the discovery of coagulation factor xiii ( fxiii ) dates back to 1940s when a  serum factor  was found to make the fibrin clot insoluble in concentrated urea solution .
 in 1960 , a case report demonstrated that the severe bleeding of a patient was due to the deficiency of fibrin stabilizing factor .
soon after this clinical finding , such fibrin stabilizing factor was formally termed fxiii in 1963 .
fxiii is a transglutaminase ( tg ) that circulates in tetrameric form ( fxiii - a2b2 ) , consisting of two a subunits ( fxiii - a ) and two b subunits ( fxiii - b ) .
the a subunit , as the pro - tg , is made up of 732 amino acids with a molecular mass of 83,000 .
fxiii - a comprised five domains : the n - terminal activation peptide ( ap - fxiii ) ( amino acids 137 ) , -sandwich ( 38184 ) , catalytic core ( 185515 ) , -barrel 1 ( 516628 ) , and -barrel 2 ( 629731 ) .
fxiii - b is a glycoprotein consisting of 641 amino acids ; its molecular mass is 80,000 .
it is a typical mosaic protein consisting of 10 short tandem repeats , called sushi domains .
fxiii - b serves as a carrier protein and is essential for the stabilizing of fxiii - a .
it accelerates cross - linking of fibrin by promoting the formation of a ternary complex between proenzyme fxiii , prosubstrate fibrinogen , and activator thrombin .
the catalytic site of fxiii - a2 is cys314 , which is normally occluded by ap - fxiii .
initiated by thrombin , ap - fxiii is cleaved and plasma fxiii - a2b2 is converted to fxiiia2 b2 .
after further disassociation of fxiii - b2 as a result of conformational change after ca binding , fxiii is finally transformed into activated fxiii ( fxiiia ) [ figure 1 ] .
fxiii - a is mainly formed by cells originated from the bone marrow . in plasma ,
all fxiii - a exists in a complexed form of fxiii - a2b2 . while the free form , fxiii - a2 is only found intracellularly , mainly in platelets , megakaryocytes , monocytes , and macrophages .
fxiii - b , synthesized by the hepatocyte , presents both as free form of fxiii - b and a complexed form of fxiii - a2b2 in the plasma .
( b ) after the initial conversion of fibrinogen into soluble fibrin by thrombin , fxiiia cross - links gln and lys residues of fibrins , which further leads to the formation of insoluble fibrin network .
ap - fxiii : activation peptide factor xiii ; fxiii : factor xiii ; fxiiia : activated factor xiii ; gln : glutamine ; lys : lysine . as a tg
the substrates of fxiii add up to more than 140 , including fibrinogen , fibronectin , and vitronectin .
the whole complement system , including c3 , c4b , c5a , can be cross - linked and immobilized by fxiii ; hence , a pro - inflammatory environment is created , providing a suitable microenvironment for cellular growth .
interaction between these proteins and signal molecules on the cellular surface may activate signal pathways .
fxiii is transformed to activated fxiii by thrombin with the help of ca and catalyzes cross - linking of fibrin , converted from fibrinogen by activated thrombin [ figure 1 ] .
fibrin cross - linking is a highly specific acyl transfer reaction consisting of two steps : ( 1 ) glutamine of the substrate forms a binary complex with the active site cysteine of the enzyme through the thioester linkage , accompanied by ammonia release ; ( 2 ) the acyl group of the binary complex is transferred to the acyl acceptor amine and form an isopeptide , releasing the enzyme at the same time .
fibrin included two -chains , two -chains , and two -chains , linked by the disulfide bond . fxiiia cross - links fibrin chains , during which -chain dimers and -chain polymers are formed .
-chain dimer formation between lysine of one -chain and glutamine of the other -chain is fast , followed by the formation of -polymers .
-chain multimers from progressive cross - linking of -chain dimers , accompanied by cross - linking between -chain and -chain , further stabilize the fibrin clot .
