Global Research Hotspots in Venous Thromboembolism Anticoagulation: A Knowledge-Map Analysis from 2012 to 2021

Background Venous thromboembolism (VTE) is a common cardiovascular disease that seriously threatens human lives. Anticoagulant therapy is considered to be the cornerstone of VTE treatment. An increasing number of studies has been updated in the VTE anticoagulation field. However, no bibliometric analyses have assessed these publications comprehensively. Therefore, our study aimed to analyze the global status, hotspots, and trends of anticoagulant therapy for VTE. Methods The relevant literature on VTE anticoagulation published between 2012 and 2021 was retrieved and collected from the Web of Science Core Collection database. VOSviewer, Cooccurrence Matrix Builder, gCLUTO, and some online visualization tools were adopted for bibliometric analysis. Results A total of 15,152 related articles were retrieved. In recent years, the research output of VTE anticoagulation gradually increased. The United States was the most productive country. International cooperation is concentrated in North America and Europe; the most influential documents, journals, authors, and organizations were also from these two continents. Research hotspots mainly focus on clinical guidelines, VTE in special populations, non-vitamin K oral anticoagulants (NOACs), and parenteral anticoagulation. The research frontiers and trends include the assessment of NOACs and the antithrombotic management of VTE complicated with coronavirus disease 2019 (COVID-19). Conclusion This bibliometric analysis provides a systematic overview of the VTE anticoagulation research, which will facilitate researchers to better understand the situation of VTE anticoagulation. Future studies should be dedicated to NOACs application and VTE-combined COVID-19 patients.


Introduction
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most frequent cardiovascular complication in hospitalized patients [1,2].Although the exact incidence of VTE is unreported, an estimated incidence of frst VTE is 0.7 to 1.4 per 1000 person-years [3,4].Meanwhile, VTE can lead to severe complications, including postthrombotic syndrome for DVT, chronic thromboembolic pulmonary hypertension for PE, and death [5].VTE is also characterized by high hospitalization costs, with estimated annual costs ranging from $13.5 to $27.2 billion in the United States [6].Anticoagulant therapy is the standard treatment for VTE, consistently recommended by various guidelines [7][8][9].
However, the anticoagulant recommendations in diferent VTE settings are diverse, especially in patients with cancer, orthopedic surgery, antiphospholipid syndrome (APS), pregnant women, and children [10][11][12][13][14].Following the rapid advances in understanding VTE and broadening approved indications of nonvitamin K oral anticoagulants (NOACs), it is necessary to summarize the progress, hotspot, and trend of VTE anticoagulation research.
Bibliometrics, which has rapidly developed in medical research, is widely used to quantitatively analyze knowledge structures and research trends in a specifc area [15,16].Te Web of Science Core Collection (WoSCC) database is a platform that contains representative and pioneering scientifc research articles, which was the preferred retrieving source for bibliometric analysis in the medical feld [17,18].Te VOSviewer is a software tool to build bibliometrics visualizing network maps based on the search outcome of the WoSCC database.In addition, biclustering analysis can efciently discover global and local information by simultaneously clustering the row and column data matrix, which is a novel bibliometric methodology to explore medical research hotspots [19].
Tere has been no bibliometric analysis conducted regarding VTE anticoagulation until now.Most of the literature on VTE anticoagulation research is limited to reviews that list or summarize the existing research and lack analysis of research hotspots or development trends, failing to provide substantive suggestions to scholars [11,20].Te present study is the frst to conduct literature bibliometric and visual analysis involving VTE anticoagulation.Compared with previous review articles, this study provides the characteristics, internal relationships, and scientifc structure of VTE anticoagulation research based on the contents of authors, journals, institutions, countries, and keywords.More importantly, biclustering analysis is carried out to provide future trends for researchers and clinicians in this feld.

Search Strategy and Data
Collection.Web of Science (WoS, Clarivate Analytics, Philadelphia, PA, USA), which contains more than 12,000 international academic journals, is one of the most comprehensive and authoritative database platforms for obtaining global academic information.Moreover, apart from the general literature search, it also possesses an essential function of citation index searching, which helps assess the academic performance of literature in a specifc feld [21,22].Literature on VTE anticoagulation was retrieved from the WoSCC Science Citation Index Expanded (SCI-EXPANDED) database, published from January 1, 2012, to December 31, 2021.Te search terms were designed according to previous studies and listed in Table S1 [23,24].Document type was limited to the article, and the language was restricted to English.Te complete information of each included article, containing the title, authors, year of publication, afliation, abstract, keywords, language, and citations, was exported into a text format.All literature was searched and downloaded independently by two reviewers (J.W. and Y.L.).Also, disagreements were discussed with the senior author (Z.G.) to reach a consensus.

