Search Results (99)

Background: Deep vein thrombosis (DVT) is a serious thromboinflammatory complication of acute ischemic stroke (AIS). The true incidence, mechanistic risk factors, and optimal prophylactic strategies remain uncertain, particularly in the era of reperfusion therapy. Methods: This systematic review and meta-analysis (IRIS-DVT) searched PubMed, Embase, Cochrane, Scopus, and Web of Science for studies reporting DVT incidence, risk factors, or prophylaxis in AIS (2004–2025). Random-effects models were used to generate pooled prevalence and effect estimates, and the certainty of evidence was graded using the GRADE framework. Results: Forty-two studies (n = 6,051,729 patients) were included. The pooled prevalence of DVT was 7% (95% CI, 6–9%), approximately seventy-fold higher than in the general population, with wide heterogeneity influenced by screening timing and diagnostic modality. Pathophysiological risk factors included higher stroke severity (NIHSS; SMD 0.41; 95% CI, 0.38–0.43), older age (SMD 0.32; 95% CI, 0.18–0.46), elevated D-dimer (SMD 0.55; 95% CI, 0.38–0.72), female sex (OR 1.33; 95% CI, 1.19–1.50), and malignancy (OR 2.69; 95% CI, 1.56–5.22), supported by moderate-certainty evidence. Respiratory infection and admission hyperglycemia showed weaker, low-certainty associations. Traditional vascular risk factors (hypertension, diabetes, atrial fibrillation, dyslipidemia) were not significantly related to DVT risk. Evidence for prophylaxis with low-molecular-weight heparin, direct oral anticoagulants, or intermittent pneumatic compression was limited and graded very low certainty. Conclusions: DVT complicates approximately one in fourteen AIS cases, reflecting a distinct thromboinflammatory process driven more by acute neurological severity, systemic hypercoagulability, and malignancy than by conventional vascular risk factors. Early systematic screening (≤72 h) and consistent use of mechanical prophylaxis are warranted. Dedicated AIS-specific mechanistic and interventional trials are urgently needed to refine prevention strategies and improve post-stroke outcomes. Full article

Peripheral artery disease is a common manifestation of atherosclerosis, characterized by insufficient tissue perfusion and chronic ischemia. Arteriogenesis and angiogenesis are essential endogenous mechanisms to restore blood flow and limit ischemic injury. The metalloprotease ADAMTS13, known for cleaving ultra-large von Willebrand factor, has been implicated in thrombotic and inflammatory regulation. However, its role in ischemic vascular remodeling remains unclear. Using a murine hind limb ischemia model, we investigated the effect of ADAMTS13 deficiency on arteriogenesis and angiogenesis by comparing male ADAMTS13^−/− and wild-type control mice. Perfusion recovery, vascular cell proliferation, immune cell infiltration, and thrombotic activity were evaluated using laser Doppler measurements, immunohistochemical analysis of adductor and gastrocnemius muscle tissues, and in vivo microscopy. ADAMTS13 deficiency did not impair perfusion recovery, collateral artery growth, or capillarization. While platelet adhesion was slightly increased in ADAMTS13^−/− mice, no thrombotic occlusions were observed. Inflammatory responses, including macrophage and neutrophil infiltration as well as macrophage polarization, were largely unaffected. Despite previous in vitro evidence indicating an angiogenic role for ADAMTS13, its absence did not compromise angiogenesis in vivo. Our findings suggest that ADAMTS13 does not play a critical role in ischemia-related angiogenesis and arteriogenesis under sterile conditions and may be relevant only in contexts involving acute and sufficiently strong thromboinflammatory stimuli. Full article

In viral infections human heat shock proteins (HSPs) play a dual role by either protecting host cells or acting on viruses’ needs. The roles of HSPs have been extensively studied in various human pathologies, but their involvement in the progression of COVID-19 remains unexplored. It makes HSPs genetic variants particularly interesting in the context of severe COVID-19 risk. In this study, 1228 subjects (199 hospitalized COVID-19 patients and 962 controls) were genotyped for 20 SNPs in genes encoding HSPs and their regulators. SNP rs7189628 DNAJA2 (effect allele [EA] T) increased the risk of severe COVID-19 in the entire group (p = 0.002), males (p = 0.00008), and smokers (p = 0.0003). SNP rs910652 HSPA12B (EA C) decreased the risk of severe COVID-19 in the entire group (p = 0.01), females (p = 0.04), and patients with normal physical activity levels (p = 0.01). SNP rs1136141 HSPA8 (EA A) increased the risk of severe COVID-19 in patients with low fruit/vegetable intake (p = 0.004). Moreover, we observed significant changes in ground-glass opacity and alterations in blood coagulation and inflammation parameters, influenced by the SNPs of BAG3, HSF2, HSPA6, HSPA8, HSPA9, and DNAJA2. The molecular mechanisms underlying these associations are discussed. Together, our study provides preliminary evidence that SNPs of HSPs can significantly modulate the risk of severe COVID-19. Full article

