Plasma soluble Urokinase-Type Plasminogen activator receptor is not associated with neurological Outcome in Patients with aneurysmal subarachnoid hemorrhage

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 2 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). 3 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. 4 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 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 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. 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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 . Copy igh © 2017 Kiiski, Jalkanen, Ala-Peija i, Hämäläinen, Moilanen, Pel ola and Tenhunen. This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe mi ed, p o ided he o iginal au ho (s) o licenso a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms.