Prophylaxis with low dose tranexamic acid in acute myeloid leukemia patients undergoing intensive chemotherapy

Abstract Patients suffering from acute myeloid leukemia (AML) carry a high risk of serious bleeding complications due to severe thrombocytopenia for long periods of time during treatment. Prior to prophylactic platelet transfusion becoming the standard of care, intracranial bleeding was a major contributor to death in AML patients. However, despite prophylactic platelet transfusions, up to 79% of patients with AML experience clinically significant bleeding during treatment. Antifibrinolytics are effective and well tolerated hemostatic agents widely used in many patient groups, and in this study, we investigated the effect of low dose tranexamic acid (TXA) in patients with AML and thrombocytopenia. We compared bleeding and thrombosis between 113 thrombocytopenic AML patients receiving TXA 500 mg three times daily (n = 36) versus no‐TXA (n = 77). Clinical information was obtained systematically from electronic medical records, and laboratory data were collected from the laboratory information system. No difference was demonstrated in number of patients with at least one bleeding episode (TXA: 89% vs. no‐TXA: 93%, p = 0.60), median number of bleeding days (TXA: 2.5 days vs. no‐TXA 2.0 days, p = 0.30), bleeding location or transfusion needs between the two groups. However, platelet count was found to be a significant risk factor for bleeding, with a probability of bleeding of 35% with a platelet count below 5 × 109/L (logistic regression, p < 0.01). We found no difference in thromboembolic events between the two groups (TXA: 8% vs. no‐TXA 10%, p = 0.99). In conclusion, treatment with low dose TXA is safe, but we found no evidence to suggest that it reduces bleeding in AML patients with thrombocytopenia.


INTRODUCTION
Acute myeloid leukemia (AML) is an aggressive cancer developed from hematopoietic stem cells in the bone marrow. Uncontrolled proliferation of immature blasts results in bone marrow failure and subsequent anemia and increased risk of bleeding and infections. Curative treatment of AML includes a series of intensive chemotherapy courses, each leading to severe thrombocytopenia for 2-3 weeks during which, regular platelet transfusions are mandatory to prevent fatal bleeding [1][2][3][4]. Prophylactic platelet transfusions at platelet counts below 10-20 × 10 9 /L are recommended and have reduced but not eliminated the risk of bleeding [2,4,5]. Antifibrinolytics such as tranexamic acid (TXA) has been used to reduce bleeding in a number of different patient groups. They are safe and have been proven effective in reducing bleeding in patients undergoing oral surgery and in women with menorrhagia [6][7][8]. TXA has also been shown to reduce the need for red blood cell (RBC) transfusions in patients undergoing abdominal surgery [9,10] and in a study on AML patients by Ben-Bassat et al. TXA reduced the need for platelet transfusions [11]. However, this study did not include a control group or the use of prophylactic platelet transfusions.
Recently, Estcourt et al. reviewed randomized trials regarding the use of antifibrinolytic agents in AML patients [12]. The review concluded that the available evidence was not sufficient to recommend routine use of antifibrinolytics as bleeding prophylaxis in AML patients. Thus, knowledge on efficacy and safety of the use of prophylactic TXA in AML patients with thrombocytopenia is sparse.

METHODS
We conducted a retrospective cohort study of AML patients treated at In some patients at both hospitals TXA was used at higher doses (1000-1500 mg three to four times daily) to treat ongoing bleeding.
However, as we wanted to examine the prophylactic effect of low dose TXA (i.e., 500 mg three times per day), data on days where patients received higher doses than 500 mg three times daily were excluded from the analysis.
We collected baseline data at diagnosis including risk factors of bleeding and thrombosis, blood type.
Clinical information, transfusion records, and diagnostic imaging were available in electronic patient records for all patients. Laboratory data were collected from the laboratory information system

RESULTS
We identified 113 patients and collected data on 2696 days, where patients were dependent on platelet transfusions to keep the platelet count above 10-20 × 10 9 /L. Of the 113 patients, 36 (32%) patients received prophylactic TXA at a dose of 500 mg three times per day (the TXA-group) whereas 77 (68%) patients did not receive TXA (the no-TXA-group). On 210 days the TXA dose was higher than 500 mg three times daily, and data from these days were excluded from analysis. No difference was observed regarding demographic or clinical characteristics between the two groups (Table 1). There was no difference in the platelet count on days where patients received platelet transfusions (10 × 10 9 /L vs. 11 × 10 9 /L, p = 0.08).
As shown in Table 1 In order to analyze the association between platelet count and bleeding we grouped platelet counts in four groups (<5, 5-10, 10-15, and >15 × 10 9 /L) and analyzed the association as described in the statistical analysis section. The probability of bleeding in the <5 × 10 9 /L group was 0.35, p < 0.01. If skin bleeding was excluded the risk of bleeding in the <5 × 10 9 /L was 0.22, p < 0.001. As shown in Figure 1, the odds-ratio of bleeding is significantly reduced with rising platelet count. We compared the <5 group with the rest using a Wald-test yielding a p-value ≤ 0.001, showing a significant difference in bleeding risk between platelet count <5 and the other groups.

DISCUSSION
This is the first study to evaluate the benefit of prophylactic TXA in AML patients with severe thrombocytopenia, whom received prophylactic platelet transfusion in concordance with current guidelines [4].
We demonstrated this low dose TXA to be safe, but it offered no reduction in clinically significant bleeding.
The dose of TXA administered in this study was low compared to other studies where no platelet prophylaxis was given in order to avoid excessive thrombosis risk [11,14].  [13,15]. Based on this study it is not possible to conclude whether the lack of effect of TXA is due to insufficient dosage or the lack of fibrinolysis in the population.
Currently two ongoing trials TREATT [16] (1 gram intravenously / We have showed that a very low platelet count is associated with increased risk of bleeding, but there seems to be no difference in risk between platelet counts of 10-15 × 10 9 /L and > 15 × 10 9 /L in this study. This is well in line with the current practice of administering prophylactic platelet transfusions when platelet count drops below 10-15 × 10 9 /L. Infections did not have an effect on bleeding risk in our analysis, which indicates that there is no reason to have different transfusion limits for patients who are infected.
The present study is limited by the retrospective collection of data that data were collected by only one person, data collection was not blinded, and that exposure and outcome data were collected from the same source. The difference in platelet transfusion threshold could lead to less bleeding in the no-TXA group, but there was no difference in the platelet count between groups on the days where platelet transfusions were administered. The study is strengthened by its relatively large study population considering the rarity of AML. Moreover, the TXA and no TXA-group were similar. Further, data were collected systematically, and variables were defined and validated prior to the final data collection.

CONCLUSIONS
In conclusion, TXA 500 mg three times daily can safely be given to AML patients in thrombocytopenia after chemotherapeutic treatment, but this prophylaxis does not seem to reduce bleeding risk.