535
Thrombogenicity of Heparinand Non-Heparin-Coated
Catheters: Clinical Trial
Daniel K. Kido 1 ,2,3
Sven Paulin 1
J . A. Alenghat 1 ,2,4
Christine Waternaux 5
William D. Rilei
Catheters used in clinical cerebral angiography were examined by scanning electron
microscopy for buildup of thrombus . In 21 (67% ) of 31 individuals studied with nonheparin-coated catheters , either cell aggregations or thrombi developed compared with
seven (28%) of 25 individuals studied with hepari n-coated catheters. The median size
of the cell aggregations and thrombi on non-heparin- and heparin-coated catheters was
significantly different (p < 0 .01). The slopes that estimated the probable rate of
thrombus formation were also significantly different ( p < 0.01). This suggests the
desirability of replacement of non-heparin-coated catheters if the angiographic procedure is extended .
The deposition of thrombi on vascu lar cath ete rs has been demonstrated in
laboratory animals and humans [1 - 3 ]. Pl atelets ad here to ca th eters soon after
they are placed within th e arteries. Later, red blood ce li s and white blood cell s
may be incorporated into th e thrombi [4] . Embolization of th ese th ro mbi may
result in cerebral dysfunction . Thi s study was und ert aken to determin e wheth er
thrombu s form ation could be red uced by th e use of hepari n-coate d cath eters.
This article appears in the September / October 1982 issue of AJNR and the November 1982
issue of AJR.
Received April 24, 198 1; accepted after rev ision March 12, 1982.
Prese nted at the annual meeting o f the American Soc iety o f Neuroradio log y, Chica90, Apri l
198 1.
Thi s wo rk was supported in part by the Biomedical Researc h Support grant , Charl es A. Dana
Researc h In stitute, Beth Israel Hospital , Boston ,
M A.
' Departm ent of Radiology, Harvard Med ical
Sc hoo l, Beth Israel Hospital , Boston , MA 021 15.
2Department of Radiology, Harva rd M edical
Sc hool, Peter Ben t Brigham Hospital, Boston, MA
02 11 5.
3Prese nt address: Departm ent o f Radiology,
University of Roches ter Medi ca l Center , Rochester , NY 14642. Address rep rint req uests to D. K .
Kido .
' Departm ent of Radiology , University o f Chicago, Chicago , IL 60637.
5Department of Bi ostati stics, Harva rd Sc hool of
Public Hea lth, Bosto n, MA 021 1 5.
AJNR 3:535-539, September/ October 1982
0195-6108 / 82 / 0305-0535 $00.00
© Ameri can Roentgen Ray Society
Subjects
During a 10 month period we studi ed th e ca th eters of 56 ad ult patient s who un derwe nt
ce rebral angiography. Th e patients we re divided into two groups: (1) Th e co ntrol g roup
compri sed those wh ose identificati on numbers ended in an odd digit; th ey we re examin ed
with no n-h eparin-coated cath eters. (2) Th e ex perimental group co mpri sed th ose whose
identification numbers ended in an even d igit ; th ey we re studi ed with heparin-coated
cath eters.
Th e cath eters were all tapered Hanafee cath eters w ith an end hole inn er diameter of
0 .04 inc h (1.0 2 mm) . Th e heparin-coated cat heters were all prepared by Am in kemi A B
(Bromm a, Sweden ) accordin g to a technique described by Lagergren and Eriksson et al.
[5- 7]. Th e techni q ue cons ists of initiall y exposing the cath eter to a cation ic surfactant,
th en to heparin, and fin all y to a glutard ialdehyde solu tio n to b in d th e heparin to the cath eter .
After th e pati ents ' groin s we re c leansed wi th Betad in e and anesth eti zed wi th 5-10 ml of
1 % xy loca ine, the ca th eters were introduced into th e femoral artery using the Seld in ger
techni q ue. Th e blood th at had refluxed into th e ca th ete rs was th en forcef ull y aspirated in to
a sy rin ge fill ed w ith isotonic sali ne and heparin (5 U/ ml), and a second, simi larly fill ed
syrin ge was rea ttac hed to th e ca th eter and used to flush it c lean. Subsequen t gu ide wire
manipul ati ons we re perform ed th ro ugh the cath eter in an att empt to place it in th e
appropri ate ce rebral vesse l. Each man ipu lation was foll owed by an aspira ti on of blood and
a flu sh of sa li ne and heparin .
