Anticoagulation and circuit clotting

Contact between blood and the different plastic surfaces and connectors of the extracorporeal circuit initiates platelet adhesion, activation of the intrinsic coagulation pathway, and clot formation. Partial clotting of dialyser fibres or membrane pores is especially important and is often underestimated: it reduces the effective exchange surface and can therefore impair dialysis efficiency.

Clotting is promoted by slow blood flow, a high haemoglobin concentration, a high ultrafiltration rate, transfusion of blood during dialysis, and lipid-containing intravenous nutrition.

Most haemodialysis sessions require anticoagulation, usually with heparin. Other options include low-molecular-weight heparin (LMWH), epoprostenol, and regional anticoagulation within the circuit using citrate or heparin–protamine. Haemodialysis can also be performed without heparin. Heparin-bonded plastics have been developed to reduce clotting within the circuit without systemic heparin. Heparin-binding dialyser membranes, such as AN69ST®, may likewise reduce the need for systemic heparin after an initial saline–heparin rinse.

Clotting during haemodialysis

Circuit clotting can contribute to anaemia, may require a blood transfusion—with the associated risk of increased HLA sensitisation—and can reduce dialysis efficiency, resulting in underdialysis. Warning signs include:

• Very dark blood in the extracorporeal circuit.

• Visible streaks in the dialyser.

• Visible clots in the bubble trap.

• Visible clots in the venous blood line.

• Clots at the arterial end of the dialyser, rather than only a few small fibrin strands.

• Venous pressure may fall if the clot forms in the dialyser upstream of the pressure monitor, or rise if the obstruction lies downstream.

• The negative arterial pressure may increase in magnitude.

Anticoagulation for dialysis

Heparin

Heparin is a glycosaminoglycan obtained from porcine or bovine tissue. It binds to antithrombin III and thereby inhibits coagulation factors II, IX, X, XI, and XII.

Its half-life is approximately 30–120 minutes. Adverse effects include pruritus, thrombocytopenia, hyperlipidaemia—particularly hypertriglyceridaemia—osteoporosis, hair loss, and hypersensitivity. The principal complication is bleeding, which has been reported in up to 50% of patients at high bleeding risk.

Heparin-induced thrombocytopenia (HIT) is uncommon but potentially serious. The source text cites an overall incidence of 2.6% among patients exposed to heparin for more than four days and an incidence approximately 30-fold lower with LMWH. Two forms are traditionally described:

Type I HIT: a mild, non-immune fall in the platelet count that resolves despite continued heparin use. The platelet count rarely falls below 100 × 10⁹/L.

Type II HIT: an antibody-mediated disorder that usually develops 5–10 days after heparin exposure. The median platelet count is approximately 55 × 10⁹/L, while profound thrombocytopenia below 15 × 10⁹/L is uncommon. It does not resolve spontaneously while heparin is continued: heparin must be stopped, and the reaction can recur with re-exposure.

Antibodies form against the heparin–platelet factor 4 complex. This promotes platelet activation and aggregation, thrombosis, and thrombocytopenia. The platelet count generally begins to recover within one to two weeks after heparin is withdrawn.

Diagnosis:

Clinical probability is assessed across four domains—the degree of thrombocytopenia, timing of onset, thrombosis, and the presence of other causes—using the 4Ts score. Laboratory evaluation then includes an immunoassay for antibodies to the PF4–heparin complex; a functional assay may be needed to confirm clinically important platelet activation.

Treatment

All heparin exposure must be stopped and a non-heparin anticoagulant used when indicated. Alternatives described in the source include danaparoid, lepirudin, fondaparinux, and argatroban. Heparin should also be avoided in the catheter lock. Locking alternatives include alteplase (tPA, 1–2 mg/mL), urokinase (1,250–2,500 IU/mL), lepirudin (1–5 mg/mL), and, more commonly, sodium citrate or taurolidine-containing solutions.

Monitoring unfractionated heparin

A commonly used bedside method is the activated clotting time (ACT). An activator is added to a blood sample and the time until clot formation is recorded; the cited normal range is 90–140 seconds. The source describes a treatment target of approximately 80% above baseline, often 200–250 seconds, with the intensity reduced toward the end of the session or heparin stopped about one hour before dialysis ends.

The activated partial thromboplastin time (aPTT) may also be used; the source gives a target range of 120–160 seconds.

