Hereditary coagulation disorders notes PDF

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Her edi t ar yCoagul at i ondi sor der s o Abnor malbl e e di ngmayr e s ul tf r om o De f ec t i v ec oagul at i on,whi c hi nc l udet hei nhe r i t edandacqui r e d c oagul at i ondi s or de r s o Pl at e l e tdi sor de r sduet ot hr omboc yt openi aori mpai r edpl at e l e t f unc t i on  Pl at e l e tf unc t i ondi sor der smayber e f e r r edt oasde f e ct s o Vasc ul arbl ee di ngdi sor der swhe r et he r ear ef r agi l ebl oodv e ss e l s o Her e di t ar yc oagul at i ondi sor der sar edefici e ncys t at e sc ause dbyl ac kofa s i ngl ec oagul at i onf ac t ort hr oughv er yr ar e l ymor et hanonef ac t ormaybe i nv ol v ed( suc hmut at i onsar er ar e) o Gene r al l yasi ngl ef ac t orde fic i enc yal l owsf ort hedi ffer e nt i at i onofa he r edi t ar ydi sor derandanacqui r e ddi s or derast hel at t e rusual l y( not al way s)i nv ol v esmor et hanonecoagul at i onf ac t or o Lac kofac t i vi t yofac oagul at i onf ac t ormaybeduet o o Quant i t at i v edef e c tduet odec r ease dorabse nts ynt he si sandr e l eas e ofaf ac t or o Qual i t at i v ede f e c tduet ot hepr oduc t i onandr e l eas eofanabnor mal c oagul at i onf ac t or o Hae mophi l i ai scat e gor i sedde pendi ngont hedefici e ncy o Hae mophi l i aAi sf ac t orVI I I : C( ci sf orcoagul ant )de fic i ency o Hae mophi l i aB i sf ac t orI X defici e ncy o Hae mophi l i aC i sf ac t orXIdefic i e ncy o VonWi l l e br andsdi s ease o Hae mophi l i as+vWD acc ountf or95% ofal lher e di t ar yc oagul at i on defic i e nci e s

Haemophi l i as Know ge nede f e ct ,i nher i t anc epat t er n,conse uence sofde f ec t ,l abor at or y i nv es t i g at i on,t r e at me ntandmanagement  Bot hhaemophi l i aAandhaemophi l i aB hav ei de nt i cali nher i t ancepat t e r ns ( Xl i nked)andhav esi mi l arc l i ni calf e at ur es  Genef orB i smuc hl ar ge rt hangenef orB  St andar dt r eat me nti sl y ophi l i s edFVI I Ic onc ent r at ef orhae mophi l i aA Exam question: Discss genetics, classification, clinical findings, treatment of haemophilia A/B  Hae mophi l i ai sar ar edi s eas ewi t hani nci de nceof1i n10, 000mal esf or Hae mophi l i aA o Ai s45t i mesmor ecommont hanHaemophi l i aB  Twodi s or der sar eus ual l ydi s t i ngui s hedby o Fami l yhi s t or y o Spec i ficc oagul at i onf ac t orass ay s  Hae mophi l i ai sc l ass i fie dasmi l d,mode r at eorse v er edependi ngupont he as saye dpl as mal e v e loft hec oagul at i onf ac t or o Le v e lofbl e edi ngi sass oc i at edwi t hquant i t yofc oagul at i onf ac t or ( s ev e r e=5%) o Ri s kofbr ai nhae mor r hagei nse v er ehaemophi l i ac s  Thel abor at or yc l ass i ficat i onl ar ge l ycor r e l at e swi t ht hec l i ni calbl e edi ng r i s ks,t husal l owi ngapr e di c t i ont obemadeaboutt hei ndi vi dualbl ee di ng r i s kandout come  Mor et han50% ofpat i ent shav emoder at eors ev er edi se ase 