After th e cath eter had been positioned in either a carot id or vertebra l art ery, a heparin
drip was started and co ntinued until the appropriate diagnostic injec ti on had been compl eted or the cath eter had been removed. Th e guide wire and ca th eter manipul ations were
perform ed eith er by a neuroradiology fell ow or a staff neurorad iologist. Th e ca th eter
properties (h eparin or non heparin) , cath eter exposure time to blood (minutes), and th e
number of inj ections made through the ca th eters we re all recorded. All test injecti ons and
536
KIDO ET AL.
S evere
S evere
Moderate
Moderate
MHll mat
M lnl stllie
NOlle
NOfle
:L·
o
40
Fig. 1.- Distribution of thrombi on
no n-h eparin- (A) and heparin- (B) coated
ca th ete rs.
-- I2
"·O>-~""I6"'~~
···-8-o~,,·>-,<
'
T IME
TIME
A
AJNR :3, September / October 1982
B
angiograms were perform ed w ith diatri zoa te meg lumine (R eno-M60). Pull-out angiograms were also ob tained on 10 heparin- and 1 2
non-heparin-coated cath eters before th ey were removed . Pull-o ut
ang iog rams were evaluated for possible thrombi . The co ntinuous
heparin flu shes were maintained during withdrawal of th e cath eters
to in sure that c lots would not form within th em. Eac h pati en t 's pedal
pul ses , groin appearanc e, and sensorium we re c hecked throughout
th e rest of th e day. A fin al assessment was made 24 hr after the
procedure by a member of th e neuroradiology staff.
As soon as th e cath eter was removed, th e distal 1 c m of the
cathet er was c ut off, pl aced in Karn ovsky [8] solution , and allowed
to fi x for 1 we ek . Th e catheter tip was then prepared for th e
scanning elec tron microscope by splitting it in half, dehydrating it
through a graded ethanol seri es, and, fin all y, by critica l point-drying
it w ith liqui d ca rbon dioxid e. Th e cat heter was mounted to permit
examin ation of half of th e ou ter and half of th e inn er surfaces. Th e
cath eter halves were then sputter-coated with 100 A of gold in a
Polaron E5000 scanning electron microscope-coating unit. All catheters were processed in a similar man ner. The catheters were
examined in an AMR-900 scanning elec tron microscope 20 kV
accelerating vo ltage.
Th e degree of ce ll agg regation and thrombu s formation visible
on th e inner and outer cath eter surfaces was graded as: none, no
ce ll s o r thrombi present ; mini scule, ce lls or thrombi covering less
th an 1 % of th e surface; minimal, cell s or thrombi cove ring 1 %-1 0 %
of th e surface; moderate , thrombi covering 10%-50% of th e surface; and severe, thrombi covering more than 50% of the surface.
In add ition , th e scanning elec tron microscope was used to determine wheth er th e cath eter tips were smooth or rough.
Th e c hi-square test was used to determine whether the difference
in th e number of thrombi in th e moderate and severe group was
stati sti ca ll y sign ificant. Th e Mann-Whitney test (a nonparametri c
meth od for testin g th e equality of medians) was used to determine
whet her th e d ifference in the median size of the ce ll agg regation s
and th ro mbi formed on heparin- and non-heparin-coated cat heters
was stati stically sign ifica nt. Only th e inner surface was evaluated
by th ese two tes ts because it was believed th at cell aggregation s
and th rombi on thi s surface were more likely to be dislodged during
angiography.
Th e probabi lity th at a c lot would appear at any given time was
ca lc ulated by fitting th e following model : p = e/l o- II ,T in the control
group , and p = ell o- II , T in th e ex perimental group, where p =
prob ability of clot forming ; /31 = in stan taneous cond itional probabi lity th at a c lot will form on a non -h eparin-coated cat heter, provided
th at none has so far ; /32 = in stantaneous co nditional probability that
a c lot wi ll form on a heparin-coated catheter, provided that none
has so far; and T = tim e in minutes. The constant /30 was found to
be unnecessary and th e estim ated prob abiliti es are: p = e( - 0.0160n
for th e nonheparin group and p = e ( - 0 .0048 T) for the heparini zed
group.
In th ese ca lc ulati o ns, th e distribution of th e length of tim e without
thrombi was assumed to be exponential. These probabilities were
subseq uen tly plotted against tim e (fig . 5) . Finally, the model fit was
evj;HUated by co mparing the predicted and observed number of
thrombi .
