The localization, origin, and impact of platelets in the tumor microenvironment are tumor type-dependent.

BACKGROUND: How platelets interact with and influence the tumor microenvironment (TME) remains poorly characterized. METHODS: We compared the presence and participation of platelets in the TME of two tumors characterized by highly different TME, PyMT AT-3 mammary tumors and B16F1 melanoma. RESULTS: We show that whereas firmly adherent platelets continuously line tumor vessels of both AT-3 and B16F1 tumors, abundant extravascular stromal clusters of platelets from thrombopoietin-independent origin were present only in AT-3 mammary tumors. We further show that platelets influence the angiogenic and inflammatory profiles of AT-3 and B16F1 tumors, though with very different outcomes according to tumor type. Whereas thrombocytopenia increased bleeding in both tumor types, it further caused severe endothelial degeneration associated with massive vascular leakage, tumor swelling, and increased infiltration of cytotoxic cells, only in AT-3 tumors. CONCLUSIONS: These results indicate that while platelets are integral components of solid tumors, their localization and origin in the TME, as well as their impact on its shaping, are tumor type-dependent.

Periodontitis in ischemic stroke: impact of Porphyromonas gingivalis on thrombus composition and ischemic stroke outcomes.

Background: Periodontitis is associated with an increased risk of ischemic stroke, but the mechanisms underlying this association remain unclear. Objectives: Our objective was to determine whether Porphyromonas gingivalis (Pg), a periodontal bacterium, could be detected within thrombus aspirates, modify thrombus composition, and endovascular therapy responses. Methods: The presence of Pg gingipain in 175 consecutive thrombi from patients with large vessel occlusion stroke enrolled in the multicenter research cohort compoCLOT was investigated by immunostaining. Thrombus blood cell composition according to gingipain status was analyzed in a subset of 63 patients. Results: Pg gingipain immunostaining was positive in 33.7% of thrombi (95% CI, 26.7%-40.8%). The percentage of near to complete reperfusion (modified Thrombolysis in Cerebral Infarction Score 2c/3) at the end of the procedure was lower in the Pgpos group than the Pgneg group (39.0% vs 57.8% respectively; adjusted odds ratio, 0.38; 95% CI, 0.19-0.77). At 3 months, 35.7% of patients in the Pgpos group had a favorable neurological outcome vs 49.5% in the Pgneg group (odds ratio, 0.65; 95% CI, 0.30-1.40). Quantitative analysis of a subset of 63 thrombi showed that neutrophil elastase content was significantly (P < .05) higher in Pgpos thrombi than in Pgneg thrombi. Conclusion: Our results indicate that intrathrombus Pg gingipain is associated with increased neutrophil content and resistance to endovascular therapy.

Exacerbation of thrombo-inflammation by JAK2V617F mutation worsens the prognosis of cerebral venous sinus thrombosis.

Cerebral venous sinus thrombosis (CVST) is an uncommon venous thromboembolic event accounting for <1% of strokes resulting in brain parenchymal injuries. JAK2V617F mutation, the most frequent driving mutation of myeloproliferative neoplasms has been reported to be associated with worse clinical outcomes in patients with CVST. We investigated whether hematopoietic JAK2V617F expression predisposes to specific pathophysiological processes and/or worse prognosis after CVST. Using an in vivo mouse model of CVST, we analyzed clinical, biological and imaging outcomes in mice with hematopoietic-restricted Jak2V617F expression, compared to Jak2WT mice. In parallel, we studied a human cohort of JAK2V617F-positive or negative CVST. Early after CVST, mice with hematopoietic Jak2V617F expression had increased adhesion of platelets and neutrophils in cerebral veins located in the vicinity of CVST. On day 1, Jak2V617F mice had a worse outcome characterized by significantly more frequent and severe intracranial hemorrhages (ICH) and higher mortality rates. Peripheral neutrophil activation was enhanced, as indicated by higher circulating platelet-neutrophil aggregates, upregulated CD11b expression, and higher myeloperoxydase (MPO) plasma level. Concurrently, immunohistological and brain homogenates analysis showed higher neutrophil infiltration and increased blood-brain-barrier disruption. Similarly, JAK2V617F-positive CVST patients tended to present higher thrombotic burden and had significantly higher SII, a systemic thrombo-inflammatory marker, compared to JAK2V617F-negative patients. In mice with CVST, our study corroborates that Jak2V617F mutation leads to a specific pattern including increased thrombotic burden, ICH and mortality. The exacerbated thrombo-inflammatory response, observed both in mice and JAK2V617F-positive patients, could contribute to hemorrhagic complications.

