Ap il 2017 | Volume 8 | A icle 1441
O iginal esea ch
published: 18 Ap il 2017
doi: 10.3389/ neu .2017.00144
F on ie s in Neu ology | www. on ie sin.o g
Edi ed by:
J. Ma c Sima d,
Uni e si y o Ma yland
Bal imo e, USA
Re iewed by:
Anke Höllig,
Uniklinik RWTH Aachen,
Ge many
Ca on Hong,
Uni e si y o Ma yland
Medical Cen e , USA
*Co espondence:
Heikki Kiiski
[email p o ec ed]
†These au ho s ha e con ibu ed
equally o his wo k.
Special y sec ion:
This a icle was submi ed
o Neu oc i ical and
Neu ohospi alis Ca e,
a sec ion o he jou nal
F on ie s in Neu ology
Recei ed: 15Feb ua y2017
Accep ed: 30Ma ch2017
Published: 18Ap il2017
Ci a ion:
KiiskiH, JalkanenV, Ala-Peija iM,
HämäläinenM, MoilanenE, Pel olaJ
and TenhunenJ (2017) Plasma
Soluble U okinase-Type Plasminogen
Ac i a o Recep o Is No Associa ed
wi h Neu ological Ou come in
Pa ien s wi h Aneu ysmal
Suba achnoid Hemo hage.
F on . Neu ol. 8:144.
doi: 10.3389/ neu .2017.00144
Plasma soluble U okinase-Type
Plasminogen ac i a o ecep o
is no associa ed wi h neu ological
Ou come in Pa ien s wi h
aneu ysmal suba achnoid
hemo hage
Heikki Kiiski1*†, Ville Jalkanen1†, Ma ika Ala-Peija i1, Ma i Hämäläinen2, Ee a Moilanen2,
Jukka Pel ola3 and Jy ki Tenhunen1,4
1 C i ical Ca e Medicine Resea ch G oup, Depa men o In ensi e Ca e, Tampe e Uni e si y Hospi al, Tampe e, Finland,
2 The Immunopha macology Resea ch G oup, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Tampe e
Uni e si y Hospi al, Tampe e, Finland, 3 Depa men o Neu ology, Uni e si y o Tampe e, Tampe e Uni e si y Hospi al,
Tampe e, Finland, 4 Depa men o Su gical Sciences, Di ision o Anes hesiology and In ensi e Ca e, Uppsala Uni e si y,
Uppsala, Sweden
Objec : Aneu ysmal suba achnoid hemo hage (aSAH) is a common cause o dea h o
long- e m disabili y. Despi e ad ances in neu oc i ical ca e, he e is s ill only a e y limi ed
abili y o moni o he de elopmen o seconda y b ain inju y o o p edic neu ological
ou come a e aSAH. Soluble u okinase- ype plasminogen ac i a o ecep o (suPAR)
has shown po en ial as a p ognos ic and as an in lamma o y bioma ke in a wide ange
o c i ical illnesses since i displays an associa ion wi h o e all immune sys em ac i a ion.
This is he i s ime ha suPAR has been e alua ed as a p ognos ic bioma ke in aSAH.
Me hods: In his p ospec i e popula ion-based s udy, plasma suPAR le els we e mea-
su ed in aSAH pa ien s (n=47) o up o 5days. suPAR was measu ed a 0, 12, and
24h a e pa ien admission o he in ensi e ca e uni (ICU) and daily he ea e un il he/
she was ans e ed om he ICU. The pa ien s’ neu ological ou come was e alua ed
wi h he modi ied Rankin Scale (mRS) a 6mon hs a e aSAH.
esul s: suPAR le els (n=47) du ing he i s 24h a e aSAH we e compa able in g oups
wi h a a o able (mRS 0–2) o an un a o able (mRS 3–6) ou come. suPAR le els du ing
he i s 24h we e no associa ed wi h he indings in he p ima y b ain CT, wi h acu e
hyd ocephalus, o wi h an imic obial medica ion use du ing 5-days’ ollow-up. suPAR
le els we e associa ed wi h gene ally accep ed in lamma o y bioma ke s (C- eac i e
p o ein, leukocy e coun ).
conclusion: Plasma suPAR le el was no associa ed wi h ei he neu ological ou come
o selec ed clinical condi ions. While suPAR is a p omising bioma ke o p ognos ica ion
in se e al condi ions equi ing in ensi e ca e, i did no e eal any alue as a p ognos ic
bioma ke a e aSAH.
Keywo ds: aneu ysmal suba achnoid hemo hage, bioma ke s, neu ological ou come, seconda y b ain inju y,
soluble u okinase- ype plasminogen ac i a o ecep o , neu oin lamma ion
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Kiiski e al. Plasma suPAR Is No P ognos ic in aSAH
F on ie s in Neu ology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 144
inT ODUcTiOn
U okinase plasminogen ac i a o ecep o (uPAR) (CD87) is
p esen on a ious immunologically ac i e cells, and i s exp es-
sion becomes ele a ed by in lamma o y condi ions and ischemic
diseases (1, 2). The soluble o m [soluble u okinase- ype plas-
minogen ac i a o ecep o (suPAR)] in se um o plasma has
eme ged as an in lamma o y bioma ke capable o e lec ing
o e all immune sys em ac i a ion (3, 4).
