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Keywords:

  • anticoagulation;
  • haemodialysis;
  • heparin;
  • low molecular weight heparin (LMWH);
  • heparin induced thrombocytopaenia (HIT)

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

The coagulation cascade is complex but well studied. Dialysis membranes and lines are inherently pro-coagulant and activate both the intrinsic and extrinsic pathways of coagulation, as well as platelets and other circulating cellular elements. To provide safe and effective dialysis, appropriate anticoagulant measures must be applied. Haemodialysis, including anticoagulation, is prescribed by dialysis doctors but delivered by dialysis nurses. The main agents used in clinical practice for anticoagulation during haemodialysis are unfractionated heparin (UF heparin) and low-molecular-weight heparin (LMWH). LMWH has a number of potential advantages, apart from cost. One of the most serious complications of the use of any form of heparin is heparin-induced thrombocytopaenia (HIT) Type II, which occurs more commonly with UF heparin than LMWH. HIT Type II risks severe morbidity and mortality and is challenging to treat successfully in both the acute and chronic phase. In HIT Type II anticoagulation must be delivered without heparin. A wide array of newer anticoagulants are becoming progressively available, each with unique advantages and disadvantages. In maintenance haemodialysis patients with an increased risk of bleeding, a ‘no heparin’ dialysis may be undertaken, or regional anticoagulation considered. Because this aspect of dialysis is so important to the safe and effective delivery of haemodialysis therapy, dialysis clinicians need to review and update their knowledge of dialysis anticoagulation on a regular basis.


THE COAGULATION CASCADE

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

The coagulation cascade is complex, multiply redundant and includes intricate checks and balances. While the complexity of the coagulation cascade has been well studied, most schemas simplify the cascade into two arms – the intrinsic pathway and the extrinsic pathway, meeting at factor X which is activated to Xa to trigger the subsequent activation of prothrombin (factor II) to thrombin (factor IIa), leading to the formation of fibrin from fibrinogen in the final common pathway.1

The intrinsic pathway is activated by damaged or negatively charged surfaces and the accumulation of kininogen and kallikrein. The activated partial thromboplastin time (APTT) tends to reflect changes in the intrinsic pathway. The extrinsic pathway is triggered by trauma or injury, which releases tissue factor. The extrinsic pathway is measured by the prothrombin test.

HAEMODIALYSIS AND CLOTTING

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Haemodialysis involves the circulation of whole blood through a dialysis circuit and artificial kidney (dialyser) both of which have the tendency to activate coagulation pathways. The dialyser is generally constructed of synthetic microfibres with narrow lumen, lacking endothelial lining and experiencing disordered flow – including both shear and turbulence. Factors that determine the thrombogenicity of different dialysis membranes include chemical composition, charge, ability to adhere or activate circulating cellular elements (including platelets) and other characteristics which activate thrombotic pathways.2 Studies suggest that cuprophane membranes may be more thrombogenic than polyacrylonitrile, which is more thrombogenic than polysulphone membranes and haemophan, with the least thrombogenic possibly being polyamide.3,4 The dialysis circuit also has a synthetic composition and artificial surfaces with dead spaces, stasis, turbulence and an air interface in the venous bubble trap.

Clotting in the dialysis circuit is triggered by both the extrinsic and the intrinsic pathways at the same time but to different degrees depending on the composition of the dialysis membrane and design and composition of the lines. Once the blood flow is initiated, plasma proteins deposit on the dialyser surface, and factor XII and high-molecular-weight kallikrein accumulate and act as initiating factors for contact coagulation – the Intrinsic Pathway. Peripheral blood leucocytes and monocytes, which contact the dialyser membrane, become adherent or activated and release blebs of surface membrane rich in tissue factor – activating the Extrinsic pathway. Platelets become activated by contact and in response to turbulent flow and high shear stress. The surface of platelets provides an enhancing environment promoting the interaction of coagulation cascade components.

These triggers activate the clotting cascade, platelet aggregation, activation and degranulation, cytokine release and activation of circulating white cells, all of which can contribute in differing degrees to the triggering of or progressive activation of the clotting cascade leading to thrombosis in the dialysis circuit.

