CASE REPORT

VON WILLEBRANDS DISEASE Presenters : Meriza Martineta Herwindo Ahmad Day / Date : Monday / 3rd October 2011 Su er!isor : dr" Se#!i $a%ianti& S "A

CHAPTER 1 INTRODUCTION 1.1 Background 'he disorder now reco(nized to be the most common inherited b#eedin( condition in humans& !on )i##ebrand*s disease +!)D,& was ori(ina##y described by -ri. !on )i##ebrand in 1/20" He described a se!ere mucocutaneous b#eedin( rob#em in a #ar(e %ami#y residin( in the A#and 1s#ands in the 2u#% o% 3othnia" 'he ro ositus was 45year5o#d (ir# who #ater b#ed to death durin( her %ourth menstrua# eriod" An in!esti(ation o% this disorder re!ea#ed a norma# coa(u#ation time& a norma# #ate#et count and a ro#on(ed b#eedin( time" Durin( the ne6t %our decades& it was be#ie!ed that this condition was most #i.e#y sue to either a !ascu#ar de%ect or to some %orm o% #ate#et dys%unction" 1t was not unti# the 1/00s that an abnorma#ity in !on )i##ebrand %actor +!)7, was im #icated in the atho(enesis o% the disorder& and e!en then the %ai#ure to di%%erentiate !)7 %rom %actor 8111 +78111, %urther com #icated studies unti# their e!entua# de%initi!e se aration throu(h (enetic c#onin( in the mid51/90s"1 -stimates o% the re!a#ence o% !)D ha!e !aried %rom about 1: o% the (enera# o u#ation to 124 c#inica##y re#e!ant cases er mi##ion o u#ation" $e!erthe#ess& e!en in the sur!eys in which the hi(her re!a#ence %i(ures ha!e been obtained& the a%%ected indi!idua#s ha!e been documented to ha!e some&

a#beit mi#d& c#inica# e!idence o% a hemostatic de%ect" 8)D ha!e been re orted in sub;ects %rom a## ethnic bac.(rounds& a#thou(h se!era# #oca#ized concentrations o% se!ere disease ha!e been documented in& %or e6am #e& 1srae#& Sweden and 1ran"1 8on )i##ebrand disease is the most common hereditary b#eedin( disorder& with biochemica# e!idence resent in 152: o% the o u#ation and biochemica# e!idence combined with a b#eedin( history o% 0"1: o% the o u#ation" 2 8)D is not as o%ten as hemo hi#ia A +78111 de%iciency, but maybe it is more %re<uent than hemo hi#ia 3 +71= de%iciency,"3 1n sur!eys er%ormed on !)D o u#ations& about 90: o% cases ha!e the mi#d ty e 1 %orm o% the disorder" 'he remainder ha!e !arious ty e 2 %orm o% the condition" 'he se!ere ty e 3 %orm o% the disease is rare& with a re!a#ence o% about 1 er mi##ion"1 As more is #earned about the under#yin( (enetic atho(enesis o% !)D& the inheritance attern o% the condition continues to be re!ised" Most cases o% ty es 1& 2A& 23 and 2M disease re resent autosoma# dominant conditions with ty e 1 disease e6hibitin( incom #ete henoty ic enetrance and !ariab#e e6 ressi!ity" 1n contrast& ty es 2$ and 3 !)D are recessi!e conditions with atients ha!in( been documented to be either homozy(ous or com ound heterozy(ous %or mutations within the !)7 (ene"1 1.2. O !"c#$%" 'his a er is com #eted in order to %u#%i## one o% the re<uirements in the Senior >#inica# Assistances ro(ram in De artment o% >hi#d Hea#th o% Ha;i Adam Ma#i. 2enera# Hos ita#/?ni!ersity o% Sumatera ?tara" 1n addition& this mana(ement" a er ro!ides readers with the .now#ed(e o% !on )i##ebrand*s disease and its

CHAPTER 2 LITERATURE REVIEW 2.1. Von W$&&" rand' D$'"a'" 8on )i##ebrand disease +!)D, is an autosoma##y inherited con(enita# b#eedin( disorder caused by a de%iciency +ty e 1,& dys%unction +ty e 2,& or com #ete absence +ty e 3, o% !on )i##ebrand %actor"2 8on )i##ebrand*s disease is a hi(h#y hetero(enous& usua##y mi#d& autosoma# dominant& inherited coa(u#ation disorder"@ 1nherited !)D is a hetero(enous disorder resu#tin( %rom a biochemica# reduction in the amount o% %unctionin( !)7" 'his disease a%%ects 1: to 2: o% indi!idua#s& ma.in( it the sin(#e most common inherited b#eedin( disorder"4 2.1.2. E)$d"*$o&og+ >#inica##y si(ni%icant !)D a%%ects a ro6imate#y 124 ersons er mi##ion o u#ation& with se!ere disease a%%ectin( a ro6imate#y 0"454 ersons er mi##ion o u#ation" Ae orts %rom screenin( unse#ected indi!idua#s indicate a hi(her re!a#ence o% !)D abnorma#ities& i"e& c#ose to 1: o% the o u#ation" 7or most a%%ected indi!idua#s& !)D is a mi#d mana(eab#e b#eedin( disorder in which c#inica##y se!ere hemorrha(e mani%ests on#y in the %ace o% trauma or in!asi!e rocedures" Howe!er& si(ni%icant !ariabi#ity o% sym tomato#o(y e6ists between %ami#y members" 1n indi!idua#s with ty es 11 and 111& b#eedin( e isodes may be se!ere and otentia##y #i%e threatenin(" 1ndi!idua#s with ty e 111 disease who ha!e corres ondin(#y #ow 78111 #e!e#s may de!e#o arthro athies& as is more common in atients with 78111 de%iciency& with com arab#e 78111 #e!e#s" Ma#es and %ema#es are a%%ected e<ua##y& howe!er& the henoty e may be more ronounced in %ema#es because o% menorrha(ia and the !isibi#ity o% easy bruisin(" $o racia# redi#ection e6ists %or !)D"0 $o in%#uence o% ethnicity on the re!a#ence o% !on )i##ebrand disease has been re orted" B

