Tinzaparin is the preferred LMWH for use in haemodialysis circuits. Dose finding studies in haemodialysis patients have shown that short term and long term use of tinzaparin is safe in this group (2-4).
The anticoagulant effect of unfractionated heparin can be predictably reversed by the administration of protamine sulfate in the event of serious bleeding. While protamine is less effective at reversing the effect of LMWHs, tinzaparin is the LMWH preparation most amenable to reversal by protamine with a neutralisation effect of 86% reported (5).
Intravenous administration of tinzaparin or unfractionated heparin should always be in accordance with a valid prescription and the dose confirmed independently by 2 registered nurses. Concurrent anticoagulation must be taken into consideration. If the patient has received a dose of tinzaparin then no unfractionated heparin may be given. 

Heparin Induced Thrombocytopaenia
Rarely, patients may be diagnosed with type II heparin-induced thrombocytopenia (HIT). This is a result of antibody formation to the heparin-platelet factor 4 complex which leads to a decline in platelet count and, more importantly, is associated with a risk of venous and arterial thrombosis.
The recommended local policy is to use Argatroban. This is a direct thrombin inhibitor, has a short half-life (45 minutes) and has hepatic clearance. It is therefore the drug of choice if invasive procedures are planned or in patients with renal impairment. Contact the renal consultants or renal pharmacist (bleep 2025) for advice.

Dialysis without anticoagulation
Where the dialysis session is less than 3 hours duration no tinzaparin may be given and heparin free dialysis should be considered.

Clotting in the dialysis circuit
Factors that may contribute to clotting in the extracorporeal circuit may include:

• Intermittent blood flow. Maintain the blood flow at the optimum rate. Adjust dialysis access if necessary.
• High haemoglobin levels may increase clotting risk. Also, additional precaution is advised if the patients haemoglobin is low and there is a risk of losing the blood lines due to clotting
• Administration of blood transfusion during dialysis.
• High UF rates.
• Large reduction in relative blood volume (RBV reading).
• Haemodiafiltration in post dilution mode. Pre dilution mode or standard HD should be set whenever there is increased risk of clotting.
• Dialysis without any anticoagulant.

Signs of blood clotting in the extracorporeal circuit may include:

• Extremely dark blood.
• Shadows or streaks in dialyser. The circuit may be flushed with 100mls of sodium chloride 0.9% to allow suspected streaks to be seen more easily.
• Visible clots in venous chamber or rising venous pressure.
• Rapid filling of transducers.
• Presence of clots at arterial side of dialyser head.
• Rising transmembrane pressure (TMP).
• High system pressure alarm.
  

Concurrent anticoagulation
Some dialysis patients may be on concurrent full dose or prophylactic dose anticoagulation with warfarin, unfractionated heparin or low molecular weight heparin. Anticoagulation for dialysis in these patients should be as follows:

1. Eligible patients

Established renal failure patients on chronic haemodialysis or haemodiafiltration (chronic kidney disease stage 5D).

2. Excluded patients

Patients in the following categories should NOT receive anticoagulation with tinzaparin without assessment by renal unit medical staff.:

• Acute kidney injury requiring emergency haemodialysis.
• Acutely unwell chronic haemodialysis or haemodiafiltration patients unless following assessment by renal unit medical staff.
• Planned haemodialysis or haemodiafiltration session of less than 3 hours.
• Patients diagnosed with heparin induced thrombocytopenia.
• Within the 12 hour period prior to planned surgery or invasive procedure.
• Within the 24 hour period following surgery or invasive procedure.
• Significant trauma, prolonged bleeding time, recent kidney biopsy, significant recent haemorrhage including intracranial haemorrhage.
• Acute cerebral infarction (stroke).

In these situations dialysis should be performed without any heparin, or according to the unfractionated heparin protocol, and each case will require individual assessment by renal unit medical staff. 

3. Routine haemodialysis

Haemodialysis sessions lasting 3-4 hours

• Rinse /prime the circuit with 1 litre of 0.9% sodium chloride or online fluid according to renal unit procedure.
• Inject prescribed dose of tinzaparin 2,500 units into the arterial port of the circuit at the start of dialysis.
• Monitor for signs of clotting within the dialysis circuit.

Haemodialysis sessions lasting longer than 4 hours

• Rinse/prime the circuit with 1 litre of 0.9% sodium chloride or online fluid according to renal unit procedure.
• Inject prescribed dose of tinzaparin 3,500 units into the arterial port of the circuit at the start of dialysis.
• Monitor for signs of clotting within the dialysis circuit.

4. Routine haemodiafiltration

• Rinse/prime the circuit with 1 litre of 0.9% sodium chloride or online fluid.
• Inject prescribed dose of tinzaparin 3,500 units into the arterial port of the circuit at the start of dialysis.
• Monitor for signs of clotting within the dialysis circuit.

