Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2021  |  Volume : 17  |  Issue : 5  |  Page : 1275--1280

Effect of microwave ablation on platelet and coagulation function in patients with BCLC-A hepatocellular carcinoma


Wenpeng Zhao1, Honglu Li1, Wei Li1, Jiang Guo1, Liang Cai1, Youjia Duan1, Xiaopu Hou1, Zhenying Diao1, Xihong Shao1, Hongliu Du1, Wei Li2, Changqing Li1,  
1 Department of Oncology Interventional Radiology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
2 Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China

Correspondence Address:
Changqing Li
Department of Oncology Interventional Radiology, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshundong Road, Beijing 100015
China

Abstract

Aim: To preliminarily evaluate the effect of microwave ablation (MWA) alone on platelet (PLT) and coagulation function in patients with BCLC-A hepatocellular carcinoma (B-A-HCC) using a retrospective method. Materials and Methods: A total of 36 patients with 48 B-A-HCCs were radically treated with MWA alone under the guidance of ultrasound between April and October 2018. PLT coagulation indexes were measured before and after MWA at 1 day, 3 days, 1 week, and 2 weeks, and blood samples (after morning fasting) were collected from cubital veins. Coagulation indexes included prothrombin time (PT), prothrombin activity (PTA), thrombin time (TT), Activated Partial Thromboplastin Time (APTT), international standardized ratio (INR), plasma fibrinogen (FIB), plasma antithrombin III (AT-III), and D dimer (DD). Overall survival (OS), recurrence-free survival (RFS), local tumor progression (LTP), and adverse reactions were also recorded. Results: All patients were radically treated with MWA alone. The median size of the lesion was 2.6 (1.5–7.0) cm3. On the first day after MWA, the level of PLT decreased significantly compared with the values before MWA and gradually returned to preoperative levels one week after MWA. One day after MWA, the levels of PT, INR, and AT-III increased markedly and the level of PTA decreased significantly, all of them gradually returned to baseline after 3 days to a week of time. 1, 3, and 7 days after MWA, the levels of FIB, and DD increased significantly, and the level of TT decreased significantly; all of them gradually returned to baseline at 2 weeks. At 6 months posttreatment, the OS and RFS rates were 100% and 91.7%, the LTP rates was 5.6%, no significant adverse reactions. Conclusion: PLT and coagulation indexes were abnormal in patients with B-A-HCC who were radically treated with MWA alone after treatment; without specific treatment, they all gradually returned to baseline within a week or two.



How to cite this article:
Zhao W, Li H, Li W, Guo J, Cai L, Duan Y, Hou X, Diao Z, Shao X, Du H, Li W, Li C. Effect of microwave ablation on platelet and coagulation function in patients with BCLC-A hepatocellular carcinoma.J Can Res Ther 2021;17:1275-1280


How to cite this URL:
Zhao W, Li H, Li W, Guo J, Cai L, Duan Y, Hou X, Diao Z, Shao X, Du H, Li W, Li C. Effect of microwave ablation on platelet and coagulation function in patients with BCLC-A hepatocellular carcinoma. J Can Res Ther [serial online] 2021 [cited 2022 May 28 ];17:1275-1280
Available from: https://www.cancerjournal.net/text.asp?2021/17/5/1275/331309


Full Text



 Introduction



Image-guided percutaneous thermal ablation techniques, such as radiofrequency ablation (RF) and microwave ablation (MWA), have been developed in recent years for the treatment of hepatocellular carcinoma (HCC). Although liver transplantation is the better treatment option for patients with early-stage HCC, however, the maximal invasive treatment, high medical bills, postoperative recurrence, and shortage of donor livers limit its wide application. Ablation techniques can be curative, minimally invasive, and easily repeatable for recurrence, it can be as effective as liver transplantation in terms of overall survival in patients with early HCC, but adverse events were fewer and miner.[1],[2],[3] Radio-frequency catheter ablation (RFCA) as a thermal ablation technique was an important method for the treatment of rapid arrhythmia. However, RFCA treatment frequently leads to an obvious increase in serum D dimer (DD) level in patients, which reflected a state of high coagulation.[4] Approximately 1.0% patients were especially at risk for thromboembolism and anticoagulation.[5],[6] There was also research indicating that RF of liver in rats had not been associated with activation of coagulation.[7] Therefore, it is significant to study whether MWA as a thermal ablation technique for the treatment of HCC would affect patients' coagulation function. The objective of this research was to preliminarily evaluate the effect of MWA alone on platelet (PLT) and coagulation function in patients with BCLC-A HCC (B-A-HCC) using a retrospective method.