P e iously, i has been shown ha uPAR exp ession is induced
in ce eb al ischemia (5) and auma ic b ain inju y (6). Mo eo e ,
i has been claimed ha uPAR may u he augmen ce eb al
inju y (7). The induc ion o uPAR exp ession on he cell su ace
is belie ed o inc ease he le els o he soluble o m o uPAR (8).
P e iously, suPAR has been shown o ha e p edic i e alue in
acu ely, c i ically ill pa ien s (9–13), including hose who ha e
su e ed b ain auma (14). Howe e , as a as we a e awa e,
suPAR concen a ions ha e no been e alua ed as a p ognos ic
bioma ke in pa ien s wi h suba achnoid hemo hage.
Aneu ysmal suba achnoid hemo hage (aSAH) is a de as a -
ing disease causing long- e m disabili y and up o 50% mo ali y
(15). A signi ican p opo ion o he pa ien s a e young and
p e iously heal hy in compa ison o indi iduals su e ing o he
ypes o s okes (16). The main causes o poo p ognosis a e
ea ly b ain inju y and delayed ce eb al ischemia (DCI), which
cause pe manen neu ological de ici s (17–19). The p edic ion o
ou come is di icul and unsa is ac o y as he seconda y inju y
p ocess in aSAH is mul i ac o ial and incomple ely unde s ood
(17, 20).
I is well es ablished ha in lamma ion plays a majo ole in
asospasm and subsequen DCI a e aSAH (21, 22). A ple ho a
o bioma ke s ha e been s udied in aSAH and DCI, e.g., neu on
and as ocy e-speci ic ma ke s (e.g., NSE, s100b, and UCHL-1),
in lamma o y bioma ke s (e.g., IL-6, HMGB-1), and molecula
adhesion and ex acellula ma ix ma ke s (e.g., MMP-9)
(16, 23–25). Howe e , none o hese pu a i e bioma ke s has so
a p o ed o be use ul in clinical decision-making. As ischemic
e en s and in lamma ion a e one cha ac e is ic ea u e o aSAH,
i seemed easonable o specula e ha ci cula ing plasma suPAR
concen a ions would inc ease du ing he acu e s age a e aSAH.
The e o e, we hypo hesized ha ei he he plasma suPAR concen-
a ion o al e na i ely i s changes o e ime could be use ul in
p edic ing he neu ological ou come ollowing aSAH.
MaTe ials anD MeThODs
The clinical da a and blood samples om his pa ien coho ha e
been used in a p e iously published s udy (25). Following eg-
is a ion in Clinical T ials (NCT02026596, h ps://clinical ials.
go ) and app o al by he ins i u ional e hics commi ee, we con-
duc ed a p ospec i e, obse a ional, single-cen e clinical s udy
in Tampe e Uni e si y Hospi al (Tampe e, Finland) in ensi e
ca e uni (ICU). The s udy popula ion consis ed o 61 consecu-
i e adul aSAH pa ien s admi ed o ou e ia y e e al cen e
du ing a 10-mon h pe iod in 2013. W i en in o med consen
was ob ained om each o he pa ien s o om hei nex o
kin. All pa ien s we e ea ed acco ding o s anda d in-house
guidelines, which included in a enous nimodipine o p e en
asospasm and ou ine labo a o y samples. In he inal analyses,
we chose o exclude hose 14 pa ien s wi h an unknown ime o
onse o symp oms o in whom he suPAR concen a ion was no
measu ed du ing he i s 24h a e he onse o symp oms. By
including only hose 47 pa ien s wi h a known onse o clinical
ic us and suPAR measu emen du ing he i s 24 h a e he
onse o symp oms, we elimina ed he possibili y ha changes in
suPAR concen a ions would be a ibu able o di e en delays o
hospi al admission a e aSAH.
The plasma suPAR concen a ion was measu ed a 0, 12, and
24h a e he admission and e e y 24h o up o 5days o un il
he pa ien was ans e ed om he ICU. Wo ld Fede a ion o
Neu ological Su geons G ading Scale, Fishe g ade, and 6-mon h
modi ied Rankin Scale (mRS) we e used o e alua e he se e -
i y o aSAH and neu ological eco e y as p e iously desc ibed
(25). The incidence o acu e hyd ocephalus was de ined as he
need o en iculos omy on a clinical basis du ing he i s 24h
a e aSAH. In ec ion was de ined as he need o an imic obial
medica ion du ing in ensi e ca e ollow-up pe iod.
As a pa o ou in-house guideline, an a e ial cannula was
ou inely inse ed. Blood samples o suPAR we e collec ed
in o EDTA-con aining ubes om he a e ial cannula and he
samples we e immedia ely cen i uged o 10min a 2,000g a
oom empe a u e. A e cen i uga ion, he plasma was collec ed
and ozen a −70°C. A e hawing, plasma suPAR le els we e
measu ed wi h a comme cially a ailable enzyme-linked immu-
noso ben assay ki acco ding o he manu ac u e ’s ins uc ions
(suPARnos ic®, Vi oGa es, Bi ke oed, Denma k). The de ec ion
limi and in e -assay coe icien o a ia ion we e 0.45ng/ml and
3.2%, espec i ely.
