Demographic Traits, Clinical Status, and Comorbidities of Patients With Thromboangiitis Obliterans in Japan.

BACKGROUND: The latest demographics, clinical and living conditions, and comorbidities of patients with thromboangiitis obliterans (TAO) in Japan are unknown.Methods and Results: We conducted a retrospective cross-sectional survey using the annual database of the Japanese Ministry of Health, Labour and Welfare medical support system for patients with TAO between April 2013 and March 2014. This study included 3,220 patients (87.6% male), with current age ≥60 years in 2,155 patients (66.9%), including 306 (9.5%) patients aged ≥80 years. Overall, 546 (17.0%) had undergone extremity amputation. The median interval from onset to amputation was 3 years. Compared with never smokers (n=400), 2,715 patients with a smoking history had a higher amputation rate (17.7% vs. 13.0%, P=0.02, odds ratio [OR]=1.437, 95% confidence interval [CI]=1.058-1.953). A lower proportion of workers and students was seen among patients after amputation than among amputation-free patients (37.9% vs. 53.0%, P<0.0001, OR=0.542, 95% CI=0.449-0.654). Comorbidities, including arteriosclerosis-related diseases, were found even in patients in their 20-30 s. CONCLUSIONS: This large survey confirmed that TAO is not a life-threatening but an extremity-threatening disease that threatens patients' professional lives. Smoking history worsens patients' condition and extremity prognosis. Long-term total health support is required, including care of extremities and arteriosclerosis-related diseases, social life support, and smoking cessation.

Top 100 cited articles in the thromboangiitis obliterans: a bibliometric analysis and visualized study.

OBJECTIVE: Thromboangiitis obliterans (TAO) is one of the most common types of peripheral arterial disease (PAD). This study aimed to explore the characteristics of the top 100 most cited articles in the TAO. METHODS: A bibliometric analysis based on the Web of Science (WOS) database was performed. Literature was retrieved and ranked by the citations. Listed below are the top 100 citations, including original articles, reviews, full-length proceeding papers, and case reports that were included for analysis. The type of literature, research areas, and languages were recorded. The trends of citations including the total citations, an analysis of publication and citation numbers were conducted each year. We analyzed citations from highly cited countries, authors, institutions, and journals. Research hotspots were gathered by a visualized analysis of author keywords. RESULTS: Most of the highly cited literature was original articles. A rising trend was observed in the number of citations per year. The peaks in the number of highly cited articles appeared in the year 1998 and 2006. The majority of the articles focused on the cardiovascular system and surgery. Journal of Vascular Surgery published most of the highly cited articles. The USA and Japan contributed nearly half the number of highly cited articles. Mayo Clinic and Nagoya University were highly cited institutions. Shionoya S and Olin JW were both the author with the largest number of citations and the most highly cited author in the reference. Articles that were highly cited most often addressed the following topics: "vasculitis", "autoimmune disease", and "critical limb ischemia". Keywords that were mostly used in recent years were "stem cell therapy", "progenitor therapy", and "immunoadsorption". The detection of bursts of author keywords showed the following: "permeability", "differentiation", and "critical limb ischemia" are recent keywords that have burst. CONCLUSIONS: In this study, the highly cited contributors in the field of TAO research were identified. Most cited articles in the top 100 focused on the cardiovascular system and surgery. Treatment and pathophysiology including stem cell therapy, progenitor therapy, genetics, autoimmunity, and inflammation are the hotspots of TAO.

Management of Buerger's disease during pregnancy.

Buerger's disease (BD), also known as thromboangiitis obliterans, is a non-atherosclerotic inflammatory disorder of unknown aetiology that affects small-sized and medium-sized vessels of the extremities. It is usually observed in middle-aged adults, especially those who smoke or use tobacco products. This condition is more frequently observed in men, although recent findings indicate an increasing prevalence among women, potentially due to increased cigarette use. The association between pregnancy and BD is rare, with only a few published cases. Previous reports have indicated that BD may worsen during gestation due to the characteristic hypercoagulable state of pregnancy. In addition, it seems to be associated with intrauterine growth restriction secondary to infarction of placental vessels. Careful obstetric management of maternal and fetal status is mandatory in pregnancies complicated with BD. We report a successful case of a pregnancy in a patient with BD treated with low-molecular-weight heparin.

