BACKGROUND:Preeclampsia is the most common complication of pregnancy, significantly affecting maternal and fetal health, and is characterized by placental and systemic endotheliopathy. Patients with preeclampsia have elevated levels of VWF (von Willebrand Factor), which is associated with poor clinical outcomes. However, whether VWF serves as a marker for endotheliopathy or contributes to the pathogenesis of preeclampsia remains poorly understood. METHODS:We investigated the role of hyperadhesive VWF in the development of preeclampsia by studying patients, evaluating mouse models, and performing in vitro experiments. RESULTS:We show that patients develop VWF- and fibrin-rich thrombosis in the placenta and have significantly elevated levels of VWF adhesive activity and placenta-derived extracellular vesicles. In mouse models, pregnant wild-type mice infused with hyperadhesive VWF alone, or in combination with placenta-derived extracellular vesicles, developed a preeclampsia-like condition, which was reduced by the VWF-cleaving metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13). Furthermore, ADAMTS13-deficient mice with high baseline VWF (ADAMTS13-/-/casa) developed a preeclampsia-like condition spontaneously, with VWF adhesive activity increasing 5.6-fold and placenta-derived extracellular vesicles increasing 2.9-fold during late pregnancy. VWF became hyperadhesive during pregnancy by undergoing conformational changes and promoted preeclampsia-associated endotheliopathy by enhancing the interaction of placenta-derived extracellular vesicles with endothelial cells. CONCLUSIONS:This study demonstrates that hyperadhesive VWF plays a causal role in preeclampsia and is a potential therapeutic target.

This study aims to construct a noninvasive preoperative prediction model for lymph node metastasis in adenocarcinoma of esophagogastric junction (AEG) using computed tomography (CT) texture characterization and machine learning. We analyzed clinical and imaging data from 57 patients with preoperative CT enhancement scans and pathologically confirmed AEG. Lesions were delineated, and texture features were extracted from arterial phase and venous phase CT images using 3D-Slicer software. Features were normalized, downscaled, and screened using correlation analysis and the least absolute shrinkage and selection operator algorithm. The lymph node metastasis prediction model employed machine learning algorithms (random forest, logistic regression, decision tree [DT], and support vector machine), with performance validated using receiver operating characteristic curves. In the arterial phase, the random forest model excelled in precision (0.86) and positive predictive value (0.86). The DT model exhibited the best negative predictive value (0.86), while the logistic regression model demonstrated the highest area under the curve (AUC; 0.78) and specificity (1.0). During the venous phase, the DT model excelled in precision (0.72), F1 score (0.76), and recall (0.80), whereas the support vector machine model had the highest AUC (0.75). Differences in AUCs between models in both phases were not statistically significant per DeLong's test, indicating comparable performance. Each model displayed strengths across various metrics, with the DT model showing consistent performance across arterial and venous phases, emphasizing accuracy and specificity. The CT texture-based machine learning model effectively predicts lymph node metastasis noninvasively in AEG patients, demonstrating robust predictive efficacy.

The search for highly sensitive and specific tumor biomarkers is essential for the evaluation of prognosis and new therapeutic targets. Immune cells in the tumor microenvironment (TME) have dual roles in promoting and suppressing tumor growth, which is crucial for the development and treatment of cancer. According to previous studies, syndecan binding protein (SDCBP) participated in biological processes like epithelial-mesenchymal transformation, angiogenesis, and exosome formation and secretion during cancer metastasis, but whether SDCBP affects immune cells infiltration in the TME remains unclear. Here, we conducted a comprehensive analysis of multiple databases to explore the expression and prognosis of SDCBP in pan-cancer and focused on the effect of SDCBP on the immune cells, particularly on macrophages. The study found that SDCBP was expressed at different levels in most tumor tissues and cells. Upregulation of SDCBP was associated with malignant progression, poor patient prognosis and treatment non-response in certain tumors. Gene set enrichment analysis suggested that SDCBP was mainly involved in regulating immunity and inflammation-related pathways, which may be closely associated with the high levels of immune cells infiltration. Further experiments confirmed that SDCBP is highly expressed in macrophages, and knockdown of SDCBP in THP-1-derived macrophages reduces their chemotaxis but does not affect their polarization and phagocytic function. Our study indicated that SDCBP involves in tumor progression and macrophages infiltration, providing novel perspectives for cancer, particularly in combination with immunotherapy.