ANTICOAGULATION FOR HAEMODIALYSIS

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Anticoagulation is routinely required to prevent clotting of the dialysis lines and dialyser membranes, in both acute intermittent haemodialysis and continuous renal replacement therapies.5 As the field of anticoagulation is constantly evolving it is important to regularly review advances in knowledge and changing practices in this area.6

The responsibility for prescribing and delivering anticoagulant for haemodialysis is shared between the dialysis doctors and nurses. Dialysis is a medical therapy, which must be prescribed by an appropriately trained doctor. The prescribing doctor usually determines which anticoagulant agent will be used and the dosage range. The doctor's prescription may include broad instructions such as ‘no heparin’, ‘low heparin’ or ‘normal heparin’. In a mature dialysis unit the dose and delivery of anticoagulant is, however, the responsibility of professional and experienced dialysis nurses, who have latitude within parameters determined by detailed written policies or standing orders. Dosing regimens, while generally safe and effective, are somewhat unscientific. In terms of monitoring, most units do not practise routine monitoring, although the anticoagulant effect of unfractionated heparin (UF heparin) can be monitored with some accuracy by the APTT or the activated clotting time tests where indicated.

The dialysis nurses know there is too much anticoagulation if the needle sites continue to ooze excessively for a prolonged period (e.g. more than 15 min) after dialysis. They know there is too little anticoagulation if there is ‘streaking’ in the dialyser, if there is excessively raised transmembrane pressure or if there is evidence of thrombus in the venous bubble trap – indicated by dark blood, swelling of the trap or rising venous pressure. The nurses know that patients dialysing with a venous dialysis catheter are at greater risk of thrombosis. With some trial and error, the right dose of anticoagulant for any patient can be empirically determined.

In normal circumstances effective and safe anticoagulation for haemodialysis can be delivered with low risk and high efficiency. The use of UF heparin, which is the most common agent used in Australia, is safe, simple and inexpensive and usually encounters few problems. However, there are risks with haemodialysis anticoagulation which are important to be aware of and which of course include the risk of bleeding. Some risks are not immediately obvious – such as inadvertent over-anticoagulation in high-risk patients because of excessive heparin volume used to lock the venous dialysis catheter at the end of dialysis.

The disadvantages of UF heparin may include lack of routine or accurate monitoring of anticoagulation effect, the need for an infusion pump and the costs of nursing time. Perhaps the most important risk is that of heparin-induced thrombocytopaenia (HIT Type II), which is greatest with the use of UF heparin.

At times the routine anticoagulation prescription needs to be varied. Additional choices include ‘no heparin’ dialysis, the use of low-molecular-weight heparin (LMWH) instead of UF heparin, and the use of regional anticoagulation. New agents and new clinical variations appear in the literature continuously.

‘NO HEPARIN’ DIALYSIS

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Dialysis without anticoagulation may be indicated in patients with a high risk of bleeding, an acute bleeding disorder, a recent head injury, planned major surgery, trauma, acute HIT syndrome or in patients with systemic anticoagulation for other reasons. The procedure involves multiple flushes of 25–50 ml of saline every 15–30 min, in association with a high blood flow rate. In some units the lines are pretreated with 2000–5000 U of UF heparin and then flushed with 1 l of normal saline, to coat the lines. This form of dialysis anticoagulation is very labour-intensive and these efforts are usually only partially effective. Partial clotting still occurs in 20% of cases with complete clotting of lines or dialyser, requiring line change, in 7% of ‘no heparin’ dialyses.7,8 The risk of clotting in this setting may be exacerbated by poor access blood flow, the use of a venous catheter, hypotension or concomitant blood transfusion. Where a venous catheter is used, there is an increased risk of catheter occlusion. ‘No heparin’ dialysis may also provide less effective dialysis and result in lower clearances.