2.1.1. D"($n$#$on

2.1.,. E#$o&og+ 8on )i##ebrand disease +!)D, is an autosoma##y inherited con(enita# b#eedin( disorder caused by a de%iciency +ty e 1,& dys%unction +ty e 2,& or com #ete absence +ty e 3, o% !on )i##ebrand %actor" 8)7 has two %unctions: 1" 1t #ays an inte(ra# ro#e in mediatin( adherence o% #ate#ets at sites o% endothe#ia# dama(e& romotin( %ormation o% the #ate#et #u(" 2" 1t binds and trans orts 78111& rotectin( it %rom de(radation by #asma roteases"2 8)7 is a #ar(e mu#timeric (#yco rotein that is synthesized in me(a.aryocytes and endothe#ia# ce##s as re5 ro5!)7" Se<uentia# c#ea!a(e re#eases mature !)7& which under(oes mu#timerization and is stored in s eci%ic ce##u#ar stora(e (ranu#es such as the )eibe#5Pa#ade body in endothe#ia# ce##s and the C5(ranu#e in #ate#ets" 1t is resent in norma# amounts in #asma& and #e!e#s can be si(ni%icant#y increased by administerin( dru(s such as desmo ressin +DDA8P, that induce the re#ease o% !)7 %rom stora(e sites into #asma" De%iciency o% !)7 resu#ts in mucocutaneous b#eedin( and ro#on(ed oozin( %o##owin( trauma or sur(ery"2 2.1.-. C&a''$($ca#$on 'he 8)D Subcommittee o% the Scienti%ic and Standardization >ommittee o% the 1nternationa# Society o% 'hrombosis and Haemostastis three ma;or cate(ories"1 'y e 1 disease com rises about 90: o% cases and resents with a artia#& mi#d5to5moderate <uantitati!e reduction o% !)7 #e!e#s" 'he !)7 in ty e 1 disease is <ua#itati!e#y norma#" 'y e 3 disease& the other <uantitati!e de%ect& occurs with a %re<uency o% about 1 er mi##ion and re resents a !irtua# absence o% !)7" 'he !arious ty e 2 %orms o% the disease in!o#!e the synthesis o% <ua#itati!e#y mutant %orms o% the rotein that mani%est abnorma#ities in ro osed the current#y acce ted c#assi%ication o% !)D in 1//@ +See 'ab#e 2"1," 'his in!o#!es

mu#timerization&

#ate#et and 78111 bindin(" 'y e 2 %orms o% !)D

account %or about 20: o% dia(nosed cases"1

Ta &" 2.1 >#assi%ication o% !on )i##ebrand disease +!)D, subty es based on the 1//@ recommendations o% the 8)D Subcommittee o% the Scienti%ic and Standardization >ommittee o% the 1nternationa# Society on 'hrombosis and Haemostatis"
'y e o% !)D 'y e 1 +D90:, 'y e 2 +D20:, 'y e 2A 'y e 23 'y e 2M 'y e 2$ 'y e 3 + re!a#ence D1 mi##ion, er De%inition and Pre!a#ence Partia# <uantitati!e de%iciency o% norma# !on )i##ebrand %actor +!)7, Eua#itati!e de%ects o% !)7 Eua#itati!e !ariants with decreased #ate#et5de endent %unction associated with the absence o% hi(h5mo#ecu#ar5 wei(ht mu#timers Eua#itati!e !ariants with increased bindin( a%%inity %or #ate#et (#yco rotein 1b Eua#itati!e !ariants with decreased #ate#et5de endent %unction associated with norma# !)7 mu#timers attern Eua#itati!e !ariants with reduced bindin( o% 78111 >om #ete absence o% !)7

8on )i##ebrand*s disease is di!ided into three subty es& with ty es 1 and 3 ha!in( <uantitati!e de%ects in the !)7 #e!e#s& and ty e 2 ha!in( <uantitati!e de%ects in !)7 structure and %unction" Detai#s o% the !arious ty e o% !on )i##ebrand*s disease are summarized in 'ab#e 2"2" 3#eedin( sym toms are usua##y mi#d in ty e 1 and increase in se!erity in ty e 2 and 3" 'y e 3 (i!es se!ere b#eedin( sym toms that are simi#ar to hemo hi#ia& inc#udin( s ontaneous b#eedin( and hemarthrosis"@

Ta &" 2.2 >#assi%ication o% !on )i##ebrand*s Disease

1nheritance 3#eedin( time !)7: A(n !)7: A>o 78111: > A1PA at #ow concentrati ons o% ristocetin !)7 mu#timer ana#ysis !)7: A>o/ !)7: A(n 78111: >/ !)7: A(n 'hera y 'y e 1 Autosoma# dominant $orma# or ro#on(ed Aeduced Aeduced $orma# or s#i(ht#y reduced Absent 'y e 2A Autosoma# dominant ?sua##y ro#on(ed Aeduced Aeduced $orma# or s#i(ht#y reduced Absent 'y e 23 Autosoma# dominant ?sua##y ro#on(ed Aeduced Aeduced $orma# or s#i(ht#y reduced 1ncreased 'y e 2M Autosoma# dominant $orma# or ro#on(ed $orma# or reduced Aeduced $orma# or s#i(ht#y reduced Absent 'y e 2$ Autosoma# dominant or recessi!e $orma# $orma# $orma# Aeduced Absent 'y e 3 Autosoma# recessi!e Pro#on(ed Mar.ed#y reduced Mar.ed#y reduced Mar.ed#y reduced Absent

$orma#

0"B51"2 G1 ?sua##y res onsi!e to DDA8P

Absence o% #ar(e and intermediat e M) mu#timers F0"B G1 8ariab#e res onse to DDA8P& 78111/!)7 %actor concentrat e i% non5 res onsi!e

Absence o% #ar(e M) mu#timers F0"B G1 DDA8P associated with thrombocyt o5 enia& use 78111/!)7 %actor concentrate

$orma#

$orma#

?sua##y !ery #ow #e!e#s o% mu#timers $A $A $o res onse to DDA8P& use 78111/ !)7 %actor concentrate

F0"B G1 8ariab#e res onse to DDA8P& 78111/!)7 %actor concentrate i% non5 res onsi!e

0"B51"2 F1 DDA8P (i!es 78111 re#ease with short sur!i!a#& may need 78111/!)7 concentrate

78111: > H 7actor 8111 acti!ityI !)7: A>o H !on )i##ebrand %actor ristocetin co%actor acti!ityI !)7: A(n H !on )i##ebrand %actor anti(enI A1PA H ristocetin5induced #ate#et a((#utinationI 78111 H 7actor 8111"

2.1... Pa#/o)/+'$o&og+ 8on )i##ebrand disease is due to an abnorma#ity& either <uantitati!e or <ua#itati!e& o% the !on )i##ebrand %actor& which is a #ar(e mu#timeric (#yco rotein that %unctions as the carrier rotein %or %actor 8111 +78111," !on )i##ebrand %actor is a#so re<uired %or norma# #ate#et adhesion" As such& !on )i##ebrand %actor %unctions in both rimary +in!o#!in( #ate#et adhesion, and secondary +in!o#!in( 78111, hemostasis" 1n rimary hemostasis& !on )i##ebrand %actor attaches to #ate#ets by its s eci%ic rece tor to (#yco rotein 1b on the #ate#et sur%ace and acts as an adhesi!e brid(e between the #ate#ets and dama(ed subendothe#ium at the

site o% !ascu#ar in;ury" 1n secondary hemostasis& !on )i##ebrand %actor rotects 78111 %rom de(radation and de#i!ers it to the site o% in;ury"B 8on )i##ebrand %actor is com osed o% dimeric subunits that are #in.ed by disu#%ide bonds to %orm com #e6 mu#timers o% #ow& intermediate& and hi(h mo#ecu#ar wei(hts" 'he sma## mu#timers %unction main#y as carriers %or 78111"B Hi(hJmo#ecu#ar wei(ht mu#timers ha!e hi(her numbers o% #ate#et5 bindin( sites and (reater adhesi!e ro erties" -ach mu#timeric subunit has bindin( sites %or the rece tor (#yco rotein 1b on nonacti!ated #ate#ets and the rece tor (#yco rotein 11b/111a on acti!ated #ate#ets" 'his %aci#itates both #ate#et adhesion and #ate#et a((re(ation& ma.in( hi(h mo#ecu#ar wei(ht mu#timers most im ortant %or norma# #ate#et %unction"B

