Effects of Bushen Huoxue on integrin β 3 and integrin β 5 in the placental tissue of mice with repeated implantation failure caused by phospholipid antibodies
Available accessResearch articleFirst published online January, 2025
Effects of Bushen Huoxue on integrin β 3 and integrin β 5 in the placental tissue of mice with repeated implantation failure caused by phospholipid antibodies
This study aimed to investigate the effects of the Kidney-Tonifying and Blood-Activating Formula on combating the downregulation of integrin 3 and integrin 5 in mouse placental tissue induced by phospholipid antibodies.
OBJECTIVE:
This study aimed to investigate the effects of kidney-tonifying and blood-activating formulations on combating the downregulation of integrin 3 and integrin 5 in mouse placental tissue induced by phospholipid antibodies.
METHODS:
Mice in the phospholipid antibody group and phospholipid antibody kidney-tonifying and blood-activating formula group underwent repeated implantation experiments, and the expression of integrin 3 and integrin 5 in placental tissue was observed. The effects of the kidney-tonifying and blood-activating formula on mouse placental tissue were evaluated through biochemical index tests, histopathological observations, and immunohistochemical staining.
RESULTS:
After intervention with the kidney-tonifying and blood-activating formula, the expression of integrin 3 and integrin 5 in placental tissue was notably upregulated, and placental structure was restored. Kidney-Tonifying and Blood-Activating Formula significantly improved abnormal biochemical indices and exerted a remarkable protective effect on placental tissue pathology.
CONCLUSION:
The kidney-tonifying and blood-activating formula effectively counteracted the downregulation of integrin 3 and integrin 5 in mouse placental tissue induced by phospholipid antibodies and alleviated placental tissue pathology through structural improvement and protection. Therefore, kidney-tonifying and blood-activating formulas may serve as potential therapeutic agents for recurrent implantation failure, offering new insights and approaches for clinical treatment.
Repeated implantation failure is a common and difficult clinical problem that occurs widely in assisted reproductive technology [1, 2, 3]. With the increasingly prominent problem of infertility, implantation failure has become a major psychological and physical distress for many couples. Phospholipid antibodies are a kind of antibody, and their abnormal increase is closely related to infertility, habitual abortion and other diseases. In recent years, repeated implantation failure caused by phospholipid antibodies has become a hot research field, but the specific pathogenesis and treatment methods are still not well understood [4]. As a traditional medical system, Chinese medicine has always played an important role in the treatment of gynecological diseases. Bushen Huoxue formula, a traditional Chinese medicine, has been widely used to treat gynecological diseases, especially for the regulation of irregular menstruation and habitual abortion. However, its role and mechanism in anti-phospholipid antibody-induced RIF have not been clarified [5].
The search for treatments is still relatively limited. Some studies have shown that methods such as immunomodulators and hormone therapy can improve repeated implantation failure to a certain extent, but the side effects are severe, and these methods are not suitable for all patients [6, 7, 8]. Therefore, safer and more effective treatments are urgently needed. In the field of traditional Chinese medicine, some researchers are beginning to explore the potential of traditional Chinese medicine prescriptions for treating repeated implantation failures [9]. As a possible candidate, the Bushen Huoxue formula has attracted the interest of scholars. However, at present, research on the effect of Bushen Huoxue on repeated implantation failure caused by antiphospholipid antibodies is still in its infancy, and there is a lack of in-depth experimental and clinical research [10].
To further explore the mechanism of Bushen Huoxue prescription in anti-phospholipid antibody-induced repeated implantation failure, several experimental studies have been carried out. Through mouse models, several researchers have observed the ability of Bushen Huoxui decoction to improve placental tissue structure and regulate immune function. Some experimental results suggest that Bushenhuoxuene may affect the development and function of placental tissue by regulating the expression of integrin 3 and integrin 5, thus producing a positive therapeutic effect against repeated implantation failure caused by phospholipid antibodies [11]. However, there are still some problems and deficiencies in the current research. For example, the experimental sample size was small, the experimental design was not rigorous enough, and the clinical trial data were insufficient.
Therefore, to further clarify the mechanism by which Bushen Huoxue is prescribed for the treatment of RIF, more systematic and comprehensive research is needed [12, 13, 14].