THE USE OF UF HEPARIN

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Unfractionated heparin was first isolated from liver (hepar) mast cells of dogs. UF heparin consists of a family of highly sulphated polysaccharides composed of anionic glycosaminoglycans. Heparin is now commercially derived from porcine intestinal mucosa or bovine lung. UF heparin is a linear molecule of approximately 45 repeating polysaccharide units of molecular weight of 4–40 kDa, averaging 12–15 kDa. When administered intravenously UF heparin generally has a half-life approximating 1.5 h. UF heparin is highly negatively charged and binds non-specifically to endothelium, platelets, circulating proteins, macrophages and plastic surfaces. In addition to removal by adherence, heparin is cleared by both renal and hepatic mechanisms and is metabolized by endothelium.

Interestingly, UF heparin has both pro- and anti-coagulant effects. Heparin can be directly procoagulant through platelet activation and aggregation. However, its main effect is anticoagulant, through its binding to anti-thrombin (anti-thrombin III or heparin-binding factor I). At high doses heparin can also bind to heparin-binding factor II – which can directly inhibit thrombin. When heparin binds anti-thrombin it causes a conformation change, which results in a 1000–40 000× increase in the natural anticoagulant effect of anti-thrombin. Heparin-bound anti-thrombin inactivates multiple coagulation factors including covalent binding of thrombin and Xa and lesser inhibition of VII, IXa, XIa, XIIa. By inactivating thrombin, UF heparin inhibits thrombin-induced platelet activation as well. Of note, UF heparin-bound anti-thrombin inactivates thrombin (IIA) and Xa equally. Only UF heparin with more than 18 repeating saccharide units inhibits both thrombin and Xa, whereas shorter chains only inhibit Xa.

For haemodialysis, UF heparin can be administered, usually into the arterial limb, according to various regimens, but most commonly is administered as a loading dose bolus followed by either an infusion or repeat bolus at 2–3 h.9 The initial bolus is important to overcome the high level of non-specific binding, following which there is a more linear dose : response relationship. The loading dose bolus may be 500 units or 1000 units and infusion may vary from 500 units hourly to 1000 units hourly, depending on whether the prescription is ‘low dose heparin’ or ‘normal heparin’. Heparin administration usually ceases at least 1 h before the end of dialysis.

The most important risk of UF heparin is the HIT syndrome (HIT Type II). Other risks or effects attributed to UF heparin that have been reported include hair loss, skin necrosis, osteoporosis, tendency for hyperkalaemia, changes to lipids, a degree of immunosuppression, vascular smooth muscle cell proliferation and intimal hyperplasia.10–12 Beef-derived heparin can be a risk for the transmission of the prion causing Jacob Creutzfeld type encephalopathy.13

LOW-MOLECULAR-WEIGHT HEPARIN

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Depolymerized fractions of heparin can be obtained by chemical or enzymatic treatment of UF heparin. These are also anionic glycosaminoglycans but have a lower molecular weight of 2–9 kDa, mostly around 5 kDa – thus consisting of 15 or fewer saccharide units. The shorter chain length results in less coagulation inhibition, but superior pharmacokinetics, higher bioavailability, less non-specific binding and longer half-life, all of which help to make LMWH dosage simpler and more predictable than UF heparin. In addition LMWH has less impact on platelet function, and thus may cause less bleeding. LMWH binds anti-thrombin III and inhibits factor Xa, but most LMWH (50–70%) does not have the second binding sequence needed to inhibit thrombin, because of the shorter chain length. In most cases the affinity of LMWH for Xa versus thrombin is of the order of 3:1. The anticoagulant effect of LMWH can be monitored by the anti-factor Xa activity in plasma. LMWH is cleared by renal/dialysis mechanisms, so dosage must be adjusted to account for this.14 When high flux dialysers are used, LMWH is more effectively cleared than UF heparin. LMWH is often administered into the venous limb of the dialysis circuit.

