhaphilia 13 revisited.

Coagulation factor XIII (F13) circulates in blood as a heterotetramer composed of an A subunit dimer and a B subunit dimer. It is activated by thrombin and crosslinks fibrin monomers. Congenital F13 deficiency demonstrates a lifelong bleeding tendency, abnormal wound healing, and recurrent miscarriages, and it first manifests as umbilical bleeding after birth. In contrast, secondary F13 deficiencies due to its overconsumption and/or hypobiosynthesis by disseminated intravascular coagulation, major surgery, liver diseases, and other disorders are rather common but rarely complicated with bleeding symptoms. Recently, consultations with physicians who have patients with hemorrhagic-acquired F13 deficiency with anti-F13 inhibitors (acquired hemorrhaphilia 13) have indicated an increase in this disease in Japan. We performed a nationwide survey, supported by the Japanese Ministry of Health, Welfare and Labor and confirmed 21 Japanese cases of this disease with anti-F13 inhibitors. Because neither prolonged clotting times nor reduced platelet counts are observed in patients with this disease, many more cases may have been overlooked. Physicians must be mindful of acquired hemorrhaphilia 13 when seeing such patients and should measure F13 activity. Products containing F13 are effective for hemostasis generally, and immunosuppressive therapy must be started immediately to eradicate anti-F13 antibodies.

Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense.

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.

Factor XIII supports platelet activation and enhances thrombus formation by matrix proteins under flow conditions.

BACKGROUND: Activated coagulation factor XIII (FXIIIa) is a transglutaminase that crosslinks fibrin at sites of vascular injury. FXIIIa also associates with blood platelets, although its role in platelet function is unclear and requires clarification. OBJECTIVES: To evaluate the ability of FXIIIa to support platelet adhesion and spreading under conditions of physiologic flow, and to identify the underpinning receptors and signaling events. METHODS AND RESULTS: Platelet adhesion to immobilized FXIIIa was measured by fluorescence microscopy, and signaling events were characterized by immunoblotting. Immobilized FXIIIa supported platelet adhesion and spreading under static conditions through mechanisms that were dually and differentially dependent on integrins α(IIb)ß(3) and α(v)ß(3). Platelet adhesion was independent of FXIIIa transglutaminase or protein disulfide isomerase activity. Moreover, adhesion was abolished by antibodies that prevented interaction with FXIIIa, but maintained when potential interactions with fibrinogen were blocked. Platelet adhesion to FXIIIa was reduced significantly by either the specific α(IIb)ß(3) antagonist tirofiban or the selective α(v)ß(3)-blocking antibody LM609, and abolished when they were used in combination. Importantly, platelet adhesion was preserved under venous and arterial flow conditions in which both integrins played essential roles. In contrast, FXIIIa stimulated the formation of filopodia and lamellipodia in adherent platelets that was mediated exclusively by α(IIb)ß(3) and eliminated by the Src-family inhibitor 4-amino-5-(4-methylphenyl-7-(t-butyl)pyrazolo(3,4-d)pyrimidine, indicating a tyrosine kinase-dependent mechanism. Crucially, under conditions of arterial shear, FXIIIa accentuated platelet recruitment by von Willebrand factor and collagen. CONCLUSIONS: Our data demonstrate a potential role for FXIIIa in supporting platelet adhesion at sites of vascular damage, particularly in association with other thrombogenic matrix proteins.

Plasma membrane factor XIIIA transglutaminase activity regulates osteoblast matrix secretion and deposition by affecting microtubule dynamics.

Transglutaminase activity, arising potentially from transglutaminase 2 (TG2) and Factor XIIIA (FXIIIA), has been linked to osteoblast differentiation where it is required for type I collagen and fibronectin matrix deposition. In this study we have used an irreversible TG-inhibitor to 'block -and-track' enzyme(s) targeted during osteoblast differentiation. We show that the irreversible TG-inhibitor is highly potent in inhibiting osteoblast differentiation and mineralization and reduces secretion of both fibronectin and type I collagen and their release from the cell surface. Tracking of the dansyl probe by Western blotting and immunofluorescence microscopy demonstrated that the inhibitor targets plasma membrane-associated FXIIIA. TG2 appears not to contribute to crosslinking activity on the osteoblast surface. Inhibition of FXIIIA with NC9 resulted in defective secretory vesicle delivery to the plasma membrane which was attributable to a disorganized microtubule network and decreased microtubule association with the plasma membrane. NC9 inhibition of FXIIIA resulted in destabilization of microtubules as assessed by cellular Glu-tubulin levels. Furthermore, NC9 blocked modification of Glu-tubulin into 150 kDa high-molecular weight Glu-tubulin form which was specifically localized to the plasma membrane. FXIIIA enzyme and its crosslinking activity were colocalized with plasma membrane-associated tubulin, and thus, it appears that FXIIIA crosslinking activity is directed towards stabilizing the interaction of microtubules with the plasma membrane. Our work provides the first mechanistic cues as to how transglutaminase activity could affect protein secretion and matrix deposition in osteoblasts and suggests a novel function for plasma membrane FXIIIA in microtubule dynamics.

Hemostatic proteins and their association with hematoma growth in patients with acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: We tested the hypothesis that proteins of hemostasia could be associated with hematoma growth (HG) in patients with acute intracerebral hemorrhage. METHODS: We prospectively studied patients with spontaneous supratentorial intracerebral hemorrhage within the first 6 hours after the onset of symptoms. HG was defined as an increase > 33% in the volume of hematoma on CT obtained 24 to 72 hours after the onset of symptoms in comparison with the CT obtained at admission. We collected admission and follow-up blood samples. We measured fibrinogen, factor XIII, thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor, plasminogen, α2-antiplasmin, tissue plasminogen activator, d-dimer, thrombomodulin, thrombin-antithrombin complex, and plasmin-antiplasmin complex. RESULTS: We included 90 patients with a mean age of 71 ± 10.8 years; 61% were men. HG was observed in 35 (39%) of the patients. Mean baseline and follow-up protein measurements showed no difference between the groups with and without HG. The analysis of variance showed that factor XIII activity decreased in the non-HG group in the 24 to 72 hours sample, whereas it increased in the HG group (P = 0.001). CONCLUSIONS: Factor XIII was the only measured protein related to HG. The levels at the follow-up sample decreased in the non-HG group and increased in the HG group. Further studies are needed to confirm this association.