Spanish consensus on managing pregnancy in women with Gaucher disease

REVIEW Open Access
© The Au ho (s) 2025. Open Access This a icle is licensed unde a C ea i e Commons A ibu ion 4.0 In e na ional License, which pe mi s use,
sha ing, adap a ion, dis ibu ion and ep oduc ion in any medium o o ma , as long as you gi e app op ia e c edi o he o iginal au ho (s) and
he sou ce, p o ide a link o he C ea i e Commons licence, and indica e i changes we e made. The images o o he hi d pa y ma e ial in his
a icle a e included in he a icle’s C ea i e Commons licence, unless indica ed o he wise in a c edi line o he ma e ial. I ma e ial is no included
in he a icle’s C ea i e Commons licence and you in ended use is no pe mi ed by s a u o y egula ion o exceeds he pe mi ed use, you will
need o ob ain pe mission di ec ly om he copy igh holde . To iew a copy o his licence, isi h p : / / c e a i e c o m m o n s . o g / l i c e n s e s / b y / 4 . 0 /. The
C ea i e Commons Public Domain Dedica ion wai e ( h p : / / c e a i e c o m m o n s . o g / p u b l i c d o m a i n / z e o / 1 . 0 /) applies o he da a made a ailable
in his a icle, unless o he wise s a ed in a c edi line o he da a.
Calde ón e al. O phane Jou nal o Ra e Diseases (2025) 20:146
h ps://doi.o g/10.1186/s13023-025-03684-6 O phane Jou nal o Ra e
Diseases
*Co espondence:
En ique J. Calde ón
[email p o ec ed]
1Ins i u o de Biomedicina de Se illa, Cen o de In es igación Biomédica
en Red de Epidemiología y Salud Pública (CIBERESP), Hospi al
Uni e si a io Vi gen del Rocío/Consejo Supe io de In es igaciones
Cien í icas/Uni e sidad de Se illa, Se ille, Spain
2Depa amen o de Medicina, Facul ad de Medicina, Uni e sidad de
Se illa, Se ille, Spain
3Vi gen Maca ena Uni e si y Hospi al, Hema ology, Se ille, Spain
4Ceu a Gene al Hospi al, Hema ology, Ceu a, Spain
5Hospi al Uni e si a io Ramón y Cajal-IRYCIS, Gene ics, CIBERER U728,
Mad id, Spain
6Fue e en u a Gene al Hospi al, Gynecology, Fue e en u a, Spain
7Vi gen del Rocio Uni e si y Hospi al, Gynecology, Se ille, Spain
8Depa amen o de Fa macología, Pedia ía y Radiología, Se ille, Spain
9Vi gen del Rocio Uni e si y Hospi al, Pedia ic, Se ille, Spain
10Je ez Gene al Hospi al, Hema ology, Je ez, Spain
11Málaga Regional Uni e si y Hospi al, Uni o Inhe i ed Me abolic
Diso de s. IBIMA-Pla a o ma BIONAND, Málaga, Spain
12Fundación Eneb o, Se ille, Spain
Abs ac
Gauche disease can ha e e ec s on he de elopmen o p egnancy, childbi h, and lac a ion, wi h impac
on heal h o bo h he mo he and he newbo n. Managemen o p egnancies in Gauche pa ien s is u he
complica ed by using o enzyme eplacemen he apy. Un o una ely, he a ailable scien i ic e idence is no
conclusi e because he e a e no p ope clinical ials on his issue. The aim o his wo k was o es ablish a
managemen guide o add ess he main clinical p oblems be o e, du ing and a e p egnancy and o p o ide
key in o ma ion o heal hca e p o essionals, pa ien s, and amilies. GRADE me hodology o e alua e he quali y
o scien i ic e idence and de elop ecommenda ions was inco po a ed o elabo a e his guide. Fo inal
ecommenda ions, a s uc u ed consensus 2- ound p ocess was ca ied ou using he Delphi me hod wi h a
Gauche expe panel. A e his p ocess, nine ecommenda ions we e elabo a ed ela ed o p e-p egnan s a us
and gene ic counseling and o managemen du ing p egnancy, se en ela ed o childbi h, and eigh ocused on
managemen a e deli e y and b eas eeding. Rega ding he quali y o he e idence, alues and p e e ences o
pa ien s we e also conside ed. A consensus guide o de ine and s anda dize p egnancy managemen in Gauche
disease conside ing he bes a ailable e idence, complemen ed by expe s’ opinions, could be a ele an ool o
help pa ien s, nu ses, midwi es and physicians wi h li le expe ience in Gauche disease who do no ha e access o
guidance om Gauche disease ea men cen e s o excellence.
Keywo ds Gauche disease, P egnancy, Guideline
Spanish consensus on managing p egnancy
in women wi h Gauche disease
En ique J.Calde ón1,2* , AliciaRod íguez-Fe nández3, I eneCalde ón-Ba u one6, Ra aelApo a-Rod íguez4,
F ancisco J.delCas illo5, Lu ga doGa cía-Díaz7, An onioGonzález-Meneses8,9, Ma ía Lou desHe mosín-Ramos10,
RaquelYahyaoui11 and IgnacioMa ín-León1,12
Page 2 o 8Calde ón e al. O phane Jou nal o Ra e Diseases (2025) 20:146
Backg ound
Gauche disease (GD: MIM#230800)) is an inhe -
i ed me abolic diso de esul ing om mu a ions in
he gene ha encodes he enzyme glucoce eb osidase
(acid β-glucosidase; EC 3.2.1.45) ha p oduces a de i-
cien ac i i y o β -glucoce eb osidase and he subse-
quen accumula ion o he glycolipid glucosylce amide
in cells o he monocy e-mac ophage sys em [1]. The
non–neu opa hic o m, named ype 1, is he mos com-
mon lysosomal s o age diso de and has a highly a iable
pheno ypical ange om o al asymp oma ic o se e e
disease wi h splenomegaly (wi h associa ed hype splen-
ism and h ombocy openia, anemia and leucopenia),
hepa omegaly, and abno mal coagula ion and o en bone
disease including bone pain, bone c ises, abno mal bone
( e)modelling, os eopenia, os eonec osis and pa hologi-
cal ac u es, and in some cases lung in ol emen [2]. In
ype 1 Gauche disease (GD), gi ls each ep oduc i e age
and he e o e he ep oduc i e heal h can be a ec ed,
including e ili y, g a idi y, p egnancy, deli e y, pos pa -
um complica ions, and lac a ion, bu he a ailable in o -
ma ion abou hese issues is sca ce and comes mainly
om case se ies epo s [3–11].