5. Incremental approach to prevent clotting in the dialysis circuit:

Step 1 – early signs of clotting may be managed with flushes of sodium chloride 0.9% into the extracorporeal circuit (50-100mls boluses repeated every15-30 minutes) to prevent the circuit from clotting. These flushes should be administered via the arterial infusion port and must be prescribed as per Patient Specific Directive for the administration of sodium chloride 0.9% injection to adult haemodialysis patients following consideration of the patient's fluid status.
Step 2 – increase tinzaparin dose for next and subsequent dialysis sessions by 1,000 units until no further clotting evident or tinzaparin dose of 4,500 units reached.
Step 3 – increase tinzaparin dose to 5,000 units at the start of treatment.
Step 4 – change tinzaparin dose to 2,500 units at the start of dialysis then repeated midway through the treatment.
Step 5 – stop tinzaparin. Change to unfractionated heparin protocol and consult medical staff for dosing.

6. Patients who continue to clot on maximum Tinzaparin.

Commence unfractionated heparin on the next dialysis session. Consider increasing the bolus dose and/or hourly infusion rate from the outset. The circuit should be observed for signs of clotting and the dose titrated until the patient can be dialysed without clotting in the circuit.

7. Reversal of tinzaparin with protamine sulfate

In cases of prolonged bleeding after removal of dialysis needles, consider reducing the dose of tinzaparin taking into account assessment of the dialysis circuit for clots and the possibility of a stenosis in the vascular access.
Consider administration of protamine sulfate if serious or uncontrolled haemorrhage occurs or if bleeding continues from a dialysis needle site for longer than 30 minutes after needle removal despite other measures including continuous pressure. Protamine sulfate should only be given following discussion with a consultant nephrologist. Administration of protamine sulfate should neutralise up to 86% of the anti-factor Xa activity of tinzaparin almost immediately (5). The anti-Xa activity of tinzaparin may not be completely reversible with protamine sulfate and may persist for up to 24 hours after administration. [6]
Protamine sulfate should be administered as a slow intravenous injection (maximum rate 5 mg per minute) to avoid hypotension, bradycardia and dyspnoea. No more than 50mg of protamine sulfate should be given in any one dose [6]. Please refer to the medusa monograph for guidance.

The effect of protamine sulfate dissipates after approximately 3 hours and if bleeding continues a further dose may be given. Management should be discussed with a haematologist as plasma products may also be used to achieve haemostasis.

Caution should be observed when administering protamine sulfate to patients who may be at increased risk of allergic reaction. These patients include those who have previously undergone procedures such as coronary angioplasty or cardio-pulmonary by-pass which may include use of protamine, diabetics who have been treated with protamine insulin, patients allergic to fish and men who have had a vasectomy or are infertile and may have antibodies to protamine.[6]

For use when the patient is not able to have tinzaparin and dialysis without anticoagulant is likely to result in clotting of the circuit.

1. Eligible patients (unfractionated heparin)

• Acute kidney injury requiring emergency haemodialysis. On Dr`s instruction.
• Planned haemodialysis or haemodiafiltration session of less than 3 hours where there is likelihood of clotting.
• Planned haemodialysis or haemodiafiltration patients who show signs of clotting in the extracorporeal circuit despite maximum tinzaparin dose.
• Within the 12 hour period prior to planned surgery or invasive procedure (minimal heparin dosing).
• Within the 24 hour period following surgery or invasive procedure (minimal heparin dosing).

2. Excluded patients (unfractionated heparin)

Patients in the following categories should NOT receive anticoagulation with unfractionated heparin without assessment by renal unit medical staff.

• Acutely unwell chronic haemodialysis or haemodiafiltration patients.
• Patients diagnosed with heparin induced thrombocytopenia.
• Significant trauma, prolonged bleeding time, recent kidney biopsy, significant recent haemorrhage including intracranial haemorrhage.
• Acute cerebral infarction (stroke).

3. Routine heparin dosing (unfractionated)

To establish unfractionated heparin regime in patients with low risk of bleeding

1. Draw up 10mls of heparin 1,000 units /ml into a 20ml luerlock syringe using a 21g needle. Attach the syringe to the haemodialysis machine prior to priming/rinsing according to manufacturer`s instructions. Please note that an increased volume of 15mls of heparin may be required if the patient requires large doses.
2. Ensure heparin is prescribed in the patient’s electronic patient record or paper medication prescription chart as per protocol.
3. Programme the machine to deliver a bolus of 1000units and hourly infusion rate at 1000 units.
4. Monitor for signs of clotting within the dialysis circuit every 30 minutes 
5. If clotting is seen administer a second bolus of 1000 units and increase the hourly rate to 1500 units.
6. Steps 4-5 may be repeated up to a maximum of 3,000 units bolus and 2,000 units hourly. Please consult medical staff if clotting persists and larger doses may be indicated. .
7. At the end of dialysis calculate the total amount of heparin administered and plan to administer this at the next dialysis session and monitor for signs of clotting. For example – if a total of 5,000 units has been given give a bolus of 1,500 units and an hourly pump set at 1,000 units. Remember to set stop time for 30 minutes before the end of dialysis if the patient has an AVF.

