Modern researches on Blood Stasis syndrome 1989–2015

Abstract

Background:

Blood Stasis syndrome (BSS) is one of the major syndromes in Traditional East Asia medicine (TEAM). Modern research of BSS began in the late1980s.

Methods:

We searched in PubMed for BSS-related articles published between 1989 and 2015. The publication information, study contents, and bibliometric indicators were documented and analyzed.

Results:

Most of the BSS-related studies were conducted by Chinese researchers in China. The number of publications on BSS-related increased rapidly in recent years, so did the quality of them. The disease diversity of BSS-related studies increased along with the number of publications. Yet the academic influence of them remained on average low; further, the diagnostic criteria of BSS were not uniform.

Conclusions:

BSS-related studies have increased in quantity and quality, but there are limitations to them which require improvement in research productivity and academic influence.

1. Introduction

Blood stasis syndrome (BSS, also known as Xueyu Zheng in Chinese or Oketsu in Japanese) is one of the major syndromes in Traditional East Asia medicine (TEAM). BSS is the compound of various manifestations including pain that occurs in a fixed location, dark-purple face or tongue, bleeding, blood spots under the skin, and an astringent pulse among other features.^[1] There are common characteristics and manifestations of BSS in different diseases. In the theory of TEAM, BSS is usually caused by internal or external factors and leads to disturbance of blood circulation.^[2] BSS has an important role in TEAM, since it is related to blood, one of the basic elements that nourishes and maintains the body's physiologic functions. Also, it is seen in almost all chronic internal diseases and external injuries.

The first descriptions of BSS can be traced back to over 2000 years ago, where it is found in the Inner Canon of Huangdi (about 200 B.C. in China). Throughout the practice of TEAM in eastern Asia, the understanding of BSS evolved gradually. But due to the lack of standard diagnosis criteria, it was difficult to summarize and communicate between different studies. Not just in scientific studies, a uniformed and objective diagnostic method for BSS is essential for clinical diagnosis and treatment.^[2]BSS is commonly seen in chronic internal diseases and external injuries; hence, the accurate identification and evaluation of BSS and the application of activating blood circulation to dissipate blood stasis are vital to the treatment via TEAM.^[1,3] The key to achieving this relies on standardized diagnosis criteria which truly reflects the nature of BSS. In the 1980s, standard diagnostic criteria for BSS were officially established by formal academic committees. In 1982, Tentative diagnostic criterion for BSS was first established by Specialized Committee of “activating blood circulation” (ABC) in China.^[4] In Japan, Diagnostic criteria for Oketsu (blood-stasis) syndrome was published by Terasawa et al^[5] in 1983. After years of applications and analyses, revised and relatively more standard diagnostic criteria were established in the late 1980s. In China, the “diagnostic criteria of Blood-stasis symptom-complex” was determined and established in the Chinese Association of Traditional Chinese Medicine, by the committee of “promoting blood circulation to remove blood stasis” in 1988.^[6] The next year in Japan, similar diagnostic criteria were established by Terasawa.^[7] Research on BSS has improved since 1989, with the establishment of the standard diagnosis criteria for BSS. It is reported that BSS is correlated to several pathogeneses including abnormal coagulation function,^[8] inflammation,^[9] and accelerated red blood cell senescence.^[10] Studies that focus on the treatment of BSS are also increasing. With more applicable diagnostic criteria established and the BSS-related studies increased, the inconsistency of BSS diagnostic criteria is drawing researchers’ attention.^[11]

Since modern research on BSS has been ongoing for >30 years, a systematic summary of them is warranted. To date, reviews on particular aspects of BSS such as certain diseases, biomarkers, and medications have been published. But there has not been any comprehensive recognition of the publication status and quality of BSS-related articles as a whole. Therefore, in this study, we systematically summarized all the articles related to BSS published from 1989 to 2015 in MEDLINE and in English, which are the most used academic database and language, hoping to gain a broad perspective of modern research of BSS.