P egnancy, labo , and deli e y in women wi h ype
1 Gauche disease can ep esen a p oblem o hem-
sel es and o clinicians due o abno mal coagula ion
and mul io gan a ec a ion. Du ing p egnancy he e is a
educ ion in hemoglobin le els and app oxima ely be-
ween 5–11% o all p egnancies ha e ges a ional h om-
bocy openia, which does no con e an inc eased isk o
ma e nal bleeding [12, 13]. Howe e , in p egnan women
wi h GD, hese al e a ions may wo sen abo e hose no -
mally associa ed wi h p egnancy, and excessi e bleeding
may complica e p egnancy, deli e y, and pos pa um,
mainly i hese women ha e impai ed pla ele unc ion [4,
14–16]. Visce omegaly may in e e e wi h no mal e al
g ow h and condi ion mode o deli e y [14]. O hopedic
complica ions ela ed o GD could also a ec he mode
o deli e y [17]. The g ea es demand o calcium o he
emale skele on occu s du ing p egnancy and lac a ion
inc easing po en ially he isk o bone c ises, os eopenia,
os eonec osis, and ac u es [4, 14, 18].
Mo eo e , p egnancy could exace ba e he cou se o
GD o induce he appea ance o new mani es a ions o
he disease [6]. The e olu ion o GD du ing p egnancy is
di e se and ela ed mainly o he se e i y o he disease
and he apy con ol a he beginning o he p egnancy
[14]. Women wi h GD can expe ience an inc ease in ol-
ume o hepa osplenomegaly, bone c ises, os eopo osis,
anemia, o wo sening o h ombocy openia [4, 14]. Fu -
he mo e, du ing p egnancy, symp oms can a ise ha
lead o he diagnosis o Gauche disease in p e iously
undiagnosed women [14].
Today, he e a e wo speci ic ways o ea GD: enzyme
eplacemen he apy (ERT) wi h se e al a ailable ecom-
binan enzymes, elagluce ase al a, imigluce ase and
aligluce ase al a, and subs a e educ ion he apy (SRT)
wi h wo di e en d ugs, eliglus a and miglus a . How-
e e , no all o hem can be used du ing p egnancy o lac-
a ion [19].
The managemen o women wi h Gauche disease ype
1 be o e becoming p egnan , du ing p egnancy, and a e
deli e y is a majo challenge o all physicians ca ing o
hese pa ien s. Howe e , he e a e no clinical ials on
his issue, bo h because o he numbe o pa ien s ha
would be necessa y and because o he e hical p oblem
ha he use o placebo would pose. In ac , only a ew
ou da ed consensus ecommenda ions o expe opin-
ion ha e been published o suppo decision-making and
guide ea men o hese pa ien s and he e a e no ecom-
menda ions abou in i o e iliza ion and p eimplan a-
ion gene ic sc eening o women wi h GD [20–23].
The pu pose o his a icle is o es ablish managemen
guidance o he GD-p egnancy ela ionship o add ess
he main clinical p oblems wi h espec o (1) gene ic
counseling, (2) ea men be o e, du ing, and a e p eg-
nancy, (3) app oach o childbi h and b eas eeding, (4)
p e en ion o hema ologic and bone complica ions in
mo he and child, and (5) key in o ma ion o pa ien s
and hei amilies.
Ma e ials and me hods
The me hodology o his p ojec is based on he 2016
Me hodological manual o de eloping clinical p ac ice
guidelines o he Spanish Na ional Heal h Sys em and
inco po a es he G ading o Recommenda ions Assess-
men , De elopmen and E alua ion (GRADE) me hod-
ology in he assessmen o he scien i ic e idence and
s eng h o he ecommenda ions [24, 25].
To de ine he objec i e o he consensus, he clinicians’
and pa ien s’ needs o decision ad ice was explo ed wi h
a su ey asking o he main disease-speci ic issues ha
conce ned hem. The de elopmen g oup designed a map
o he heal hca e p ocess o p egnancy in GD, s uc u -
ing he p ocess in o 4 s eps o chap e s (p e-p egnancy
and gene ic counseling; p egnancy; childbi h, and pos -
p egnancy and b eas eeding). Fo each chap e , he
g oup speci ied he po en ial issues ha clinicians and
pa ien s could es ablish on each pa o he heal hca e
p ocess, add essing mu ually exclusi e aspec s in each
issue, esul ing in 56 PICO (popula ion, in e en ion,
compa ison, ou come) i ems.
E idence sea ch
S udies published be ween Janua y 2000 and Ap il 2021
we e sea ched. The sea ch s a egy was no es ic ed by
language o a icle ype.
Page 3 o 8Calde ón e al. O phane Jou nal o Ra e Diseases (2025) 20:146
Fo he PubMed sea ch s a egy, he key wo ds ‘Gau-
che disease’ AND ‘p egnancy’ OR ‘ e ili y’ OR ‘child-
bi h’ OR ‘labo ’ OR ‘gene ic counseling’ OR ‘baby
eeding’ OR ‘mo he ou comes’ OR ‘child ou comes’ we e
used. The same s a egy was execu ed in he o he da a-
bases using he app op ia e con olled ocabula y. The
ollowing elec onic da abases we e also explo ed o p i-
ma y s udies: Scopus, EBSCO, Academic Sea ch Com-
ple e, CINAHL, Biomedical Re e ence.
Due o he sca ci y o bibliog aphy a ailable, o he
esou ces including g ey li e a u e om di e en sou ces
and hand-sea ching o hose high-yield jou nals and con-
e ence p oceedings ha ha e no al eady been hand-
sea ched o opinion a icles, guidelines, consensus, and
he e e ences suppo ing hose documen s we e also
e iewed.
S udies selec ion
The s udies ound h ough he sea ch s a egy we e
sc eened by wo e iewe s (EJC, IML), who e iewed all
o hem and gi en he ew s udies collec ed, wi h he sole
c i e ion o excluding he epea ed a icles.
Da a ex ac ion
Th ee au ho s (EJC, IML, ARF) independen ly classi ied
he s udies by ype and ied o unde ake da a ex ac ion
o ge he e idence s anda d o ca e a ailable o ou ou
clinical scena ios p oposed.
