
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

MD-D-24-03297
00052
10.1097/MD.0000000000039566
3
3600
Research Article
Systematic Review and Meta-Analysis
Immunothrombosis: A bibliometric analysis from 2003 to 2023
Hou Mengyu PhD mengyu_hou@163.com
a
Wu Jingxuan MD jingxuan_wu_rw@163.com
a
Li Jiangshuo PhD jiangshuo_li_rw@163.com
a
Zhang Meijuan PhD meijuan_zhang_rw@163.com
a
Yin Hang MD hang_yin_rw@163.com
a
Chen Jingcheng PhD jingcheng_chen_rw@163.com
a
Jin Zhili PhD zhili_jin_rw@163.com
a
https://orcid.org/0000-0003-3463-5023
Dong Ruihua PhD a*
a Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
* Correspondence: Ruihua Dong, Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China (e-mail: Ruihua_Dong_RW@163.com).
13 9 2024
13 9 2024
103 37 e3956627 3 2024
10 8 2024
14 8 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background:

Immunothrombosis is a physiological process that constitutes an intravascular innate immune response. Abnormal immunothrombosis can lead to thrombotic disorders. With the outbreak of COVID-19, there is increasing attention to the mechanisms of immunothrombosis and its critical role in thrombotic events, and a growing number of relevant research papers are emerging. This article employs bibliometrics to discuss the current status, hotspots, and trends in research of this field.

Methods:

Research papers relevant to immunothrombosis published from January 1, 2003, to May 29, 2023, were collected from the Web of Science Core Collection database. VOSviewer and the R package “Bibliometrix” were employed to analyze publication metrics, including the number of publications, authors, countries, institutions, journals, and keywords. The analysis generated visual results, and trends in research topics and hotspots were examined.

Results:

A total of 495 target papers were identified, originating from 58 countries and involving 3287 authors from 1011 research institutions. Eighty high-frequency keywords were classified into 5 clusters. The current key research topics in the field of immunothrombosis include platelets, inflammation, neutrophil extracellular traps, Von Willebrand factor, and the complement system. Research hotspots focus on the mechanisms and manifestations of immunothrombosis in COVID-19, as well as the discovery of novel treatment strategies targeting immunothrombosis in cardiovascular and cerebrovascular diseases.

Conclusion:

Bibliometric analysis summarizes the main achievements and development trends in research on immunothrombosis, offering readers a comprehensive understanding of the field and guiding future research directions.

bibliometric
bibliometrix
immunothrombosis
visual analysis
VOSviewer
the Capitalâ€™s Funds for Health Improvement and Research2022-2Z-20215 Ruihua Dongthe Capitalâ€™s Funds for Health Improvement and Research2022-2Z-20216 Jingxuan WuNational Major Science and Technology Projects of China 10.13039/501100013076 2018ZX09711003-014-001 Ruihua DongOPEN-ACCESSTRUE
SDCT
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pmc1. Introduction

Immunothrombosis is a pathological process of intravascular innate immunity formed by the mutual interaction of immune cells and coagulation substances, considered as one of the physiological processes in host defense.[1] Key factors involved in immunothrombosis include platelets,[2] neutrophils,[3] the complement system,[4] and the coagulation factors.[5] Some infectious or noninfectious factors, upon activating the immune system, lead to the interaction of immune cells, especially neutrophils, with activated platelets.[6] Platelets can be activated either directly by the pathogen’s stimulation or through the endothelial system or inflammatory response.[7] The interaction between platelets and leukocytes not only promotes the further recruitment of immune cells but also facilitates platelet adhesion and aggregation, triggering a cascade of coagulation reactions.[8] In addition, the involvement of neutrophil extracellular traps (NETs) and the complement system intensifies the entire process.[4,9] Immunothrombosis arises from the coordinated interaction of the immune system, complement system, and coagulation system.

Under normal circumstances, intravascular immunothrombosis is beneficial for capturing and clearing pathogens invading the bloodstream. However, uncontrolled immunothrombosis leads to pathological thrombus formation.[10] Dysregulated inflammatory states such as sepsis,[11] systemic lupus erythematosus (SLE),[12] acute respiratory distress syndrome,[13] stroke,[14] venous thromboembolism (VET),[15] and coronary artery disease,[16] leads to progressive thrombus formation. In excessive inflammation, inflammasomes promote coagulation triggered by tissue factor (TF), while neutrophils-platelets interaction fosters NETs and thromboxane A2 formation, resulting in thrombosis.[15]

The outbreak of COVID-19 has shifted researchers’ focus towards immunothrombosis, as it has been demonstrated to play a significant role in the disease progression and adverse outcomes in COVID-19 patients.[17] In recent years, with an increasingly in-depth study of immunothrombosis in COVID-19, the roles of NETs, inflammatory factors, the complement system, endothelial system, and TF in immunothrombosis have been more clearly elucidated.[4,18]

Bibliometrics is a discipline that involves reviewing literature to predict the development of scientific research in a particular field.[19] Bibliometrics can efficiently and accurately summarize the development and trends in research content within a specific field, thus providing guidance for subsequent work.[20] This article utilized data from articles related to immunothrombosis recorded in the Web of Science Core Collection (WOSCC) database from 2003 to 2023. The analysis involved 495 target documents using VOSviewer and the Bibliometrix R package. The development process, current status, frontier discoveries, and future trends in the field of immunothrombosis were analyzed from the perspectives of basic data, the information of co-occurrence relationships, and the cluster analysis. The aim of this study is to provide reference points for subsequent research in this field.

