Long-term outcomes and prognostic factors of major amputation in thromboangiitis obliterans after drug therapy and endovascular procedures: A real-world cohort study
Thromboangiitis obliterans (TAO) is a rare inflammatory vasculopathy that affects mainly male smokers. The main manifestations are symptoms of limb ischemia, such as intermittent claudication or severe claudication and rest pain. In cases of critical limb ischemia (CLI), limb necrosis can lead to limb loss. TAO is a type of segmental recurrent inflammatory thrombotic occlusion that involves mainly the small arteries and veins of the extremities, and its etiology remains unknown. The lesions tend to extend from the distal artery to the proximal artery. – Although TAO has been acknowledged for more than 100 years, effective treatments remain limited. It is still not known whether the initial process in TAO is thrombosis or vascular inflammation (angiitis), and as a consequence, it is difficult to determine whether managing inflammation or thrombosis could save the limbs of TAO patients. Therefore, the most effective treatment is smoking cessation. , However, as drugs are continuously updated, TAO patients are gradually treated with antiplatelet or vasodilator drugs, such as beraprost, cilostazol, sarpogrelate, and aspirin, which are utilized in the treatment of TAO. – Additionally, anticoagulant therapy for thrombotic lesions has been attempted. Furthermore, with improvements in interventional technology and materials, some TAO patients have undergone endovascular procedures (EPs). – Both drug therapy (DT) and EPs improve early symptoms and even limb salvage in TAO patients. It remains to be determined if there is a difference in the long-term outcome of limb loss between TAO patients treated with DT alone and those treated with EP. Most of the current literature reports appear to be confined to comparisons of short-term or medium-term effects, and the number of cases is typically small. The aim of this study was to compare the long-term outcomes of major amputation between TAO patients treated with DP alone and those treated with EP. In addition, the factors influencing major amputation in TAO patients were analyzed. 