Consensus p ocess
A consensus was eached among nine expe ienced GD
expe s om 6 special ies ela ed o Gauche disease
ca e (hema ologis s, in e nis s, gene icis , biochemis ,
pedia ician, gynecologis ) and a midwi e. Fo he ecom-
menda ion decision we used a s uc u ed 2 ound Delphi-
RAND consensus Me hod. This me hod is a s uc u ed
communica ion echnique, o iginally de eloped as a sys-
ema ic, in e ac i e o ecas ing me hod ha elies on a
panel o expe s. The p ocess in ol es mul iple ounds o
anonymous su eys. A e each ound, a acili a o p o-
ides a summa y o he expe s’ o ecas s and easons o
hei judgmen s. Expe s a e encou aged o e ise hei
ea lie answe s in ligh o he eplies o o he membe s
o hei panel. This i e a i e p ocess is epea ed un il he
g oup eaches a consensus. Key ea u es o he Delphi-
RAND me hod include anonymi y, con olled eedback,
and s a is ical agg ega ion o g oup esponses [26].
In he i s ound, membe s o he expe panel we e
asked o a e ag eemen wi h each s a emen , on a
9-poin Like scale, anging om s ongly ag ee o
s ongly disag ee (highe sco e co esponding wi h
ag eemen ). No a emp s we e made o o ce consensus.
The 2- ound p ocess was designed o de e mine
“whe he disc epan a ings a e due o eal clinical
disag eemen o e he use o he p ocedu e (‘ eal’ dis-
ag eemen ) o o a igue o misunde s anding (‘a i-
ac ual’ disag eemen ), and o add ess any emaining
signi ican disco d and ob ain consensus. Fo ha pu -
pose, he ou come o he i s ound was analyzed by
he acili a o /expe in he Delphi me hod (IM), and
he esul s we e e iewed by he coo dina o s (EC, AR),
which e ised some s a emen s ha p esen ed syn ax/
communica ion issues. A summa y epo desc ibing
ound 1 g oup esponses was sen o he nine GD expe s
included in he panel ia email. S a emen s anked wi h
a median sco e o 7 o highe we e conside ed “s ong”
ag eemen (51.3%) and, hus, comple e, while median
sco es anked 4 o 6 we e conside ed “unce ain” ag ee-
men (27,6%), and median sco es anked 1 o 3 we e con-
side ed “disag eemen (21%). S a emen s ha achie ed
a median sco e o 7 o highe in ound 1 bu had some
ankings om indi idual expe s om 1 o 6 we e con-
side ed o o e on in he second ound. The s a emen s
ha did no each ag eemen o disag eemen we e e al-
ua ed and e-p oposed wi h an explica i e ex du ing he
second ound o Delphi.
Values and p e e ences o pa ien s we e also con-
side ed h ough a b ains o ming mee ing wi h pa ien
associa ions.
Th ee (EC, AR, IM) membe s o he panel w o e a
d a o he ecommenda ions wi h he esul s o Del-
phi consensus. Panel membe s we e asked o e iew
he ecommenda ions and gi e hei ag eemen wi h a
‘yes / no’ esponse (“yes” indica ing ag eemen wi h he
e ised s anda d and inclusion in he consensus ecom-
menda ions and ‘no’ indica ing exclusion om he con-
sensus ecommenda ions). Mino edi ing (e.g., g amma
and s uc u e) was allowed, bu no change o in en was
made. Finally, he inal d a o he ecommenda ions was
app o ed by all panel membe s.
Resul s
Ve y li le e idence add essing GD and p egnancy was
ounded. Bibliog aphy sea ch p o ided 36 e e ences ha
we e classi ied as 3 p ospec i e obse a ional se ies, wi h
a o al o 64 p egnancies; 6 e ospec i e obse a ional
se ies wi h a o al o 505 p egnancies; 9 case eco ds; and
8 na a i e e iews and opinion a icle mainly ocused
on p e-p egnancy and gene ic counseling. The quali y
o e idence was low due o he he e ogenei y o publica-
ion da es, sample sizes, ea men s, and ou come da a
epo ed, wi h ag eemen among e iewe s.
Thi y- wo ecommenda ions we e d a ed, 9 o p e-
p egnan and gene ic counseling, 9 o he p egnancy
pe iod, 7 o childbi h and 7 o pos pa um and b eas -
eeding. Fo h ee PICOs he panel did no ag ee on a
ecommenda ion ( e ili y issues in GD pa ien s, delays
in he mena che o women wi h GD, and speci ic ole o
Page 4 o 8Calde ón e al. O phane Jou nal o Ra e Diseases (2025) 20:146
midwi es in he p ocess o ca e). The s eng h o ecom-
menda ions ag eemen was 24 s ong ( ecommenda ion
can apply o mos pa ien s in mos ci cums ances) and 8
weak ( he bes cou se o ac ion may di e depending on
ci cums ances o pa ien o socie y alues. O he al e na-
i es may be equally easonable).
The ques ions ela ed o ecommenda ions o ganized
by ou s eps in he ca e p ocess, along wi h he s eng h
o hei suppo be ween he panel membe s (in b ack-
e s), a e shown below.
Panel ecommenda ions
Ac ions be o e p egnancy
1.1 Should all pa ien s wi h Gauche ’s disease (GD)
who wish o bea child en be o e ed gene ic
p econcep ion counseling? Yes (S ong Ag eemen ).
1.2 Can assis ed ep oduc ion echniques be used in
pa ien s wi h GD and e ili y p oblems? Yes (S ong
Ag eemen ).
Fu he mo e, assis ed ep oduc ion echniques a e com-
pa ible wi h enzyme e-placemen he apy (ERT): Yes
(S ong Ag eemen ).
Commen : Because al e a ions in he unc ion o num-
be o pla ele s may a ec in i o e iliza ion (IVF),
he panel ecommends a pe sonalized app oach o cope
wi h all he de e minan s o GD s a us in each pa ien ,
oge he wi h he numbe o pla ele s, o hei unc-
ionali y when his is g ea e han 100,000 /mm3, which
is when hese unc ionali y es s a e eliable. I is also
needed o assess isks om he use o ace yl salicylic acid
(ASA), o imp o e ep oduc i e ou comes and a oid he
isk o h ombosis by IVF. So ha he isk/bene i balance
he isk o e al loss o o a ian punc u e bleeding, and a
sha ed decision on assis ed ep oduc ion could be made.
