Introduction
Hyperfibrinolysis
Pathophysiology
Disorders associated with HF
Diagnosis
Mode of action of tranexamic acid
Intravenous administration
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Prophylaxis and treatment of bleeding due to a local or systemic hyperfibrinolysis in adults and children over the age of 1 year |
Bleeding in which hyperfibrinolysis is considered to be involved:
Menorrhagia and metrorrhagia Gastrointestinal bleeding Bleeding in urinary tract infections, postoperative bleeding following prostate or urinary tract surgery |
Ears, nose and throat (ENT) surgery (adenoidectomy, tonsillectomy, dental extractions) |
Gynecological surgery or obstetric hemorrhage |
Abdominal and thoracic surgery and other major surgery, e. g. cardiac surgery |
As antidote in bleeding requiring immediate treatment while on fibrinolytic treatment |
Oral administration
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Hypermenorrhea (menorrhagia) |
Prostatectomy |
Epistaxis |
Conisation of the cervix |
Prophylaxis of recurrent bleeding in traumatic hyphema |
Dental extraction and other interventions in ENT area in patients with hereditary coagulopathies |
Mucosal bleeding in patients with coagulopathies |
Hereditary angioneurotic edema |
Gastrointestinal disturbances (nausea, vomiting, diarrhea) |
Drop of blood pressure/dizziness following a too fast intravenous administration |
Incidental allergic skin reactions |
Infrequent temporal vision impairment |
Convulsions |
Hypersensitivity to TXA |
Early pregnancy, in late pregnancy only when vitally indicated |
Disturbances of color vision |
Massive bleeding in the upper urinary tract (risk of ureter obstruction due to clot) |
Acute venous or arterial thrombosis |
Severe renal impairment |
History of convulsions |
Intrathecal and intraventricular injection, intracerebral administration (risk of cerebral edema and convulsions) |
Diseminated intravascular coagulation (DIC) without severe hemorrhage |
According to the SmPC the following dosage guidelines apply to adults [27]: |
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1. Oral administration (1 tablet = 0.5 g).
The recommended standard dose is 2–3 times daily 2–3 tablets (1–1.5 g), daily dosage 2–4.5 g |
2. Intravenous administration (1 ampoule = 5 ml = 0.5 g) in fibrinolysis:
The recommended standard dose is 2–3 times daily 0.5–1 g (1–2 ampoules à 5 ml) by slow intravenous injection (1 ml/min) |
3. Intravenous administration in general fibrinolysis:
The recommended standard dose is 1 g (2 ampoules à 5 ml) every 6–8 h by slow intravenous injection (1 ml/min), corresponding to 15 mg/kg body weight |
Tranexamic acid in acute hemorrhagic events
Trauma patients
Postpartum hemorrhage
Authors |
N
| Method | Results |
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Vaginal delivery
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Dulcoy-Bouthers et al. [40] | 144 | RCT, double-blind 4 g TXA + 1 g/h in 6 h = 10 g | Bleeding duration ↓ Progression to severe PPH (>800 ml) ↓ |
Yang et al. [41] | 400 | RCT (prospective, double-blind) 0.5 g vs 1.0 g TXA vs. PAMBA* | Total blood loss ↓ |
Gungorduk et al. [42] | 454 | RCT TXA 1.0 g vs. placebo | Blood loss ↓ Progression to severe PPH (>500 ml) ↓ |
Bouet et al. [43] | 289 | Retrospective single centre analysis of policy before and after use of high dose TXA 10 g | No difference in blood loss |
Cesarean delivery
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Goswami et al. [44] | 90 | RCT (prospective, double-blind) 10 mg/kg TXA in 20 min, then 10 vs. 15 mg/kg TXA vs placebo | Total blood loss in both TXA groups ↓ significantly less with 15 mg/kg |
Gai et al. [45] | 180 | RCT (multi centre, prospective, randomized controlled) 1 g TXA over 5 min, 10 min before CS vs not | Blood loss until 2 h after delivery ↓ |
Abdel Aleem et al. [46] | 740 | RCT (Single centre, open, controlled) 1 g TXA over 10 min, 10 min before CS vs. not | Blood loss until 2 h after delivery ↓ Hemoglobin decline ↓ |