 Materials and Methods



Patients

The ethical guidelines of the World Medical Association Declaration of Helsinki were followed in the study, and the study protocol was approved by the ethical committee of the institute.

A total of 36 consecutive patients with B-A HCC who were candidates for MWA were included in the study from April and October 2018, of which single lesion in 26 patients, multiple lesions (2–3) in 10 cases. Diagnostic criteria of HCC were performed according to the guidelines for the diagnosis and treatment of primary liver cancer in China (2017).

The eligibility criteria were: (1) patients aged 18–80 years; (2) tumor clinical stage is BCLC-A: single lesion, diameter ≤5 cm, liver function Child-Pugh class A or B; the number of the lesion ≤3, diameter ≤3 cm, liver function Child-Pugh class A or B; no vascular cancer embolus, surrounding invasion and distant metastasis; (3) patients who did not receive any anti-cancer treatment, such as surgery, radiotherapy, chemotherapy, ablation, and targeted drugs; (4) patients with no serious organ dysfunction syndrome, such as heart, brain, liver, and kidney problems; (5) distance of tumor from the left and right hepatic duct and common bile duct ≥5 mm; (6) tumor could be observed clearly under the guidance of ultrasound, the puncture tract was safe.

The exclusive criteria were as follows: (1) severe liver malfunction (Child–Pugh score >9, serum total bilirubin level >3 mg/dl and prothrombin time-international normalized ratio >1.5); (2) severe hepatic atrophy, expected ablated area would be larger than one-third of liver volume; (3) one-third of lesion volume exposed surfaces of liver; (4) esophageal and gastric variceal bleeding patients in the last 6 months; (5) active infection or intra-hepatic bile duct dilation; (6) uncorrectable coagulopathy (PLT < 30 × 109/L, PT >30s, PTA <40%); and (7) obstinate massive ascites and hepatic encephalopathy.

Equipment

We used a KV2100 Microwave tumor treatment device (Nanjing Kangyou Microwave Energy Sources Institute, China; frequency, 2450 MHz; needle type, internal water-cooling; electrode diameter, 15 G; electrode length, 180 mm; power, 0–100 W; distance from the aperture of the MW emission to the needle tip, 11 mm); ultrasound machine was LOGIQ P6 (GE, USA), using broadband convex array probe (frequency, 1–5 MHz).

Treatment

The procedure was performed under local anesthesia, and the vital signs were monitored under ECG monitor. The patient was given pethidine hydrochloride injection and diazepam injection 30 min before the treatment. The microwave therapy instrument was in good working condition. All patients took the supine position or left lateral decubitus position and must follow the principle that the lesions were more apparent in ultrasonic imaging. Microwave electrodes were inserted precisely into lesions under ultrasound guidance. Therapeutic planning was performed, internal echoes change of lesion and manifestations of intrahepatic and perihepatic abnormalities were observed by ultrasound in the real time. Simultaneously, the operator observed the response of patients such as pain, gave additional analgesic and sedative drugs when necessary. Routine ablation needle track was inserted to prevent implantation metastasis and pressure dressing was performed to prevent hemorrhage after the procedure. After the treatment, regular follow-up examinations would continue for >6 months.

Blood examination indicator

Coagulation indexes and PLT were measured before and after MWA at 1 day, 3 days, 1 week, and 2 weeks, blood samples were collected from cubital veins after morning fasting. Coagulation indexes included prothrombin time (PT), prothrombin activity (PTA), thrombin time (TT), activation of some thrombin time (APTT), international standardized ratio (INR), plasma fibrinogen (FIB), plasma antithrombin III (AT-III), and DD. All the above indexes were detected strictly at the laboratory department in the hospital according to the reagent supplies user manual and equipment specification. Coagulation indexes were measured by ACL top-700 automatic analyzer (USA, IL, Inc.), and PLT were measured by using a DXH800 Hematology analyzer (USA, Beckman Coulter, Inc.).