CLEXANE® (ENOXAPARIN)

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Clexane® (Sanofi-Aventis, New South Wales, Australia) is one of the most commonly used LMWH in Australia and has the longest half-life. It is predominantly renally cleared. Clexane has been found to have linear pharmacokinetics over the clinical dosing range.15 The dose generally correlates with patient weight and Clexane can be predictably dosed per kg, in normals; however, dose reduction need to be made in the elderly, in the presence of renal impairment and in very obese patients, to avoid life-threatening bleeding. Clexane generally does not accumulate in 3/week dialysis regimens, but there is a risk of accumulation in more frequent schedules. There is no simple antidote and in the case of severe haemorrhage-activated factor VII concentrate may be required. On the other hand patients dialysing with a high flux membrane, as compared with a low flux membrane, may require a higher dose because of dialysis clearance. Effect and accumulation can be monitored by the performance of anti-Xa levels. A common target range is 0.4–0.6 IU/ml anti-Xa but a more conservative range (0.2–0.4 IU/ml) is recommended in patients with a high risk of bleeding – the product insert should always be consulted.

The use of LMWH such as Clexane for haemodialysis anticoagulation is well supported in the literature.16–18 In this context Clexane can be administered as a single dose and generally does not require to be monitored. It is as yet unclear whether Clexane can successfully anticoagulate patients for long overnight (nocturnal) haemodialysis. Against the utility of LMWH, the purchase price of LMWH still significantly exceeds UF heparin.

The other available forms of LMWH such as Dalteparin (Fragmin®; Pfizer Australia, New South Wales, Australia), Nadroparin, Reviparin Tinzaparin and newer LMWH vary somewhat, especially in anti-Xa/anti-IIa effect. The higher this ratio the more Xa selective the agent and consequently the less effect protamine has on reversal. Clexane has a high anti-Xa/anti-IIa ratio of 3.8, and is less than 60% reversible with protamine.18

IS LMWH BETTER?

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

A topical question is whether LMWH is better suited to be a routine dialysis anticoagulant than UF heparin.18,19 Of great significance is the lower incidence of HIT Type II, a devastating and deadly complication, in patients exposed to LMWH compared with UF heparin. Another advantage of LMWH is the longer duration of action and predictability of dosage effect, allowing the convenience of a single subcutaneous injection at the start of dialysis without the need for routine monitoring. The use of LMWH is reported to cause less dialysis membrane-associated clotting, fibrin deposition and cellular debris.2 LMWH has less non-specific binding to platelets, circulating plasma proteins and endothelium. UF heparin induces inhibition of mineralocorticoid metabolism20 and reduced adrenal aldosterone secretion, but LMWH has been shown to have less inhibition in this regard. Other deleterious effects associated with UF heparin are also generally less common with the use of LMWH including the risk of osteoporosis, hair loss, endothelial cell activation and adhesion molecule activation.

A meta-analysis including 11 studies was published in 2004 and showed that LMWH and UF heparin were similarly safe and effective in preventing extracorporeal circuit thrombosis, with no significant difference in terms of bleeding, vascular compression time or thrombosis.21

The Caring for Australasians with Renal Impairment (CARI) guidelines (2004/2005) have supported that there is no apparent difference in terms of dialysis adequacy between UF heparin or LMWH and no clear difference in terms of risk of thrombosis or haemorrhage.22 LMWH is however recommended as the agent of choice for routine haemodialysis by the European Best Practice Guidelines.23

The single factor weighing against the use of LMWH as the routine form of anticoagulation for dialysis is cost. More and more dialysis units are assessing the cost/benefit ratio as in favour of the routine use of LMWH for haemodialysis because of the potency, ease of administration, predictable clinical effect and low rate of side effects.

ANTI-XA MONITORING

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Anti-Xa monitoring may be used for dosing adjustment of LMWH, to ensure therapeutic dosing or to exclude accumulation prior to a subsequent dialysis.24 Because of the high bioavailability, dose-independent clearance by renal mechanisms, and predictable effect, there is generally no need to monitor routinely. Commercial assays for anti-Xa monitoring are widely available. The test involves adding the patient's serum to a test tube loaded with excess exogenous Xa and anti-thrombin. Residual Xa (unbound) binds to a chromogenic Xa substrate reagent. Standard or calibration curves are constructed for each different LMWH agent. The normal anti-Xa level is zero. Each laboratory provides an agent-specific therapeutic range. For LMWH and other anticoagulant dosage recommendations see Fischer6 and Davenport.18

REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

The aim of regional anticoagulation is to restrict the anticoagulant effect to the dialysis circuit and prevent systemic anticoagulation, for instance in patients at increased risk of bleeding.

