Guideline for the use of Tranexamic Acid in Reducing the Need for Blood Transfusion

1. Licensed Indications
2. Use in Haemorrhage
3. Tranexamic Acid is not indicated for use
4. Cautions for the use of Tranexamic Acid
5. Reactions
6. Dose and Administration
7. Cost implications of Tranexamic Acid Treatment
8. Documentation
   Glossary
   References
   Appendix 1 (Flowchart)

Introduction

Tranexamic acid (TXA) can be used to prevent or treat bleeding by inhibiting fibrinolysis. With the need to conserve blood supplies, and awareness of the benefits of avoiding non-essential blood transfusion in many clinical scenarios, there is increasing evidence that tranexamic acid is a safe and effective measure to reduce blood loss. TXA is commonly given to surgical patients to reduce bleeding and the need for blood transfusion.  A recent large multinational randomised controlled trial in patients with massive traumatic haemorrhage showed a significant reduction in mortality in those receiving tranexamic acid (CRASH-2) which is being followed by a further international randomised controlled trial on the use of TXA in traumatic brain injury (CRASH-3) see: http://crash3.lshtm.ac.uk/files/1914/9157/4617/Protocol_summary_v2_for_translation_FINAL.pdf

NICE Guidelines: NG24, 2015 state hospitals may improve clinical outcomes and cut costs by reducing the need for blood transfusions (with their associated risks). Tranexamic acid is an inexpensive antifibrinolytic pharmacological agent that can be administered before and during surgery to reduce bleeding and therefore the need for blood transfusions. There is strong evidence that it is clinically effective and that its use will reduce mortality and costs. Also, Depending on the reduction in the number of units of blood transfused, there may be a saving in the range of £146–£689 per person. Use of tranexamic acid may also reduce length of hospital stay, which will result in efficiency savings, see:
https://www.nice.org.uk/guidance/ng24 and refer to recommendations for alternatives to transfusion for patients having surgery.

Tranexamic acid is an antifibrinolytic, not a procoagulant agent and there is no convincing evidence to support an increased risk of venous or arterial thromboembolism. Its use is recommended in the current Leeds Teaching Hospitals NHS Trust (LTHT) guidelines on managing massive haemorrhage in neonates, paediatrics, adults, trauma, and obstetrics and in ruptured abdominal aortic aneurysm.

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1. Licensed Indications

Haemorrhage caused by general or local fibrinolysis such as:

• Management of haemorrhage due to the administration of a fibrinolytic agent
• Thoracic and abdominal surgery and other major surgical intervention such as cardiovascular surgery
• Gastrointestinal bleeding
• Menorrhagia and metrorrhagia
• Haemorrhagic urinary disorders, further to prostate surgery or surgical procedures affecting the urinary tract
• Ear Nose Throat surgery (adenoidectomy, tonsillectomy, dental extractions)
• Gynaecological surgery or disorders of obstetric origin
• Hereditary angioedema

Tranexamic acid may also be used short-term for haemorrhage or risk of haemorrhage in increased fibrinolysis or fibrinogenolysis, haemorrhagic complications in association with thrombolytic therapy and haemorrhage associated with disseminated intravascular coagulation with predominant activation of the fibrinolytic system

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2. Use of Tranexamic Acid in acute Haemorrhage:

Massive Traumatic Haemorrhage:
The CRASH-2 trial (published June 2010) clearly showed that patients with massive haemorrhage secondary to trauma given early tranexamic acid (within 3 hours of trauma) had a reduced mortality compared to the placebo group. CRASH-2 used a loading dose of 1g intravenous tranexamic acid over 10 minutes followed by 1g tranexamic acid intravenous infusion in 100ml sodium chloride 0.9% or glucose 5% over 8 hours.