Cl i ni calmani f es t at i ons  Thos ewi t hsever edi sease dev e l ops pont aneousj oi ntbl ee ds ( haemar t hr os i s)andmusc l ehaemot omas,i naddi t i ont obl e edi ngaf t ermi nor i nj ur i es ,acc i dent sandsur gi calpr oce dur es o 30% hav enof ami l yhi s t or y  Thos ewi t hmoder at edi seasedonott endt obl ee ds pont ane ousl ybut dev e l opbot hj oi ntbl ee dsandhae mat omasaf t ermi l dt r auma.Theyal so bl ee dext ensi v e l yaf t erur ge ncyordent ale xt r ac t i on  Thos ewi t hmi l ddi s easedonotbl eeds pont ane ousl y .The ydohowe v erbl ee d af t ers ur ge r y ,s i gni ficantt r aumaordent alext r ac t i on  Ani nf antwi t hhae mophi l i awi l lbr ui s eandbl ee dmor eeasi l yt hanheal t hy i ndi vi dual Haemophi l i aA-genet i cs  Thege nef orf ac t orVI I Ii sl ocat edont hel ongar m ofc hr omos omeX atq28  Genei sl ar geands pans186kbpwi t h26exons  Fac t orVI I Ipr e cur sorpr ot ei ni smai nl ys ynt hesi se di nt hel i v erhepat oc yt es wi t hMW of293kDa.Somei ssynt hes i se di ns pl e en  Fac t orVI I Ici r c ul at e sboundt ovWF( car r i erpr ot e i n)wi t har at i oof1f ac t or VI I It o50v WF  Mut at i onsar ei de nt i fiabl ei n90% ofcas esofhae mophi l i aA. o Commonmut at i onsc ont ai ne dononl i nedat abase  De f ec t sr e sul ti nabse nc eorl ow l ev e lFVI I I  Thr e et ypesofmut at i onsoc c urwi t ht hi sf ac t or o Gr os sge ner ear r angement s o I nse r t i onsorde l e t i onsofge ne t i cs eque nce o Si ngl ebas esubs t i t ut i ons  Al lt y pe sofmut at i oncanl eadt ose v er edi se as ebutt hemos tc l i ni cal l y i mpor t antge ne t i cabnor mal i t ywhi c hi sr e sponsi bl eappr oxi mat e l y40% of s ev e r ehaemophi l i aAcas e si sFVI I Ii nt r on22i nver s i on Haemophi l i aBgenet i cs  Fac t orI Xi savi t ami nK depende nts er i nepr ot e ase o Requi r e spos tt r ans l at i onalYcar boxyl at i onofi t sgl ut amylr es i due( Vi t K depe nde nt )  I ti sc odedbyage neats pec i ficr egi onq27ont hec hr omos omeX  Spans34kbofDNAcont ai ni ngonl y8exonsenc odi ng2. 8kbmRNAwhi c h t r ansl ati nt opr ot ei nof415ami noaci ds  Pr i mar i l ysynt hes i se di nt hel i v er  Maj or i t yofmut at i ons( 80%)ar epoi ntmut at i ons,r emai nderar e o Spl i c es i t e o Fr ameshi f t o Gr os sde l e t i ons  AKAChr i s t masdi se ase I nher i t anceofhaemophi l i as  Bot har eX l i nke dr e ce ss i v edi sor de r saffec t i ngmal esal mos texc l usi v e l y  Whe r ef emal ei scar r i ert her ei s50: 50c hanc eofwhe t hers onsar eaffec t edby hae mophi l i aordaught e ri scar r i er o Gene r al l yunaffec t e dbutmaybegi v enFVI I Iconce nt r at eaf t e rsur ge r y

 Offs pr i ngofhae mophi l i amal esandnor malf emal es :Al lsonsunaffec t e d,al l daught er sar ecar r i er s  I ns ome30% ofcase st her ei snoknownf ami l yhi s t or y-s pont aneous mut at i on Pr egnancycouns el l i ngandt est i ng  Al lf emal e swhoar eobl i gat eorpos s i bl ecar r i e r sshoul dbeoffer e dgene t i c c ouns e l l i ng  Maj or i t yofi ndi vi dual swi t hhaemophi l i aAorB now hav ei dent i fiabl e mut at i ons.I fmut at i onwi t hi nf ami l yi sknownpot ent i alcar r i er scanbe s cr e ene d-ge ne t i ct es t i ngwi t hDNApr obe s  Pr enat aldi agnos i scanbecar r i eroutbyc hor i oni cvi l l usat810wee ksorby amni oc e nt e si sat16wee ks .Foe t alDNAc annow bede t e c t edi nmat e r nal bl oodandbeus edi npr e nat aldi agnos i s  Fol l owi ngg ene t i ct es t i ngonas i ngl eembr y oni cc e l l–I VFcanenabl eembr y o s e l ec t i on How f emal escanbeaffect ed I . Ext r e mel yoni z at i on( 1of2Xc hr omos omesi si nac t i v at ed)oft heFVI I Ior FI Xi ncar r i er swi t hmos tofe xpr e ss i onf r om haemophi l i aX c hr omos ome I I . Hemi zy gosi t yoft heX c hr onome t erf orexampl eX0i nTur nersyndr ome I I I . Offs pr i ngofhaemophi l i acmal eandf emal ecar r i er I V. Nor mandyv ar i antofVonWi l l e br andsdi seas e( de f e c t i v ebi ndi ngofvWFt o FVI I I ) V. Acqui r edhaemophi l i aduet odev e l opmentofaut oant i bodi es Maki ngadi agnos i s o Fol l owi ngbi r t hofmal ei nf antt oaknowncar r i erofhae mophi l i a,f ol l owi ng t es t sar eper f or me d o Pr ot hr ombi nTi me( PT) -moni t or sext r i nsi cpat hwayFVI I IandFI Xnot i nt hi ss os houl dbenor mal o Ac t i vat e dPar t i alThr ombopl as t i nTi me( APTT) -moni t or si nt r i nsi c pat hway( nor mal =2236s )  I fFVI I Ii sl ow andnof ami l yhi s t or yl i ke l yt obeVon Wi l l e br andsdi seas eshoul dcar r youtvWFas saysf orac t i vi t y andant i ge n o Fi br i nogenl e v e l o FVI I IorFI Xass ay s( i ni t i almi xi ngorc or r ec t i ons t udi escanbe per f or med)–Par al l e lf ac t orass ays  Enabl esde t er mi nat i onofse v er i t yofdi se ase