Sekhavat et al. [47] | 90 | RCT (prospective, randomized, double-blind) 1 g TXA over 10 min, 10 min before CS vs. not | Blood loss until 2 h after delivery ↓ Hemoglobin decline ↓ |
Halder et al. [48] | 100 | Case-control study TXA before CS vs not | Blood loss until 2 days postpartum ↓ Hemoglobin decline ↓ |
Movafegh et al. [49] | 100 | RCT (prospective, double-blind, randomized, controlled) 10 mg/kg TXA vs placebo | Blood loss until 2 h postpartum ↓ Hemoglobin decline ↓ |
Sentürk et al. [50] | 223 | RCT (prospective, double-blind, placebo controlled) 10 mg/kg for 5 min, 10 min before CS vs placebo | Intra- and postoperative blood loss ↓ |
Xu et al. [51] | 174 | Randomized case-control study 10 mg/kg TXA before CS or not | Blood loss until 2 h postpartum ↓ Progression to PPH ↓ |
Gohel et al. [52] | 100 | Randomized, prospective case-control study 1 g TXA over 5 min | Blood loss until 2 h postpartum ↓ |
Shahid et al. [53] | 74 | RCT (prospective, randomized, double-blind) 1 g TXA | Intraoperative blood loss ↓ |
Gungorduk et al. [54] | 660 | RCT (prospective, double-blind, placebo controlled) 1 g TXA | Intraoperative blood loss ↓ |
Accordingly, the European Society of Anaesthesiology (ESA) recommends administration of TXA in the case of peripartum and postpartum hemorrhage in order to reduce the extent of blood loss, the duration of bleeding and the need for allogeneic blood products (1B) [3]. Moreover, there is a 2C recommendation for the administration of TXA prior to cesarean section. In the case of antepartum hemorrhage TXA administration may be taken into consideration (2B) [3].An international interdisciplinary expert consensus recommends for the treatment of postpartum hemorrhage the administration of 2 g TXA i. v. prior to supplementing fibrinogen, with dosages ranging from 1 to 3 g [58].
Menometrorrhagia
The recommended dose is 2–3 tablets TXA (1–1.5 g) 3–4 times a day for 3–4 days (starting immediately after onset of heavy bleeding). In the case of excessive bleeding the dose may be increased but should not exceed a maximum daily dose of 4 g [27].
Mucocutaneous bleeding with coagulopathies
Gastrointestinal bleeding
Tranexamic acid in elective applications
Orthopedic surgery
The ESA recommends the use of TXA in the case of total hip endoprostheses (TEP), knee joint replacement and major spinal surgery (2A) [3]. It should be pointed out, however, that TXA may cause hypercoagulability in some patient groups (pre-existing thromboembolic events, hip fracture/cancer surgery, age > 60 years, women). It is therefore recommended to perform an individual risk-benefit analysis rather than administer TXA routinely (2A).
Cardiovascular surgery/coronary artery bypass graft (CAGB) interventions
The ESA guidelines recommend the use of TXA prior to CABG interventions (1A); likewise, intraoperative administration of TXA should be considered in order to reduce perioperative bleeding in the course of high, medium and low-risk cardiovascular surgery (1A). Also, topical (see footnote 3) application of TXA in the thoracic cavity is recommended to reduce postoperative blood loss after CABG (1C).
TXA dosages in cardiac surgery with cardio-pulmonary bypass (CPB) currently relate mostly to those used in the BART Study [9]: TXA bolus 30 mg/kg BW prior to CPB, followed by continuous infusion with 16 mg/kg BW/h up to the end of the operation [9]. It should be noted that open heart surgery in particular carries a higher risk of seizures caused by even moderate doses of TXA (24 mg/kg BW/day) [84].
Liver surgery
Orthotopic liver transplantation
Treatment of hyperfibrinolysis (confirmed by the presence of microvascular blood oozing and/or thrombelastography or rotation thromboelastometry, TEG/ROTEM measurement) with antifibrinolytics is recommended; lowest effective doses are uncertain, TXA being currently administered in gradually increasing dosages of 1–2 g [3].
