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| Dr Warren Laskey is currently director of interventional cardiology at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. Before that he was director of the cardiac catheterisation laboratory and associate director of the division of cardiology at the University of Maryland School of Medicine and, subsequently, director of the cardiac catheterisation laboratory at the National Naval Medical Center in Bethesda, Maryland. He is the author of over 100 publications on diverse areas of clinical cardiology with an emphasis on interventional cardiology, and served as co-principal investigator of the Contrast Media Utilization in High Risk PTCA (COURT) Trial. |
Radiographic contrast media and thrombosis:
the more we know, the more we need to know
Warren K Laskey
Division of Cardiology, Uniformed Services University of
the Health Sciences, Bethesda, MD, USA
Address for correspondence:
Dr WK Laskey, MD
Division of Cardiology, A-3060
Uniformed Services University of the Health Sciences
4301 Jones Bridge Road, Bethesda, MD 20814
Tel: +1-(301)-295-3623
Fax: +1-(410)-360-7306
Email: warrenlaskey@earthlink.net
Abstract
The diverse effects of radiographic contrast media (RCM) on virtually all organ systems extend to the haemostatic system. Before the advent of non-ionic RCM, little controversy surrounded these effects, i.e. inhibition of thrombin generation, disruptive effects on arterial endothelium and inhibition of platelet aggregation. Thus, ionic high osmolar contrast media (HOCM) were viewed as having ‘anti-coagulant’ and ‘anti-thrombotic’ properties. The fact that these inhibitory properties were chiefly in vitro phenomena, that significant dilution occurred in the circulation resulting in any local (inhibitory) effects being transient and that differentiation of effects caused by ionicity or osmolality were limited by the availability of RCM other than HOCM all contributed to the origin of the ‘clotting controversy’ when non-ionic RCM was introduced.
The following review takes its motivation from the clinical perspective. Thrombosis is viewed as the end result of the pathological interaction of vessel wall, blood flow and formed elements of the blood. The interaction of ionic and non-ionic RCM with each of these elements is discussed.While consensus exists with respect to the in vitro and in vivo anti-coagulant properties of RCM (inhibition of thrombin formation), less consensus focuses on the in vitro and in vivo effects of RCM on platelet function. Furthermore, extension of the in vitro data to the clinical setting is problematic given the lack of clinical data suggesting a pro-thrombotic effect of non-ionic RCM. As many of the potentially deleterious effects on endothelial and/or platelet function are the result of either RCM ionicity or osmolality, the results of studies with non-ionic, iso-osmolar RCM are discussed.
Introduction
Radiographic contrast media (RCM) are among the
most widely used pharmaceutical agents in
cardiovascular medicine. However, RCM have only one
desirable feature – the enhancement of radiographic
contrast – and a plethora of undesirable effects.
Fortunately, the majority of the latter are transient in
nature and do not pose a clinically significant hazard to
the patient. Serious adverse effects of RCM may be
categorised by organ specificity, e.g. RCM-related
nephropathy, or more generally by system specificity,
e.g. cardiovascular effects. In this review, the focus will
be on the interaction of RCM with those elements of
the haemostatic system in man that have clinical
relevance. A basic distinction between clotting and
thrombosis is made at the outset: clotting is physiological
and best assessed ex vivo; thrombosis is distinctly
pathological and very much an in vivo process.
Virchow’s triad – the hypothesis that thrombosis is the
end result of the interaction of the blood vessel wall,
blood flow and formed elements of the blood – remains
central to our thinking, notwithstanding the exponential
increase in the knowledge base in all three areas. In fact,
our increasing understanding of the inter-relationship
between thrombosis and inflammation can be seen as
an extension of Virchow’s seminal observations.
Therefore, the following discussion of the issue(s)
surrounding RCM and thrombosis will focus on the
three elements of Virchow’s triad.
RCM and the vessel wall
The least intensively studied of the properties of RCM –
their interaction with vessel wall components – has
perhaps the most important clinical implications for
thrombosis. Ionic RCM, irrespective of osmolality, exhibit
the most disruptive effects on normal endothelium in
vitro1 and ex vivo2 while non-ionic iso-osmolar dimers
appear least disruptive.1 Not surprisingly, in the setting
of abnormal endothelium, the effects of RCM should be
even more pronounced. Specifically, these effects extend
from abnormal histological appearance, including
destruction,1,3 to the inhibition of nitric oxide
production.4 The specific effects of RCM on endothelial
cell release of inflammatory cytokines and, conversely,
the effects of cytokines on endothelial functions are
only beginning to be appreciated. Given the increasingly evident inter-dependence between inflammation and
thrombosis,5 the potential for RCM to contribute to
both local thrombosis and inflammation superimposed
on abnormal endothelium is of immediate relevance.