7i(ure 2"1 Structure and domains o% !on )i##ebrand %actor" B 'he disco!ery o% a de#etion o% !)7 +c"2215/BBK432 L B04/de# M "As B4K2#y1B9de#N, in B o% 12 white ty e 3 !)D atients %rom 0 unre#ated %ami#ies and its absence in / Asian atients #ed Suther#and et a# to de!e#o a (enomic D$A5based assay %or the de#etion o% !)7 e6ons @ and 4" 'his de#etion was a#so %ound in 12 o% 3@ ty e 1 !)D %ami#ies and associated with a s eci%ic !)7 ha #oty e& which the in!esti(ators noted may indicate a ossib#e %ounder ori(in" Additiona# studies demonstrated the resence o% the mutation in other ty e 1 !)D atients and a %ami#y that e6 ressed both ty e 1 and ty e 3 !)D"0

Suther#and et a# re ort the c"2215/BBK432 L B04/de# mutation as a no!e# cause o% both ty e 1 and ty e 3 !)D and su((est that screenin( %or this mutation in other ty e 1 and ty e 3 !)D atient o u#ations may c#ari%y its contribution to !)D that arises %rom <uantitati!e !)7 de%iciencies"0 2.1.0. C&$n$ca& 1an$("'#a#$on Mucocutaneous b#eedin( is the ha##mar. o% !)D& with atient showin( sym toms that inc#ude easy bruisin(& e ista6is& menorrha(ia& b#eedin( a%ter denta# e6traction or ear& nose& throat ostsur(ica# b#eedin(& rocedures& b#eedin( %rom minor wounds& ost artum b#eedin(& (astrointestina# b#eedin(& and rare attern o% inheritance& both ma#es and

;oint hemarthrosis or centra# ner!ous system b#eedin("@ )ith an autosoma# dominant %ema#es with !)D& can ha!e b#eedin( sym toms" 8on )i##ebrand disease has !ariab#e enetration& o% the (ene& so that the o%%s rin( o% a erson with !)D can inherit the (ene without ha!in( abnorma# !)7 #e!e#s and without ha!in( b#eedin( sym toms" 'his erson can then ass on to their o%%s rin(& who cou#d ha!e b#eedin( sym toms" @ 2.1.2. D$agno'#$c In%"'#$ga#$on' and D$agno'$' 1n order to ma.e the dia(nosis o% !on )i##ebrand*s disease& there needs to be a combination o% mucocutaneous b#eedin( sym toms in the atient and abnorma# !)7 #aboratory tests combined with a %ami#y history o% b#eedin(" 4 'he %o##owin( #aboratory tests are necessary to estab#ish the dia(nosis o% !)D such as #ate#et count& b#eedin( time& 78111& !)D:A(n& !)D:A>o and 2P1b" Oaboratory e6aminations are easy to estab#ish i% it is %ound the norma# #ate#et counts& b#eedin( time more than 10 minutes& and 78111& !)D:A(n& !)D:A>o or 2P1b #e!e# are under @0 u/d#" Howe!er& it wi## become di%%icu#t i% the resu#t are norma# +the mi#d ty e %or e6am #es, so that we need more s eci%ic test such as mu#timer o% !)D ana#ysis"9

Screenin( tests %or !)D inc#ude the %o##owin(: 1" >3> count" Assess #ate#et number and mor ho#o(y& which shou#d be norma# in most atient with !)D& e6ce t those with ty e 23 !)D" 4 'he com #ete b#ood count may show e!idence o% iron5de%iciency anemia due to chronic b#ood #oss& and ty e 23 !)D is o%ten associated with a mi#d thrombocyto enia"1 2" P' and aP'' are a#so measured as art o% the wor.u " 'he aP'' is mi#d#y ro#on(ed in a ro6imate#y 40: o% atient with !)D" 'he ro#on(ation is secondary to #ow #e!e#s o% 78111 because one o% the norma# %unctions o% !)7 is to rotect 78111 %rom de(radation" 'he P' shou#d be within re%erence ran(es" Pro#on(ations o% both the P' and the aP'' si(na# a rob#em with ac<uisition o% a ro er s ecimen or a disorder other than or in addition to !)D"0 3" 3#eedin( time may be ro#on(ed" Howe!er& it is im ortant to note that many atient with ro!en !)D ha!e a norma# aP'' and b#eedin( time and that the resu#ts o% these screenin( studies must be inter reted in the conte6t o% the atient*s c#inica# history" A#thou(h some hemato#o(ist no #on(er use the b#eedin( time in their dia(nostic wor#5u o% otentia# !)D& its use is sti## ;usti%ied to e!a#uate the resence o% one o% the di%%erentia# dia(noses %or !)D& #ate#et dys%unction"1 S eci%ic assays inc#ude the %o##owin(: 'he #aboratory testin( common#y in!o#!es seria# determinations o% #asma %actor 8111 +78111:>, #e!e#& !)7 anti(en +!)7:A(n, #e!e#& and ristocetin co%actor acti!ity +!)7:A>o," 'he !)7:A>o is a measurement o% the abi#ity to a((#utinate #ate#ets in the resence o% !)7 and ristocetin" 'he !)7:A>o is used as a measurement o% !)7 acti!ity" 1% the 78111:> acti!ity& the !)7:A(n& and the !)7:A>o are a## #ow to unmeasureab#e& the the atient has ty e 3 !on wi##ebrandIs disease" 1% the !)7:A>o to !)7:A(n ratio is ro ortiona#& 0&B to 1&2& then the atient has a norma# !)7 structure& and has either ty e 1 or ty e 2$ !)D" 1% the !)7:A>o to !)7:A(n ratio is discordant& #ess than 0&B& then there is

an abnorma# !)7 structure& and the atient has ty e 2A& ty e 23& or ty e 2M !)D"@ 'o se arate ty e 1 %rom ty e 2$ !)D& the ratio o% 78111:> to !)7:A(n is used" 1% the ratio is (reater than or e<ua# to one& then it is concordant& and the atient has ty e 1 !)D" 1% the ratio is #ess than one& then sus ect ty e 2$ !)D& and a %actor 8111 bindin( assay is used to con%irm the dia(nosis" 'his measures the a%%inity o% !)7 %or %actor 8111& and wi## distin(uish ty e 2$ !)D %rom mi#d hemo hi#ia A" 'he P7A5100 #ate#et %unction ana#yzer is sensiti!e to a## ty es o% !on )i##ebrand*s disease e6ce t ty e 2$& where it (i!es norma# resu#t"@ 'o se arate ty e 2A& ty e 23& ty e 2M !)D& !on )i##ebrand mu#timer ana#ysis and ristocetin5induced #ate#et a((#utination +A1PA, at #ow concentrations o% ristocetin are used" 'he !on )i##ebrand*s mu#timer assay is an a(arose (e# e#ectro horesis that se arates #ow& intermediate& and hi(h mo#ecu#ar wei(ht mu#timers o% !)7" 'he A1PA test is used to se arate ty e 23 !)D %rom the other ty e 2 subty es" Most !on )i##ebrand*s disease subty es show a !ery #ow res onse in this assay when #ow concentration o% ristocetin are used" 1n ty e 23 !)D& there is a hy erres onsi!eness to ristocetin& and the assay shows an e#e!ated #e!e# o% a((#utination at #ow ristocetin concentration"@ 2.1.3. D$(("r"n#$a& D$agno'$' 'he di%%erentia# dia(nosis o% !on )i##ebrand*s disease is hemo hi#ia" Di%%erences between !)D and hemo hi#ia are dis #ayed in tab#e 2"3"2