1.3 In he e en ha he spouse is a GD ca ie o
he dono is unknown, should a p e-implan a ion
gene ic diagnosis be o e ed in an IVF-a ec ed
woman?: Yes. (Weak Ag eemen ). Commen : I
a GD ca ie is de ec ed, i should be equi ed o
in es iga e possible pseudo-de iciencies o he
enzyme glucoce eb osidase. E en in Ashkenazi Jews
i can be done when he Gauche si ua ion o he
spouse is unknown, o acili a e he de ec ion o
speci ic mu a ions in he emb yo. Howe e , because
he isk/bene i balance ega ding e al loss and
o a ian punc u e bleeding is unknown, a p ocess
o sha ed decision-making wi h he pa ien and
amily is manda o y as well as planned anno a ion
o he ou come da a in an ac i e GD p egnancy
sub- egis y.
1.4 F om he pe spec i e o he pa ien ’s heal h, is he e
e e a eason o a physician o discou age p egnancy
in a woman wi h GD?: Yes (S ong Ag eemen ).
Commen : The e a e no eugenic condi ions, bu he
e olu ion o he pa ien ’s disease can condi ion a p eg-
nancy, especially due o mode a e o se e e pulmona y
hype ension (PH) ha his is e y a e, and he isk is
la gely es ic ed o GD1 women who ha e unde gone
a splenec omy o GD ype 3 pa ien s wi h known lung
disease. The e is a s ong ag eemen ha nei he ane-
mia (Hb < 10g/dl), no h ombocy openia (< 70,000dl),
no hepa omegaly o splenomegaly (> 2 imes no mal),
no os eopo osis a e eason o discou age p egnancy.
Al hough i is impo an o ha e good communica ion
wi h he pa ien abou possible isks and concomi an
need o ac on hose isks, such as he need o calcium,
i amin D, o o he s. In addi ion, he e a e concu en
illnesses no di ec ly ela ed o GD (e.g., uncon olled
se e e a e ial hype ension, b i le diabe es melli us,
sys emic lupus e y hema osus, psychia ic p oblems,
e c.) when p egnancy could be discou aged.
1.5 Should a comp ehensi e GD pa ien s assessmen
ha e been pe o med p io o a planned p egnancy?
Yes. (S ong Ag eemen ).
Commen s: The panel ecommends 3–6 mon hs be o e
p egnancy as a way o ha e ime o co ec GD p ob-
lems du ing p egnancy. Tha assessmen should include
in addi ion o he ou ine con ols o a pa ien wi h GD,
a bone densi ome y and ca diac ul asound o ule ou
PH, gi en he g ea ma ginal bene i de- i ed om i s
de ec ion, despi e i is an uncommon complica ion. In
case o inconclusi e ca diac ul asound o bo de line o
PH, he e e ence echnique is igh hea ca he e iza ion.
This is an in asi e echnique, and isk/bene i should be
assessed and he decision o do should be made in ag ee-
men wi h he pa ien .
1.6 How long be o e concep ion should women
wi h GD s op bisphosphona es ea men ?
Bisphosphona es should be suspended a leas 6
mon hs be o e p egnancy, o longe o hose long-
las ing bisphosphona es, which should be suspended
be o e he end o he pe iod o in ended e ec .
(S ong Ag eemen ).
1.7 In splenec omized pa ien s who wan o plan
a p egnancy some special measu es should be
aken in o accoun ? Yes. (S ong Ag eemen ).
They should be accina ed agains pneumococcus,
meningococcus, Haemophilus in luenzae and
in luenza. Cen e s o disease con ol and p e en ion
(CDC) ecommend ha all adul s wi hou spleen
Page 5 o 8Calde ón e al. O phane Jou nal o Ra e Diseases (2025) 20:146
o ge a p ima y se ies o COVID-19 accine plus
boos e doses when eligible [27]. In addi ion, a
ca diac ul asound has o do o ule ou PH.
1.8 P egnancy and ERT: GD pa ien s on ERT should
no suspend o modi y such ea men o hei
p egnancy e en in he i s imes e .
Asymp oma ic GD pa ien s wi hou ERT a e a comp e-
hensi e GD e alua ion should no s a ea men be o e
p egnancy.
GD pa ien s wi h mild symp oms wi hou ERT should
s a ea men be o e p egnancy. A doses o 60 uni s/kg
e e y wo weeks. (S ong Ag eemen ).
1.9 P egnancy and subs a e educ ion he apy (SRT):
Pa ien s on ea men wi h Miglus a o Eliglus a
should discon inue such ea men a leas 3 mon hs
be o e p egnancy. And hey mus change o ERT
be o e p egnancy. (S ong Ag eemen ).
Gauche disease managemen du ing p egnancy
2.1 Fo a p egnan GD woman, is he s anda d
ecommended con ol ca e designed o women
wi h high- isk p egnancies su icien ly speci ic
o p egnancy in a woman wi h GD? No. (S ong
Ag eemen ).
A speci ic p og am adap ed o he pa icula ci cum-
s ances o each p egnan Gauche pa ien , led by an
expe mul idisciplina y eam, is equi ed.
2.2 Wha speci ic check-ups should be ca ied
ou du ing he i s imes e o p egnancy in a
GD pa ien ? Measu emen o lysoGb1 and/o
chi o iosidase and/o , calcium, i amin D and
i amin B12 le els. (S ong Ag eemen ).
2.3 Can pa ien s wi h GD who a e p egnan wi h
IVF ecei e ea men wi h Aspi in? Yes. (Weak
Ag eemen ). Condi ioned o h ombocy openia and
no mal pla ele unc ion.
2.4 Should p e en i e supplemen s be added o
p egnan women wi h GD? Yes. (S ong Ag eemen ).
Calcium and i amin D should be added. Rega ding i a-
min B12, p e en i e p o ision should be made o ensu e
he daily dose equi ed be o e and du ing p egnancy due
o i s special isk o anemia and neu opa hy.
In addi ion, when low B12 le els we e de ec ed a he
ime o diagnosis o p egnancy (up o week 9), B12 should
be p o ided a he apeu ic doses.
2.5 Wha speci ic ou ine check-ups should be ca ied
ou du ing he second and hi d imes e s o
p egnancy in he GD woman? Measu emen o
lysoGb1 and/o chi o iosidase and/o lysoGb1,
calcium le els, and i amin D. (S ong Ag eemen ).
2.6 A e o he ou ine p egnancy check-ups needed
du ing he hi d imes e in pa ien s wi h GD? Yes.
(S ong Ag eemen ). A s udy o pla ele unc ion and
ul asound e alua ion o li e and spleen sizes should
be pe o med i hey we e no pe o med be o e
du ing p egnancy con ol.