Objectives: Post-acute venous thromboembolism (VTE) is a well-recognized complication of COVID-19, driven by persistent endothelial dysfunction and thromboinflammation. Identifying simple clinical predictors of VTE may optimize therapy and limit adverse outcomes. We propose a pragmatic risk-stratification approach, based on clinical and echocardiographic parameters. Methods: We conducted a retrospective cohort study in a Romanian tertiary hospital (March 2020–April 2022) in 54 adults with laboratory-confirmed COVID-19 and imaging-confirmed VTE. Demographics, comorbidities, laboratory markers, and echocardiographic variables—particularly tricuspid annular plane systolic excursion (TAPSE), peripheral oxygen saturation (SpO₂), and left-ventricular end-diastolic diameter (LVEDD)—were collected. The primary outcome was the percentage of patients receiving systemic thrombolysis. Statistical analyses included Mann–Whitney U tests, chi-square, Spearman correlations, and multivariable logistic regression. Results: The mean age was 61.2 ± 14.7 years, and 63% were men. Eleven patients (20.4%) underwent thrombolysis. Compared with conservatively managed patients, those receiving thrombolysis had lower TAPSE (13.0 vs. 20.8 mm), lower SpO₂ (90.1 vs. 97.0%), and smaller LVEDD (24.4 vs. 46.1 mm); all differences were statistically significant. Each 1 mm decrease in TAPSE and 1% decrease in SpO₂ increased the likelihood of thrombolysis (adjusted odds ratios 1.58 and 1.34, respectively). Inflammatory markers and right-ventricular diameter were not associated with treatment. Conclusions: Reduced TAPSE, lower SpO₂, and decreased LVEDD identify post-COVID VTE patients at elevated risk of hemodynamic compromise requiring thrombolysis. A point-of-care assessment incorporating these variables may improve early risk stratification and guide therapeutic decisions. Full article

The circulatory and immune systems function in close coordination to maintain homeostasis and act as a frontline defense against infections. However, under certain conditions, this interaction becomes dysregulated, leading to thromboinflammation, a pathological process marked by the concurrent and excessive activation of coagulation, inflammation, and endothelial dysfunction. During viral infections, this phenomenon can markedly worsen clinical outcomes. Evidence indicates that viruses such as dengue, chikungunya, influenza, and SARS-CoV can trigger thromboinflammatory responses involving platelet activation, the release of procoagulant and pro-inflammatory mediators, and the formation of thrombi within blood vessels. While this response may initially help contain viral dissemination, in cases of high viremia it can progress to disseminated intravascular coagulation (DIC), hemorrhage, and multiple organ failure. This review compiles current evidence on thromboinflammatory mechanisms induced by arboviral and respiratory viruses and examines how these processes contribute to diseases’ pathogenesis and clinical severity. Full article

Background/Objectives: Acute ischemic stroke is a leading cause of mortality and long-term disability globally, with limited reliable early predictors of functional outcomes and survival. This study aimed to assess the prognostic value of two novel predictors: the hypoperfusion intensity ratio calculated from mean transit time and time-to-drain maps (HIR-MTT–TTD), derived from computed tomography perfusion (CTP) imaging parameters, and the Inflammation–Coagulation Index (ICI), which integrates systemic inflammatory (C-reactive protein and white blood cell count) and hemostatic (D-dimer) markers. Methods: This prospective, single-center observational study included 60 patients with acute ischemic stroke treated with intravenous thrombolysis and underwent pre-treatment CTP imaging. HIR-MTT–TTD evaluated collateral status and perfusion deficit severity, while ICI integrated C-reactive protein (CRP), white blood cell (WBC) count, and D-dimer levels. Functional outcomes were assessed using the National Institutes of Health Stroke Scale (NIHSS), Barthel Index, and modified Rankin Scale (mRS) at 24 h, 3 months, and 1 year. Results: Of 60 patients, 53.3% achieved functional independence (mRS 0–2) at 1 year. Unadjusted Cox models showed HIR-MTT–TTD (HR = 6.25, 95% CI: 1.48–26.30, p = 0.013) and ICI (HR = 1.08, 95% CI: 1.00–1.17, p = 0.052) were associated with higher 12-month mortality, worse mRS, and lower Barthel scores. After adjustment for age, BMI, smoking status, and sex, these associations became non-significant (HIR-MTT–TTD: HR = 2.83, 95% CI: 0.37–21.37, p = 0.314; ICI: HR = 1.07, 95% CI: 0.96–1.19, p = 0.211). Receiver operating characteristic (ROC) analysis indicated moderate predictive value, with ICI (AUC = 0.756, 95% CI: 0.600–0.867) outperforming HIR-MTT–TTD (AUC = 0.67, 95% CI: 0.48–0.83) for mortality prediction. Conclusions: The study introduces promising prognostic tools for functional outcomes. Elevated HIR-MTT–TTD and ICI values were independently associated with greater initial stroke severity, poorer functional recovery, and increased 1-year mortality. These findings underscore the prognostic significance of hypoperfusion intensity and systemic thrombo-inflammation in acute ischemic stroke. Combining the use of the presented indices may enhance early risk stratification and guide individualized treatment strategies. Full article

