when a vessel is torn or injured , several mechanisms such as vascular spasm , platelet plug formation and blood clotting lead to permanent closure of vessels and bleeding stop ( 1 , 2 ) . any contact of blood with damaged endothelial cells and exposed collagen converts prothrombin into thrombin by prothrombin activator ( 3 , 4 ) . then in a tandem reaction manner , thrombin converts fibrinogen to fibrin , which traps platelets , blood cells , and plasma to form a clot ( 2 , 3 ) . prothrombin activator is synthesized through two ways , however the two pathways continuously affect each other : 1 ) the extrinsic pathway starting from damage to the vessel wall and surrounding tissues and 2 ) the intrinsic pathway that begins inside the blood ( 5 ) . in the extrinsic pathway , injured tissue releases a complex called tissue factor ( tf ) ( 3 , 6 ) . the factor is formed by tissue membrane phospholipids plus lipoprotein complex . in the presence of calcium ions , tf along with coagulation factor vii ( fvii ) act as an enzyme , to convert factor x ( fx ) into activated factor x ( fxa ) ( 7 , 8) . fxa is immediately combined with tissue phospholipids or other phospholipids released from platelets and along with factor v ( fv ) , form a complex called prothrombin activator . in the presence of calcium ions , within a few seconds , the prothrombin complex breaks into thrombin and coagulation process initiates ( 3 , 5 ) . for the formation of prothrombin activator in the intrinsic pathway , vascular damage activates factor xii ( fxii ) and releases platelet phospholipids ( 9 , 10 ) . when fxii is released , it turns into a proteolytic enzyme called fxiia by changes in molecular shape ( 11 ) . fxiia as an enzyme activates factor xi ( fxi ) and initiates the second step in the intrinsic pathway ( 9 , 11 , 13 ) . finally , fixa with factor viiia ( fviiia ) and platelet phospholipids activate fx ( 10 ) . subsequently , the steps of the intrinsic pathway are the same as the last step of the extrinsic pathway ( 4 , 5 ) . following blood vessel rupture , tf begins extrinsic pathway while fxii and platelets contact with tissue collagen initiates intrinsic pathway ( 12 ) . there is one fundamental difference : the extrinsic pathway is completed quickly ( within 15 sec ) and the final clot is only limited by the released level of tf and values of circulating f , fvii and fv . however , the intrinsic pathway is usually much slower and clotting takes 1 to 6 min ( 4 , 15 ) . a relevant literature search of pubmed was performed using the keywords coagulation factors , nonsense - mediated mrna decay , and premature translation termination codons . coagulation factors are a family of glycosylated plasma proteins that need to be activated to induce and enhance the coagulation process . deficiency of coagulation factors can be quantitative or qualitative ( 16 - 18 ) . hemophilia a ( fviii deficiency ) is the most common severe inherited bleeding disorder ( 19 , 20 ) . the disease is created as a result of the f8 gene defect , which is located on the x chromosome . thus , males are affected and females are carriers of the disease and usually do not have bleeding symptoms . clinical signs of hemophilia a , vary according to the level of coagulation factor so that the patients are divided into severe , moderate and mild types ( 21 ) . in severe hemophilia the patients do not have spontaneous bleeding , except in the case of trauma , surgery , or tooth extraction ( 21 - 23 ) . hemophilia b ( fix deficiency ) is x - linked as well and has clinical signs similar to hemophilia a. the severity of clinical complications is associated with the level of factor deficiency so that the values below 5% are conducive to spontaneous bleeding ( 24 - 26 ) . fxi deficiency is a rare recessively inherited mild bleeding disorder representing increased hemorrhage tendency following trauma or surgery . in contrast to hemophilias a and b , in fxi deficiency also called hemophilia c , severity of the symptoms does not correlate with the factor levels . the factor stabilizes fibrin clots and is found in two forms ; homodimers composing of subunits a , which are found only within the cell and heterodimers consisting of subunits a and b , present extracellularly in plasma . genes encoding subunit a and subunit b are located on chromosome 6 and chromosome 1 , respectively . fvii is a vitamin k - dependent factor and activates internal and external pathways of coagulation in a complex with tf , as is mentioned earlier . fvii deficiency is typically transmitted in an autosomal recessive manner and the corresponding gene , f7 is located on chromosome 13 . clinically , varying signs range in severity from lethal to mild or even asymptomatic forms ( 31 , 32 ) . clinical characteristics place fx deficiency among the most severe forms of the rare coagulation defects . patients generally experience epistaxis , mucosal bleeding , hemarthrosis , hematomas and even cns bleeding . human f10 gene maps to the long arm of chromosome 13 , approximately 2.8 kb downstream