Be o e he s a is ical analysis, he suPAR measu emen s we e
di ided in o consecu i e 24h in e als, s a ing om he onse o
symp oms. I suPAR was measu ed mo e han once pe in e al,
he mean concen a ion was used. In a subg oup o 22 pa ien s
who had up o 5-days’ ollow-up, we also checked whe he he
pa ien had been ea ed o DCI. Ini ia ion o his ea men was
based on clinical e alua ion. S a is ical analyses we e pe o med
wi h R ( e sion 3.3.2 o Mac Os X). Fishe ’s exac es was used
wi h he ca ego ical a iables. Due o he non-no mal dis ibu-
ion o measu ed bioma ke s, Mann–Whi ney U- es was used
o be ween-g oup compa isons. Co ela ions we e e alua ed
wi h Spea man’s co ela ion es . Linea eg ession was used in
he ime in e al analyses.
esUlTs
The basic cha ac e is ics o he s udy coho and he subse o
pa ien s wi h 5-day ollow-up ha e been p e iously epo ed
(25). The ime cou se o plasma suPAR concen a ions in he
wo g oups acco ding o neu ological ou come a e depic ed in
Figu e1.
Plasma suPAR concen a ions du ing he i s 24h a e aSAH
we e compa able in he g oups wi h a a o able (mRS 0–2) and an
un a o able (mRS 3–6) ou come (Figu e2A). Simila ly, no di -
e ences we e de ec ed in he suPAR le els be ween hose pa ien s
p esen ing wi h se e e (WFNS 4–5) s. non-se e e (WFNS 1–3)
FigU e 1 | soluble u okinase- ype plasminogen ac i a o ecep o (suPa ) le els in all pa ien s and a all ime in e als. Values a e g ouped acco ding
o whe he he pa ien s had a a o able o an un a o able neu ological ou come. Do s ep esen indi idual pa ien alues. The line ep esen s g oup median.
FigU e 2 | soluble u okinase- ype plasminogen ac i a o ecep o (suPa ) le els du ing he i s 24h a e aneu ysmal suba achnoid hemo hage
be ween pa ien s (n=47) wi h a a o able o an un a o able neu ological ou come (a). suPAR le els a he end o 5-day ollow-up be ween pa ien s
(n=22) wi h a a o able o an un a o able neu ological ou come (B).
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Kiiski e al. Plasma suPAR Is No P ognos ic in aSAH
F on ie s in Neu ology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 144
indings in e ms o hei clinical s a us on admission (Table1).
Fu he mo e, he plasma suPAR concen a ion du ing he i s
24h was no associa ed wi h he indings om he p ima y b ain
CT (Fishe g ade) wi h acu e hyd ocephalus o wi h an imic o-
bial medica ion du ing he 5-days’ ollow-up (Table1). Age o e
70yea s was a s ong p edic o o an un a o able neu ological
ou come, i.e., only one pa ien o e 70 yea s expe ienced a
neu ologically a o able ou come (p=0.037, Table2).
suPAR was measu ed daily up o 5days a e he admission
unless he pa ien died o was ans e ed om he ICU. In he 22
pa ien s in whom we had suPAR concen a ions measu ed up o
5days, ou pa ien s achie ed a a o able neu ological ou come
TaBle 2 | The ela ionship be ween neu ological ou come and age.
age≤70 age>70 p-Value
0.037
Modi ied Rankin Scale (mRS) 0–2 15 1
mRS 3–6 20 11
Fishe ’s exac es was used.
TaBle 1 | soluble u okinase- ype plasminogen ac i a o ecep o
(suPa ) concen a ions (n=47) wi hin 24h om aneu ysmal
suba achnoid hemo hage and he associa ion wi h selec ed clinical
condi ions.
suPa (ng/ml) Mean sD Median iQ p-Value
Modi ied Rankin Scale 0.234
0–2 (n=16) 2.30 0.75 2.21 1.73–2.77
3–6 (n=31) 2.66 0.96 2.37 2.06–3.05
Wo ld Fede a ion o
Neu ological Su geons
g ading scale
0.803
1–3 (n=28) 2.59 1.05 2.26 2.00–2.79
4–5 (n=19) 2.47 0.66 2.41 2.00–2.86
Fishe 0.240
1–2 (n=14) 2.36 0.93 2.05 1.67–2.78
3–4 (n=33) 2.61 0.90 2.41 2.07–2.80
In ec ion 0.402
Yes (n=14) 2.55 0.64 2.61 2.21–2.88
No (n=33) 2.53 1.01 2.22 1.92–2.79
Acu e hyd ocephalus 0.845
Yes (n=19) 2.54 0.83 2.27 2.09–2.80
No (n=28) 2.53 0.97 2.34 1.92–2.83
Mann–Whi ney U- es was used.
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Kiiski e al. Plasma suPAR Is No P ognos ic in aSAH
F on ie s in Neu ology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 144
(mRS 0–2). The linea eg ession did no de ec any s a is ically
signi ican ele a ion o suPAR le els du ing he 5-days’ ollow-up
in pa ien s wi h ei he a a o able (mRS 0–2) o an un a o able
(mRS 3–6) neu ological ou come (Figu e3). In addi ion, a day
i e, plasma suPAR concen a ions we e compa able in he wo
g oups (Figu e2B).
Delayed ce eb al ischemia ea men was ini ia ed in 16/22
pa ien s du ing he hospi al s ay in he subg oup in which we
had a leas a 5-day ICU ollow-up. Nei he DCI ea men no
in ec ion o acu e hyd ocephalus was associa ed wi h plasma
suPAR concen a ions (Table3).
The peak plasma suPAR concen a ion du ing he 5days o
ollow-up was posi i ely co ela ed wi h peak le els o C- eac i e
p o ein (CRP) (p=0.039) and leukocy e numbe s (p=0.006).