2. Materials and methods

2.1. Data sources and filtration

This study collected literature from the WOSCC database for analysis. The Web of Science is the most commonly used database for bibliometric analysis, and its recorded data is considered the most comprehensive and reliable.[21] The literature retrieval strategy for this study was “(((((TS = (Immunothrombosis)) OR TS = (Thromboinflammation)) OR TS = (Thromboinflammatory)) OR TS = (immunothrombus)) OR TS = (Immunothrombotic)) OR TS = (Thromboplasminflammation),” with the index date set from January 1, 2003, to May 27, 2023. The document types selected were “Article,” “Review Article,” or “Early Access.” After cleaning the initially retrieved literature data, articles with insufficient relevance to the research content in the field of immunothrombosis and duplicate publications were excluded, resulting in a total of 495 target papers.

2.2. Bibliometric analysis

Apply VOSviewer to gather basic information on authors, countries, institutions, sources, citations, keywords, and references from the target papers.[22] Utilize the Bibliometrix R package to compile information on the annual publication volume of target papers, distribution of authors’ nationalities, core journals, and the evolution trend of keywords, along with thematic information.[23]

3. Results

A total of 686 publications in the past 20 years were preliminarily included, then 495 publications (284 articles and 211 reviews) were selected after screening. The 495 publications were published in 223 journals with 3287 authors from 1011 research institutions in 58 countries, citing a total of 27,940 references.

3.1. Publications

Over the past 2 decades, there has been an overall upward trend in the publication volume of papers within the field of immunothrombosis. Papers related to immunothrombosis were first published in 2005, but before 2015, the annual publication volume in this field was consistently below 10 papers per year. After 2015, there has been a steady increase in the annual publication volume, with a rapid surge observed from 2019 onwards, reaching the highest value in 2022. Figure 1 illustrates the temporal distribution of paper publication volume in the field of immunothrombosis.

Figure 1. Number of annual publications in the field of immunothrombosis.

3.2. Authors

According to the Price Law,[24] authors with no <3 papers were defined as the core authors in the field of immunothrombosis, resulting in a total of 141 core authors. Table 1 presents information on the top 5 most productive authors in terms of publication volume in this field.

Table 1 Publication information for high-productivity core authors.

Rank	Author	Documents	Citations	Average citation	H-index	
1	Bo Nilsson	12	644	53.7	12	
2	Kristina N Ekdahl	10	458	45.8	10	
3	Steffen Massberg	9	2107	234.1	9	
4	Jason S Knight	9	245	27.2	7	
5	Tom Eirik Mollnes	9	49	5.4	3	

To further clarify the collaboration among core authors, VOSviewer was used to generate a co-authorship knowledge map, illustrating their collaboration relationships as shown in Figure 2. The 141 core authors were categorized into 34 clusters, with 25 being independent clusters that did not collaborate with each other. The remaining 9 clusters collaborated, forming one large research group. Analysis of Figure 2A reveals that within this large research group, there are collaborative relationships among clusters represented by core authors such as Bo Nilsson, John D. Lambris, Konstantinos Ritis, Jason S. Knight, Steffen Massberg, Behnood Bikdeli, Bernhard Nieswandt, and Frederik Denorme.

Figure 2. Authors’ cooperation analysis. (A) Nodes with the same color belong to the same cluster, the size of nodes represents the publication volume, and the thickness of connecting lines indicates the number of collaborations. (B) Node size represents the total citation count for each author, node color indicates the average time between publications, with colors closer to yellow indicating more recent publications. The thickness of lines between nodes represents the number of collaborations between authors.

Analysis of Figure 2B indicates that within the largest collaborative group, there are significant differences in the average publication time among various research teams. Clusters represented by Bo Nilsson and Bernhard Nieswandt had an average publication time before 2018, indicating early involvement in this field. Steffen Massberg individual average publication time is in 2018, but among the collaborators, the average publication time is later than 2020. This suggests that Steffen Massberg, as one of the early pioneers in the field, has facilitated the formation of newer research groups. Groups led by Tom Eirik Mollnes, Jason S. Knight, and Behnood Bikdeli have an average publication time after 2020, indicating later engagement in the field.

The research focus of Tom Eirik Mollnes’ team (group 1) mainly involves the role of the complement system in promoting thrombosis and inflammation.[25,26] Behnood Bikdeli group (group 3) focuses on the clinicopathologic features of thrombosis in COVID-19 patients,[27] treatment strategies,[28] and the clinical application of anticoagulants in COVID-19 patients.[29] In addition, Behnood Bikdeli has an average citation per paper of 426.0, garnering widespread attention.