10

Ta &". 2.,. Di%%erences between !)D and hemo hi#ia A"

sym toms Se6ua# distribution 7re<uency Abnorma# rotein Mo#ecu#ar wei(ht 7unctions Site o% synthesis >hromosomes 1nhibitor %re<uency Oaboratory tests History aP'' 7actor 8111 !)7:A(n !)7:A>o !)7 mu#timers 8on )i##ebrand*s disease Hemo hi#ia A 3ruisin( and e ista6is Point b#eedin( menorrha(ia or mucosa# b#eedin( Ma#es H %ema#es 1:200 to 1:400 !)7 0&0520 6 100 Da P#ate#et adhesions -ndothe#ia# me(a.aryocytes >hromosome 12 Aare Abnorma# $orma# or ro#on(ed 3order#ine or decreased Decrease or absent Decrease or absent $orma# or abnorma# = chromosomes 1@524: o% atients Abnorma# Pro#on(ed Decrease or absent $orma# or increased $orma# or increased $orma# ce## Musc#e b#eedin( Ma#es 1:0000 ma#es 7actor 8111 290 .Da >#ottin( co%actor or QQ

2.1.4. Pr"%"n#$on Ad!ise atients to a!oid medications with .nown anti #ate#et e%%ects" A#thou(h as irin is rare#y ta.en by chi#dren& o!er5the5counter com ounds containin( acety#sa#icy#ic acid o%ten are used by ado#escents" 1bu ro%en and other nonsteroida# anti5in%#ammatory dru(s +$SA1Ds, are re!ersib#e cyc#oo6y(enase inhibitors and may cause intestina# b#eedin(" 'he ris.s o% these and other medicines with anti #ate#et e%%ects shou#d be considered in #i(ht o% the se!erity o% the !on )i##ebrand disease""

Patients shou#d be instructed about their coa(u#ation disorder and shou#d

be aware o% the conditions in which they wi## re<uire ro hy#actic thera y" Mi#d acti!ity restrictions may be necessary"B

2.1.15. T/"ra)+ 11

'reatment o% atient with !on )i##ebrand*s disease has to address two ob;ecti!es in order to contro# b#eedin(: the abnorma# #ate#et adhesion and the #ow %actor 8111 #e!e#s& there are two treatments o% choice& Desmo ressin +DDA8P, and or trans%usion with a !)7/%actor 8111 concentrate" Anti%ibrino#ytic thera y is an im ortant to ad;unct to either o% these thera ies %or b#eedin( that in!o#!es mucous membranes" -stro(ens raise #asma !)7 #e!e#s& but in un redictab#e amounts" Ora# contrace ti!es may be use%u# in reducin( the se!erity o% menorrha(ia in women with !on )i##ebrand*s disease"@ Desmo ressin +DDA8P, Desmo ressin +15deamino595d5ar(inine !aso ressin& DDA8P, is a synthetic ana#o( o% the antidiuretic hormone !aso ressin" 1ts in%usion increase #asma !)7 and 78111 #e!e#s by two5to ei(ht5%o#d within 1 hour o% administration" 'his e%%ect is resumed to be due to the re#ease o% !)7 %rom endothe#ia# ce## stores +)eibe#5Pa#ade bodies, with secondary stabi#ization o% additiona# 78111"1 Desmo ressin can be administrated by the intra!enous& subcutaneous or intranasa# route" Pea. res onses wi## be achie!ed within 30 and /0 min with the intra!enous and intranasa# routes& res ecti!e#y" 'he usua# arentera# dose is 0&3 R(/.( +to a ma6imum o% 20 R(,& in%used intra!enous#y in 10540 mO o% norma# sa#ine o!er about 20 min" the dose o% the hi(h#y concentrated intranasa# re aration is 140 R( %or chi#dren under 40 .( and 300 R( %or #ar(er chi#dren"1 Desmo ressin is a sa%e and (enera##y !ery e%%ecti!e hemostatic a(ent" 1ts on#y common side5e%%ects are %acia# %#ushin(& mi#d headache and minima# chan(es to b#ood ressure and heart rate" A## these e%%ects can be minimized by increasin( the duration o% the in%usion and administerin( the dru( with the atient #yin( down" 'he most serious side5e%%ects that can de!e#o are se!ere hy onatremia and seizures" >hi#dren under 2 years o% a(es are es ecia##y rone to this com #ication& and their %#uid inta.e shou#d be reduced to maintenance #e!e# %or the 2@ hours %o##owin( desmo ressin administration" 1n addition& with re eated doses o% the dru(& seria# monitorin( o% the serum sodium shou#d be underta.en"1

12

'he other #imitation to this a(ent is the de!e#o ment o% tachy hy#a6is with re eated administration" )hen (i!en at re eated inter!a#s o% 2@ hours or shorter& the ma(nitude o% !)7 and 78111 increments achie!ed o%ten %a##s to a ro6imate#y B0: o% that documented with the initia# dose" 'his is resumab#y re#ated to a artia# Se6haustionT o% the endothe#ia# ce## stores" 'he reduced !)7 increments obtained with re eated desmo ressin in%usion are on#y a re#ati!e #imitation to its use %or se!era# consecuti!e days and it wi## o%ten sti## be e%%ecti!e in this c#inica# settin("1 'he #asma !)7 and 78111 res onse shou#d be e!a#uated in e!ery atient with a thera eutic tria# o% the a(ent& re%erab#y rior to the %irst treatment" 'his is necessary as not a## atients& articu#ar#y those with se!ere ty e 1 or ty e 2 !)D& res ond ade<uate#y to this thera y" 'his thera eutic tria# shou#d a#so inc#ude testin( %or !)7 and 78111 #e!e#s at @ hours ost administration as some !)7 mutants may show a si(ni%icant#y reduced #asma ha#%5#i%e"1 Most atients with mi#d/moderate ty e 1 !)D shou#d res ond satis%actori#y to desmo ressin in%usion& and %or this common %orm o% the disease the concominant use o% desmo ressin and anti%ibrino#ytic thera y shou#d be su%%icient %or most c#inica# situation" 1n contrast& desmo ressin has on#y been re orted !ery rare#y to be e%%ecti!e in ty e 3 atients and shou#d not be consideredthe treatment o% choice %or this o u#ation" 'he thera eutic e%%ect o% desmo ressin in the ty e 2 !ariant %orms o% !)D is !ariab#e" Some ty e 2A atients are !ery ade<uate#y treated and this atient (rou wi## be e!ident %rom a thera eutic tria# in%usion"1 Desmo ressin is contraindicated in ty e 23 !)D atient because o% ossib#e worsenin( o% thrombocyto enia with increased #e!e#s o% the atient*s abnorma# !)7" 'y e 2$ atients ha!e a (ood initia# increase in 78111 #e!e#s with desmo ressin& but the increased #e!e#s are short5#i!ed because o% the #ac. o% stabi#ization o% the 78111 mo#ecu#e by !)7" @ 3#ood com onent thera y 'reatment o% !)D with b#ood com onent trans%usion is re<uired %or ma;or denta# and sur(ica# rocedures& %o##owin( trauma and to treat #i%e5threatenin( b#eedin(" >ryo reci itate& the standart com onent used %or !)D thera y durin(