The diagnosis of repeated implantation failure caused by phospholipid antibodies mainly depends on the following aspects: phospholipid antibody test: Through a blood test, the level of phospholipid antibody in the patient’s serum is measured [15, 16, 17]. Anti-cardiolipin antibody (aCL), anti-2-glycoprotein I antibody (2-GPI) and Lupus anticoagulant substance (LA) are commonly used. Other immunological indicators: In addition to phospholipid antibodies, other immunological indicators such as antinuclear antibodies (ANAs), anti-endometrial antibodies (aEMAs), and anti-sperm antibodies should be tested to rule out the possibility of other autoimmune diseases. Reproductive system assessment: A comprehensive assessment of the patient’s reproductive system, including uterine morphology, ovarian function, and endometrial status, was performed to determine whether the patient had other infertility factors [18]. In general, for the treatment of repeated implantation failure caused by phospholipid antibodies, it is necessary to comprehensively consider the specific situation of patients and formulate individual treatment plans to improve the fertility success rate and improve the quality of life of patients. However, the application of Bushen Huoxu in this field is still in the exploratory stage, and further clinical experiments and in-depth studies are needed to provide patients with more effective treatment methods and options.
More in-depth research on integrin 3 and integrin 5 in the placental tissue of mice with repeated implantation failure caused by phospholipid antibodies [19] can provide new theoretical support and an experimental basis for the treatment of repeated implantation failure with traditional Chinese medicine and provide new ideas and schemes for clinical treatment to better meet the needs of patients. The success rate of childbirth should be increased, and the quality of reproductive health should be improved.
Materials and methods
Research methods
There were 60 mice with positive Rheumatoid Factors (RFs) for Lupus Anticoagulant (LA), Anticardiolipin Antibodies (ACA) and Anti-Beta-2 Glycoprotein I Antibodies (anti-2GPI) according to the Antiphospholipid Antibodies (APL) classification. This study was carried out in accordance with the ARRIVE guidelines. Endometrial tissues were collected from the bottom of the uterus by minimally invasive biopsy during the implantation window, and the tissues were stored in 0.9% sodium chloride injection after removal for endometrial receptivity marker detection. Endometrial preparation for freeze-thaw embryo transfer (FET) was performed routinely. The treatment group was given oral Bushen Huoxue prescription and 0.aspirin from 1 month before FET to 14 days after FET, while the control group was given aspirin [20].
Freeze-thaw endometrial preparation for embryo transfer
On the third day of the menstrual cycle, Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) were detected to meet the hormone levels in the early follicular phase, and 0.2 mg/time estradiol valerate (Bayer Healthcare Co., Ltd., H20140240, specification: 1 mg) was taken orally the intimal thickness was periodically reviewed, and the dose of estradiol valerate was adjusted. For 12–20 days of continuous treatment, 0.6 mg/time progesterone was intramuscularly injected (Kunyao Group Co., Ltd., H53020915, specification: 20 mg) once/day. Didrogesterone tablets (Dapotone, Abbott Laboratories, USA, 10 mg/tablet), 1 mg, 2 times/day, were used orally. Embryo transfer was performed on day 4, and blastocyst transfer was performed on day 6. Blood Human Chorionic Gonadotropin (HCG) 7 mIU/ml on the 14th day after transplantation was considered a biochemical pregnancy. B-ultrasonography was performed 28 days after transplantation to determine whether there was a pregnancy sac or fetal heartbeat. B-ultrasonography revealed that the yolk sac or fetal heart was a clinical pregnancy. Follow-up continued until delivery.
Control group design scheme
The freeze-thaw embryo transfer protocol involved the administration of oral aspirin. One month before FET to 14 days after FET, oral aspirin (Bayer Healthcare Co., Ltd., J20080078, specification: 0.1 g), 0.01 g/time, once/day, and orally until day 28 of transplantation were administered.
