In a Review published in the March 2007 issue of the journal, Hedges and colleagues described the existing options to prevent or treat uremic bleeding. Their article did not include tranexamic acid. Use of this anti-fibrinolytic drug to manage uremic bleeding has a solid pathophysiological basis. The bleeding disorder of chronic renal failure (CRF) has been classically defined as an acquired defect of primary hemostasis, and alterations in almost every component of this system have been reported. Prolongation of bleeding time is characteristic of the defect.1
The protracted, chronic, mild systemic inflammation of uremia is associated with activation of the clotting system and, more significantly, with activation of fibrinolysis.2 The generation of increased amounts of thrombin and plasmin might have a pathogenic role in the defect of platelet function.1 We reasoned that inhibition of hemostatic activation could improve formation of platelet plugs. Adjusted doses of low-molecular-weight heparin and tranexamic acid were simultaneously administered to patients with advanced CRF and prolonged bleeding time before entry to dialysis and/or transplantation programs. Preliminary analysis of the results indicated that the observed shortening of bleeding time was associated with improvement of fibrinolytic—but not of clotting—activation markers. As such, the study was continued with administration of tranexamic acid alone. The bleeding times of 25 of 37 (68%) patients with plasma creatinine of 760.2 ± 398.0 µmol/l (8.6 ± 4.4 mg/dl) improved or normalized after 6 days of tranexamic acid (20–25 mg/kg/day).3 The study was designed to allow the megakaryocyte release of new platelets not damaged by exposure to a milieu with hemostatic activation. Correction of bleeding time was associated with improved platelet aggregation/secretion, normalization of fibrin/fibrinogen degradation products, increased numbers of plasmin–antiplasmin complexes, and reduced levels of circulating plasminogen. In a subsequent study we found that improvement of bleeding time occurred as soon as 24–48 hours after intake of tranexamic acid,4 indicating some functional recovery of circulating platelets once activation of fibrinolysis was controlled. One patient suffered nausea and vomiting possibly induced by tranexamic acid, but no other adverse effects (including thrombotic events) were observed. The lack of response in around one-third of patients indicates that other mechanisms might also be involved in the hemostatic defect.
A series of studies, including case reports, pilot and case-control studies, by Sabovic, Vujkovac and colleagues5,6,7,8,9 showed clinical and/or laboratory responses to tranexamic acid in CRF patients with bleeding resulting from a diverse range of causes, including polycystic kidney disease, major bleeding of the upper gastrointestinal tract, colonic angiodysplasia and subdural hematoma.
Considering all available evidence, the response to tranexamic acid in patients with CRF seems to be better than the response to the more commonly used approaches described by Hedges et al. Tranexamic acid exerts its effect more rapidly than estrogens and erythropoietin, is safer than cryoprecipitates, and at least as effective as desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) for improvement of bleeding time.10,11 The end point assessed during most of the studies reviewed by Hedges et al., as well as during our own studies, is the effect of treatment on bleeding time. From a clinical stand-point, however, this end point has very limited value as a predictor of bleeding in, for example, patients undergoing renal biopsy.12 As such, the different treatment options for uremic bleeding should be tested further in controlled and comparative studies in a clinical setting to determine their true efficacy. Failure of one treatment can be resolved by adding another to the regimen; each has a different 'target' and no adverse effects associated with combined use have been reported. We have used tranexamic acid and DDAVP concomitantly to prevent and treat bleeding in patients with CRF, and more frequently in patients with hereditary disorders of primary hemostasis, with no adverse effects.
Applying the evidence-based criteria used by Hedges et al. (see below for definitions), we believe the 'strength of recommendation' for tranexamic acid as first-line therapy to be Class I, the same as that proposed for DDAVP. We disagree with Hedges et al. that the 'strength of evidence' category for DDAVP should be Category A. We believe that the 'strength of evidence' category for both DDAVP and tranexamic acid is Category B.
Strength of Recommendation, Class I—recommended; the given test or treatment is useful and should be performed or administered.
Strength of Evidence, Category A—evidence based on: meta-analyses of randomized controlled trials with homogeneity with regard to the direction and degree of results between individual studies; at least three well-executed randomized controlled trials involving large numbers of patients from more than one center (often includes data from an international population).
Strength of Evidence, Category B—evidence based on: few (1 or 2) well-executed randomized controlled trials involving large numbers of patients; meta-analyses of randomized controlled trials with conflicting conclusions with regard to the direction and degree of results between individual studies; randomized controlled trials involving small numbers of patients OR with significant methodological flaws (e.g. bias, high drop-out rate, flawed analysis); nonrandomized studies (e.g. cohort, case-control, observational).
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The authors declare no competing financial interests.
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Downey, P., Tagle, R., Pereira, J. et al. Tranexamic acid and uremic bleeding: evidence-based treatment recommendations. Nat Rev Nephrol 3, E2 (2007). https://doi.org/10.1038/ncpneph0528