Predictors of Thrombocytopenia After Transcatheter Aortic Valve Implantation: A Retrospective Study at a Single Japanese Center

Yasutaka Yamada (  sj8919@cc.saga-u.ac.jp ) Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Saga, Japan https://orcid.org/0000-0003-2792-5516 Daisuke Miura Department of Anesthesia, Saga Medical Center KOSEIKAN, Saga, Japan Ayako Takamori Clinical Research Center, Saga University Hospital, Saga, Japan Eijiro Nogami Department of Thoracic and Cardiovascular Surgery, Saga Medical Hospital, Saga, Japan Junji Yunoki Department of Thoracic and Cardiovascular Surgery, Saga Medical Hospital, Saga, Japan Yoshiro Sakaguchi Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Saga, Japan


Study population
This retrospective study included patients who underwent transfemoral TAVI for severe aortic valve stenosis at our institution between March 2014 and August 2019. We excluded patients who underwent transapical or trans-subclavian TAVI. The retrospective study protocol complied with the Declaration of Helsinki and was approved by the institutional review board of the Faculty of Medicine, Saga University (20190703, September 30, 2019), which waived the requirement for informed consent. Study details were published on the institution's website and patients were allowed to opt-out of the research use of their data.

TAVI procedures
The TAVI procedures were performed in a hybrid operating room under general anaesthesia, with TAVI access and valve size selected based on three-dimensional computed tomography measurements.
Transarterial access was established percutaneously or after cut-down in a standard manner. Decisions regarding vascular access, valve type, and valve size were made by the institution's cardiovascular team.
Patients were treated using either Edwards Sapien XT or Sapien 3 BEVs (Edwards Lifesciences, Irvine, CA, USA), or Medtronic CoreValve, EvoluteR or EvolutePro self-expanding valves (SEVs; Medtronic, Minneapolis, MN, USA). Rapid right ventricular pacing was performed during balloon dilation for a native aortic valve and at the time of BEV implantation. We used transoesophageal echocardiography to con rm appropriate valve positioning and identify any para-valvular leak, which prompted balloon postdilation if necessary. All patients received unfractionated heparin to maintain a minimum activated clotting time of > 250 s during the procedure. Protamine (1 mg for each 100 U heparin) was routinely administered at the time of vascular closure, which was performed in a standard manner. The contrast agent was iopamidol, which is iodinated, non-ionic, and has low osmolarity. The tracheal tube was removed in the operating room if normal results were observed for respiratory status and circulatory dynamics. All patients were admitted to the intensive care unit after surgery.

De nitions and data collection
Baseline parameters were selected based on the last evaluation before the procedure. Variables included age, sex, BMI, hypertension, diabetes mellitus, cancer, peripheral artery disease, cerebrovascular disease, chronic kidney disease, known coronary artery disease, atrial brillation, pacemaker implantation, Society of Thoracic Surgeons Predictive Risk of Mortality score, logistic EuroSCORE, echocardiographic ndings, valve type (BEV or SEV), contrast medium volume, operating time, intraoperative blood loss, blood transfusion, percutaneous cardiopulmonary support (PCPS), balloon post-dilation, and laboratory parameters. Procedural events were de ned according to the Valve Academic Research Consortium-2 criteria [19].
Platelet counts were measured using a Sysmex XN-900 system (JACLaS, Tokyo, Japan) before TAVI, day 0, day 1, day 2, day 3, day 5, day 7, and then as needed. The nadir platelet count was de ned as the lowest count after TAVI. The DPC was calculated as 100% × (baseline platelet count -nadir platelet count) / (baseline platelet count), and the results were categorised as a DPC of ≥ 50% or < 50%.
Clinicodemographic characteristics, intraoperative ndings, and clinical outcomes were compared between the groups with DPCs of ≥ 50% and < 50%.

Statistical analysis
Categorical variables were reported as number (percentage) and compared using the chi-squared test or Fisher's exact test. Continuous variables were reported as median (interquartile range [IQR] and range) and compared using Student's t-test or the Mann-Whitney U test. Multivariate logistic regression analysis was performed to identify factors that might predict a DPC of ≥ 50%. Potentially relevant factors were selected from variables with a univariate P-value < 0.05 and previously reported factors [5,8,10,[13][14][15]: coronary artery disease, left ventricular ejection fraction, aortic valve area, contrast medium volume, and blood transfusion. The results were reported as odds ratios (ORs) and 95% con dence intervals (CIs). Signi cant differences were identi ed using two-sided P-values of < 0.05. All analyses were performed using JMP Pro software (version 13; SAS Institute Inc., Cary, NC, USA).
The baseline characteristics of the patients according to DPC categorisation are shown in Table 1.  Patients with a DPC of ≥ 50% were signi cantly older (85.3 years vs. 83.5 years, P = 0.031) and had a signi cantly lower BMI (21.7 kg/m 2 vs. 23.1 kg/m 2 , P = 0.016). There were no signi cant inter-group differences in operation time, contrast medium volume, intraoperative blood loss, blood transfusion, use of PCPS, balloon post-dilation, or the various clinical outcomes (Table 2).  However, the group with a DPC of ≥ 50% was more likely to receive BEVs (90.5% vs. 75.4%, P = 0.019). Table 3 shows the results of the analyses of factors that predicted a DPC of ≥ 50% after TAVI.