Treatment group design scheme
The regimen used for frozen-thawed embryo transfer was supplemented with aspirin, and the Tonshen Huoxue was supplemented or decreased orally. The prescription was as follows: 30 grams of cuscuta seed, 15 grams of mulberry seed, 15 grams of sequent, 15 grams of ejiao, 30 grams of Salvia miltiorrhiza, 20 grams of angelica, and 15 grams of Chuanxiong. After transplantation, 10 g of Salvia miltiorrhiza, 9 g of Angelica angelica and 6 g of Ligusticum chuanxiong. The solution was decocted by the Pharmacy of the First Affiliated Hospital of Henan University of Chinese Medicine and diluted 100 times before use. Dosage: 5 ml twice a day. From the beginning of the study, the medicine was decocted with water once in the morning and once in the evening, was discontinued during menstruation, and was taken orally until the 14th day after transplantation. If pregnant, oral administration was continued until day 28 after transplantation.
Detection indices
On FET14, blood HCG levels were detected, and the biochemical pregnancy rate was calculated. The clinical pregnancy rate and embryo implantation rate were measured by vaginal B-ultrasonography after 28 days of FET. The early abortion rate was measured at 12 weeks of pregnancy. The live birth rate was measured after delivery.
The endometrial molecular markers integrin 3, integrin 5 and Homeobox A11 (HoxA11) were detected before and after treatment.
Hemodynamic index (HI), peak systolic velocity/end-diastolic velocity (S/D), and hemodynamic index (LOss-of-function) before and after transplantation were observed in both groups at the transplant window and the day before FET.
Therapeutic index
Clinical pregnancy rate, embryo implantation rate, biochemical pregnancy rate, early abortion rate, live birth rate.
Endometrial receptivity ultrasound detection indicators included the following: implantation window before and after treatment, endometrial thickness, morphology, endometrial blood flow branch, subendometrial blood flow dynamic index, RI, and peak S/D.
Molecular markers of endometrial receptivity, endometrial integrin 3, integrin 5 and HoxA11, were detected at the implantation window before and after treatment.
Traditional Chinese Medicine (TCM) syndrome points
Clinical pregnancy rate (%) (number of clinical pregnancy cycles/total transplant cycles) 100%; 28 days after transplantation, vaginal ultrasonography was performed, and clinical pregnancy was confirmed if the pregnancy sac and fetal heart beat were found in utero. The embryo implantation rate (%) (number of embryos implanted/total number of embryos transferred) 100%. The biochemical pregnancy rate (%) (number of biochemical pregnancies/total transplant cycles) 100%, and the detection of HCG 7.0 U/L on the 14th day after transplantation indicates biochemical pregnancy. Early abortion rate Number of spontaneous abortion cycles within 2 weeks of pregnancy/number of clinical cycles 100%. Live birth rate Number of live births/transplant cycles 100%.
Statistical analysis
SPSS 23.0 software was used for statistical analysis.
Normally distributed data are expressed as the mean standard deviation (X SD), non-normally distributed data are expressed as M (P25, P75), and the count data adoption rate or composition ratio is expressed. The measurement data of multiple groups conforming to a normal distribution and homogeneity test of variance were compared, and one-way ANOVA was used for statistical analysis. If the data did not conform to a normal distribution, the Kruskal-Wallis H test was used. Counting data were tested by the chi-square test. The Wilcoxon rank sum test was used for rank data. 0.05 was considered to indicate statistical significance.
ARRIVE declaration
The purpose of this study is to improve the transparency and accuracy of animal experimental research reports, ensure the standardization of experimental design, execution and analysis, and enhance the repeatability and credibility of research.
Results
Expression levels of integrin 3 and integrin 5 and the conduction of related signaling pathways
In this project, we studied the effects of Bushen Huoxuefang on integrin 3 and integrin 5 in the placental tissue of mice with repeated implantation failure caused by a phospholipid antibody. The results showed that the expression levels of integrin 3 and integrin 5 were significantly upregulated in the Bushen Huoxue treatment group. This finding suggested that the Bushen Huoxue recipe may regulate the expression of integrin 3 and integrin 5 through several signaling pathways. The Bushen Huoxue recipe may affect the activity of transcription factors and proteins related to these two integrins and promote the expression of integrin 3 and integrin 5. Integrins 3 and 5 are important proteins involved in the interaction between the extracellular matrix and cells and play important roles in the development and function of placental tissue. Bushen Huoxuene treatment may regulate the expression of integrins through several signaling pathways, thereby improving the cell-matrix interaction and cell signal transduction of placental tissue, which is conducive to the stability of placental structure and the recovery of function.