Among independent research groups, the group represented by Marie Ebeyer-Masotta (group 4) has the most recent average publication year, which is April 2022. Among the emerging research groups formed after 2020, the group represented by Jason S. Knight (group 2) has the highest total publication volume. Their research primarily focuses on the mechanisms and treatment strategies of immunothrombosis in antiphospholipid syndrome (APS).[30–32] Dennis McGonagle (group 5) has an average publication year of 2021 and has contributed 8 papers to this field, with a total citation of 644. His research focuses on the immunological mechanisms, disease characterization, and treatment targets of immunothrombosis in COVID-19.[33–35] Felicity N. E. Gavins (group 6), as a corresponding author, has published 6 articles, with research mainly related to the discovery of treatment targets for immunothrombosis.[36–38]

3.3. Countries and institutions

This study conducted a statistical analysis of publication information for 58 countries involved in the field of immunothrombosis, visualizing and analyzing the collaboration among countries with more than 5 papers. Table 2 presents the top 5 high-productivity countries in terms of publication volume. The cooperation between countries with more than 5 papers was showed in Figure 3. Figure 3A illustrates the global distribution of the frequency of author affiliation appearances, with research institutions located in the United States appearing most frequently, followed by Germany and Italy. This suggests that researchers affiliated with institutions in these countries are more active in the field of immunothrombosis. Figure 3B shows the country-wise distribution based on the corresponding author’s location. Among the top 10 countries in terms of publication volume, the number of single country publications (SCP) and multiple country publications and the SCP ratio (SCP/total articles) are presented. Researchers from Australia (SCP ratio: 53.3%) and the UK (SCP ratio: 57.5%) tend to initiate international collaborations involving multiple institutions, while researchers from Italy (SCP ratio: 87.5%) and France (SCP ratio: 88.2%) prefer collaboration with researchers from their own country.

Table 2 High-productivity country information.

Rank	Country	Publications	Citations	Average citation	Number of collaborations	
1	USA	156	8298	53.2	24	
2	Germany	88	4954	56.3	23	
3	UK	63	2151	34.1	23	
4	Italy	43	1671	38.9	20	
5	China	41	731	17.8	13	

Figure 3. Analysis of the cooperation between countries. (A) Global distribution of the occurrence frequency of authors’ institutions. (B) Multiple country publications and Single country publications number of corresponding authors in the top 10 most productive countries. (C) Network visualization map of countries cooperation. The size of the node represents the number of publications, the thickness of the link represents the amount of cooperation between 2 countries, and the color of the node represents average citation per paper of the country.

To better analyze the collaboration between countries, Figure 3C presents a co-occurrence map of countries with a total publication volume of at least 5 papers. The United States, the United Kingdom, Germany, and Italy engage in frequent collaborations with multiple countries, with U.S. researchers being the most active in participating in international collaborative research. Additionally, it can be seen that the top 3 countries in terms of average citation per paper, Greece, Australia, and Belgium, have 19, 16, and 13 collaborating countries, respectively (an additional file shows this in more detail, see Table S1, Supplemental Digital Content, http://links.lww.com/MD/N522). This information suggests that participating in multi-country collaborations is beneficial for enhancing research quality.

Analyzing the affiliations of authors can provide further insights into the background of research teams in the field of immunothrombosis. Table 3 compiles information on the top 11 institutions by publication volume. To better analyze the collaboration between research institutions, a co-occurrence knowledge graph was generated for institutions with a publication volume of at least 5 papers (Fig. 4). Among the 59 eligible institutions, 56 institutions have formed collaborative relationships. All of the top 11 most productive institutions are all prestigious traditional institutions in Europe and the United States.

Table 3 Information on research institution publication volume.

Rank	Organization	Publications	Citations	Average citation	
1	University of Michigan	16	902	56.4	
2	University of Uppsala	16	600	37.5	
3	Linnaeus University	14	481	34.4	
4	University of Pennsylvania	13	1132	87.1	
5	University of Birmingham	12	506	42.2	
6	Harvard Medical School	11	1963	178.4	
7	University of Oslo	11	59	5.4	
8	Democritus University of Thrace	10	1087	108.7	
9	KU Leuven	10	664	66.4	
10	University of Leeds	10	648	64.8	
11	Norwegian University of Science and Technology	10	49	4.9	

Figure 4. Network visualization map of institutions cooperation.

3.4. Sources

This study analyzed 495 target papers published in 223 journals, with 36 journals having a publication volume of at least 3 papers, totaling 275 published articles, accounting for 55.6% of the total papers in this field. Table 4 displays the top 5 journals by publication volume, all of which belong to the Web of Science Journal Impact Factor Quartile 1 journals, with a focus on hematology. Figure 5 presents the basic information of core journals in the field of immunothrombosis. Using Bradford Law, bibliometrix identified the core journals in this field, as shown in Figure 5A.

Table 4 Core journal information.

