The heparins: all a nephrologist should know

Gerd R. Hetzel1 and Christoph Sucker2

1 Department of Nephrology and 2 Department of Hemostasis and Transfusion Medicine, Heinrich Heine University Medical Center, Duesseldorf, Germany

Correspondence and offprint requests to: PD Dr med. Gerd Rüdiger Hetzel, Department of Nephrology, University Medical Center, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Email: hetzel{at}med.uni-duesseldorf.de



   Introduction
 Top
 Introduction
 Chemical structure and mechanism...
 Pharmacokinetics
 Clinical use of heparins...
 The problem of HIT-II
 Conclusion
 References
 
For decades, the use of unfractionated heparin (UFH) has been the basic principle of anticoagulation in patients at risk of or with established thromboembolic disorders. Nowadays, low molecular weight heparins (LMWHs) are increasingly used in this setting, because they are as effective but more convenient than UFH. The advantages of LMWHs include a longer elimination half-life, a lower incidence of heparin-induced thrombocytopenia type II (HIT-II), a lower risk of osteopenia and a more predictable anticoagulant effect that reduces the need for routine laboratory monitoring. Major clinical trials have demonstrated superior therapeutic efficacy in patients with acute coronary syndrome or venous thromboembolism compared with UFH [1–3]. However, most trials excluded subjects at risk for unpredictable pharmacokinetics such as the severely obese, the very elderly and patients suffering from chronic kidney disease stage IV and V. In renal failure, the elimination half-life of all LMWHs is significantly prolonged. Thus, severe and even fatal bleeding complications have been reported after unadjusted dosing [4–8]. Although the use of these agents is not strictly contraindicated in patients with advanced renal failure, there are currently no data indicating superior efficacy and safety compared with UFH. It is therefore essential to know the relevant data concerning the pharmacology and pharmacokinetics of different heparins in order to render an individual decision in patients at risk of bleeding. In the following, we summarize the main information for the nephrologist to know.



   Chemical structure and mechanism of action
 Top
 Introduction
 Chemical structure and mechanism...
 Pharmacokinetics
 Clinical use of heparins...
 The problem of HIT-II
 Conclusion
 References
 
UFH is a mixture of polyanionic branched glycosaminoglycans with a wide range of mol. wts between 6000 and 30 000 Da (mean mol. wt 15 000 Da, ~45 monosaccharide chains). It is isolated from porcine intestinal mucosa or bovine lung. In humans, heparin is found in mast cells and basophilic granulocytes. Additionally, heparin-like anticoagulants are expressed on the surface of endothelial cells and modulate the haemostatic process by interacting with components of haemostasis such as antithrombin (AT) and von Willebrand factor. Administered in pharmacological doses, 30% of UFH binds to AT with high affinity, thus leading to a conformational change, which converts AT from a slow to a very rapidly (1000 times) acting inhibitor of thrombin. Apart from thrombin, AT interacts with coagulation factor Xa, and other components of plasmic haemostasis such as factors IXa, XIa and XIIa, plasmin, kallikrein and trypsin. The key chemical sequence for binding heparin to AT is a pentasaccharide composed of three sulfated glucosamins and two uronic acids. By inactivating thrombin, UFH inhibits not only fibrin formation but also thrombin-induced platelet activation. In contrast, anticoagulant effects of thrombin, particularly inactivation of coagulation factors Va and VIIIa by thrombin–thrombomodulin-induced activation of protein C, are also inhibited by UFH.

The inactivation of thrombin by the heparin–AT complex needs a heparin molecule composed of at least 18 monosaccharides. In contrast, smaller molecules containing the above-mentioned pentasaccharide sequence are sufficient to inhibit factor Xa. This explains why LMWHs (mean mol. wt 3000–9000 Da), which are prepared from UFH through chemical or enzymatic depolymerization, exhibit a stronger inhibition of factor Xa compared with thrombin (Figure 1). The relationship between thrombin and factor Xa inactivation differs among different LMWHs (Table 1). In this context, the recently introduced synthetic pentasaccharide fondaparinux that actually represents a very short LMWH selectively inhibits factor Xa but does not inactivate thrombin. The use of this agent for anticoagulation of a haemodialysis patient with HIT-II has recently been reported [9].



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Fig. 1. Mechanism of action: UFH vs LMWH.