Patients The study was conducted at a regional medical center, a 3200-bed general university-affiliated hospital. Consecutive patients who were diagnosed with TAO at Ganzhou People's Hospital between 2012 and 2022 were included in this retrospective real-world study and were approved by the ethics committee and institutional review board of the Ganzhou People's Hospital (Approval Number: TY-ZKY2024-012-01), while the requirement of obtaining informed consent from the subjects was waived off by the same committee. All procedures performed in studies were in accordance with the Helsinki Declaration of 1975 as revised in 2013. The reporting of this study conformed to the STROBE guideline. The baseline characteristics of the patients included sex, age, age at onset, disease duration, initial plasma D-dimer, smoking status, wound grade, site of lower extremity lesions, migratory superficial phlebitis, Raynaud's phenomenon, CLI, Rutherford classification, and DT. Study definitions Major amputation was defined as the time to amputation of the diseased leg above the ankle , and was analyzed on the basic of the treated limb, whereas minor amputation was represented for the most part by toe or transmetatarsal amputations. Wound grade: In the Society of Vascular Surgery (SVS) Wound, Ischemia, and foot Infection classification system, wounds are stratified or graded from grade 0 through grade 3 on the basis of size, depth, severity, and anticipated difficulty achieving wound healing. Distal runoff is scored according to modified SVS criteria used for determining bypass runoff (using the cumulative score for the distal popliteal [maximum 9 × 1] and each of the tibial vessels [maximum 9 each], for a maximum possible total score of 19). Smoking status: Smoking patients at diagnosis who stopped smoking at 1 year were considered as “former smoking.” Smoking status was verified at each follow-up visit on the basic of self-reports. Patients were regarded as “current smoking” if they stated that they had resumed smoking during follow-up or at the time of amputation. Disease duration: Given the lack of a standardized definition for complete recovery from TAO disease, we defined the disease duration as the period from the initial diagnosis of TAO to the last follow-up, or to the time of loss to follow-up or death. Inclusion criteria From January 2012 to December 2022, all hospitalized patients who were diagnosed with TAO and aged ≥18 years were enrolled. Exclusion criteria (a) The diagnosis did not meet the diagnostic criteria of the Japanese Ministry of Health, Labor and Welfare (JMHLW) ; (b) the lesion did not involve the lower limbs. Treatment methods All smoking patients were initially asked to quit smoking and subsequently received clinical interventions. On the basic of the information available in the medical records, the treatment methods included EP and DT. All patients were administered antiplatelet drugs such as sarpogrelate (100 mg three times daily), aspirin (100 mg once daily), cilostazol (100 mg twice daily), and beraprost (40 µg three times daily). Additionally, some patients with a positive D-dimer (>0.50 mg/L) result for the first time were given a low dose (2.5 mg twice daily) of rivaroxaban. Some patients were treated with combination drugs, such as sarpogrelate and aspirin, aspirin and cilostazol, and aspirin and rivaroxaban. Some patients were treated with EP in addition to DT. The EP was chosen by the interventional physicians within the same group based on the digital subtraction angiography image and the condition of catheter and guide wire traversal through the affected vasculature during the intervention. The EPs included catheter-directed thrombolysis (CDT), percutaneous transluminal angioplasty (PTA), and CDT+ PTA. A thrombolytic catheter was inserted into the occluded vessel segment when CDT was performed. Urokinase was continuously administered via the thrombolytic catheter at a maximum rate of 50,000 units per hour and 1.2 million units per day. In certain patients, occluded blood vessels were successfully dilated using PTA balloons. For the PTA procedure, we commonly employ a 0.035-inch microwire and a 0.035-inch system balloon. For below-the-knee lesions, we usually utilize a 0.018/0.014-inch microwire and 0.018/0.014-inch system balloons. For some TAO patients, CDT and PTA procedures were conducted consecutively. The technical success for EP was defined as successful use of a device or technique to reestablish vessel patency with residual stenosis <30%. Grouping For this analysis, the patients were further divided into the DT and EP+ DT groups according to the treatments they received. Follow-up Long-term follow-up was sustained for all patients after treatment, except for those who were lost to follow-up. The follow-up examination was conducted by the physicians involved in the clinical management of the patients. The follow-up process included both outpatient and telephone consultations. Throughout the follow-up period, limb events were documented. Statistical analysis The homogeneity of variance of the measurement data was tested via two independent samples t tests, and the heterogeneity of variance was tested via the rank sum test. Count data were analyzed by the χ 2 test. Kaplan‒Meier survival curve analysis was used to compare the differences in major amputation rates between the two groups. GraphPad Prism 8 was used for plotting. Univariate and multivariate Cox regression analyses were used to analyze the factors associated with major amputation in patients with TAO. Treatment method, , gender, disease duration, wound grade, CLI, runoff score, and smoking status , were included in the Cox regression analysis as previously studies. Variables with two-tailed p -values <0.05 in the univariate analysis were included in the multivariate regression model to determine the independent factors for major amputation. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. All tests were two-sided, with a significance level of 0.05. The statistical analyses were performed with SPSS software (IBM SPSS Statistical software, version 29). 

The study was conducted at a regional medical center, a 3200-bed general university-affiliated hospital. Consecutive patients who were diagnosed with TAO at Ganzhou People's Hospital between 2012 and 2022 were included in this retrospective real-world study and were approved by the ethics committee and institutional review board of the Ganzhou People's Hospital (Approval Number: TY-ZKY2024-012-01), while the requirement of obtaining informed consent from the subjects was waived off by the same committee. All procedures performed in studies were in accordance with the Helsinki Declaration of 1975 as revised in 2013. The reporting of this study conformed to the STROBE guideline. The baseline characteristics of the patients included sex, age, age at onset, disease duration, initial plasma D-dimer, smoking status, wound grade, site of lower extremity lesions, migratory superficial phlebitis, Raynaud's phenomenon, CLI, Rutherford classification, and DT. 

Major amputation was defined as the time to amputation of the diseased leg above the ankle , and was analyzed on the basic of the treated limb, whereas minor amputation was represented for the most part by toe or transmetatarsal amputations. Wound grade: In the Society of Vascular Surgery (SVS) Wound, Ischemia, and foot Infection classification system, wounds are stratified or graded from grade 0 through grade 3 on the basis of size, depth, severity, and anticipated difficulty achieving wound healing. Distal runoff is scored according to modified SVS criteria used for determining bypass runoff (using the cumulative score for the distal popliteal [maximum 9 × 1] and each of the tibial vessels [maximum 9 each], for a maximum possible total score of 19). Smoking status: Smoking patients at diagnosis who stopped smoking at 1 year were considered as “former smoking.” Smoking status was verified at each follow-up visit on the basic of self-reports. Patients were regarded as “current smoking” if they stated that they had resumed smoking during follow-up or at the time of amputation. Disease duration: Given the lack of a standardized definition for complete recovery from TAO disease, we defined the disease duration as the period from the initial diagnosis of TAO to the last follow-up, or to the time of loss to follow-up or death. 

