Discussion
The novelty of this study
Blood viscoelasticity testing was performed using TEG 6s platelet mapping over 3 days after TAVI. In addition, by calculating the elasticity of the blood clots, the coagulation and platelet functions were separated, and their changes were examined. TEG 6s platelet mapping measures the strength of blood clots formed by whole blood components, such as coagulation factors (except von Willebrand factor), platelets, fibrinolytic system and inflammatory cells. It is believed to reflect clinical events better, including bleeding and thromboembolic events.
As a conventionally used parameter, MA does not necessarily have a linear relationship with actual blood clot strength. However, the blood clot elasticity (G) used in this study was calculated from MA using the formula: G = (5000 × MA) / (100 – MA), which more accurately reflects actual blood clot strength. Therefore, it is reasonable to calculate platelet function from the difference in G with and without platelet activation.11
Changes in platelet and coagulation function
First, maximal platelet aggregation capacity, expressed as Gp, decreased for 3 days after TAVI. Platelet counts also decreased similarly. These results are generally consistent with a report based on conventional platelet aggregation assays9 and a report about the time course of platelet counts.13 It is unclear in this study whether the decreased platelet count brought about the decreased platelet function; this should be clarified in prospective studies.11
Next, MAActF, which represents coagulation capacity excluding platelet function, was significantly elevated on POD 3. In addition, the RHKH value, which reflects the time until the initiation of clot formation by coagulation factors, was significantly shorter on POD 1 and POD 3 than preoperatively. These results suggest that coagulation capacity is enhanced after TAVI. This was not reflected by conventional coagulation test results, including PT-INR, APTT and fibrinogen levels.
Finally, concerning maximum clot strength MAHKH, previous studies have shown that the MAHKH value transiently increases immediately after TAVI and normalises 6 hours postoperatively.8 The present results show that MAHKH decreases from POD 1 to POD 3, indicating an antithrombotic change that may have resulted from a stronger effect of decreased platelet function than increased coagulation capacity after TAVI. These results may suggest that patients are more at risk for bleeding than for thromboembolism in the immediate post-TAVI period. In light of the above, there may be room for reconsidering antiplatelet therapy in the search for appropriate antithrombotic therapy after TAVI. Large-scale clinical studies that compare the occurrence of thromboembolic events, and bleeding events, among others, may be needed.
Effects of antiplatelet drugs
Compared with other reports using TEG 6s,14 15 this study gives the impression of a higher proportion of patients with HTPR of MAADP. Possible reasons for this include the fact that 18%–23% of the Japanese population is clopidogrel resistance due to genetic polymorphisms in CYP2C19,16 as well as the influence of the protocol of administration. Loading dose was not administered at the start of clopidogrel administration.
On the other hand, some patients were classified into LTPR of MAADP. Another study using VerifyNow has also reported a hyper-response to clopidogrel was observed in one-third of patients undergoing TAVI and was related to bleeding.17 Detecting these patients may be important. Similarly, there were large individual differences in MAAA, even among patients taking aspirin, suggest the need for personalised tailor-made therapy regarding antiplatelet therapy after TAVI.
It should also be noted that the thromboelastography (TEG) cut-off values used in this study are currently based on perioperative studies for percutaneous coronary intervention (PCI) patients. In the perioperative PCI period, the target lower limit of MAADP associated with bleeding complications was often 31 mm14; however, in the perioperative TAVI period, 47 mm or less was associated with bleeding.3 Considering these reports, the cut-off values that predict clinical events in the perioperative period for TAVI and PCI may differ. Furthermore, embolisms, such as in stent thrombosis, may be of greater concern after PCI; in contrast, bleeding complications from the surgical procedure may be of more concern after TAVI. Extensive studies are awaited regarding appropriate cut-off values for bleeding/embolic complications in the perioperative TAVI period.
Changes in platelet aggregation capacity mediated by ADP/TXA2 receptors
In patients not taking clopidogrel, GADP represents ADP receptor-stimulated platelet aggregation, which is reduced for 3 days after TAVI. In patients not taking aspirin, GAA represents TXA2 receptor-mediated platelet aggregation, which did not change significantly during the TAVI perioperative period. These results suggest that platelet activation by the ADP system is suppressed for 3 days postoperatively, whereas activation by the TXA2 system is less affected. The postoperative decrease in GAA in aspirin-treated patients might also reflect reduced platelet activation by the ADP system.
Furthermore, the different effects of TAVI on the ADP and TXA2 systems suggest that platelet function suppression mechanisms other than reduced platelet counts may be at work. Previous studies have shown that platelet reactivity to ADP is reduced by increased expression of CD39 (an ADPase and ATPase), when shear stress occurs.18 19 In TAVI, blood turbulence occurs after valve implantation.20 This may be responsible for the suppression of the ADP system. Further case series may be needed to investigate the effect of TAVI on the TXA2 system.
Clinical implications
The key results and clinical implications of this study are shown in figure 4. Previous studies have shown that blood turbulence after TAVI activates the coagulation cascade, resulting in thrombosis,20 21 which is a potential cause of thromboembolism after TAVI. Traditionally, this thrombotic tendency has been noted in the perioperative TAVI period, and antiplatelet therapy has been primarily administered similarly to the post-PCI period. However, the present study results show that platelet function is decreased, especially, ADP receptor-mediated platelet aggregation capacity was reduced, and coagulation capacity is increased after TAVI, resulting in decreased maximum clot strength, representing a postoperative antithrombotic effect. This suggests the need to reconsider protocols using antiplatelet agents in the postoperative period. Specifically, ADP receptor antagonist loading pre-TAVI could be redundant or even should be avoided. Also, pausing direct OAC in patients with atrial fibrillation could possibly carry a higher risk of thromboembolism due to the increased coagulation capacity.
Figure 4Key results and clinical implications.
In addition, there was a great deal of individual variability in the antiplatelet therapy effects, particularly in some patients taking clopidogrel, who were at high risk of bleeding as determined by TEG 6s platelet mapping. Finally, since the study results show that ADP receptor-mediated platelet aggregation is suppressed after TAVI, individual platelet function monitoring, particularly in patients taking clopidogrel, might be preferable.
Limitations
First, this study’s sample size was small. Therefore, we could not investigate the association between TEG 6s data and clinical outcomes.
Second, TEG 6s platelet mapping was the only platelet function assay used in this study and was not investigated in combination with other assays. However, there was some evidence that TEG 6s platelet mapping provides a more accurate estimate of in vivo platelet aggregation capacity than conventional platelet aggregation tests.22 23 Since conventional platelet aggregation tests are expensive, time-consuming, and do not necessarily reflect clots strength, it might be worthwhile to consider whether platelet function testing by TEG could be an alternative.
In addition, the minimum preoperative antiplatelet medication in this study was relatively short (3-day preoperative period). However, most participants in this study (86%) had taken antiplatelet agents for at least 5 days before surgery, and Gp, which represents maximum platelet aggregation capacity, is reportedly unaffected by antiplatelet medication. Moreover, GADP/AA was mainly studied in patients not using the corresponding antiplatelet agent.
Finally, although the methodology of measuring ADP/TXA2 receptor-mediated platelet aggregation capacity from GADP/AA seems reasonable, it has not been reported so far, and its validity needs to be examined in the future.