UF heparin/protamine

Historically, the use of UF heparin/protamine was prototypical of regional anticoagulation. UF heparin is infused into the arterial line and protamine into the venous line. Protamine is a basic protein that binds heparin, forming a stable compound and eliminating its anticoagulant effect. Full neutralization of heparin can be achieved with a dose of 1 mg protamine/100 units heparin but protamine has a shorter half-life than heparin so there may be an increased risk of bleeding 2–4 h after dialysis. Most authors agree that the procedure can be technically challenging and has no significant advantage over ‘low-dose’ heparin regimens. Reactions to protamine are not uncommon and may be serious. As all forms of heparin are absolutely contraindicated in HIT Type II this form of regional anticoagulation cannot be used in that syndrome.

Citrate regional anticoagulation

Citrate binds ionized calcium and is a potent inhibitor of coagulation. Regional citrate regimens generally utilize iso-osmotic trisodium citrate or hypertonic trisodium citrate infusion into the arterial side of the dialysis circuit. This methodology avoids the use of heparin and limits anticoagulation to the dialysis circuit – effects which can be used for routine dialysis,25 in patients at increased risk of bleeding26 or for dialysis anticoagulation in the stable phase of HIT Type II.

The citrate–calcium complex is partially removed by the dialyser. The procedure may require, or be enhanced by, the use of calcium and magnesium-free dialysate. A low bicarbonate dialysate is also recommended to reduce the risk of alkalosis, especially in the setting of daily dialysis, as citrate is metabolized to bicarbonate. To neutralize the effect of citrate, calcium chloride solution is infused into the venous return at a rate designed to correct ionized calcium levels to physiologic levels. Plasma calcium must be measured frequently, e.g. second hourly, with prompt result turnaround. As commercial citrate for this purpose is not available in Australia, Ferrari et al. has recently published an approach with locally prepared citrate and point-of-care calcium testing.27

The procedure can be complex and high risk. There is a requirement for two infusion pumps and point of care calcium measurement. Either high or low calcium levels in the patient may risk severe acute complications. Hypertonic citrate may risk hypernatraemia. The metabolism of citrate generates a metabolic alkalosis. Nevertheless, the technique has been used with great success in some hands, with few bleeding complications and improved biocompatibility with reduced granulocyte activation and less deposition of blood components in the lines or on the dialyser.2 Simplified protocols have been proposed.28

Prostacyclin regional anticoagulation

This form of regional anticoagulation utilizes prostacyclin as a vasodilator and platelet aggregation inhibitor. It has a very short half-life of 3–5 min and is infused into the arterial line. Of importance prostacyclin is adsorbed onto polyacrylonitrile membranes. Side effects of this therapy can include headache, light headedness, facial flushing, hypotension and excessive cost.29

HEPARIN-INDUCED THROMBOCYTOPAENIA

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

There are two well-described syndromes of HIT, the first relatively benign and the second potentially devastating.

HIT Type I

HIT type I occurs in 10–20% of patients treated with UF heparin. Mild thrombocytopaenia occurs (<100 000) as a result of heparin activation of platelet factor 4 (PF4) surface receptors, leading to platelet degranulation. The mechanism is non-immune and early in onset, after the initiation of heparin. The syndrome generally resolves spontaneously within 4 days despite the continuation of heparin. There are generally no sequelae of clinical significance.