Ways of administering heparin

The circuit is usually primed with saline containing heparin. The patient is then connected while heparin is administered. Heparin may be given as an initial bolus followed by a slow infusion, or as repeated boluses. The source reports no proven overall superiority of one approach over the other.

Continuous-infusion method

• Reliable and straightforward for nursing staff.

• The initial dose is usually 2,000–3,500 units, or approximately 50 units/kg.

• Heparin is infused continuously into the arterial line at 500–2,000 units/hour. Monitoring is performed hourly and may be more frequent in a new patient. The cited ACT target is 200–250 seconds, although some centres use a lower target.

• The infusion rate is adjusted according to the measured clotting time.

• Heparin is stopped approximately 60 minutes before the end of dialysis.

Repeated-bolus method

• The initial dose is usually 4,000–5,000 units; some centres start with only 1,000–2,000 units.

• A second dose of 1,000–2,000 units may be given when ACT falls to roughly 50% above the initial value, generally after about two hours. Some centres omit the second dose.

• Two or three heparin doses are commonly required.

• If ACT does not rise to approximately 80% above baseline, the initial dose may need to be increased. ACT can be checked three minutes after heparin injection.

• People with severe or longstanding uraemia may require lower doses.

• The last dose is usually given at least one hour before the session ends.

Reduced-dose heparin

This approach is used in patients with a moderate bleeding risk. The cited ACT target is approximately 40% above baseline, 1.25 times baseline, or 150–200 seconds. It may be achieved with 500 units every 30 minutes or a continuous infusion of 250–2,000 units/hour, commonly 500–600 units/hour.

Heparin-free haemodialysis

Anticoagulation is normally used to prevent clotting of the extracorporeal circuit. In some situations, however, the danger of bleeding must be weighed against the risk of circuit clotting, cited here as approximately 5%, and complete avoidance of systemic anticoagulation may be prudent or essential. Examples include active bleeding, pericarditis, a coagulation disorder, thrombocytopenia, intracranial haemorrhage, and recent surgery.

Heparin-binding membranes such as AN69ST® may reduce the need for systemic heparin. Patients with type II HIT, however, must not be exposed to any heparin, including heparin used for the initial rinse.

One commonly described heparin-free protocol

• Prime the circuit with heparinised saline containing 3,000–5,000 units of heparin per litre of saline. This step is not suitable for a patient in whom every heparin exposure is contraindicated, such as active type II HIT.

• Drain the priming solution and do not return it to the patient.

• Use a high blood-flow rate, above 400 mL/min where the access and prescription allow it.

• Flush the circuit every 15–30 minutes with 25–200 mL of saline while temporarily clamping the arterial line. Evidence that this improves outcomes is limited.

• Account for the additional flush volume when setting net ultrafiltration.

• Inspect the dialyser carefully and monitor venous pressure for early signs of clotting.

• Avoid transfusion through the circuit except, when required, during venous return at the end of treatment.

• The method is nursing-intensive.

Regional anticoagulation

Two approaches can confine anticoagulation mainly to the extracorporeal circuit: heparin followed by protamine neutralisation before the blood returns to the patient, or regional citrate anticoagulation.

Regional heparin with protamine reversal

This method is now rarely used and is generally avoided; it has largely been replaced by genuinely heparin-free techniques.

Heparin is infused at the dialyser inlet, while protamine is infused into the venous line. ACT is maintained at 200–250 seconds within the circuit and also checked in blood returning to the patient, where it should have returned to the pre-heparin baseline. Approximately 1 mg of protamine is used to neutralise 100 units of heparin.

Disadvantages:

• Accurate monitoring and selection of the correct protamine dose are difficult.

• More importantly, rebound bleeding can occur after approximately 2–4 hours—and occasionally as late as 10 hours—when heparin dissociates from protamine. The bleeding may be severe.

• Protamine can cause flushing, hypotension, and bradycardia.

Regional citrate anticoagulation

Regional citrate anticoagulation is used routinely in many centres. It is a reliable and effective means of preventing circuit clotting, but it requires meticulous nursing care and continuous monitoring and can cause major adverse effects if it is not managed correctly.

Citrate binds ionised calcium, which is required at several steps in the coagulation cascade. Citrate is infused into the early arterial limb of the blood tubing, calcium is omitted from the dialysate, and calcium is infused into the venous limb before blood is returned to the patient. Ionised calcium in the extracorporeal circuit is therefore reduced to a very low concentration, suppressing coagulation. This protocol requires calcium-free dialysate and carefully controlled calcium replacement.

