In those patients who ceased dual antiplatelet therapy for at least 7 days, we did not observe any significant change in platelet aggregation in neither the TRAPtest (P = 0.261), or in the ASPItest (P = 0.294), or in the ADPtest (P = 0.167) after the application of tranexamic acid (group 1, Fig. 1). In contrast, in those patients who did not cease dual antiplatelet therapy, we observed a significant increase in arachidonic acid-induced [295 (280/470) AU*min vs. 214 (83/409) AU*min, P = 0.01] and ADP-induced platelet aggregation [560 AU*min (400/760 AU*min) vs. 470 AU*min (282/550 AU*min), P = 0.013], whereas platelet aggregation following stimulation with thrombin receptor activating peptide-6 did not change significantly [980 (877/1009) AU*min, median (25th/75th percentile) after tranexamic acid vs. 867 (835/961) AU*min before tranexamic acid, P = 0.464].
The main result of the present study was that application of the lysine analogue tranexamic acid resulted in a statistically significant increase in both arachidonic acid-induced and ADP-induced platelet aggregation selectively in those patients who did not cease preoperative dual antiplatelet therapy with aspirin and clopidogrel.
In the present study, platelet function was analysed using the MEA device performing whole-blood analyses. In fact, light transmission aggregometry (LTA) using platelet-rich plasma is considered to be the gold standard for assessing the platelet response to agonists such as arachidonic acid or ADP.20 However, LTA measurements require a specialised laboratory, are time consuming and weakly standardised. Furthermore, the logistical demands of LTA make it difficult to use in daily clinical practice.21 In contrast, the MEA is based on impedance aggregometry which was first described by Cardinal and Flower.18 MEA does not require a specialised laboratory and is useful for point-of-care analysis due to its use of a single-use test cell, integrated computer analysis and documentation and electronic pipetting. Its high specificity and sensitivity in platelet function analyses have already been demonstrated in several studies, also in comparison to LTA.22
Arachidonic acid-induced and ADP-induced platelet aggregation in MEA were thought to be dependent on the platelet count, haematocrit and general functional integrity of platelets.23,24 As we did not detect any differences in either conventional coagulation parameters, haematocrit or platelet count (Table 2) or in thrombin receptor-induced platelet aggregation in the TRAPtest at baseline in the two groups, our results indicate tranexamic acid treatment effects. As platelet aggregation in the ASPItest and the ADPtest increased equally, we suspected that there was a ‘direct’ effect of tranexamic acid on receptor-mediated platelet aggregation. Two other studies including patients suffering from chronic renal failure have investigated the influence of tranexamic acid on platelet function. Performing in-vitro closure time measurements with the Platelet Function Analyzer PFA-100 (Siemens Healthcare Diagnostics, Eschborn, Germany) and investigating the skin bleeding time, they assumed that tranexamic acid treatment resulted in a significant improvement in platelet function.25,26 In that case, how can the observed improvement in platelet function be explained? Both platelet adhesion to the subendothelial matrix and platelet aggregation are mediated mainly via glycoprotein Ib and glycoprotein IIb/IIIa receptors.
The plasma proteinase plasmin is known to multifactorially affect platelet function. It was shown to induce platelet activation by stimulating the protease-activating receptor 4 (PAR4).27 Plasmin-induced platelet activation was described to be similar to platelet activation due to thrombin.10 Furthermore, plasmin was shown to activate the complement cascade by generating activated complement factors C3a and C5a,28 which are known to induce platelet dysfunction and contribute to perioperative haemorrhage.29–31 Finally, plasmin was shown to induce a proteolytic degradation and redistribution of platelet glycoprotein Ib and IIb/IIIa receptors and thereby reduce platelet adhesion and aggregation.32,33 In this context, Lindvall et al.34 described an improvement in platelet function following the substitution of aprotinin. This corroborates the hypothesis that the main effect of influencing platelets function by the use of antifibrinolytics may be due to a reduction of plasmin-induced platelet inhibition.
The present study did not assess either the concentration of platelet glycoprotein Ib or IIb/IIIa receptors nor the plasma level of fibrinogen, von Willebrand factor, plasmin or plasminogen. Therefore, final conclusions concerning the mechanism of action of tranexamic acid in increasing arachidonic acid-induced and ADP-induced platelet aggregation partially in patients treated with dual antiplatelet therapy could not be drawn.
There were some limitations to this study. First, the study population was small and observational. Study results may be prone to alpha and beta errors, especially as the power analysis was based on hypothetical variables. Second, we analysed only one time point after tranexamic acid administration, so no information about duration of the effect of tranexamic acid on platelet function could possibly be derived from the data. Third, platelet function in response to tranexamic acid was assessed only by MEA and not using the gold standard for platelet function testing, the LTA. This method might have provided different results.
Despite these limitations, this study may be of clinical relevance. Although ex-vivo platelet function did not return to normal values after the substitution of tranexamic acid, this study leads to the assumption, that tranexamic acid may represent a pharmacological option to partially increase platelet aggregation in patients treated with dual antiplatelet therapy who come for cardiac or noncardiac surgery. As the design of the present study did not allows us to draw any conclusions concerning causal relationships between tranexamic acid and platelet function due to methodical limitations, randomised and placebo-controlled studies on larger study populations that also include healthy volunteers without any pharmacological therapy are needed to confirm our findings and to evaluate the potentially dose-dependent applicability of tranexamic acid to partially reverse the effects of dual antiplatelet therapy.
The study was performed with departmental founding from the Clinic for Anesthesiology, Intensive Care Medicine and Pain Therapy, J.-W. Goethe University Hospital, Frankfurt, Germany. K.G. received speaking honoraria from Dynabyte, Munich, Germany.
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