Results
Cell aggregations and thrombi were more frequently demonstrated on the inner surfaces of non-heparin-coated catheters (21 of 31) than on heparin-coated catheters (seven of
25) (fig . 1). A further breakdown showed that there were
more moderate and severe grade thrombi on the inner
surface of non-heparin-coated catheters (10 of 31) than on
heparin-coated catheters (one of 25) (p < 0.05). Although
the outer surfaces were not analyzed statistically, it was
evident that cell aggregations and thrombi formed more
frequently on the outer surfaces of non-heparin-coated catheters (15 of 31) than they did on heparin-coated catheters
(five of 25). The number of cell aggregations and thrombi
that formed on the outer surface was the same or less than
the amount that formed on the inner surface in 49 of 56
catheters . The non-heparin-coated catheters were used for
a mean time of 79 ± 45 min and the heparin-coated catheters for a mean time of 71 ± 44 min.
The non-heparin-coated catheters formed cell aggregations and thrombi that conformed to all four grades. Those
that covered less than 1 % of the catheter surfaces usually
co nsisted of poorly organized clusters of cells that could not
be considered to be thrombi. Sometimes these aggregations
were related to catheter surface defects that had occurred
either during manufacture or during guide wire manipulations . Some red blood cell aggregations appeared to have
und ergone echinocyte transformation. The cell aggregations that covered 1 % -1 0 % of the catheter surfaces were
usually larger and better formed, and many could be considered to be thrombi . These cell aggregations were usually
oval but could take a variety of forms . When thrombi became
more extensive, they frequently coalesced and grew irregul arly into the lumen; less frequently, they formed flat sheets
(fig. 2). Sometimes these more extensive thrombi , which
were always in th e moderate or severe grades, had a cellular
appearance; at other times, they had a more fibrinoid appearance . Sometimes the cellular thrombi were made up of
ech inocytes (fig. 3 ). The thrombi on the heparin-coated
catheters did not appear markedly different from those on
the non-heparin-coated catheters except for one moderatesized thrombus (fig . 4). This thrombus differed from the
AJNR :3, Se ptember / Oc to ber 1982
THROMBUS WITH HEPARIN AND NONHEPARIN CATHETER S
A
537
B
Fig. 2. - Sheet of thro mbu s o n no n-heparin-coa ted ca th eter. A , Thro mbus is jux taposed with normal-a ppea ring ca theter surface ( x 170). S , Fi brin network
has enm eshed red blood cell s and pl atelets ( x 1 ,700).
Fig. 3. - Cellul ar thro mbus co mposed mainl y o f ech in oc yt es in non-heparin -coated ca th eter ( x 1 ,700).
other moderate and severe thrombi by having small aggregations of cells that rose into th e lum en of the cath eter.
Ce ll aggreg ations and thrombi were not only more frequent in the non heparinized group , but th eir medi an size
was significantly larger. The Mann-Whitney test showed thi s
differenc e to be significant at p < 0.01. In addition , th e area
covered by thrombi on a non-heparin-coated catheter, at
any given time , was estimated to be roughly one grad e
higher than it would have been on a corresponding heparinco ated c ath eter.
Th e probability that cell aggregations and thrombi would
appear on th e inn er surfaces of heparin- and non-h eparinc oated catheters w as plotted over 200 min from data present in figure 1 (fig . 5) . Th e estimated slopes and , th erefore,
th e estimated probabiliti es of thrombi formin g, are sig nifica ntly different in th e hepariniz ed and non heparinized
groups (p < 0 .01) . The sta nd ard erro r for th e no nheparinized slope wa s 0 .0039 and for th e heparini zed slope was
0 .001 8 . At 1 hr, 25 % of heparin- and 62 % of no n-heparin coat ed cath eters could be ex pected to have developed ce ll
aggregation s or thrombi , whil e at 2 hr, 4 4 % of th e form er
group and 8 5 % of th e latter group could be ex pected to
have d eve loped thrombi. The ex pec ted number of ce ll aggregation s and thrombi at any g iven tim e co rrelated well
wi th th e obse rved num ber.
Although th e two typ es of cath eters showed different
numbers of ce ll aggregati ons and thrombi, th e tw o g roups
of pati ents sh owed no sig nifi cant differences in age , ge nde r ,
or admitting di ag noses. Th e presence of th rombi also
showed no signifi cant difference wh en it was co rrelated with
the number of injecti ons o r th e roughn ess of th e cath eter
tip . An almost equ al number of rough cath eter tip s w as
prese nt in th e hepariniz ed and nonh epariniz ed cath eter
g roup s. Pull-out ang iog rams, whi c h were obtain ed in more
th an o ne-third of individ uals, we re norm al in both g roup s of
pati ents . No c hang es in pedal pul se or neurolog ic statu s
were noted in th e first 24 hr after angi ography in either
g ro up . Groin hemato mas appeared in fo ur of 25 individu als
studi ed w ith heparin-coated cath eters as compared with two
of 3 1 in d ividu als studi ed with non-heparin -coated cath eters.