Commen s: Mul iple me hods o in i o pla ele unc-
ion e alua ion, such as pla ele unc ion analyze (PFA)-
100/200, pla ele agg egome y, low cy ome y, and
cone and pla ele analyze , can be used o assess p ima y
hemos asis. PFA-100/200 is widely used o assess pla e-
le unc ion and has been p oposed o assess he isk o
p esu gical bleeding as a eplacemen o he ‘skin bleed-
ing ime’ [28]. Howe e , his me hod has no been es ed
on GD. The e is only one s udy in pa ien s wi h GD using
he cone pla ele (le ) analyze [29]. In his s udy, pla e-
le agg ega ion de ec was no associa ed wi h mucosal
bleeding and educed pla ele adhesion was [29]. How-
e e , he e is no speci ic in o ma ion o ei he me hod in
p egnan women wi h GD.
Al hough in case o cesa ean deli e y, he low ans-
e sa incision is ecommended, an ul asound s udy in
he las imes e is ecommended o documen o ule
ou hepa osplenomegaly (Weak Ag eemen ).
2.7 Should magne ic esonance imaging es s be
pe o med on p egnan GD pa ien s su e ing om
bone c ises o exace ba ions o bone pa hology? Yes.
(S ong Ag eemen ).
2.8 Du ing p egnancy an exace ba ion o he GD
should lead o pe o m a dose adjus men o enzyme
eplacemen ea men ?” Yes, (S ong Ag eemen ).
2.9 Should p ena al gene ic diagnosis be o e ed in
p egnan women wi h GD? Yes, when he pa ne
is a ca ie o in IVF when he dono is unknown.
The e o e, a p e-concep ional gene ic s udy o ca ie
s a us in couples is always ecommended o iden i y
emb yos ha only will ca y one GD mu a ion o
who will ha e wo mu a ions and he e o e will
be a ec ed by GD and also o be able o decide
depending on he ype and isk o he kind o
mu a ions. (Weak Ag eemen ).
Gauche disease ca e du ing childbi h
3.1 Whe e should he deli e y o a p egnan woman
wi h GD ake place? In a hospi al wi h GD expe ise.
(S ong Ag eemen ).

Page 6 o 8Calde ón e al. O phane Jou nal o Ra e Diseases (2025) 20:146
Commen : GD equi es an icipa ing any possible compli-
ca ions, such as immedia e access o a blood bank.
3.2 Should cesa ean deli e y be ecommended o
pa ien s wi h GD? No. (S ong Ag eemen ).
3.3 Is aginal deli e y possible in GD pa ien s wi h hip
p os hesis? Yes. (Weak Ag eemen ).
Commen : wi h auma ology and ehabili a ion planned
suppo .
3.4 Does he p esence o hepa osplenomegaly p e en o
pe o m a cesa ean sec ion i necessa y? No. (S ong
Ag eemen ).
In case o cesa ean deli e y, he low ans e sal incision
is ecommended. (See ecommenda ion 2.6).
3.5 Wha would con aindica e epidu al anes hesia in
a p egnan woman wi h GD? P esence o pla ele
coun less han 70,000/mm3 o impai ed pla ele
unc ion. (S ong Ag eemen ).
3.6 Do p egnan women wi h GD ha e a highe
isk o misca iage? Unce ain. Commen : The
a ailable li e a u e is inconclusi e due o biases and
inconsis en e-sul s, sugges ing he need o u he
esea ch compa ing wi h non-GD p egnan sample.
3.7 Do p egnan GD women ha e a highe isk o
bleeding o pos pa um in ec ions? Yes. (S ong
Ag eemen ).
Pos pa um ca e
4.1 Should he newbo n (NB) unde go gene ic es ing
o GD? No. (S ong Ag eemen ).
I i is no known whe he he a he may be a ca ie o
a Gauche mu a ion, he newbo n should be gi en an
enzyma ic d ied d op es (neona al sc eening) ins ead o
a gene ic es . Howe e , spo adically he e may be alse
nega i es om he d y d op, in which case i he clinical
suspicion is high, he es could be epea ed, o a gene ic
s udy could be conside ed.
4.2 Does a newbo n wi hou Gauche disease bo n o
a mo he wi h he disease need any di e en con ol
han usual NBs? Yes. (Weak Ag eemen ).
Only in case he mo he has p esen ed some complica-
ion du ing p egnancy. O he wise, he child only needs
he s anda d ca e in he NBs.
4.3 Should b eas eeding be ecommended o GD
mo he s? Fo how long? Yes, up o 6 mon hs. (S ong
Ag eemen ).
Al hough in case o se e e os eopo osis o uncon olled
GD s a us o he mo he i is sugges ed o a oid b eas -
eeding. (Weak Ag eemen ).
4.4 Should ERT be main ained du ing b eas eeding? A
wha dose? Yes, a he same p e ious dose. (S ong
Ag eemen ).
4.5 Should GD nu sing mo he s ecei e i amin D and
calcium supplemen s? Yes. (S ong Ag eemen ).
4.6 Can GD nu sing mo he s be ea ed wi h
bisphosphona es? No. (S ong Ag eemen ).
4.7 Can GD nu sing mo he s be ea ed wi h Miglus a
o Eliglus a ? No. (S ong Ag eemen ).
The s eng h o he ecommenda ions is summa ized in
Tables1, 2, 3 and 4.
Clinical ques ions no add essed in he consensus p ocess
and ha equi e u he esea ch
Do pa ien s wi h GD (women and men) ha e e ili y
p oblems g ea e han he non-a ec ed popula ion?
Do pa ien s wi h GD ha e delayed mena che?
Wha is he ole o midwi es in he managemen o
childbi h o a pa ien wi h GD?.
