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THE NORMAL INSTRINSIC PATHWAY The interactions of the coagulation factors involve in the instrinsic !

ath"a# are illustrate in fig$ %&'($ the initial activation sti)ulus is surface contact activation of factor *II +Hage)an factor, to !ro uce *IIa$ This reaction is facilitate -# the !resence of high )olecular "eight .ininogen an the conversation of !re.alli.rein to the active !rotease/ .alli.rein$ Although his first sto! is e0tre)el# i)!ortant in the la-orator# )easure)ent of the intrinsic !ath"a#/ the !artial tro)-o!lastin ti)e +PTT,/ it is not associate "ith clinical -lee ing ten enc#$ 1actor *IIa activates factor *I/ "hich in turn activates factor *I +Christ)as factor,$ 1actor I*a then catal#2es he cleavage of factor *$ the reaction -et"een factors I* A an * is facilitate -# -in ing -oth factors -# calciu) -ri ges to a !hos!holi!i surface such as the surface of an activate !latelet$ This reaction re3uires the !resence of activate factor 4III as a cofactor to achieve a )a0i)u) reaction rate$ 1actor I* is a single chain g#l#co!rotein !ro uce in the liver as one of the vita)in 5 6 e!en ent factors$ Its activation -# factor *Ia involves a cleavage of t"o successive internal !e!ti e -on s to for) a t"o'chain serine !rotease$ 1actor 4III a!!ears to -e s#nthesi2e -# the liver an !erha!s -# l#)!hoi tissue un er the control of single *'lin.e gene$ It circulates as a !rocoagulant attache to vW1$ The latter relationshi! is e0tre)el# i)!ortant$ When the vW1 level is re uce / factor 4III is )ore ra!i l# cleare fro) !las)a/ effectivel# re ucing the activit# level$ In or er to !artici!ate as a cofactor in the activation of factor */ factor 4III )ust first -e cleave -# thro)-in to for) factor 4IIIa$ He)o!hilia A The )olecular -asis of he)o!hilia A has no" -een efine $ The factor 4III gene is a ver# large/ (78'.- gene on the * chro)oso)e$ Al)ost half the !atients "ith he)o!hilia A e0hi-it an inversion of a )a9or !ortion of the 4III gene "ith a resultant loss of activit#$ The re)ain er sho" various !oint )utation/ insertions/ an eletions that )a# involve as little as one -ase !air to the entire gene$ The )ost severe he)o!hiliacs generall# have an inversion or eletion of )a9or !ortion of the * chro)oso)e geno)e an ver# lo" levels of factor 4III antigen an activit#$ Other )utations/ inclu ing sto! co on an !oint )utation an )inor eletions/ result in )il er isease$ In so)e of these !atients/ the re uction in the factor 4III level is less !ronounce "hereas in others a functionall# a-nor)al !rotein is !ro uce $ The latter can -e e)onstrate -# sho"ing a iscre!anc# -et"een the i))unologic )easure)ent of factor 4III antigen +!rotein, an the coagulation assa# of factor 4III activit#$ As a rule of thu)-/ the clinical severit# of the !atient:s -lee ing isor er is -est correlate "ith the factor 4III activit# level$ Severe he)o!hiliacs have factor 4III activit# levels less than ( !ercent of nor)al +less than ;$;( <=)l, an are usuall# iagnose uring chil hoo -ecause of fre3uent/ s!ontaneous he)orrhages into 9oints/ )uscles an vital organs$ The# re3uire fre3uent treat)ent "ith factor 4III re!lace)ent an even then are at ris. of evelo!ing 3 !rogressive/ efor)ing arthro!ath#$ Even a level of etecta-le factor 4III activit# of ( to > !ercent of nor)al is enough to re uce severit# of the isease$ These !atients are at increase ris. of he)orrhage "ith surger# or trau)a -ut have )uch less ifficult# "ith s!ontaneous he)arthroses or he)ato)as$ Patients "ith factor levels greater than 8 !ercent are onl# )il l# affecte an )a# go un iagnose "ell into a ult life$ The# are at ris./ ho"ever/ for e0cessive

