Antifibrinolytic Drugs

Antifibrinolytic drugs prevent the breakdown of fibrin clot. Tranexamic acid is the main drug; aminocaproic acid is an alternative. They reduce bleeding and mortality in trauma and postpartum haemorrhage when given early, reduce blood loss in surgery and heavy menstrual bleeding, and are used for mucosal bleeding in bleeding disorders. Benefit falls with delay, and they must be avoided in active thrombosis.

Mechanism. Lysine analogues that bind plasminogen’s lysine-binding sites, preventing plasminogen binding to fibrin and conversion to plasmin. At high concentrations they also inhibit plasmin directly.

Pharmacokinetics. Tranexamic acid oral bioavailability about 35%; intravenous half-life 2 to 3 hours; renal elimination (about 95% unchanged), so accumulation in renal impairment is the main safety issue. Aminocaproic acid half-life 1 to 2 hours.

Tranexamic acid dosing.

• Trauma with significant bleeding (within 3 hours of injury): 1 g intravenously over 10 minutes, then 1 g over 8 hours.
• Postpartum haemorrhage: 1 g intravenously over 10 minutes within 3 hours of birth, repeat 1 g if bleeding continues after 30 minutes or restarts within 24 hours.
• Surgery with expected major blood loss: 10 to 15 mg/kg intravenously before incision, then 1 g over 8 hours or as directed (cardiac surgery regimens vary and higher doses increase seizures).
• Heavy menstrual bleeding: 1 g orally three times daily (up to 1.5 g three times daily) for up to 4 days; maximum 4 g daily.
• Epistaxis or mucosal bleeding: 500 mg to 1 g orally or intravenously; topical 5% mouthwash 10 mL four times daily for 2 days in bleeding disorders and dental extractions.
• Children: 15 mg/kg (maximum 1 g) over 10 minutes, then 2 mg/kg/h for at least 8 hours or as directed.

Renal adjustment (intravenous or oral). Creatinine 120 to 249 micromol/L: 15 mg/kg twice daily; 250 to 500 micromol/L: 15 mg/kg once daily; over 500 micromol/L: 7.5 mg/kg once daily (or half of those oral doses).

Aminocaproic acid. 4 to 5 g orally or intravenously in the first hour, then 1 g hourly for up to 8 hours or until bleeding stops; maximum 30 g in 24 hours; used where tranexamic acid is unavailable.

Aprotinin. A plasmin inhibitor withdrawn or restricted in many regions because of renal and cardiovascular risk.

• First-line. Trauma haemorrhage and postpartum haemorrhage as early as possible; elective surgery with high blood loss (orthopaedic, cardiac, spinal); heavy menstrual bleeding; epistaxis.
• Alternative. Aminocaproic acid when tranexamic acid is unavailable; topical tranexamic acid for wounds and dental surgery.
• Specialist. Haemophilia and von Willebrand disease (mucosal bleeding, dental procedures); hereditary haemorrhagic telangiectasia; hyperfibrinolysis in liver transplantation and acute promyelocytic leukaemia (with care).
• Emergency. Major trauma, postpartum haemorrhage, gastrointestinal bleeding only in specific settings (not routinely advised), and traumatic brain injury with mild to moderate severity within 3 hours.

Selection. Give immediately at the first sign of bleeding in trauma or postpartum haemorrhage, alongside definitive control; do not wait for laboratory tests. Avoid after 3 hours in trauma unless hyperfibrinolysis is shown.

Contraindications. Active venous or arterial thromboembolic disease; history of convulsions (relative); subarachnoid haemorrhage (cerebral oedema and infarction); haematuria from the upper urinary tract (clot colic and retention); disseminated intravascular coagulation with thrombosis (relative); hypersensitivity.

Serious adverse effects. Thromboembolism (rare at usual doses); seizures at high doses, in cardiac surgery and in renal impairment; visual disturbance with prolonged use; hypotension with rapid injection; nausea, vomiting and diarrhoea; allergic reactions.

Major interactions. Combined hormonal contraceptives (thrombosis); factor IX complex, activated prothrombin complex concentrates and recombinant factor VIIa (additive thrombosis); all-trans retinoic acid (thrombosis in promyelocytic leukaemia); thrombolytics are antagonised.

Common prescribing errors.

• Wrong-route injection: intrathecal tranexamic acid causes seizures, arrhythmia and death; confuse with local anaesthetic ampoules.
• No dose reduction in renal impairment.
• Delay beyond 3 hours in trauma.
• Excess dosing in cardiac surgery.
• Use in haematuria from the upper tract.

Special groups.

• Pregnancy: used in postpartum haemorrhage; avoid antenatal use without clear indication.
• Breastfeeding: small amounts in milk; acceptable.
• Children: 15 mg/kg (maximum 1 g), then 2 mg/kg/h.
• Older adults: reduce dose with renal impairment.
• Kidney: accumulates; reduce the dose by creatinine band.
• Liver: no adjustment.
• East Africa: early tranexamic acid in trauma and postpartum haemorrhage is lifesaving where it can be given in the first hour; availability in peripheral facilities should be confirmed and stocked with emergency drugs.

Monitoring. Blood pressure, bleeding, signs of thrombosis, renal function, urinary output in haematuria, visual symptoms with prolonged oral use, and seizure risk with high doses.

Referral and escalation. Ongoing haemorrhage (urgent surgical or obstetric control, blood products); thrombosis; seizure; wrong-route injection (emergency resuscitation and intensive care).

Comparison with alternative classes. Antifibrinolytics are cheap, widely available and effective in early bleeding, but do not replace surgical control, blood products or factor replacement. Hormonal therapy and levonorgestrel intrauterine systems are alternatives for heavy menstrual bleeding.