2. Materials and methods

2.1. Data sources and searches

Since 1989 was the milestone for modern research of BSS, we searched for all articles related to BSS in PubMed from 1st January 1989 to 31th December 2015. The search term was (“blood stasis syndrome” [All Fields]) AND (“1989/01/01” [PDat]: “2015/12/31” [PDat])). The ethical approval was not necessary since all the data we collected were from those published articles, this research did not involve any privacy of any individual, and the research process would not result in any harm or discomfort to anyone.

2.2. Inclusion/exclusion criteria

The articles which were selected should meet all the inclusion criteria as followed:

• (1)The definition of BSS in the article was within the theory of TEAM.
• (2)The main content of the article should focus on BSS.
• (3)The article was written in English.
• (4)The publication date should between 1st January 1989 and 31th December 2015

Those articles not in English or which studied Western medicine-defined blood stasis were not included.

2.3. Data extraction

The publication information and bibliometric indicators were collected from those included articles. The documented indices included:

• (1)Publication information, including journal, year of publication, article type, country of author's affiliation.
• (2)Study contents, including diseases, main subjects of study, characteristics of study, the diagnostic criteria of BSS used in research, intervention if applied.
• (3)Bibliometric indicators, including total cites in Web of Science (WOS), Scopus and Google Scholar respectively, h-index, and the impact factor (IF) of the journal in publication year. h-index and IF were extracted from WOS and annual Journal Citation Reports (JCR).

Three authors (LD, GC, and JH) participated in articles searching, screening, and data extracting. All of the information extracted were supervised and verified by 1 author (JL). Any discrepancies were discussed among all of the authors for consensus.

2.4. Data analysis

Data analysis and visualization were performed via SPSS 17.0 and Microsoft Excel 2010. Data were presented by counts, percentage, and frequency.

3. Results

3.1. Selection of studies

Searching PubMed with the term of “blood stasis,” we identified 807 items published between 1st January 1989 and 31th December 2015. By reading the title and abstract, we excluded 544 non-English language articles. By reading the abstract and the whole articles, we excluded 108 articles that did not focus on BSS in the theory of TEAM. Eventually 155 articles were included in this analysis. Figure 1 shows the flowchart of article searching and screening. Table 1                   shows the detailed information of all the included articles. Tables 2 and 3 show the diagnostic criteria and modeling methods these articles applied in their researches. The number in Diagnostic criteria/modeling methods column of Table 1                   was referred to those in Tables 2 and 3

Figure 1.

Article searching and screening process. The article inclusion process was under the inclusion established in Materials and Methods section.

Table 1.

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 1 (Continued).

General and bibliometric information of included BSS-related articles (sorted by total citation).

Table 2.

Applied diagnostic criteria for BSS (sorted by frequency).

Table 3.

Animal and cell modeling methods.

3.2. General information of included articles

Among the 155 BSS-related articles, 127 of them (81.94%) were original articles, 22 of them (14.19%) were review (including systematic review and meta-analysis), 6 (3.87%) were others (such as conference abstract, academic opinion). Authors’ affiliations were most commonly in China (144 out of 155, 92.9%). Only 11 articles were authored by authors outside of China, including 7 articles from Japan and 4 articles from Korea. One of the second authors was Norwegian.

The year of publication is graphed in Fig. 2. An increase of publication is observed from 2009, with a peak from 2012 to 2014.

Figure 2.

Annual publication and articles types of BSS-related articles. Different types of articles were addressed in different colors; the trend line of publications was also drawn. BSS = blood stasis syndrome.

3.3. Diseases categories

The names of diseases were documented and classified into different categories according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10, version 2016).^[12] Among the 155 BSS-related articles, 112 (72.26%) were not specified to particular diseases, 46 (29.68%) articles focused on coronary heart disease (CHD), which was the largest proportion in disease classification. Followed by 13 (8.39%) in different types of cancer/tumor, 8 (5.16%) in stroke, 7 (4.52%) in skin diseases, 5 (3.23%) in diabetes, 4 (2.58%) in hypertension, metabolic diseases, nervous system diseases, and kidney diseases respectively, 3 (1.94%) in heart failure and gastrointestinal diseases, respectively, and 1 (0.65%) in arrhythmia. Cardiovascular diseases were the most common disease categories, especially CHD. Such results coincided with the epidemiology of clinical BSS ^[13] and reflected the high interest in CHD-BSS in BSS studies.