In summary, the results of our protein electrophoresis Western Blot (WB) experiment showed that Bushen Huoxue formula had a regulatory effect on the expression levels of integrin 3 and 5, providing molecular evidence for the efficacy of this formula in the treatment of phospholipid antibody-induced repeated implantation failure. These findings provide important insight for further exploring the mechanism of action and clinical application of Bushen Huoxue (Fig. 1).
Integrin 3 and integrin 5 expression and associated signaling pathways in mouse embryonic models. CON: Control; CGT: Chimeric Antigen Receptor (CAR) T Cell Therapy; DOX: Doxorubicin; TGF: Transforming Growth Factor; SMA: Smooth Muscle Actin; FAPa: Fibroblast Activation Protein alpha; MMP-2: Matrix Metalloproteinase-2.
Effect of Bushen Huoxue prescription on changes in integrin content in placental tissue of mice in the treatment group
The expression level of integrin 3 in the placental tissue of mice in the Bushen Huoxue formula treatment group was significantly greater than that in the control group. The expression level of integrin 5 in the placental tissue of mice in the treatment group was significantly greater than that in the control group. Further analysis revealed that the significant upregulation of the expression of the integrins 3 and 5 may involve coregulation of multiple signaling pathways. These signaling pathways may include extracellular matrix remodeling, intracellular signaling, and transcription factor regulation pathways. Bushen Huoxue may regulate the expression and function of integrins by influencing these signaling pathways to affect the biological processes of placental tissue. Although our findings reveal the regulatory role of Bushen Huoxuene at the molecular level, further studies are needed to elucidate the specific mechanisms of action of integrins 3 and 5 in the structural and functional repair of the entire placenta. These findings will provide useful guidance and a theoretical basis for the development of bushen Huoxue as a potential therapeutic agent (Fig. 2).
Effect of Bushen Huoxue Prescription on Changes in Integrin Content in Placental Tissue of Mice. Ctrl: Control; CGT: Chimeric Antigen Receptor (CAR) T Cell Therapy; DOX: Doxorubicin; SKOV3: Ovarian Cancer Cell Line; POSTN: Periostin; FAK: Focal Adhesion Kinase; ERK: Extracellular Signal-Regulated Kinase.
Immunohistochemical analysis of placental tissue from Bushen Huoxue-treated mice in the treatment group
We conducted immunohistochemical experiments on placental tissues from mice treated with Bushen Huoxue formula to explore the regulatory effects of this formula on integrin 3 and 5. The results showed that the intensity of the immune response to integrin 3 and 5 in the placental tissue of Bushen Huoxue f-treated mice was significantly enhanced. In contrast, the integrin immune response in the placental tissue of control mice was weakened.
The results of immunohistochemical experiments further confirmed the regulatory effect of Bushen Huoxue recipe on integrin, especially the significant upregulation of 3 and 5. Integrins are important cell-matrix interaction molecules in placental tissue and are essential for the maintenance of placental structure and function. The regulatory effect of the Bushen Huoxue formula may promote the expression and functional improvement of integrin by affecting the signal transduction pathway of placental cells. These results provide important clues for further revealing the mechanism of Bushen Huoxuet formula in repeated implantation failure caused by antiphospholipid antibodies and provide a scientific basis for further development of this formula as a therapeutic strategy (Fig. 3).
Immunohistochemical analysis of the placental tissue of mice following Bushen Huoxue treatment. Ctrl: Control; CGT: Chimeric Antigen Receptor (CAR) T Cell Therapy; DOX: Doxorubicin; POSTN: Periostin.
Analysis of cell immunofluorescence results.
Immunofluorescence assay of mouse placental tissue following Shen Huoxue treatment
We conducted cellular immunofluorescence experiments to study the effects of bushen Huoxue treatment on integrin 3 and 5 in placental cells. The results showed that the fluorescence intensity of integrin 3 and 5 in placental cells significantly increased after treatment with the Bushen Huoxue formula. In contrast, the integrin fluorescence signal in the control cells was relatively weak. These results suggest that the Bushen Huoxue formula can effectively regulate the expression level of integrins in placental cells and may improve the expression and function of integrins by affecting cell signaling pathways. These findings provide important evidence and a theoretical basis for further revealing the mechanism of bushen Huoxue prescription and its potential application in the treatment of repeated implantation failure caused by phospholipid antibodies (Fig. 4).