Table 1 Recommenda ions o p epa e o p egnancy
Recommenda ion S eng h
All pa ien s, men o women, who wish o bea child en
should ecei e a gene ic p econcep ion counseling
S ong
Women wi h GD and e ili y p oblems can use assis ed
ep oduc ion echniques
S ong
P e-implan a ion gene ic diagnosis in cases o in i o
e iliza ion should do when he spouse is a GD ca ie in all
cases, o he dono is unknown in Ashkenazi Jews
Weak
P egnancy is discou aged in case o mode a e-se e e pul-
mona y hype ension
S ong
A comp ehensi e GD women assessmen mus be pe -
o med 3–6 mon hs p io o a planned p egnancy
S ong
Women unde bisphosphona es ea men mus s op i a
leas 6 mon hs be o e p egnancy, o longe o hose long-
las ing bisphosphona es
S ong
Splenec omized women who wan o plan a p egnancy
mus accina e agains pneumococcus, meningococcus,
Haemophilus in luenzae, and lu
S ong
Asymp oma ic GD women wi hou enzyme eplacemen
he apy do no need s a ea men be o e p egnancy
S ong
Women wi h GD wi h mild symp oms wi hou speci ic
ea men should s a enzyme eplacemen he apy be o e
p egnancy
S ong
Pa ien s on ea men wi h Miglus a o Eliglus a mus
swi ch such ea men o enzyme eplacemen he apy a
leas 3 mon hs be o e p egnancy
S ong
Page 7 o 8Calde ón e al. O phane Jou nal o Ra e Diseases (2025) 20:146
Conclusions
Women wi h Gauche disease ype 1 a e usually diag-
nosed jus be o e o du ing hei ep oduc i e age and
many al e a ions ela ed o he disease can a ec ep o-
duc ion capaci y o he no mal de elopmen o p eg-
nancy and deli e y [2, 14]. Today, we ha e di e en
op ions o e ec i e ea men o Gauche disease ype 1,
bu we lack speci ic guidelines on hei use in p egnan
women wi h GD [19].
In his wo k, a managemen guide ha includes 32
ecommenda ions o suppo he decision-making o
physicians ca ing o women wi h ype 1 GD who wan
o become p egnan o a e p egnan has been de eloped
h ough a igo ous and ep oducible me hodology.
Fo easy use o his guide, ecommenda ions ha e been
g ouped wi hin he ou p incipal a eas o ac ion o s eps
iden i ied by he expe panel whe e i is necessa y o
make decisions when a woman decides deciding o ha e
child en: be o e concep ion, du ing p egnancy, a ound
he pa um, and du ing lac a ion.
I is hoped ha a consensus guidance, such as his, o
de ine and s anda dized he managemen o p egnancy in
GD in ligh o he bes a ailable e idence, complemen ed
by he opinions o a panel o expe s, could be a ele an
ool o help pa ien s, nu ses, midwi es and doc o s wi h
li le expe ience in Gauche disease.
Au ho con ibu ions
All au ho s ha e con ibu ed o he guideline de elopmen p ocess o
planning, w i ing, and e ising o he manusc ip . All au ho s ead and
app o ed he inal manusc ip .
Funding
This esea ch was unded by Eneb o Founda ion (EF), wi h esou ces om i s
232021 p og am o which Sano i-Genzyme has con ibu ed. The unde s had
no ole in he design o he s udy; in he collec ion, analyses, o in e p e a ion
o da a; in he w i ing o he manusc ip , o in he decision o publish he
esul s.
Da a a ailabili y
Da a sha ing no applicable o his a icle as no da ase s we e gene a ed o
analysed du ing he cu en s udy.
Table 2 Recommenda ions du ing p egnancy
Recommenda ion S eng h
The s anda d ecommended con ol ca e o p egnan
women is no enough o GD women which need a speci ic
p og am adap ed o he ci cums ances o each case, led by
an expe mul idisciplina y eam
S ong
Du ing he i s imes e o p egnancy o chi o iosidase
and/o lysoGb1, calcium, i amin D and i amin B12 le els
mus be measu emen
S ong
Women wi h GD who a e p egnan h ough in i o
e iliza ion can ecei e ea men wi h Aspi in i hey
ha e no mal pla ele unc ion and ha e no signi ica i e
h ombocy openia
Weak
Calcium and i amin D mus be added du ing p egnancy,
and a p e en i e supply o i amin B12 mus be made o
ensu e he equi ed daily dose o o be adminis e ed in
he apeu ic doses i low le els a e de ec ed in labo a o y
con ols
S ong
Du ing he second and hi d imes e s o p egnancy o
chi o iosidase and/o lysoGb1, calcium and i amin D le els
mus be measu emen
S ong
A s udy o pla ele unc ion mus do du ing he hi d
imes e
S ong
An ul asound s udy in he las imes e is ecommended o
documen o ule ou hepa osplenomegaly
Weak
In case o bone c ises o exace ba ions o bone pa hology
du ing p egnancy, a magne ic esonance imaging s udy
mus be pe o med
S ong
In case o exace ba ions o GD du ing p egnancy, a dose
adjus men o ea men mus be pe o med.
S ong
P ena al gene ic diagnosis migh be o e ed in p egnan
women wi h GD when he pa ne is a ca ie o GD o in he
case o in i o e iliza ion when he dono is unknown.
Weak
Table 3 Recommenda ions du ing childbi h
Recommenda ion S eng h
The deli e y o a p egnan woman wi h GD mus occu in a
hospi al ha has immedia e access o a blood bank
S ong
Cesa ean deli e y is no necessa y o pa ien s wi h GD S ong
Vaginal deli e y is possible in GD pa ien s wi h a hip
p os hesis wi h planned auma ology and ehabili a ion
suppo
Weak
I necessa y, he p esence o hepa o-splenomegaly does
no p e en he ope a ion o a cesa ean sec ion, bu he low
ans e sal incision is ecommended
S ong
The p esence o a pla ele coun s less han 70,000/mm3 o
impai ed pla ele unc ion con adic s epidu al anes hesia in
a p egnan woman wi h GD
S ong
Bleeding and in ec ions should be moni o ed especially in
p egnan women wi h GD du ing hei deli e y
S ong
Table 4 Recommenda ions a e deli e y
Recommenda ion S eng h
I an enzyma ic d y d op es (neona al sc eening) can be
o e ed, he newbo n does no need a gene ic es o GD.
Spo adically he e may be alse nega i es om he d y d op,
in which case i he clinical suspicion is high, he es could
be epea ed, o a gene ic s udy could be conside ed
S ong
A newbo n o a GD mo he only needs s anda d ca e o
newbo ns unless he mo he has p esen ed some complica-
ion du ing p egnancy
Weak
B eas eeding mus be ecommended o GD mo he s up o
6 mon hs unless she has se e e os eopo osis o an uncon-
olled s a us o he GD
Weak
Enzyme eplacemen he apy mus be main ained a he
same p e ious dose du ing b eas eeding
S ong
Nu sing mo he s wi h GD mus ecei e i amin D and
calcium supplemen s
S ong
Nu sing mo he s wi h GD canno be ea ed wi h
bisphosphona es
S ong
Nu sing mo he s wi h GD canno be ea ed wi h Miglus a
o Eliglus a
S ong
Page 8 o 8Calde ón e al. O phane Jou nal o Ra e Diseases (2025) 20:146
Decla a ions
E hical app o al and consen o pa icipa e
No applicable.