13

the 1/B0s and 1/90s& is no #on(er the materia# o% choice" $o e%%ecti!e !ira# attenuation rocess has yet been de!ised %or cryo reci itate and thus the ris. o% !ira# transmission has re#e(ated this b#ood com onent to a rare a#ternati!e thera y in this condition"1 'he b#ood com onent current#y used are #asma5deri!ed& intermediate5 urity 78111 concentrates +i"e& Humate5P and A# hanate, that ha!e under(one a !ariety o% !ira# inacti!ation ste s to re!ent !ira# in%ection" 'he #atest hi(h5 urity and u#tra5hi(h5 uruty 78111 concentrates& such as the monoc#ona##y uri%ied concentrates and recombinant 78111& ha!e a !ery #ow !)7 content and are not use%u# in this conte6t" 1nterestin(#y& a#thou(h this intermediate5 urity 78111 concentrates are %re<uent#y used with (ood e%%ect in !)D& their re(u#atory a ro!a# %or this ur ose is hi(h#y !ariab#e"1 Most dosin( recommendations %or the treatment o% !)D eith b#ood com onent in%usions are based on 78111 unit increments +intermediate5 urity 78111 concentrates are now o%ten #abe#ed with both 78111:> and !)7:A>o otencies," 'he dose o% intermediate5 urity concentrate re<uired to e#e!ate #asma 78111 to the re<uired #e!e# is ca#cu#ated in the same way as recommended %or hemo hi#ia A"1 the dosin( o% Humate5P& the re aration used most common#y in 'he >hi#dren*s Hos ita# o% Phi#ade# hia& Pennsy#!ania& is based on the !)7:A>o unit +1? !)7:A>o," 1n (enera#& a dose o% @0 to 90 1? !)7:Aco/.( shou#d be (i!en e!ery 12 hours" 'he duration o% thera y is dictated by the c#inica# situation& but in most cases& atient shou#d be treated %or 2@ to @9 hours %o##owin( trauma or sur(ica# rocedures"3 Ae eat in%usions o% these concentrates in !)D atients can resu#t in su ra hysio#o(ic 78111 #e!e#s and there has been a su((estion that these hi(h 78111 #e!e#s may contribute to a ris. %or !enous thrombosis"1 Ad;uncti!e thera ies 1n addition to treatments that s eci%ica##y address the !)7 de%icit& there are se!era# ad;uncti!e thera ies that are e%%ecti!e at reducin( b#ood #oss in these atients" 'he anti%ibrino#ytic a(ents& trane6amic acid and aminoca roic acid& ha!e been used as hi(h#y e%%icacious a(ents either a#one or as com #ements to

1@

desmo ressin and b#ood com onent thera y in both ro hy#actic and thera eutic situations" 'hey shou#d be administered 2 hours rior to an antici ated& hemostatic cha##en(e and continued %or B510 days a%ter the cha##en(e" 'he thera eutic ora# doses are 24 m(/.( e!ery 059 hours %or trane6amic acid and 1005200 m(/.( e!ery 0 hours %or aminoca roic acid" 3oth a(ents are a#so a!ai#ab#e as intra!enous re arations and trane6amic acid has a#so been demonstrated to be e%%ecti!e as amouthwash" 3oth dru(s are usua##y we## to#erated& aside %rom occasiona# mi#d (astrointestina# u set" -stro(en thera y has a#so been shown to be an e%%ecti!e measure in reducin( menstrua# b#eedin( and the %re<uency and ma(nitude o% noseb#eeds" 1 P#ate#et trans%usions may be he# %u# in some atients with !)D whose disease is re%ractory to other thera ies" >ryo reci itate and %resh %rozen #asma contain %unctiona# !)7 but shou#d be a!oided whene!er ossib#e because o% the otentia# transmission o% !ira# disease" An additiona# drawbac. o% %resh %rozen #asma is the #ar(e in%usion !o#ume re<uired"0 Ta &". 2.-. Aecommended 'reatment in !on )i##ebrand Disease 2
'y e 1 'y e 2A 'y e 23 'y e 2$ 'y e 2M 'y e 3 P#ate#et5 y e seudo5 !)D P#ate#et trans%usi on

Se!ere hemorrha( esI Ma;or sur(ica# rocedures Mi#d hemorrha( esI Minor sur(ica# rocedures

DDA 8P

78111:!) 7 concentrat es

78111:!) 7 concentrat es

78111:!) 7 concentrat es

78111:!) 7 concentrat e

78111:!) 7 concentrat es

78111:!) 78111:!) 78111:!) 78111:!) 78111:!) 7 7 7 7 7 concentrat concentrat concentrat concentrat concentrat es +may es es +may es +may es res ond res ond res ond to to to DDA8P, DDA8P, DDA8P, Ora# DDA 78111:!) 78111:!) 78111:!) 78111:!) 78111:!) sur(ica# 8P 7 7 7 7 7 rocedures and concentrat concentrat concentrat concentrat concentrat -A>A es and es and es and es and es and -A>A -A>A -A>A -A>A -A>A Abbre!ations: DDA8P& desmo ressinI -A>A& amicarI %actor 8111: !)7 concentrates