Diagnostic criteria for Buerger's disease: International Consensus of VAS - European Independent Foundation in Angiology/Vascular Medicine.

Buerger's disease (BD) remains a debilitating condition and early diagnosis is paramount for its effective management. Despite many published diagnostic criteria for BD, selective criteria have been utilized in different vascular centers to manage patients with BD worldwide. A recent international Delphi Consensus Study on the diagnostic criteria of BD showed that none of these published diagnostic criteria have been universally accepted as a gold standard. Apart from the presence of smoking, these published diagnostic criteria have distinct differences between them, rendering the direct comparison of patient outcomes difficult. Hence, the expert committees from the Working Group of the VAS-European Independent Foundation in Angiology/Vascular Medicine critically reviewed the findings from the Delphi study and provided practical recommendations on the diagnostic criteria for BD, facilitating its universal use. We recommend that the 'definitive' diagnosis of BD must require the presence of three features (history of smoking, typical angiographic features and typical histopathological features) and the use of a combination of major and minor criteria for the 'suspected' diagnosis of BD. The major criterion is the history of active tobacco smoking. The five minor criteria are disease onset at age less than 45 years, ischemic involvement of the lower limbs, ischemic involvement of one or both of the upper limbs, thrombophlebitis migrans and red-blue shade of purple discoloration on edematous toes or fingers. We recommend that a 'suspected' diagnosis of BD is confirmed in the presence of a major criterion plus four or more minor criteria. In the absence of the major criterion or in cases of fewer than four minor criteria, imaging and laboratory data could facilitate the diagnosis. Validation studies on the use of these major and minor criteria are underway.

Recent advances of oxidative stress in thromboangiitis obliterans: biomolecular mechanisms, biomarkers, sources and clinical applications.

Oxidative stress (OS) has been identified as a key factor in the development of Thromboangiitis Obliterans (TAO). The detection of OS levels in clinical and scientific research practice is mainly based on the measurement of oxidative stress such as reactive oxygen species (ROS), reactive nitrogen species (RNS) and lipid peroxides. These markers are typically assessed through a combination of physical and chemical methods. Smoking is known to the state of OS in TAO, and OS levels are significantly increased in smokers due to inadequate antioxidant protection, which leads to the expression of apoptotic proteins and subsequent cell injury, thrombosis and limb ischemia. There, understanding the role of OS in the pathogenesis of TAO may provide insights into the etiology of TAO and a basis for its prevention and treatment.

Buerger's Disease - A Clinical Case.

Buerger's disease is a distal segmental nonatherosclerotic vasculopathy that involves the inferior and superior limbs of smoker males younger than 45 years old. This article aims to describe a clinical case and revise the literature about Buerger's disease. A 45-year-old smoker male repeatedly visited the emergency department for refractory pain and inflammatory signs in the right hallux. After developing ulcers in the right foot, Doppler ultrasonography revealed segmental occlusion of distal arteries of that limb. It was also observed in arteriography "corkscrew" collaterals. Autoimmune, thrombophilic and cardiovascular diseases were excluded. Analgesia, antibiotics and alprostadil were implemented. As a result, the patient stopped smoking and was submitted to minor amputation with complete healing, after which he remained asymptomatic. Buerger's disease is a diagnosis of exclusion. Therefore, smoking cessation is the most effective treatment and is crucial to prevent disease progression.

Network pharmacology-based approach to research the effect and mechanism of Si-Miao-Yong-An decoction against thromboangiitis obliterans.