4. Minimal heparin dosing (unfractionated)

To establish a minimal heparin regime for patients who are Within the 12 hour period prior to planned surgery or invasive procedure or are within the 24 hour period following surgery or invasive procedure. Consider heparin free dialysis for these patients if possible. For AKI patients following agreement of the consultant physician

1. Draw up 10mls of heparin 1,000 units /ml into a 20ml luerlock syringe using a 21g needle. Attach the syringe to the haemodialysis machine prior to priming/rinsing according to manufacturer`s instructions.
2. Ensure heparin is prescribed in the patient’s electronic patient record or paper medication prescription chart as per protocol.
3. Programme the machine to deliver a bolus of 500 units and hourly infusion rate at 500 units.
4. Monitor for signs of clotting within the dialysis circuit every 30 minutes
5. If clotting is seen, administer a second bolus of 500 units and increase the hourly rate to 1000 units
6. Steps 4-5 may be repeated until a maximum accumulated dose of 5000 units in total has been administered. Please consult medical staff if this dose has been reached and there are still signs of clotting in the circuit
7. The total amount of heparin given must not exceed 5,000 units in the dialysis session if the patient is within 24hrs pre or post vascular access surgery.

6. Reversal of unfractionated heparin with protamine sulfate

In cases of prolonged bleeding after removal of dialysis needles, consider reducing the dose of heparin taking into account assessment of the dialysis circuit for clots and the possibility of a stenosis in the vascular access.

Consider administration of protamine sulfate if serious or uncontrolled haemorrhage occurs or if bleeding continues from a dialysis needle site for longer than 30 minutes after needle removal despite other measures including continuous pressure. Protamine sulfate should only be given following discussion with a consultant nephrologist.
The dose is dependent on amount of heparin and the time elapsed since it was administerd. Heparin is continuously being excreted. 1mg of protamine will usually neutralise at least 100 units of heparin. The dose of protamine sulfate should be reduced if more than 15 minutes have elapsed since IV injection. If the patient is receiving an intravenous infusion of heparin, the infusion should be stopped and protamine sulfate given by slow intravenous injection. The maximum rate for Protamine sulfate injection is 5 mg per minute. This is to avoid hypotension, bradycardia and dyspnoea. Please refer to the medusa monograph for guidance.

The effect of protamine sulfate dissipates after approximately 3 hours and if bleeding continues a further dose may be given. Management should be discussed with a haematologist as plasma products may also be used to achieve haemostasis.

Caution should be observed when administering protamine sulfate to patients who may be at increased risk of allergic reaction.

*Following consideration of the patient`s fluid status, flushes of NaCl 0.9% may be administered as per PSD to assist in visualising clots.

*Following consideration of the patient`s fluid status, flushes of NaCl 0.9% may be administered as per PSD to assist in visualising clots.

*Following consideration of the patient`s fluid status, flushes of NaCl 0.9% may be administered as per PSD to assist in visualising clots.

1. European best practice guidelines for haemodialysis (Part 1). Nephrol Dial Transplant 2002; 17(Suppl 7):63-71.

2. Ryan KE, Lane DA, Flynn A, Ireland HA, Curtis JR. Dose finding study of a low molecular weight heparin, Innohep, in haemodialysis. Thrombosis and Haemostasis 1991; 66 (3) 277-282.

3. Simpson HKL, Baird J, Allison M, Briggs JD et al. Long term use of the low molecular weight heparin tinzaparin in haemodialysis. Haemostasis 1996; 26:90-97.

4. Lord H, Jean N, Dumont M, Kassis J, Leblanc M. Comparison between tinzaparin and standard heparin for chronic hemodialysis in a Canadian center. Am J Nephrol. 2002; 22(1):58-66.

5. Crowther MA, Berry LR, Monagle PT, Chan AKC. Mechanisms responsible for the failure of protamine to inactivate low molecular weight heparin. British Journal of Haematology 2002, 116; 178-186.

6. Summary of Product Characteristics Prosulf Injection 10mg/ml, Wockhardt, updated 9/5/18. Accessed online at www.medicines.org.uk/emc on 4/2/19.
t increased risk of allergic reaction.