Rank	Journal	Publications	Citations	Average citation	Impact factor	H-index	Journal impact factor quartile/rank	Proportion of open-access publications	
1	Frontiers in Immunology	50	1303	26.06	8.787	20	Q1(35/162)	99.52%	
2	International Journal of Molecular Sciences	24	176	7.33	6.208	7	Q1(69/297)	96.25%	
3	Thrombosis and Haemostasis	19	483	25.42	6.830	9	Q1(18/78)	14.26%	
4	Journal of Thrombosis and Haemostasis	17	942	55.41	16.041	12	Q1(5/78)	24.83%	
5	Blood	14	1375	98.21	25.669	9	Q1(2/78)	2.24%	

Figure 5. Core journals in the field of immunothrombosis. (A) Core journals identified by the Bradford law. (B) The cumulative publication volume of the top 5 core journals from 2005 to 2023. (C) The annual average publication volume of the top 5 core journals from 2005 to 2023.

Figure 5B illustrates the cumulative publication volume of the top 5 core journals from 2005 to 2023, with Frontiers in Immunology having the highest overall publication volume, while the other 4 core journals show no significant differences in publication volume. Figure 5C presents the annual average publication volume of core journals, highlighting that the Journal of Thrombosis and Haemostasis was the earliest to publish articles in this field (since 2005). Since 2018, Frontiers in Immunology has consistently had the highest annual publication volume. Notably, the International Journal of Molecular Sciences contributed mostly in 2022, making it a relatively new journal in the core group.

3.5. Keywords

This study conducted an analysis of the author keywords in 495 target papers, selecting keywords that appeared no fewer than 10 times (a total of 80). A keyword co-occurrence knowledge map was generated, as shown in Figure 6. Detailed information about keyword clusters can be found in Table 5, and information on the top 20 high-frequency keywords, ranked by occurrence frequency, is provided in Table 6.

Table 5 Cluster information for keywords.

Cluster	Cluster color	Topic	Keywords	
1	Purple	The composition and mechanism of the intravascular innate immune system	Innate immunity, Toll-like receptors, microparticles.	
2	Yellow	Mechanism of neutrophil extracellular trap inducing immunothrombosis in immune system diseases	Neutrophil extracellular traps (NETs), tissue factor (TF), sepsis, acute lung injury, disseminated intravascular coagulation (DIC), activated protein C, critically ill patients, factor pathway inhibitor, nuclear factor kappa-B (NF-κB).	
3	Green	Immunothrombosis in cardiovascular and cerebrovascular diseases	Thrombosis, inflammation, platelet, thromboinflammation, platelet activation, Von Willebrand factor (vWF), neutrophils, P-selectin, deep vein thrombosis, ischemic stroke, in vivo, stroke, venous thrombosis, extracellular traps, atherosclerosis, hemostasis, mice, acute ischemic stroke, glycoprotein Ib-alpha (GP1BA), arterial thrombosis, monocytes, myocardial infarction.	
4	Red	Immunothrombosis in COVID-19	COVID-19, complement, endothelial cells, expression, venous thromboembolism, infection, risk, coagulopathy, endothelial dysfunction, mortality, systemic lupus erythematosus, complement activation, complications, management, thrombocytopenia, antiphospholipid syndrome, heparin, plasminogen activator inhibitor-1, pathogenesis, antiphospholipid antibodies, cytokines, inhibition, thromboembolism, antibodies, anticoagulation, oxidative stress, plasma, respiratory distress syndrome, risk factors.	
5	Blue	Molecular mechanism of immunothrombosis	Immunothrombosis, activation, coagulation, tissue factor expression, mechanisms, disease, receptor, adhesion, cells, injury, protein, in vitro, thrombin, DNA, cytokine storm, endothelium, thrombin generation.	

Table 6 High-frequency keywords.

Rank	Keyword	Occurrences	Rank	Keyword	Occurrences	
1	COVID-19	161	11	Platelet activation	51	
2	Thrombosis	152	12	vWF	50	
3	Inflammation	144	13	Neutrophils	48	
4	Platelet	120	14	Complement	43	
5	NETs	103	15	Endothelial cells	41	
6	Thromboinflammation	97	16	Expression	38	
7	Immunothrombosis	90	17	Innate immunity	38	
8	Activation	83	18	Sepsis	38	
9	Coagulation	77	19	P-selectin	35	
10	TF	68	20	Venous thromboembolism	31	

Figure 6. Network visualization of author keywords. The color of the nodes represents the clusters to which the keywords belong, the size of the nodes represents the frequency of keyword occurrence, and the thickness of the lines connecting nodes indicates how frequently different keywords appear together in the same paper.

High-frequency keywords summarize the research focuses in the field of immunothrombosis. “COVID-19” is the most frequently appearing keyword. “Thrombus formation” and “inflammation” are the physiological processes of immunothrombosis. “Platelets” are the material basis for the process of immunothrombosis. “NETs” represent an important mechanism inducing thrombus formation. “TF,” “ Von Willebrand factor (vWF),” “complement,” and “P-selectin” are key molecules on immunothrombosis process.

Analyzing the average publication years of keywords provides insights into the changing trends of research hotspots in the field of immunothrombosis. Figure 7 visualizes the relationship between the frequency of occurrence and the average publication year of these 80 keywords. Among the 80 high-frequency keywords, most have an average publication year around 2020. “P-selectin,” “adhesion,” and “in vivo” appeared earlier (in 2018 or earlier), while “endothelial dysfunction,” “complications,” and “plasminogen activator inhibitor-1 (PAI-1)” appeared later, around 2022, indicating emerging research hotspots.