Bibliometric Analysis.
Te essential characteristics of the included articles, containing the total number of literature, the ranking of afliated institutions, productive funding agencies, research felds, and authors, were analyzed using intrinsic functions of the WoSCC database and Microsoft Excel (2019).Furthermore, annual publication trends were analyzed through the Online Analysis Platform (https:// bibliometric.com/)[25].VOSviewer (version 1.6.10),created by Leiden University, Leiden, the Netherlands, was applied to generate diferent scientifc landscapes and networks.Te construction of networks was mainly based on coauthorship, cooccurrence, citation, bibliographic coupling, or cocitation and themes.Coauthorship relations are confrmed when the authors, institutions, and countries or regions were cosigned in published papers; co-occurrence analysis calculates correlation strength by the frequency of occurrences at the same time between keywords.Te citation analysis refers to the connection between the two documents by direct reference.Bibliographic coupling analysis assesses the similarity between two pieces of literature by examining the references they share, and cocitation analysis evaluates the relationship between two pieces of literature by analyzing how often they are cited together.In the overlay visualization map, it is worth noting the node colors represent the average publication year.Bibliographic Item Cooccurrence Matrix Builder Version 2.0 (BICOMB 2.0), designed by Professor Lei Cui from China Medical University, was used to retrieve a high-frequency keywordssource articles matrix [23].Ten, the matrix was input into gCLUTO 1.0 (Graphical clustering toolkit, gCLUTO; Karypis Lab, 2014) software to achieve mountain and matrix visualizations.Te parameter settings of gCLUTO are adjusted to the suitable for biclustering analysis [26].Finally, the repeated bisection was selected as the clustering method, the similarity function chose cosine, and I 2 was set to the criterion function.

Publication Output Patterns.
Totally, 15152 articles involved in VTE anticoagulation topics were obtained in the WoSCC database from 2012 to 2021.Tere were 740 articles excluded due to language restrictions.Another 4720 articles, containing 2957 reviews, 887 abstracts, 455 editorials, 341 letters, and 80 other publication forms, were eliminated because they were nontarget article forms.We fnally included 9692 articles that met the eligibility criteria for further bibliometric analysis (Figure 1).47 S1B).Cardiovascular system cardiology (3088), hematology (2600), general internal medicine (1631), surgery (1167), and pharmacology pharmacy (779) were the top 5 research domains (Figure S1C).S2. 1, while the top 100 cited papers are listed in Table S3.Te majority of these articles were clinical guidelines that focused on prophylaxis and treatment of VTE.Additionally, articles that specifcally addressed VTE anticoagulation in populations with cancer, surgery, antiphospholipid syndrome (APS), and pregnancy were also abundant.Clinical trials studying the efcacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) for anticoagulation in VTE, as well as research on the combination of thrombotic disease and COVID-19, have also garnered signifcant attention.Te average number of citations for the top 100 most-cited papers was 545, with a range from 194 to 3104.

Analysis of Citations. Te top 10 most-cited documents in research on anticoagulation for venous thromboembolism (VTE) are presented in Table
Te ranking of the 10 most active journals, authors, organizations, and countries in publications on VTE anticoagulation is listed in Table 2. Chest, with an impact factor of 9.41, was the most-cited journal and produced 54 articles that received 15253 citations.Agnelli G from the University of Perugia, who contributed 59 pieces of literature, was the most-cited author (cited 8416 times) (Figure S2A).
McMaster University was ranked the highest-cited institution, having published 395 articles that received 35845 citations (Figure S2B).In addition, the USA, the most-cited nation, had 3505 papers cited 89355 times, with a total link strength of 60415 (Figure S2C).

Analyses of Bibliographic Coupling and Cocitation.
Te results of bibliographic coupling analysis for authors, documents, journals, and countries are presented in Figure S3.In the network visualization of documents, 8 clusters were identifed.