2-antiplasmin ( a2 at ) is one of the substrates of fxiii that can be cross - linked to fibrin , further strengthening its antifibrinolytic ability
. other substrates of fxiii include plasminogen activator inhibitor 2 , plasminogen , and thrombin activatable fibrinolysis inhibitor , whose roles in fibrinolysis and thrombosis remain to be studied .
fxiii deficiency is a rare type of disorder that often causes bleeding manifestations , sometimes life - threatening central nerve system ( cns ) bleeding .
a research of 190 patients with congenital fxiii deficiency revealed that major clinical manifestations include umbilical bleeding of neonates , deep soft tissue hematoma , prolonged wound bleeding , mucosal bleeding ( gum bleeding , epistaxis , prolonged menstrual bleeding ) , and cns bleeding .
patients may develop antibodies for fxiii - a or fxiii - b from autoimmune or neoplastic disease and usages of certain medications .
fxiii deficiency has been found in children with malignant disease including acute myeloid leukemia and acute lymphoblastic leukemia ( all ) , and solid tumor such as neuroblastoma , non - hodgkin lymphoma and disseminated alveolar rhabdomyosarcoma , with the presence of bleeding manifestations .
one research focused on pulmonary embolism ( pe ) demonstrated that patients with pe ( n = 71 ) have lower fxiii levels than patients without ( n = 4 9 ) .
similar results were observed in fibrinogen level , indicating that lower level of fxiii in patients with pe might be a result of consumption during clot formation .
studies have also shown that the role of fxiii in thrombosis may be affected by factors such as age and gender .
two studies with 955 and 278 patients , respectively , reported that increased fxiii plasma concentration was associated with increased incidence rate of myocardial infarction and peripheral artery disease in female patients .
inflammatory cells such as macrophages and neutrophils will migrate to the wounded area due to the chemotactic effect induced by cytokines .
angiogenesis then starts under the influence of growth factors such as vascular endothelial growth factor ( vegf ) , fibroblast growth factor , and transforming growth factor - g .
the newly synthesized small vessels , together with fibrin , will form the granulation tissue .
fxiii also plays an important part in the process . besides the significant role in the coagulation cascade , immobilized fxiiia in the tissue of the wound supports platelet adhesion through integrins ( iib3 and v3 ) on the surface of the platelet , a process independent of fxiiia tg activity , thus stabilizing the provisional matrix at the very early stage of wound healing .
bacteria are immobilized via cross - linking to fibrin fibers by the action of fxiii .
fxiii is also able to cross - link with many molecules such as fibronectin and vitronectin , which adheres to the integrin of inflammatory cells that would migrate to the wound later . as a result ,
adhesion of the inflammatory cells is enhanced , and integrin - related signal pathway is activated .
it is found that fibronectin plays a potential role in the activation of macrophage , and cross - linked vitronectin can inhibit apoptosis of neutrophils .
vegf receptor-2 ( vegfr-2 ) and v3 on the surface of vascular endothelial cells are both signal molecules in angiogenesis , which can be activated by fibronectin and vitronectin when cross - linked with fxiii .
the role of fxiii in wound healing is supported by research in both animal studies and clinical cases .
exposure to dextran sulfate sodium ( dss ) causes mucosa damage of colon in mice .
the colon damage of wild - type mice was found to recover better than fxiii mice after dss exposure .
a research study including 31 patients of crohn 's disease ( cd ) reported that plasma fxiii level was lower in patients with active cd than patients in remission , indicating fxiii consumption during the healing of damaged colons .
another study including 249 patients of ulcerative colitis showed that plasma fxiiia was lower in more severe patients ( measured by clinical activity index , endoscopic and histologic scores ) .
immunohistochemistry also reported fxiii localization in extracellular matrix of damaged mucosa , a strong evidence of fxiii participating in wound healing process .
researchers have found abnormal fxiii expression level or activity in patients with leukemia and solid tumors .
the cellular form of fxiii ( fxiii - a2 ) is present mainly in platelets , megakaryocytes , monocytes , and macrophages .