From January 2012 to December 2022, all hospitalized patients who were diagnosed with TAO and aged ≥18 years were enrolled. 

(a) The diagnosis did not meet the diagnostic criteria of the Japanese Ministry of Health, Labor and Welfare (JMHLW) ; (b) the lesion did not involve the lower limbs. 

All smoking patients were initially asked to quit smoking and subsequently received clinical interventions. On the basic of the information available in the medical records, the treatment methods included EP and DT. All patients were administered antiplatelet drugs such as sarpogrelate (100 mg three times daily), aspirin (100 mg once daily), cilostazol (100 mg twice daily), and beraprost (40 µg three times daily). Additionally, some patients with a positive D-dimer (>0.50 mg/L) result for the first time were given a low dose (2.5 mg twice daily) of rivaroxaban. Some patients were treated with combination drugs, such as sarpogrelate and aspirin, aspirin and cilostazol, and aspirin and rivaroxaban. Some patients were treated with EP in addition to DT. The EP was chosen by the interventional physicians within the same group based on the digital subtraction angiography image and the condition of catheter and guide wire traversal through the affected vasculature during the intervention. The EPs included catheter-directed thrombolysis (CDT), percutaneous transluminal angioplasty (PTA), and CDT+ PTA. A thrombolytic catheter was inserted into the occluded vessel segment when CDT was performed. Urokinase was continuously administered via the thrombolytic catheter at a maximum rate of 50,000 units per hour and 1.2 million units per day. In certain patients, occluded blood vessels were successfully dilated using PTA balloons. For the PTA procedure, we commonly employ a 0.035-inch microwire and a 0.035-inch system balloon. For below-the-knee lesions, we usually utilize a 0.018/0.014-inch microwire and 0.018/0.014-inch system balloons. For some TAO patients, CDT and PTA procedures were conducted consecutively. The technical success for EP was defined as successful use of a device or technique to reestablish vessel patency with residual stenosis <30%. 

For this analysis, the patients were further divided into the DT and EP+ DT groups according to the treatments they received. 

Long-term follow-up was sustained for all patients after treatment, except for those who were lost to follow-up. The follow-up examination was conducted by the physicians involved in the clinical management of the patients. The follow-up process included both outpatient and telephone consultations. Throughout the follow-up period, limb events were documented. 

The homogeneity of variance of the measurement data was tested via two independent samples t tests, and the heterogeneity of variance was tested via the rank sum test. Count data were analyzed by the χ 2 test. Kaplan‒Meier survival curve analysis was used to compare the differences in major amputation rates between the two groups. GraphPad Prism 8 was used for plotting. Univariate and multivariate Cox regression analyses were used to analyze the factors associated with major amputation in patients with TAO. Treatment method, , gender, disease duration, wound grade, CLI, runoff score, and smoking status , were included in the Cox regression analysis as previously studies. Variables with two-tailed p -values <0.05 in the univariate analysis were included in the multivariate regression model to determine the independent factors for major amputation. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. All tests were two-sided, with a significance level of 0.05. The statistical analyses were performed with SPSS software (IBM SPSS Statistical software, version 29). 