Journal of Interventional Cardiology
A biclustering analysis of keywords was performed simultaneously to identify hotspots.Keywords were extracted from the retrieved articles, and synonyms were merged.High-frequency keywords, defned as those occurring over 50 times, are listed in Table S4.Figures 5 and 6 show the mountain and matrix visualization diagrams of highfrequency keywords-source articles matrix, with specifc keywords of clusters as shown in Table S5.Five clusters were identifed after adjusting the clustering parameter confguration as follows: (0): oral anticoagulant therapy for VTE;

Analyses of Temes and Trend Topics.
A total of 177 terms occurred more than 250 times.Figure 7(a) shows four theme clusters of VTE anticoagulation in diferent colors.Te red cluster involved comprehensive guidelines around VTE, including the causes, diagnosis, and treatment of VTE.Te green cluster referred to the primary and secondary outcomes of VTE.Te blue cluster focused on the efcacy and safety of oral anticoagulants for VTE.Also, the yellow cluster concerned parenteral anticoagulation prophylaxis of

Discussion
Tis study draws a comprehensive overview of the current research status and hotspots in the feld of VTE anticoagulation based on an analysis of the 9692 documents.Te number of articles in this feld is growing rapidly, with the USA, Canada, and Italy being the top three productive countries.Te keyword "Venous thromboembolism" had close links to "anticoagulants" and "rivaroxaban," indicating that rivaroxaban, as a representative of NOACs, is a critical point in the treatment of VTE.Te main focus of the articles included in the analysis was on clinical guidelines, special patient populations, NOACs application, and parenteral therapy of VTE anticoagulation.Future research interests will likely include evidence-based medicine for NOACs and studies on VTE patients combined with COVID-19.

Contributors in the VTE Anticoagulation Field. Te rising annual number of publications on VTE anticoagulation
suggests that this topic remains a hot topic.Te largest publication volume is in the USA, which may be attributed to the abundant research workers and rich funding agencies [27].Citations were a relatively proximate way to assess the impact of the published research [28].Most of the highly cited countries, documents, and journals were located in North America and Europe, representing the high quality of articles in these areas.Te top-cited author, Agnelli G, primarily concentrated on assessing oral factor Xa inhibitors for VTE and thromboprophylaxis for cancer-associated VTE patients, suggesting that these two aspects might be of current concern [29][30][31][32][33].

International Collaborations.
International collaboration has been shown to bring various benefts to the development of medical discipline [34].However, there was no information on international cooperation in the feld of VTE anticoagulation.Te USA was found to be the bellwether country in collaborating with other countries, while Canada and European countries also had strong links and produced a considerable amount of literature.However, countries such as China and Japan ranked as the top 4 and top 6, and most productive countries, respectively, had limited international collaboration impact outside the top 15.Te management of VTE with anticoagulation was a complex process that needed comprehensive guidelines concerning epidemiology, risk factors, diagnosis, prevention, treatment, and prognosis of VTE to guide best practices.Terefore, high-quality guidelines such as evidence-based clinical practice guidelines of antithrombotic therapy and prevention of thrombosis, 9th edition formulated by the American College of Chest Physicians (ACCP-9), provided narrow therapeutic index anticoagulants as efective and safe as possible, and they have attracted signifcant attention in academic circles based on our analysis [38].Meanwhile, the particular column of ACCP-9, including antithrombotic therapy for VTE [39], prevention of VTE in orthopedic surgery patients [40], prevention of VTE in nonorthopedic surgical patients [41], oral anticoagulant therapy [42], and prevention of VTE in nonsurgical patients, was also highly cited articles [43].In addition, guidelines formulated by the European Society of Cardiology (ESC) [7], National Institute for Health and Care Excellence (NICE) [8], European Society for Vascular Surgery (ESVS) [44], and American Society of Hematology (ASH) [45] also recommend the best strategies for VTE anticoagulation.Still, they have fewer citations than the ACCP-9 guidelines, probably due to their relatively recent publication.Normative anticoagulation recommended by guidelines is not equal to efective anticoagulation.Individualized anticoagulation therapy should be adopted for diferent patients.Te risk stratifcation of VTE adopting correlation risk scoring model and bleeding risk scoring model may be potential hotspots in future guidelines, which will be helpful for clinicians to screen patients with the best prevention benefts and then develop individualized prevention strategies.