DDA 8P

P#ate#et trans%usi on

P#ate#et trans%usi on and -A>A

14

Ta &". 2... 2uide#ines %or !)7/7actor 8111 >oncentrate Dosin( in !on )i##ebrand*s Disease 3 'y e o% b#eedin( Dose +78111 $umber o% Duration o% units, 1n%usions thera ies Ma;or sur(ery @0540 ?nits/.( -!ery 2@ to @9 Maintain 78111 hours G40: %or at #east B days Minor sur(ery 205@0 ?nits/.( -!ery 2@ to @9 Maintain 78111 hours G30: %or at #east 45 B days Denta# e6traction 205@0 ?nits/.( Sin(#e Maintain 78111 G30: %or u to 0 hours& use anti%ibrino#ytic S ontaneous or 205@0 ?nits/.( Sin(#e ?sua##y one dose is osttraumatic su%%icient& but may b#eedin( re eat as necessary ti## b#eed reso#!es 1.1.11. Progno'$' 'he indi!idua#s with !on )i##ebrand disease ha!e a #i%e#on( tendency toward easy bruisin(& %re<uent e ista6is& and menorrha(ia" B Patients with ty e 1 and 11 disease rare#y ha!e se!ere b#eeds and (enera##y ha!e norma# #i%e e6 ectancy and <ua#ity o% #i%e" 'y e 111 disease*s ro(nosis is simi#ar to that o% hemo hi#ia A" O!era## se!erity (enera##y im ro!es with a(e"/ 1.1.12. Ac6u$r"d %on W$&&" rand' D$'"a'" Aare#y& !on )i##ebrand*s disease may be ac<uired at an o#der a(e" 'his %orm may be caused by an antibody that inacti!ates the !on )i##ebrand %actor +monoc#ona# (ammo athy& mu#ti #e mye#oma,& or there may be an increased e6 ression o% the !)7 rece tors on a tumor& autoimmune disease& in a thrombositosis& or in essensia# thrombocythermia that binds (reater amounts o% circu#atin( !)7"10 Desmo ressin in%usion is the initia# treatment o% choice %or achie!in( hemostasisI #asma deri!ed 78111/!)7 concentrates are the second choice" 1n either case c#earance o% the !on )i##ebrand %actor wi## be acce#erated and #e!e#s must be monitored" 1812& #asma haresis& and/or immunosu dru(s may be use%u# %or e#iminatin( antibody" 2 ressi!e

10

CHAPTER , 1EDICAL REPORT ,.1. O !"c#$%" 'his a er is written to re ort a case o% a 12 years and 10 months and 1@ days o#d (ir#& who was admitted to the Pediatric $on 1n%ection ?nit o% Ha;i Adam Ma#i. 2enera# Hos ita#& with the wor.in( dia(nosis o% !on )i##ebrand*s Disease" ,.2. Ca'" M& a 12 years and 10 months and 1@ days o#d (ir#& with body wei(ht o% 33 .(& and body hei(ht o% 1@2 cm& was admitted to the Pediatric $on 1n%ection ?nit o% Ha;i Adam Ma#i. 2enera# Hos ita# on Bth Se tember 2011 at 19"00 with chie% com #ain o% b#eedin( (um which started since 4 days a(o" - ista6is was not %ound" Pa#e was %ound since 4 days a(o" 7e!er was not %ound& cou(h was not %ound& sneeze and co#d was not %ound" De%ecation was %ound norma##y& urination was %ound norma##y" History o% re!ious i##ness : 'he atient was a re eated atient o% Pediatric Hemato5Onco#o(y ?nit since 2000 and has been dia(nosed with !on )i##ebrand*s Disease and a#so has been (i!en 77P routine#y" History o% dru( usa(e: PA> and 77P trans%ussion 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:& '3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L -ar/$ose Mouth $ec. 'hora6 : : : in norma# ran(e : b#eedin( (um +L,

Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5,

1B

HA H1006/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er : not a# ab#e. S #een : schu%%ner 1 -6tremities : Pu#se: 100 6/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" : !on )i##ebrand*s Disease :5

)or.in( Dia(nosis Di%%erentia# Dia(nosis 'reatment :

187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein

1n!esti(ation : 5 5 >om #ete 3#ood >ounts >ross match

19

>om #ete 3#ood >ounts ana#ysis done in -mer(ency ?nit

T"'# R"'u&# Co*)&"#" B&ood Coun#' H 7gr89 2"40 0 , RBC 715 :** 9 1"@2 WBC 715,:**,9 2"91 H"*a#ocr$# 789 /"1/ , , PLT 715 :** 9 13B 1CV 7(&9 0@"/ 1CH 7)g9 19"10 1CHC 7gr89 2B"/ RDW 789 1/"0 D$(("r"n#$a& T"&&$ng N"u#ro)/$& 789 40"10 L+*)/oc+#" 789 30"00 1onoc+#" 789 10"40 Eo'$no)/$& 789 B"@0 Ba'o)/$& 789 1"3@0 , A 'o&u#" n"u#ro)/$& 715 :;&9 1"@1 A 'o&u#" &+*)/oc+#" 715,:;&9 0"900 A 'o&u#" *onoc+#" 715,:;&9 0"2/B , A 'o&u#" "o'$no)/$& 715 :;&9 0"210 A 'o&u#" a'o)/$& 715,:;&9 0"039 1or)/o&og+ Er+#roc+#" < an$'oc+#o'$' /$)oc/ro*$c *$croc+#" L"ucoc+#" < =$#/$n nor*a& rang" T/ro* oc+#" < =$#/$n nor*a& rang" Nor*a& Va&u" 12"051@"@ @"B45@"90 @"4511 305@2 1405@40 B459B 24531 33530 11"051@"9 33590 205@0 259 150 051 2"350"4 1"453"B 0"250"@ 050"10 050"1

P#annin(: Ae<uired amount o% PA>: +1152"40, 6 @ 6 33 H 111@ cc H 0V ba(s W 1B4 cc Abi#ity to trans%use : 3 6 33 H // cc H 100 cc

1/

>o&&o= U) 753:54:25119 on 0.55 a* S : 3#eedin( (um +L,& a#e +L, O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:& '3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L -ar/$ose/Mouth Mouth $ec. 'hora6 : : : in norma# ran(e : b#eedin( (um +L,

Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H1006/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5,

Abdomen

So%t& non tender&

erista#tic +L, $

Oi!er : not a# ab#e. S #een : schu%%ner 1 -6tremities : Pu#se: 100 6/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease P : O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein

A: 5 PA> trans%usion 1

20

>o&&o= U) 753:54:25119 on 0.55 )*

S : 3#eedin( (um +L,& a#e +L, O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:& '3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L -ar/$ose Mouth $ec. 'hora6 : : : in norma# ran(e : b#eedin( (um +L,

Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H1006/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5,

Abdomen

So%t& non tender& erista#tic +L, $ Oi!er : not a# ab#e. S #een : schu%%ner 1

-6tremities

Pu#se: 100 6/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH(

?ro(enita# : 7ema#e& within norma# ran(e A : !on )i##ebrand*s disease P : O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein

Premedication rocedure o% PA> trans%usion 1 1" Ainse $a># 0"/: 40 cc 2" 1n;" 7urosemide 33 m( 3" 1n;" De6amethasone 1B m( @" PA> trans%usion 100 cc 4" Ainse $a># 0"/: 40 cc 3#ood 2rou : O $o" 3a( Start 7inish : 1B@5392010B :4 m :B m

21

>o&&o= U) 754:54:25119 on 0.55 a* S : 3#eedin( (um +5,& a#e +L, O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:& '3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H /06/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er : not a# ab#e. S #een : schu%%ner 1 -6tremities : Pu#se: /0 6/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease P :
O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein

A: 5 PA> trans%usion 11

22

>o&&o= U) 754:54:25119 on 0.55 )*

S : 3#eedin( (um +5,& a#e +L, O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:& '3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H /06/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: /0 6/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease P : O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein

Premedication rocedure o% PA> trans%usion 11 1" Ainse $a># 0"/: 40 cc 2" 1n;" 7urosemide 33 m( 3" 1n;" De6amethasone 1B m( @" PA> trans%usion 100 cc 4" Ainse $a># 0"/: 40 cc 3#ood 2rou : O $o" 3a( Start 7inish : 1BB5/04190B : B"14 m : 10"30 m

