The Rationale for, and Role of, Heparin in Peritoneal Dialysis
Sharad Goel, Madhukar Misra, Rajiv Saran, Ramesh Khanna
The administration of intraperitoneal (IP)
heparin enjoys time-honored use and is felt to be
side-effect free. It is administered whenever fibrin is detected
in the dialysate effluent. It is believed that there is
no absorption of heparin across the peritoneal
cavity. The aim of this article was to review the
rationale behind the administration of IP heparin, to show
that absorption and side effects may occur, and to
present recent evidence that questions the routine use of
this drug as an additive to dialysate fluid.
Heparin, peritonitis, intraperitoneal,
From:Division of Nephrology, University Hospital and Clinics, Columbia, Missouri, USA.
Peritoneal dialysis (PD) is the renal
replacement modality for 16% of the end-stage renal
disease (ESRD) population (1,2). During the course of
regular PD, peritoneal fibrin is occasionally seen in
the dialysate (3). However, this is more common
when the course of disease is complicated by
peritonitis. The appearance of fibrin in the PD effluent can
lead to catheter blockage and, if excessive and
unopposed, can in theory result in peritoneal adhesions and
loss of peritoneal-membrane function (2). These
complications, it is believed, can be prevented by the
timely administration of intraperitoneal (IP) heparin.
This belief, coupled with the perception that IP use
of heparin is risk free, has made heparin the most common additive to PD fluid. The aim of this
article is to re-examine the evidence for this practice.
Heparin: structure and mode of action
Heparin is an acidic, anionic, sulfated
glycosaminoglycan (GAG) of variable molecular
weight (mean: 15000 d; range: 1800 - 30000). Only a
portion of the molecule in commercial use contains
a specific pentasaccharide sequence that is
responsible for binding to antithrombin III (AT-III). This
process causes conformational changes in AT-III resulting
in a multifold increase in its inhibitory potential.
This heparin-AT-III complex, besides inhibiting
thrombin formation, causes inhibition of activated
coagulation factors IX, X, XI, and XII as well.
Heparin also exerts its anticoagulatory actions
by mechanisms independent of AT-III, such as HC-II binding to prothrombin, direct binding to
coagulant factors, and release of endogenous GAGs
with anticoagulant activity (4,5).
The mode of action of IP heparin is not
precisely known. Studies (6,7) found that AT-III levels in
the dialysate are normally 1.5% of the plasma
levels (0.52 ± 0.1 mg/dL vs 33.6 ± 4 mg/dL), and this
level is felt by some authors (6) to be too low to
explain the anticoagulant action of heparin during stable
PD. Others (7) feel that even these levels would
suffice. During peritonitis there is a general outpouring
of proteins into the peritoneal cavity resulting in a
high level of AT-III (7). Whether heparin exerts
its anticoagulant effect by AT-III-independent effects
in the peritoneum is not known.
In 8 stable patients on continuous
ambulatory peritoneal dialysis (CAPD) it was shown that
heparin activity in dialysate decreased with time. With a
dose of 2.5 U/mL to 5 U/mL the activity decreased by
half of the initial level after 1 to 2 hours (7).
Indications for IP heparin: standard practice
It is customary at most centers to add
heparin whenever fibrin or blood or both is seen in
the drainage bag. Fibrin formation is occasionally observed during routine dialysis, but more
commonly when the PD catheter is being inserted and at the
onset of peritonitis. Once started, heparin is added to
each bag until the return-drainage dialysate is
clear. Patients are educated on the appearance of fibrin
and the method of administering heparin, and asked to
call the dialysis center if the anticipated clearing
of the dialysate does not occur.
What dose of IP heparin to use?
Dosing is based on clinical observations, and
varies from center to center with a range for
CAPD/IPD (intermittent PD) of 100 to 2500 U/L of
Gries et al. (8) observed the effect of two
different heparin concentrations (7500 U/L and 500 U/L)
on dialysate fibrinopeptide A (FPA) concentrations
in 6 patients. FPA is a specific marker for
thrombin action on fibrinogen, and hence of fibrin
formation. Heparin given intraperitoneally reduced the
fibrin production as measured by FPA; however, there
was no difference in reduction of fibrin formation
between the two different concentrations of heparin (FPA
with 7500 U/L heparin: 20.6 ± 5.6 ng/mL; 500 U/L:
22.8 ± 6 ng/mL; no heparin: 152.2 ± 11.8 ng/mL).