Figure 7. Overlay visualization of keywords average publication year. The size of nodes represents the frequency of keyword occurrence, the thickness of the lines connecting nodes indicates how frequently different keywords appear together in the same paper, and the color of nodes represents the average publication year of the keyword.

3.6. Hotspots and frontiers

A thematic map (Fig. 8) was generated for the keywords, with the horizontal axis representing the relevance to the field and the vertical axis representing the development level of the theme. Thus, research topics represented by various keywords were divided into 4 quadrants.

Figure 8. The thematic map of keywords.

Motor themes: These represent research topics with high relevance to the field and rapid development. In recent years, “complement system,” “vWF,” and “fibrinogen” have become key in exploring the mechanisms of immunothrombosis. The relationship between immunothrombosis and processes like “hemostasis,” “VET,” and “pulmonary embolism (PE)” is a major research focus.

Basic themes: These indicate topics with lower development but high relevance, serving as the foundation of research in the field. Research related to “thrombosis,” “platelet,” “inflammation,” and “NETs” is fundamental, exploring the processes and mechanisms of immunothrombosis. Under the “COVID-19” theme, studies analyze the connection between the coagulation system and the immune system after COVID-19 infection from the perspective of immunothrombosis.

Niche themes: These refer to low-relevance but highly developing niche topics. “Blood-brain barrier,” “middle cerebral artery,” “leukocyte,” “immunohistochemistry,” “microthrombi,” “endotheliopathy,” “microthrombosis,” and “extracellular vesicle” are relatively novel topics with fewer associated papers.

Emerging or declining themes: The topics in this quadrant represent either newly discovered or declining themes. There are 5 themes in this quadrant, these topics have seen fewer explorations in recent years.

Considering that the concept of “immunothrombosis” was first defined in papers published in 2013, and in light of the widespread outbreak of COVID-19 in 2019, leading to an in-depth investigation of the connection between COVID-19 and immunothrombosis, three-time intervals, namely 2005 to 2013, 2014 to 2018, and 2019 to 2023, were chosen to generate keywords Sankey diagram (Fig. 9).

Figure 9. Sankey diagram of keywords evolution.

As depicted in Figure 9, before the term “immunothrombosis” emerged, the research focus in this field was on “thrombosis” and “inflammation.” From 2014 to 2018, the emphasis shifted towards “inflammation,” and new keywords such as “ischemic stroke,” “acute coronary syndrome,” and “middle cerebral artery occlusion” were introduced. This period reflected researchers’ recognition of the role of immunothrombosis in cardiovascular and cerebrovascular diseases. Additionally, the appearance of “thrombin” and “platelet” indicated a growing interest in understanding the mechanisms of immunothrombosis.

4. Discussion

4.1. General information

The annual publication volume in the field of immunothrombosis reflects the progress of this domain. Despite the search data covering the period from 2003 to 2023, there were no reported studies before 2005. From 2005 to 2013, the average annual publication volume in the field of immunothrombosis was 1.6 papers, with a total of 14 publications, indicating a relatively sparse research landscape in this area. The earliest published study discovered that platelet was an essential role in the cascade of inflammatory reactions.[39] During this period, research focused more on the interaction between platelets and leukocytes, with platelet-expressed Toll-like receptor (TLR) 2 and P-selectin participating in the processes of thrombosis and/or inflammatory reactions.[2,40] On the other hand, the binding of endothelial cell E-selectin to neutrophils led to the capture of platelets, causing vascular damage.[41] Before the concept of “immunothrombosis” was defined, researchers described this phenomenon as “Thromboinflammation” or “Thromboinflammatory.” From 2014 to 2018, there was a significant increase in the number of publications in this field, with an average annual publication volume of 14.2 papers, indicating that the confirmation of the concept stimulated the development of related research in the field. In 2019, the annual publication volume was 44 papers, whereas the average annual publication volume increased to 91.5 papers after 2020. It is worth noting that among the 366 target publications published since 2020, a total of 289 papers are related to immune dysregulation and thrombosis, of which 180 papers focusing specifically on COVID-19, accounting for 62% (for more details, see Table S2, Supplemental Digital Content, http://links.lww.com/MD/N523). This indicates that a surge in annual publications of thrombosis application is closely related to the prevalence of COVID-19.

The collaboration among core authors reflects the level of activity among researchers in the field, and the formation of research teams also indicates the vitality of the field. All high-productivity authors in Table 1 belong to the large research group in Figure 2B. This suggests that close collaboration among core authors may promote the publication of articles and enhance research quality, accelerating the development of the field of immunothrombosis. Figure 2B showed that new research groups are gradually emerging and developing under the experienced researchers such as Steffen Massberg and John D Lambris. Additionally, among the 25 independent research teams, 14 (64%) have an average publication time later than 2019. All these factors indicate that research on this field is in a continuous upward trend of development.