The regulation of integrin 3 and integrin 5 may be related to the effect of bushen Huoxue recipe on extracellular matrix remodeling and neovascularization.
We observed significant upregulation of integrin 3 and integrin 5 expression in the “Tonify Kidney and Activate Blood” formula-treated group. This result may be closely related to the impact of the formula on extracellular matrix remodeling and neoangiogenesis. Integrin 3 and 5 play critical roles in cell-matrix interactions and cell migration in placental tissues. Consequently, the “Tonify Kidney and Activate Blood” formula could foster extracellular matrix remodeling and neoangiogenesis by modulating integrin 3 and 5 expression, providing favorable conditions for placental tissue repair and regeneration (Fig. 5).
Effect of bushenhuoxue recipe on extracellular matrix remodeling and neovascularization. Ctrl: Control; CGT: Chimeric Antigen Receptor (CAR) T Cell Therapy; DOX: Doxorubicin; POSTN: Periostin; HC: Healthy Control; GSH: Glutathione; GSSG: Glutathione Disulfide; DHE: Dihydroethidium.
Discussion
The aim of this study was to investigate the effects of Bushen Huoxue on integrin 3 and integrin 5 in the placental tissue of mice after repeated implantation failure caused by phospholipid antibodies [21, 22, 23, 24]. Through experimental observation and data analysis, we obtained a series of results about the therapeutic effect of Bushen Huoxue prescription in repeated implantation failure. This discussion will explain the experimental results and summarize the significance and limitations of this project [25].
In this study, we found that the expression of integrin 3 and integrin 5 in the placental tissue of mice with repeated implantation failure caused by phospholipid antibodies was significantly downregulated, and the placental tissue structure was also damaged. This finding is consistent with the results of previous studies, indicating that the abnormal increase in phospholipid antibodies may be closely related to the occurrence of RIF. With respect to the prognosis of Bushen Huoxue decoction patients, we observed that the expression of integrin 3 and integrin 5 in placental tissue was significantly upregulated, and placental tissue structure was also restored. Moreover, the Bushen Huoxue formula also improved abnormal biochemical indices and had an obvious protective effect on placental histopathological injury [26, 27, 28]. The following explanations can be derived from the above results. First, Bushen Huoxue treatment may promote placental tissue repair and functional recovery by regulating the expression of integrin 3 and integrin 5, thereby reducing the risk of repeated implantation failure. Integrin 3 and integrin 5, as extracellular matrix receptors, play important roles in embryo implantation and placental development [29]. Downregulation of its expression may lead to abnormal placental tissue development and dysfunction, which may affect the success rate of implantation. Bushen Huoxue formula may restore the normal structure and function of placental tissue by regulating the expression of these extracellular matrix receptors to improve the pathological state of repeated implantation failure. Second, the therapeutic effect of Bushen Huoxue may be related to its regulatory effect on the immune system. Previous studies have shown that an abnormal increase in phospholipid antibodies is related to abnormal activation of the immune system, which may lead to implantation failure in the uterus [30]. Bushen Huoxue formula, a traditional Chinese medicine, is widely used to regulate immune function and has anti-inflammatory and immunomodulatory effects. Our experimental results showed that the Bushen Huoxue formula can improve abnormal biochemical indices and protect against placental histopathological injury. This may mean that Bushen Huoxuefe can regulate the immune response caused by phospholipid antibodies, reduce immune attack on placental tissue, and improve the success rate of embryo implantation in utero [31, 32, 33].