They demonstrated that the lower (500 U/L) of the
two doses of heparin was sufficient to prevent the formation of fibrin. At the University of
Missouri- Columbia our standard practice, therefore, is to
use 500 U/L for both CAPD and IPD.
Does IP heparin have a systemic effect?
The aim of IP instillation of heparin is to get a
local fibrinolytic effect without systemic
anticoagulation. The traditional view is that, with the doses
used, virtually no heparin gets across the
peritoneal membrane. Part of the reason for this could be
the anionic charge of heparin and its large
molecular weight. This view has been supported by studies
that showed that, if administered as recommended,
IP heparin had no effect on blood coagulation (7).
Pharmacokinetic studies addressing
the question of heparin absorption across the peritoneum in humans are lacking. A study done in
an animal model demonstrated significant recovery
of heparin from systemic circulation. In this
study 99-Tc-labeled heparin was given
intraperitoneally along with dialysate in a New Zealand white
rabbit model. Three different protocols were used: a
single 15-minute cycle with heparin 500 U/L, 6
successive 15-minute cycles with heparin 500 U/L, and
a single 3-hr cycle with heparin 2500 U/L. Labeled heparin was found in blood, organs, and urine.
The total amount of recovery ranged from 1.5% to
20%, and depended on the amount of heparin used and
the duration of its presence in the rabbit
peritoneal cavity (9).
Interestingly, a patient on CAPD with
deep-vein thrombosis (DVT) was successfully treated with
low-molecular-weight heparin with resulting
therapeutic antifactor-Xa activity in the plasma of 0.5 to 0.8
units. (Dose used: 6000 to 8000 antifactor Xa
U/2-L dialysate bag, given four times a day) (10). Thus
the belief that the absence of an effect of IP heparin
on systemic coagulation implies an absence of
transfer across peritoneal membrane may be inaccurate.
Potential problems with adding IP heparin
The anticipated side effects expected from the use
of IP heparin are mainly local ones. However, the knowledge that there is absorption of small
amounts of heparin across the peritoneal membrane
requires one to be alert to the possibility of systemic
side effects, such as formation of heparin antibodies,
with accompanying problems of thrombocytopenia
(4), osteoporosis (11), and increase in transaminases (12).
Locally, apart from the potential for
increased infection, there is the possibility of mesothelial
cell injury. During PD the mesothelial cell
undergoes continuous sloughing and regeneration. Addition
of heparin to human peritoneal mesothelial cell
cultures inhibited their growth (13).
In a study on Staphylococcus
epidermidis biofilm, heparin was shown to antagonize the
antibacterial activity of rifampin (14). However no effect was
seen on the activity of penicillin, cephalosporins,
clindamycin, tobramycin, or vancomycin (15).
Having concluded that IP heparin use is not
as risk-free as previously believed, it is time to take
a fresh look at the rationale on which this practice
is based, and the benefits obtained from it. The
two questions that need to be asked are, first, does
heparin inhibit fibrin formation? and, second, is there a
need for a fibrinolytic agent?
Does heparin reduce fibrin formation?
The answer to this question is an unequivocal yes.
Indirect evidence for this was first provided
by showing that higher dialysate-inflow and
-outflow rates were achieved in 6 patients on CAPD
when heparin was added to the dialysate, compared to
when it was not (16). This was confirmed by
measuring fibrinogen-A in the dialysate from patients on
PD (17). Gries et al. were able to show that the addition
of heparin (500 U/L) reduced fibrin formation
(FP-A) from 153.4 ± 16.8 ng/mL to 11.6 ± 2.6 ng/mL
(P < 0.05) in the dialysate (17).
This was also confirmed by Tabata and
Is exogenous fibrinolysis required?
A not very well recognized fact is that the
peritoneal mesothelium has synthetic activity. It is involved
in the synthesis and secretion of mesothelial
surface fluids, which are responsible for the phenomenon
of boundary lubrication of slowly moving surfaces.
This liquid consists of phospholipids, mainly
phosphatidylcholine and serine, with high surfactant
and water-repelling properties (19,20).
The mesothelium of rats and guinea pigs has
been shown to have fibrinolytic activity. Heparin is
not synthesized by the mesothelial cells, but other
GAGs, such as hyaluron, are.