BACKGROUND:Gastric cancer invades local tissue extensively and metastasizes through the circulation to remote organs. Patients with metastasized gastric cancer have poor clinical outcomes. The vasculature in the cancer niche is developed poorly, thus allowing cancer cells to be released into the circulation. However, it is poorly understood how cancer cells adhere to and transmigrate through the fully developed endothelium in remote organs and what key adhesive ligands are involved in the process. Here, we report results from a study designed to investigate the role of hyperadhesive VWF (von Willebrand factor) in promoting the pulmonary metastasis of gastric cancer. METHODS:We used mouse models to investigate the roles of hyperadhesive VWF in the pulmonary metastasis of gastric cancer. The findings from these mouse models were validated through in vitro experiments that specifically examined how VWF promoted gastric cancer-derived extracellular vesicles to activate endothelial cells and analyzed established databases of patients with gastric cancer. RESULTS:VWF in cancer-bearing mice became hyperadhesive and mediated the adhesion of gastric cancer-derived extracellular vesicles to the endothelium, where gastric cancer-derived extracellular vesicles caused endothelial permeability and promoted the transmigration of cancer cells to the interstitial tissue of the lungs. Reducing VWF adhesive activity by the metalloprotease ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type motifs, type 13) prevented the pulmonary metastasis of gastric cancer cells in mice. We further validated the findings in mice through targeted in vitro experiments and by associating VWF with the outcomes of patients with gastric cancer through established databases of patients with gastric cancer using bioinformatics tools. CONCLUSIONS:We show how VWF becomes hyperadhesive to promote the pulmonary metastasis of gastric cancer through its interaction with gastric cancer-derived extracellular vesicles and that the hyperadhesive activity of VWF is reduced by ADAMTS-13 to prevent the metastasis.

B‑cell acute lymphoblastic leukemia (B‑ALL) is a type of acute lymphoblastic leukemia that originates from B cells. It typically occurs in children and adolescents, but it can also appear in adults. Sorting nexin 10 (SNX10) has recently been identified as a significant regulatory factor in various tumors, although its specific roles remain contested. However, its function in B‑ALL has not been previously explored. The present study investigated the role of SNX10 in B‑ALL pathogenesis. Bioinformatics analysis identified SNX10 as a Core Hub gene in the B‑ALL signaling network, with significantly reduced expression in patients with B‑ALL. These findings were corroborated through analysis of clinical bone marrow samples and B‑ALL cell lines. Functional in vitro studies revealed that SNX10 knockdown markedly inhibited B‑ALL cell proliferation, increased apoptosis, and arrested cells in the G0/G1 phase. By contrast, SNX10 overexpression enhanced cell proliferation, suppressed apoptosis and promoted G2/M phase progression. Proteomic analysis further implicated the PI3K/Akt signaling pathway in mediating the effects of SNX10. Specifically, SNX10 overexpression increased the phosphorylation levels of PI3K and Akt, while SNX10 knockdown had the opposite effect. In vivo experiments demonstrated that elevated SNX10 expression accelerated leukemia progression in a mouse model. Collectively, these findings highlighted the pivotal role of SNX10 in promoting B‑ALL cell proliferation via the PI3K pathway, highlighting its potential as a therapeutic target for B‑ALL and providing a foundation for future investigations.

Gastric cancer is one of the most common malignant tumors in the world. The occurrence of chemotherapy resistance seriously affects the survival and prognosis of middle and advanced patients. Enhancing DNA repair ability is one of the important mechanisms of chemotherapy resistance. ADAM9, a member of the disintegrin and metalloproteinase family, is involved in many biological processes, such as tumor cells proliferation, apoptosis, invasion and migration, vascular invasion, and drug resistance. In this study, we found that the high expression of ADAM9 in gastric cancer tissues was associated with a variety of clinicopathological factors and poor prognosis in patients. Gastric cancer cells with high ADAM9 expression reduced sensitivity to Cisplatin, decreased DNA damage, increased expression of ATM and CHK2, the key proteins in DNA damage repair pathway, and improved cancer cells survival rate. Further studies showed that the expression of ADAM9 was selectively interfered with gastric cancer cells, the expression levels of ATM and CHK2 were decreased, while the expression of damage protein γ-H2AX was significantly increased, the degree of DNA damage was increased, and the sensitivity of gastric cancer cells to Cisplatin was significantly enhanced. It is suggested that ADAM9 is involved in Cisplatin resistance in gastric cancer cells, and its mechanism is related to the activation of ATM-CHK2 pathway in DNA damage repair. These data demonstrate that ADAM9 plays a pro-cancer role and mediates Cisplatin resistance in gastric cancer, which may be a new target to overcome chemotherapy resistance.