BACKGROUND: Si-Miao-Yong-An decoction (SMYAD) is a conventional therapeutic formula for treat thromboangiitis obliterans (TAO), consisting of four Chinese herbs: Lonicerae japonicae Thunb. (Jinyinhua), Scrophularia ningpoensis Hemsl. (Xuanshen), Angelica sinensis (Oliv.) Diels (Danggui) and Glycyrrhiza uralensis Fisch. (Gancao). However, the mechanism of SMYAD in TAO treatment remains unclear. METHODS: Components, as well as potential targets of SMYAD in TAO therapy, were downloaded from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Subsequently, with the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server, the gene ontology (GO) biological processes and the Kyoto encyclopedia of genes and genomes (KEGG) signalling pathways of the targets enrichment were performed. Next, based on STRING online database, the protein interaction network of vital targets was built and analysed. Molecular docking and calculation of the binding affinity were performed using AutoDock. The PyMOL software was employed to observe docking outcomes of active compounds and protein targets. Based on the predicted outcomes of network pharmacology, in vivo and in vitro tests were performed for validation. In vivo experiment, the TAO rats model was established using sodium laurate injection into the femoral artery. The symptoms as well as pathological changes of the femoral artery were observed. Besides, the predicted targets were verified by the RT-qPCR, in vitro experiment. The cell viability in LPS-induced human umbilical vein endothelial cells (HUVECs) was detected using CCK-8 kit, and the predicted targets were also verified by the RT-qPCR. RESULTS: In the network pharmacology analysis, we obtained 105 chemical components in SMYAD and 24 therapeutic targets. We found that the mechanism SMYAD in TAO therapy was primarily associated with inflammation and angiogenesis by constructing multiple networks. Quercetin, vestitol and beta-sitosterol were important compounds, and interleukin-6 (IL6), MMP9, and VEGFA were key targets. According to molecular docking, active compounds (quercetin, vestitol and beta-sitosterol) and targets (IL6, MMP9 and VEGFA) showed good binding interactions. In in vivo experiment, SMYAD ameliorated the physical signs and pathological changes, inhibited the expression of IL6 and MMP9, and enhanced the expression of VEGFA. In an in vitro experiment, SMYAD increased the cell viability of LPS-induced HUVECs and the expression of VEGFA, and reduced the expression of IL6 and MMP9. CONCLUSIONS: This study showed that SMYAD improves TAO symptoms and inhibits the development of TAO. The mechanism could be associated with anti-inflammatory and therapeutic angiogenesis.

Cannabis arteritis presenting with Raynaud's and digital ulcerations: a case-based review of a controversial thromboangiitis obliterans-like condition.

Thromboangiitis obliterans (TAO), or Buerger's disease, is a non-atherosclerotic inflammatory disease of the small and medium-sized arteries, veins, and nerves of the legs and arms, strongly associated with the use of tobacco products in young adults. Cannabis arteritis (CA), an entity with similar clinical and pathological features, has been described in marijuana users as a subtype of TAO. Distinction between TAO and CA is challenging, given that most patients use tobacco and marijuana products concomitantly. Herein, we report the case of a male in his late forties who was referred to rheumatology with a 2-month history of hand swelling and bilateral painful digital ulcers with blue discoloration on his fingers and toes. The patient reported daily use of marijuana in blunt wraps and denied tobacco use. His laboratory work-up was negative for scleroderma and other connective tissue diseases. His angiogram confirmed the diagnosis of thromboangiitis obliterans, which was attributed to cannabis arteritis. The patient was started on aspirin and nifedipine daily and discontinued marijuana use. His symptoms resolved within 6 months and have not recurred for more than a year with continued avoidance of marijuana. Our case is one of the few that features primarily marijuana-driven CA and highlights the importance of not only considering marijuana use but also blunt wrap use in patients presenting with Raynaud's phenomenon and ulcerations as cannabis use rises globally.

A Multicenter Prospective Interventional Trial of Therapeutic Angiogenesis Using Bone Marrow-Derived Mononuclear Cell Implantation for Patients With Critical Limb-Threatening Ischemia Caused by Thromboangiitis Obliterans.