The plasma suPAR concen a ion was posi i ely co ela ed wi h
he leukocy e coun du ing he i s 24h (p=0.049). In con as ,
suPAR le els we e no associa ed wi h age (Table4).
DiscUssiOn
The p esen s udy aimed o e alua e he po en ial p ognos ic alue
o plasma suPAR concen a ions a e an aSAH. In con as o ou
wo king hypo hesis, plasma suPAR did no show any associa ion
wi h neu ological ou come, su i al, acu e hyd ocephalus, clini-
cal in ec ion, o DCI in ou pa ien coho .
The in lamma o y eac ion and inc ease o sys emic in lam-
ma o y media o s in aSAH is well documen ed (22, 26). E en
hough subs an ial e idence is accumula ing in he li e a u e
highligh ing he signi ican ole o neu oin lamma ion in he
ou come o aSAH, i is s ill unclea which, i any, in lamma o y
bioma ke s can be used o guide clinical decision-making. The
appa en biphasic na u e o he in lamma o y esponse a e aSAH
makes his challenge e en mo e demanding. Neu oin lamma ion
seems o ha e p ope ies, which can be conside ed in some cases
as p o ec i e, bu in o he s, as dele e ious, e.g., depending on
he magni ude o he esponse, ime-poin a e he ic us when
ac i a ion o he in lamma o y esponse occu s, and he ype o
cells ec ui ed in he esponse (27). Hence, i is no su p ising
ha he e is inconsis ency ega ding he p ognos ic alue o many
in lamma o y bioma ke s such as IL-6 and HMGB1 a e aSAH
(19, 25, 28, 29). Ne e heless, al hough no bioma ke has been
iden i ied, hese s udies ha e inc eased ou unde s anding o he
in lamma o y p ocess in aSAH and, in ac , also no el in lamma-
o y bioma ke s a e claimed o ha e some p ognos ic po en ial,
e.g., oll-like ecep o 4 (30).
suPAR is conside ed as an in lamma o y bioma ke and
media o , a p oposal ha is well suppo ed in he li e a u e.
P e iously, inc eased se um o plasma suPAR le els ha e been
pos ula ed as a p ognos ic ac o o poo ou come in c i ically
ill pa ien s wi h an in lamma o y condi ion (31). The plasma
suPAR concen a ions in ou aSAH coho we e low compa ed
o sep ic and non-sep ic ICU pa ien s wi h o gan dys unc ion
(32). Nosocomial in ec ions, o gan dys unc ion, and SIRS a e
equen a e aSAH (33, 34). Al hough he alue o suPAR has
been e i ied in in ec ions and o gan dys unc ion (13, 32, 35), we
did no de ec high le els o suPAR, e en la e in he cou se o
in ensi e ca e. One possible con ounding ac o dis inguishing
aSAH om o he acu e neu ological condi ions is ha all o ou
pa ien s ecei ed nimodipine o p e en DCI. Nimodipine has
been shown o dec ease plasminogen ac i a o inhibi o 1 (PAI-1)
ac i i y (36). As PAI-1 is he majo inhibi o o u okinase plasmi-
nogen ac i a o (uPA), plasminogen ac i i y and ib inolysis may
inc ease as a consequence o dec eased PAI-1 ac i i y. UPA can
clea e he GPI-ancho on cell su ace, bu since a co ec a io o
uPA is equi ed o clea age, i is possible ha excess uPA due o
nimodipine may inhibi he clea age o suPAR om he cell su -
ace (4, 8). suPAR also displays uPA dose dependence o binding
o i onec in (37), which may al e suPAR le els. Fu he mo e,
p e ious epo s ha e desc ibed suPAR- agmen elease om
ac i a ed neu ophils (38) and inhibi ion o neu ophil ac i a ion
by wo calcium an agonis s, elodipine, and nimodipine (39),
he eby suppo ing he concep ha nimodipine may indeed be
he ac o modi ying he suPAR esponse in ou pa ien coho .
This specula i e hypo hesis and hus he po en ial di ec e ec o
nimodipine on plasma suPAR concen a ions could no be u he
es ed/e alua ed in ou pa ien coho . Mo eo e , as nimodipine
is conside ed as pa o cu en bes p ac ice, i would be une hi-
cal o es ablish a con ol g oup no ecei ing nimodipine a e
aSAH. Any u he expe imen s o es his hypo hesis will need
o be conduc ed as p eclinical/animal s udies.
O e all, he suPAR esponse, i.e., he inc ease in he plasma
concen a ions o suPAR obse ed in his s udy, was a he
modes in compa ison wi h ha obse ed in o he c i ically ill
pa ien s, e en hough he e was biochemically logical co ela ion
TaBle 4 | soluble u okinase- ype plasminogen ac i a o ecep o and i s
associa ion wi h leukocy e coun , c- eac i e p o ein (c P), and age.
spea man ho p-Value
Day 1 (n=47)
Leukocy e coun 0.289 0.049
CRP 0.261 0.077
AGE 0.228 0.123
5-day in ensi e ca e uni ollow-up (n=22)
Maximum leukocy e coun du ing ollow-up 0.568 0.006
Maximum CRP du ing ollow-up 0.443 0.039
Age 0.143 0.527
TaBle 3 | soluble u okinase- ype plasminogen ac i a o ecep o
(suPa ) le els on day i e om aneu ysmal suba achnoid hemo hage
pa ien s (n=22) in whom he e was 5-days’ in ensi e ca e uni ollow-up
da a and hei associa ion wi h selec ed clinical condi ions.
suPa (ng/ml) Mean sD Median iQ p-Value
Modi ied Rankin Scale 0.187
0–2 (n=4) 2.24 0.72 2.18 1.99–2.43
3–6 (n=18) 2.95 0.81 2.90 2.49–3.70
Delayed ce eb al ischemia
ea men
0.854
Yes (n=16) 2.80 0.79 2.64 2.18–3.32
No (n=6) 2.89 1.00 3.12 2.25–3.48
In ec ion 0.511
Yes (n=11) 2.97 0.81 3.09 2.60–3.67
No (n=11) 2.68 0.86 2.46 2.01–3.17
Acu e hyd ocephalus 0.511
Yes (n=11) 2.70 0.91 2.64 1.91–3.45
No (n=11) 2.95 0.77 3.09 2.32–3.39
Mann–Whi ney U- es was used.
FigU e 3 | soluble u okinase- ype plasminogen ac i a o ecep o (suPa ) le els o pa ien s wi h a ollow-up o up o 5days (n=22). Do s ep esen
indi idual pa ien alues. Reg ession line is calcula ed wi h linea eg ession. Values a e g ouped acco ding o a o able (p=0.584) o non- a o able (p=0.158)
neu ological ou come.
5
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F on ie s in Neu ology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 144
be ween suPAR le els and gene ally accep ed in lamma o y
bioma ke s (CRP, leukocy e coun ). The co ela ion, howe e ,
was weak in compa ison o p e iously epo ed esul s (35, 40)
possibly indica ing ha he e a e nume ous ac o s in luencing
in lamma o y bioma ke s and media o s in aSAH. In addi ion,
al hough highe age was associa ed wi h poo ou come pe se,
in ou pa ien coho , we obse ed no co ela ion be ween age
and plasma suPAR le els. This inding con adic s he esul s o
se e al p e ious s udies (10, 13, 41, 42). Finally, he low incidence
(29.8%) o nosocomial in ec ions in ou pa ien coho may pa -
ially explain he obse ed low plasma suPAR le els.
E en hough se um suPAR le els ha e been shown o be
ele a ed in ischemic s oke (43) and in ce eb ospinal luid (CSF)
ollowing dis up ion o he blood–b ain ba ie (44), no ma ked
ele a ion o plasma suPAR was ound in pa ien s ei he diagnosed
wi h DCI o acu e hyd ocephalus. Fu he analyses will be neces-
sa y o cla i y po en ial impo ance o suPAR elease o CSF in
pa ien s wi h DCI and acu e hyd ocephalus. In o de o e eal
he ac ual ole o suPAR as a bioma ke o media o in aSAH,
i would be wo hwhile e alua ing he po en ial alue o suPAR
le els in CSF in diagnosing en iculi is ela ed o en iculos-
omy ca he e .

6
Kiiski e al. Plasma suPAR Is No P ognos ic in aSAH
F on ie s in Neu ology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 144
Ou s udy has some limi a ions. Fi s , we had some pa ien s
ha we e los o ollow-up. In o he wo ds, we we e no able o
ob ain samples la e in he cou se o he acu e illness as pa ien s
had ei he died o been ans e ed o some o he heal h-ca e
acili y. These pa ien s ep esen wo ex emes, i.e., ei he he bes
o he wo s ou come, and his may ha e al e ed he esul s o ou
analysis. Second, ou sample size was limi ed. In pa icula , only
ou pa ien s wi h a a o able neu ological ou come emained
in he inal analyses on day 5. Howe e , some o ou pa ien s
expe ienced mild whe eas o he s had e y se e e p esen a ions
o aSAH. We ollowed suPAR le els du ing he whole ICU s ay
and suPAR le els we e cons an ly low wi h no high peaks being
obse ed. This sugges s ha aSAH does no induce high suPAR
le els in plasma o hey a e dep essed by some aspec o he
ea men , o example, adminis a ion o he calcium an agonis .
Thi d, ou s udy is a single-cen e s udy. Al hough ou uni is a
e ia y e e al hospi al wi h a high pa ien in lux, single-cen e
bias is possible. Despi e hei ela i ely low numbe s, i is o
in e es ha hose pa ien s wi h a good neu ological ou come
had ema kably low plasma suPAR le els wi h a e y small SD
(Figu e2B). Ou p e ious s udies ha e sugges ed ha while high
suPAR le els may be p ognos ic o poo ou come, in con as , a
low plasma suPAR concen a ion is p edic i e o a good ou come
(11, 45). In he p esen s udy, he numbe o pa ien s is limi ed,
bu he same phenomenon may apply o aSAH.
cOnclUsiOn
This s udy epo s he i s popula ion-based p ospec i e,
obse a ional esul s e alua ing plasma suPAR concen a ions
in aSAH. Plasma suPAR le els we e no associa ed wi h neu o-
logical ou come o selec ed clinical condi ions. While suPAR is a
p omising bioma ke in se e al condi ions equi ing in ensi e
ca e, based on his s udy, i does no seem o be use ul as a p og-
nos ic bioma ke in pa ien s wi h aSAH.
eThics sTaTeMenT
The s udy was app o ed by he E hics Commi ee o Pi kanmaa
Hospi al Dis ic . W i en in o med consen was ob ained om
each o he pa ien s o om he nex o kin.
aUThO cOnT iBUTiOns
HK con ibu ed o s udy concep ion, neu ological ou come
e alua ions, s a is ical analyses, and d a ed o he manusc ip .