HIT Type II

This syndrome is much more serious and devastating than HIT Type I. HIT Type II generally occurs within the first 4–10 days of exposure to heparin. Late onset is less common. HIT Type II is mediated by immunoglobulin G antibodies against the heparin–PF4 complex. The mechanism of HIT Type II, which results in both platelet activation and activation of the coagulation cascade, has been elucidated in a recent paper by Davenport.30 Heparin binds to platelet factor IV and the unit forms an epitope to which antibodies may form. Antibodies may form in 20–30% of exposed patients, with only 1–3% of patients with detectable antibody developing clinical heparin-induced thrombocytopenia.31

Severe platelet reduction occurs rapidly, but generally the platelet count remains above 20 000. Clinical HIT Type II is reported to occur in 2–15% of patients exposed to heparin, more commonly in females and surgical cases. In dialysis patients the incidence varies between 2.8% and 12%.32,33 HIT Type II occurs in incident patients or after re-exposure to heparin after an interval. Of importance the incidence is 5–10 times more common with UF heparin than with patients receiving only LMWH. The risk with LMWH is reportedly very low, in the order of <1%.34,35

HIT Type II syndrome has two clinical phases. In the acute phase there is significant thrombocytopaenia and high risk of thromboembolic phenomena. Avoidance of heparin and systemic anticoagulation are essential. In the second phase, signalled by recovery of platelet levels, heparin must still be avoided (for a prolonged period if not forever) but systemic anticoagulation is not required. Dialysis anticoagulation remains a challenge as all forms of heparin must be avoided.

With the onset of HIT Type II, heparin must be immediately discontinued, even before confirmatory results are available. Available tests for HIT Type II include detection of antibodies against heparin–PF4 complex, detection of heparin-induced platelet aggregation or platelet release assays – but none is totally reliable. HIT acute phase will not resolve while heparin is continued and HIT will recur on rechallenge with either UF heparin or LMWH. Once HIT is established after exposure to UF heparin, there is a >90% cross-reactivity with LMWH.24

Untreated, there is a major risk of venous and arterial thrombosis, estimated at >50% within 30 days. Most of the clots are described as venous. Arterial thrombi are often platelet-rich white thrombi (white clot syndrome) which can cause limb ischaemia and cerebral or myocardial infarcts.

In patients with HIT Type II all heparin products must be avoided, including topical preparations, coated products as well as intravenous preparations. Systemic anticoagulation without heparin is mandatory in the acute phase. For haemodialysis, patients may have ‘no heparin’ dialysis or anticoagulation with non-heparins. The available agents commonly used include Danaparoid (Orgaron®; Schering Plough, New South Wales, Australia), Hirudin, Argatroban, Melagatran and Fondaparinux.18 Alternatively, regional citrate dialysis has proved effective in this setting. Each approach or alternative agent provides its own challenges and there may be a steep learning curve. Both UF heparin and LMWH are contraindicated. Venous catheters must not be heparin locked, but can be locked with recombinant tissue plasminogen activator or citrate (DuraLock-c®; TekMed Australia, Victoria, Australia; trisodium citrate 46.7%).36 Other alternatives to consider may include switching the patient to peritoneal dialysis or using warfarin.33 In the longer term it may be possible to cautiously reintroduce UF heparin, or preferably LMWH, without reactivating HIT Type II.37

DANAPAROID (ORGARON)

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Currently, this agent remains drug of choice in most Australian hospitals for HIT Type II, in part because it may have unique features, which interfere with the pathogenesis of HIT Type II.18 Danaparoid is extracted from pig gut mucosa and is a heparinoid of molecular weight of 5.5 kDa. It consists of 83% heparan sulphate, 12% dermatan sulphate and 4% chondroitin sulphate. Danaparoid binds to anti-thrombin (heparin cofactor I) and heparin cofactor II and has some endothelial mechanisms, but has minimal impact on platelets and a low affinity for PF4. It is more selective for Xa than even the LMWH (Xa : thrombin binding : Danaparoid 22–28 : 1; LMWH 3:1 typically). There is low cross-reactivity with HIT antibodies (6.5–10%) although it is recommended to test for cross-reactivity before use of Danaparoid in acute HIT Type II. Danaparoid has a very long half-life of about 25 h in normals and longer with chronic renal impairment (e.g. 30 h). There is no reversal agent. Clinically, significant accumulation should be tested by anti-Xa estimation before any invasive procedure.38