Extracellular vesicles (EVs) play a pivotal role in intercellular communication and are closely linked to cancer progression and metastasis. Our previous studies have shown that gastric cancer cell-derived EVs can promote tumor metastasis by increasing the permeability of the endothelial barrier. However, it remains unclear which effector molecule in the EV structure is the key factor of EV-mediated tumor metastasis and the underlying molecular mechanism. In this study, we found that CD147 is a key molecule highly expressed in gastric cancer-derived EVs and confirmed the role of CD147-high EVs from gastric cancer cells in promoting endothelial dysfunction and tumor metastasis. Our results showed that CD147-high EVs activated the VEGF/AKT/eNOS/NO and AKT/mTOR/p70S6K signaling pathways, leading to endothelial cytoskeletal reorganization and internalization of VE-cadherin, which significantly compromised endothelial barrier integrity, increased vascular leakage, enhanced transendothelial migration of tumor cell, and promoted the formation of metastatic tumors. Furthermore, detection of CD147 levels in gastric cancer tissues and plasma EVs indicated that high CD147 expression was associated with advanced tumor stage, poor prognosis, and reduced survival. Our findings suggest that CD147-high EVs are critical mediators of tumor-endothelial interactions and potential diagnostic and prognostic biomarkers for gastric cancer. Their potential as therapeutic targets for gastric cancer is underscored.

Gastric cancer remains a significant global health burden with limited treatment options and high mortality. Syndecan-binding protein (SDCBP), a scaffolding protein involved in tumor differentiation, has attracted attention as a potential therapeutic target in cancers. However, its precise role in gastric cancer progression is not fully understood. In this study, through bioinformatics analysis and gastric cancer samples detection, we discovered that SDCBP was highly expressed in gastric cancer tissues, which was correlated with clinicopathological features such as tumor invasion depth and distant metastasis, and exhibited heterogeneity across histological or molecular subtypes. Elevated SDCBP expression promoted the proliferation, invasion and migration of gastric cancer cells, and modulated epithelial-mesenchymal transition (EMT) via the ERK signaling pathway. Xenograft experiments in mice confirmed that inhibiting SDCBP or ERK signaling could delay cancer progression. We also found that gastric cancer cells with SDCBP knockdown were able to inhibit the M2 polarization of cocultured macrophages, reduce chemotaxis and enhance phagocytosis of macrophages. Therefore, SDCBP plays a crucial role in driving gastric cancer progression. Targeting SDCBP in gastric cancer can partially reverse the malignant phenotype, and SDCBP is expected to be a promising therapeutic target for gastric cancer.