Discussion
This study revealed that TAVI was strongly associated with a DPC, the nadir platelet count was reached on approximately postoperative day 3, and a large DPC was associated with BEV use and low BMI. Our ndings regarding the nadir platelet count agree with previous reports that the nadir platelet count is reached on day 2-3 and begins to recover on day 5 [4,[6][7][8][9].
It remains unclear whether post-TAVI thrombocytopenia differs according to the use of BEVs or SEVs [13].
Three studies and a sub-group analysis from a recent systematic review revealed that BEVs were associated with a higher risk of post-TAVI thrombocytopenia [7,8,11,13]. Our study also revealed similar results, although the underlying mechanisms remain unclear. The TAVI procedure may be associated with mechanical platelet destruction, increased coagulation, and in ammation-related platelet consumption [13], while other reports have suggested that thrombocytopenia is associated with BEV use because of endothelial damage and shear stress factors [7,[20][21][22][23]. Thus, it is possible that differences in prosthesis design and/or implantation technique generate variable degrees of endothelial damage and shear stress, which might underly the relationship between BEV use and thrombocytopenia [8,21]. For example, BEV use might generate greater shear stress because of the balloon that is used during deployment. Hernandez-Enriquez et al. evaluated patients who received SEVs or BEVs and reported that the average DPC was 32.5 ± 13.9% [8], which is noticeably lower than the average DPC in our study (51 ± 13%). We suspect this difference is related to the greater proportion of BEV use in our study (84% vs. 57% of cases) [8]. Furthermore, Jilaihawi et al. [6] evaluated thrombocytopenia after only BEV implantation and reported that the average DPC was 61 ± 15%, which agrees with our result.
Use of contrast agents may also in uence the DPC [5,10], which may be related to the agent's chemical properties, immune-allergic reactions, or genetic predisposition [7,8,10,23]. For example, Mitrosz et al. reported that the DPC after TAVI using a BEV (Edwards Sapien XT) was associated with the contrast agent volume [5]. However, we did not observe any signi cant inter-group differences in the contrast agent volume, although we used smaller amounts (86.7 ± 26.0 mL) than those used by Mitrosz et al. (229.0 ± 74.3 mL) [5]. Our ability to use less contrast agent is likely related to the use of the transoesophageal echocardiography to con rm appropriate valve positioning.
A large DPC was associated with low BMI, which is also associated with mortality and thrombocytopenia risk after other high-risk percutaneous cardiac procedures [25,26]. Moreover, patients with low BMI have increased risks of thrombocytopenia and acute myocardial infarction-related mortality, regardless of revascularisation status [26,27]. Four reports have evaluated whether post-TAVI thrombocytopenia was associated with BMI [7,8,15,16], although only Flaherty et al. reported a signi cant association [15]. Therefore, the relationship between post-TAVI thrombocytopenia and low BMI remains controversial, as previous reports have mainly evaluated European and American patients, who tend to have higher BMI than Japanese patients [7,8,15,16]. For example, the mean BMI in our study (22 kg/m 2 ) was lower than the mean BMI in the aforementioned studies: 28.7 ± 4.7 kg/m 2 [7], 26.0 ± 5.2 kg/m 2 [8], 29 kg/m 2 [15], and 26.9 kg/m 2 [16]. To the best of our knowledge, this is the rst report to examine whether low BMI was associated with post-TAVI DPC among Japanese patients, who are more likely to have lower BMI and may be more prone to developing more severe thrombocytopenia. The relationship between thrombocytopenia and low BMI remains unclear, although large amounts of uids are infused during the perioperative period in TAVI patients, and patients with a low BMI may be more susceptible to haemodilution, leading to a large DPC. Furthermore, we did not detect any instances of infection, sepsis, or disseminated intravascular coagulation leading to thrombocytopenia. Moreover, the mean intraoperative blood loss was 84.6 ± 115 mL, which suggests that thrombocytopenia was not likely related to platelet loss.
In conclusion, the present study revealed that low BMI and BEV use were associated with a larger DPC after TAVI in Japanese patients with severe aortic valve stenosis. Platelet count monitoring count after TAVI, especially when using BEV devices, is essential for Japanese patients, who are more likely to have a lower BMI.

Limitations
This study has several limitations that should be acknowledged. First, the retrospective analysis of a small patient population is prone to bias related to unidenti ed confounders, and the results should be interpreted with caution. Second, use of PCPS is higher in our study compared to previous reports [28]. The reason for this is that prophylactic PCPS is used proactively for high risk cases of haemodynamic instability in our institution. We did not observe any signi cant inter-group differences in the use of PCPS, but the results should be interpreted with caution. Third we cannot completely exclude the possibility of heparin-induced thrombocytopenia (HIT), as PF4 antibody detection was not performed because no patients had suspected HIT. Nevertheless, previous reports have suggested that HIT has little role in post-TAVI thrombocytopenia [4,15,16].