HIRUDIN

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Hirudin was originally discovered in the saliva of leeches. Hirudin binds thrombin irreversibly at its active site and the fibrin-binding site. Recombinant or synthetic variants are also available – including Lepirudin, Desirudin and Bivalirudin. Hirudin and its cogeners are polypeptides of molecular weight of 7 kDa with no cross-reactivity to the HIT antibody. Hirudin has a prolonged half-life and is renally cleared, so its half-life in renal impairment is more than 35 h. Studies have confirmed that Hirudin can be used as an anticoagulant for haemodialysis.39 Hirudin has no cross-reactivity with UF heparin or LMWH; however, Hirudin and its analogues are antigenic in their own right, and up 74% of patients receiving Hirudin i.v. can develop anti-Hirudin antibodies, which can further prolong the half-life. Because of the tendency to form antibodies, Hirudin can be difficult to use, as anaphylaxis can occur with a second course. The APTT may be used to monitor Hirudin anticoagulant effect but the relationship is not necessarily linear. There is no antidote to Hirudin, but it is removed to some extent by haemofiltration or plasmapheresis but not haemodialysis.

ARGATROBAN

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Argatroban is a synthetic derivative of L-arginine.40 It appears to be the treatment of choice in the USA. It acts as a direct thrombin inhibitor and binds irreversibly to the catalytic site. There is a short half-life of 40–60 min, which is not effected by renal function. Hepatic clearance means prolonged duration of action in patients with liver failure. The anticoagulant effect can be monitored by a variant of the APTT – the ecarin clotting time. There is no available reversal agent.

MELAGATRAN

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Another direct thrombin inhibitor, this drug is available orally as a prodrug, which is taken twice a day. This agent is renally cleared and has a prolonged half-life. There is no antidote. Reports of hepatotoxicity have impeded further drug development. It has been suggested that Melagatran may have a role in anticoagulation between dialysis treatments in patients with HIT Type II.

FONDAPARINUX

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Fondaparinux is a synthetic pentasaccharide of 1.7 kDa, and is a copy of an enzymatic split product of heparin. It is a synthetic analogue of the pentasaccharide sequence in heparin that mediates the anti-thrombin interaction. Fondaparinux has a high affinity for anti-thrombin III but no affinity for thrombin or PF4. Fondaparinux can be administered i.v. or s.c. and monitored by the use of anti-Xa testing. With a prolonged half-life it can be administered alternate days. As Fondaparinux is renally cleared, it may accumulate in renal failure. It is removed to some degree by high flux haemodialysis or haemodiafiltration.

CONCLUSION

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES

Anticoagulation is an essential part of the safe and effective delivery of haemodialysis and physicians accredited to prescribe dialysis must have a fundamental understanding of anticoagulation therapy in different dialysis settings. It is essential for nephrologists to have a good understanding of the relative merits of UF heparin and LMWH, and to develop an approach to the clinical management of HIT Type II and other important heparin-related complications. There is continual development of new anticoagulant drugs and associated clinical recommendations, so this is an area that dialysis clinicians should revisit at timely intervals.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. THE COAGULATION CASCADE
  4. HAEMODIALYSIS AND CLOTTING
  5. ANTICOAGULATION FOR HAEMODIALYSIS
  6. ‘NO HEPARIN’ DIALYSIS
  7. THE USE OF UF HEPARIN
  8. LOW-MOLECULAR-WEIGHT HEPARIN
  9. CLEXANE® (ENOXAPARIN)
  10. IS LMWH BETTER?
  11. ANTI-XA MONITORING
  12. REGIONAL ANTICOAGULATION FOR HAEMODIALYSIS
  13. HEPARIN-INDUCED THROMBOCYTOPAENIA
  14. DANAPAROID (ORGARON)
  15. HIRUDIN
  16. ARGATROBAN
  17. MELAGATRAN
  18. FONDAPARINUX
  19. CONCLUSION
  20. REFERENCES