Antifibrinolytic Drugs

Antifibrinolytic drugs stabilise clots by blocking the breakdown of fibrin by plasmin. Given early, they reduce bleeding and death in trauma and postpartum haemorrhage, reduce blood loss in surgery, and treat heavy menstrual bleeding and mucosal bleeding in bleeding disorders. They do not replace surgical control, blood products or correction of coagulopathy.

Members. Tranexamic acid and aminocaproic acid (synthetic lysine analogues). Aprotinin, a serine protease inhibitor, is restricted or withdrawn in most regions because of kidney and mortality concerns.

Mechanism. Lysine analogues bind the lysine binding sites of plasminogen, preventing its attachment to fibrin and its conversion to plasmin. At high concentrations they also inhibit plasmin directly. Tranexamic acid is about 10 times more potent than aminocaproic acid.

Pharmacokinetics. Tranexamic acid has oral bioavailability of about 35%, a half-life of about 2 hours and renal clearance (95% unchanged), so accumulation occurs in renal impairment. Aminocaproic acid has a half-life of about 2 hours and renal clearance.

• Tranexamic acid: oral, intravenous and topical forms; the main drug in use worldwide; supported by evidence in trauma and postpartum haemorrhage.
• Aminocaproic acid: oral and intravenous; used where tranexamic acid is unavailable.
• Aprotinin: cardiac surgery only, in specialist units where available.

• Major trauma with significant bleeding: tranexamic acid 1 g intravenously over 10 minutes, then 1 g infused over 8 hours, started within 3 hours of injury (best within the first hour). Later treatment can increase risk.
• Postpartum haemorrhage: tranexamic acid 1 g intravenously over 10 minutes within 3 hours of birth, together with uterotonics, repeated once after 30 minutes if bleeding continues.
• Heavy menstrual bleeding: tranexamic acid 1 g orally three times daily for up to 4 days from the start of bleeding.
• Surgery with high blood loss (cardiac, orthopaedic, spinal, liver): tranexamic acid 10 to 15 mg/kg intravenously before incision, with a repeat dose or infusion if the operation is long. Lower dose regimens limit seizure risk in cardiac surgery.
• Dental extraction in haemophilia or anticoagulated patients: tranexamic acid 5% mouthwash 10 mL four times daily for 2 to 5 days, or 15 to 25 mg/kg orally two to three times daily.
• Epistaxis and haematuria in bleeding disorders: oral or topical tranexamic acid.
• Upper gastrointestinal bleeding: not recommended, because of thrombosis risk without clear benefit.
• Aminocaproic acid: 4 to 5 g intravenously or orally over the first hour, then 1 g/hour until bleeding is controlled (maximum 30 g daily).
• Selection: use as early as possible in bleeding where fibrinolysis contributes, and combine with surgical, obstetric and transfusion measures.

Contraindications. Active thromboembolic disease (deep vein thrombosis, pulmonary embolism, arterial thrombosis), disseminated intravascular coagulation with thrombosis, subarachnoid haemorrhage (relative, because of cerebral ischaemia and oedema), and haematuria from the upper urinary tract (clot retention risk), and hypersensitivity.

Adverse effects. Nausea, vomiting and diarrhoea, dizziness, visual disturbance, thrombosis (small risk, higher in those with risk factors), hypotension with rapid injection, and seizures with high doses, especially in cardiac surgery and kidney failure. Aminocaproic acid adds myopathy and rhabdomyolysis.

Interactions. Combined oral contraceptives and other prothrombotic drugs raise thrombosis risk. Procoagulant concentrates (prothrombin complex concentrate, fibrinogen concentrate, factor VIIa) add thrombosis risk. Thrombolytic drugs are opposed. Tretinoin raises thrombosis risk.

Monitoring. Bleeding, signs of thrombosis, visual symptoms, kidney function, and blood pressure during injection. Inject slowly (no faster than 100 mg/minute).

Referral and escalation. Bleeding that continues after tranexamic acid needs surgical, obstetric or haematology input. Chest pain, dyspnoea or limb swelling needs urgent assessment for thrombosis.

Special groups. Renal impairment: reduce the dose (serum creatinine 120 to 250 micromol/L: 15 mg/kg twice daily, 250 to 500: 15 mg/kg daily, over 500: 7.5 mg/kg daily). Pregnancy: used in postpartum haemorrhage. Breastfeeding: small amounts enter milk, generally acceptable. Children: weight-based dosing. Older adults: renal function check.