In vitro, pure human mesothelial cells
deprived of the underlying subserosa were shown to
have fibrinolytic activity (21). Tissue-specific and
urokinase-like plasminogen-activators (t-PA, u-PA) could be detected in normal and inflamed
peritoneum. Plasminogen activator inhibitors (PAI)
were detectable only in inflamed peritoneal cells
(22). Other workers have shown the presence of PA
and PAI in human PD effluent (23).
There is an ongoing presence of natural
coagulant and fibrinolytic activity in the peritoneal cavity.
There exists a need to ascertain whether, during
peritoneal dialysis, the mesothelial fibrinolytic activity
suffices to prevent fibrin deposition without the addition
of exogenous fibrinolytics like heparin.
Two separate studies have recently addressed
Sitter and co-workers (24) compared levels
of coagulation and fibrinolysis markers in PD
effluents from patients without peritonitis in a 6-month
interval (Group 1, n = 18) with those from patients with
acute peritonitis (Group 2, n = 5).
The markers used were prothrombin
fragments F1 and F2, (F1+2), thrombin-antithrombin
III complex (TAT), and fibrin monomer (FM) (as parameters of ongoing coagulation), and
fibrinogen degradation products (FDP), as a marker
There was high fibrinolytic and
coagulant activity not only during peritonitis but also in
clinically stable patients. However, the
balance between intraperitoneal generation and
degradation of fibrin was disturbed in untreated patients in
the group with peritonitis (Group 2) as evidenced by
a higher FM/FDP ratio (61 vs 27). This indicated
that during peritonitis increased fibrin formation resulted. Seven days after treatment with
IP antibiotics and heparin all markers of
coagulation and fibrinolysis normalized.
They then addressed the question of whether
these changes during peritonitis could be explained
by altered expression of PAs or PAI in the
mesothelial cells. They measured levels of tissue-specific
plasminogen activator (t-PA), urokinase-like
plasminogen activator (u-PA), plasminogen inhibitors-1
(PAI-1), and tissue factor in mesothelial cells cultured
under basal conditions, and exposed to TNFa,
IL-1-a, LPS, and tissue factor. These studies showed that
on exposure to inflammatory mediators, especially
TNFa, cultured mesothelial cells down regulate
t-PA production, and enhance expression of PAI-1
and tissue factor, hence tilting the balance in favor
of coagulation in PD peritonitis. Thus an
imbalance between IP coagulation and fibrinolysis
during peritonitis in favor of coagulation does occur.
But does it occur in all patients?
This question was addressed in a study
by Nadig et al. (23), who collected 194 dialysate samples from 17 patients over a period of
24 months. They measured thrombin-antithrombin III (TAT) complexes as an indicator of
thrombin formation, D-dimers as an indicator of
fibrinolysis, and plasminogen activator inhibitor-1
(PAI-1). Samples were divided into three groups
depending on the leukocyte count: no peritonitis (n =
117), mild peritonitis (n = 31), and severe peritonitis
(n = 31). The results of the analysis are shown in Table I.
In the majority of the samples (Figure 1)
there was linear correlation between the TAT-c and
D-dimer levels. In 15 samples (Figure 2), 11 of
which were from 2 patients with peritonitis, there was
an imbalance between intraperitoneal coagulation
and fibrinolysis; this was secondary to high PAI-1
activity ( >40 ng/mL). They concluded that routine IP
heparin was not indicated even in the presence of
peritonitis, and that low D-dimer levels in dialysate at
initial sampling could identify the minority of cases
that had an imbalance favoring coagulation.
Figure 1: Thrombin-antithrombin (TAT) complexes and D-dimers in 179 samples (62 peritonitis) with PAI-I levels £ 40 ng/mL (23).
Figure 2: Thrombin-antithrombin (TAT) complex and D-dimers in 15 samples (11 peritonitis) with PAI-I levels ³ 40 ng/mL (23).
There normally exists a balance between
fibrinolytic and coagulant activity in the
peritoneum during the stable state, as well as in the
majority of cases with peritonitis. Heparin is effective
in reducing fibrin formation, but at the risk of
some systemic and local side effects. If the studies
of Nadig and co-workers are further confirmed, the use of heparin should be restricted to the
minority of patients with defects in fibrinolysis due to
high levels of PAI-1. This subset could be identified
by demonstrating low levels of D-dimer at the time of dialysate sampling.
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Sharad Goel, md, Division of Nephrology,
University Hospital and Clinics, Columbia, Missouri, 65212, USA.