Because of the risk of citrate toxicity, including arrhythmia, the source describes the use of a 4% citrate solution rather than a more concentrated trisodium-citrate preparation.

Citrate anticoagulation reduces bleeding risk while helping keep the circuit free of clots. Its disadvantages include greater cost than heparin and the potential for several electrolyte and metabolic disturbances.

Complications of citrate anticoagulation

• Disturbances of ionised calcium, including hypocalcaemia or hypercalcaemia.

• Hypernatraemia caused by sodium citrate. The source therefore specifies preparing the citrate solution in aqueous dextrose.

• Acid–base disturbances because citrate is metabolised, principally by the liver, to bicarbonate. The source suggests reducing the dialysate bicarbonate concentration to approximately 25 mEq/L when this protocol is used.

Other methods of anticoagulation during haemodialysis

Low-molecular-weight heparin (LMWH)

European guidance has favoured LMWH because it is easy to administer, effective, and associated with fewer adverse effects in some studies, particularly lipid and potassium disturbances and bleeding. It has become the first-line anticoagulant for routine haemodialysis in many European centres. LMWH is produced by fractionating unfractionated heparin.

It has a stronger relative inhibitory effect on factor Xa, may cause less hair loss, and often requires less monitoring than unfractionated heparin. Rates of thrombocytopenia and lipid disturbance may also be lower.

LMWH must not be used in type II HIT because antibodies can cross-react.

It is generally given as a single dose at the start of haemodialysis. Examples in the source are enoxaparin 0.7–1 mg/kg or a fixed dose of 40 mg; the cited reduced dose for a patient at high bleeding risk is 0.25 mg/kg.

If monitoring is required, anti-factor Xa activity can be measured, although routine monitoring is not usually necessary.

Epoprostenol

Epoprostenol inhibits platelet aggregation and causes vasodilatation.

The source describes an intravenous infusion of 5 ng/kg/min, with a range of 4–8 ng/kg/min. Hypotension is common. Other adverse effects include headache, flushing, nausea, vomiting, chest pain, and abdominal pain. Treatment is very expensive.

Danaparoid

Danaparoid is a low-molecular-weight glycosaminoglycan mixture containing heparan sulphate. It is expensive.

The usual regimen described in the source is an intravenous bolus of 3,750 units—2,500 units if body weight is below 55 kg—or 40 units/kg before each of the first two dialysis sessions, followed by a reduction to 3,000 or 2,000 units. Anti-factor Xa activity is monitored, with a cited target of 0.5–0.8 units/mL. A dose of 100–400 units/hour is described for continuous renal replacement therapy.

Recombinant hirudin (lepirudin)

Hirudin was originally derived from leeches. Lepirudin binds directly to thrombin and inhibits thrombin-mediated coagulation and platelet activation. It is given as a single dose at the start of haemodialysis, cited here as 0.08–0.15 mg/kg. It is effective but expensive and has a long half-life, so repeated administration can lead to bleeding.

Patients may develop non-neutralising antibodies to hirudin that prolong or enhance its anticoagulant effect. Repeat dosing may therefore be required only after 6–12 days. Monitoring can be performed with aPTT, with a cited target ratio of 1.5–2.5 times control.

Argatroban

Argatroban is a direct thrombin inhibitor and is particularly useful in patients with type II HIT. The source describes an initial dose of 10 mg into the dialysis circuit, or 250 micrograms/kg, followed by 25 mg/hour or 0.5–2 micrograms/kg/min.

The dose must be reduced in liver disease because argatroban is metabolised hepatically.

It can be monitored using aPTT, with a cited target of 1.5–2.0 times control. The source also reports an activity target of 0.2–0.4 units/mL.

Nafamostat mesilate

Nafamostat mesilate is a short-acting serine-protease inhibitor with antithrombin activity. The source describes an infusion rate of 20–40 mg/hour. It can cause hyperkalaemia.

Fondaparinux

Fondaparinux is a synthetic pentasaccharide that binds to antithrombin III and selectively inhibits factor Xa. Its half-life is prolonged in kidney failure and is longer than that of LMWH.

The source describes its use in some patients with HIT and a dose of approximately 2 mg intravenously before haemodialysis.