Re iew
Blood Pu i
Hepa in 2.0: A New App oach o
he In ec ion C isis
Malin-The es Se e a, b Daniel Co am c Lui G. Fo ni c, d Jan T. Kiels ein a
aMedical Clinic V, Neph ology | Rheuma ology | Blood Pu i ica ion, Academic Teaching Hospi al B aunschweig,
B aunschweig, Ge many; bMic obial P o eomics, Helmhol z Cen e o In ec ion Resea ch, B aunschweig, Ge many;
cIn ensi e Ca e Uni , Royal Su ey Hospi al NHS Founda ion T us , Guild o d, UK; dDepa men o Clinical &
Expe imen al Medicine, School o Biosciences & Medicine, Uni e si y o Su ey, Guild o d, UK
Recei ed: Ap il 3, 2020
Accep ed: May 11, 2020
Published online: July 2, 2020
Jan T. Kiels ein
Academic Teaching Hospi al B aunschweig
Medical Clinic V Neph ology | Rheuma ology | Blood Pu i ica ion
Salzdahlume S aße 90, DE–38126 B aunschweig (Ge many)
j.kiels ein @ klinikum-b aunschweig.de
© 2020 S. Ka ge AG, Basel
ka ge @ka ge .com
www.ka ge .com/bpu
DOI: 10.1159/000508647
Keywo ds
An ibio ic esis ance · Ex aco po eal he apy · Blood
pu i ica ion
Abs ac
In Ap il 2020, he US Food and D ug Adminis a ion g an ed
eme gency use au ho iza ion o ce ain medical de ices o
be used in pa ien s wi h co ona i us disease 2019 (CO-
VID-19). This included ex aco po eal blood pu i ica ion de-
ices. This na a i e e iew will gi e a b ie o e iew ega d-
ing some o he ex aco po eal de ices ha could be used o
ea COVID-19 pa ien s, including he Se aph® 100 Mi-
c obind® A ini y Blood Fil e , p oduced by ExThe a Medical
(Ma inez, CA, USA), i s licensed in he Eu opean Economic
A ea in 2019. The Se aph® 100 con ains ul ahigh molecula
weigh polye hylene beads wi h end poin -a ached hepa in
and is app o ed o he educ ion o pa hogens om he
bloods eam ei he as a single agen o as an adjunc o con-
en ional an i-in ec i e agen s. Bac e ia, i uses, ungi, and
oxins ha e been shown o bind o he immobilized hepa in
in a simila way o he in e ac ion wi h hepa an sul a e on he
cell su ace. This binding is non e e sible and as such, he
pa hogens a e emo ed om he bloods eam. In his e-
iew, we desc ibe he pa hophysiological basis and a ionale
o using hepa in o pa hogen emo al om he blood as
well as explo ing he echnology behind he adap a ion o
hepa in o dep i e i o i s sys emic an icoagulan ac i i y. In
addi ion, we summa ize he in i o da a as well as he a ail-
able p eclinical es ing and published clinical epo s. Final-
ly, we discuss he eno mous po en ial o his echnology in
an e a o inc easing an ibio ic esis ance and high mo ali y
associa ed wi h sepsis and conside he applica ion o his as
a possible ea men op ion o COVID-19.
© 2020 S. Ka ge AG, Basel
In oduc ion
Ex aco po eal The apies in Pa ien s wi h COVID-19
By Ap il 30, 2020, he se e e acu e espi a o y syn-
d ome co ona i us-2 (SARS-CoV-2) had in ec ed mo e
han 3 million people globally and had claimed he li e o
some 217,769 indi iduals. The ongoing pandemic con in-
ues o s e ch heal hca e sys ems a ound he wo ld o he
limi and will con inue o do so o he mon hs o come.