Neutrophil activation in patients treated with endovascular therapy is associated with unfavorable outcomes and mitigated by intravenous thrombolysis.

BACKGROUND: Accumulating evidence indicates that neutrophil activation (NA) contributes to microvascular thromboinflammation in acute ischemic stroke (AIS) due to a large vessel occlusion. Preclinical data have suggested that intravenous thrombolysis (IVT) before endovascular therapy (EVT) could dampen microvascular thromboinflammation. In this study we investigated the association between NA dynamics and stroke outcome, and the impact of IVT on NA in patients with AIS treated with EVT. METHODS: A single-center prospective study was carried out, including patients treated with EVT for whom three blood samples (before, within 1 hour, 24 hours post-EVT) were drawn to measure plasma myeloperoxidase (MPO) concentration as a marker of NA. Unfavorable outcome was defined as a modified Rankin score of 3-6 at 3 months. RESULTS: Between 2016 and 2020, 179 patients were included. The plasma MPO concentration peaked significantly 1 hour post-EVT (median increase 21.0 ng/mL (IQR -2.1-150)) and returned to pre-EVT baseline values 24 hours after EVT (median change from baseline -0.8 ng/mL (IQR -7.6-6.7)). This peak was strongly associated with unfavorable outcomes at 3 months (aOR 0.53 (95% CI 0.34 to 0.84), P=0.007). IVT before EVT abolished this 1 hour post-EVT MPO peak. Changes in plasma MPO concentration (baseline to 1 hour post-EVT) were associated with unfavorable outcomes only in patients not treated with IVT before EVT (aOR 0.54 (95% CI 0.33 to 0.88, P=0.013). However, we found no significant heterogeneity in the associations between changes in plasma MPO concentration and outcomes. CONCLUSIONS: A peak in plasma MPO concentration occurs early after EVT and is associated with unfavorable outcomes. IVT abolished the post-EVT MPO peak and may modulate the association between NA and outcomes.

Thrombus composition and thrombolysis resistance in stroke.

A State of the Art lecture titled "Thrombus Composition and Thrombolysis Resistance in Stroke" was presented at the ISTH Congress in 2022. Intravenous thrombolysis (IVT) remains the only pharmacologic option to re-establish cerebral perfusion at the acute phase of ischemic stroke. IVT is based on the administration of recombinant tissue plasminogen activator with the objective of dissolving fibrin, the major fibrillar protein component of thrombi. Almost 30 years on from its introduction, although the clinical benefits of IVT have been clearly demonstrated, IVT still suffers from a relatively low efficacy, with a rate of successful early recanalization below 50% overall. Analyses of thrombectomy-recovered acute ischemic stroke (AIS) thrombi have shown that apart from occlusion site, thrombus length, and collateral status, AIS thrombus structure and composition are also important modulators of IVT efficacy. In this article, after a brief presentation of IVT principle and current knowledge on IVT resistance, we review recent findings on how compaction and structural alterations of fibrin together with nonfibrin thrombus components such as neutrophil extracellular traps and von Willebrand factor interfere with IVT in AIS. We further discuss how these new insights could soon result in the development of original adjuvant therapies for improved IVT in AIS. Finally, we summarize relevant new data presented during the 2022 ISTH Congress.

CD31 signaling promotes the detachment at the uropod of extravasating neutrophils allowing their migration to sites of inflammation.