BACKGROUND: Thromboangiitis obliterans (TAO) can lead to the development of critical limb-threatening ischemia (CLTI). Despite conventional treatments, such as smoking cessation or revascularization, young patients (<50 years) still require limb amputation. Therapeutic angiogenesis using bone marrow-derived mononuclear cell (BM-MNC) implantation has been tested and shown to have reasonable efficacy in CLTI. In this multicenter prospective clinical trial, we evaluated the safety and efficacy of BM-MNC implantation in CLTI patients with TAO.Methods and Results: We enrolled 22 CLTI patients with skin perfusion pressure (SPP) <30 mmHg. The primary endpoint of this trial is the recovery of SPP in the treated limb after a 180-day follow-up period. Secondary endpoints include the pain scale score and transcutaneous oxygen pressure (TcPO2). One patient dropped out during follow-up, leaving 21 patients (mean age 48 years, 90.5% male, Fontaine Class IV) for analysis. BM-MNC implantation caused no serious adverse events and increased SPP by 1.5-fold compared with baseline. Surprisingly, this effect was sustained over the longer term at 180 days. Secondary endpoints also supported the efficacy of this novel therapy in relieving pain and increasing TcPO2. Major amputation-free and overall survival probabilities at 3 years among all enrolled patients were high (95.5% and 89.5%, respectively). CONCLUSIONS: BM-MNC implantation showed safety and significant efficacy in CLTI patients with TAO.

Protective Effects and Potential Mechanism of Tongxinluo on Mice with Thromboangiitis Obliterans Induced by Sodium Laurate.

OBJECTIVE: To investigate the effects of Tongxinluo (TXL) on thromboangiitis obliterans (TAO) and the underlying mechanisms. METHODS: Ninety male C57/BL6J mice were randomly divided into 6 groups according to a random number table: the sham group, TAO model group, Compound Danshen Tablet (CDT) group, and the high-, medium-, and low-dose TXL groups. All mice except the sham group were injected with sodium laurate (0.1 mL, 5 mg/mL) in the femoral artery to establish TAO mouse model. After modeling, mice in the sham and TAO model groups were intragastrically administered 0.5% (w/v) sodium carboxymethylcellulose, mice in the CDT group were intragastrically administered 0.52 g/kg CDT, and mice in the TXL-H, TXL-M, and TXL-L groups were intragastrically administered 1.5, 0.75, and 0.38 g/kg TXL, respectively. After 4 weeks of gavage, the recovery of blood flow in the lower limbs of mice was detected by Laser Doppler Imaging. The pathological changes and thrombosis of the femoral artery were observed by morphological examination. The expressions of tumor necrosis factor α (TNF-α) and inducible nitric oxide synthase (iNOS) in the femoral artery wall were detected by HE staining. Levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1α (6-keto-PGF1α), endothelin-1 (ET-1), interleukin (IL)-1ß and IL-6 were measured using enzyme-linked immunosorbent assay (ELISA). Levels of activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT) and fibrinogen (FIB) were detected by a fully automated biochemical analyzer. RESULTS: TXL promoted the restoration of blood flow in the lower limbs, reduced the area of thrombosis in the femoral artery, and alleviated the pathological changes in the femoral artery wall. Moreover, the levels of TXB2, ET-1, IL-6, IL-1ß, TNF-α and iNOS were significantly lower in the TXL groups compared with the model group (P<0.05 or P<0.01), while the level of 6-keto-PGF1α was significantly higher (P<0.01). In addition, APTT, PT, and TT were significantly prolonged in TXL groups compared with the model group (P<0.05 or P<0.01), and FIB levels were significantly decreased compared with the model group (P<0.01). CONCLUSIONS: TXL had a protective effect on TAO mice, and the mechanism may involve inhibition of thrombosis and inflammatory responses. TXL may be a potential drug for the treatment of TAO.

Integrated pharmacokinetics and pharmacometabolomics to reveal the synergistic mechanism of a multicomponent Chinese patent medicine, Mailuo Shutong pills against thromboangiitis obliterans.