Objective To investigate the impact of serine/threonine-protein kinase 1(AKT1)-mediated autophagy in hepatocellular carcinoma(HCC)cells on their sensitivity to 125I seed irradiation.Methods ① iProX database and STRING12.0 website were utilized to analyze the proteomic data of HCC before and after 125I seed irradiation to explore the differentially expressed proteins and associated functional connections.Meanwhile,The Cancer Genomics Atlas(TCGA)database was employed to analyze the relationship between AKT1 expression level and the survival of HCC patients.② Human HCC cell lines HUH7 and Hep3B were exposed to continuous irradiation from 125I radioactive seeds with an initial apparent activity of 0.8 mCi per seed for approximately 120 h,accumulating a total dose of 8 Gy,while the control cells were cultured under normal condition for 120 h.③ Autophagy inhibitor,chloroquine(CQ)and inducer,rapamycin(RAPA)were used to treat the HCC cells respectively to establish the CQ group and the RAPA group.The lentiviral transfection technique was employed to construct the HCC cells with overexpressed AKT1,namely the AKT1 group.The HCC cells treated in the same way were continuously irradiated with 125I seeds for 120 h to construct the CQ+125I group,the RAPA+125I group,and the AKT1+125I group.④The changes in microtubule-associated protein light chain 3(LC3),p62,AKT1 and p-AKT1 were detected by Western blotting.Cell immunofluorescence assay was employed to observe the expression of autophagy related proteins,such as LC3.The colony forming ability and apoptotic rate were detected with plate cloning assay and flow cytometry.Results ① Continuous irradiation with 125I seeds resulted in decreased expression of p62 and increased ratio of LC3Ⅱ/LC3Ⅰ(P＜0.05)when compared with the negative control(NC)group.Immunofluorescence assay revealed more green fluorescence spots of LC3.When compared with the 125I group,the CQ+125I group had significantly increased expression of p62(P＜0.01),decreased ratio of LC3Ⅱ/LC3Ⅰ(P＜0.01),lower apoptotic rate(P＜0.01),and more colony formations(P＜0.01).In contrast,the results in the RAPA+125I group were opposite to those of the CQ+125I group.② Analysis on the iProX database showed that the expression of AKT1 was decreased in the irradiated group,and analysis on the TCGA database indicated that high expression of AKT1 predicted a poor prognosis for HCC patients(P＜0.01).③After irradiation with 125I seeds,the expression of AKT1 at both the RNA and protein levels was decreased in the 125I group(P＜0.01).After overexpression of AKT1,the level of autophagy was decreased(P＜0.05).Irradiation of HCC cells with overexpressed AKT1 using 125I seeds could partially restore the level of autophagy.In the AKT1+125I group,the expression of AKT1,pAKT1 and p62 were all decreased,and the ratio of LC3Ⅱ/LC3Ⅰwas increased than the AKT1 group(P＜0.05).④ The apoptotic rate of the AKT1+125I group was lower than that of the 125I group(P＜0.05)and higher than that in the AKT1 group(P＜0.05).In HUH7 cells,the clonogenic ability of the AKT1+125I group was higher than that of the 125I group(P＜0.05).In Hep3B cells,the clonogenic ability of the AKT1+125I group was higher than that of the 125I group,and the clonogenic ability of the AKT1 group was higher than that of the NC group(P＜0.05).Conclusion 125I seed irradiation induce lethal autophagy in HCC cells by reducing the expression of AKT1,providing a new theoretical basis for the implantation of 125I radioactive seeds in the treatment of HCC.

Gastric cancer (GC) is a prevalent malignant tumor and ranks as the second leading cause of death among cancer patients worldwide. Due to its hidden nature and difficulty in detection, GC has a high incidence and poor prognosis. Traditional treatment methods such as systemic chemotherapy, radiotherapy, and surgical resection are commonly used, but they often fail to achieve satisfactory curative effects, resulting in a very low 5-year survival rate for GC patients. Currently, targeted therapy and immunotherapy are prominent areas of research both domestically and internationally. These methods hold promise for the treatment of GC. This article focuses on the signaling pathways associated with the development of GC, as well as the recent advancements and applications of targeted therapy and immunotherapy. The aim is to provide fresh insights for the clinical treatment of GC.

ABSTRACT Cells of gastric cancer invade local tissue extensively and also metastasize through the circulation to remote organs. Patients with metastasized gastric cancer have poor outcomes. Cancer cells are known to release extracellular vesicles (EVs) that contribute to cancer progression, but how cancer cell-derived EVs promote cancer growth and metastasis remains poorly understood. We have recently reported that levels of circulating gastric cancer cell-derived EVs (gcEVs) and the adhesive ligand von Willebrand factor (VWF) are associated with cancer metastasis and poor prognosis of patients, but the underlying mechanism of this gcEV-VWF interaction was not known. Here we report results from a study designed to investigate the synergistic action of VWF and gcEVs in vitro and in mouse models. We showed that VWF in cancer-bearing mice was hyperadhesive and became microvesicle-bound. EV-bound VWF mediated the adhesion of gcEVs to the endothelium to disrupt endothelial integrity and facilitate the transendothelial migration of cancer cells and pulmonary metastasis. Reducing VWF adhesive activity by the metalloprotease ADAMTS-13 or promoting gcEV clearance by the scavenging factor lactadherin prevented pulmonary metastasis in mice. These results highlight the synergistic action of gcEVs and VWF in promoting gastric cancer metastasis and identifying new targets for its prevention. Key point: Author contributions Hyperadhesive VWF becomes microvesicle-bound to induce endothelial leakage and promote the pulmonary metastasis of gastric cancer in mice. Reducing VWF activity by ADAMTS-13 and accelerating microvesicle clearance by lactadherin reduces pulmonary metastasis of gastric cancer.