Activation of von Willebrand factor and release of
intercellular adhesion molecules and pro-inflammatory
cytokines have all been detected in clinical studies6–10
and confirm in vitro observations.
Injured or denuded endothelium predisposes to
thrombosis via a number of pathways, most notably the
activation of Factor VII by tissue factor. The critical role
of platelet activation and aggregation will be discussed
below but is mentioned here given the fundamental
role of platelet activation by damaged endothelium.
Furthermore, the ionicity and/or osmolality of RCM
may be critical in the dynamic balance between local
thrombosis and lysis. Controversy exists with respect to
effects of RCM on the fibrinolytic system with some
studies suggesting activation11 and others indicating
inhibition12 of the lytic system. Differences between
in vitro and in vivo data further confound this issue.
RCM and blood flow
In regions of high flow velocity and shear stress,
platelet activation is likely to occur.13 These abnormal
haemodynamics are also seen in association with
endothelial cell injury and dysfunction. Conversely, in
regions of low velocity flow and low shear, stasis and
activation of the clotting cascade are likely to occur. In
fact, observation of the clotting cascade activation led
to many of the initial concerns surrounding the
facilitation of clot formation with non-ionic RCM.14
However, the clinical implications of clot formation in
static blood admixed with RCM14 are unclear. Additional
studies have shown that the anticoagulant effects of
RCM were preserved in both glass and plastic syringes,
irrespective of ionicity.15 It should be emphasised that,
at both extremes of shear stress, the sine qua non for
thrombosis in man is the presence of an ‘abnormal
surface’ – thus highlighting, again, the importance of
endothelial integrity.
In one of the few areas of concordance between in vivo
and in vitro data, both ionic and non-ionic RCM inhibit
the ‘clotting cascade’ and, ultimately, thrombin
formation.16 Prolongation of clotting times correlate
with the extent of inhibition of thrombin formation in
vitro. Ionic RCM, irrespective of osmolality, consistently
possess greater anticoagulant properties in vitro
compared with non-ionic RCM.16,17 The relevance of this
observation to the patient receiving systemic thrombin
inhibitors is less clear. From a theoretical standpoint,
the viscosity of RCM might contribute to altered blood
flow patterns and, therefore, shear stress. However,
given the extensive dilution undergone by RCM during a
first pass, with resultant local concentrations generally
under 1%, any significant alteration in local viscosity
is unlikely.18
RCM and formed elements of the blood
Given the central role of the platelet in physiological
haemostasis and pathological thrombosis, the extensive
literature on the effects of RCM on platelet function is
appropriate. However, no greater area of controversy
surrounding the effects of RCM exists than in the
interaction of platelets with RCM. Here again,
differences among in vitro studies as well as between
in vitro and in vivo studies have led to considerable
uncertainty about the implications of these interactions
(or lack thereof) as well as their clinical relevance.
Studies in vitro were spurred by the inception of
non-ionic RCM and concerns surrounding their
‘pro-thrombotic’ potential.14,19,20 Unfortunately,
inter-study differences in methodology, definitions and
experimental conditions resulted in conflicting data
with respect to the effects of RCM on ‘platelet
function’. This term, however, encompasses platelet
adhesion, activation, degranulation and, ultimately,
aggregation. It is also important to note that, in
addition to these diverse measures of platelet function,
clinically relevant differences exist in the extent of
activation by various agonists (e.g. collagen, thrombin or thromboxane). Thus, although ionic RCM inhibited
thrombin-mediated platelet ‘activation’ to a greater
extent than non-ionic RCM, neither class of RCM
activated platelets by themselves.21 There is evidence of
a ‘platelet-activating effect’ associated with non-ionic
low osmolal RCM (degranulation and surface antigen
expression) but not with ionic low osmolal RCM.22
However subsequent studies using more physiological
means of assessing platelet function (e.g. flowing blood
platelet aggregometry) demonstrated the independence
of degranulation and ionicity and the over-riding
importance of osmolality.23 In addition, again using a
platelet function assay simulating more physiological
conditions, Sakariassen et al. demonstrated a lack of
concordance between degranulation and platelet
thrombus formation.24,25
Data obtained in vivo tend to support the results of
studies of platelet function under ‘physiological’
conditions, i.e. no evidence of pro-thrombotic potential
for non-ionic RCM.18,26 The clinical literature provides
strong support for the safety of non-ionic RCM during
cardiac angiography27 as well as a lack of evidence of
enhanced thrombogenicity.28 It is noteworthy that the
act of vascular invasion, per se, is associated with
systemic evidence of activation of coagulation and
inflammation;29–31 factors rarely controlled for in any
study. Presently, the controversy centres on the role of
RCM during coronary interventional procedures. These
clinical circumstances represent a most extreme
pro-thrombotic milieu and should facilitate the
detection of the pro-thrombotic potential of RCM.