The number of articles focused on cardiovascular diseases increased rapidly from 2010 (Fig. 3). Although the number of publications gradually increased (Fig. 2), the range of disease categories broadened, and the gaps between different diseases were shortened, these results indicate a growth of diversity in BSS studies.

Figure 3.

Disease classification of BSS-related articles. Different diseases were addressed in different colors. BSS = blood stasis syndrome.

3.4. Research content and Intervention categories

Among the 155 BSS-related articles, there were 90 articles using humans as research subjects in clinical trials. In total, 58 (64.44%) out of the 90 focused on the BSS syndrome, including syndrome characteristics, syndrome distribution in different diseases, and syndrome differentiation. However, 32 (35.56%) out of the 90 articles focused on efficacy evaluation and comparison of different interventions. Also, 18 articles applied the rules of randomized clinical trial (RCT). It is noteworthy that there were 12 RCTs published in the last 5 years. On the other hand, more comprehensive and profound omics technologies were used in recent years. Twenty-four BSS-related articles explored the BSS characteristics or intervention via genomics, transcriptomics, proteomics, and metabolomics, mostly published since 2012. The contents and technologies contained in the articles show the quality and depth of BSS-related researches increased accordingly as more articles were published.

Despite the range of research subjects, there were 63 articles that applied interventions, including 26 (41.27% of 63) patent medicine (pill, capsule, pounder, injection, so on), 25 (39.68%) herbal formula, 11 (17.46%) herbal extracts, and 1 (1.59%) acupuncture. The variation of intervention-year can be seen in Fig. 4. Though the total amounts of patent medicine and herbal formula are close, the number of studies on patent medicine increased in recent years while the proportion of herbal formula shrank. With the modern exploration of TEAM developing, studies with patent medicines seem to be improving, with results that appear more convincing.^[14–16] Herbal medicine is also one of the vital components in TEAM. It is more widely used in clinical practice. With the growth in BSS-related research, it is necessary to improve and expand herbal formula research.

Figure 4.

Intervention-year variation of BSS-related articles. Interventions including patent medicine, herbal formula, herbal extracts, and acupuncture were addressed in different colors. BSS = blood stasis syndrome.

3.5. Academic influence analysis

The total number of citations and the h-index of every BSS-related article were extracted from WOS, Scopus, and Google Scholar. There were 721, 820, and 1343 cites in WOS, Scopus, and Google Scholar for the 155 BSS-related articles respectively, averagely 4.65, 5.29, and 8.66 cites for each article. According to the citation-year analysis (Fig. 5), the annual citation amount was low before 2009 and has increased since 2010. Citation is related to the articles’ quality, publication type, and research content. The significant increase of citation after 2010 might be due to the increase of both numbers of publications and research quality.

Figure 5.

Academic influence indices in every year. Total citation in WOS, Scopus and Google Scholar, h-index, and amount of article has h-index ≥2 were presented in the line chart. WOS = web of science.

A peak in citations in 2000 was contributed by 2 relatively high-quality articles published in influential journals. One of them was a review of herbal products with the function of promoting blood circulation and removing blood stasis. The other was a pharmacokinetics analysis on herbal formulae.

The Schubert h-index (h-index) was introduced by András Schubert in 2009.^[17] It has been widely used to measure the direct and indirect citation influence of single publications. Normally an article with h-index≥2 is considered influential. The average h-index of 155 BSS-related articles is 1.39. There are 43 (27.74%) articles with h-index≥2. Only 3 articles’ h-index were higher than 10. As can be seen in Fig. 5, the tendency of the h-index coordinated with the total number of citations, but articles with h-index≥2 are seldom, the proportion of influential articles are small, despite the number of publications and study quality increasing.