Tranexamic acid may also benefit those adult patients who have sustained trauma with significant haemorrhage and:

• have a heart rate > 110 beats / minute  OR
• have a systolic BP < 90mmHg  OR
• have triggered the use of the massive haemorrhage in trauma policy  OR
• are considered to be at risk of significant haemorrhage by the trauma team leader

     AND

• Present early enough for the initial tranexamic acid bolus dose to be given within 3 hours of the time of injury

The LTHT guidelines for management of massive haemorrhage in adults, children or neonates recommend giving tranexamic acid within 3 hours of onset whilst infusing massive transfusion pack 1. For further information, see: http://nww.lhp.leedsth.nhs.uk/Search/guidelineresults.aspx?gword=massive%20haemorrhage

Obstetric Haemorrhage:
The recently published 2017 WOMAN Trial results encompassing 20,000 patients across 21 countries showed a 31% reduction in maternal deaths following postpartum haemorrhage when TXA was used within 3 hours of haemorrhage.
See: http://thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)30638-4.pdf

In 2011 a Cochrane Collaboration review concluded that tranexamic acid is effective in reducing postpartum haemorrhage (defined as > 400 ml) after vaginal delivery or caesarian section. In most studies, tranexamic acid was given shortly after vaginal delivery, or at the start of surgery.

The current LTHT guideline for Management of Obstetric Haemorrhage (2018) recommends consideration of giving tranexamic acid, especially if there is evidence of hyperfibrinolysis. 
See LTHT guideline at: http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?ID=2146 

Surgical Haemorrhage:
Tranexamic acid has been used for many years to reduce blood loss in cardiac surgery and there are numerous observational studies and clinical trials of its use in elective and emergency orthopaedic surgery, especially hip and knee arthroplasty. The orthopaedic literature generally supports the use of tranexamic as a blood conservation strategy, often used in combination with intra- or postoperative cell salvage procedures. There is no evidence that tranexamic acid significantly increases the risk of peri-operative thromboembolism.

NICE Transfusion Guidelines: NG24, 2015 during surgery advise staff to:

• include using tranexamic acid as part of the hospital protocol for adults undergoing surgery

• Offer tranexamic acid to adults undergoing surgery who are expected to have at least moderate blood loss (greater than 500 ml)
• Consider tranexamic acid for children undergoing surgery who are expected to have at least moderate blood loss (greater than 10% blood volume)
• Do not routinely use cell salvage without tranexamic acid
• Consider intra-operative cell salvage with tranexamic acid for patients who are expected to lose a very high volume of blood for example in cardiac and complex vascular surgery, major obstetric procedures, and pelvic reconstruction and scoliosis surgery

Medical Patients with Haemorrhage:
Tranexamic acid is commonly used as an oral preparation in patients with congenital bleeding disorders, such as haemophilia or von Willebrand’s disease to treat or prevent mucosal haemorrhage, such as epistaxis or oral bleeding.

Tranexamic acid may be used as a useful adjunct to platelet transfusion to reduce mucosal bleeding in haemato-oncology patients with mucosal haemorrhage.

It is also widely used in the management of menorrhagia.

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3. Tranexamic Acid is contra-indicated for use in:

• Patients with acute deep vein thrombosis (DVT), pulmonary embolism (PE) or arterial thrombosis
• History of convulsions
• Hypersensitivity to tranexamic acid or any of the ingredients
• Severe renal impairment due to risk of accumulation

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4. Cautions for use of Tranexamic acid:

• Patients with indwelling cardiac stent
• In case of haematuria from the upper urinary tract, there is a risk for urethral obstruction
• Disseminated intravascular coagulation (DIC). If tranexamic acid is given it must be restricted to those in whom there is predominant activation of the fibrinolytic system with acute severe bleeding.
• Patients with a previous thromboembolic event (use tranexamic acid only if there is a strong medical indication)

NB: Intravenous injections should be given very slowly. Tranexamic acid should not be administered by the intramuscular route.
When deciding on the use of tranexamic acid in individuals with the above conditions, it is recommended to consider the balance of risks against the benefits of using tranexamic acid and how these may affect patient outcome.

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5. Reactions

• Nausea, vomiting
• Diarrhoea
• Thromboembolic events (see notes above)
• Convulsions (mainly with very high dose therapy as occasionally used in cardiac surgery)
• Hypersensitivity reactions including anaphylaxis
• Impairment of colour vision (discontinue) and visual disturbances (discontinue)

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6. Dose and Administration

The dose of tranexamic acid may change depending on patient condition and in renal impairment; seek advice from pharmacy or Consultant Haematologist.