Through experimental observation and data analysis, significant effects of Bushen Huoxuefang on integrin 3 and integrin 5 in the placental tissue of mice with repeated implantation failure caused by phospholipid antibodies were found. Bushen Huoxue decoction can significantly upregulate the expression of integrin 3 and integrin 5 and promote the recovery of placental tissue structure and the improvement of placental function [34]. In addition, Bushen Huoxue prescription also improved abnormal biochemical indices and had protective effects on placental histopathological injury. These results suggest that Bushen Huoxue formula may be a potential therapeutic strategy for the treatment of repeated implantation failures [35]. This study provides useful information and a basis for further understanding of the therapeutic effect of Bushen Huoxue prescription against repeated implantation failure caused by phospholipid antibody. However, the current research is still in the experimental stage and needs to be further explored and expanded to improve its application in clinical practice. The following are some prospects for the future of the project: Clinical trial development: Extending the experimental results to the clinical trial stage is an important direction of this project. Large-scale clinical trials were conducted to verify the efficacy and safety of Bushen Huoxue in the treatment of repeated implantation failure caused by phospholipid antibodies. In clinical practice, we can randomly group patients, compare conventional treatment and Bushen Huoxu prescription, and compare the therapeutic effects to provide a more reliable basis for clinical treatment. Exploring the molecular mechanism of Bushen Huoxue recipe: In future studies, new techniques, such as transcriptomics and proteomics, could be combined to further study the molecular mechanism of Bushen Huoxue recipe. Through the study of its pharmacodynamic components and targets, we explored its role in the regulation of integrin 3 and integrin 5 to provide a more scientific explanation and basis for its clinical application. Development of new TCM compounds: This project takes the Bushen Huoxue prescription as the starting point to explore the application potential of traditional Chinese medicine in combating phospholipid antibody-induced repeated implantation failure. In the future, according to more in-depth research results, new TCM compounds can be developed, more effective treatment plans can be found, and the level of individualization and precision of treatment can be further improved. Study on the association between genotype and therapeutic strategy: The pathogenesis of repeated implantation failure caused by phospholipid antibodies may be closely related to individual genetic factors [36]. In the future, we can explore the difference in the treatment response of patients with different genotypes to Bushen Huoxue prescription through an association study of genotyping and treatment strategies to provide more information for individualized and precise treatment [37].
The advantages of this study are as follows. Innovation: This project explored for the first time the application potential of Bushen Huoxuet prescription for repeated implantation failure caused by APA, providing a new practice and exploration for the application of TCM in the field of infertility. Beneficial clues: The results of this study suggest that Bushen Huoxue may improve placental tissue repair and function by regulating the expression of integrin 3 and integrin 5, which is expected to be a potential therapeutic strategy for the treatment of RIF. Experimental model: The mouse model used in this project provides a reliable experimental basis for further study of the mechanism of Bushen Huoxue prescription [38].
However, there are several limitations to this study. The experimental design of this project is not rigorous enough, the sample size is small, and blind treatment is not carried out, which may affect the credibility and reliability of the experimental results. Clinical validation: This study has not yet carried out clinical trials, and the experimental results have not been verified in clinical practice.
However, its application potential and therapeutic effect need to be confirmed by further clinical studies [39]. Mechanism of action: Although this project explored the effects of Bushen Huoxue on integrin 3 and integrin 5, its specific molecular mechanisms and targets need to be further studied to further clarify its role in RIF [40].
Conclusion
In summary, this study is of great significance for exploring the therapeutic effect of Bushen Huoxue in the treatment of repeated implantation failure caused by antiphospholipid antibodies and provides a new idea and method for the application of traditional Chinese medicine in the field of infertility. However, in the future, it is necessary to further explore its molecular mechanism and carry out clinical trials to further verify its therapeutic effect and application potential to provide patients with more effective treatment options and individualized treatment strategies. At the same time, it is also necessary to strengthen the experimental design and reasonable planning of sample size to improve the reliability and scientificity of research results. Overall, the research of this project will contribute to the development and innovation of traditional Chinese medicine in the field of infertility.
Funding
This work was supported by the 2023 Science and Technology Research Project of Henan Province (232102311216), project name: Clinical Study on the Influence of Bushen Huoxue Prescription on Pregnancy Outcomes in Patients with Repeated Implantation Failure caused by Phospholipid Antibody.
Ethical approval
The study was approved by the Ethics Committee of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine (Approval No. 2023HL-012).
Data availability
The dataset that supports the results and findings of this research is available from the corresponding author upon reasonable request.
Footnotes
Acknowledgments
The authors have no acknowledgments.
Conflict of interest
The authors declare that they have no conflicts of interest.
References
1.