Cu en ly, he e is no es ablished d ug he apy a ail-
able o co ona i us disease 2019 (COVID-19). P omis-
ing he apies including emdesi i awai u he con i -
ma o y e idence [1], ha e been shown o be unsuccess ul
Se e /Co am/Fo ni/Kiels ein
Blood Pu i
2
DOI: 10.1159/000508647
(lopina i - i ona i ) [2], o may e en ha e undesi able
e ec s (chlo oquine and hyd oxychlo oquine) [3]. Thus,
he sea ch o al e na i e ea men s a egies in c i ically
ill pa ien s wi h COVID-19 con inues. Aside om pha -
macological in e en ions, se e al ex aco po eal s a e-
gies ha e been discussed and indeed u ilized [4]. As AKI
is commonly obse ed in c i ically ill pa ien s wi h CO-
VID-19, wi h app oaching 46% o all ARDS pa ien s, e-
nal eplacemen he apy is equen ly necessa y [5, 6].
O he ex aco po eal ea men op ions ha e ecen ly
been e iewed in he con ex o COVID-19 [4, 7]. In b ie ,
he in e en ion deemed mos p omising is he ex aco -
po eal ea men o cy okine elease synd ome, wi h IL-6
being conside ed o be he mos impo an causa i e cy-
okine. In e es ingly de ec able se um SARS-Co -2 RNA
in he blood o COVID-19 pa ien s has been shown o be
associa ed wi h ele a ed IL-6 concen a ion and poo
p ognosis [8]. High- olume hemo il a ion [9] and he a-
peu ic plasma exchange dec ease in lamma o y cy okine
le els including, bu no limi ed o, IL-6 in pa ien s wi h
sepsis [10]. In pa ien s wi h sepsis, he apeu ic plasma ex-
change using esh ozen plasma has been shown o im-
p o e he disequilib ium o coagula ion ac o s by e-
mo ing p o- and eplacing an icoagulan ac o s [11], an
in e en ion ha migh be o p omise in he hype coagu-
la i e s a e o COVID-19 pa ien s. This p ocedu e could
also be coupled wi h he adminis a ion o con alescen
plasma [12]. A simple app oach o dec easing he le el
o p oin lamma o y cy okines includes use o he Cy o-
So b® ca idge, which consis s o a highly po ous high-
ech polyme ha can bind o a wide ange o in lamma-
o y media o s, including cy okines [13]. In pa ien s wi h
sep ic shock and high endo oxin ac i i y due o supe im-
posed bac e ial in ec ions, polymyxin B hemope usion
may also be conside ed despi e disappoin ing clinical i-
als [14].
Human
An i
in ec i e
agen
Pep ide
backbone
Cell su ace
Bac e ia Bac e ia
Vi us
Cell Immobilized hepa in
Vi us
Hepa an
sul a e
Se aph
Se aph
Non po ous
se aph media
Fig. 1. S uc u al simila i ies be ween he
HS on cell su aces and hepa in bound o
polye hylene beads in he Se aph® 100
cause in ec i e agen s in he blood ha is
pumped h ough he Se aph® 100 o ad-
he e o he hepa in-coa ed il e media and
no eci cula ed back sys emically, he eby
being emo ed ( o be e isibili y, sizes
a e ela i e bu no ue o scale). HS, hepa-
an sul a e.
Colo e sion a ailable online
A New App oach o he In ec ion C isis
3
Blood Pu i
DOI: 10.1159/000508647
Hepa in: An Essen ial Medicine
The i s WHO essen ial d ugs lis , published in 1977,
s a ed a p ocess o objec i e selec ion o d ugs ha should
be made eadily a ailable o e e ybody due o hei e i-
cacy, sa e y, cos -e ec i eness, and ele ance o he ca e
o pa ien s. Hepa in was on he o iginal lis h ough i s use
as an an icoagulan employed o p ophylaxis o h om-
bosis h ough he ea men o myoca dial in a c ion and
emains he mos widely used an icoagulan o ex aco -
po eal ea men s anging om hemodialysis o ex aco -
po eal memb ane oxygena ion. Despi e i s almos ubiqui-
ous usage, i s molecula s uc u e is ill-de ined, being a
nega i ely cha ged biopolyme wi h wide a ia ion in mo-
lecula weigh composed p incipally o epea ing isul-
a ed disaccha ide uni s [15]. The an icoagulan ac i i y o
hepa in is based on a dual ac ion, inhibi ion o h ombin
gene a ion and inhibi ion o h ombin ac i i y h ough
he p o ease inhibi o an i h ombin III (AT-III). Mo e-
o e , hepa in has many o he pha macological p ope ies,
including an i-in lamma o y, an i i al, an iangiogenesis,
an ineoplas ic, and an ime as a ic e ec s h ough high a -
ini y in e ac ions wi h a a ie y o media o s, including
p o eases, p o ease inhibi o s, chemokines, cy okines,
g ow h ac o s, and hei espec i e ecep o s [15].