-lee ing "ith a )a9or surgical !roce ure$ Wo)en carriers can also -e at ris. "ith surger#$ L#oni2ation of the * chro)oso)e is not !urel# ran o) an can result in lo" levels of factor 4III or I*$ HEMOPHILIA ? He)o!hilia ? !atients have a si)ilar clinical s!ectru) of isease$ 1actor *II levels of less than ( !ercent are associate "ith severe -lee ing/ "hereas )ore )o erate isease is seen in !atients "ith levels of ( to > !ercent$ Patients "ith factor I* levels of -et"een > an @; !ercent generall# have ver# )il isease$ This situation reflects the si)ilarit# in genetic in trans)ission$ He)o!hilia ? can result fro) a nu)-er of genetic )utation inclu ing eletions/ !oint )utations/ an fra)e shift efects involving the factor I* gene on the long ar) of the chro)oso)e$ Most !atients sho" an a-sence of factor I* activit# -ecause of functionall# a-nor)al !roteinA less co))onl# there is an a-sence of -oth factor I* antigen an activit#$ One rare )utation +1I* Le# en, !ro uces a he)o!hilia ? !icture in chil ren that resolves at !u-ert# as factor I* !ro uction increases$ The )ost characteristic clinical )anifestation of the he)o!hilias is the -lee ing into the large 9oints of the u!!er an lo"er e0tre)ities$ This con ition usuall# -egins once the affecte chil reaches the to ler stage an then increases n fre3uenc# as the chil -eco)es )ore active$ Often/ one or t"o 9oints -eco)e the !rinci!al targets of re!eate he)arthroses$ With ti)e/ ths situation can result in a chronic s#novitis/ estruction of cartilage an -one/ an a !rogressive fle0ion contracture$ ?lee ing into )uscle +ilio!soas/ gastrocne)ius/ an fle0or )uscles of the ar), or soft tissues "ith the for)ation of large s!rea ing he)ato)as is also co))on$ Ba)age to )uscles results in further )uscle atro!h# an contractures$ Other -lee ing )anifestations inclu e he)aturia/ intracranial he)orrhage/ )ucous )e)-rane -lee ing an !rolonge -lee ing follo"ing )inor trau)a or surger#$ The )il er he)o!hiliac )a# not -e etecte until surger# is !erfor)e or the !atient has a ental e0traction$ <suall#/ the !roce ure is co)!lete "ithout evi ence of unusual -lee ing$ Ho"ever/ "ithin a fe" hours/ the surgical "oun or tooth soc.et -egins to oo2e/ "oun healing is isru!te an -loo flo"s into surroun ing tissues$ He)ato)a for)ation in the !har#ngeal an retro!har#ngeal areas can threaten the !atenc# of the air"a# an !resent a )e ical e)ergenc#$ Large su-!eriosteal or )uscle -lee s can on occasion lea to the for)ation of a he)o!hilic !seu otu)or$ These are c#st'li.e structures containing serosanguinous or ar. -ro"n viscous )aterial -oun to a fi-rous )e)-rane$ Over ti)e/ !seu otu)ors e0!an an i)!inge on a 9acent structures$ Those that arise fro) a su-!eriosteal -lee / usuall# involving the !elvis or fe)urs/ ero e -one to for) large c#stic lesions$ Pen#aringan INSTRINSIC ATAS NORMAL Intera.si fa.tor .oagulasi #ang terli-at ala) 9alur instrinsic iilustrasi.an ala) ara$ %&' ($ sti)ulus a.tivasi a"al a alah !er)u.aan .onta. a.tivasi fa.tor *II +fa.tor Hage)an, untu. )enghasil.an *IIa$ Rea.si ini ifasilitasi oleh .eha iran .ininogen -erat )ole.ul tinggi an !erca.a!an !re.alli.rein .e !rotease a.tif/ .alli.rein$ Mes.i!un -erhenti !erta)a sangat !enting ala) !engu.uran la-oratoriu) 9alur intrinsi./ "a.tu tro)-o!lastin !arsial +PTT,/ ti a. ter.ait engan .ecen erungan !en arahan .linis$