NOACs Application in VTE Anticoagulation.
For decades, vitamin K antagonists (VKAs) and low molecular weight heparins (LMWHs) have been the primary anticoagulants used for managing VTE.Recently, the use of NOACs, particularly the direct factor Xa inhibitor rivaroxaban, has gained extensive attention due to its advantages, such as a single target mechanism, oral administration, no routine monitoring, and a lower risk of food-drug interaction [46].Te fve III clinical trials, HOKUSAI-VTE [47], EINSTEIN-DVT [48], EINSTEIN-PE [30], AMPLIFY [31], RE-COVER [49], and RE-COVER II [50], have been highly cited, which were the robust evidence of NOACs.Also, the secondary analysis of these trials also occupied a high impact on this feld [51].Consequently, NOACs are recommended as the frst-line treatment for general VTE patients and have rapidly become a research hotspot.In addition, the recommendation of NOACs in other clinical settings, especially cancer-associated VTE, was also undergoing extensive development [52][53][54][55].Terefore, further research is needed to assess the risks or benefts of NOACs in diferent oncologic settings [56].

VTE Anticoagulation in Special
Situations.Te thrombotic or bleeding risk of VTE in special populations, including orthopedic surgery, cancer, children, pregnant women, and APS, is higher than that in usual patients, posing certain challenges for decision-making clinicians [57][58][59][60][61].In our analysis, we found that the leading research point in VTE patients undergoing orthopedic surgery is pharmacologic and mechanical thromboprophylaxis, in which LMWHs, fondaparinux, low-dose heparin, adjusteddose VKAs, and aspirin are recommended anticoagulants in major orthopedic surgeries, and LMWHs has established its front-line treatment position [62,63].On the contrary, in patients with cancer-associated VTE, NOACs gradually become an alternative to LMWHs alone or LMWHs concurrently with a VKA [52].Te anticoagulation selection in diferent tumor types is diverse.For example, a high risk of venous thrombosis often accompanies active and advanced tumors.Terefore, the future topic is how to select anticoagulant drugs for this population while combining applicability and safety.Additionally, for pediatric and pregnant VTE, clinical options were based on traditional anticoagulant regimens, mainly belonging to of-label drugs and lacking good compliance.Anticoagulation of pregnant VTE will continue concerned with the impact of medication on pregnancy, fetus, and even lactation, as well as alternative treatments for heparin-induced thrombocytopenia.Dabigatran and rivaroxaban have been approved for the indications of pediatric VTE in 2021, which indicates the evaluation regarding the efcacy and safety of NOACs in the real world will be the future direction for those people [64].Finally, in APS patients with low-risk VTE, NOACs are selected due to warfarin intolerance or previous unstable international normalized ratio of warfarin.Terefore, whether to continue NOACs would be a concerning issue for these people [65].

Parenteral Anticoagulation in VTE Patients.
Cluster 3 inferred that the studies concerning VTE parenteral anticoagulation were mainly focused on major orthopedic surgery, especially total hip arthroplasty (THA) and total knee arthroplasty (TKA).Heparin, LMWHs, and fondaparinux were high-frequency keywords.Te ACCP-9 guidelines clearly recommend LMWHs over fondaparinux in patients with THA or TKA, regardless of the duration of surgery [66].However, fondaparinux, relying on the low adverse reaction strength, has also become an alternative for heparin-induced thrombocytopenia patients.Meanwhile, the timing of parenteral anticoagulant therapy, preoperative, postoperative, or perioperative period, is the research direction for further refnement of clinical treatment decisions [67].

Strengths and Limitations.
Our study was the frst bibliometric analysis focused on the articles involved in VTE anticoagulation.However, this study presents some limitations.First, although the WoSCC database was quite authoritative, other databases such as PubMed, Scopus, and Google Scholar were not considered in our analysis.Terefore, follow-up research should include a multidatabase to avoid high-quality research omission.Second, an inherent bias of bibliometric articles is that recently published studies lacked adequate citation time.Tird, the phenomenon of self-cite may infuence the accuracy of citation analysis.Fourth, the TS search, which included keywords plus, might cover several unrelated articles and reduce the accuracy of the included literature.Furthermore, some research hotspots may be lost due to the exclusion of reviews and non-English articles.Tese shortcomings need to be addressed and improved in future studies.