23

>o&&o= U) 715:54:25119 on 0.55 a* S : 3#eedin( (um +5,& a#e +L, O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:&
'3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H 10@6/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: 10@ 6/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e"

A : !on )i##ebrand*s disease P :

A: 5 O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein PA> trans%usion 111

Ad!ise %rom dr" $e##y Aosdiana& S "A+X,: 77P trans%usion 9 units

2@

>o&&o= U) 715:54:25119 on 0.55 )* S : 3#eedin( (um +5,& a#e +L, O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:&
'3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H 10@6/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: 10@ 6/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease

P :
O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein

Premedication rocedure o% PA> trans%usion 111 1" Ainse $a># 0"/: 40 cc 2" 1n;" 7urosemide 33 m( 3" 1n;" De6amethasone 1B m( @" PA> trans%usion 100 cc 4" Ainse $a># 0"/: 40 cc 3#ood 2rou : O $o" 3a( Start 7inish : 02@/040 : @"30 m : 9"00 m

24

>o&&o= U) 711:54:25119 on 0.55 a* S : 3#eedin( (um +5,& a#e +L, O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:&
'3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H /26/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: /2 6/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease

P :
A: 5 O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein PA> trans%usion 18

Premedication rocedure o% PA> trans%usion 18 1" Ainse $a># 0"/: 40 cc 2" 1n;" 7urosemide 33 m( 3" 1n;" De6amethasone 1B m( @" PA> trans%usion 100 cc 4" Ainse $a># 0"/: 40 cc 3#ood 2rou : O $o" 3a( Start 7inish : 2B05@/B0B00 : 11"30 am : 2"00 m

20

>o&&o= U) 711:54:25119 on 0.55 )* S : 3#eedin( (um +5,& a#e +L, O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:&
'3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H /26/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: /2 6/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease

P :
O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein

Premedication rocedure o% 77P trans%usion +@ units, 1" Ainse $a># 0"/: 40 cc 2" 1n;" 7urosemide 33 m( 3" 1n;" De6amethasone 1B m( @" PA> trans%usion 100 cc 4" Ainse $a># 0"/: 40 cc Start 7inish 3#ood 2rou : O $o" 3a( : 2924B0/& 2924920& 341B0B/ 2544BBB09 : 03"00 m : 00"30 m

2B

>o&&o= U) 712:54:25119 on 0.55 a* S : 3#eedin( (um +5,& a#e +L, YY O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:&
'3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L Y -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H 1006/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: 1006/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease

P :
A: 5 O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein PA> trans%usion 8

29

>o&&o= U) 712:54:25119 on 0.55 )* S : 3#eedin( (um +5,& a#e +L, YY O 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:&
'3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L Y -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H 1006/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: 1006/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease

P :
O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein

Premedication rocedure o% PA> trans%usion 8 1" Ainse $a># 0"/: 40 cc 2" 1n;" 7urosemide 33 m( 3" 1n;" De6amethasone 1B m( @" PA> trans%usion 100 cc 4" Ainse $a># 0"/: 40 cc 3#ood 2rou : O $o" 3a( Start 7inish : @/B0002 : 0@"24 m : 0B"00 m

2/

>o&&o= U) 71,:54:25119 on 0.55 a* S : 3#eedin( (um +5,& a#e +L, YY O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:&
'3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L Y -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H 996/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: 996/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease

P :
A: 5 O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein PA> trans%usion 81

Premedication rocedure o% PA> trans%usion 81 1" Ainse $a># 0"/: 40 cc 2" 1n;" 7urosemide 33 m( 3" 1n;" De6amethasone 1B m( @" PA> trans%usion 100 cc 4" Ainse $a># 0"/: 40 cc 3#ood 2rou : O $o" 3a( Start 7inish : 3@45392@221 : 12"00 m : 02"00 m

30

>o&&o= U) 71,:54:25119 on 0.55 )* S : 3#eedin( (um +5,& a#e +L, YY O 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:&
'3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L Y -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H 996/1& re(u#ar& murmur +5, AA H 296/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: 996/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease

P :
O2 152 #/i nasa# canu#e 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein

Premedication rocedure o% PA> trans%usion 811 0" Ainse $a># 0"/: 40 cc B" 1n;" 7urosemide 33 m( 9" 1n;" De6amethasone 1B m( /" PA> trans%usion 1 ba( 10" Ainse $a># 0"/: 40 cc 3#ood 2rou : O $o" 3a( Start 7inish : 492@221 : 01"30 am +1@/0//2011, : 0@"00 am +1@/0//2011,

31

>o&&o= U) 71-:54:25119 on 0.55 a* S : 3#eedin( (um +5,& a#e +L, YY O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:&
'3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : L/L Y -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H /26/1& re(u#ar& murmur +5, AA H 2@6/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: /26/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease

P :
A: 5 5 O2 152 #/i ./ 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein PA> trans%usion is done Hb ana#ysis ost trans%ussion

32

>o&&o= U) 71-:54:25119 on ,.55 )* S : 3#eedin( (um +5,& a#e +5, O: 2enera# Status: Sensorium: A#ert& 'em : 30"3U>& 33: 33 .(& P3: 1@1 cm& 33/?: B9:&
'3/?: /3:& 33/'3: /@: Anemic +L,& Dys nea +5,& >yanosis +5,& -dema+5,& 1cteric +5, Ooca#ized Status : Head : -ye: Oi(ht Ae%#e6: L/L & isochoric u i#& Pa#e 1n%erior >on;uncti!a a# ebra : 5/5 -ar/$ose/Mouth $ec. 'hora6 : : : in norma# ran(e Oym h nodes en#ar(ement +5,& Simetris Fusiformis& Aetraction +5, HA H /26/1& re(u#ar& murmur +5, AA H 2@6/1& re(u#ar& wheezin( +5/5,& ronchi +5/5, Abdomen : So%t& non tender& erista#tic +L, $ Oi!er -6tremities : : not a# ab#e. S #een : schu%%ner 1 Pu#se: /26/i re(u#ar& ressure/!o#ume: ade<uate& warm acra#& c#ubbin( %in(er +5,& >a i##ary re%i## time F 3T& b#ood ressure: 100/00 mmH( ?ro(enita# : 7ema#e& within norma# ran(e" A : !on )i##ebrand*s disease

P :
A: 5 5 5 O2 152 #/i ./ 187D $a># 0"/: 1B40 cc/2@ hours H B3 (tt/i micro Z a%% Ae(u#ar mea# diet 1B40 .ca# with 00 (r rotein PA> trans%usion is done Hb ana#ysis ost trans%usion is 11"B (r: D1schar(ed