Consen o publica ion
No applicable.
Compe ing in e es s
An onio González-Meneses has ecei ed g an o esea ch and hono a ia
o lec u es and a el expenses om Sano i and Takeda. Ignacio Ma ín León
has ecei ed esea ch g an s om Sano i-Genzyme and Ro i, and speake
hono a ium om Sano i-Genzyme. Raquel Yahyaoui has ecei ed a speake
hono a ium om Sano i Genzyme and Takeda. F ancisco J del Cas illo has
ecei ed esea ch g an s and speake hono a ium om Sano i-Genzyme.
Ra ael Apo a-Rod íguez, Alicia Rod íguez-Fe nández, En ique J. Calde ón,
Lu ga do Ga cia-Diaz, Ma ía Lou des He mosin-Ramos and I ene Calde ón
Ba u one decla e ha hey ha e no con lic o in e es o he opic o his
a icle.
Recei ed: 12 July 2023 / Accep ed: 20 Ma ch 2025
Re e ences
1. Ae s JMFG, Kuo CL, Lelie eld LT, an de Boe DEC, O e klee HS, A ola M.
Glycosphingolipids and lysosomal s o age diso de s as illus a ed by gauche
disease. Cu Opin Chem Biol. 2019;53:204–15. h p s : / / d o i . o g / 1 0 . 1 0 1 6 / j . c b p a .
2 0 1 9 . 1 0 . 0 0 6.
2. Nalysnyk L, Ro ella P, Simeone JC, Hamed A, Wein eb N. Gauche disease
epidemiology and na u al his o y: a comp ehensi e e iew o he li e a u e.
Hema ology. 2017;22:65–73. h p s : / / d o i . o g / 1 0 . 1 0 8 0 / 1 0 2 4 5 3 3 2 . 2 0 1 6 . 1 2 4 0 3 9
1.
3. Wein eb NJ, Camelo JS J , Cha ow J, McClain MR, Mis y P, Belma oug
N, In e na ional Collabo a i e Gauche G oup. (ICGG) gauche egis y
NCT00358943) in es iga o s. gauche disease ype 1 pa ien s om he ICGG
gauche egis y sus ain ini ial clinical imp o emen s du ing Twen y yea s o
imigluce ase ea men . Mol Gene Me ab. 2021;132:100–11. h p s : / / d o i . o g /
1 0 . 1 0 1 6 / j . y m g m e . 2 0 2 0 . 1 2 . 2 9 5.
4. Els ein Y, Eisenbe g V, G ano sky-G isa u S, Rabinowi z R, Samuelo A, Zim an
A, Els ein D. P egnancies in gauche disease: a 5-yea s udy. Am J Obs e
Gynecol. 2004;190:435–41. h p s : / / d o i . o g / 1 0 . 1 0 1 6 / j . a j o g . 2 0 0 3 . 0 8 . 0 0 6.
5. G ano sky-G isa u S, Aboula ia Y, Diaman YZ, Ho owi z M, Ab ahamo A,
Zim an A. Gynecologic and obs e ic aspec s o Gauche ’s disease: a su ey o
53 pa ien s. Am J Obs e Gynecol. 1995;172(4 P 1):1284–90. h p s : / / d o i . o g / 1
0 . 1 0 1 6 / 0 0 0 2 - 9 3 7 8 ( 9 5 ) 9 1 4 9 4 - 3.
6. Komninaka V, Fle a i P, Ma inakis T, Ka kale sis G, Malakou L, Repa K. Ou -
comes o p egnancies in pa ien s wi h gauche disease: he expe ience o a
cen e o excellence on a e me abolic Disease-Gauche disease, in G eece.
Eu J Obs e Gynecol Rep od Biol. 2020;254:181–7. h p s : / / d o i . o g / 1 0 . 1 0 1 6 / j . e j
o g b . 2 0 2 0 . 0 9 . 0 2 7.
7. Lau H, Belma oug N, Deegan P, Goke -Alpan O, Schwa z IVD, Shanka SP,
Panahloo Z, Zim an A. Repo ed ou comes o 453 p egnancies in pa ien s
wi h gauche disease: an analysis om he gauche ou come su ey. Blood
Cells Mol Dis. 2018;68:226–31. h p s : / / d o i . o g / 1 0 . 1 0 1 6 / j . b c m d . 2 0 1 6 . 1 0 . 0 0 3.
8. Pe domo Ama IA, Solano T ujillo MH. E olución clínica y pa aclínica de 9
emba azos En 4 Pacien es Con En e medad de gauche Tipo 1 En El se icio
de hema ología de Un hospi al Docen e asis encial. P og Obs e Ginecol.
2014;57:362–7.
9. Apo a-Rod íguez R, Escoba -Vedia JL, Na a o-Cas o AM, Aguila -Ga cía G,
Cab e a-To es A. Algluce ase enzyme eplacemen he apy used sa ely and
e ec i ely h oughou he whole p egnancy o a gauche disease pa ien .
Haema ologia. 1998;83:852–64.
10. Aladag H, Aladag M. Nine heal hy deli e ies in ou p egnan women
wi h enzyme eplacemen he apy in gauche disease. Ann Med Res.
2023;30:278–81.
11. Su aksha A, F aha K. Gauche disease and ep oduc ion. J Gynecol Women’s
Heal h. 2023;24:556143. h p s : / / d o i . o g / 1 0 . 1 9 0 8 0 / J G W H . 2 0 2 3 . 2 3 . 5 5 6 1 4 3.
12. Pa el P, Balanchi adze N. Hema ologic indings in p egnancy: A guide o he
in e nis . Cu eus. 2021;13:e15149. h p s : / / d o i . o g / 1 0 . 7 7 5 9 / c u e u s . 1 5 1 4 9.
13. Cines DB, Le ine LD. Th ombocy openia in p egnancy. Blood. 2017;130:2271–
7. h p s : / / d o i . o g / 1 0 . 1 1 8 2 / b l o o d - 2 0 1 7 - 0 5 - 7 8 1 9 7 1.
14. Zim an A, Mo is E, Mengel E, Kaplan P, Belma oug N, Hughes DA, Malino a V,
Hei ne R, Sob ei a E, M sić M, G ano sky-G isa u S, Ama o D, om Dahl S. The
emale gauche pa ien : he impac o enzyme eplacemen he apy a ound
key ep oduc i e e en s (mens ua ion, p egnancy and menopause). Blood
Cells Mol Dis. 2009;43:264–88. h p s : / / d o i . o g / 1 0 . 1 0 1 6 / j . b c m d . 2 0 0 9 . 0 4 . 0 0 3.
