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Tranexamic acid is a synthetic derivative of the amino acid lysine that exerts its antifibrinolytic effect through the reversible blockade of lysine binding sites on plasminogen molecules.
Intravenously administered tranexamic acid (most commonly 10 mg/kg followed by infusion of 1 mg/kg/hour) caused reductions relative to placebo of 29 to 54% in postoperative blood losses in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), with statistically significant reductions in transfusion requirements in some studies. Tranexamic acid had similar efficacy to aprotinin 2 × 106 kallikrein inhibitory units (KIU) and was superior to dipyridamole in the reduction of postoperative blood losses. Transfusion requirements were reduced significantly by 43% with tranexamic acid and by 60% with aprotinin in 1 study. Meta-analysis of 60 trials showed tranexamic acid and aprotinin, unlike ε-aminocaproic acid (EACA) and desmopressin, to reduce significantly the number of patients requiring allogeneic blood transfusions after cardiac surgery with CPB.
Tranexamic acid was associated with reductions relative to placebo in mortality of 5 to 54% in patients with upper gastrointestinal bleeding. Meta-analysis indicated a reduction of 40%.
Reductions of 34 to 57.9% versus placebo or control in mean menstrual blood loss occurred during tranexamic acid therapy in women with menorrhagia; the drug has also been used to good effect in placental bleeding, postpartum haemorrhage and conisation of the cervix. Tranexamic acid significantly reduced mean blood losses after oral surgery in patients with haemophilia and was effective as a mouthwash in dental patients receiving oral anticoagulants.
Reductions in blood loss were also obtained with the use of the drug in patients undergoing orthotopic liver transplantation or transurethral prostatic surgery, and rates of rebleeding were reduced in patients with traumatic hyphaema. Clinical benefit has also been reported with tranexamic acid in patients with hereditary angioneurotic oedema.
Tranexamic acid is well tolerated; nausea and diarrhoea are the most common adverse events. Increased risk of thrombosis with the drug has not been demonstrated in clinical trials.
Conclusions: Tranexamic acid is useful in a wide range of haemorrhagic conditions. The drug reduces postoperative blood losses and transfusion requirements in a number of types of surgery, with potential cost and tolerability advantagesover aprotinin, and appears to reduce rates of mortality and urgent surgery in patients with upper gastrointestinal haemorrhage. Tranexamic acid reduces menstrual blood loss and is a possible alternative to surgery in menorrhagia, and has been used successfully to control bleeding in pregnancy.
Tranexamic acid exerts its antifibrinolytic effect by blocking lysine binding sites on plasminogen molecules and thereby inhibiting the interaction of plasminogen and the heavy chain of plasmin with lysine residues on the surface of fibrin. Although plasmin can still be formed under these circumstances, it is unable to bind to and degrade fibrin.
Tranexamic acid is 6 to 10 times more potent in terms of binding to plasminogen/plasmin than the other synthetic antifibrinolytic agent ε-aminocaproic acid (EACA). Suppression of fibrinolysis by tranexamic acid is manifested in surgical patients by reductions in blood levels of D-dimer, but the drug has no effect on blood coagulation parameters. Concurrent administration of heparin does not influence the activity of tranexamic acid.
Maximum plasma concentrations of tranexamic acid are attained within 3 hours of an oral dose; the presence of food in the gastrointestinal tract has no effect on the pharmacokinetic parameters of the drug. Elimination after intravenous administration is triexponential, and over 95% of each dose is eliminated as unchanged drug in the urine. The total cumulative excretion after an intravenous dose is approximately 90% after 24 hours.
Of the total amount of circulating tranexamic acid, 3% is bound to plasminogen. The drug crosses the blood-brain barrier and the placenta, but excretion into breast milk is minimal. Tranexamic acid is not detectable in saliva after systemic (oral) administration, and mouthwashing with 5% w/v aqueous solutions of the drug results in plasma drug concentrations below 2 mg/L.