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Adi agnos i sofhae mophi l i as houl dbesus pec t edi fac hi l dhasahi s t or yof e xce ss i v ebr ui si ngorbl e edi ngorpr es e nt swi t hswol l enpai nf ulj oi ntor musc l ehaemat oma Maj or i t yofc hi l dr e nwi t hmode r at eorse v er ehae mophi l i awi l lpr e se ntby45 y ear sofage . Shoul dt es tf ori nhi bi t or soff ac t or sal s o

Cl i ni calmani f es t at i ons 1.Joi ntbl ee ds -mos tc ommonsi t esf ors pont aneousbl ee di ng 2.Musc l ebl ee ds 3.I nt r acr ani albl e eds-mos tc ommoncauseofdeat hi nbl e edi nghaemophi l i ac s 4.Hae mat ur i a-s pont aneoushaemat ur i ai sc ommon 5.GIbl e eds 6.Nos ebl eeds 7.Gum bl ee ds( poordent alhygi ene) Dent alt r eat ment :Mi norde nt alwor ksuchassc al i ngandpol i s hi ngcanbe per f or medwi t houtf ac t orr epl ac ement .Ext r ac t i onmayr e qui r ef ac t orconce nt r at e s ordes mopr es si n( use df ormi l dormoder at e s)ort r ans geni caci d( pr e v ent sfibr i n bei ngbr okendown) Sur ger y:Maj orsur ge r ymus tbepr ec e de dbyquant i t at i onoff ac t orl ev e l st he ymus t bemor et han50% t oe nsur eade quat el ev e l sf ort hepr oc edur e .Thuspr ophyl ac t i c t r eat menti sr equi r edandadequat el ev e l smus tbesuppl i e dpos t oper at i v e l yt o e nsur epr operwoundheal i ng.Mi norsur ge r yal soe nt ai l smoni t or i ngandpos si bl e t r eat mentdependi ngonr i s kofbl ee di ng Tr eat mentandmanagement  Tr eat mentofhaemophi l i ashoul dal waysbec ar r i edoutatac ent r et hathas s pec i al i s tandexper t i sei nt hi sfie l d( CUH andSt .James ’ )  Fr es hf r oz enpl asmahasbee nut i l i se dsi nce1940’ s . o Canbeuse dt ot r e atal lc l ot t i ngf ac t ode fici enci es o I nf usi ngl ar gev ol umesofpl asmaasat her apeut i cf ort hede fic i enc y f ac t or  Cr y opr ec i pi t at epr oduc edbyf r e ez e t haw me t hodhashi ghl e v e l sofFVI I Iand fibr i nog enandi ss t i l lus ede s pe ci al l yi nunder de v e l ope dc ount r i esori n e mer g enci e si ndev e l opedar e as  Maj orpot e nt i alc ompl i cat i on:Tr ans f usi ont r ans mi t t e di nf ec t i on o Vi r ali nac t i vat i oni snow ar equi r eme ntf orpl asmader i v ed c once nt r at e s  Heatt r e at ment  Sol v entde t er g entt r eat me nt  Nanofil t r at i on  Chr omat ogr aphi cpur i ficat i on o Sc r ee nedf orHI V,He pB,HepC andHumanTc e l ll ymphot r ophi c vi r us o Nuc l ei caci dt es t i ngi sext r eme l ys ens i t i v ef orde t e c t i ngmi nut e quant i t i esofvi r use s o The r ei sas mal lwi ndow pe r i odwher esome onecanbee xpos e dand t hemar keri sunde t ec t abl e-donorwontbes cr e ene doutasr e sul t– vi r ali nac t i vat i ont ec hni que sshoul de l i mi nat et hi sr i s k.



Humanpl asmader i v edc onc ent r at e sar emadef r om pool e ddonat i ons . Thous andsofuni t sofpl asmaf r om donor sar euse dt opr oduces pec i fic c oagul at i onf ac t orc once nt r at ed o I nj ec t i onofFVI I Ii si nt r amusc ul arandmus tbedone3t i mesper wee k.