1a.tor *IIa )enga.tif.an fa.tor *I/ #ang !a a gilirann#a )enga.tif.an fa.tor *I +Natal fa.tor,$ 1a.tor I*a .e)u ian )eng.atalisis ia !e)-elahan fa.tor *$ rea.si antara fa.tor I* A an * ifasilitasi oleh )engi.at .e ua fa.tor oleh 9e)-atan .alsiu) .e !er)u.aan fosfoli!i se!erti !er)u.aan se-uah !latelet ia.tif.an$ Rea.si ini )e)erlu.an a an#a fa.tor 4III a.tif se-agai .ofa.tor untu. )enca!ai la9u rea.si )a.si)u)$ 1a.tor I* a alah g#l#co!rotein rantai tunggal #ang ihasil.an i ala) hati se-agai salah satu vita)in 5 ' fa.tor e!en en$ Its a.tivasi oleh fa.tor *ia )eli-at.an !e)-elahan ua i.atan !e!ti a -erturut'turut internal untu. )e)-entu. se-uah !rotease serin ua rantai$ 1a.tor 4III ta)!a.n#a isintesis oleh hati an )ung.in oleh 9aringan li)foi i -a"ah .en ali gen ter.ait'* tunggal$ Ini -ere ar se-agai !rocoagulant ter!asang .e vW1$ Hu-ungan #ang tera.hir ini sangat !enting$ 5eti.a ting.at vW1 -er.urang/ fa.tor 4III le-ih ce!at i-ersih.an ari !las)a/ efe.tif )engurangi ting.at a.tivitas$ Bala) rang.a -er!artisi!asi se-agai .ofa.tor ala) a.tivasi fa.tor */ fa.tor 4III !erta)a harus i-elah oleh tro)-in untu. )e)-entu. fa.tor 4IIIA$ He)ofilia A Basar )ole.ul he)ofilia A .ini telah i efinisi.an$ Cen fa.tor 4III a alah gen/ #ang sangat -esar (78'.- !a a .ro)oso) *$ Ha)!ir se!aruh !asien engan he)ofilia A !a)eran inversi se-agian -esar ari gen 4III engan .erugian resultan a.tivitas$ Titi. sisan#a )enun9u..an -er-agai )utasi/ sisi!an/ an !engha!usan terse-ut )ung.in )eli-at.an se i.it se-agai salah satu !asangan -asa .e seluruh gen$ Yang !aling !arah !en erita he)ofilia u)u)n#a )e)ili.i inversi atau !engha!usan -agian uta)a ari geno) .ro)oso) * an ting.at #ang sangat ren ah antigen fa.tor 4III an a.tivitas$ Lainn#a )utasi/ ter)asu. )utasi .o on -erhenti an titi. an !engha!usan .ecil/ )en#e-a-.an !en#a.it ringan$ Bala) -e-era!a !asien/ !enurunan ting.at fa.tor 4III .urang 9elas se ang.an i lain !rotein fungsional nor)al ihasil.an$ Yang tera.hir ini a!at i e)onstrasi.an engan )enun9u..an !er-e aan antara !engu.uran fa.tor 4III .e.e-alan antigen +!rotein, an u9i .oagulasi fa.tor 4III a.tivitas$ Se-agai aturan !ra.tis/ ting.at .e!arahan .linis gangguan !en arahan !asien ter-ai. -er.orelasi engan ting.at a.tivitas fa.tor 4III$ !en erita he)ofilia -erat )e)ili.i ting.at a.tivitas fa.tor 4III .urang ari ( !ersen ari nor)al +.urang ari ;/;( < = )l, an -iasan#a i iagnosis sela)a )asa .ana.'.ana. .arena sering/ !er arahan s!ontan .e ala) sen i/ otot an organ'organ vital$ Mere.a )e)-utuh.an !engo-atan sering engan !enggantian fa.tor 4III an -ah.an .e)u ian -eresi.o )enge)-ang.an 3 !rogresif/ -er efor)asi arthro!ath#$ ?ah.an ting.at ter ete.si a.tivitas fa.tor 4III ( sa)!ai > !ersen ari nor)al su ah cu.u! untu. )engurangi .e!arahan !en#a.it$ Pasien'!asien ini )engala)i !ening.atan risi.o !en arahan engan o!erasi atau trau)a teta!i )engala)i .esulitan a!alagi engan he)arthroses s!ontan atau he)ato)a$ Pasien engan ting.at fa.tor le-ih -esar ari 8 !ersen han#a se i.it ter!engaruh an )ung.in a.an !ergi ter iagnosis engan -ai. .e ala) .ehi u!an e"asa$ Mere.a -era a ala) -aha#a/ na)un/ untu. !er arahan #ang -erle-ihan engan !rose ur !e)-e ahan -esar$ !e)-a"a Pere)!uan 9uga a!at -erisi.o

engan o!erasi$ L#oni2ation ari .ro)oso) * ti a. )urni aca. )enga.i-at.an ren ahn#a ting.at fa.tor 4III atau I*$ He)ofilia ?

an

a!at

He)ofilia ? !asien )e)ili.i s!e.tru) .linis !en#a.it #ang sa)a$ 1a.tor *II ting.at .urang ari ( !ersen #ang ter.ait engan !en arahan !arah/ se ang.an !en#a.it #ang le-ih )o erat terlihat !a a !asien engan ting.at ( sa)!ai > !ersen$ Pasien engan fa.tor I* ting.at antara > an @; !ersen u)u)n#a )e)ili.i !en#a.it #ang sangat ringan$ Situasi ini )encer)in.an .esa)aan geneti. ala) trans)isi$ He)ofilia ? a!at hasil ari se9u)lah )utasi geneti. ter)asu. !engha!usan/ )utasi titi./ an cacat !ergeseran fra)e )eli-at.an gen fa.tor I* !a a lengan !an9ang .ro)oso)$ 5e-an#a.an !asien )enun9u..an ti a. a an#a a.tivitas fa.tor I* .arena !rotein fungsional a-nor)alA .urang u)u) a a ti a. a an#a .e ua antigen fa.tor I* an a.tivitas$ Satu )utasi lang.a +1I* Lei en, )enghasil.an ga)-ar he)ofilia ? !a a ana.'ana. #ang )en#elesai.an i !u-ertas se-agai )ening.at.an !ro u.si fa.tor I*$ Manifestasi .linis !aling .has ari he)o!hilias a alah !er arahan .e ala) sen i -esar e.stre)itas atas an -a"ah$ 5on isi ini -iasan#a i)ulai setelah ana. ter.ena )enca!ai taha! -alita an .e)u ian )ening.at.an fre.uensi n se-agai ana. )en9a i le-ih a.tif$ Sering.ali/ satu atau ua sen i )en9a i target uta)a he)arthroses iulang$ Bengan "a.tu/ ths situasi a!at )enga.i-at.an sinovitis .ronis/ !erusa.an tulang ra"an an tulang/ an contracture leng.ungan !rogresif$ Pen arahan .e ala) otot +ilio!soas/ gastrocne)ius/ an otot fle.sor ari lengan, atau 9aringan luna. engan !e)-entu.an he)ato)a )en#e-ar.an -esar 9uga u)u)$ 5erusa.an otot )en#e-a-.an atrofi otot le-ih lan9ut an .ontra.tur$ )anifestasi !er arahan lainn#a ter)asu. he)aturia/ !er arahan intra.ranial/ !en arahan sela!ut len ir an -er arah -er.e!an9angan setelah trau)a .ecil atau !e)-e ahan$ Para !en erita he)ofilia ringan )ung.in ti a. ter ete.si sa)!ai o!erasi ila.u.an atau !asien )e)ili.i e.stra.si gigi$ ?iasan#a/ !rose ur terse-ut selesai tan!a -u.ti !er arahan #ang ti a. -iasa$ Na)un/ ala) -e-era!a 9a)/ so.et lu.a -e ah atau gigi )ulai cairan/ !en#e)-uhan lu.a terganggu an arus arah .e 9aringan se.itarn#a$ !e)-entu.an he)ato)a i aerah faring an retro!har#ngeal a!at )enganca) !atensi 9alan na!as an )e)-eri.an arurat )e is$ -er arah su-!eriosteal -esar atau otot !a a .ese)!atan a!at )engarah !a a !e)-entu.an !seu otu)or Ter)ofili.$ Ini a alah stru.tur .ista se!erti serosanguinous atau gela! )engan ung -ahan vis.os co.lat teri.at .e )e)-ran fi-rosa$ Seiring "a.tu/ !seu otu)ors )e)!erluas an )e)engaruhi stru.tur -er e.atan$ Mere.a #ang )uncul ari su-!eriosteal -er arah/ -iasan#a )eli-at.an !anggul atau fe)urs/ )engi.is tulang untu. )e)-entu. lesi .isti. -esar$