Cardiac Surgery. Perioperative treatment with tranexamic acid (most commonly as an intravenous loading dose of 10 mg/kg followed by an infusion of 1 mg/kg/hour) resulted in significant reductions in postoperative blood losses (mostly measured over 12 to 24 hours) in randomised, double-blind comparisons with placebo in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Losses via mediastinal drains were reduced by 29 to 54% relative to placebo, and statistically significant reductions in red blood cell transfusion requirements were reported in some but not all studies. Inconsistency in results with respect to reduction or elimination of transfusions may have been caused in part by variation between institutions in transfusion criteria.
The protease inhibitor aprotinin has been the most frequently used comparator in randomised but nonblind studies of tranexamic acid in patients undergoing cardiac surgery with CPB. Postoperative blood losses (over 6 hours) were reduced to a similar extent by tranexamic acid 10 mg/kg intravenously followed by infusion of 1 mg/kg/hour and aprotinin 2 × 106 kallikrein inhibitory units (KIU) intravenously in 1 study, with both treatments being superior to dipyridamole. Similar effects on postoperative blood losses with the 2 drugs were reported in 2 further studies. Both agents significantly reduced postoperative transfusion requirements in one of these trials (by 43 and 60% with tranexamic acid and aprotinin, respectively; both p < 0.05 vs control group). Other studies have shown greater reductions in 24-hour blood losses with aprotinin or EACA than with tranexamic acid, but definitive conclusions cannot be drawn from these trials because of inconsistent transfusion data and small patient numbers.
A meta-analysis of 60 randomised clinical trials of haemostatic agents in cardiac surgery with CPB showed tranexamic acid to be associated with a significant decrease (relative to placebo or no treatment) in the proportion of patients requiring allogeneic blood transfusions. A similar effect was found with aprotinin but not with EACA or desmopressin.
Acute Upper Gastrointestinal Bleeding. Reduction of blood transfusion requirements with tranexamic acid therapy in patients with upper gastrointestinal bleeding was first described in 1973. In randomised double-blind studies, predominantly in patients with peptic ulceration or erosion, reductions relative to placebo in mortality rates have ranged from 5 to 54% with tranexamic acid (4.5 to 6g daily for 5 to 7 days in most studies); statistical significance between tranexamic acid and placebo was obtained in the largest published trial.
Meta-analysis of studies of tranexamic acid in patients with upper gastrointestinal haemorrhage showed the drug to be associated with reductions relative to placebo of 20 to 30% in rates of rebleeding, 30 to 40% in the need for surgery and 40% in mortality rates.
Oral Surgery. Proportions of patients with postoperative bleeding complications ranged from 0 to 6.7% when mouthwashes of tranexamic acid were used after oral surgery in patients receiving oral anticoagulant therapy. The corresponding range in patients who received placebo was 13.3 to 40%. In patients with haemophilia, 5 days’ treatment with tranexamic acid 1g 3 times daily orally resulted in a mean blood loss after oral surgery of 61.2ml, compared with an 84.1ml loss with placebo, and reduced consumption of clotting factors (14.3 vs 78.6% of patients).
Other Surgery. Substantial and statistically significant reductions relative to placebo in mean postoperative blood losses (57 and 65.9%) were reported in 2 trials after perioperative tranexamic acid therapy in patients undergoing total knee arthroplasty, with significant reductions in transfusion requirements. Clinical benefit relative to placebo was obtained after intravenous infusion of tranexamic acid 40 mg/kg/hour in 1 study in patients undergoing orthotopic liver transplantation, with no episodes of hepatic artery or portal vein thrombosis occurring within 1 month of surgery.
Four-week incidences of haemorrhage after transurethral prostatic surgery in a randomised study in 100 men were 24% after treatment with tranexamic acid (1g 3 times daily orally) and 56% in patients who received no antifibrinolytic therapy.