BACKGROUND: Mailuo Shutong Pills (MLST) have displayed pharmacological activity against thromboangiitis obliterans (TAO). However, the active ingredients and therapeutic mechanism of MLST against TAO remained to be further clarified. PURPOSE: The aim of this study was to explore the active components of MLST and their synergistic mechanism against TAO by integrating pharmacokinetics (PK) and pharmacometabolomics (PM). METHODS: TAO model rats were established by sodium laurate solution. Firstly, the efficacy of MLST was evaluated by gangrene score, blood flow velocity, and hematoxylin-eosin (H&E) staining. Secondly, PK research was conducted on bioavailable components to characterize their dynamic behaviors under TAO. Thirdly, multiple plasma and urine metabolic biomarkers for sodium laurate-induced TAO rats were found by untargeted metabolomics, and then variations in TAO-altered metabolites following MLST treatment were analyzed utilizing multivariate and bioinformatic analysis. Additionally, metabolic pathway analysis was performed using MetaboAnalyst. Finally, the dynamic link between absorbed MLST-compounds and TAO-associated endogenous metabolites was established by correlation analysis. RESULTS: MLST significantly alleviated gangrene symptoms by improving the infiltration of inflammatory cells and blood supply in TAO rats. Significant differences in metabolic profiles were found in 17 differential metabolites in plasma and 24 in urine between Sham and TAO rats. The 10 bioavailable MLST-compounds, such as chlorogenic acid and paeoniflorin, showed positive or negative correlations with various TAO-altered metabolites related to glutamate metabolism, histidine metabolism, arachidonic acid metabolism and so on. CONCLUSION: This study originally investigated the dynamic interaction between MLST and the biosystem, providing unique insight for disclosing the active components of MLST and their synergistic mechanisms against TAO, which also shed light on new therapeutic targets for TAO and treatment.

The Effect of Smoking Cessation on the Technical Success of Endovascular Treatment for Thromboangiitis Obliterans.

PURPOSE: To show that smoking cessation improves the technical success of lower extremity endovascular treatment in patients with thromboangiitis obliterans (TAO), or Buerger disease. MATERIALS AND METHODS: One hundred two patients with TAO who underwent endovascular treatment for chronic limb-threatening ischemia or severe claudication of lower extremities in a tertiary hospital between 2015 and 2022 were included in this retrospective study. Data on serum cotinine levels were available for the last 45 patients, and 38 patients constituted the study population. Per the institution's protocol, patients were instructed to quit smoking 15 days before the intervention. However, cotinine levels showed that some of the patients continued smoking. Technical and recanalization successes were assessed as the primary end points. The secondary end point was the improvement in Rutherford scores at the 1-month follow-up. The McNemar test was used to compare the proportion of recanalized arteries after the intervention. RESULTS: Thirty-seven men and 1 woman (mean age, 42.9 years ± 10.1) were evaluated. The overall technical success rate was 86.8% in the study group. The technical success rate was significantly higher in the nonsmoker group (n = 24 [96%]) than in the smoker group (n = 8 [61.5%]; P = .006). One-month clinical data were available for 100% of the patients. The Rutherford category of the nonsmoker group was significantly lower at the 1-month follow-up. In addition, the Wilcoxon signed-rank test revealed lower Rutherford scores after the intervention in the nonsmoker group. The adverse event rate was 8%. One (2.7%) patient in the smoker group underwent a minor amputation. CONCLUSIONS: Cessation of smoking before endovascular therapy improved technical success and recanalization rates in patients with TAO.

Do Patients With Arterial Occlusive Disease of Different Etiologies Benefit Equally From Cilostazol?