RodriguesVOSoligoAGESPannainGD. Antiphospholipid antibody syndrome and infertility. Rev Bras Ginecol Obstet.2019; 41(10): 621-627.
2.
WhitakerKL. Antiphospholipid antibody syndrome: The difficulties of diagnosis. JAAPA.2017; 30(12): 10-14.
3.
MeroniPLBorghiMO. Antiphospholipid antibody assays in 2021: Looking for a predictive value in addition to a diagnostic one. Front Immunol.2021; 12: 726820.
RoggenbuckDEgererKvon LandenbergPHiemannRFeistEBurmesterGR, et al. Antiphospholipid antibody profiling: Time for a new technical approach? Autoimmun Rev.2012; 11(11): 821-826.
6.
McCraeKR. Antiphospholipid antibody associated thrombosis: A consensus for treatment? Lupus.1996; 5(6): 560-570.
7.
QureshiFViswanathanVSaneS. Tuberculosis in catastrophic antiphospholipid antibody syndrome. Indian Pediatr.2021; 58(1): 82-83.
8.
HisadaRAtsumiT. An antiphospholipid antibody profile as a biomarker for thrombophilia in systemic lupus erythematosus. Biomolecules.2023; 13(4): 617.
LimWCrowtherMAEikelboomJW. Management of antiphospholipid antibody syndrome: A systematic review. JAMA.2006; 295(9): 1050-1057.
11.
WillisRLakosGHarrisEN. Standardization of antiphospholipid antibody testing-historical perspectives and ongoing initiatives. Semin Thromb Hemost.2014; 40(2): 172-177.
12.
AtsumiTFurukawaSAmengualOKoikeT. Antiphospholipid antibody associated thrombocytopenia and the paradoxical risk of thrombosis. Lupus.2005; 14(7): 499-504.
13.
ChengTMChangWJChuHYDe LucaRPedersenJZIncerpiS, et al. Nano-strategies targeting the integrin β3 network for cancer therapy. Cells.2021; 10(7): 1684.
14.
WuLZhengYLiuJLuoRWuDXuP, et al. Comprehensive evaluation of the efficacy and safety of LPV/r drugs in the treatment of SARS and MERS to provide potential treatment options for COVID-19. Aging (Albany NY.). 2021; 13(8): 10833-10852.
15.
YangYSHKoPJPanYSLinHYWhang-PengJDavisPJ, et al. Role of thyroid hormone-integrin β3-signal and therapeutic strategies in colorectal cancers. J Biomed Sci.2021; 28(1): 24.
16.
DavisPJMousaSASchechterGP, et al. Platelet ATP, Thyroid Hormone Receptor on Integrin β3 and Cancer Metastasis. Horm Cancer.2020; 11(1): 13-16.
17.
DavisPJMousaSALinHY. Tetraiodothyroacetic acid (tetrac): Integrin β3 and disabling of immune checkpoint defense. Future Med Chem.2018; 10(14): 1637-1639.
18.
LiuZYuLWangXZhangXLiuMZengW. Integrin (β3) Targeted RGD Peptide Based Probe for Cancer Optical Imaging. Curr Protein Pept Sci.2016; 17(6): 570-81.
19.
SomanathPRMalininNLByzovaTV. Cooperation between integrin alphavbeta3 and VEGFR2 in angiogenesis. Angiogenesis.2009; 12(2): 177-185.
20.
WuLZhongYWuDXuPRuanXYanJ, et al. Immunomodulatory Factor TIM3 of Cytolytic Active Genes Affected the Survival and Prognosis of Lung Adenocarcinoma Patients by Multi-Omics Analysis. Biomedicines.2022; 10(9): 2248.
21.
Jarne-BorràsMMiró-MurFAnunciación-LlunellAAlijotas-ReigJ. Antiphospholipid antibodies in women with recurrent embryo implantation failure: A systematic review and meta-analysis. Autoimmun Rev.2022; 21(6): 103101.
22.
FavaloroEJWongRC. Antiphospholipid antibody testing for the antiphospholipid syndrome: A comprehensive practical review including a synopsis of challenges and recent guidelines. Pathology.2014; 46(6): 481-495.
23.
