Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2569-2574
Uremic Bleeding: Closing the Circle After 30 Years of Controversies?
By
Marina Noris and
Giuseppe Remuzzi
From the Mario Negri Institute for Pharmacological Research, Bergamo,
Italy; and the Unit of Nephrology and Dialysis, Azienda Ospedaliera,
Ospedali Riuniti di Bergamo, Bergamo, Italy.
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INTRODUCTION |
MORGAGNI IN HIS "Opera
Omnia"-Epistola Anatomico-Medica XLI-1764, Sermo est de Urinae
Suppressione,1 was the first to recognize the remarkable
association between bleeding and renal dysfunction, which became a
clinical problem in the early days of dialysis, when patients sometimes
died from excessive bleeding from the gastrointestinal tract or
abdominal organs.2,3
Modern dialysis techniques and the use of erythropoietin to correct
anemia4 have reduced the frequency of uremic bleeding, which, however, still limits surgery and invasive procedures in these patients.
The cause of uremic bleeding has been the subject of a major debate in
the last 30 years. The pathogenesis is considered multifactorial (Table 1); however, platelet-platelet and
platelet-vessel wall interactions appear to be of crucial
importance.5,6 Studies found that, in uremics, skin
bleeding time (influenced by platelet and vascular function as well as
by red blood cells), although far from ideal, is still a reliable
predictor of clinical bleeding.2,7
It has always been difficult to investigate the nature of platelet
dysfunction in uremia, because dialysis has a complex influence on
platelets and coagulation.8-10 Emblematic is the case of
platelet function tests that may be worsened11,12 or
improved12-14 at the end of an average dialysis.
Circumstantial evidence exists that platelets are activated by the
dialysis membrane, becoming refractory to further stimuli, which would
explain the paradoxical effect of depuration on platelet function
tests.15 In the search for the cause of uremic bleeding,
abnormalities of platelet 
-granules with lower than normal content
of ADP and serotonin14,16 and defective arachidonate
metabolism17 have been widely reported, but which of the
above-noted actually triggered the clinical syndrome remained
controversial.18 More recent evidence implicates acquired defects in specific receptors that impair platelet binding to fibrinogen and von Willebrand factor (vWF),13 although the
role of vWF in uremic bleeding has been controversial for more than 20 years.19-22
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EARLY STUDIES AND THE PROPOSED ROLE OF GUANIDINOSUCCINIC ACID |
Because uremic platelets in normal plasma function normally, early
studies18,23 suggested that molecules retained in uremic blood did induce platelet dysfunction. An extensive search for the
toxin involved was frustrating until the late 1960s, when Horowitz et
al24,25 first reported that uremic, but not normal plasma,
inhibited platelet factor 3 activation, measured as prolongation of the
Stypven time test,24,25 and ADP-induced
aggregation.25 The finding, indicating an inhibitor of
platelet function in uremic plasma, could not be reproduced with
increasing concentrations of urea, creatinine, or guanidinoacetic acid.
Rather consistently, however, guanidinosuccinic acid, when added to
normal platelets, dose-dependently prolonged Stypven time and blocked
ADP-induced aggregation.25
Guanidinosuccinic acid accumulates in uremics who need an alternative
pathway for ammonia detoxification (Fig 1)
to compensate for the reduced efficiency of urea cycle enzymes
inhibited by excess products.26,27 Peritoneal dialysis,
which removed guanidinosuccinic acid from uremic blood, also corrected
the inhibitory action of uremic plasma on normal
platelets,25 reinforcing the link between guanidinosuccinic
acid and abnormal hemostasis, the toxin being defined as the "x
factor in uremic bleeding."28 This association was
furthermore reinforced by another study.29 However, for 30 years thereafter, despite intensive research on uremic bleeding, the
story of guanidinosuccinate was largely neglected.
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| Fig 1.
An alternative pathway of L-arginine metabolism leading
to the formation of guanidinosuccinic acid. The accumulation of urea in
uremic plasma exerts an inhibitory effect on the enzymes of the urea
cycle. This activates alternative metabolic pathways such as the
transamidination of arginine leading to guanidinosuccinic acid
formation.27 It has been proposed that guanidinosuccinic
acid can also be formed by enzymatic cleavage of argininesuccinate,
another product of the urea cycle.
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FROM GUANIDINOSUCCINIC ACID TO NITRIC OXIDE (NO): IS THE LINK STRONG? |
Accumulation of guanidinosuccinic acid in uremic blood depends on
amidine being transferred to aspartic acid from
L-arginine,26 a recognized intermediate of the urea cycle.