Study population and baseline characteristics From 2012 to 2022, 185 TAO patients in a single center were recruited. However, 31 patients failed to meet the diagnostic criteria of the JMHLW, and 4 patients with only upper extremity TAO lesions were excluded. Thus, the remaining 150 TAO patients with 175 lower limb lesions were included in the study . There were 136 male individuals. The average age at onset was 41.3 years. The median duration of the disease was 8 years, with the longest being 17 years. A total of 142 patients had a history of smoking. Fifty-six patients did not have lower extremity ulcers upon initial admission. All 150 patients received DT, and among them, 69 also underwent the EP of PTA and/or CDT. The technical success rate in the EP group was 82.6%. The patients were classified into two groups on the basic of the treatment method used: the DT group and the EP+ DT group. There was no difference in the type of DT received by the two groups. Apart from the site of the lower extremity lesions, there were no statistically significant differences in the baseline characteristics between the two groups . Follow-up outcomes The shortest follow-up period was 1 year, the longest was 13 years, and the average follow-up period was 6 years. During the follow-up, nine patients and four patients were lost to follow-up in the two groups, respectively. Five and one patients in the two groups died during the follow-up, respectively. One patient treated with EP died of lung cancer at the age of 65. Among the five patients who received DT alone, two experienced heart failure, two succumbed to pulmonary infections, and one died due to trauma. The average age at death for these five patients was 64.4 years. The patency of the target vessels was observed in merely eight patients following EP, resulting in a long-term patency rate of 11.6%. Minor amputations occurred in 16 and 22 patients, respectively. The follow-up revealed that major amputation was performed in 19 and 21 patients in the respective groups, accounting for 26.7%. Thirty-five TAO patients with claudication were included in this study. Among them, one patient who received EP treatment underwent major amputation during the follow-up period. Kaplan‒Meier curves for major amputation in the two groups were not different . There was no significant difference in the follow-up results between the two groups . Factors for major amputation were analyzed by modeling Treatment method, sex, disease duration, wound grade, CLI, runoff score, and smoking status were included in the univariate Cox regression analysis. The p -values of disease duration, wound grade, CLI, runoff score, and smoking status were found to be <0.05. These factors were subsequently included in the multivariate analysis via Enter method, and the results revealed that a model including three factors was established. Disease duration (HR, 0.865; 95% CI [0.783–0.979], p = 0.005), wound grade (HR, 2.240; 95% CI 1.565–3.207], p < 0.001), and current smoking (HR, 3.075; 95% CI 1.317–7.812], p = 0.009) were independent factors for the major amputation of TAO , while the two factors of CLI and runoff score in the model were (HR, 2.454; 95% CI [0.304–19.785], p = 0.399) and (HR, 1.193; 95% CI [0.705–2.017], p = 0.511), respectively. 

From 2012 to 2022, 185 TAO patients in a single center were recruited. However, 31 patients failed to meet the diagnostic criteria of the JMHLW, and 4 patients with only upper extremity TAO lesions were excluded. Thus, the remaining 150 TAO patients with 175 lower limb lesions were included in the study . There were 136 male individuals. The average age at onset was 41.3 years. The median duration of the disease was 8 years, with the longest being 17 years. A total of 142 patients had a history of smoking. Fifty-six patients did not have lower extremity ulcers upon initial admission. All 150 patients received DT, and among them, 69 also underwent the EP of PTA and/or CDT. The technical success rate in the EP group was 82.6%. The patients were classified into two groups on the basic of the treatment method used: the DT group and the EP+ DT group. There was no difference in the type of DT received by the two groups. Apart from the site of the lower extremity lesions, there were no statistically significant differences in the baseline characteristics between the two groups . 

The shortest follow-up period was 1 year, the longest was 13 years, and the average follow-up period was 6 years. During the follow-up, nine patients and four patients were lost to follow-up in the two groups, respectively. Five and one patients in the two groups died during the follow-up, respectively. One patient treated with EP died of lung cancer at the age of 65. Among the five patients who received DT alone, two experienced heart failure, two succumbed to pulmonary infections, and one died due to trauma. The average age at death for these five patients was 64.4 years. The patency of the target vessels was observed in merely eight patients following EP, resulting in a long-term patency rate of 11.6%. Minor amputations occurred in 16 and 22 patients, respectively. The follow-up revealed that major amputation was performed in 19 and 21 patients in the respective groups, accounting for 26.7%. Thirty-five TAO patients with claudication were included in this study. Among them, one patient who received EP treatment underwent major amputation during the follow-up period. Kaplan‒Meier curves for major amputation in the two groups were not different . There was no significant difference in the follow-up results between the two groups . 

Treatment method, sex, disease duration, wound grade, CLI, runoff score, and smoking status were included in the univariate Cox regression analysis. The p -values of disease duration, wound grade, CLI, runoff score, and smoking status were found to be <0.05. These factors were subsequently included in the multivariate analysis via Enter method, and the results revealed that a model including three factors was established. Disease duration (HR, 0.865; 95% CI [0.783–0.979], p = 0.005), wound grade (HR, 2.240; 95% CI 1.565–3.207], p < 0.001), and current smoking (HR, 3.075; 95% CI 1.317–7.812], p = 0.009) were independent factors for the major amputation of TAO , while the two factors of CLI and runoff score in the model were (HR, 2.454; 95% CI [0.304–19.785], p = 0.399) and (HR, 1.193; 95% CI [0.705–2.017], p = 0.511), respectively. 

