Concerns regarding the safety of transfused blood have led to the development of a range of interventions to minimise blood loss during major surgery. Anti-fibrinolytic drugs are widely used, particularly in cardiac surgery, and previous reviews have found them to be effective in reducing blood loss, the need for transfusion, and the need for re-operation due to continued or recurrent bleeding. Three formulas of anti-fibrinolytic drugs are in use: aprotinin, tranexamic acid (TXA) and epsilon aminocaproic acid (EACA). TXA is about eight times more active than its analogue EACA. Aprotinin has proven to be effective in reducing blood transfusions in cardiac surgery, but there are some concerns about its side effects and was withdrawed by the FDA in 2008 . Therefore the most studied anti-fibrinolytic drug for a variety of surgical and medical indications has been TXA. TXA is a synthetic lysine analogue antifibrinolytic agent. It is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin, by binding to specific sites of both plasminogen and plasmin, a molecule responsible for the degradation of fibrin. TXA has been in clinical use for many years and has important health and economic implications in high, middle, and low income countries. TXA has been available for more than 20 years and was first approved by the US Food and Drug Administration (FDA) in 1986 for short-term use (2 to 8 days) as an injection to reduce or prevent bleeding during tooth extraction in haemophilia patients.
TXA can be used topical (gauze saturated with TXA) or systemic in oral surgery [15,16]. Whether topical is as effective (or even better) as systemic use of TXA has to be proven.
Surgery of urinary tracts leads to increasing urokinase challenging hemostasis. A recent meta-analysis investigated the effect of lysine analogues in pelvic surgery including urinary tract surgery (next to gynaecologic procedures) . The study showed a significant reduction of blood loss and blood transfusion during pelvic surgery. More data will be required to definitively assess adverse events.
During liver surgery hyperfibrinolysis may exist either due to underlying disease or due to the operation itself for which TXA can be administered. However in end-stage liver disease there is increasing evidence of a prothrombotic tendency , warranting care with the administration of TXA.
Most studies with regard to TXA have been done in total hip and total knee replacement and spinal surgery. Two meta-analyses have been conducted with regard to TXA in total hip replacement [7,8]. They both showed a statistically significant reduction in intraoperative, postoperative, and total blood loss as well as a significant reduction in allogeneic blood transfusion requirements in the TXA group compared to the control group. A few meta-analysis of use of TXA in unilateral knee replacement have been published recently [9-11]. The use of TXA significantly reduced postoperative drainage, total blood loss, and blood transfusion requirements. VTE as an adverse event of TXA use was addressed both in total hip and knee replacement, but could not be commented upon due to the design of the investigated studies. Furthermore there are discussions whether TXA should be used intravenously, topically or both . A recent meta-analysis of 9 controlled studies of use of TXA in spinal surgery showed reduced blood loss and less transfusion when TXA was used; the studies were not powered to evaluate safety .
Although there is insufficient evidence from large randomized controlled trials , for patients with haemophilia, Von Willebrand disease and Glanzmann thrombasthenia TXA is often (topically or systematically) administered with positive effects.
In trauma patients the effect of TXA was studied in the CRASH-2 trial (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage). All-cause mortality was significantly reduced with TXA (14.5 vs. 16.0%), and the risk of death due to bleeding was also significantly reduced . It should be noted that the study was mostly conducted in non-high income countries. A recent Cochrane analysis showed that TXA safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events . The ongoing CRASH-3 study which is conducted in patients with isolated traumatic brain injury should resolve remaining uncertainties with regard to effect of TXA in those patients . For non-traumatic subarachnoidal bleeding (SAB) the Dutch ULTRA study will assess whether there is effect of adding TXA to standard care of SAB (to prevent recurrent bleeding from the aneurysm) with regard to functional outcome .
Many studies with TXA have been conducted in cardiopulmonary bypass operations. The optimum dose of TXA has been discussed widely, with regard to anti-fibrinolytic effectivity, prevention of blood loss and side effects (especially convulsive seizures) . During a consensus meeting it was recommended not to exceed a maximum TXA total dose of 100 mg/kg in patients over 50 years of age undergoing pump surgery in open heart procedures . Recent studies have again addressed this issue [4,5]. For children undergoing cardiac surgery calculations of TXA doses have been studied as well .
Tranexamic acid has been recommended for mildly and moderately bleeding patients on DOACs (in addition to local management of bleeding site and withdrawal of drug), although evidence of its effect is low .
The use of TXA has been studied in pregnant women both in post partum haemorrhage and elective caesarian section. A recent meta-analysis on treatments for primary post-partum haemorrhage recommended further studies to assess the effect of TXA . Currently, this is studied in the WOMAN trial (World Maternal Antifibrinolytic Trial), which results are expected soon . A positive effect of TXA on blood loss in elective caesarian section has been shown in a recent study . For menstruating women TXA can reduce menstrual blood loss and quality of life , as well as for women with a congenital bleeding disorder . As for benign and oncological surgery meta-analysis show (some) advantage of TXA use .
Tranexamic acid (Cyklokapron ®)
- Intravenous Solution 100mg/ml, ampul (vial) 5 ml
- Topical Solution 50 mg/ml
- Oral Tablet 500 mg (it can be divided into two)
The effect of tranexamic acid on thromboembolic events and mortality remains uncertain.
- Patients with or at elevated risk for thrombosis
- Fibrinolytic conditions following consumption coagulopathy
- History of convulsion
- Renal failure (dose adjustment)
- Pregnancy (only use at strict conditions)
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