 

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Table 1. The heparins: chemistry and specific action on factor-Xa

 
Danaparoid is a low molecular weight heparinoid, which is isolated from porcine intestinal mucosa. During the production of this agent, UFH and its fragments are eliminated, leaving a mixture of heparan sulfate (84%), dermatan sulfate (12%) and chondroitin sulfate A and C (4%) as active components. There is a high selectivity regarding factor Xa inactivation (Table 1) and a low affinity for platelet factor 4 (PF4), allowing its use in patients with established HIT-II, which is discussed later.

The AT–heparin complex binds covalently to thrombin, factor Xa and other coagulation factors, thereby irreversibly inhibiting their procoagulant activity. Thereafter, heparins dissociate from the complex and may be reutilized, while the protease–AT–complex is cleared through the reticuloendothelial system. Due to their polyanionic structure, heparins bind not only to AT but also to a myriad of different proteins and cell membranes. These so-called unspecific interactions are much stronger in UFH compared with LMWH and danaparoid due to longer polysaccharide chains. After binding to endothelial cells, synthesis of heparan sulfate is amplified, which augments the anticoagulatory effect possibly in combination with the release of tissue factor pathway inhibitor [10]. In vivo, a rise in plasma free fatty acids after activation of lipoprotein lipase can be demonstrated in patients exposed to heparins. In very high concentrations, heparins may paradoxically induce platelet aggregation. Furthermore, they bind unspecifically to a multitude of plasma proteins and platelet-associated proteins such as PF4, thrombospondin, complement factors and ß-thromboglobulin. Heparins augment the clearance of histamine and suppress the synthesis of aldosterone. Further research is necessary to assess the clinical relevance of these non-anticoagulatory effects of heparins.



   Pharmacokinetics
 Top
 Introduction
 Chemical structure and mechanism...
 Pharmacokinetics
 Clinical use of heparins...
 The problem of HIT-II
 Conclusion
 References
 
There is only marginal intestinal absorption of all heparins, which makes parenteral application strictly necessary. Due to unspecific interactions, the anticoagulatory bioavailability of UFH after a first bolus injection is only ~30%. The early clearance through unspecific binding is high and saturable, but highly variable and difficult to predict. An initial bolus application is mandatory to reach a sufficient anticoagulation with UFH. After saturation of unspecific binding sites, there is an almost linear dose–response relationship. The slower non-saturable clearance of UFH mainly depends on hepatic metabolism and renal clearance of desulfated fragments. As a consequence, dose reduction in patients with impaired hepatic or renal function is necessary to avoid overdosage.

LMWHs with their reduced polysaccharide chain length have superior pharmacokinetic properties compared with UFH in patients with normal renal function. Following subcutaneous application, the bioavailability reaches 100% even at low absolute doses, with a longer dose-independent elimination half-life compared with UFH. Due to less unspecific binding to platelets, endothelial cells, macrophages and osteoblasts, there is a lower incidence of side effects such as HIT-II or osteopenia after chronic use. The main pharmacological limitation is that LMWHs are principally cleared by the renal route, and that their biological half-life is prolonged in patients with renal failure.



   Clinical use of heparins in patients with renal failure
 Top
 Introduction
 Chemical structure and mechanism...
 Pharmacokinetics
 Clinical use of heparins...
 The problem of HIT-II
 Conclusion
 References
 
The antithrombotic properties of UFH were first described almost 90 years ago [11]. Up to now, there have been different dosing schedules in patients with renal failure. For anticoagulation during haemodialysis, repeated bolus application, continuous infusion and combinations of both have been used alternately. Due to a considerable interindividual variability of pharmacokinetics, fixed dosing is usually inappropriate. Monitoring of the anticoagulatory effect by the activated partial thromboplastin time (aPTT) or the activated clotting time (ACT) after application of the initial bolus is reasonable and needful. A pitfall may be differences in commonly used aPTT assays regarding the sensitivity to detect heparin. So far, >300 different laboratory methods are available with significantly differing aPTT results for a given heparin plasma concentration [12,13]. Despite long experience in the therapy with UFH, no reliable studies comparing the complication rates in patients with normal compared with those with impaired renal function are currently available. Furthermore, it was stressed in a recent review that the difficulties in monitoring the effects of UFH are significant drawbacks in the interpretation of studies comparing the effects of UFH and LMWH [14]. The use of suboptimal doses of UFH narrows the conclusions that can be drawn from these studies. However, it highlights the problems that exist with regard to monitoring of UFH.

