Low Molecular Weight Heparin (LMWH)


 

Dalteparin, Enoxaparin, Tinzaparin 


  Issues for Surgery


Increased risk of venous thromboembolism if omitted.

Increased risk of bleeding if continued.

Increased risk of spinal haematoma in patients receiving neuraxial anaesthesia if continued.


  Advice in the Perioperative period


Elective Surgery

Check serum potassium levels and platelet count pre-operatively (see Further Information).

Prophylactic Doses
Last dose to be given a minimum of 12 hours prior to surgery – see figure 1. (See Further Information)

Figure 1 – timing of administration of prophylactic LMWH prior to surgery

Therapeutic Doses
Last dose to be given a minimum of 24 hours prior to surgery – see figure 2.

Figure 2 – timing of administration of therapeutic LMWH prior to surgery

* if possible (to minimise the time between last dose and operation whilst still allowing for reasonable anticoagulation coverage), consider bringing the treatment dose forward by a few hours each day over a number of days prior to surgery until patient is administering at 8am in the morning and follow advice for once daily administration in the morning (before 8am).

Emergency Surgery

If there is insufficient time to follow the advice for elective surgery, and rapid reversal of the effects of LMWH are required, protamine sulfate is a specific antidote (but only partially reverses the effects)1, 2 – discuss with Haematologist.

Perioperative Considerations (see also Further Information)

Neuraxial (Spinal/Epidural) Anaesthesia or Lumbar Punctures – Prophylactic Doses
Therapeutic anticoagulation with warfarin is an absolute contraindication to neuraxial anaesthesia. Warfarin should only be recommenced once an epidural/nerve catheter has been removed5.    - Prophylactic doses

Insertion or removal of the catheter should be performed 12 hours after the last dose of LMWH3, 4, 5, 6, 7, 8. Once a catheter has been inserted, the next dose of LMWH should be administered a minimum of 4 hours post-insertion7, 8.

Neuraxial (Spinal/Epidural) Anaesthesia or Lumbar Punctures – Therapeutic Doses
Insertion of the catheter should be performed 24 hours after the last dose of LMWH3, 4, 5, 6, 7, 8. The use of therapeutic LMWH whilst the catheter is in place is not recommended1, 8.

Once a catheter has been removed, LWMH administration (prophylactic and treatment doses) can resume 4 hours after removal and in the presence of adequate haemostasis9.

Post-operative Advice

Prophylactic Doses
Commence a minimum of 2 hours post-operatively (4 hours for patients with indwelling catheters – see Perioperative Considerations above) and only in the presence of adequate haemostasis3

Treatment Doses (If to be continued Post-op)
Commence once adequate haemostasis has been established (except for patients with indwelling catheters – see Perioperative Considerations above). Consider use of prophylactic doses of LMWH until the treatment dose can be safely resumed.

Bridging Therapy
For patients who have been given LMWH as bridging therapy in place of their usual anticoagulant (e.g. warfarin), the LMWH should not be started until at least 48 hours after surgery. Follow the advice provided by the Pre-operative Assessment Team / Haematology Team post-operatively if appropriate.


Monitor serum potassium, especially with prolonged use (> 7 days) – see Further Information.

Monitor platelet count, especially with prolonged use – see Further Information.

Monitor renal function – dose adjustment may be necessary if there is a decline in renal function (consult product literature).


  Interaction(s) with Common Anaesthetic Agents


None1, 9.


  Interaction(s) with other Common Medicines used in the Perioperative Period


Hyperkalaemia (see also Further Information)

Both LMWH and Non-Steroidal Anti-inflammatory Drugs (NSAIDs) can increase the risk of hyperkalaemia1 (also see below under Enhanced Anticoagulant Effect).

Both LMWH and trimethoprim can increase the risk of hyperkalaemia1.

Enhanced Anticoagulant Effect

LMWH is predicted to increase the risk of bleeding events when given with NSAIDs – caution is advised, especially in those patients undergoing regional anaesthesia1, 2, 3, 4, 5, 6, 9.

The UK manufacturer of dalteparin advises that because heparin interacts with high doses of penicillin increasing the risk of haemorrhage2, 4, 9, an interaction with dalteparin cannot be ruled out. The clinical relevance is unclear but bear the potential interaction in mind in case of any unexpected outcome with concurrent use9. This predicted interaction is not cautioned with enoxaparin or tinzaparin5, 6.