In our analysis of high-productivity authors and institutions, we found that establishing collaboration between countries and institutions is beneficial for increasing both the quantity and quality of research papers. Countries such as the United States, the United Kingdom, and Germany not only hold the top 3 positions in terms of the number of papers but also maintain close international collaboration relationships between nations and institutions affiliated with these high-productivity Western countries. It is noteworthy that Harvard Medical School has achieved high citation numbers through multiple involvements in high-quality research rather than leading the research itself.[8]

The journals publishing articles related to immunothrombosis are all classified as Journal Impact Factor Quartile 1 journals, meaning that publications related to immunothrombosis have been recognized by mainstream academic journals. Interestingly, there is an association between the proportion of open-access (OA) articles in journals and their publication and citation volumes. OA journals such as Frontiers in Immunology and International Journal of Molecular Sciences contribute significantly to the publication of articles. On the other hand, traditional subscription-based journals like the Journal of Thrombosis and Haemostasis and Blood have higher average citations per paper. The publication volume of OA journals is notably higher than that of non-OA journals, suggesting that OA journals have contributed to the dissemination of research outcomes in the field of immunothrombosis and facilitated equitable access to knowledge. Traditional journals, meanwhile, have contributed relatively more high-quality research.

4.2. Keywords cluster

4.2.1. Cluster 1: the intravascular innate immune system

Cluster 1 encompasses research content that can be summarized as the composition and functional mechanisms of the intravascular innate immune system, emphasizing the significance of platelet pattern recognition receptors. The intravascular innate immune system consists of blood cascade systems (complement, coagulation, and fibrinolysis systems), blood cells (leukocytes, platelets), and endothelial cells. This intrinsic intravascular immune system mediates immune responses and thrombosis to purify the blood. Essentially, it protects the body, but dysregulation of the intravascular innate immune system leads to thromboinflammation.[5]

Platelets play a crucial role in preventing inflammation-related bleeding and protecting tissue cells from damage. Platelet-leukocyte interactions are at the core of intravascular innate immunity and contribute to thrombosis.[42] The TLRs on the surface of platelet membranes play essential roles in mediating platelet aggregation, platelet-leukocyte binding, NETs activation, and thrombin formation. TLR4, TLR1/2, and TLR9 can activate downstream signaling pathways through the PI3K/Akt pathway, participating in immunothrombosis.[43] Additionally, platelet-derived extracellular vesicles play a crucial role in recruiting leukocytes and facilitating intravascular immunothrombosis. Platelet-derived extracellular vesicles can serve as biomarkers for disease progression and severity.[44]

Furthermore, the complement system is an integral part of the intravascular innate immune system, serving as its backbone. Coagulation factors in the blood, including thrombin and FXa, can cleave complement Component 5 (C5), leading to the formation of complement C3a and C5a, as well as the membrane attack complex C5b-9. This process results in cell lysis and death.[45]

4.2.2. Cluster 2: the relationship between NETs and immunothrombosis

In Cluster 2, the relevant research topics of the keywords includes mechanisms by which NETs induce immunothrombosis in different diseases and therapeutic targets related to NETs. NETs are DNA mesh structures modified with histones and granule proteins, representing a unique link between inflammation and thrombosis. Overall, the histones in the structure of NETs can stimulate platelet aggregation, while providing a scaffold for the adhesion of red blood cells. Simultaneously, NETs capture platelet adhesion molecules (vWF, fibrinogen, fibronectin) from the plasma, supporting the formation of thrombin-dependent fibrin, thereby stabilizing thrombosis.[46]

In cardiovascular diseases, neutrophils aggregate in the vascular lesions, releasing NETs to promote the intravascular thrombosis.[47] In this process, key roles are played by peptidylarginine deiminase (PAD) 4, vWF, platelet TLR4, P-selectin, high mobility group protein 1, neutrophil solute carrier family 44 member 2, and TF.[48]

In COVID-19, the live COVID-19 virus can stimulate the release of NETs from human neutrophils in a dose-dependent manner through PAD4-mediated citrullination.[49] Simultaneously, COVID-19 triggers the activation of the complement system, where complement C3 activates platelets, NETs, and TF expression.[4] Therefore, there is a strong correlation between NETs and the severity of COVID-19 respiratory diseases.[50,51] The combined action of complement, platelets, NETs, and the TF/thrombin axis contributes to the formation and exacerbation of immunothrombosis within the pulmonary and renal microcirculation of patients, leading to organ failure.

In systemic lupus erythematosus, regulated in development and DNA damage responses 1 regulates autophagy-driven NETs formation, enriching NETs with TF and interleukin (IL) 17A, which are crucial factors in promoting immunothrombosis and tissue fibrosis, respectively.[12] In sepsis, lipopolysaccharide induces the activation of PAD and the formation of NETs mediated by the PAD-NETs-citrullinated histone H3 pathway. Additionally, lipopolysaccharide activates platelets in a platelet TLR4-dependent manner, promoting thrombin production and leading to immunothrombosis.[52]

Targeting the characteristics of NETs in immunothrombosis, corresponding treatment strategies include targeting thromboregulatory protein,[53] targeting the orosomucoid 1 gene,[54] inhibiting vWF,[55] inhibiting DNA degradation and the complement system,[56] inhibiting PAD4,[50] and using Fostamatinib.[57]