Apart from these aspects, the main studies comparing LMWH with UFH in the treatment of venous thromboembolism and acute coronary syndromes showed better therapeutic results for LMWH without an increased bleeding risk [1,3,15]. In a meta-analysis of clinical trials, the rate of major bleeding events was 1.3% for enoxaparin compared with 1.1% for UFH, respectively [2]. According to these results, LMWHs have been increasingly used. Their superior pharmacokinetic profile without the need for routine drug monitoring makes them easy to handle. However, it is disputable and currently unknown whether these potential advantages are also present in patients with renal failure. As outlined above, the elimination half-time of all LMWHs is significantly increased in this condition.

Interestingly, there are considerably more data regarding the use of LMWH for anticoagulation in haemodialysis than in patients with stage III or IV kidney disease. In Germany, four different LMWHs (enoxaparin, dalteparin, nadroparin and tinzaparin) have been approved for use in haemodialysis or haemofiltration. All manufacturers recommend a single bolus injection at the beginning of the dialysis session; however, attention should be paid to the need for an individual dosing schedule or regular drug monitoring. The possibility of achieving sustained anticoagulation after a single bolus injection reflects the prolonged elimination half-life of LMWHs in renal failure and is in accordance with previously published data [16–18]. There is no relevant elimination of LMWH through either haemodialysis or haemofiltration [16,18], explaining an almost first order elimination profile [19]. The negative electrical charge of heparins and the presence of LMWH–AT–factor Xa complexes that are not eliminated by haemodialysis but they are responsible for the anticoagulatory effect might explain the low permeability of LMWHs, which could theoretically be filtered with high-flux membranes (mol. wt 3000–9000 Da).

The slow elimination of LMWHs after a single bolus injection might lead to a sustained anticoagulation. For enoxaparin, effective anti-factor Xa concentrations have been reported for up to 10 h [19]. In this regard, there are possible differences from other LMWHs such as reviparin and tinzaparin, for which a faster decline of anti-factor Xa activity has been reported [20,21]. Comparative studies with regard to pharmacokinetic and clinical end-points for different LMWHs in patients with renal failure do not exist. Furthermore, there is uncertainty as to whether LMWHs offer any advantage compared with UFH for anticoagulation during haemodialysis. In a recent meta-analysis, no differences regarding bleeding events and stability of the extracorporeal circuit have been observed [22]. However, the authors criticize the heterogeneous design (especially the definition of a bleeding event) of different clinical studies and recommend a decision to be made on the basis of an individual risk assessment in each patient.

The data regarding the optimum anticoagulation strategy in patients with stage III and IV renal failure are even more conflicting. Severe and even fatal bleeding complications have been described in this setting after unadjusted dosage of LMWHs [4–8]. Therefore, all manufacturers of LMWHs impose restrictions or contraindications on the use of these agents in severe renal failure. However, that does not mean that the use of UFH with monitoring of aPTT is necessarily safer. Although this was an exclusion criterion, ~2% of patients in two major trials (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events, ESSENCE and Thrombolysis in Myocardial Infarction, TIMI 11B) had a calculated creatinine clearance <30 ml/min. These patients had a significantly increased risk of major haemorrhage compared with those without severe renal impairment, whether they were treated with UFH or enoxaparin [6].

Most pharmacokinetic studies show a positive correlation between the anti-factor Xa effect of LMWHs and the creatinine clearance [23,24]. In a post hoc analysis of the TIMI 11A study (Thrombolysis in Myocardial Infarction), the creatinine clearance emerged as the most important determinant of heparin clearance, elimination pharmacokinetics and anti-factor Xa activity of enoxaparin [25]. Trough levels but not peak levels rose after repeated administration in patients with a creatinine clearance <40 ml/min, indicating a possible accumulation of the substance. The authors conclude that either dose reduction (0.5–0.75 mg/kg instead of 1.0–1.25 mg/kg) or dose adaptation based on anti-factor Xa monitoring is worthwhile to avoid bleeding complications through LMWH overdosage. A comparable correlation between anti-factor Xa effect and creatinine clearance as well as the risk of accumulation was also shown for nadroparin even in patients with mild renal insufficiency [26]. Divergent and possibly advantageous data were obtained for the LMWH tinzaparin. A clinical study including 30 elderly patients with a mean creatinine clearance of 40.6±15.3 ml/min (range 20–72) showed neither a correlation between anti-factor Xa activity and renal function nor an accumulation of tinzaparin [27]. This was confirmed by an observational study including 200 patients between 70 and 102 years of age with a mean creatinine clearance of 51.2±22.9 ml/min [28].