The current real-world study demonstrated that the addition of EP did not seem to increase limb salvage rates in TAO patients in the long term compared with DT alone. Multivariate Cox regression analysis revealed that disease duration, wound grade, and current smoking were the influencing factors for major amputation in TAO patients, whereas wound grade and current smoking were the risk factors for major amputation. Disease duration was a protective factor for major amputation in TAO patients. TAO, also called Buerger's disease, is an inflammatory condition affecting small- and medium-sized arteries and veins. The most serious consequence of TAO is limb loss in young adults. Nevertheless, owing to its unknown etiology, there is still no effective treatment for TAO, apart from smoking cessation. The antiplatelet and vasodilator drugs employed in this group included sarpogrelate, aspirin, cilostazol, and beraprost. Sarpogrelate has been utilized in the treatment of TAO for an extended period, and its application in the treatment of TAO in China has also been reported. Aspirin, cilostazol, and beraprost have gradually been confirmed for use in TAO patients and have shown certain efficacy. , , , In addition, there is a question of whether patients with TAO benefit from anticoagulation. Some Chinese scholars have investigated anticoagulant therapy for TAO, involving 18 patients with TAO. The drugs used were low molecular weight heparin or warfarin, and anticoagulant therapy could alleviate the inflammation and symptoms of TAO. However, the use of direct oral anticoagulants in TAO has been less reported. Only one case has been documented. We observed elevated D-dimer levels in TAO patients, and the imaging data also revealed an arterial thrombus component. Thus, anticoagulation therapy appeared appropriate. We also administered low-dose anticoagulation therapy with rivaroxaban in patients with high D-dimer levels. This approach was inspired through the COMPASS trial. With the advancement of interventional materials and techniques, EP for TAO has been continuously enriched. From initial straightforward balloon dilation to drug-coated balloon dilation, endovascular radiofrequency ablation and atherectomy have been utilized. Owing to the existence of thrombosis, a combined EP of PTA+ CDT for TAO has also been reported. Previously, we analyzed the clinical data of EP for TAO patients and discovered that the EP was advantageous for lower limb preservation in TAO patients in the short term. However, these patients also received DT. Additionally, many more TAO patients have received DT alone. Therefore, we may question whether limb preservation in TAO patients is due to the effect of the EP or that of DT. The rates of major amputation were 25.9% and 27.5%, respectively, in the two groups. The overall rate of major amputation was 26.7%. Statistical analysis revealed no significant difference in major amputations between the two groups. In other words, despite the increase in EP, the long-term prognosis of the lower limbs of TAO patients did not appear to improve. The result may be attributed to the relatively low long-term patency rate of the target vessel in the EP group. The low patency rate of the target vessels in patients with TAO may be associated with the vasculitis characteristic of TAO, and EP is unlikely to resolve the underlying vasculitis in these vessels. In the long term, compared with DT alone, the EP offered little benefit in terms of limb preservation for TAO patients, but it increased the cost for these patients. However, the rate of major amputation in these patients was higher than that reported previously. In some cases, this is related to the definition of major amputation. Many studies have defined above-knee amputation as major amputation, , which evidently reduces the number of above-ankle and belt-knee amputations. Second, it was also associated with the follow-up period. The longest follow-up among the patients was 13 years, and the average follow-up time exceeded 6 years. The absolute number of major amputations clearly increased as the follow-up period increased. Many studies have followed up with TAO patients within 1–3 years after treatment. , , , Finally, this finding might also be related to the severity of the disease in the TAO patients. CLI was present in 76.7% of these patients. Univariate Cox regression analysis revealed that treatment methods, such as DT and EP, were not influencing factors for major amputation in TAO patients. Cox regression analysis revealed three independent factors for major amputation in TAO patients: wound grade, current smoking status, and disease duration. Limb wounds are the most severe symptom of TAO. It is well known that the more severe the degree of lower limb ischemia is, the greater the risk of tissue necrosis and ulcer formation. The clinical manifestations of TAO patients are intermittent claudication, rest pain, and wounds that gradually develop due to the increasing degree of ischemia. The present study further confirmed that the more severe the wound was, the greater the risk of major amputation in TAO. In a study of 344 TAO patients in northeastern Turkey, 185 patients had wounds, among which only 30 healed, and all 155 patients