33

>om #ete 3#ood >ounts ana#ysis done in Patho#o(y >#inic

T"'# Co*)&"#" B&ood Coun#' H 7gr89 RBC 7150:**,9 WBC 715,:**,9 H"*a#ocr$# 789 PLT 715,:**,9 1CV 7(&9 1CH 7)g9 1CHC 7gr89 RDW 789 LED 7**:/our9 D$(("r"n#$a& T"&&$ng N"u#ro)/$& 789 L+*)/oc+#" 789 1onoc+#" 789 Eo'$no)/$& 789 Ba'o)/$& 789 A 'o&u#" n"u#ro)/$& 715,:;&9 A 'o&u#" &+*)/oc+#" 715,:;&9 A 'o&u#" *onoc+#" 715,:;&9 A 'o&u#" "o'$no)/$& 715,:;&9 A 'o&u#" a'o)/$& 715,:;&9 1or)/o&og+ Er+#roc+#" < ? L"ucoc+#" R"'u&# 11"B0 4"/2 0"49 3/"30 144 00"@ 1/"0 2/"4 2B"0 14 49"B 2/"/ 10"9 0"30 0"300 3"90 1"/B 0"B1 0"02 0"02 Nor*a& Va&u" 12"051@"@ @"B45@"90 @"4511 305@2 1405@40 B459B 24531 33530 11"051@"9 F20 33590 205@0 259 150 051 2"350"4 1"453"B 0"250"@ 050"10 050"1

< =$#/$n nor*a& rang"

T/ro* oc+#" < $g #/ro* oc+#"' 7@9

3@

,.,.

D$'cu''$on 8on )i##ebrand disease +!)D, is an autosoma##y inherited con(enita#

b#eedin( disorder caused by a de%iciency +ty e 1,& dys%unction +ty e 2,& or com #ete absence +ty e 3, o% !on )i##ebrand %actor" Mucocutaneous b#eedin( is the ha##mar. o% atient with !)D& such as easy bruisin(& e ista6is& menorrha(ia& b#eedin( a%ter denta# e6traction or ear& nose& throat rocedures& b#eedin( %rom minor wounds& ostsur(ica# b#eedin(& ost artum b#eedin(& (astrointestina# b#eedin(& and rare ;oint hemarthrosis or centra# ner!ous system b#eedin(" M& a 12 years and 10 months and 1@ days o#d (ir#& with body wei(ht o% 33 .(& and body hei(ht o% 1@2 cm& was admitted to the Pediatric $on 1n%ection ?nit o% Ha;i Adam Ma#i. 2enera# Hos ita# on Bth Se tember 2011 at 19"00 with chie% com #ain o% b#eedin( (um which started since 4 days a(o" - ista6is was not %ound" Pa#e was %ound since 4 days a(o" 7e!er was not %ound& cou(h was not %ound& sneeze and co#d was not %ound" De%ecation was %ound norma##y& urination was %ound norma##y" History o% re!ious i##ness : 'he atient was a re eated atient o% Pediatric Hemato5Onco#o(y ?nit since 2000 and has been dia(nosed with !on )i##ebrand*s Disease and a#so has been (i!en 77P routine#y" History o% dru( usa(e: PA> and 77P trans%usion" 'he dia(nosis o% !on )i##ebrand*s Disease in this atient was made based on history ta.in( es ecia##y %rom history o% re!ious i##ness that the atient has been dia(nosed with !on )i##ebrand*s Disease and a#so has been (i!en 77P routine#y and %rom hysica# e6amination mucosa# b#eedin( was %ound" 1n this case& the atient has sym toms o% b#eedin( (um and a#e" Desmo ressin & b#ood com onent thera y that current#y used are #asma5 deri!ed& intermediate5 urity 78111 concentrates +i"e& Humate5P and A# hanate, and ad;uncti!e thera y such as anti%ibrino#ytic a(ents trane6amic acid and aminoca roic acid are considered as the dru( o% choice %or treatin( !)D" P#ate#et trans%ussion may be he# %u# in some atients with !)D whose disease is re%ractory to other thera ies" An additiona# drawbac. o% %resh %rozen

34

#asma is the #ar(e in%usion !o#ume re<uired" Howe!er& in this case PA> and 77P trans%ussion is use%u# %or treatin( the #ow #e!e# o% hemo(#obin& ha!in( a c#inica# im ro!ement o% this atient and sto the mucosa# b#eedin(" ,.-. Su**ar+ A case re ort o% !on )i##ebrand*s Disease in a 12 year o#d (ir# who was admitted to the Pediatric 1n%ection ?nit o% Ha;i Adam Ma#i. 2enera# Hos ita# on Bth Se tember 2011 was made" 'he dia(nosis was estab#ished %rom history ta.in( and hysica# e6amination" 'he atient went home at 1@th Se tember 2011 due to c#inica# im ro!ements obser!ed by the atient*s arents"

30

RE>ERENCES 1" Oi##icra & Da!id" 2000" Von Willebrand Disease. 1n: Arceci AP& Hann 1M& Smith OP& eds" Pediatric Hemato#o(y" 3rd ed" ?X: 3#ac.we## Pub#ishin( OtdI 4/95000" 2" Oanz.ows.y& Phi#i " 2004" Manual of Pediatric Hematology and Oncology. @th ed" ?SA: -#se!ierI 2/4532B" 3" >orri(an& PP" 2000" Penyakit Perdarahan dan Trombosis. 1n: 3ehrman& A-& X#ie(man A& Ar!in AM& eds" $e#son 1#mu Xesehatan Ana. eds" 14 !o#" 2" Pa.arta: Penerbit 3u.u Xedo.teran -2>" 1B@0" @" )ic.#und& 3rian M" 200@" The leeding !hild" !ongenital and #c$uired Disorders. 1n: Hi##yer >D& Strauss A2& Ouban $O>& eds" Handboo. o% Pediatric 'rans%ussion Medicine" ?SA: -#se!ierI 221523@" 4" 2a#ardy& Pau#" 200B" Disorders of !oagulation and Thrombosis. 1n: [aoutis O3& >hian( 8)& eds" >om rehensi!e Pediatric Hos ita# Medicine" >hina: MosbyI B405B4/" 0" Po##a.& -#eanor S" 200/" Von %illebrand Disease. A!ai#ab#e %rom : htt ://emedicine"medsca e"com/artic#e/200//05o!er!iew MAccessed 19 Se tember 2011N" B" 2ei#& Pohn D" 2010" Pediatric Von Willebrand Disease. A!ai#ab#e %rom : htt ://emedicine"medsca e"com/artic#e//4/9245o!er!iew MAccessed 19 Se tember 2011N" 9" 2atot& D" 2000" Penyakit &on Willebrand. 1n: Permono 3H& Sutaryo& ?(rasena 1D2& )indiastuti -& Abdu#sa#am M& eds" 3u.u A;ar Hemato#o(i5On.o#o(i Ana." Pa.arta: 3adan Penerbit 1DA1" 1B95191" /" 'as.er A>& Mc>#ure AP& Acerini >O" 2010" O'ford Handbook of Paediatrics. ?X: O6%ord ?ni!ersity Press" 10" 3aech#i -& 3ombe#i '" 200B" 3#eedin( Diasthesis and thrombo hi#ic Diasthesis: 8on )i##ebrand Disease" 1n: Sie(entha#er )& eds" Di%%erentia# Dia(nosis in 1nterna# Medicine: 7rom Sym tom to Dia(nosis" 2ermany: 2eor( 'hieme 8er#a(" @01"

3B