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.

Key words

Heparin, peritonitis, intraperitoneal, fibrinolytic, coagulation

From:

Division of Nephrology, University Hospital and Clinics, Columbia, Missouri, USA.

Introduction

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 dialysate (1,2).

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 co-workers (18).

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 this problem.

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 of fibrinolysis.

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).

Conclusion

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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Corresponding author:
Sharad Goel, md, Division of Nephrology, University Hospital and Clinics, Columbia, Missouri, 65212, USA.