3.6. Diagnostic criteria diversity

The diagnostic criteria or definition of BSS in the included articles were documented. Though the basic recognitions and definitions of BSS were similar among different countries, regions, and research groups, the diagnostic criteria used in different studies were strikingly inconsistent. Of all the 155 BSS-related articles, 59 articles did not mention the diagnostic criteria or definition of BSS they implied, 38 of which were original articles (29.92% of all the original articles). Among the rest of BSS-related articles, a total of 27 different kinds of diagnostic criteria were applied in human related researches respectively (Table 2), and 11 different methods were used in animal or cell modeling experiments (Table 3).

Among the 27 different diagnostic criteria for BSS, 9 were established by national or state academic committees, 5 were established by ministerial or provincial agencies, 3 were from text books, and the rest of them were published in journals by individual authors. Among these diagnostic criteria, The Criterion of Chinese Medicine Syndrome-differentiation for CHD by Cardiovascular Branch of Chinese Association of Integrative Western & Chinese Medicine (1991),^[18]Guiding principle of clinical research on new drugs of TCM by Ministry of Health, China (2002),^[19] and The diagnostic criteria of blood stasis syndrome by Special Committee of Promoting Blood Circulation and Removing Blood Stasis, Chinese Association of Integrative Western & Chinese Medicine (1987)^[20] were used most frequently (in 13, 11, and 9 studies respectively). Though 104 articles stated the BSS diagnostic criteria they used, only 10 articles listed the detailed diagnostic terms or scales, the rest only named the diagnostic criteria with references. Other than this, 8 studies relied on clinical judgment, which is based on the judgment of >1 practitioner.

In the basic animal and cell experimental studies, 11 different techniques were used to simulate the state of BSS, including adrenaline hydrochloride injection and ice-water soak, artificial myocardial infarction or middle cerebral artery occlusion, exhaustive swimming exercising, metabolic syndrome via diet control, hypoxia, H₂O₂-induced oxidative injury and so forth. Though some of the techniques were used in several studies, there are unresolved questions about the validity of these experimental approaches in BSS research as well as problems in the inconsistency of the research approach applied in different studies.

4. Discussion

This bibliometric analysis summarized modern research on BSS from 1989 to 2015. It contains all of the BSS-related articles in PubMed written in English, including clinical trials, cross-sectional studies, case series, case reports, reviews, academic opinions, and so forth. Our findings show that there were few studies on BSS in English in PubMed for an extended period, with a significant growth from 2009 peaking between 2012 and 2014. With the growth in publication, the amount of different types of articles increased accordingly, especially clinical trials and experimental studies.

Our findings also show that despite the concept of BSS being common within the different branches of TEAM, BSS-related articles in these years are mostly authored by Chinese researchers. So far the academic concept and scholarly communication of BSS are mostly under the theory of Traditional Chinese medicine (TCM, one of the main components and origin of TEAM). It is beneficial to explore BSS in united academic system, but cooperation and communication between countries and groups in different disciplines and diseases are also vital for the development and promotion of the research products.

A wide range of diseases not limited to CHD, hypertension, stroke, different types of cancer, diabetes, arrhythmia, obesity, dyslipidemia, gastric ulcer, hepatitis B, psoriasis, primary glomerular disease, and rheumatoid arthritis were addressed in BSS-related studies. Most of these are chronic internal diseases. In the theory of TEAM, BSS is most commonly seen in chronic illness.^[13,21,22] Continuous disturbances of the inner environment can lead to impaired blood circulation and cause BSS. Hence, BSS is the major syndrome of the above chronic diseases.

Though the number of publications and their citations of BSS-related studies increased in recent years, the academic influence of these still remains relatively low. The average citation for each article is 4.65 to the search date of this study. 27.74% of the articles had h-index higher than 2, only 3 articles’ h-index were higher than 10. The proportion of influential articles is small, especially as the number of publications and quality of the studies are increasing. Of all the BSS-related articles contained in PubMed, 97 out of the 155 articles were published in 3 journals (Chinese Journal of Integrative Medicine, Evidence Based Complementary and Alternative Medicine, and Journal of Traditional Chinese Medicine), whose IFs are between 0.5 and 2. The fact that most studies are published in only 3 complementary and alternative medicine (CAM) journals indicates a probable reason for the low impact of the research. Had the studies been published more widely and especially in non-CAM more mainstream journals, they would have gotten a wider audience and received more attention. It is thus important for authors of future studies to plan their studies more carefully with an eye to targeting publication in more mainstream journals with higher impact factors. This, in turn, will require a further raising of standards for research.