Gastric cancer (GC) is one of the most common gastrointestinal malignancies worldwide. In the past decade, with the development of early diagnostic techniques, a clear decline in GC incidence has been observed, but its mortality remains high. The emergence of new immunotherapies such as immune checkpoint inhibitors (ICIs) has changed the treatment of GC patients to some extent. However, only a small number of patients with advanced GC have a durable response to ICI treatment, and the efficacy of ICIs is very limited. Existing studies have shown that the failure of immunotherapy is mainly related to the development of ICI resistance in patients, but the understanding of the resistance mechanism is still insufficient. Therefore, clarifying the mechanism of GC immune resistance is critical to improve its treatment and clinical benefit. In this review, we focus on summarizing the mechanisms of primary or acquired resistance to ICI immunotherapy in GC from both internal and external aspects of the tumor. At the same time, we also briefly discuss some other possible resistance mechanisms in light of current studies.

Von Willebrand factor (VWF) is an adhesive ligand critical for maintaining hemostasis. However, it has also been increasingly recognized for its role in cancer development because it has been shown to mediate the adhesion of cancer cells to endothelial cells, promote the epithelial–mesenchymal transition, and enhance angiogenesis. We have previously shown that gastric cancer cells synthesize VWF, which mediates the interaction between the cancer and endothelial cells to promote cancer growth. Here, we report results from a clinical observational study that demonstrate the association of VWF in plasma and on the surface of extracellular vesicles (EVs) with the pathological characteristics of gastric cancer. We found that patients with gastric cancer had elevated and intrinsically hyperadhesive VWF in their peripheral blood samples. VWF was detected on the surface of EVs from cancer cells, platelets, and endothelial cells. Higher levels of these VWF-bound EVs were associated with cancer aggression and poor clinical outcomes for patients. These findings suggest that VWF+ EVs from different cell types serve collectively as a new class of biomarkers for the outcome assessment of gastric cancer patients.

The endothelium is the critical barrier that controls transendothelial communications. Blood vessels in cancer tissue are poorly developed and highly permeable. However, it is poorly understood how circulating cancer cells released through these "leaky" vessels break the intact vasculature of remote organs to metastasize. We investigated the roles of cancer cell-derived extracellular vesicles (CEVs) in regulating cancer metastasis by analyzing samples from gastric cancer patients, performing in vitro experiments, and studying mouse models. We made several novel observations. First, the rate of metastasis was closely associated with plasma levels of CEVs in patients with gastric cancer. Second, cultured endothelial cells endocytosed CEVs, resulting in cytoskeletal rearrangement, low expression of the junction proteins cadherin and CD31, and forming large intercellular gaps to allow the transendothelial migration of cancer cells. The dynamin inhibitor Dynasore prevented these CEV-induced changes of endothelial cells by blocking CEVs endocytosis. Third, CEVs disrupted the endothelial barrier of cancer-bearing mice to promote cancer metastasis. Finally, lactadherin promoted the clearance of circulating CEVs to reduce metastasis. These results demonstrate the essential role of CEVs in promoting the metastasis of gastric cancer.

Gastrodiae Rhizoma and its active constituents are known to exhibit neuroprotective effects in Alzheimer’s disease (AD). However, the effect of Rhizoma Gastrodiae water extract (WERG) on AD and the detailed mechanism of action remain unclear. In this study, the mechanism of action of WERG was investigated by the microbiome–gut–brain axis using a D-galactose (D-gal)/AlCl3-induced AD mouse model. WERG improved the cognitive impairment of D-gal/AlCl3-induced mice. The expression level of p-Tauthr231 in the WERG-H treatment group was decreased, and p-Tauthr231 was found negative in hippocampal DG, CA1, and CA3 regions. Here, the diversity and composition of the gut microbiota were analyzed by 16sRNA sequencing. WERG-H treatment had a positive correlation with Firmicutes, Bacilli, Lactobacillus johnsonii, Lactobacillus murinus, and Lactobacillus reuteri. Interestingly, the Rikenellaceae-RC9 gut group in the gut increased in D-gal/AlCl3-induced mice, but the increased L. johnsonii, L. murinus, and L. reuteri reversed this process. This may be a potential mechanistic link between gut microbiota dysbiosis and P-TauThr231 levels in AD progression. In conclusion, this study demonstrated that WERG improved the cognitive impairment of the AD mouse model by enriching gut probiotics and reducing P-TauThr231 levels.