Adults:
In massive haemorrhage: 1gram intravenously over 10 minutes within 3 hours of the onset of haemorrhage (as per CRASH-2 trial) followed by a further 1gram intravenous infusion in 100ml sodium chloride 0.9% or glucose 5% over 8 hours 
Routine use in adults:

• By mouth: 1 to 1.5grams, 2-3 times per day
• Intravenous (by slow injection 100mg/min): 0.5grams to 1gram 2-3 times per day
• Following an initial intravenous injection continuous intravenous infusion: 25 to 50 mg/kg over 24 hours
• Reduce doses in renal impairment

Dose adjustment in renal impairment (adults):

Give loading dose i.e. 1 to 1.5grams by mouth or 0.5 to 1g intravenously

Followed by subsequent dosage:

• Creatinine Clearance: 20-50ml/min    IV 10mg/kg (max 1g) 12 hourly or by mouth 25mg/kg 12 hourly

• Creatinine Clearance: 10-20ml/min    IV 10mg/kg 24 hourly or by mouth 25mg/kg 12-24 hourly

• Creatinine Clearance < 10ml/min       IV 5mg/kg 24 hourly or by mouth 12.5mg/kg 12-24 hourly

This is data taken from the Renal Drug Handbook Fourth Edition. The SPC states that tranexamic acid is contra-indicated in severe renal impairment 
Children (dose is weight/age specific):
In massive haemorrhage: administer 10mg/kg intravenous tranexamic acid over 10 minutes within 3 hours of the onset of haemorrhage (dose depends on age & weight of the child) then further intravenous infusion of 2mg/kg/hour over at least 8 hours or until bleeding stops.
Routine use in neonates/children:

• The injection is not licensed in children under 1 year but if there are no other options, see below BNFc dose advice:
• By mouth: 1 month – 18 years: 15-25mg/kg (max. 1.5g) 2-3 times daily
• Intravenous (by slow injection over at least 10 minutes):
  • Neonate (less than 1 month): 10mg / kg 2-3 times daily (this dose is not in any of the usual paediatric dosing literature but has been extrapolated from the paediatric dosing)
  • 1 month – 18 years: 10mg/kg (max. 1g) 2-3 times daily
  • Following an initial intravenous injection continuous intravenous infusion: 45mg/kg over 24 hours

Reduce dose in renal impairment - see product literature or contact Medicines Information 
Intravenous tranexamic acid should be diluted up to 5mls with 0.9% sodium chloride and administered over at least 10 minutes.
Do not add directly to blood or administer via the same administration line as penicillin.

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7. Cost implications of tranexamic acid treatment

• Cost of tablets (2017): 500mg, 60 tablet pack = £4.42
• Cost of injection (2017):  100mg/ml, 5ml ampoule = £1.50

Therefore 2 x 1g IV doses for use in managing massive haemorrhage = £6.00

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8. Documentation

Best practice is to clearly document response to the treatment and patient outcome when tranexamic acid has been used as part of treatment for managing massive haemorrhage. Any reaction to the product should be noted and reported through the usual pharmacy drug alert channels.

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Glossary

CRASH-2 trial: A large (20,000 patients) randomised placebo controlled trial among trauma patients with, or at risk of, significant haemorrhage, of the effects of antifibrinolytic treatment on death and transfusion requirement 

Fibrinolysis: A normal ongoing process that dissolves fibrin and results in the removal of small blood clots 

Conisation of the cervix: Conisation of the cervix is defined as excision of a cone-shaped or cylindrical wedge from the cervix uteri that includes the transformation zone and all or a portion of the endocervical canal. It is used for the definitive diagnosis of squamous or glandular intraepithelial lesions, for excluding microinvasive carcinomas, and for conservative treatment of cervical intraepithelial neoplasia

Traumatic hyphaema: Hyphaema is blood in the front (anterior) chamber of the eye. It may appear as a reddish tinge, or it may appear as a small pool of blood at the bottom of the iris or in the cornea.

Hereditary angioneurotic oedema: A genetic form of angioedema. Persons with it are born lacking an inhibitor protein (called C1 esterase inhibitor) that normally prevents activation of a cascade of proteins leading to the swelling of angioedema.

WOMAN Study: A large (20,000 patients) randomised, double-blind, placebo-controlled international trial among women with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section assigned to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. Results showed Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.

Appendix 1 (Flowchart)