it was found that fxiii - a2 expression level of tumor cells was significantly elevated in patients with acute myelomonocytic leukemia ( aml - m4 ) and acute monocytic leukemia ( aml - m5 ) .
abnormal fxiii activity has been found in patients with solid tumors . a research including 28 patients of nonsmall cell lung cancer ( nsclc ) found that fxiii activity level of patients in advanced - stage is higher than that of patients in early - stage and healthy controls , indicating that fxiii activity level could be potentially used as a marker of advanced nsclc .
vairaktaris et al . analyzed 130 patients of oral squamous cell carcinoma and 135 healthy controls and found that l allele was associated with higher oral cancer risk .
it was observed that patients with ll homozygotes had a 3-fold higher risk for oral cancer , while in vl , the risk was 2-fold higher .
fibrins are found in neoplastic tissues , as well as many tumor - associated macrophages ( tams ) which express fxiii - a2 .
fxiii - a2 released from damaged tams was involved in the stabilization of fibrin network which facilitated tumor growth .
fxiii was found to be involved in tumor metastasis in the research of mice by limiting natural killer cell - mediated clearance of micrometastatic tumor cell
. however , the role of fxiii in tumorigenesis is still unclear , and the relationship between fxiii and leukemia and solid tumors needs to be further elucidated .
bone remodeling is a life - long process , involving osteoclasts that resorb bone and osteoblasts that form new bone tissues .
bone extracellular matrix is essential in the process by facilitating cell attachment , cell differentiation , and bone mineralization .
researches in mice have reported the activation of fxiii - a gene in osteocytes of long bones ( femur ) and flat bones ( calvaria and mandible ) .
a 37,000 protein expressed in bone and was confirmed to be the active product of fxiii - a after posttranslational proteolytic processing .
the protein was able to stabilize the interaction of microtubules with the plasma membrane , making it possible for the secretion of exosomes which contain collagen and fibronectin , both of which were predominant composition of bone extracellular matrix .
collagen and fibronectin secreted outside the cell could form stable interaction with osteonectin and osteopontin , catalyzed by tg .
the deposition of ca and collagen would decrease after suppression of tg activation , indicating the important role tg played in the mineralization and collagen deposition of bone extracellular matrix .
however , other researches have observed mineralization and collagen deposition of extracellular matrix in tg2 and fxiii - a knockout mice . another protein of 37,000 , with similar function to the active product of fxiii - a mentioned above , has been found .
it is reasonable to believe that other kinds of protein may also be involved in bone remodeling .
a systemic review by sharief and kadir found 127 ( 66% ) miscarriages in 192 pregnancies of 63 women with congenital fxiii deficiency .
for those without prophylactic therapy , as high as 91% of 136 pregnancies resulted in miscarriage .
fxiii - a is present in normal uterus , implantation tissues , and placenta in normal pregnant women , but missing in women of congenital fxiii deficiency .
extravillous cytotrophoblasts formed the cytotrophoblastic shell which stabilized the interaction between embryo and decidua of uterus .
it was reported that fxiii - a was missing in the placenta in woman with fxiii deficiency , leading to insufficient formation of the cytotrophoblastic shell .
the cross - linking between proteins such as fibrin and fibronectin was also important for the attachment of placenta to uterus .
however , a research including 536 cases reported that the plasma level of fxiii could not predict recurrent miscarriage .
one potential explanation is that fxiii in plasma is not equal to that in placenta tissues while the latter is the key to pregnancy loss .
fxiii has been treated as merely a coagulation factor for a long time by the medical community .
recent studies have shown that fxiii , with the essence of tg , is involved in many more processes besides coagulation such as wound healing , bone extracellular matrix stabilization , and the interaction between embryo and decidua of uterus , as well as some rare processes [ table 1 ] .
the expression and activity level of fxiii also changes in leukemia and solid tumors , but its underline mechanism is still unknown and more research is needed .
 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 . 
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