BACKGROUND: Cilostazol is a guideline-recommended drug that improves intermittent claudication and quality of life in patients with chronic atherosclerotic peripheral arterial disease. The drug is used for most etiologies of arterial occlusive diseases in clinical practice. This study aimed to evaluate whether patients benefit equally from cilostazol regardless of etiology. METHODS: Patients on cilostazol were divided into 4 groups according to arterial occlusive disease etiology: (1) atherosclerosis, (2) diabetic angiopathy, (3) embolism/thrombosis, and (4) Buerger disease. Patients' maximum walking distance, ankle-brachial index score and distal tissue oxygen saturation (Sto2), clinical improvement onset time, ability to reach maximum benefit time, vascular surgeries, and wounds were compared before they started cilostazol and after 12 months. Results were evaluated at a statistical significance of P < .05. RESULTS: In 194 patients, 307 target extremities were evaluated in the 4 disease groups. After cilostazol use, maximum walking distance, ankle-brachial index score, and distal Sto2 increased significantly in all groups (P < .001), but distal Sto2 in the diabetic angiopathy and Buerger disease groups was significantly lower than in the atherosclerosis group (P < .001). Ankle-brachial index and distal Sto2 differences in the Buerger disease group were significantly lower (both P < .001). The vascular surgery counts decreased significantly in the atherosclerosis and embolism/thrombosis groups (P = .019 and P = .004, respectively). CONCLUSION: Patients with nonatherosclerotic arterial occlusive disease also benefit from cilostazol, but patients with Buerger disease or diabetic angiopathy seem to benefit less. Combining cilostazol with anticoagulant or antiaggregant agents and closer monitoring of these patients may produce better results.

Psychiatric sequelae of thromboangiitis obliterans: a case report and review of the literature.

BACKGROUND: Peripheral manifestations secondary to progressive vascular occlusions are characteristic of the rare condition termed thromboangiitis obliternas (TAO) or Buerger's disease. The central manifestations of this disease are however poorly characterized, particularly those of psychiatric nature, and their prevalence is largely unknown. Speculations have been made around the polymorphic nature and triggers of observed psychopathology in TAO; much however remains to be unraveled in this area. CASE PRESENTATION: We present the case of a 33-year-old Caucasian male who developed first episode of psychosis at the age of 29 years. There was no history of previous mental illness either in the patient, or in any of his family members. He had been a long- term heavy smoker and was experiencing progressive lower limb claudication since the age of 22 years; however, all inflammatory, autoimmune and atherosclerotic markers were negative. His psychosis was characterized by retention of a warm affect, and despite some amelioration, was generally resistant to a fair trial of several anti-psychotic medications including Clozapine. CONCLUSION: The pathophysiology of psychosis secondary to Buerger's is not yet well characterized which adds to the complexity of managing these cases. Recognizing that cerebral manifestations of this disease may evolve several years after the onset of peripheral thromboangiitic features is important for following the natural history and considering measures that may reduce the burden of illness.

Acute phase reactant proteins in Buerger's disease: Is it a systemic disease?

Aim: The aim of this study was evaluating acute phase reactant (APR) proteins including high sensitivity C-reactive protein (hsCRP), pentraxin 3 (PTX3), fibrinogen, complement C3, hepcidin, and albumin in patients suffering from Buerger's disease (BD) compared to controls.Methods: The APRs were evaluated in 92 cases of BD patients and 90 healthy age and sex matched controls of blood from Iran and Turkey. The diagnosis was done according to Shionoya's criteria. However, patients with age less than 40 were included, instead of those less than 50. The diagnosis was confirmed by angiography or CT angiography. The patients were categorized into active and quiescent phases of the disease according to clinical manifestation. Patients with rest pain, non-healing ulcer, and gangrene were categorized in the active phase of the disease and the patients with unchanged claudication for more than 6 months without trophic lesions or gangrene were categorized in the quiescent phase of the disease.Results: The serum level of PTX3, hsCRP, fibrinogen, C3, and hepcidin in BD was significantly higher than controls (p < 0.004). Also, albumin in the BD group was significantly lower than controls (p < 0.001). In patients that categorized in the active phase, fibrinogen, C3, and hsCRP were significantly higher and albumin was significantly lower compared to patients in the quiescent phase. No significant difference was found between the level of PTX3 and hepcidin in the patients in active and quiescent phases of the disease.Conclusion: The pattern of the level of APRs in BD seems more likely systemic inflammatory disorder than atherosclerosis obliterans. More clinical trials for evaluating the efficacy of anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids as a part of management of BD are required. Also, according to low level of albumin in TAO, a protein rich diet might be beneficial for BD patients in the active phase of their disease.