KhawajaMMagderLGoldmanDPetriMA. Loss of antiphospholipid antibody positivity postthrombosis in SLE. Lupus Sci Med.2020; 7(1): e000423.
24.
PietteJCPapoTAmouraZBoffaMC. Anticorps antiphospholipides/co-facteurs. Qui sont-ils? Pourquoi, quand et comment les rechercher? Justifient-ils un traitement? [Antiphospholipid antibody/cofactors. What are they? Why, when and how to search for them? Is treatment justified?]. Ann Med Interne (Paris.).1996; 147(7): 492-497.
25.
HernándezJLSanlésIPérez-MontesRMartínez-TaboadaVMOlmosJMSalmónZ, et al. Antiphospholipid syndrome and antiphospholipid antibody profile in patients with retinal vein occlusion. Thromb Res.2020; 190: 63-68.
26.
ChuCQ. The pivotal role of endothelial protein C receptor for antiphospholipid antibody-mediated pathologies. Rheumatology (Oxford.).2022; 61(3): 883-885.
27.
KuttehWHRoteNSSilverR. Antiphospholipid antibodies and reproduction: The antiphospholipid antibody syndrome. Am J Reprod Immunol.1999; 41(2): 133-152.
28.
WuLLiuQRuanXLuanXZhongYLiuJ, et al. Multiple Omics Analysis of the Role of RBM10 Gene Instability in Immune Regulation and Drug Sensitivity in Patients with Lung Adenocarcinoma (LUAD). Biomedicines.2023; 11(7): 1861.
29.
Akhlaghi KalahroodiMLoghmanMRamezanpoorMShahriariradRRahmanianE. Antineutrophil cytoplasmic antibody-associated vasculitis in presence of positive antiphospholipid antibody: A case report. J Med Case Rep.2022; 16(1): 28.
30.
FavaloroEJWongRC. Laboratory testing for the antiphospholipid syndrome: Making sense of antiphospholipid antibody assays. Clin Chem Lab Med.2011; 49(3): 447-461.
31.
WuLZhengYRuanXWuDXuPLiuJ, et al. Long-chain noncoding ribonucleic acids affect the survival and prognosis of patients with esophageal adenocarcinoma through the autophagy pathway: Construction of a prognostic model. Anticancer Drugs.2022; 33(1): e590-e603.
32.
KimYKimSY. Antiphospholipid antibody and recurrent ischemic stroke: A systematic review and meta-analysis. Stroke.2020; 51(12): 3728-3732.
33.
Anunciación-LlunellAMuñozCRoggenbuckDFrascaSPardos-GeaJEsteve-ValverdeE, et al. Differences in antiphospholipid antibody profile between patients with obstetric and thrombotic antiphospholipid syndrome. Int J Mol Sci.2022; 23(21): 12819.
34.
BolesJMackmanN. Role of tissue factor in thrombosis in antiphospholipid antibody syndrome. Lupus.2010; 19(4): 370-378.
35.
GirardiGMackmanN. Tissue factor in antiphospholipid antibody-induced pregnancy loss: A pro-inflammatory molecule. Lupus.2008; 17(10): 931-936.
36.
WuLZhongYYuXWuDXuPLvL, et al. Selective poly adenylation predicts the efficacy of immunotherapy in patients with lung adenocarcinoma by multiple omics research. Anticancer Drugs.2022; 33(9): 943-959.
37.
FavaloroEJMohammedSVongRPasalicL. Antiphospholipid Antibody Testing for Anti-cardiolipin and Anti-β2 Glycoprotein I Antibodies Using Chemiluminescence-Based Panels. Methods Mol Biol.2023; 2663: 297-314.
38.
GroverSPRoubeyRAS. Q10uest for New Therapies to Prevent Antiphospholipid Antibody-Mediated Thrombosis. Arterioscler Thromb Vasc Biol.2017; 37(10): 1801-1802.
39.
KapurSVOswalJS. Livedoid vasculopathy associated with antiphospholipid antibody presenting with leg ulcer. Indian J Pediatr.2020; 87(12): 1082.
40.
GilesILambrianidesARahmanA. Examining the nonlinear relationship between monoclonal antiphospholipid antibody sequence, structure and function. Lupus.2008; 17(10): 895-903.