We also found that of all the BSS-related articles, one-third did not state the diagnostic criteria of BSS, the authors only claimed the presence of BSS, or gave a simple description of it. For those that stated the criteria they used in their researches, the diagnostic criteria varied with up to 27 different kinds established by different academic committees and agencies. Though some of them are different editions of the same criteria, the inconsistency of the BSS diagnostic criteria is highly problematic. This inconsistency has weakened the comparability and the validity of BSS-related studies. Different inclusion criteria may lead to different research Results. In the animal and cell experiments, the different modeling methods similarly weaken the findings and their impact. Those articles without specific diagnostic criteria tend to have lower numbers of citations in WOS, Scopus, and Google Scholar than the average and especially those with developed criteria. Furthermore, the fact that many BSS criteria were established in China may be an indication that there is significant disagreement within China. Such circumstances might be one of the reasons that slow progress of recognition and citation and the low academic interest were achieved in BSS-related researches for the past decades. Thus, of major concern is the notion that while there is clinical agreement about the presence and use of BSS in treatment, the scientific community has not yet identified all its varieties. In that case, a globally applicable concept of BSS and well-reckoned diagnostic criteria are needed to comprehensively cover different diseases, gender, living and working environment, cultural factors, and so on. It is evidently that some biomarkers have been identified and recommended for pattern identification in different diseases, syndromes, and populations.^[3] Using unique biomarkers to subsidiarily identify BSS and its subtypes is an objective approach to eliminate these differences.

Modern research on BSS has been conducted over recent decades. In our overview of publications, we see that it is the right time to integrate the resources and enhance the quality and productivity of BSS-related studies. For future studies, we have some recommendations. First, cooperation between different groups in different fields, and countries need to increase to address some of the issues raised by our review. Second, studies to establish a uniform validated standard for diagnosis and evaluation criteria of BSS are needed. More investigation and cooperation is needed to achieve this. Third, once this standard has been developed and validated more objective biomarkers for BSS need to be identified. More objective biomarkers are the key to the modernization of BSS in medical practice. Fourth, clinical and experimental studies on BSS should be more objective, scientific, apply more restricted rules, and advanced technologies. Fifth, studies of BSS should return to clinical practice, do they result in enhanced treatment of BSS? The efficacy and safety evaluation of existing herbal formulae, patent medicines, and extracts, as well as the development of new drugs for BSS are important.

There are some limitations in our study. We only included articles published between 1989 and 2015, since we aimed to focus on the modern researches of BSS under validated diagnosis criteria, which were published in the late 1980s. However, the articles that we have found did not all follow these same criteria and in fact there are wide range of different criteria and inconsistency in how BSS has been identified in the studies. This weakens our findings, but at the same time reveals the need for further studies. Additionally, publication bias was also a limitation in this study. We only included articles written in English, which are more likely read by the researchers worldwide. This is because one of the intentions of this research is to estimate the exploration and the promotion of BSS worldwide, English is the most suitable language to evaluate the outcomes. Thus, we did not include articles published in the China national knowledge infrastructure (CNKI), China, which contain a large quantity of BSS-related articles in Chinese. We plan to perform a comparative search between Medline and CNKI to analysis the BSS-related articles’ variations between English and Chinese in the future.

5. Conclusions

To sum up, the publication of BSS-related articles increased continuously, especially in the last 5 years. Study quality has improved along with the number of publications. The diversity of BSS-related studies increased, whereas CHD-BSS is still the most researched area. Intervention studies of BSS inclined more to patent medicine; more attention should be drawn to herbal formulae as well. The diagnostic criteria for BSS are still not unified. With the basis of increasing numbers of publications, studies with high impact are still seldom. The researchers need to consider how to increase the productivity and expand the influence of their research products while finishing the study; key among this will be addressing the issue of inconsistency of criteria to identify BSS.