Effective neutrophil migration to sites of inflammation is crucial for host immunity. A coordinated cascade of steps allows intravascular leukocytes to counteract the shear stress, transmigrate through the endothelial layer, and move toward the extravascular, static environment. Those events are tightly orchestrated by integrins, but, while the molecular mechanisms leading to their activation have been characterized, the regulatory pathways promoting their detachment remain elusive. In light of this, it has long been known that platelet-endothelial cell adhesion molecule (Pecam1, also known as CD31) deficiency blocks leukocyte transmigration at the level of the outer vessel wall, yet the associated cellular defects are controversial. In this study, we combined an unbiased proteomic study with in vitro and in vivo single-cell tracking in mice to study the dynamics and role of CD31 during neutrophil migration. We found that CD31 localizes to the uropod of migrating neutrophils along with closed ß2-integrin and is required for essential neutrophil actin/integrin polarization. Accordingly, the uropod of Pecam1-/- neutrophils is unable to detach from the extracellular matrix, while antagonizing integrin binding to extracellular matrix components rescues this in vivo migratory defect. Conversely, we showed that sustaining CD31 co-signaling actively favors uropod detachment and effective migration of extravasated neutrophils to sites of inflammation in vivo. Altogether, our results suggest that CD31 acts as a molecular rheostat controlling integrin-mediated adhesion at the uropod of egressed neutrophils, thereby triggering their detachment from the outer vessel wall to reach the inflammatory sites.

Neuroimaging is the new "spatial omic": multi-omic approaches to neuro-inflammation and immuno-thrombosis in acute ischemic stroke.

Ischemic stroke (IS) is the leading cause of acquired disability and the second leading cause of dementia and mortality. Current treatments for IS are primarily focused on revascularization of the occluded artery. However, only 10% of patients are eligible for revascularization and 50% of revascularized patients remain disabled at 3 months. Accumulating evidence highlight the prognostic significance of the neuro- and thrombo-inflammatory response after IS. However, several randomized trials of promising immunosuppressive or immunomodulatory drugs failed to show positive results. Insufficient understanding of inter-patient variability in the cellular, functional, and spatial organization of the inflammatory response to IS likely contributed to the failure to translate preclinical findings into successful clinical trials. The inflammatory response to IS involves complex interactions between neuronal, glial, and immune cell subsets across multiple immunological compartments, including the blood-brain barrier, the meningeal lymphatic vessels, the choroid plexus, and the skull bone marrow. Here, we review the neuro- and thrombo-inflammatory responses to IS. We discuss how clinical imaging and single-cell omic technologies have refined our understanding of the spatial organization of pathobiological processes driving clinical outcomes in patients with an IS. We also introduce recent developments in machine learning statistical methods for the integration of multi-omic data (biological and radiological) to identify patient-specific inflammatory states predictive of IS clinical outcomes.

DHA, RvD1, RvD5, and MaR1 reduce human coronary arteries contractions induced by PGE2.

In patients with coronary artery disease (CAD), plasma levels of pro-inflammatory lipid mediators such as PGE2 and TxA2 are increased. They could increase vascular contraction while EPA and DHA could reduce it. Studies have been mostly conducted on animal vessels. Therefore, the aim of the study was to investigate if EPA, DHA, and DHA-derived metabolites: RvD1, RvD5 and MaR1 can modulate contraction of human coronary arteries (HCA) induced by PGE2 or TxA2 stable analogue (U46619). DHA and EPA relaxed HCA pre-contracted with PGE2. 18 h-incubation with DHA but not EPA reduced the PGE2-induced contractions. Pre-incubation with RvD1, RvD5 and MaR1 reduced the PGE2-induced contractions. Indomethacin did not significantly modify the PGE2 responses. L-NOARG (inhibitor of nitric oxide synthase), reduced only the PGE2-induced contractions in RvD1-treated rings. Finally, FPR2/ALX, GPR32 and LGR6 receptors are detected in HCA by immunofluorescence. Our results indicate that DHA and its metabolites could be beneficial for HCA blood flow and could be a therapeutic perspective for patients with CAD.

High thrombus platelet content is associated with a lower rate of first pass effect in stroke treated by endovascular therapy.

Background and purpose: First pass effect (FPE), the occurrence of complete reperfusion after one pass with no rescue attempt during endovascular therapy (EVT), is associated with the best clinical outcome after an acute ischemic stroke (AIS). Previous studies evaluating FPE occurrence according to EVT technical strategies, occlusion locations, or thrombus composition have provided controversial results. Here, we performed a correlation analysis between FPE occurrence and AIS thrombus cellular composition, as assessed using quantitative biochemical assays. Patients and methods: Homogenates of AIS thrombi from 250 patients were prepared by mechanical grinding. Platelet, red blood cell (RBC), and leukocyte contents of AIS thrombi were respectively estimated by quantification of GP (glycoprotein) VI, heme, and DNA in thrombus homogenates. FPE was defined as a modified Thrombolysis in Cerebral Infraction (mTICI) score of 2C or 3 after a single EVT device pass. Results: AIS thrombi successfully removed after a single pass were poorer in GPVI (0.098 ± 0.023 vs 0.111 ± 0.024 ng/mg, p < 0.001) compared to those whose removal had required several passes. GPVI content was also significantly associated with a higher number of device passes and a longer procedure time. No such significant correlation was found with DNA and heme content. Discussion and conclusion: Thrombus platelet content may hamper thrombus removal by EVT. This result suggests that adjunctive therapies or functionalization of retrieval devices targeting platelets may improve EVT efficacy.

Composition and Organization of Acute Ischemic Stroke Thrombus: A Wealth of Information for Future Thrombolytic Strategies.

During the last decade, significant progress has been made in understanding thrombus composition and organization in the setting of acute ischemic stroke (AIS). In particular, thrombus organization is now described as highly heterogeneous but with 2 preserved characteristics: the presence of (1) two distinct main types of areas in the core-red blood cell (RBC)-rich and platelet-rich areas in variable proportions in each thrombus-and (2) an external shell surrounding the core composed exclusively of platelet-rich areas. In contrast to RBC-rich areas, platelet-rich areas are highly complex and are mainly responsible for the thrombolysis resistance of these thrombi for the following reasons: the presence of platelet-derived fibrinolysis inhibitors in large amounts, modifications of the fibrin network structure resistant to the tissue plasminogen activator (tPA)-induced fibrinolysis, and the presence of non-fibrin extracellular components, such as von Willebrand factor (vWF) multimers and neutrophil extracellular traps. From these studies, new therapeutic avenues are in development to increase the fibrinolytic efficacy of intravenous (IV) tPA-based therapy or to target non-fibrin thrombus components, such as platelet aggregates, vWF multimers, or the extracellular DNA network.

Illustrated State-of-the-Art Capsules of the ISTH 2022 Congress.

The ISTH London 2022 Congress is the first held (mostly) face-to-face again since the COVID-19 pandemic took the world by surprise in 2020. For 2 years we met virtually, but this year's in-person format will allow the ever-so-important and quintessential creativity and networking to flow again. What a pleasure and joy to be able to see everyone! Importantly, all conference proceedings are also streamed (and available recorded) online for those unable to travel on this occasion. This ensures no one misses out. The 2022 scientific program highlights new developments in hemophilia and its treatment, acquired and other inherited bleeding disorders, thromboinflammation, platelets and coagulation, clot structure and composition, fibrinolysis, vascular biology, venous thromboembolism, women's health, arterial thrombosis, pediatrics, COVID-related thrombosis, vaccine-induced thrombocytopenia with thrombosis, and omics and diagnostics. These areas are elegantly reviewed in this Illustrated Review article. The Illustrated Review is a highlight of the ISTH Congress. The format lends itself very well to explaining the science, and the collection of beautiful graphical summaries of recent developments in the field are stunning and self-explanatory. This clever and effective way to communicate research is revolutionary and different from traditional formats. We hope you enjoy this article and will be inspired by its content to generate new research ideas.

Intratumoral Platelets: Harmful or Incidental Bystanders of the Tumor Microenvironment?