of the f7 gene , and its mutation is inherited as an autosomal recessive allele ( 33 , 34 ) . fv deficiency is commonly inherited in an autosomal recessive fashion due to reduced plasma levels of the factor . common characteristics of fv deficiency are epistaxis , bruising , and mucosal bleeding , however , some patients have experienced cns bleeding . von willebrand factor ( vwf ) is synthesized by endothelial cells and megakaryocytes and plays two major roles in hemostasis : first , it serves as a specific carrier of fviii in circulation . secondly , vwf high multimers act as a bridge between subendothelial tissues and platelet . in the presence of such strings , the platelets slow down , move away from the rapid flow of the blood and accumulate at the site of vascular damage ( 36 - 38 ) . von willebrand disease ( vwd ) is an autosomal bleeding disorder with a different mode of inheritance ( 39 ) . partial quantitative vwf defects lead to the vwd type1 that is associated with a variety of bleeding manifestations and typically inherited as an autosomal dominant disorder . however , qualitative abnormalities of vwf cause the vwd type2 . inheritance of this type of the disease is generally autosomal dominant , although some cases are characterized by autosomal recessive transmission ( 40 , 41 ) . vwd type3 is the rarest but the most serious form of the disease and is frequently associated with consanguinity ( 39 ) . in type3 , plasma vwf decreased to low quantity levels as well as fviii due to its dependence on vwf ( 20 ) . human vwf is encoded by the vwf gene , which is identified on chromosome 12 ( 40 ) . despite the low prevalence of hemorrhagic diseases , a large number of mutations have been identified related to various disease types . by the same token , a remarkable portion of the genetic abnormalities is ended in null alleles arising by small insertions and deletions , nonsense and splice site mutations ( 39 , 42 ) . mutations of promoter or enhancer that play an eminent role in eukaryotic transcription , result in impaired gene transcription and mrna expression level reduction ( 43 ) . another impact of gene mutation on protein synthesis can be traced back to the cell protective mechanisms against translation errors in order to reduce abnormal proteins . by removing mrna transcripts that contain premature translation termination codons ( ptc ) , nonsense - mediated mrna decay ( nmd ) prevents the biogenesis of defective or truncated polypeptides before completing the translation process ( 44 ) . rapid degradation of mrna containing ptc was first observed 30 years ago in saccharomyces cerevisiae . since then , nmd has been found in many other eukaryotes including man . in most cases the translation of ptc - containing transcripts in the absence of nmd , lead to the accumulation of harmful truncated proteins in the cell . nmd regulates several disease - causative genes such as -globin and dystrophin ( 45 , 46 ) . although the major role of nmd is elimination of unusual transcripts , in recent years , the researchers have found that many physiological mrnas , coding full - length proteins , are also substrates for nmd ( 47 ) . among coagulation factor genes , nmd has been reported in fxiii . arg661stop mutation on exon14 of f13a reduces gene expression of mutant allele by 10 to 30 times compared to wild - type allele ( 48 ) . the mechanism has also been described for fv deficiency . a 2-bp deletion in exon13 of f5 gene that causes ptc in codon 900 following platelet mrna isolation of heterozygous individuals , it became clear that the mutation containing cdna much less expressed compared to wild - type transcript ( 49 ) . common mutation , glu117stop located on exon5 of f11 gene has been reported in different populations with fxi deficiency . further evaluation of heterozygous mrnas showed that only wild - type allele is expressed suggesting that the allele with ptc has undergone nmd ( 50 ) . one of the earliest evidence of nmd in coagulation disorders was described in 1991 by nichols and colleagues on a family of vwd type3 . instead , by an increased expression , wild - type allele compensated for the reduction . the authors concluded that such a mechanism could explain the wide range severity of vwd type1 and type3 ( 51 ) . it should be noted that another analysis on platelet mrna bearing a ptc mutation revealed no mrna level reduction in a vwd type3 family . expression studies showed that the gene defect causes a truncated protein , which was retained in the transfected cells ( 52 ) . a research conducted in italy studied nmd mechanism of vwf mutations in 3 unrelated patients who had at least one truncating mutation . ptc - introducing mutation in the first patient ( intron 19 ) was c.2546 + 3 g > c and in the second patient ( intron 50 ) was c.8155 + 6 t > c. the third was c.6182delt in a vwd type3 patient . sequencing results showed that the c.8155 + 6 t > c causes the deletion of exon 50 and the ptc in exon 51 , which is located only 23 bp upstream of the last exon - exon junction . the two other mrnas bearing ptc were selectively eliminated by nmd mechanism and only the expression of wild - type transcript was detected in heterozygous individuals . the results showed that the sensitivity of nmd depends on ptc location ( 53 ) . in this regard , investigations on two splice site mutations c.1109 + 2t > c and c.1534 - 3c > a and a nonsense mutation p.q77x , all causing ptc , demonstrated an allele - specific reduction of the mrna ( 54 ) . analysis of 7 different potential splice site mutations showed degradation of ptc - introducing alleles of either platelets or leukocytes mrna . nmd was suggested as a general mechanism to prevent the biogenesis of vwf truncated proteins ( 55 ) . we also studied c.7674 - 7675insc located on vwf exon 45 in a large consanguine type3 family . quantitative analysis of rt - pcr products showed that the levels of mrna bearing ptc have been dramatically reduced by decay mechanism ( 42 ) . one of those genes is f8 , which escapes nmd through various mutations and codes transcript variants . the nmd resistance occurs not only following missense , silent , and splice site mutations but also , there is evidence of escaping nonsense mutations from nmd ( 53 ) . in 2003 david et al , found no support for the presence of nmd mechanism followed by nonsense mutations in hemophilia a. in this study , a series of mrnas containing nonsense mutations were obtained from peripheral blood lymphocytes . studies revealed that in all cases the transcripts were reproduced ( 56 ) . to investigate the basis of inhibitor creation in haemophilia patients , expression studies were carried out on 6 different nonsense mutations spread throughout the six fviii domains . the results demonstrated that regardless of nonsense mutations , f8 transcription occurred normally and truncated proteins were produced ( 57 ) . recently , to elucidate the transcriptional effects of potential splice site mutations in haemophilia a , a comparison study of in - silico prediction and mrna analysis was performed . they observed the expression of all defective transcripts and introduced mrna study as a reliable approach to discover splicing alterations ( 58 ) . the importance of mrna study has already been described on different f8 splice site mutations where they detected defective transcripts ( 59 ) . taken together the absence of nmd in haemophilia can be evidence of a connection between x - linked traits and mrna decay . it must be taken into account that the nmd is involved in mammalian x chromosome dosage compensation . however , by inhibiting the nmd process , yin et al showed that autosomal genes are more likely to undergo nmd than x - linked genes . in their study , overall mrna expression was increased in favor of autosomal genes indicating their susceptibility to the nmd ( 60 ) . these pieces of evidence support the view that the transcriptome analysis provides new insights into the real impact of nmd on human disease . the considerations suggest the need for mrna analysis to augment the results of genomic dna mutation detection . excluding the f8 , nmd could be referred to as a general mechanism that prevents biogenesis of coagulation factor truncated proteins . in fact , there is substantive indication that the decay mechanism is skewed towards bleeding disorder genes . as this is a topic on which conflicting data were reported in the literature , more study
objective(s):haemostasis prevents blood loss following vascular injury . 
 it depends on the unique concert of events involving platelets and specific blood proteins , known as coagulation factors . 
 the clotting system requires precise regulation and coordinated reactions to maintain the integrity of the vasculature . 
 clotting insufficiency mostly occurs due to genetically inherited coagulation factor deficiencies such as hemophilia.materials and methods : a relevant literature search of pubmed was performed using the keywords coagulation factors , nonsense - mediated mrna decay and premature translation termination codons . 
 search limitations included english language and human - based studies.results:mutations that cause premature translation termination codons probably account for one - third of genetically inherited diseases . 
 transcripts bearing aberrant termination codons are selectively identified and eliminated by an evolutionarily conserved posttranscriptional pathway known as nonsense - mediated mrna decay ( nmd ) . 
 there are many pieces of evidence of decay among coagulation factor genes . 
 however , the hemophilia gene ( f8 ) does not seem to be subjected to nmd . since the f8 gene is located on the x - chromosome , a connection between x - linked traits and mrna decay could be assumed.conclusion:considering that not all genes go through decay 
 , this review focuses on the basics of the mechanism in coagulation genes . 
 it is interesting to determine whether this translation - coupled surveillance system represents a general rule for the genes encoding components of the same physiological cascade .