Tranexamic acid

Why this drug is interesting

Tranexamic acid is one of the very few emergency drugs whose evidence base consists of trials large enough to detect small mortality differences reliably. CRASH-2 randomised over 20,000 patients; CRASH-3 nearly 13,000; WOMAN and HALT-IT each around 20,000 and 12,000 respectively. Most of what we give in resus rests on nothing like this.

That scale produced an unusually clean set of answers — including a negative one. HALT-IT tested tranexamic acid in gastrointestinal bleeding, found no benefit and more venous thromboembolism, and the authors concluded it should not be used for that indication outside a trial. A drug that works in trauma and postpartum haemorrhage does not work in every bleed, and knowing which is which is the substance of this monograph.

Pharmacology

Mechanism

Tranexamic acid is a synthetic derivative of the amino acid lysine. Plasminogen and plasmin bind fibrin through lysine-binding sites; tranexamic acid occupies those sites competitively, preventing plasminogen from docking onto fibrin and being converted to active plasmin at the clot surface.

The result is that fibrinolysis is inhibited and formed clot is stabilised. This is the key conceptual point: tranexamic acid does not make clot, does not replace clotting factors and does not correct coagulopathy. It stops the clot you have already made from being dissolved.

Kinetics

Onset

Rapid after IV administration; antifibrinolytic effect within minutes

Distribution

Wide; crosses the placenta and reaches CSF at roughly a tenth of plasma concentration

Half-life

Approximately 3 hours

Metabolism

Minimal — largely unmetabolised

Excretion

Renal, over 90% unchanged in urine

Renal excretion of unchanged drug means dose reduction is required in renal impairment, and it explains why accumulation is a concern in patients with poor kidneys who receive repeated doses. It is otherwise a pharmacologically undemanding drug: stable at room temperature, cheap, and requiring no reconstitution — attributes that matter enormously for prehospital and low-resource use.

Trauma — CRASH-2

CRASH-2 randomised 20,211 adult trauma patients with, or at risk of, significant haemorrhage to tranexamic acid or placebo, within 8 hours of injury.³

The absolute risk reduction is modest — about 1.5% — but in a cheap, widely available drug applied to a very large population, that is a substantial number of lives. The regimen used in CRASH-2 is the regimen that entered practice, and remains the standard UK trauma dose.

Head injury — CRASH-3

CRASH-3 randomised 12,737 patients with traumatic brain injury.⁴ It is the trial most often misquoted in both directions, so the numbers are worth stating precisely.

The practical UK position that emerged is that tranexamic acid is reasonable in TBI within 3 hours, with the clearest rationale in patients who are not in the most severe category. Follow your regional major trauma network's protocol, which will have taken a position on this.

Postpartum haemorrhage — WOMAN

The WOMAN trial studied tranexamic acid in postpartum haemorrhage.⁵ The regimen differs from the trauma one and is worth knowing separately:

• 1 g by intravenous injection
• If bleeding continues after 30 minutes, or stops and restarts within 24 hours, a second 1 g dose

Death due to bleeding was reduced, with the effect again concentrated in early treatment — 1.2% vs 1.7% when given within 3 hours of giving birth. Hysterectomy rates were not reduced, which is a useful corrective to over-claiming: the benefit is on death from bleeding, not on every important obstetric outcome.

Gastrointestinal bleeding — HALT-IT, and why not to

HALT-IT tested a high-dose 24-hour regimen — 1 g loading dose followed by 3 g infused over 24 hours — in patients with acute gastrointestinal bleeding.⁶

Two features are worth noting when interpreting this. The dose was considerably higher and the infusion far longer than the trauma regimen, which may contribute to the thrombotic signal. And the pathophysiology differs — upper GI bleeding is not characterised by the early systemic hyperfibrinolysis of major trauma, so the mechanistic rationale was always weaker than it appeared.

Neither observation rescues the indication. HALT-IT is a large, well-conducted trial with a clear answer, and it should be followed.

Contraindications, cautions and adverse effects

Contraindications

• Hypersensitivity to tranexamic acid
• Active intravascular clotting / current thromboembolic disease
• Subarachnoid haemorrhage — historically contraindicated on the basis of increased cerebral ischaemia; specialist neurosurgical protocols vary and should govern
• Severe renal impairment requires substantial dose reduction rather than being an absolute bar — check the SmPC and local guidance

Cautions

• History of venous or arterial thromboembolism
• Renal impairment — dose reduction required; the drug is renally cleared unchanged
• Haematuria of upper urinary tract origin — clot retention and ureteric obstruction have been reported
• Seizure risk — dose-related, and predominantly described with high doses in cardiac surgery

Adverse effects

Tranexamic acid is generally very well tolerated at trauma doses. Nausea, vomiting and diarrhoea are the commonest complaints. Hypotension occurs with rapid intravenous injection, which is the practical reason the loading dose is given over 10 minutes rather than pushed. Visual disturbance and, rarely, seizures are described, the latter mainly at the high doses used in cardiac surgery.

Practical use in the ED

1. Establish the time of injury first. Everything else follows from whether you are inside three hours.
2. Give the loading dose over 10 minutes, not as a bolus — rapid injection causes hypotension in a patient who can ill afford it.
3. Do not let it displace haemorrhage control. Tranexamic acid stabilises clot; it does not stop arterial bleeding, replace blood, or substitute for a tourniquet, pelvic binder, surgeon or interventional radiologist.
4. Remember the second gram. The 8-hour infusion is part of the trauma regimen and is the component most often omitted during transfers between departments — hand it over explicitly.
5. Do not give it for GI bleeding. This is the change in practice that HALT-IT should have produced and which has been slow to land in some departments.

Critical appraisal

1. The trials are large, pragmatic and mostly independent of industry — a genuinely unusual strength. The CRASH programme's design deliberately favoured wide eligibility and simple outcomes, which improves generalisability at the cost of granularity.
2. Much of CRASH-2's recruitment came from low- and middle-income settings with different baseline trauma care. Whether the same absolute benefit accrues in a mature trauma system with rapid surgical haemorrhage control and major haemorrhage protocols is a fair question, and the honest answer is that the effect may be smaller.
3. The three-hour rule rests on subgroup analysis by timing, albeit pre-specified and mechanistically coherent. It is strong enough to act on and not strong enough to treat as a law of nature.
4. CRASH-3's headline is a negative primary outcome. Practice adopted a subgroup result. That may well be right, but clinicians should know which they are relying on.
5. HALT-IT is the most important trial for calibration. It demonstrates that the benefit is indication-specific rather than a general haemostatic property — and it is the reason to resist extending tranexamic acid to every bleeding patient on mechanistic grounds alone.

References

1. 1
   Tranexamic acid — dosing and safety monograph. BNF, NICE. bnf.nice.org.uk
2. 2
   Cyklokapron 100 mg/mL Solution for Injection — Summary of Product Characteristics. electronic Medicines Compendium. Source of the ~3 hour elimination half-life and of the licensed indication and dosing, against which the trauma and PPH regimens are off-label. Verified 21 Aug 2026; corroborated in product 12772 and product 11894. Consult the preparation stocked locally, particularly for renal dose adjustment.
3. 3
   CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010;376(9734):23–32. See also the full HTA report. PMC
4. 4
   CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet 2019;394(10210):1713–23. Lancet32233-0/fulltext)
5. 5
   WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet 2017;389(10084):2105–16. Lancet30638-4/fulltext)
6. 6
   HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet 2020;395(10241):1927–36. PubMed
7. 7
   NICE NG39. Major trauma: assessment and initial management. National Institute for Health and Care Excellence.