Liver resection
According to ESA recommendations [3] antifibrinolytic therapy should be considered in patients with cirrhosis of the liver and liver resection (2C).
Prostate surgery
After initial intravenous therapy during the first three postoperative days, 2–3 tablets (1–1.5 g) may be given twice or three times daily for 7 days or until hematuria can no longer be detected macroscopically [27].
Conisation and gynecologic oncologic surgery
Pediatrics and pediatric surgery
Excessive fibrinolysis (e. g. liver transplantation, medication induced) |
Adjuvant as hemostatic agent, in hemophilia and von Willebrand disease (e. g. dentistry, not in renal bleeding!) |
Mucosal bleeding (topicala, oral, intravenous), exception: bleeding of the upper urinary tract |
PAI 1 deficiency, α2-plasmin inhibitor deficiency, hereditary telangiectasia |
Adjuvant in:
acquired thrombocytopenia cardiac surgery bypass surgery |
Perioperative antifibrinolytic therapy to reduce blood loss and transfusion needs is proposed for both heart surgery and non-cardiac surgical interventions (2A) [3].
Children and adolescents | Bolus | Maintenance dose from day 0 | |
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<50 kg | Oral | 15–25 mg/kg on preceding evening or 1.5–2× dosage on day of surgery | 15–25 mg/kg 3–4× daily |
Intravenous | 10–15 mg/kg on day of surgery | 10–15 mg/kg 3× daily | |
≥50 kg | Oral | 1.0–1.5 g on preceding evening or 1.5–2× dosage on day of surgery | 1.0–1.5 g 3–4× daily |
Intravenous | 0.5–1.0 g on day of surgery | 0.5–1.0 g 3× daily |
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oral: 15–25 mg/kg BW up to a maximum of 1.5 g 2–3× daily
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i. v.: For currently approved indications for children from the first year of life onwards 20 mg/kg BW/day; for these indications, only limited data on efficacy, dosages and safety are so far available.
Epistaxis and tonsillectomy
In the case of epistaxis TXA is at first applied topically to the nasal mucosa (moistened strip of gauze) by tamponading the nose cavum; if recurrent bleeding is expected the patient should be given 2 tablets (1 g) 3 times a day for 4–10 days before the tamponade is removed. In patients with a body weight less than 30–50 kg pediatric dose recommendations should be strictly adhered to.
Neurosurgical interventions and subarachnoid hemorrhage
The joint guidelines of the Austrian Neurological Society (Österreichische Gesellschaft für Neurologie, ÖGN) and the German Neurological Society (Deutsche Gesellschaft für Neurologie, DGN) published in 2008 explicitly do not recommend a prophylactic administration of antifibrinolytics for SAH (↓↓) [117], a position that was repeated in the updated version of 2012 [118].
TXA not recommended by the authors
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Renal failure
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Epilepsy
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Benign gynecological interventions (e. g. myomectomy)
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In combination with activated factor concentrate (FEIBA, factor VIII inhibitor bypass activity; 1 ml = 25 E* factor VIII inhibitor bypass activity; see footnote 3)
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Fibrinolysis due to disseminated intravascular coagulation without any significant bleeding
Summary
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In some fields of application there is a need to define the optimum TXA dosage, since, side by side with the dose recommendations found in current summaries of product characteristics (SPC), both clinical studies and the practice of centres with considerable experience have in the meantime provided evidence that numerous other regimes, such as half doses, administration of a bolus, administration twice, preoperatively and postoperatively, seem to be equally effective.
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As to the risk of thromboembolic complications findings are still partly contradictory, and it is not yet clear which patients are at risk at all and which of them run the highest risk.
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This is also true of seizures observed with higher TXA doses and in the course of cardiac surgery.
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It would be highly desirable to develop better and more sensitive diagnostic methods to differentiate more easily between hyperfibrinolytic conditions and other coagulopathies or DIC. Likewise, suitable tests ought to be developed to identify more precisely patients that might be treated with TXA and those likely not to benefit from such treatment.