Statistical analysis

Normally distributed data were reported as the mean ± standard deviation, nonnormally distributed data were reported as the median and interquartile range, and the paired t-test was used to analyze the change of each index before and after the treatment. When P < 0.05, the difference was considered statistically significant. Statistical analysis was performed by anSPSS19.0 software (SPSS, IBM Company, Chicago, IL, USA).

 Results



Patients and tumors

A total of 48 lesions in 36 patients were radically treated with MWA alone. The treatment was successfully completed, and satisfactory results were obtained. The mean diameter of the lesion was 2.2 ± 0.9 (1.0–4.1) cm, the median size of the lesion was 2.6 (1.5–7.0) cm3, the median size of ablation area was 11.9 (3.6–31.2) cm3. Ablation area was significantly greater than the size of the lesions [Figure 1], it usually extended >0.5 cm in radius, so that we could decrease the rates of local recurrence. At 6 months posttreatment, two patients complained of local recurrence and one patient complained of distant metastasis; The overall survival and RFS rates were 100% and 91.7%, the LTP rates was 5.6%, no significant adverse reactions. The more detailed information on patients and lesions are shown in [Table 1].{Figure 1}{Table 1}

Variations of platelet and coagulation function

The mean PLT counts were 124.6 ± 53.6 (51–239) 109/L before ablation and were 115.9 ± 47.5 (45–225) 109/L after ablation. On the 1st day after the treatment, PLT counts had an obvious descent, there was a significant difference (P < 0.05). Later, it gradually increased and returned to the preoperative level, as shown in [Table 2] and [Figure 2].{Table 2}{Figure 2}

About coagulation parameters the levels of PT, INR, and AT-III were 14.6 ± 1.1 (12.9–17.0) s, 1.2 ± 0.1 (1.0–1.4), 77.2 ± 16.9 (42–107) mg/L, respectively, and increased markedly compared with those before the treatment (P < 0.05). The level of PTA was 79.6 ± 8.9 (62–98)%, and decreased significantly compared with those before the treatment. The above indexes were all gradually returned to baseline after 3–7 days. 1, 3, 7 days after MWA, the level of FIB and DD were 2.8 ± 0.6 (1.8–4.1) mg/dl, 4.1 ± 0.7 (3.0–5.7) mg/dl, 3.9 ± 0.6 (2.9–5.3) mg/dl and 1.7 ± 1.2 (0.3–4.9) mg/L, 1.8 ± 1.1 (0.4–4.2) mg/L, 1.7 ± 1.1 (0.4–4.1) mg/L, respectively and were higher than those before pretreatment (P < 0.05), the level of TT was 15.8 ± 1.3 (15.0–19.2) s, 14.7 ± 2.6 (8.7–18.6) s, 15.0 ± 2.7 (8.9–20.4) s and was significantly reduced after treatment. All the indexes items gradually returned to baseline at 2 weeks. Details are shown in [Table 3] and [Figure 3], [Figure 4], [Figure 5].{Table 3}{Figure 3}{Figure 4}{Figure 5}

Adverse events

According to the classification standard of adverse event of international society for interventional radiotherapy (SIR), there were no significant adverse reactions (SIR-C degree adverse events, needed hospital treatment) in all patients. The most reported adverse events during follow-up visits were treatment area pain, the Visual Analog Scale (VAS) was used to assess the pain severity (0–10 points, 0: no pain, 10: the most pain), and VAS scores were measured after treatment. The mean pain score was 3.1 ± 0.8 (range, 1–5) points, and no patient reported that the pain scores were >5 points. No special management was needed in 31 patients (SIR-A degree adverse events, did not require any treatment), pain was disappeared 1–2 days after treatment; 5 patients (SIR-B degree adverse events, require outpatient treatment) relieved after oral nonsteroidal anti-inflammatory analgesic administration for 3 days. A fever of <38.5°C (SIR-B degree adverse events) after treatment was observed in 26 patients and gradually subsided after taking oral ibuprofen in the outpatient department. One patient had lower PLT count (5.6 × 109/l) in peripheral blood before treatment, 1 day after treatment, she got even worse in PLT count (4.2 × 109/l) and had large ecchymosis in skin around the puncture site, gradually dissipates with no treatment in about 2 weeks [Figure 6]. Details are shown in [Table 4].{Figure 6}{Table 4}

 Discussions



RFCA as a thermal ablation technique is one of the most effective invasive treatment methods for rapid arrhythmia. Some research showed that this therapy could cause abnormal PLT activation and changes in coagulation, and there was significant risk which could set off thrombus formation, especially in 2 weeks after treatment. Therefore, the drugs that prevent anti-coagulation and inhibit PLT activation need to be administered to prevent the formation of thrombus after treatment.[6],[8],[9],[10]

The same as a thermal ablation techniques, it was worthy to study whether MWA had the same effect on PLT activation and coagulation function in the patients with HCC. The results indicated that PLT and PTA had an obvious descent and PT, INR, AT-III increased significantly than those of pretreatment. All the above indexes gradually returned to baseline at 3–7 days after treatment.