4.2.3. Cluster 3: immunothrombosis in cardiovascular and cerebrovascular diseases

Cluster 3 primarily focuses on the connection between inflammatory responses and thrombosis. Targeting immunothrombosis in diseases such as VET, atherosclerosis and stroke is a novel approach for treating these thromboembolic disorders. The interaction between platelets and leukocytes identified as a crucial link in triggering thrombotic diseases.[58]

In venous thrombosis, platelets play a more significant role in recruiting and activating neutrophils and less as hemostatic cells. Platelets recruit neutrophils to the site of inflammation, participating in the initiation of venous thrombus formation and leading to NETs-induced immunothrombosis.[59,60] In arterial thrombosis, T helper type 1 cells promote the formation of atherosclerotic plaques, and the destabilization and rupture of these plaques activate platelets. Simultaneously, TF secreted by immune cells triggers a cascade of coagulation reactions, ultimately resulting in arterial thrombosis.[61] Additionally, platelet-derived Gremlin-1 acts as an inflammatory mediator, inducing acute coronary syndrome.[62]

For immunothrombosis in venous thrombosis, promising therapeutic targets include proline-rich tyrosine kinase 2,[63] enhancing CD39 expression,[64] targeting the Grb2-associated binder 2/mucosa-associated lymphoid tissue lymphoma translocation protein 1 axis with mucosa-associated lymphoid tissue lymphoma translocation protein 1 inhibitors.[65] In the context of immunothrombosis in arterial thrombosis, potential effective strategies involve targeting P-selectin,[66] inhibiting FXIIa,[67] inducing histamine deficiency,[68] regulating the annexin A1/formyl peptide receptor 2/ALX (AnxA1/FPR2/ALX pathway),[37] interferon λ1/IL-29 treatment,[69] and inhibiting Rho-associated coiled-coil protein kinase.[70]

Additionally, targeting CD39,[71] the NETs-vWF axis,[55,72] PAD4, and NADPH oxidase,[36] inhibiting CD147,[73] and suppressing plasma kallikrein all have inhibitory effects on the formation of stroke.[74]

4.2.4. Cluster 4: immunothrombosis in COVID-19

The terms in Cluster 4 are all related to the connection between COVID-19 and immunothrombosis, covering research directions such as the pathological mechanisms, clinical biomarkers and potential therapeutic targets of immunothrombosis in COVID-19. Distinct from general pneumonia, vascular neutrophil recruitment, NETs, and immunothrombosis are typical features of COVID-19.[75] In some COVID-19 patients, PE may primarily result from locally induced immunothrombosis by COVID-19 rather than deep venous thrombosis.[76] COVID-19 alters the transcription of platelets, promoting thrombosis.[77] On the other hand, COVID-19 shifts the gene expression profile of monocytes from a typical innate immune response to a pro-thrombotic characteristic, making them highly sensitive to platelets and facilitating platelet aggregation and thrombosis.[78] COVID-19 induces immunothrombosis through NETs, endothelial dysfunction induction,[79] promoting TF-mediated inflammatory responses, and coagulation.[80] Considering the characteristics of immunothrombosis in COVID-19, potential therapeutic targets include the C-type lectin member 5A and TLR2,[81] antithrombin,[82] C-C motif chemokine ligand 2,[83] the complement system, NETs,[4] and IL-6.[84] Based on these targets, potential drugs for treating critically ill COVID-19 patients include complement inhibitors,[85] kininase/kinin inhibitors,[86] α2-macroglobulin,[87] PAD4 inhibitors,[88] and activated protein C analogs.[89] Additionally, biomarkers such as receptor for advanced glycation end products, SARS-CoV-2 nucleocapsid antigen, IL-6, IL-10, tumor necrosis factor receptor-1,[90] IL-4,[91] D-dimer/endogenous thrombin potential ratio,[92] neutrophil-to-platelet ratio,[93] clot lysis time, soluble thrombomodulin, plasminogen activator inhibitor-1, and plasminogen can be used to predict severe COVID-19.[94]

4.2.5. Cluster 5: molecular mechanism of immunothrombosis

Cluster 5 illustrates the detailed mechanisms through which immunothrombosis induces various immune system diseases or contributes to disease development. Within the innate immune system, the blood vessels ensure their structural integrity and protection against pathogen invasion through coagulation. TF is a crucial initiator of the coagulation cascade, and the clot composed of fibrin serves as the scaffold for immunothrombosis. Erythrocytes act as bait to attract pathogens, while platelets, by initiating the complement system, releasing chemotactic factors, and expressing P-selectin, recruit leukocytes, activate FXII, and induce NETs, linking inflammation and coagulation. This process guides immune cells to the infected sites within the circulation.[1] It is noteworthy that TF plays a central role in triggering the process of immunothrombosis. Innate immune signals induce the expression of the TF gene in immune cells through NF-κB and activate stimulator of interferon genes and inflammasomes to trigger TF release,[95] driving the coagulation cascade.[96] Therefore, targeting TF is currently a widely studied therapeutic strategy.