Triple-negative breast cancer (TNBC) is highly invasive, has a high rate of recurrence and is associated with a poor clinical outcome when compared with non-TNBC due to a lack of effective and targeted treatments. The coatomer protein complex subunit β2 (COPB2) is upregulated in various types of malignant cancer. The present study demonstrated that COPB2 expression levels were significantly upregulated in breast carcinoma HS-578T cells (clonal cells originating from TNBC) when compared with non-TNBC MCF-7 cells. HS-578T cells also exhibited higher rates of proliferation, invasion and transendothelial migration when compared with MCF-7 cells. Moreover, it was identified that genetically silencing the COPB2 gene using a lentivirus-short hairpin RNA inhibited the proliferative, colony formation, migratory and invasive properties of the TNBC HS-578T cells. Mediation of the COPB2 silencing effect may be associated with regulating the phosphorylation of serine/threonine kinase AKT in the PI3K/AKT signaling pathway. These results suggested the importance of COPB2 in promoting the proliferation of TNBC cells and identified COPB2 as a potential novel therapeutic target.

Tissue factor (TF) has been extensively studied for tumor metastasis, but its role in mediating cancer cell adhesion to vasculature remains unknown. This study aimed to measure the ability of TF to mediate the adhesion of breast cancer cells to human umbilical vein endothelial cells (HUVECs). MDA-MB-231 cells expressed the highest TF level and adhered more to HUVECs under static and flow conditions, a neutralizing TF antibody abolished the enhanced adhesion of MDA-MB-231 cells to HUVECs. Recombinant human soluble TF (rTF) bonded β1integrin on HUVECs surfaces, β1 or α3integrin antibody combined with TF antibody abolished more cell-cell adhesion. These data suggested that TF mediated adhesion of breast cancer cells to endothelial cells may rely on β1integrin on HUVECs surfaces.

Preeclampsia is a pregnancy-induced condition that impairs the mother's health and results in pregnancy termination or premature delivery. Elevated levels of placenta-derived extracellular vesides (pcEV) in the circulation have been consistently associated with preeclampsia, but whether these vesicles induce preeclampsia or are the product of preeclampsia is not known. Guided by a small cohort study of preeclamptic patients, we examined the impact of pcEV on the pathogenesis of preeclampsia in mouse models. We detected pcEV in pregnant C56BL/6J mice with a peak level of 3.8 +/- 0.9x10(7)/mL at 17-18 days postcoitum. However, these pregnant mice developed hypertension and proteinuria only after being infused with vesicles purified from injured placenta. These extracellular vesicles released from injured placenta disrupted endothelial integrity and induced vasoconstriction. Enhancing the dearance of extracellular vesides prevented the development of the extracellular vesicle-induced preeclampsia in mice. Our results demonstrate a causal role of pcEV in preeclampsia and identify microveside dearance as a new therapeutic strategy for the treatment of this pregnancy-associated complication.

Traumatic brain injury-induced coagulopathy (TBI-IC) causes life-threatening secondary intracranial bleeding. Its pathogenesis differs mechanistically from that of coagulopathy arising from extracranial injuries and hemorrhagic shock, but it remains poorly understood. We report results of a study designed to test the hypothesis that von Willebrand factor (VWF) released during acute TBI is intrinsically hyperadhesive because its platelet-binding A1-domain is exposed and contributes to TBI-induced vascular leakage and consumptive coagulopathy. This hyperadhesive VWF can be selectively blocked by a VWF A2-domain protein to prevent TBI-IC and to improve neurological function with a minimal risk of bleeding. We demonstrated that A2 given through intraperitoneal injection or IV infusion reduced TBI-induced death by >50% and significantly improved the neurological function of C57BL/6J male mice subjected to severe lateral fluid percussion injury. A2 protected the endothelium from extracellular vesicle-induced injury, reducing TBI-induced platelet activation and microvesiculation, and preventing a TBI-induced hypercoagulable state. A2 achieved this therapeutic efficacy by specifically blocking the A1 domain exposed on the hyperadhesive VWF released during acute TBI. These results suggest that VWF plays a causal role in the development of TBI-IC and is a therapeutic target for this life-threatening complication of TBI.