Postoperative administration of tranexamic acid as approach to reduce blood loss after open-heart surgery

1 Introduction

The extent of blood loss associated with on-pump open-heart surgery is influenced by both patient demographics and the surgical procedure. In addition to bleeding from the surgical site, which can partially be identified and stopped through repeat thoracotomy, massive bleeding is associated with the dysregulation of hemostasis due to CPB. This comprises among others hemodilution caused by infusion of crystalloid solutions, hypothermia, platelet dysfunction and overactivation of fibrinolysis. Described patient-related risk factors for an increased perioperative blood loss are high age, low BMI [1], diabetes mellitus and impaired renal function. Besides, highly complex and emergency surgeries favor perioperative bleeding [2]. In consequence, massive blood loss is associated with a high need for transfusions and an increased rate of repeat thoracotomy, postoperative renal failure, myocardial infarction and cerebrovascular insufficiency [3].

Addressing the pathophysiology of perioperative hyperfibrinolysis, the increased release of t-PA due to the surgical trauma results in the activation from plasminogen to plasmin. The serine protease plasmin degrades fibrin enzymatically. Its degradation products can be detected as D-dimers. The extend of hyperfibrinolysis is regulated by plasminogen activator inhibitor (PAI) and highly specific plasmin inhibitor α₂-antiplasmin [4]. PAI inactivates plasminogen activators as well as thrombin and activated protein C [5]. A₂-antiplasmin binds competitively to the lysin binding site for plasmin [6]. Therefore, essential risk factors featuring hyperfibrinolysis are a hereditary deficiency of PAI and α₂-antiplasmin [7]. Unspecific laboratory signs of hyperfibrinolysis are an increased plasma concentration of t-PA, PAI and D-dimers [5, 8]. Diagnostic specification relies on viscoelastic methods such as rotational thromboelastometry (ROTEM^®; TEM International, Munich, Germany).

To avoid diffuse bleeding resulting from hyperfibrinolysis, it is a common approach to prophylactically administer antifibrinolytic agents such as TXA. At the University Heart Center in Dresden all patients receive 1 g TXA before CPB. TXA inhibits fibrinolysis by reversibly binding lysine receptor sites on plasminogen and plasmin, preventing the degradation of fibrin [4]. Although there are many studies published on the administration of TXA before CPB demonstrating a reduction in perioperative blood loss and the consumption of blood products [9–11], the postoperative administration of TXA with the intent of treating bleeding is scarcely investigated.

2 Methods

3 Results

4 Discussion

In this trial, we found no evidence that additional dosing of TXA reduces postoperative blood loss. Until today, there is only a small number of reliable investigations examining postoperative TXA dosing.

Casati et al. (n = 510) compared two different postoperative doses to a placebo group. They found no significant differences in terms of postoperative blood loss or transfusion requirements. The authors concluded that the postoperative use of TXA should be restricted to patients with massive blood loss and signs of hyperfibrinolysis only [13]. In contrast to the findings from our trial and Casati et al., Katoh et al. (n = 93) as well as Jimenez et al. (n = 160) concluded that additional TXA dosing reduces postoperative blood loss. Both compared higher doses in a prophylactic, non-therapeutic approach [14, 15].

Many theories exist to hypothesize why postoperative administration of TXA might fail to be beneficial in preventing bleeding complications. There may be a prolonged effect of the prophylactically administered dose of TXA beyond the duration of cardiac surgery, which appears plausible when factoring its elimination half-life and pharmacokinetics in particular. Furthermore, it is uncertain whether the activation of the fibrinolytic system contributes significantly to perioperative bleeding complications, especially in the context of open-heart surgery and CPB featuring a complex dysfunction of hemostasis. Additionally, hyperfibrinolysis is assumed to be a self-limiting process and is less likely thought to increase during the postoperative period [16].

Apart from having no significant impact on the blood loss, the postoperative administration of TXA did not reduce transfusion requirements. Although meta-analyzes reveal a significant benefit when compared to placebo [9, 18], there is no evidence that different intraoperative dosages [19, 20] or its postoperative administration are superior [14].

The non-significant higher rate of renal impairment in patients with postoperative administration of TXA, might be explained by the higher non-significant postoperative blood loss as a major risk factor, the slightly worse preoperative renal function and, not to be ruled out, as a side-effect of TXA dosing. Beyond these, our retrospective analysis reveals that the postoperative use of TXA is safe in terms of mortality and adverse events, in particular regarding thromboembolic events such as myocardial infarction and stroke. These findings are consistent with trials investigating TXA dosing after CPB [21].

5 Conclusions

In this study, postoperative administration of an additional dose of TXA was not shown to significantly reduce blood loss or transfusion requirements. It is recommended to carry out a larger scale prospective, randomized placebo-controlled trial investigating the impact of postoperative TXA dosing on blood loss, transfusion requirements and adverse effects after heart surgery. If there is no evidence for its benefit, the postoperative administration of TXA should be restricted to patients with massive blood loss and signs of hyperfibrinolysis only. Besides, available point-of-care testing should be considered for the detection and treatment of bleeding complications due to hyperfibrinolysis.

Conflict of interest

The authors declare that there is no conflict of interest.