Reduced Anticoagulant Effect

The UK manufacturer of dalteparin advises that the anticoagulant effect might be reduced by tetracyclines (e.g. doxycycline, tigecycline)4, 9. The clinical relevance is unclear but bear the potential interaction in mind in case of any unexpected outcome with concurrent use2. This interaction is not cautioned with enoxaparin or tinzaparin5, 6.

The UK manufacturer of dalteparin advises that the anticoagulant effect might be reduced by cyclizine4, 9.

They UK manufacturer of enoxaparin states that systemic corticosteroids affect haemostasis5, hence may reduce the anticoagulant effect. This interaction is not noted with dalteparin or tinzaparin4, 6.


  Further Information


Timing of Pre-operative Doses of Prophylactic LMWH

LMWH preparations have varying licenses for surgical patients (for prophylaxis of deep-vein thrombosis (DVT)) on the timing of pre-operative doses. Depending on the LMWH and the dose, licensing varies from administration 1 – 2 hours pre-operatively to the evening before surgery1, 4, 5, 6. In practice, prophylactic doses are usually always commenced a minimum of 12 hours pre-operatively where appropriate.

Neuraxial Anaesthesia

In patients undergoing epidural or spinal anaesthesia or spinal puncture, the prophylactic use of heparin may be very rarely associated with epidural or spinal haematoma resulting in prolonged paralysis or permanent paralysis. The risk is increased by the use of epidural or spinal catheter for anaesthesia, by the concomitant use of drugs affecting haemostasis such as NSAIDs and by traumatic or repeated puncture4, 5, 6.

Treatment doses are contraindicated in patients who receive neuraxial anaesthesia due to the risk of spinal haematoma1, 4, 5, 6.

Thrombocytopenia and Heparin-induced Thrombocytopenia (HIT)

Thrombocytopenia usually occurs within 3 weeks (between 5th and 21st day) following the initiation of therapy4, 5. Signs of severe thrombocytopenia (HIT) include 30% reduction in platelet count, thrombosis or skin allergy1. The risk of HIT is higher in postoperative patients, mainly after cardiac surgery, and in patients with cancer5. Platelet counts should be monitored just before treatment and at regular intervals if the LMWH is continued for a prolonged period post-operatively4, 5, 6. If HIT is suspected or confirmed, the LMWH should be stopped and an alternative anticoagulant be given1, 4, 5 – discuss with Haematologist.

Hyperkalaemia

Inhibition of aldosterone secretion by LMWH can result in hyperkalaemia. Patient with diabetes mellitus, chronic renal failure, acidosis, raised plasma potassium or those taking potassium-sparing drugs seem to be more susceptible. The risk appears to increase with duration of therapy (> 7 days)1, 4, 5, 6.

Monitoring

LMWH have less effect on platelet aggregation than unfractionated heparin. They have no significant effect on blood coagulation tests such as activated partial thromboplastin time (APTT)1, 4, 5. Therapy may be monitored by measurement of plasma anti-factor Xa activity but monitoring is less frequently required than with heparin since LWMH has a more predictable effect2. Routine monitoring is not usually required but may be necessary in patients at increased risk of bleeding (e.g. renal impairment, or those at extremes of body weight)1, 2, 4.

 

  References


  1. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 28th August 2019]
  2. Low-molecular-weight Heparins. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 28th August 2019]
  3. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. British Journal of Anaesthesia. 2011; 107 (S1):i96 – i106
  4. Summary of Product Characteristics – Fragmin® (dalteparin) 5000 IU. Pfizer Limited. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text May 2016]
  5. Summary of Product Characteristics – Clexane® (enoxaparin) pre-filled syringes. SANOFI. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text September 2018]
  6. Summary of Product Characteristics – innohep® (tinzaparin) 20,000 IU/ml. Leo Laboratories Limited. Accessed via www.medicines.org.uk 28/08/2019 [date of revision of the text November 2018]
  7. Davies G and Checketts MR. Regional anaesthesia and antithrombotic drugs. Continuing Education in Aanesthesia, Crtical Care & Pain. 2012; 12: 1
  8. The Association of Anaesthetists of Great Britain & Ireland, The Obstetric Anaesthetists’ Association and Regional Anaesthesia UK. Regional Anaesthesia and Patients with Abnormalities of Coagulation. Anaesthesia. 2013; 68:966-72
  9. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 28th August 2019]