If so, what were the causes of these changes? The study confirmed that tissue carbonization and microthrombus formation were seen in the ablated area when the tissue temperature raised up to 100 or impedance increased abruptly.[11] In the meantime, heat effect generated by the microwave electrodes led to hemolysis in the circulation system, which in turn stimulated PLT aggregation and induced microthrombosis in blood vessels. Local tissue injury and inflammatory reaction in the ablated area released bioactivity mediums and touched off coagulation system. PT mainly reflected whether extrinsic coagulation pathway was normal or not and deficiency of a coagulation factor would extend PT; INR was the ratio of the prothrombin time and normal control subjects, as platelet fell, it would result in INR significantly increased. AT-III was produced by liver and endothelial cells, its activity was inhibited when it was combined with coagulation factors, and the lack of coagulation factor caused a subsequent spike in AT-III. The local temperature of the ablated area was above 100°C in the treatment for HCC. Local thrombosis formation and microthrombosis in the circulation system resulted in transient decreases of PLT. The consumption of coagulation factor in the thrombus formation could notably increase PT, INR, and AT-III compared with the values before treatment. MWA of hepatocellular cancer, not like RFCA, acted directly on the circulation system. As exogenous pyrogen and local inflammatory response disappeared, the organism would eventually repair by itself. The level of PLT, PT, INR, and AT-III gradually returned to baseline at 3–7 days.

The findings from this study suggested that the levels of FIB and DD were higher than pretreatment, TT was significantly reduced after treatment, and all them gradually returned to baseline at 2 weeks. What was the reason behind it? FIB was a principal protein which was synthesized by liver during the process of blood coagulation. A state of stress, acute inflammation, or thermal damage resulted in an increase in FIB. DD was a specific molecular marker in the process of fibrinolysis, elevated levels of DD reflected activation of blood coagulation and plasminogen activation system.[5] TT reflected the level of FIB and heparin substance in the plasma, the increase in FIB resulted in the decrease in TT time. Microthrombus was formed in the circulation systems and the ablated areas in early after therapy, which caused FIB and DD to rise and TT to decline gradually after 1 day, they reached the peak or bottom on the 3rd day, microthrombus gradually dissolved after stopping bleeding, fibrinolysis system would be activated gradually. Therefore, all the above indexes gradually returned to baseline at 2 weeks.

Based on the outcome of the research, thrombosis prophylaxis or hemostatic support should be considered with caution after MWA, because PLT and coagulation function in patients only showed sensitive short-term changes and all indexes gradually returned to baseline at 1–2 weeks after treatment. If we rashly took relevant measures and countermeasures, it would increase the risk of hemorrhage or thrombosis and even increase mortality, and this was confirmed in the study.[12] If patients had lower counts of PLTs in peripheral blood before treatment, and PLTs counts got even worse or coagulation indexes continued to deteriorate at 1–2 weeks after treatment, which must make us be vigilant highly and take corresponding measures to reduce the risk of bleeding.

The shortcomings of this research were the small sample size, the lack of evidence proved by the systematic experimental study, and the exclusion of potential confounders. Further researches are required to confirm the results of the study and the conclusions drawn.

 Conclusion



Patients with B-A HCC who were radically treated with MWA alone under the guidance of ultrasound had an abnormal coagulation state within 1-week treatment; without specific treatment, PLT and various indicators of coagulation function gradually returned to baseline at 2 weeks. After 1–2 weeks, if multiple indexes were still abnormal, it should be paid more attention and active measures should be taken.

Acknowledgment

The subject is supported by the Scientific Research Foundation of Beijing Ditan Hospital.

Financial support and sponsorship

This article was supported by research fund program of Beijing Ditan Hospital (DTDR201806).

Conflicts of interest

There are no conflicts of interest.

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