Conclusion
We conducted a bibliometric analysis based on the WOSCC database to study the characteristics of VTE anticoagulation research over the past decade.Te research output is generally on the rise.Globally, the USA is the leading country in this feld.Te most infuential documents, journals, and institutions were also from North America.Meanwhile, the cooperation and exchanges of countries and institutions need to strengthen, especially in developing countries or Asia.Agnelli G is an outstanding contributor to this domain.Currently, the research on VTE anticoagulation mainly focuses on the updation of VTE anticoagulation guidelines, assessment of the NOACs application, VTE management in special settings, and exploration of VTE combined with COVID-19, which may also be the trend of future research.Te results of this
(a)).A word cloud was also created to show the occurrence rates of keywords (Figure4(b)).

Figure 3 : 1 : 1255 9
Figure 3: Bibliometric analysis of the coauthorship.(a) Te cooperation of authors; (b) the cooperation of institutions; (c) and (d) the cooperation of countries or regions.Diferent colors indicate diferent clusters, the circle size indicates the number of publications, and the thickness of lines indicates the strength of the linkage.
(1): prophylaxis for VTE patients combined with surgery and cancer; (2): parenteral anticoagulant treatment for VTE; (3): thrombosis characteristics in unique settings: children, people with APS and COVID-19; (4): clinical guidelines on the epidemiology, risk factors, diagnosis, treatment, and prognosis of VTE.Te peak of clusters 0 and 1 was red and steep, indicating a relatively high concentration of similarity in research topics within these clusters.Tese clusters may refect the hot topics in VTE anticoagulation research over the past decade.

Figure 5 :Figure 4 :
Figure5: Mountain visualization map of high-frequency keywords biclustering in documents of VTE anticoagulant.Each hill represents a cluster, the distance between the mountains indicates the similarity between clusters, the height of the slope is proportional to the similarity of keywords within the cluster, the volume is proportional to the number of keywords contained in the cluster, and the color of the peak is proportional to the internal standard deviation of the cluster.Red means low standard deviation, while blue means high standard deviation.

Figure 6 :
Figure 6: Matrix visualization map of high-frequency keywords biclustering in documents of VTE anticoagulant.Row labels are highfrequency keywords, and column labels are source documents.Te left dendrogram represents the connection between high-frequency keywords, and the upper dendrogram represents the connection between source documents.Black horizontal lines separate clusters.Color represents the value in the original data matrix, and the deeper red color reveals a higher frequency of keywords.

Figure 7 :
Figure 7: Bibliometric analysis of theme terms.(a): Distribution of the theme terms.(b): Overlay visualization map of the topic trends.Te circle size indicates the number of occurrences, the thickness of the lines indicates the strength of linkage, and the diferent colors indicate diferent clusters (a) and the average publication year (b), respectively.
shows that 61 out of 115 countries have published relevant articles over 10.Te USA contributed the most documents, 3505, citing 89355 items and a total link strength of 2492.Te closest cooperation nations with the USA were Canada, Germany, and England, with a link strength of 393, 236, and 226, respectively.Te top ten coauthorship link strength countries, organizations, and authors in VTE anticoagulation topics are listed in Table 21) from the University of Insubria and Goldhaber SZ (link strength with Ageno W, 19) from Harvard Medical School.McMaster University has published 395 related articles with 35845 citations and a total link strength of 1222 (Figure 3(b)).Te primary partner organizations are the Trombosis and Atherosclerosis Research Institution (link strength with McMaster University, 83) and the University of Ottawa (link strength with McMaster University, 59).Te national cooperation network map (Figures 3(c) and 3(d))

Table 2 :
Te top ten most active journals, authors, organizations, and countries in the feld of VTE anticoagulation.
[71]70]TE Patients Combined withTe novel COVID-19 pandemic has swept the globe in recent three years.As a universal cardiovascular disease, VTE has emerged as an essential consideration for COVID-19 patients.Te incidence of VTE in the COVID-19 population was relatively high, which might be attributed to COVID-19 leading to systemic coagulation activation and the potential drug-drug interactions between investigational therapies for COVID-19 and established agents used for VTE[68].Meanwhile, hospitalized patients share similar risk factors for VTE, including advanced age, obesity, immobility, history of cancer, admission to intensive care units, and prior VTE history, with a higher risk of VTE[69,70].Besides the incidence, the diagnosis and treatment of VTE combined with COVID-19 patients also had extensive attention.However, the current medical knowledge of COVID-19 is still not comprehensive and in-depth.Terefore, the research frontiers in this feld are devoted to conducting clinical trials to ofer reliable and high-quality anticoagulation strategies[71].