Research on L-arginine and its metabolites has exploded in the last few
years since L-arginine has been recognized as a major substrate of NO
synthase.30-32 NO is a potent modulator of vascular tone
that limits platelet adhesion to endothelium33 and
platelet-platelet interaction increasing the formation of cell cyclic
GMP.34-36
NO synthesis from L-arginine implies activation of specific synthase
enzymes (2 constitutive and an inducible isoform).37 The
role of NO in primary hemostasis rests on findings that the skin
bleeding time is prolonged in healthy volunteers38 inhaling NO. In patients with adult respiratory distress syndrome,39 NO-inhalation induced an increase in plasma cyclic GMP, prolongation of
bleeding time, and inhibition of ex vivo platelet aggregation and
P-selectin expression. Fibrinogen binding was also inhibited, which
suggests that NO-dependent inhibition of platelet aggregation may be
caused by a decrease in fibrinogen binding to the platelet GP IIb/IIIa
receptor.39
NO and NO metabolites are markedly enhanced in the circulation of rats
with extensive surgical ablation of renal mass and progressive renal
failure.40 This depends on upregulation of both inducible
and endothelial constitutive NO synthase enzymes that occurs in
uremia.40 Because monomethyl-L-arginine (L-NMMA), an NO
inhibitor, normalized platelet dysfunction and bleeding time of uremic
rats, a role of excessive NO was suspected in uremic bleeding
tendency.41 Consistently, intravenous infusion of L-NMMA reduced in vivo NO production and significantly shortened bleeding time
in healthy humans.42 The findings that the vascular
expression of NO-forming enzymes and plasma concentrations of NO
metabolites in uremic rats were normalized by conjugated
estrogens43 (the best pharmacological tool for controlling
bleeding in experimental44 and human45,46
chronic renal insufficiency) are further evidence of the crucial
importance of NO in uremic bleeding. Once more, enhancing NO
availability by L-arginine fully abolished the beneficial effect of
estrogens and reinduced bleeding47 in rats. Thus, simply
limiting NO synthesis is enough to block excess bleeding and restore
normal hemostasis in experimental uremia. Data are available in humans
showing that platelets from uremic patients on hemodialysis generate
more NO than healthy subjects48
(Fig 2). In addition, uremics
have higher levels of NO in the exhaled air49 and higher
plasma levels of NO metabolites50-53 than normal humans.
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| Fig 2.
(Top) NO formation and intracellular cyclic GMP in
platelets from controls and uremic patients. (Bottom) NO formation by
human endothelial cells (HUVEC) exposed to control or uremic plasma.
*P < .01 versus controls. (Modified and reprinted with
permission from Noris et al.48,57)
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The biochemical nature of the findings listed above was addressed by
studies showing that uremic plasma, unlike normal plasma, was a potent
inducer of NO in umbilical48 or microvascular endothelial cells.54 This reflects accumulation in uremic plasma of
substances that potently induce NO synthesis. Among putative
candidates, at least 2 (tumor necrosis factor and interleukin-1
)
circulate in supranormal amounts in uremics, being released by
monocytes activated on dialysis membranes48,55-57 and/or on
challenge with endotoxin, which can cross the dialysis membrane and
reach the blood, albeit in small amounts.58 If care is
taken to reduce cytokine activation by the use of more biocompatible
membranes, NO formation is controlled and its concentrations in blood
may even decrease at the end of an average dialysis.49,50
Also, heparin, which is used as anticoagulant during dialysis, might contribute to increased NO production in dialysis patients, as indicated by its capability to promote NO production by cultured human
endothelial cells.59
Old data on the worsening or ameliorating effects of dialysis on
bleeding may therefore be explained by the effect of different dialysis
membranes and procedures on circulating cell activation and NO formation.
NO is mostly but not exclusively formed from L-arginine. Most of the
endogenous guanidines, such as guanidino acetate and propionate,
guanidine, and methylguanidine, which accumulates in uremic plasma in
micromolar concentrations,25,29,60 had no effect on
isolated rat aortas61,62 used as a biological indicator of
NO formation. In contrast, guanidinosuccinic acid relaxed
isolated rat aortas in a dose-dependent fashion62
(Fig 3). The vasodilatory properties of
guanidinosuccinic acid were dependent on an intact
endothelium62 and implied increased cyclic GMP formation in
vessels. Vasodilation and cyclic GMP formation were both attenuated by
NO inhibitors such as monomethyl-L-arginine and
hemoglobin,62 indicating that NO mediated guanidinosuccinic acid-induced aortic relaxation.
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| Fig 3.