The tumor microenvironment (TME) has gained considerable interest because of its decisive impact on cancer progression, response to treatment, and disease recurrence. The TME can favor the proliferation, dissemination, and immune evasion of cancer cells. Likewise, there is accumulating evidence that intratumoral platelets could favor the development and aggressiveness of solid tumors, notably by influencing tumor cell phenotype and shaping the vascular and immune TME components. Yet, in contrast to other tumor-associated cell types like macrophages and fibroblasts, platelets are still often overlooked as components of the TME. This might be due, in part, to a deficit in investigating and reporting the presence of platelets in the TME and its relationships with cancer characteristics. This review summarizes available evidence from clinical and animal studies supporting the notion that tumor-associated platelets are not incidental bystanders but instead integral and active components of the TME. A particular emphasis is given to the description of intratumoral platelets, as well as to the functional consequences and possible mechanisms of intratumoral platelet accumulation.

Impact of COVID-19 on thrombus composition and response to thrombolysis: Insights from a monocentric cohort population of COVID-19 patients with acute ischemic stroke.

BACKGROUND: Resistance to fibrinolysis, levels of procoagulant/antifibrinolytic neutrophil extracellular traps (NETs), and the severity of acute ischemic stroke (AIS) are increased by COVID-19. Whether NETs are components of AIS thrombi from COVID-19 patients and whether COVID-19 impacts the susceptibility of these thrombi to thrombolytic treatments remain unknown, however. OBJECTIVES: We aimed to characterize AIS thrombi from COVID-19 patients by immunohistology and to compare their response to thrombolysis to that of AIS thrombi from non-COVID-19 patients. PATIENTS/METHODS: For this monocentric cohort study, 14 thrombi from COVID-19 AIS patients and 16 thrombi from non-COVID-19 patients, all recovered by endovascular therapy, were analyzed by immunohistology or subjected to ex vivo thrombolysis by tissue-type plasminogen (tPA)/plasminogen. RESULTS: COVID-19 AIS thrombi were rich in neutrophils and contained NETs, but not spike protein. Thrombolysis assays revealed a mean resistance profile to tPA/plasminogen of COVID-19 AIS thrombi similar to that of non-COVID-19 AIS thrombi. The addition of DNase 1 successfully improved thrombolysis by potentiating fibrinolysis irrespective of COVID-19 status. Levels of neutrophil, NETs, and platelet markers in lysis supernatants were comparable between AIS thrombi from non-COVID-19 and COVID-19 patients. CONCLUSIONS: These results show that COVID-19 does not impact NETs content or worsen fibrinolysis resistance of AIS thrombi, a therapeutic hurdle that could be overcome by DNase 1 even in the context of SARS-CoV-2 infection.

Intravenous abciximab as a rescue therapy for immediate reocclusion after successful mechanical thrombectomy in acute ischemic stroke patients.

Immediate reocclusion after mechanical thrombectomy (MT) for acute ischemic stroke (AIS) is a rare but devastating condition associated with poor functional outcome. The aim of this study was to gain insights into the mechanisms underlying immediate reocclusion, and to evaluate the efficacy and safety of the glycoprotein IIb/IIIa antagonist abciximab, for its treatment. Clinical data were collected from April 2015 to April 2019 in a monocentric prospective registry of AIS patients treated by MT. All patients with immediate reocclusion were retrospectively selected and subdivided into 2 groups according to abciximab treatment status. In vitro, the separate and combined effects of abciximab and alteplase on clot formation in whole blood under flow conditions were further investigated in microfluidic chambers. From 929 MT-treated patients, 21 had post-MT immediate reocclusion. Abciximab treatment in reocclusion patients (n = 10) led to higher rate of final recanalization (p < .001) while it did not increase bleeding complications. Flow chamber experiments revealed that, in contrast to alteplase, abciximab efficiently limits thrombus accretion from flowing blood by blocking platelet aggregation. Our results underscore a key role for platelet aggregation and the potential of Glycoprotein IIb/IIIa antagonists as a rescue therapy in post-MT immediate reocclusion.

A Novel Mouse Model for Cerebral Venous Sinus Thrombosis.