APS is a typical immunothrombosis disorder. In vitro studies have found that antiphospholipid antibodies can promote the expression of TF, induce the release of pro-inflammatory cytokines, and trigger immunothrombosis by inducing NETs.[31]

In sepsis, pathogens directly activate endothelial cells and platelets through their pathogen-associated molecular patterns, triggering NETs and leading to uncontrolled immunothrombosis in the microcirculation.[11]

In acute respiratory distress syndrome, accompanying lung damage, platelets promote the recruitment of immune cells by expressing intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin. The formation of platelet–neutrophil complexes activates triggering receptors expressed on myeloid cells-1, leading to the release of a large amount of pro-inflammatory cytokines and chemokines, further inducing immunothrombosis.[13]

In respiratory diseases associated with RNA virus infections, immunothrombosis may be based on a positive feedback mechanism. Thrombin, through the activation of protease-activated receptor 1/2, maintains and amplifies the pro-thrombotic and pro-inflammatory effects exposed to viral RNA mimics like poly(I:C) on endothelial cells.[97]

4.3. Further development

The overall trend in the research topics related to immunothrombosis is illustrated in Figure 9. Over the past 20 years, researchers initially observed the correlation between thrombosis and inflammatory reactions in clinical cases, recognizing the crucial role of platelets in the immune system and the involvement of leukocytes in the process of thrombosis. After the introduction of the concept of “immunothrombosis,” researchers shifted their focus to the role of immunothrombosis in cardiovascular and cerebrovascular diseases.

However, with the outbreak of COVID-19 in 2019, thromboembolic events in COVID-19 patients garnered unprecedented attention from researchers. Future research directions for researchers may be guided by the results in Figure 8. The primary research focus continues to center on the formation of immunothrombosis in COVID-19. In-depth molecular mechanism studies can still be conducted on NETs and platelets as crucial components of immunothrombosis. Additionally, the complement system, vWF, and fibrinogen are expected to become new hotspots for in-depth research, as their roles in immunothrombosis are not yet fully understood. In terms of related diseases, targeting immunothrombosis and developing clinical drug strategies for diseases such as COVID-19, APS, PE, coronary artery disease, and VET will be crucial research directions in the future. Besides, topics within niche themes may provide researchers with more perspectives. Research directions such as brain ischemia, middle cerebral artery occlusion, and neuroprotection are worthy of attention.[58,98,99]

4.4. Limitations

One limitation of this study is that all data were collected solely from WOSCC, potentially omitting articles from other databases such as PubMed and Scopus. Additionally, the number of published articles in the field of immunothrombosis increased significantly in 2023, with new research findings emerging rapidly. During the course of this study, the latest publications in this field were not included for analysis. These factors contribute to incomplete data collection, which may introduce certain limitations to the findings presented in this paper.

5. Conclusions

Immunothrombosis is a physiological process of mutual influence between the immune system and the coagulation system. It represents a form of innate immunity within blood vessels. This study employs bibliometric methods to analyze the development and frontier research topics in the field of immunothrombosis over the past 20 years. The number of research papers in this field is growing rapidly, with emerging research groups continuously contributing.

Research focus in the field of immunothrombosis has evolved from the initial study of the interaction between platelets and leukocytes to the current exploration of key components such as NETs, the complement system, and TF. Inhibiting inflammatory reactions has emerged as a potential new strategy for treating thromboembolic diseases. On the other hand, achieving a balance between immune responses and coagulation during disease treatment and modulating the extent of immunothrombosis have become critical considerations. Finding treatment targets that are more specific and controllable presents one of the current challenges in this field.

Author contributions

Conceptualization: Mengyu Hou, Ruihua Dong.

Data curation: Mengyu Hou, Jingxuan Wu.

Formal analysis: Jiangshuo Li, Meijuan Zhang, Hang Yin.

Funding acquisition: Jingxuan Wu, Ruihua Dong.

Methodology: Mengyu Hou.

Supervision: Ruihua Dong.

Visualization: Mengyu Hou, Jingxuan Wu.

Writing – original draft: Jingcheng Chen, Zhili Jin.

Writing – review & editing: Ruihua Dong.

Supplementary Material

Abbreviations:

APS antiphospholipid syndrome

C5 complement component 5

IL interleukin

NETs neutrophil extracellular traps

OA open-access

PAD peptidylarginine deiminase

SCP single country publication

TF tissue factor

TLR Toll-like receptor

VET venous thromboembolism

vWF Von Willebrand factor

WOSCC Web of Science Core Collection

This work was supported by the Capital’s Funds for Health Improvement and Research (2022-2Z-20215, 2022-2Z-20216) and the National Science and Technology Major Project of the Ministry of Science and Technology of China (2018ZX09711003-014-001).

Ethical approval is not required. Because our data was collected through the Web of Science Core Collection (WOSCC) database, and our research does not involve human or animal experiments.

The authors have no conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Supplemental Digital Content is available for this article.

How to cite this article: Hou M, Wu J, Li J, Zhang M, Yin H, Chen J, Jin Z, Dong R. Immunothrombosis: A bibliometric analysis from 2003 to 2023. Medicine 2024;103:37(e39566).
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