required amputation, including 19 major amputations. Current smoking status is an independent risk factor for major amputation among TAO patients, and smoking cessation can lower the risk of major amputation. Smoking is the most definite, or perhaps the sole, cause of TAO. , , Aside from smoking, no other factors, such as arteriosclerosis, hypertension, diabetes, and hyperlipidemia, have been identified. Otherwise, TAO should not be diagnosed. , As age increases, TAO patients gradually coexist with these factors, and it becomes difficult to distinguish them from arteriosclerosis obliterans at this point. TAO not only became accepted as a disease entity but also came to epitomize the ills of smoking. Le Joncour and associates published the largest series to date on the long-term outcomes of patients with TAO from a Western country. As shown in many other studies, patients who stopped using tobacco had a significantly lower risk of amputation than did those who continued smoking. , Recently, several Japanese scholars’ latest demographic studies on Japanese TAO patients revealed that, compared with never-smokers, the amputation rate of patients with a history of smoking was 1.437 times greater than that of never-smokers. Continual smoking might even influence the outcome of EPs. Nevertheless, the fate of ischemic limbs in patients with Buerger's disease, on the basic of other researchers’ 30 years of experience, demonstrated no significant difference in the limb salvage rate between ex-smokers and smokers. These results do not support any advantageous effect of smoking cessation on long-term remission in patients with Buerger's disease. Interestingly, our study further revealed that disease duration served as a protective factor against major amputation in TAO patients. Many major amputations took place within the first few years of the illness, and as patients grow older, the likelihood of major amputation decreases. Ohta, T. and colleagues investigated the clinical course of 118 TAO patients and discovered that 17 had major amputations, among which 14 underwent major amputations within the first 50 years of life. No patient who was over the age of 60 underwent amputation. This might be associated with the fact that TAO is a self-limiting disease. After an initial period of treatment and smoking cessation, patients might lose only a few toes without amputation for a considerable time, especially after they reach the age of 60 years, regardless of whether they are still smoking at this point. Patients over 60 years of age seem to have self-healing TAO, and the disease becomes inactive. , , Even if they continue to smoke for a long time afterward, amputation is not necessary. However, if they continue to smoke before the age of 60, it may result in recurrent wounds and even major amputation. Therefore, the criteria for self-healing in TAO could be the focus of future research on TAO. In univariate analysis, CLI and runoff were identified as factors for major amputation in TAO patients. However, these factors did not retain their significance as independent predictors in multivariate analysis. This discrepancy may be attributed to the specific characteristics of the study population and data. Nonetheless, CLI remains significantly associated with major amputation in TAO patients. , , The present study had several limitations. First, this was a single-center retrospective study, and owing to the low incidence of TAO, the number of reported cases was limited. With respect to the follow-up time, the follow-up time for some early cases was adequate, but for new cases in recent years, the follow-up time was insufficient. Third, owing to the retrospective nature of this study, the smoking status was self-reported and might have been misclassified. The patients in this study were treated without vascular bypass, which could affect the prognosis of the affected limbs and might be associated with the high rate of major amputation in these patients. Finally, the limb prognosis following EP for TAO patients in our single center might difficult be generalizable to all TAO patients. Therefore, the ideal treatment mode for TAO requires multicenter prospective controlled studies in the future. However, TAO is a rare disease, making it difficult to achieve this goal. 

In conclusion, this single-center study demonstrated that the addition of EPs to the management of patients with TAO seemed not to improve the prognosis of the affected limbs in the long term compared with DT alone. We further verified that the wound grade and current smoking status were risk factors for major amputation, whereas the disease duration of TAO was a protective factor for major amputation. 

sj-docx-1-sci-10.1177_00368504251320766 - Supplemental material for Long-term outcomes and prognostic factors of major amputation in thromboangiitis obliterans after drug therapy and endovascular procedures: A real-world cohort study Supplemental material, sj-docx-1-sci-10.1177_00368504251320766 for Long-term outcomes and prognostic factors of major amputation in thromboangiitis obliterans after drug therapy and endovascular procedures: A real-world cohort study by Hailiang Xie, Jiying Lu, Guofu Zheng, Xiaochun Liu and Weiqing Chen in Science Progress 