In three of th e six ind ividu als who deve loped hemato mas,
neith er th e inn er nor o ute r surfaces of th e catheters showed
any ce ll agg regatio ns o r thro mbi (two heparin ized , o ne
no n he pariniz ed). No compli ca ti o ns resulted fro m th ese hemato mas.
KIDO ET AL.
538
AJNR:3 , September / October 1982
B
A
Fig . 4 .-M oderate grade th rom bu s on hepa rin-coated ca theter. trreg utar small co llecti ons o f cells pro trude into ca theter tumen. A , x 230. B , x 2,300.
100
ICONTRO Li
80
P
(b lood clot)
••••••
60
(%)
. . . . . IH EPAR INi
40
o
20 o ••
0
•••
•••
•
100
TIME
200
(min)
Fig. 5 .-Probability that bt ood ctot woutd appea r on heparin- and nonhepa rin - (con trot) coa ted ca th eters.
Discussion
The potentially serious seque lae of embolization from
catheters have led to several atte mpts to reduce thrombus
formation. Some investigators have attempted to identify the
thrombogenic properties of various cath ete rs [3, 9 , 10).
Others have premedicated the patients with salicylates ,
dextran, and heparin [9 , 11-13). The catheters have also
been coated with heparin. Initially, these efforts were unsuccessful because heparin leached from the catheters
wh en th ey were exposed to blood [2, 14-16). This drawback
was overco me by the development of a technique that
stabilizes heparin to catheters [5 , 6]. We have used these
stably-bound heparin-coated catheters to determine
wh ether th eir use would reduce thrombus formation as
detected by a scanning electron microscope . Our results
suggest that, within similar time frames, heparin-coated
catheters accumulate fewer thrombi and, thus, should reduce cerebral embolic complications . However, although
heparin coating reduces thrombus formation , it does not
eliminate it as an earlier report suggests [17].
The importance of thrombus formation on the inner surface of catheters li es in the fact that these thrombi are likely
to be dislodged during injections of contrast material and
guide wire manipulations. In contrast, thrombi on the outer
surfaces are less likely to be dislodged because they are
only subject to the constant flow of arterial blood and its
relatively small pressure variations. However, the fact that
few thrombi were seen on the outer surface of both groups
of catheters may be deceiving and may really indicate that
thrombi had been stripped from the outer surfaces during
their withdrawal.
The identification of echinocytes in many cell aggregations and thrombi may be important. It is known that normal
biconcave red blood cells (discocytes) can undergo a variety
of c hanges, one change being its transformation into
spheres covered with crenations or spicules (echinocytes)
[18]. The transformation of red blood cells into echinocytes
may occur after several isotonic sodium chloride washes
and in the presence of heparin [18, 19]. Transformation
under these cond ition s may be significant since an analogous situation exists when normal saline and heparin is
flushed through a catheter in an attempt to keep it c lean
and dripped through the catheter to keep it open. The
echinocyte transformation may also occur when normal red
blood cells come into contact with substances such as
barbiturates , phenylbutazone, and salicylates and with
changes in the environment itself (i.e. , pH and tonicity of
the medium) [20, 21]. The change in tonicity of the medium
may be especially important during the injection of a con-
AJNR :3, September/ October 1982
THROMBU S WITH HEPAR IN AND NONHEPARIN CATHETERS
trast material such as Reno-M-60, since this agent has five
times the mi ll iosmole concentration of normal plasma.
An awareness that about two-thirds of non heparin catheters can be expected to have cell aggregations or thrombi
at 1 hr shou ld encourage the cerebral angiographer to
perform the procedure with a concern for time. If the arteriogram is undu ly pro l ongf~ d , one might consider replacing
the catheter or using a heparin-coated catheter. Our suggestion, when using non-heparin-coated catheters, is that
this replacement be considered at 1 hr and be mandatory
by 2 hr, the cell aggregates being rather low grade at 1 hr
but moderate to severe grade at 2 hr. The angiographer
shou ld also remember the interdepend ence of thrombus
format ion and technique since the rate of thrombus formation on the inner surface of the catheter is largely related to
the amount of blood that is all owed to reflu x into the lumen .
Finally, the angiographer should remember that rough guide
wire manipu lations may abrade the catheter surface and
make it more susceptible to thrombus formation and that
repeated injections of contrast material and saline may
change the very nature of the thrombus itself.
ACKNOWLEDGMENT
We th ank Sheila Bartek for aid in co llecting th e samples and
preparing them for the scanning electron microsco pe .
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