Traumatic brain injuries (TBI) represent a leading cause of morbidity and mortality globally. Whilst clinical care has significantly improved in recent years, there is still significant scope to improve patient outcomes, particularly in relation to quality of life. However, there is a window of opportunity for clinical intervention, since most of the mortality and morbidity is associated with secondary injury processes that arise after the initial trauma. In the brain, as with any tissue, inflammation plays an important role in the response to injury. However, particularly with severe injuries, an excessive inflammatory response can have detrimental effects. Following TBI, inflammation can lead to the development of cerebral oedema and a rise in intracranial pressure. Without effective control, these processes can rapidly lead to patient deterioration. This narrative review focusses on the role of inflammation in TBI in order to examine the strategies that may help improve patient outcomes. Whilst there is clearly a relationship between the development of cerebral oedema, rising intracranial pressure (ICP), and poor patient prognosis, there are also discrepancies in terms of their impact on patient outcomes. In addition to causing a rise in ICP, this review examines in what other ways inflammation and the development of cerebral oedema may contribute to the injury process. The potential for these factors to impact upon microvascular function and reduce cerebral tissue perfusion and oxygenation is explored. In addition, the impact of TBI on glymphatic function is discussed. Following an evaluation of the potential injury processes, the scope for intervention and the development of novel therapeutic approaches is explored. Full article

The COVID-19 pandemic, caused by SARS-CoV-2, has led to a wide range of acute and chronic disease manifestations. While most infections are mild, a significant number of patients develop severe illness marked by respiratory failure, thromboinflammation, and multi-organ dysfunction. In addition, post-acute sequelae—commonly known as long-COVID—can persist for months. Recent studies have identified the emergence of diverse autoantibodies in COVID-19, including those targeting nuclear antigens, phospholipids, type I interferons, cytokines, endothelial components, and G-protein-coupled receptors. These autoantibodies are more frequently detected in patients with moderate to severe disease and have been implicated in immune dysregulation, vascular injury, and persistent symptoms. This review examines the underlying immunological mechanisms driving autoantibody production during SARS-CoV-2 infection—including molecular mimicry, epitope spreading, and bystander activation—and discusses their functional roles in acute and post-acute disease. We further explore the relevance of autoantibodies in maternal–fetal immunity and comorbid conditions such as autoimmunity and cancer, and we summarize current and emerging therapeutic strategies. A comprehensive understanding of SARS-CoV-2-induced autoantibodies may improve risk stratification, inform clinical management, and guide the development of targeted immunomodulatory therapies. Full article

Soluble CD40 ligand (sCD40L) is a molecule known for its thromboinflammatory properties and may act as a biomarker for platelet activation. Platelets are the principal producers of sCD40L, which is recognized for its impact on platelet function. However, its contribution to the platelet hyperreactivity observed in SARS-CoV-2 infection remains poorly understood. During viral infection, platelets function as crucial intermediaries, engaging with both viruses and leukocytes; and serve as a substantial source of inflammatory mediators, promoting thromboinflammation and immunothrombosis. While platelet hyperactivation is associated with the severity and mortality of COVID-19, the precise function of sCD40L in this setting remains inadequately defined. This study examined the role of platelet-derived sCD40L in platelet activation, aggregation, and thrombosis associated with COVID-19. Platelets from blood samples of 160 patients—102 with non-severe cases and 58 with severe cases—demonstrated heightened activation and aggregation, as well as elevated sCD40L release. In a mouse thrombosis model, sCD40L intensified thrombus development. These findings underscore the essential function of platelet-derived sCD40L in the pathophysiology of COVID-19 and endorse the therapeutic potential of targeting CD40L-mediated pathways to mitigate thromboinflammatory consequences. Full article