Hepa in Binding o Bac e ia and Vi uses
Hepa an sul a e (HS) sequences a e highly nega i ely
cha ged, pa ially sul a ed, ca bohyd a e po ions o p o-
eoglycans ha a e p esen on he su ace o almos all
mammalian cells. HS chains a e buil h ough al e na ing
D-glucosamine and glucu onic acids (L-idu onic and D-
glucu onic acids) and as such a e s uc u ally ela ed o
hepa in a ying only in he saccha ide chains [16]. Aside
om co e ing he cell su ace HS can be ound in he in-
acellula milieu and ex acellula ma ix and in e ac
wi h nume ous soluble and insoluble ligands, including
cy okines and g ow h ac o s [17]. Mo eo e , many bac-
e ia, i uses, and oxins adhe e o human cells ia he HS
as well as su ace p o eins. Cha ge, o elec os a ic in e -
ac ion, is he main mechanism behind his binding wi h
he nega i ely cha ged HS a ac ing he basic amino ac-
ids o su ace p o eins [18]. Examples o his include he
he pes simplex i us HSV-1, which a aches o cell su -
ace p o eoglycans h ough he glycop o ein complex (gB
and gC [19]) and hepa i is B i us which uses a la ge en-
elope p o ein o bind o cells [20]. O no e, i has ecen -
ly been demons a ed ha SARS-CoV-2 a aches o hepa-
in h ough i s su ace p o ein Spike 1 ecep o -binding
domain [21]. Gi en ha many bac e ia bind o HS o hep-
a in, i ollows ha po en ially exploi ing such adhesion
pa hways o “ ap” bac e ia and i uses and emo e hem
om he ci cula ion h ough an ex aco po eal ea men
may be a p omising app oach. Addi ionally, hepa in also
has a di ec e ec on bac e ia and i uses. Fo example,
hepa in, eleased om mas cells and basophils h ough
issue damage, educes hepcidin exp ession and in e -
up s he i on a ailabili y o Mycobac e ium ube culo-
sum [22] and also he cy opa hogenici y o he human
immunode iciency i uses has been shown o be educed
by 50% by hepa in a a concen a ion o 4.7 μg/mL [23].
The e is also an obse ed inhibi o y e ec o hepa in on
he pes simplex i us ha can bind o cell su ace HS as
well as o hepa in [24]. I ollows ha manipula ion o his
binding a ini y o mic oo ganisms o HS and equi alen s
could lead o po en ial he apeu ic in e en ions. The
Se aph® 100 Mic obind® A ini y Blood Fil e is an ex-
aco po eal hemope usion de ice whose unc ional
co e, ha is, polye hylene beads (diame e o 0.3 mm)
wi h immobilized hepa in bound o i , mimics a na u-
ally mammalian cell su ace (Fig.1). The s uc u e o his
adso be eplica es o some deg ee he HS on he cell su -
ace and, he e o e, may ul ill he equi emen s necessa y
o bind mic oo ganisms. The a achmen o he hepa in
o he polye hylene beads (app oxima ely 2 mg hepa in/g
Fig. 2. Se aph® 100 is measu ing 22 × 7 cm. A e p iming wi h a
olume o 160 mL, he en i e assembly weighs abou 400 g. Elec-
on mic oscopic image (magni ica ion 144×) om he hepa in-
coa ed beads – he ac i e ing edien o he Se aph® 100.
Colo e sion a ailable online
Se e /Co am/Fo ni/Kiels ein
Blood Pu i
4
DOI: 10.1159/000508647
beads) is such ha only insigni ican amoun s o hepa in
a e eleased sys emically [25, 26]. This is shown using
elec on mic oscopy in Figu e 2.