Recombinant clotting factors are produced by Inserting the relevant gene Into a cell line. Following cell culture, the clotting factor is secreted into and harvested from culture medium

Pr i mar ypr ophyl axi s  Shownt hatc onv er t i ngase v er ehaemophi l i act oonewi t hmoder at edi se ase byr e gul ari nf usi onsofc oagul at i onf ac t orc onc ent r at e sr educ est henumber ofs pont ane ousj oi ntbl ee ds ,r educ i ngr e sul t i ngj oi ntdamageandnow r e commendedf oral lc hi l dr enwi t hs ev e r edi s ease  I nI r e l andandUKpr ophyl axi st e ndst obei nt r oduc edaf t eroneort wo s pont aneousj oi ntbl eeds  I ni t i alpr ophyl axi si sgi v enbys t affatt het r eat mentce nt r e ,butwi t ht r ai ni ng par ent sandol derc hi l dr e ncanadmi ni s t erpr ophyl axi s . Compl i cat i onsofcoagul at i onf act orconcent r at est her apy I . Al l oant i bodyf or mat i oni . e .I nhi bi t ordev e l opment .Fac t orVI I I ant i bodi esar ef oundi n30% ofhaemophi l i acswhoar ege t t i ngr e gul ar i nf us i onswi t hFac t orVI I Iconc ent r at es I I . I nf ec t i ons:HI V,HepB andC,Par v ovi r usB19 I I I . v CJD I V. I mmuner egul at i on V. Thr ombos i s VI . Anaphyl axi s Ot hert r eat ment s i . Des mopr e ss i ni sav asopr es si nanal oguet hatcanr e l eas eFVI I IandvWF f r om t heendot he l i alce l l s .Canbeuse df ormi l dhaemophi l i a.( Nousei n s ev e r eduet ol ac kofs t or e s) i i . Tr anexami caci di sanant i fibr i nol yt i cage ntandi sus e f ulwhe r et her ei s muc os albl ee di ngands houl dbegi v e nr out i ne l yt ohaemophi l i ac shavi ng dent alext r ac t i on i i i . Genet her apy:bec ausei ti sonl ynec es sar yt omai nt ai nf ac t orl ev e l sgr eat e r t han1% t opr ev e ntmos tmor t al i t yandmor bi di t yass oc i at edwi t h hae mophi l i a,genet he r apyt r i al susi ngvi r alandnonvi r alv ec t or sar ei n pr ogr ess

I nhi bi t or s  Al l oant i bodi e sdev e l opi nupt o30% ofc hi l dr enwi t hsev e r ehaemophi l i awho r e ce i v et r eat me ntwi t hFVI I Ic onc ent r at e  Ant i bodi esar er ar ei nhae mophi l i aB ( l e sst han3%)  Ant i bodi esar emor el i ke l yt ode v e l op o Be f or et heageoffiv e o Whe r et he r ei saf ami l yhi s t or yofi nhi bi t orde v e l opment  Fac t orEi ghti nhi bi t or ybypassac t i vi t y( FEI BA)andFVI I a( akanov ose v en) ar epr oduc t sus edf orpat i ent swi t hant i bodi e s.Por ci nef act oral s ogi ve n. FVI I Iwi t hi mmunogl obul i nhasal sobee nadmi ni st e r ed Tr eat ment sont heway A.Rec ombi nantc l ot t i ngf ac t or swi t hnohumanorani malpr ot ei nsi nt he manuf ac t ur i ngpr ot e i ns B.Rec ombi nantf ac t or sf orr ar erdefic i enc i essuc hasFX andFXI C.Rec ombi nantf ac t or swi t hl onge rhal fl i v e s D.Rec ombi nantpor ci neFVI I If orus eofi nhi bi t orpat i e nt s E.Rec ombi nantvWFc once nt r at es F.Genet her apywhe r enor malFVI I IorFI Xge nei si nt r oduc edi npat i ent swi t h hae mophi l i a

Haemophi l i aC o o o o o

AKARos e nt hal ’ sdi se as ei sadi s or derofv ar i abl ec l i ni c alse v er i t yaffec t i ng bot hge nde r s Pr edomi nant l yoc c ur si nJe wsofAshke naz ides ce nt I nUSAi t st houghtt oaffec t1i n100, 000ofadul tpopul at i onmaki ngi t10% asc ommonashaemophi l i aA Cause dbydefic i enc yoff ac t orXIandi sdi st i ngui s hedf r om haemophi l i aA andB byt hef ac ti tdoe snotl eadt obl e edi ngi ntt hej oi nt s Fur t her mor ei thasaut os omali nher i t anc esi ncege nef orf ac t orXIi sl oc at ed onc hr omos ome4...