Gynaecology. Reductions of 34 to 57.9% versus placebo or control in mean menstrual blood loss were reported in women with menorrhagia receiving 2 to 3 cycles of treatment with tranexamic acid. The drug was at least as effective as nonsteroidal anti-inflammatory therapy and more effective than etamsylate (ethamsylate) or norethisterone. Efficacy of tranexamic acid in the control of bleeding has also been reported in individual patients with placental abruption or postpartum haemorrhage. A mean 71% reduction in postoperative blood loss was noted in a double-blind study in patients who received tranexamic acid 1.5g daily orally for 12 days after conisation of the cervix. In another double-blind study, 1 of 38 patients who received tranexamic acid and 4 of 37 who received placebo experienced late bleeding after cervical conisation with suturing; the difference between groups was not statistically significant.
Other Indications. An oral dosage of tranexamic acid lg 3 times daily significantly reduced the frequency of secondary ocular haemorrhage after traumatic hyphaema in controlled trials; further data from a case series of 340 children showed rates of rebleeding of 1.1% and 9.6% in patients who received tranexamic acid and no antifibrinolytic therapy, respectively.
Reductions versus placebo in number and severity of attacks of oedema in patients with hereditary angioneurotic oedema were reported in 2 randomised, double-blind studies of tranexamic acid, and clinical benefit was obtained with the drug (1.5g orally 3 times daily) in 6 of 7 patients described in a case series.
There was a significant reduction (from 24% with placebo to 9% with tranexamic acid therapy for up to 4 weeks) in the rate of rebleeding in a randomised double blind placebo-controlled study in 479 patients with subarachnoid haemorrhage. However, overall outcome was not improved with tranexamic acid after 3 months; this was attributed to an increase in incidence of cerebral ischaemia.
Tranexamic acid is well tolerated. Adverse events are uncommon and usually manifest as nausea or diarrhoea, or occasionally as orthostatic reactions. Results of controlled clinical studies have not confirmed concerns over the possibility of an increased thrombotic tendency in patients treated with inhibitors of fibrinolysis. No increases in incidence of thrombotic events were reported with tranexamic acid in studies of patients undergoing cardiac surgery with CPB or in a retrospective case analysis of 256 women with bleeding disorders in pregnancy. No muta-genic activity or harmful fetal effects of tranexamic acid have been reported.
Retinal changes seen in dogs after very high dosages of tranexamic acid for 1 year have not been reported in humans receiving the drug at therapeutic dosages. However, disturbances in colour vision have been documented, and patients who develop this symptom should discontinue therapy.
Dosage and Administration
Tranexamic acid is presented in a variety of formulations for oral (tablets and syrup) or intravenous use. A dosage of 500mg to 1g by slow intravenous injection 3 times daily or 1 to 1.5g 2 to 3 times daily orally is recommended for local fibrinolysis. For general fibrinolysis, a single dose of 1g or 10 mg/kg by slow intravenous injection is recommended.
Patients undergoing cardiac surgery have most commonly received tranexamic acid intravenously as a 10 mg/kg dose before CPB and an infusion of 1 mg/kg/hour thereafter. A daily dosage of 4.5 to 6g daily (divided into 3 to 6 doses) for 5 to 7 days (intravenous followed by oral therapy) has been used most frequently in patients with upper gastrointestinal bleeding.
Patients with haemophilia who are about to undergo oral surgery require 1 to 1.5g orally every 8 hours, and a 4.8 to 5% mouthwash, used for 2 minutes 4 times daily for 7 days, has shown good efficacy in dental patients receiving anticoagulant therapy.
Intravenous infusion of 10 mg/kg before release of tourniquet may be used in patients undergoing knee arthroplasty, and treatment with oral tranexamic acid 6 to 12g daily for 4 days has been used in patients undergoing transurethral prostate surgery. Intravenous infusion of 40 mg/kg/hour has been used to good effect in patients undergoing orthotopic liver transplantation.
Women with menorrhagia should receive tranexamic acid 1 to 1.5g 3 to 4 times daily orally for 3 to 4 days. Dosages of 1.5g or 1 to 1.5g orally 3 times daily are recommended for conisation of the cervix or traumatic hyphaema, respectively, and oral treatment with 1.5g 3 times daily is recommended for the management of hereditary angioneurotic oedema.
Tranexamic acid is contraindicated in patients with a history of thromboembolic disease, and dosage reductions are recommended in patients with renal insufficiency.
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- Tranexamic Acid
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