In i o Da a
Bac e ia
As indica ed, he possession o hepa in-binding p o-
eins is common in bac e ia and as such, one could en is-
age simila binding p ope ies wi h he Se aph® 100 il e
h ough cha ge in e ac ions [27]. Indeed, S aphylococcus
au eus and he highly esis an s ain, MRSA, ha e been
demons a ed o adhe e o he hepa inized beads [28].
This is summa ized in Figu e 3.
Vi uses
HS binds ce ain i uses and, in some cases, media es
a ge cell in ec ion. The e o e, neu alizing in ec ion
wi h i uses ha use HS o cellula a achmen by com-
pe i i e inhibi ion o binding wi h he Se aph® 100 can
be en isaged. Indeed, such p inciples a e al eady em-
ployed o diagnos ic pu poses whe e hepa in is bound o
ca bon nano ubes and used as a bio ecogni ion elemen
o dengue i us ins ead o an an ibody assay [29].
The heo y ha such an ex aco po eal de ice can e-
mo e i uses om blood has been seen in p eclinical es s
ha showed a educ ion o i al load: up o 87% o Zika
i us, 79% o CMV, and 62% o adeno i uses. Fu he -
mo e, ecen in i o da a ha e also shown ha SARS-
CoV-2 can be emo ed by he Se aph® 100.
Cy okines
Gi en he ole o cy okines in he in lamma o y cas-
cade associa ed wi h sepsis, much a en ion has ocused
on mi iga ing he “cy okine s o m.” Axelsson e al. [26]
ha e in es iga ed he adhesion o p oin lamma o y cy o-
kines o hepa inized beads. Vascula cell adhesion mole-
cule, IL-6, TNF-alpha, RANTES, in e e on-gamma, and
an i h ombin, suspended in dona ed blood, we e s udied.
The e was a signi ican educ ion, especially o TNF-al-
pha, which was educed by app oxima ely 59% (Fig.4).
The magni ude o his e ec in i o has been deba ed bu
no been clinically s udied ye [30].
D ug Clea ance
An ibio ics and ela ed he apeu ics play a pi o al ole
in he ea men o bloods eam in ec ions and sepsis. I
ollows ha i any ex aco po eal de ice emo es an imi-
c obial agen s, his may nega e any po en ial bene i . The
emo al cha ac e is ics o 18 an i-in ec i e d ugs was
es ed in a li e size in i o app oach using human plasma,
which ci cula ed wi h a low a e o 250 mL/min o 1 h
h ough he Se aph® 100. Samples we e aken a e 5′, 15′,
S.au eus
MRSA
S.pneumoniae
E. aecalis
E. aecalis (VRE)
90
80
70
60
50
40
E. aecium
S.epide midis
MR-S.epide midis
S.pyogenes
K.pneumoniae
K.pneumoniae (CRE)
E.coli
E.coli (CRE)
S.ma cescens
A.baumannii
Cy omegalo i us
Zika- i us
Adeno i us
G am-posi i e bac e ia
Reduc ion, %
G am-negi i e
bac e ia
Vi uses
Fig. 3. In i o binding o bac e ia o he
Se aph® 100 shown a educ ion o CFU
(a e age o 3). Mini ca idges we e condi-
ioned wi h 2.0 mL o PBS, hen 2.0 mL o
FBS, hen 2.0 mL o PBS p io o inocula-
ion. Cul u es we e dilu ed in de ib ina ed
ho se blood o ~2–3 × 105 CFU/ml. A sam-
ple o each es inoculum was immedia ely
ha es ed and enume a ed o ind he ini-
ial bac e ial concen a ion. 2.0 mL o di-
lu e es inoculum was epea edly il e ed
h ough he mic ocolumns, wi h enume a-
ions o emaining bac e ia on he hi d il-
a e.
Colo e sion a ailable online
A New App oach o he In ec ion C isis
5
Blood Pu i
DOI: 10.1159/000508647
30′, and 60′ min. The e was no clinical ele an educ ion
o he an i-in ec i e agen s ha included an ibio ics, an-
i i al, and an i ungal medica ion [31].
Clinical Use o he Se aph® 100
The CE ma k s udy consis ed o 15 pa ien s unde go-
ing hemodialysis. The p ima y ou come measu e was o
demons a e he sa e y o he Se aph® 100 Mic obind®
A ini y Blood Fil e in a hemodialysis ci cui assessed by
a e o ad e se e en s du ing he p ocedu e and 14 days
he ea e . The seconda y ou come measu e was he e-
duc ion o bac e ia in blood passed h ough he Se aph®
100 Mic obind® A ini y Blood Fil e o e he 4-h ea -
men . The numbe o bac e ia was assessed by colony-
o ming uni s/mL o ime o posi i i y o blood cul u es.
All ea men s we e well ole a ed wi h no signi ican
changes in i al signs, including blood p essu e o hea
a e du ing he 4-h ea men bu , o no e, a signi ican
inc ease in oxygen sa u a ion (p = 0.02) was no ed. This
obse a ion may e lec he emo al o sepsis media o s
ha in luence endo helial unc ion, including hepa in-
binding p o ein, his ones, and ul a-la ge on Willeb and
ac o leading o changes in he pulmona y ascula u e
mani es as an inc ease in SpO2. Fo hose pa ien s wi h
bac e emia (4 ou o 15), a signi ican educ ion o bac e-
ial load by he Se aph® 100 was demons a ed wi h a
signi ican inc ease in ime o posi i i y (p = 0.03). The
documen ed clinical applica ions demons a e ha he
Se aph® 100 can be used in di e en modes o enal e-
placemen he apy om in e mi en hemodialysis o
p olonged in e mi en hemodialysis as well as in a CRRT
machine o up o 24 h.
Co ona i us Disease 2019
The Se aph® 100 has been used in Eu ope since 2019
o he educ ion o pa hogens om he blood. Au ho i-
za ion o eme gency use in pa ien s wi h COVID-19 ad-
mi ed o he ICU wi h con i med o imminen espi a-
o y ailu e was g an ed by he US FDA on Ap il 17, 2020.
An online egis y was ecen ly es ablished o e alua e he
clinical e ec o his in e en ion (ClinicalT ials.go
Iden i ie : NCT04361500). Wha is he a ionale o use
he Se aph® 100 in COVID-19 pa ien s? Fi s , he e is
elimina ion o he i us om he blood as i had been
shown in i o o se e al i uses (Fig.3). In suppo o
his heo y is he obse a ion ha SARS-CoV-2, h ough
he su ace p o ein Spike 1 ecep o -binding domain, a -
aches o hepa in [21]. Vi emia has been shown o be
p esen in 41% [32] o pa ien s in gene al and in up o 50%
o c i ically ill pa ien s wi h SARS-CoV-2 [6]. Mo eo e ,
de ec able se um SARS-Co -2 RNA (RNAaemia) in CO-
VID-19 pa ien s has been shown o be associa ed wi h
ele a ed IL-6 concen a ion and poo p ognosis [8], so
dec easing RNAaemia migh also help o blun he (o e -
whelming) in lamma o y esponse. Second, he de elop-
men o a seconda y hemophagocy ic lymphohis iocy o-
sis mani es by a cy okine s o m may play an impo an
ole in de e mining ou come, so media ing his esponse
may be o use [33]. A signi ican educ ion o p oin lam-
ma o y cy okines has been shown o he Se aph® 100 in
i o [26], highligh ing u he po en ial he apeu ic ben-
e i . Also, o no e is he obse a ion wi hin he ini ial sa e-
y s udy and subsequen clinical epo s imp o emen in
oxygen sa u a ion is demons a ed, al hough he pa ho-
physiology behind his is, as ye , unde e mined. One el-
e an componen migh be he imp o emen o pulmo-
na y mic oci cula ion in COVID-19 pa ien ha exhibi
a de anged coagula ion unc ion [34]. Las bu no leas ,
in pa ien s on enal eplacemen he apy, he use o d ugs
like Remdesi i may be p ohibi i e in e ms o side e ec
p o ile and, hence ex aco po eal he apies may be he
only op ion.
70
60
50
40
30
20
10
0
Reduc ion a io, %
VCAM IL-6 TNF-alpha In e e on-γ
Adhesion o p oin lamma o y cy okines
■ Hepa inized beads
■ Con ol beads
Fig. 4. In i o clea ance o p oin lamma-
o y cy okines om sep ic pa ien s by Se -
aph mic ocolumns. Signi ican educ ion
o p oin lamma o y cy okines e sus con-
ols ha e been aken om a publica ion o
Axelsson e al. [26].
Colo e sion a ailable online

Se e /Co am/Fo ni/Kiels ein
Blood Pu i
6
DOI: 10.1159/000508647
Fu u e Di ec ions
Sepsis emains a leading cause o mo ali y in c i i-
cally ill pa ien s. This applies in pa icula o in ec ions
wi h mul id ug- esis an bac e ia gi en he limi a ions in
a ailable ea men s. De elopmen o new an ibio ic
d ugs as well as he inc eased p esc ibing o “olde ” an i-
bio ics may p ese e con empo a y an ibio ics and a oid
he sp ead o esis ance in o de o o e come his g owing
medical and cos issue. Al hough he e a e se e al o he
app oaches o emo e in ec ious agen s om he blood-
s eam, he Se aph® 100 is he i s licensed de ice in he
EU bu also he only one ha akes a WHO essen ial med-
icine, hepa in, o he nex unc ional le el.
Conclusions
The ole o ex aco po eal echniques in he manage-
men o he c i ically ill is an a ea o g ea expansion. The
ou ine use o enal eplacemen he apy wi hin in ensi e
ca e uni s shows how hese ha e been adop ed and he
ecen expansion in he p o ision o ex aco po eal mem-
b ane oxygena ion bo h enous- enous and enous-a e-
ial unde lines he mo e owa d inc eased ex aco po eal
echnologies. De elopmen o new memb anes and il e s
wi h ailo ed, pe sonalized app oaches as pa o hese
ci cui s is almos ce ainly he nex di ec ion o a el.
The applica ion o columns wi h a speci ic binding p o ile
and he di ec a ge ing o in ec ious agen s may well be
he nex s ep.
Acknowledgemen
We hank Man ed Rohde, Helmhol z Cen e o In ec ion Re-
sea ch, B aunschweig, Ge many, o he elec on mic oscopic im-
age.
Disclosu e S a emen
Jan T. Kiels ein ecei ed esea ch suppo om ExThe a Med-
ical. Lui G. Fo ni has ecei ed hono a ia o lec u ing o Ex he a
Medical.
Funding Sou ces
The au ho s did no ecei e any unding.
Au ho Con ibu ions
All au ho s we e in ol ed in ex ac ing and colla ing e e enc-
es and w i ing he sc ip . J.T.K. and L.F. had he inal say on he
manusc ip ’s con en .
Re e ences
1 G ein J, Ohmaga i N, Shin D, Diaz G, Aspe g-
es E, Cas agna A, e al. Compassiona e use o
emdesi i o pa ien s wi h se e e co id-19.
N Engl J Med. 2020; NEJMoa2007016. Online
ahead o p in .
2 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan
G, e al. A ial o lopina i - i ona i in adul s
hospi alized wi h se e e Co id-19. N Engl J
Med. 2020; 382: 1787–99.
3 Abena PM, Decloed EH, Bo ieau E, Suleman
F, Adejumo P, Sam-Agudu NA, e al. Chlo o-
quine and hyd oxychlo oquine o he p e-
en ion o ea men o no el co ona i us
disease (COVID-19) in a ica: cau ion o in-
app op ia e o -label use in heal hca e se -
ings. Am J T op Med Hyg. 2020; 102: 1184–8.
4 Ronco C, Reis T, De Rosa S. Co ona i us epi-
demic and ex aco po eal he apies in in en-
si e ca e: si is pacem pa a bellum. Blood Pu-
i . 2020; 49(3): 255–8.
5 Fanelli V, Fio en ino M, Can aluppi V, Gesu-
aldo L, S allone G, Ronco C, e al. Acu e kid-
ney inju y in SARS-CoV-2 in ec ed pa ien s.
C i Ca e. 2020; 24(1): 155.
6 D ehe M, Ke s en A, Bickenbach J, Bal anz
P, Ha mann B, Co nelissen C, e al. The
Cha ac e is ics o 50 Hospi alized COVID-19
Pa ien s Wi h and Wi hou ARDS. D sch
A z ebl In . 2020; 117: 271–8.
7 Ronco C, Reis T. Kidney in ol emen in CO-
VID-19 and a ionale o ex aco po eal he -
apies. Na Re Neph ol. 2020; 16(6): 308–10.
8 Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng
Y, e al. De ec able se um SARS-CoV-2 i al
load (RNAaemia) is closely co ela ed wi h
d as ically ele a ed in e leukin 6 (IL-6) le el
in c i ically ill COVID-19 pa ien s. Clin In ec
Dis. 2020; ciaa449. Online ahead o p in .
9 Ronco C, Te a C, Ma iano F, W a en ML,
Bonello M, Bo doni V, e al. In e p e ing he
mechanisms o con inuous enal eplacemen
he apy in sepsis: he peak concen a ion hy-
po hesis. A i O gans. 2003; 27(9): 792–801.
10 Knaup H, S ahl K, Schmid BMW, Idowu TO,
Busch M, Wiesne O, e al. Ea ly he apeu ic
plasma exchange in sep ic shock: a p ospec-
i e open-label non andomized pilo s udy
ocusing on sa e y, hemodynamics, ascula
ba ie unc ion, and biologic ma ke s. C i
Ca e. 2018; 22(1): 285.
11 S ahl K, Schmid JJ, Seelige B, Schmid
BMW, Wel e T, Halle H, e al. E ec o he -
apeu ic plasma exchange on endo helial ac i-
a ion and coagula ion- ela ed pa ame e s in
sep ic shock. C i Ca e. 2020; 24(1): 71.
12 Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, e
al. E ec i eness o con alescen plasma he -
apy in se e e COVID-19 pa ien s. P oc Na l
Acad Sci U S A. 2020; 117(17): 9490–6.
13 F iesecke S, T äge K, Schi ek GA, Molna Z,
Bach F, Kogelmann K, e al. In e na ional eg-
is y on he use o he Cy oSo b® adso be in
ICU pa ien s: s udy p o ocol and p elimina y
esul s. Med Klin In ensi med No med.
2019; 114: 699–707.
14 Dellinge RP, Bagshaw SM, An onelli M, Fos-
e DM, Klein DJ, Ma shall JC, e al. E ec o
a ge ed polymyxin B hemope usion on 28-
day mo ali y in pa ien s wi h sep ic shock
and ele a ed endo oxin le el: he EUPHRA-
TES andomized clinical ial. JAMA. 2018;
320(14): 1455–63.
15 Hao C, Xu H, Yu L, Zhang L. Hepa in: an es-
sen ial d ug o mode n medicine. P og Mol
Biol T ansl Sci. 2019; 163: 1–19.
A New App oach o he In ec ion C isis
7
Blood Pu i
DOI: 10.1159/000508647
16 Sh i e Z, Capila I, Venka a aman G, Sa-
sisekha an R. Hepa in and hepa an sul a e:
analyzing s uc u e and mic ohe e ogenei y.
Handb Exp Pha macol. 2012; 207: 159–76.
17 Li JP, Kusche-Gullbe g M. Hepa an sul a e:
biosyn hesis, s uc u e, and unc ion. In Re
Cell Mol Biol. 2016; 325: 215–73.
18 Cagno V, Tseligka ED, Jones ST, Tappa el C.
Hepa an sul a e p o eoglycans and i al a -
achmen : ue ecep o s o adap a ion bias?
Vi uses. 2019; 11(7): 11.
19 Shukla D, Liu J, Blaiklock P, Shwo ak NW, Bai
X, Esko JD, e al. A no el ole o 3-O-sul a ed
hepa an sul a e in he pes simplex i us 1 en-
y. Cell. 1999; 99(1): 13–22.
20 Schulze A, G ipon P, U ban S. Hepa i is B i-
us in ec ion ini ia es wi h a la ge su ace p o-
ein-dependen binding o hepa an sul a e
p o eoglycans. Hepa ology. 2007; 46(6): 1759–
68.
21 Myc o -Wes C, Su D, Elli S, Guimond S,
Mille G, Tu nbull J. The 2019 co ona i us
(SARS-CoV-2) su ace p o ein (Spike) S1 Re-
cep o Binding Domain unde goes con o -
ma ional change upon hepa in binding.
BioRxi . 2020 [pos ed 2020 Ma 02]. A ail-
able om: h ps: //www.bio xi .o g/con en /1
0.1101/2020.02.29.971093 1. doi: h ps: //doi.
o g/10.1101/2020.02.29.971093.
22 Ab eu R, Essle L, Loy A, Quinn F, Gi i P.
Hepa in inhibi s in acellula Mycobac e i-
um ube culosis bac e ial eplica ion by e-
ducing i on le els in human mac ophages. Sci
Rep. 2018; 8(1): 7296.
23 I o M, Baba M, Sa o A, Pauwels R, De Cle cq
E, Shige a S. Inhibi o y e ec o dex an sul-
a e and hepa in on he eplica ion o human
immunode iciency i us (HIV) in i o. An i-
i al Res. 1987; 7(6): 361–7.
24 He old BC, Ge be SI, Polonsky T, Bel al BJ,
Shaklee PN, Holme K. Iden i ica ion o s uc-
u al ea u es o hepa in equi ed o inhibi-
ion o he pes simplex i us ype 1 binding.
Vi ology. 1995; 206(2): 1108–16.
25 La m O, La sson R, Olsson P. A new non-
h ombogenic su ace p epa ed by selec i e
co alen binding o hepa in ia a modi ied e-
ducing e minal esidue. Bioma e Med De-
ices A i O gans. 1983; 11(2–3): 161–73.
26 Axelsson J, Fe ei a M, Adol sson L, McC ea
K, Wa d R, La m O. Cy okines in blood om
sep ic pa ien s in e ac wi h su ace-immobi-
lized hepa in. ASAIO J. 2010; 56(1): 48–51.
27 Ros and KS, Esko JD. Mic obial adhe ence o
and in asion h ough p o eoglycans. In ec
Immun. 1997; 65(1): 1–8.
28 Ma sby-Bal ze I, Be gs om T, McC ea K,
Wa d R, Adol sson L, La m O. A ini y aphe -
esis o ea men o bac e emia caused by
S aphylococcus au eus and/o me hicillin- e-
sis an S. au eus (MRSA). J Mic obiol Bio-
echnol. 2011; 21(6): 659–64.
29 Wasik D, Mulchandani A, Ya es MV. A hep-
a in- unc ionalized ca bon nano ube-based
a ini y biosenso o dengue i us. Biosens
Bioelec on. 2017; 91: 811–6.
30 Dileo MV, Fede spiel WJ. Scaling issues in he
a icle en i led “cy okines in blood om sep-
ic pa ien s in e ac wi h su ace-immobilized
hepa in”. ASAIO J. 2010; 56(4): 383–5.
31 Schmid JJ, Eden G, Se e MT, Winkle M,
Kiels ein JT. In- i o elimina ion o an i-in-
ec i e d ugs by he Se aph® 100 Mic obind®
a ini y blood il e . Clin Kidney J. s aa063,
h ps: //doi.o g/10.1093/ckj/s aa063
32 Zheng S, Fan J, Yu F, Feng B, Lou B, Zou Q,
e al. Vi al load dynamics and disease se e i y
in pa ien s in ec ed wi h SARS-CoV-2 in Zhe-
jiang p o ince, China, Janua y-Ma ch 2020:
e ospec i e coho s udy. BMJ. 2020; 369:
m1443.
33 Meh a P, McAuley DF, B own M, Sanchez E,
Ta e sall RS, Manson JJ, e al. COVID-19:
conside cy okine s o m synd omes and im-
munosupp ession. Lance . 2020; 395(10229):
1033–4.
34 Han H, Yang L, Liu R, Liu F, Wu K, Li J, e al.
P ominen changes in blood coagula ion o
pa ien s wi h SARS-CoV-2 in ec ion. Clin
Chem Lab Med. 2020. h ps: //doi.o g/10.1515/
cclm-2020-0188. 32172226.