VJ con ibu ed o pa ien ec ui men , s a is ical analyses, and
d a ed he manusc ip . MA-P con ibu ed o pa ien ec ui -
men , e alua ion o he ini ial clinical se e i y, e alua ion o
he ini ial compu ed omog aphy indings, and d a ed he
manusc ip . MH con ibu ed o he labo a o y analysis o suPAR
and d a ed he manusc ip . EM con ibu ed o he labo a o y
analysis o suPAR and d a ed he manusc ip . JP con ibu ed o
neu ological ou come e alua ions, and d a ed he manusc ip .
JT con ibu ed o s udy concep ion, s a is ical analyses, and
d a ed he manusc ip .
FUnDing
The s udy was inancially suppo ed by he Compe i i e S a e
Resea ch Financing o he Expe Responsibili y a ea o Tampe e
Uni e si y Hospi al.
eFe ences
1. Fuh man B. The u okinase sys em in he pa hogenesis o a he oscle osis.
A he oscle osis (2012) 222:8–14. doi:10.1016/j.a he oscle osis.2011.10.044
2. Smi h HW, Ma shall CJ. Regula ion o cell signalling by uPAR. Na Re Mol
Cell Biol (2010) 11:23–36. doi:10.1038/n m2821
3. Backes Y, an de Sluijs KF, Tuip de Boe AM, Ho s a JJ, Vlaa AP,
De e mann RM, e al. Soluble u okinase- ype plasminogen ac i a o ecep o
le els in pa ien s wi h bu n inju ies and inhala ion auma equi ing mechan-
ical en ila ion: an obse a ional coho s udy. C i Ca e (2011) 15:R270.
doi:10.1186/cc10550
4. Thunø M, Macho B, Eugen-Olsen J. suPAR: he molecula c ys al ball. Dis
Ma ke s (2009) 27:157–72. doi:10.3233/DMA-2009-0657
5. Pe sson M, Ös ling G, Smi h G, Ham e o s V, Melande O, Hedblad B,
e  al. Soluble u okinase plasminogen ac i a o ecep o : a isk ac o o
ca o id plaque, s oke, and co ona y a e y disease. S oke (2014) 45:18–23.
doi:10.1161/STROKEAHA.113.003305
6. Bescho ne R, Schluesene HJ, Nguyen TD, Magdolen V, Lu he T, Pedal I,
e al. Lesion-associa ed accumula ion o uPAR/CD87- exp essing in il a ing
g anulocy es, ac i a ed mic oglial cells/mac ophages and up egula ion
by endo helial cells ollowing TBI and FCI in humans. Neu opa hol Appl
Neu obiol (2000) 26:522–7. doi:10.1046/j.0305-1846.2000.287.x
7. Nagai N, Okada K, Kawao N, Ishida C, Ueshima S, Collen D, e al. U okinase-
ype plasminogen ac i a o ecep o (uPAR) augmen s b ain damage in a
mu ine model o ischemic s oke. Neu osci Le (2008) 432:46–9. doi:10.1016/j.
neule .2007.12.004
8. Høye -Hansen G, Ploug M, Beh end N, Rønne E, Danø K. Cell-su ace
accele a ion o u okinase-ca alyzed ecep o clea age. Eu J Biochem (1997)
243:21–6. doi:10.1111/j.1432-1033.1997.0021a.x
9. Donadello K, Scolle a S, Taccone FS, Co ajes C, San onoci o C, Co es DO,
e al. Soluble u okinase- ype plasminogen ac i a o ecep o as a p ognos ic
bioma ke in c i ically ill pa ien s. J C i Ca e (2014) 29:144–9. doi:10.1016/j.
jc c.2013.08.005
10. Haup TH, Pe e sen J, Ellekilde G, Klausen HH, Tho ball CW, Eugen-
Olsen J, e al. Plasma suPAR le els a e associa ed wi h mo ali y, admission
ime, and Cha lson Como bidi y Index in he acu ely admi ed medical pa ien :
a p ospec i e obse a ional s udy. C i Ca e (2012) 16:R130. doi:10.1186/
cc11434
11. Jalkanen V, Yang R, Linko R, Huh ala H, Okkonen M, Va pula T, e al. suPAR
and PAI-1 in c i ically ill, mechanically en ila ed pa ien s. In ensi e Ca e Med
(2013) 39:489–96. doi:10.1007/s00134-012-2730-x
12. Zimme mann HW, Koch A, Seidle S, T au wein C, Tacke F. Ci cula ing solu-
ble u okinase plasminogen ac i a o is ele a ed in pa ien s wi h ch onic li e
disease, disc imina es s age and ae iology o ci hosis and p edic s p ognosis.
Li e In (2012) 32:500–9. doi:10.1111/j.1478-3231.2011.02665.x
13. Hu unen R, Sy jänen J, Vuen o R, Hu me M, Huh ala H, Laine J, e  al.
Plasma le el o soluble u okinase- ype plasminogen ac i a o ecep o as a
p edic o o disease se e i y and case a ali y in pa ien s wi h bac e aemia:
a p ospec i e coho s udy. J In e n Med (2011) 270:32–40. doi:10.1111/j.