Cerebral venous sinus thrombosis (CVST) is an uncommon cause of stroke resulting in parenchymal injuries associated with heterogeneous clinical symptoms and prognosis. Therefore, an experimental animal model is required to further study underlying mechanisms involved in CVST. This study is aimed at developing a novel murine model suitable and relevant for evaluating injury patterns during CVST and studying its clinical aspects. CVST was achieved in C57BL/6J mice by autologous clot injection into the superior sagittal sinus (SSS) combined with bilateral ligation of external jugular veins. Clot was prepared ex vivo using thrombin before injection. On days 1 and 7 after CVST, SSS occlusion and associated-parenchymal lesions were monitored using different modalities: in vivo real-time intravital microscopy, magnetic resonance imaging (MRI), and immuno-histology. In addition, mice were subjected to a neurological sensory-motor evaluation. Thrombin-induced clot provided fibrin- and erythrocyte-rich thrombi that lead to reproducible SSS occlusion at day 1 after CVST induction. On day 7 post-CVST, venous occlusion monitoring (MRI, intravital microscopy) showed that initial injected-thrombus size did not significantly change demonstrating no early spontaneous recanalization. Microscopic histological analysis revealed that SSS occlusion resulted in brain edema, extensive fibrin-rich venular thrombotic occlusion, and ischemic and hemorrhagic lesions. Mice with CVST showed a significant lower neurological score on post-operative days 1 and 7, compared to the sham-operated group. We established a novel clinically CVST-relevant model with a persistent and reproducible SSS occlusion responsible for symptomatic ischemic and hemorrhagic lesions. This method provides a reliable model to study CVST physiopathology and evaluation of therapeutic new regimens.

Modeling Large Vessel Occlusion Stroke for the Evaluation of Endovascular Therapy According to Thrombus Composition.

More than 40% of endovascular therapy (EVT) fail to achieve complete reperfusion of the territory of the occluded artery in patients with acute ischemic stroke (AIS). Understanding factors influencing EVT could help overcome its limitations. Our objective was to study the impact of thrombus cell composition on EVT procedures, using a simulation system for modeling thrombus-induced large vessel occlusion (LVO) in flow conditions. In an open comparative trial, we analyzed the behavior of size-standardized platelet-rich and red blood cells (RBC)-rich thrombi during simulated stent retriever-mediated EVT procedures. Sixteen simulated EVT procedures were performed (8 RBC- vs. 8 platelet-rich thrombi). Platelet-rich thrombi were associated with a higher number of stent retriever passes (p = 0.03) and a longer procedure duration (p = 0.02) compared to RBC-rich thrombi. Conversely, RBC-rich thrombi released more embolic fragments than platelet-rich thrombi (p = 0.004). Both RBC-rich and platelet-rich thrombi underwent drastic compaction after being injected into the in vitro circulation model, and histologic analyses showed that these EVT-retrieved thrombi displayed features comparable to those previously observed in thrombi from patients with AIS patients having LVO, including a marked structural dichotomy between RBC- and platelet-rich areas. Our results show that the injection of in vitro-produced thrombi in artificial cerebrovascular arterial networks is suitable for testing recanalization efficacy and the risk of embolization of EVT devices and strategies in association with thrombus cell composition.

Lymphatic blood filling in CLEC-2-deficient mouse models.

C-type lectin-like receptor 2 (CLEC-2) is considered as a potential drug target in settings of wound healing, inflammation, and infection. A potential barrier to this is evidence that CLEC-2 and its ligand podoplanin play a critical role in preventing lymphatic vessel blood filling in mice throughout life. In this study, this aspect of CLEC-2/podoplanin function is investigated in more detail using new and established mouse models of CLEC-2 and podoplanin deficiency, and models of acute and chronic vascular remodeling. We report that CLEC-2 expression on platelets is not required to maintain a barrier between the blood and lymphatic systems in unchallenged mice, post-development. However, under certain conditions of chronic vascular remodeling, such as during tumorigenesis, deficiency in CLEC-2 can lead to lymphatic vessel blood filling. These data provide a new understanding of the function of CLEC-2 in adult mice and confirm the essential nature of CLEC-2-driven platelet activation in vascular developmental programs. This work expands our understanding of how lymphatic blood filling is prevented by CLEC-2-dependent platelet function and provides a context for the development of safe targeting strategies for CLEC-2 and podoplanin.

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.

PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.

Glenzocimab does not impact glycoprotein VI-dependent inflammatory haemostasis.

Not available.