15. Iosco ich A, Els ein Y, Halpe n S, Va ashsky E, G isa u-G ano sky S, Els ein D.
Anes hesia o obs e ic pa ien s wi h gauche disease: su ey and e iew. In
J Obs e Anes h. 2004;13:244–50. h p s : / / d o i . o g / 1 0 . 1 0 1 6 / j . i j o a . 2 0 0 4 . 0 5 . 0 0 3.
16. Simchen MJ, Oz R, Shenkman B, Zim an A, Els ein D, Kene G. Impai ed
pla ele unc ion and pe ipa um bleeding in women wi h gauche disease.
Th omb Aemos . 2011;105:509–14. h p s : / / d o i . o g / 1 0 . 1 1 6 0 / T H 1 0 - 0 7 - 0 5 0 3.
17. Hughes D, Mikosch P, Belma oug N, Ca ubbi F, Cox T, Goke -Alpan O, Kind-
ma k A, Mis y P, Poll L, Wein eb N, Deegan P. Gauche disease in bone: om
pa hophysiology o p ac ice. J Bone Min Res. 2019;34:996–1013. h p s : / / d o i . o
g / 1 0 . 1 0 0 2 / j b m . 3 7 3 4.
18. Lujano-Neg e e AY, Rod íguez-Ruiz MC, Skinne -Taylo CM, Pe ez-Ba bosa L,
Ca denas de la Ga za JA, Ga cía-He nández PA, Espinosa-Banuelos LG, Gu i-
e ez-Leal LF, Jezzini-Ma ínez S, Gala za-Delgado DÁ. Bone me abolism and
os eopo osis du ing p egnancy and lac a ion. A ch Os eopo os. 2022;17:36. h
p s : / / d o i . o g / 1 0 . 1 0 0 7 / s 1 1 6 5 7 - 0 2 2 - 0 1 0 7 7 - x.
19. Kong W, Lu C, Ding Y, Meng Y. Upda e o ea men o gauche disease. Eu J
Pha macol. 2022;926:175023. h p s : / / d o i . o g / 1 0 . 1 0 1 6 / j . e j p h a . 2 0 2 2 . 1 7 5 0 2 3.
20. Cox TM, Ae s JM, Belma oug N, Cappellini MD, om Dahl S, Goldbla J,
G abowski GA, Hollak CE, Hwu P, Maas M, Ma ins AM, Mis y PK, Pas o es GM,
Tylki-Szymanska A, Yee J, Wein eb N. Managemen o non-neu onopa hic
gauche disease wi h special e e ence o p egnancy, splenec omy, bisphos-
phona e he apy, use o bioma ke s and bone disease moni o ing. J Inhe i
Me ab Dis. 2008;31:319–36. h p s : / / d o i . o g / 1 0 . 1 0 0 7 / s 1 0 5 4 5 - 0 0 8 - 0 7 7 9 - z.
21. G ano sky-G isa u S, Belma oug N, om Dahl S, Mengel E, Mo is E, Zim an
A. The managemen o p egnancy in gauche disease. Eu J Obs e Gynecol
Rep od Biol. 2011;156:3–8. h p s : / / d o i . o g / 1 0 . 1 0 1 6 / j . e j o g b . 2 0 1 0 . 1 2 . 0 2 4.
22. Rosenbaum H. Managemen o women wi h gauche disease in he ep o-
duc i e age. Th omb Res. 2015;135(Suppl 1):S49–51. h p s : / / d o i . o g / 1 0 . 1 0 1 6 /
S 0 0 4 9 - 3 8 4 8 ( 1 5 ) 5 0 4 4 3 - X. E a um in: Th omb Res 2015;136:489.
23. Belma oug N, He aoui D. Maladie de gauche e G ossesse [Gauche disease
and p egnancy]. P esse Med. 2009;38(Suppl 2):S217–23. h p s : / / d o i . o g / 1 0 . 1 0
1 6 / S 0 7 5 5 - 4 9 8 2 ( 0 9 ) 7 3 6 6 3 - 2.
24. G upo de abajo sob e GPC. Elabo ación de guías de p ác ica clínica en el
Sis ema Nacional de Salud. Manual me odológico [In e ne ]. Mad id: Plan
Nacional pa a el SNS del MSC. Ins i- u o A agonés de Ciencias de la Salud-
IACS. 2016. (Guías de p ác ica clínica en el SNS: IACS N.◦ 2016/0I). A ailable
om: h p s : / / p o a l . g u i a s a l u d . e s / e g p c / m a n u a l - e l a b o a c i o n - a c u a l i z a c i o n /
[accessed 16.04.23].
25. Guya GH, Oxman AD, Vis GE, Kunz R, Falck-Y e Y, Alonso- Coello P, Schüne-
mann HJ, GRADE Wo king G oup. GRADE: an eme ging consensus on a ing
quali y o e idence and s eng h o ecommenda ions. BMJ. 2008;336:924–6.
26. Fi ch K, Be ns ein S, Aguila MD, Bu nand B, LaCalle JR, Láza o P, an he Loo
M, McDonnelll J, Vade J, Kahan JP, edi o s. The RAND/UCLA app op ia eness
me hod use ’s manual. San a Mónica: RAND Heal h; 2001.
27. Cen e s o Disease Con ol and P e en ion. Asplenia and Adul Vaccina ion
[In e ne ] A ailable om: h p s : / / w w w . c d c . g o / a c c i n e s / a d u l s / e c - a c / h e a l
h - c o n d i i o n s / a s p l e n i a . h m l [accessed 26.04.23].
28. Koscielny J, Zieme S, Rad ke H, Schmu zle M, P uss A, Sinha P, Salama A,
Kiesewe e H, La za R. A p ac ical concep o p eope a i e iden i ica ion
o pa ien s wi h impai ed p ima y hemos asis. Clin Appl Th omb Hemos .
2004;10:195–204. h p s : / / d o i . o g / 1 0 . 1 1 7 7 / 1 0 7 6 0 2 9 6 0 4 0 1 0 0 0 3 0 1.
29. Spec e G, Ro h B, Ronen G, Rosenga en D, Els ein D, Zim an A, Va on D,
Re el-Vilk S. Pla ele adhesion de ec in ype I gauche disease is associa ed
wi h a isk o mucosal bleeding. B J Haema ol. 2011;153:372–8.
Publishe ’s no e
Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in
published maps and ins i u ional a ilia ions.