1365-2796.2011.02363.x
14. Yu L, Wu X, Wang H, Long D, Yang J, Zhang Y. Diagnos ic and p ognos ic sig-
ni icance o suPAR in auma ic b ain inju y. Neu ol India (2014) 62:498–502.
doi:10.4103/0028-3886.144439
15. Zacha ia BE, Hickman ZL, G obelny BT, DeRosa P, Ko che ko I, Duc ue AF,
e al. Epidemiology o aneu ysmal suba achnoid hemo hage. Neu osu g Clin
N Am (2010) 21:221–33. doi:10.1016/j.nec.2009.10.002
16. Ca pen e KL, Czosnyka M, Jalloh I, Newcombe VF, Helmy A, Shannon RJ,
e al. Sys emic, local, and imaging bioma ke s o b ain inju y: mo e needed,
7
Kiiski e al. Plasma suPAR Is No P ognos ic in aSAH
F on ie s in Neu ology | www. on ie sin.o g Ap il 2017 | Volume 8 | A icle 144
and be e use o hose al eady es ablished. F on Neu ol (2015) 6:26.
doi:10.3389/ neu .2015.00026
17. Budohoski KP, Guil oyle M, Helmy A, Huuskonen T, Czosnyka M,
Ki ollos R, e al. The pa hophysiology and ea men o delayed ce eb al isch-
aemia ollowing suba achnoid haemo hage. J Neu ol Neu osu g Psychia y
(2014) 85:1343–53. doi:10.1136/jnnp-2014-307711
18. Rowland MJ, Hadjipa lou G, Kelly M, Wes b ook J, Pa inson KT. Delayed
ce eb al ischaemia a e suba achnoid haemo hage: looking beyond aso-
spasm. B J Anaes h (2012) 109:315–29. doi:10.1093/bja/aes264
19. Sa a zadeh AS, Vajkoczy P, Bijlenga P, Schalle K. Moni o ing in neu o-
in ensi e ca e – he challenge o de ec delayed ce eb al ischemia in high-
g ade aneu ysmal SAH. F on Neu ol (2014) 5:134. doi:10.3389/ neu .2014.
00134
20. Macdonald RL, Plu a RM, Zhang JH. Ce eb al asospasm a e suba achnoid
hemo hage: he eme ging e olu ion. Na Clin P ac Neu ol (2007) 3:256–63.
doi:10.1038/ncpneu o0490
21. Dumon AS, Dumon RJ, Chow MM, Lin CL, Calisanelle T, Ley KF, e al.
Ce eb al asospasm a e suba achnoid hemo hage: pu a i e ole o in lam-
ma ion. Neu osu ge y (2003) 53:123–35. doi:10.1227/01.NEU.0000068863.
37133.9E
22. Mille BA, Tu an N, Chau M, P adilla G. In lamma ion, asospasm, and b ain
inju y a e suba achnoid hemo hage. Biomed Res In (2014) 2014:384342.
doi:10.1155/2014/384342
23. Chou SH, Robe son CS; Pa icipan s in he In e na ional Mul i-disciplina y
Consensus Con e ence on he Mul imodali y Moni o ing. Moni o ing
bioma ke s o cellula inju y and dea h in acu e b ain inju y. Neu oc i Ca e
(2014) 21(Suppl 2):S187–214. doi:10.1007/s12028-014-0039-z
24. Hong CM, Tosun C, Ku land DB, Ge zanich V, Sch eibman D, Sima d JM.
Bioma ke s as ou come p edic o s in suba achnoid hemo hage – a sys ema ic
e iew. Bioma ke s (2014) 19:95–108. doi:10.3109/1354750X.2014.881418
25. Kiiski H, Tenhunen J, Ala-Peija i M, Huh ala H, Hämäläinen M, Långsjö J,
e al. Inc eased plasma UCH-L1 a e aneu ysmal suba achnoid hemo hage
is associa ed wi h un a o able neu ological ou come. J Neu ol Sci (2016)
361:144–9. doi:10.1016/j.jns.2015.12.046
26. Kiiski H, Långsjö J, Tenhunen J, Pel ola J. Time-cou ses o plasma IL-6 and
HMGB-1 e lec ini ial se e i y o clinical p esen a ion bu do no p edic poo
neu ologic ou come ollowing suba achnoid hemo hage. eNeu ologicalSci
(2016) 6:55–62. doi:10.1016/j.ensci.2016.11.010
27. Lucke-Wold BP, Logsdon AF, Mano anjan B, Tu ne RC, McConnell E,
Va es GE, e  al. Aneu ysmal suba achnoid hemo hage and neu oin lam-
ma ion: a comp ehensi e e iew. In J Mol Sci (2016) 17:497. doi:10.3390/
ijms17040497
28. Höllig A, Remmel D, S o el-Wagne B, Schube GA, Cobu n M, Clusmann H.
Associa ion o ea ly in lamma o y pa ame e s a e suba achnoid hemo hage
wi h unc ional ou come: a p ospec i e coho s udy. Clin Neu ol Neu osu g
(2015) 138:177–83. doi:10.1016/j.clineu o.2015.08.030
29. Zhu XD, Chen JS, Zhou F, Liu QC, Chen G, Zhang JM. Rela ionship be ween
plasma high mobili y g oup box-1 p o ein le els and clinical ou comes o
aneu ysmal suba achnoid hemo hage. J Neu oin lamma ion (2012) 9:194.
doi:10.1186/1742-2094-9-194
30. Ma C, Zhou W, Yan Z, Qu M, Bu X. Toll-like ecep o 4 (TLR4) is co ela ed
wi h delayed ce eb al ischemia (DCI) and poo p ognosis in aneu ysmal
suba achnoid hemo hage. J Neu ol Sci (2015) 359:67–71. doi:10.1016/j.