Dose-response curve showing the relaxation elicited by
guanidinosuccinic acid in the rat aorta preparation. The NO-synthase
inhibitor L-NMMA reverses the effect of guanidinosuccinic acid in the
rat aorta. GSA, guanidinosuccinic acid. L-NMMA,
N-monomethyl-L-arginine. (Modified and reprinted with permission from
Thomas and Ramwell.62)
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Challenging human cultured endothelium with increasing amounts of
guanidinosuccinic acid promoted release of NO metabolites in the cell
supernatant, an effect that was neutralized by specific NO synthase
inhibitors.63 Concentrations of guanidinosuccinic acid
maximally inducing NO release in vitro (Fig
4) were remarkably close to the ones measured in uremic plasma before
dialysis.63 Lower, although still significant stimulation
was observed with concentrations close to those found in vivo in
postdialysis blood,63 whereas the concentrations reached in
normal plasma had no effect on NO synthesis.
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| Fig 4.
Effect of guanidinosuccinic acid on NO synthesis
(analyzed by measuring the concentration of the stable NO metabolites,
nitrites). *P < .05, **P < .01 versus vehicle.
L-NMMA, N-monomethyl-L-arginine. (Reprinted with permission from
Todeschini et al.63)
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That guanidine derivatives structurally related to L-arginine can form
NO rests on recent data that many N-substituted arginines, such as
benzoyl L-arginine, induce vascular relaxation and inhibit platelet
function.61,64 On the other hand, guanidino compounds (guanidinoacetate, guanidinopropionate, guanidinosuccinate, and guanidine) have been found in micromolar concentrations in human vascular endothelium.61 Interestingly, guanidinosuccinate
is the only guanidine derivative related to L-arginine that mimics perfectly the biological activities of NO ranging from vasodilation to
antiproliferative effect on smooth muscle cells.61 Like NO, GSA also inhibits platelet function, as documented by platelet aggregation studies on human platelet-rich plasma stimulated with ADP
(Horowitz et al25 and Fig 5).
Pretreatment with the NO inhibitor N
-nitro-L-arginine65
completely restored ADP-induced irreversible platelet aggregation (Fig
5), which would indicate that NO mediates the effect of GSA on platelet
function. The in vivo relevance of these data is evidenced by data that
GSA (1 mg/kg) prolonged the bleeding time of rats when injected
intravenously (Macconi et al, abstract submitted to the Congress of the
American Society of Nephrology, 1999). The bleeding time
was significantly lengthened (P < .05) over basal 5 minutes
after GSA injection (49% ± 11.9% increase over basal, n = 4) and
reached maximal increase after 30 minutes (114% ± 30%, n = 4, P < .01 v basal). Administration of the specific NO
inhibitor, N-nitro-L-arginine methyl ester (30 and 60 mg/kg),66 significantly attenuated the effect of GSA on
bleeding time (30 minutes: 65% ± 8% increase over basal, n = 4, P < .05 v GSA alone).
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| Fig 5.
Representative platelet aggregation tracings induced by
ADP (1 µmol/L) in normal human platelet-rich plasma with the addition
of buffer or GSA (500 µmol/L, 30 seconds of preincubation; A). GSA
inhibited the second wave of platelet aggregation induced by 1 µmol/L
ADP. N-nitro-L-arginine (1 to 2 mmol/L, 1 minute of preincubation)
overcame GSA effect and restored ADP-induced irreversible platelet
aggregation (B). As a positive control, L-arginine (30 seconds of
preincubation) inhibited platelet aggregation when added at a
concentration  1 mmol/L (C). (Macconi et al, abstract submitted to
the Congress of the American Society of Nephrology,
1999).
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Thirty years ago, those researchers were right: guanidinosuccinic acid,
which accumulates in uremic patients, induced them to bleed. Data now
accumulating tend to suggest that this was due to an exuberant
formation of NO by uremic vessel, which here we find to be
guanidinosuccinic acid-dependent.
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ACKNOWLEDGMENT |
Data and concepts presented in this report are derived from the
contributions of the following persons in our laboratories to whom we
are indebted: Carla Zoja, Ariela Benigni, Marta Todeschini, Daniela
Corna, Daniela Macconi, Sistiana Aiello, Paola Boccardo, and Flavio
Gaspari. The authors sincerely thank our colleagues Manuela Livio,
Maria Benedetta Donati, and Giovanni De Gaetano, who, in 30 years of
research in uremic bleeding, have contributed substantially by their
stimulating discussion and exchange of information to the contents of
this report.
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FOOTNOTES |
Submitted December 23, 1998; accepted June 7, 1999.
Supported in part by a grant from Fondazione CARIPLO, Italy.
Address reprint requests to Marina Noris, Chem Pharm D, "Mario
Negri" Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy.
| |
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