The authors of a recently published meta-analysis concluded that (i) most well designed studies demonstrate increased factor Xa activities in patients with diminished renal function; (ii) there may be differences among LMWHs concerning the effect of impaired renal function on pharmacokinetics; and (iii) no uniform critical cut-off value for the creatinine clearance predicting an increased bleeding risk can be defined for all LMWH preparations [29]. Although there is conflicting evidence regarding the correlation between anti-factor Xa activity and clinical bleeding manifestations [30,31], an anti-factor Xa activity of 0.6–1.0 IU/ml with a twice daily injection schedule is currently regarded as effective systemic anticoagulation [32]. Whether algorithm-based dose adjustments as recently shown for enoxaparin [33] or the development of new bedside tests [34] might improve the safety and efficacy of LMWH therapy in patients with renal failure has to be assessed in prospective clinical studies. As long as the superiority of a distinct heparin has not been clearly demonstrated, it should be considered that sufficient antagonism with protamine sulfate is possible for UFH but not for LMWH [35].

A recommendation regarding the clinical use of heparins in patients with renal failure requires a separate consideration of therapy and prophylaxis of thrombosis. Since the safety of standard doses of LMWH in patients with severe renal impairment has to be strongly questioned, we recommend the use of UFH to provide full therapeutic anticoagulation. UFH has a shorter half-life and can be easily monitored by the aPTT.

For prophylactic anticoagulation, an increased incidence of bleeding complications has not been reported in patients receiving LMWHs. The advantages of LMWHs with a lower risk of HIT-II and particularly the lower risk of osteopenia support the use of LMWHs especially for long-term thromboprophylaxis. Although higher anti-factor Xa activities in patients with severe renal failure compared with individuals with normal or moderately reduced renal function have been reported [36], we currently use LMWHs for thromboprophylaxis and have not experienced bleeding complications. However, clinical trials are urgently needed and the lack of data is notable. In particular, the role of heparin in the development of renal osteodystrophy should be investigated further. Prolonged treatment with UFH can lead to a loss of bone mass and osteoporotic fractures [37,38]. It is estimated that ~30% of pregnant women receiving long-term UFH therapy will lose 10% of their bone mass, and 2% will have symptomatic vertebral fractures [39–41]. LMWHs are associated with a lower incidence of osteoporotic fractures than UFH, even with prolonged use during pregnancy [42–44]. To our knowledge, no comparable studies are available in patients receiving long-term heparin therapy either in the field of haemodialysis or in prophylaxis of thrombotic events.



   The problem of HIT-II
 Top
 Introduction
 Chemical structure and mechanism...
 Pharmacokinetics
 Clinical use of heparins...
 The problem of HIT-II
 Conclusion
 References
 
HIT-II is the most frequent drug-induced thrombocytopenia. This disorder is caused by IgG antibodies that bind to PF4. Consequently, PF4–IgG complexes form on the platelet surface and on endothelial cells that release tissue factor 4. The occupancy of the platelet Fc receptor leads to platelet activation and to additional release of PF4. Platelet function as well as plasmic coagulation are consequently activated, leading to thromboembolic events. It is important to note that none of the available assays, i.e. determination of antibodies directed against the heparin–PF4 complex, assessment of heparin-induced platelet aggregation (HIPA) and assessment of platelet activation by heparin through different release assays, definitely confirm or rule out the presence of this potentially life-threatening complication. In a prospective study of 100 patients after cardiac surgery, 50 patients had a positive result in the PF4–heparin antibody enzyme immunoassay; in 20 of them, platelet activation by heparin was demonstrated. Of these patients, however, only two developed thrombocytopenia and only one had a thrombotic event [45]. These findings illustrate that the diagnosis of HIT-II may be difficult to establish, particularly in thrombocytopenic patients with additional risk factors for thrombocytopenia such as sepsis or bleeding.

Obviously, there are remarkable differences concerning the incidence of HIT-II in different clinical settings. Apart from the duration of heparin therapy, the risk of developing HIT-II is influenced by two major variables: (i) the type of heparin being used (bovine lung UFH>porcine intestine UFH>porcine intestine LMWH); and (ii) the status of patients (post-operative>medical>obstetric) [46]. In patients undergoing chronic haemodialysis, the prevalence of PF4–heparin antibodies was 2.8–12% [47–52]. Whether this considerably high prevalence is of clinical relevance is still controversially discussed [50,51]. However, in a recent retrospective analysis, a significantly increased morbidity and mortality due to bleeding and thromboembolic events was reported for dialysis patients with HIT-II antibodies [52].