jns.2015.10.018
31. Backes Y, an de Sluijs KF, Mackie DP, Tacke F, Koch A, Tenhunen JJ,
e al. Use ulness o suPAR as a biological ma ke in pa ien s wi h sys emic
in lamma ion o in ec ion: a sys ema ic e iew. In ensi e Ca e Med (2012)
38:1418–28. doi:10.1007/s00134-012-2613-1
32. Donadello K, Scolle a S, Co ajes C, Vincen JL. suPAR as a p ognos ic bio-
ma ke in sepsis. BMC Med (2012) 10:2. doi:10.1186/1741-7015-10-2
33. Laban KG, Rinkel GJ, Ve gouwen MD. Nosocomial in ec ions a e
aneu ysmal suba achnoid hemo hage: ime cou se and causa i e pa hogens.
In J S oke (2015) 10:763–6. doi:10.1111/ijs.12494
34. S e ens RD, Nyquis PA. The sys emic implica ions o aneu ysmal suba achnoid
hemo hage. J Neu ol Sci (2007) 261:143–56. doi:10.1016/j.jns.2007.04.047
35. Koch A, Voig S, K uschinski C, Sanson E, Dücke s H, Ho n A, e al. Ci cula ing
soluble u okinase plasminogen ac i a o ecep o is s ably ele a ed du ing he
i s week o ea men in he in ensi e ca e uni and p edic s mo ali y in
c i ically ill pa ien s. C i Ca e (2011) 15:R63. doi:10.1186/cc10037
36. Roos Y, Le i M, Ca oll TA, Beenen LFM, Ve meulen M. Nimodipine inc eases
ib inoly ic ac i i y in pa ien s wi h aneu ysmal suba achnoid hemo hage.
S oke (2001) 32:1860–2. doi:10.1161/01.STR.32.8.1860
37. Sidenius N, Andol o A, Fesce R, Blasi F. U okinase egula es i onec in
binding by con olling u okinase ecep o oligome iza ion. J Biol Chem (2002)
277:27982–90. doi:10.1074/jbc.M111736200
38. Pliye BK. Ac i a ed human neu ophils apidly elease he chemo ac ically
ac i e D2D3 o m o he u okinase- ype plasminogen ac i a o ecep o (uPAR/
CD87). Mol Cell Biochem (2009) 321:111–22. doi:10.1007/s11010-008-9925-z
39. Haga Y, Dumi escu A, Zhang Y, S ain-Malmg en R, Sjöquis PO. E ec s o cal-
cium blocke s on he cy osolic calcium, H2O2 p oduc ion and elas ase elease
in human neu ophils. Pha macol Toxicol (1996) 79:312–7. doi:10.1111/j.
1600-0773.1996. b00015.x
40. Gallie a E, D ago L, Ma azzi MG, Romanò C, Vassena C, Co si Romanelli MM.
Soluble u okinase- ype plasminogen ac i a o ecep o (suPAR) as new
bioma ke o he p os he ic join in ec ion: co ela ion wi h in lamma o y
cy okines. Clin Chim Ac a (2015) 441:23–8. doi:10.1016/j.cca.2014.11.029
41. Eugen-Olsen J, Ande sen O, Linnebe g A, Ladelund S, Hansen TW, Langkilde A,
e al. Ci cula ing soluble u okinase plasminogen ac i a o ecep o p edic s
cance , ca dio ascula disease, diabe es and mo ali y in he gene al popula-
ion. J In e n Med (2010) 268:296–308. doi:10.1111/j.1365-2796.2010.02252.x
42. Pe sson M, Engs öm G, Bjö kbacka H, Hedblad B. Soluble u okinase
plasminogen ac i a o ecep o in plasma is associa ed wi h incidence o
CVD. Resul s om he Malmö Die and Cance S udy. A he oscle osis (2012)
220:502–5. doi:10.1016/j.a he oscle osis.2011.10.039
43. Olson FJ, Thu ison T, Ryndel M, Hoye -Hansen G, Fage be g B. Soluble
u okinase- ype plasminogen ac i a o ecep o o ms in plasma as ma ke s
o a he oscle o ic plaque ulne abili y. Clin Biochem (2010) 43:124–30.
doi:10.1016/j.clinbiochem.2009.09.028
44. Ga cia-Monco JC, Coleman JC, Benach JL. Soluble u okinase ecep o
(uPAR, CD 87) is p esen in se um and ce eb ospinal luid in pa ien s wi h
neu ologic diseases. J Neu oimmunol (2002) 129:216–23. doi:10.1016/
S0165-5728(02)00186-8
45. Jalkanen V, Vaahe salo J, Pe ilä V, Ku ola J, Va pula T, Tiainen M, e  al.
The p edic i e alue o soluble u okinase plasminogen ac i a o ecep o
(suPAR) ega ding 90-day mo ali y and 12-mon h neu ological ou come in
c i ically ill pa ien s a e ou -o -hospi al ca diac a es . Da a om he p o-
spec i e FINNRESUSCI s udy. Resusci a ion (2014) 85:1562–7. doi:10.1016/j.
esusci a ion.2014.08.017
Con lic o In e es S a emen : The au ho s decla e ha he esea ch was con-
duc ed in he absence o any comme cial o inancial ela ionships ha could be
cons ued as a po en ial con lic o in e es .
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