A meta-analysis of studies reported before 1999 found
a reduced rate of abrupt vessel closure during
interventional procedures with use of a low osmolar
ionic agent (ioxaglate) compared with non-ionic low
osmolar agents.32 However, in this study no difference was observed in rates of abrupt closure between
ioxaglate and the iso-osmolar, non-ionic dimer
iodixanol. Furthermore, despite the large sample size,
this study failed to identify a difference in an overall
composite rate of serious adverse events between
ioxaglate and non-ionic comparators.32 Therefore, it is
worth noting that several recent large-scale, multicentre,
randomised, controlled trials have demonstrated
the safety of non-ionic RCM during coronary
interventional procedures.33,34
Expanding on the importance of osmolality as well as
ionicity, the Contrast Media Utilization in High Risk
PTCA (COURT) trial demonstrated enhanced safety of
the non-ionic, iso-osmolal dimer iodixanol compared
with the ionic, low osmolal dimer ioxaglate during
coronary interventional procedures.35 These intriguing
findings were also noted in the Visipaque™ vs. Isovue®
in Cardiac Catheterization (VICC) trial36 – a more
contemporary version of the COURT trial. In the VICC
trial, in-hospital adverse event rates during coronary
intervention were lower with iodixanol compared with a
non-ionic, low osmolar RCM, iopamidol. From a practical
standpoint, it becomes increasingly difficult to
demonstrate RCM-specific platelet dysfunction given
the universal use of potent ‘anti-platelet’ agents during
coronary intervention. Nevertheless, it remains intuitive
that RCM, with the least likelihood of interfering with
platelet and endothelial function, would be the most
desirable, particularly in ‘high-risk’ settings.
The interaction of RCM with white blood cells is another
area of clinical relevance. As white blood cells are rich
sources of chemokines and cytokines that are both
pro-inflammatory and pro-thrombotic, the effects of RCM
osmolality and ionicity may have relevance at the local
level. Osmolality, as a major stimulator of MAP kinase and
NFkB,37,38 may exacerbate local inflammation and thrombosis. Such a result might be reflected in acute and/or
short-term adverse sequelae, despite systemic
anti-coagulation and anti-platelet treatment.
Conclusions
In summary, a considerable database of preclinical
information indicates that all RCM possess
anti-coagulant activity, i.e. they inhibit thrombin
formation, and that ionic RCM exhibit greater inhibition
of thrombin formation than non-ionic RCM.
Furthermore, RCM have variable effects on specific
measures of platelet function and although no agents
are frankly pro-thrombotic, ionic RCM exhibit greater
morphological and functional deterioration in
endothelial cells compared with non-ionic agents, and the osmolality of RCM may be an
important (negative) determinant of their
pro-thrombotic potential.
The clinical literature supports the overall safety of
non-ionic RCM during cardiac angiography. Recent
randomised controlled clinical trials indicate that the
use of the non-ionic, iso-osmolar dimer iodixanol
during high-risk coronary interventional procedures is
associated with a measurable benefit compared with
either ionic or non-ionic RCM. Given the complexity of
the relationship between vascular endothelial function,
inflammation and thrombosis, further study of the
effects of RCM on these determinants of procedural
outcomes is needed.
Key Learning
• This article reviews the pathological basis for thrombosis
• The effects of RCM on the elements of thrombosis are reviewed from the standpoint of
ionicity
and osmolality
• RCM can exert effects on blood vessel walls, blood flow and formed elements of the
blood
• Areas of consensus regarding the effects of RCM are noted:
- RCM inhibit thrombin formation and disrupt endothelial cells (ionic > non-ionic agents)
- Clinical data indicate safety of low osmolar non-ionic RCM in diagnostic cardiac
angiography
- Clinical data indicate safety of iso-osmolar non-ionic RCM in coronary intervention
• Areas where a lack of consensus exists reflect differences between in vivo and in vitro
data:
- RCM effects on fibrinolysis and platelet function are variable
- Ionicity and osmolality of RCM are important negative determinants in interactions with
platelets and white blood cells
• The relationship between endothelial function, thrombosis and inflammation is viewed
as essential
to the understanding of the influence of contrast media on thrombosis |
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