The initial event in HIT-II, i.e. the binding of heparin to PF4, depends on chain length and degree of sulfation of the used heparin, which provides a possible explanation for the lower incidence of HIT-II in patients treated with LMWHs. However, switching therapy from UFH to LMWH is absolutely inappropriate if the diagnosis of HIT-II has been established. Currently, there are only unsatisfactory therapeutic approaches in patients with HIT-II and renal failure. The use of danaparoid is approved in Germany, although a considerably high cross-reactivity with PF4–heparin antibodies amounting up to 30% was reported [53–54]. A retrospective analysis of 708 HIT-II cases found an adequate therapeutic efficacy of danaparoid (remission or stabilization of thrombocytopenia, control of thromboembolism, lack of serious side effects) in 546 cases (77%). Again, significant cross-reactivity with HIT-II testing was evident; however, the relevance of this finding was questioned as most patients experienced clinical stabilization under treatment with this agent [55]. In patients with impaired renal function, the elimination half-life is prolonged, reaching 31 h in haemodialysis patients compared with 18 h in healthy volunteers [56]. Furthermore, there is a considerable risk of accumulation at least in patients on chronic haemodialysis [57]. We currently use the direct thrombin inhibitor hirudin for systemic anticoagulation (which is necessary in all patients with apparent HIT-II). However, the elimination half-life of this agent may be extremely prolonged in renal failure, thus leading to accumulation after repeated doses. In vitro, we found a poor correlation between aPTT and hirudin blood levels >0.7 µg/ml. Though in our opinion ecarin clotting time is the preferred test for the monitoring of the substance, there still remains a considerable risk of bleeding and of anaphylactic reactions in patients with poor renal function [58,59].

Only limited data are available for alternative substances in the treatment of patients on chronic haemodialysis with HIT antibodies. Nafamostate, a very short-acting serine protease inhibitor, has been used in some patients; however, many authors reported anaphylactic side effects [60,61]. Recently the use of fondaparinux, the above-mentioned synthetic selective inhibitor of factor Xa without any in vitro cross-reactivity with HIT-II antibodies, was reported in a patient with HIT-II [9]. However, the elimination half-life of fondaparinux is significantly prolonged due to a ~5-fold lower plasma clearance in patients with renal failure [62]. Further investigations have to focus on parmacokinetic data and clinical risk in these patients. In a recently published paper, it was shown that argatroban could be used in different treatment regimens during haemodialysis [63]. Argatroban is a direct thrombin inhibitor; however, unlike hirudin, the substance is metabolized in the liver and its pharmacokinetics are not significantly affected by renal dysfunction [64]. Therefore, argatroban, which will probably be approved within a short time, might be a promising substance that can be used in patients with HIT-II and renal failure without relevant pharmacokinetic problems and thus without additional bleeding risks.



   Conclusion
 Top
 Introduction
 Chemical structure and mechanism...
 Pharmacokinetics
 Clinical use of heparins...
 The problem of HIT-II
 Conclusion
 References
 
There is considerable uncertainty regarding the use of heparins in patients with advanced renal failure. The advantages of LMWHs over UFH with regard to bioavailability and reproducible pharmacokinetics are at least partially lost in this setting. There is evidence of a higher prevalence of major haemorrhagic events in patients with renal failure compared with those with normal renal function. However, whether this rate is any greater with LMWH compared with UFH currently remains unclear. From our point of view, a strict monitoring of anticoagulation is necessary with both UFH and LMWH in the presence of renal insufficiency. The different LMWHs should be regarded as distinct substances with their own pharmacokinetic profile. We recommend that centres use one agent only in patients with chronic kidney diseases regardless of the clinical indication, with an initial glomerular filtration rate-related dose reduction and a close monitoring using aPTT or anti-factor Xa-assays.

Whether new substances currently used in single patients with HIT-II will play a more important role in the future remains to be demonstrated. Large-scale pharmacokinetic and clinical outcome studies comparing different anticoagulants in patients with chronic kidney disease are urgently needed.

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 Chemical structure and mechanism...
 Pharmacokinetics
 Clinical use of heparins...
 The problem of HIT-II
 Conclusion
 References
 

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Received for publication: 1. 6.05
Accepted in revised form: 14. 6.05





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