Autoimmune diseases (AIDs) are chronic, heterogeneous conditions developing from an aberrant immune response, impacting particular organs or multiple systems. This systematic review attempted to investigate and evaluate the correlation between autoimmune diseases and cardiovascular disease (CVD), emphasizing immunological and pathophysiological mechanisms. A comprehensive search for relevant research was conducted on the PubMed, SCOPUS, and ScienceDirect databases, resulting in the identification of 28 studies that met the inclusion criteria. Of the cohort studies, 26 (92.8%) demonstrated a significant association between autoimmune diseases and increased cardiovascular risk. The major mechanisms include chronic inflammation, endothelial dysfunction, oxidative stress, and immune cell dysregulation. Essential biological components, including T cells, B cells, and neutrophils, were identified as contributors to atherosclerotic processes through cytokine secretion, expression of adhesion molecules, and thrombogenic activity. In contrast, two studies (7.1%) found no statistically significant association. In conclusion, autoimmune diseases significantly increase cardiovascular risk through complicated immunological mechanisms. Comprehending these pathways could influence future therapeutic approaches to reduce cardiovascular complications in affected patients. Full article

Sepsis remains a critical global health challenge characterized by life-threatening organ dysfunction arising from a dysregulated host response to infection. Immunothrombosis refers to the intersection of immune activation and coagulation pathways, particularly relevant in the context of sepsis. A growing body of evidence identifies immunothrombosis, a tightly interwoven process between innate immunity and coagulation. While immunothrombosis serves as a host defense mechanism under physiological conditions, its aberrant activation in sepsis precipitates microvascular thrombosis, organ ischemia, and progression toward disseminated intravascular coagulation (DIC). This review provides a comprehensive overview of the cellular contributors to immunothrombosis, including neutrophils, monocytes, platelets, and endothelial cells, and elucidates the signaling cascades, such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and inflammasome activation, that govern their interplay. We further highlight emerging molecular mediators, including extracellular traps, tissue factor expression, and cytokine amplification loops, that collectively promote pathological thromboinflammation. A deeper understanding of these interconnected pathways offers critical insights into the pathogenesis of sepsis and unveils potential targets for timely intervention. Ultimately, this review aims to bridge immunological and hematological perspectives to inform the development of novel therapeutic strategies against sepsis-induced coagulopathy. Full article

(1) Background: The hemostatic system and tumor biology display a tight and reciprocal interaction where clotting products enhance tumor growth and dissemination, and the tumor, in turn, triggers a hypercoagulable and inflammatory state. Evaluating circulating biomarkers related to thrombo-inflammatory may provide a promising tool for predicting tumor outcomes, especially in non-small cell lung cancer (NSCLC) characterized by unfavorable outcomes. (2) Aim: In a prospective cohort of NSCLC patients, we evaluated whether thromboinflammatory biomarkers could predict early disease progression (DP) during the first 6 months of first-line anticancer treatment. (3) Methods: 719 newly diagnosed advanced-stage NSCLC patients were included. Complete blood cell count, high-sensitivity C-reactive protein (hs-CRP), FVIII, fibrinogen, D-dimer, thrombin-antithrombin (TAT) complexes, and prothrombin fragment1+2(F1+2) were tested in blood samples collected before starting chemotherapy. DP was gathered during follow-up. (4) Results: The 6-month cumulative incidence rate for DP was 49%. Univariable Cox regression analysis identified metastatic status, BMI, hemoglobin, leukocytes, hs-CRP, FVIII, fibrinogen, TAT, and D-dimer as significant predictors of DP. In a multivariable analysis that included all previously significant variables, only hs-CRP and D-Dimer levels remained strongly associated with DP. The two variables were used to establish a risk stratification model that significantly identified patients at high risk of DP at 6 months (HR 2.9; 95% CI, 2.3–3.7), which can be applied to 3, 9, and 12 months. (5) Conclusions: Our model easily and precisely estimates early DP during chemotherapy. If externally validated, this model can significantly enhance the allocation of medical resources in managing advanced NSCLC, ensuring that patients receive the most effective care possible. Full article

Endothelial dysfunction plays a central role in COVID-19 pathogenesis, by affecting vascular homeostasis and worsening thromboinflammation. This imbalance may contribute to blood–brain barrier (BBB) disruption, which has been reported in long COVID-19 patients with neurological sequelae. The kallikrein–kinin system (KKS) generates bradykinin (BK), a proinflammatory peptide that induces microvascular leakage via B2R. Under inflammatory conditions, BK is converted to Des-Arg-BK (DABK), which activates B1R, a receptor upregulated in inflamed tissues. DABK is degraded by ACE2, the main SARS-CoV-2 receptor; thus, viral binding and ACE2 downregulation may lead to DABK/B1R imbalance. Here, we investigated these interactions using human brain microvascular endothelial cells (HBMECs), as a model of the BBB. Since endothelial cell lines express low levels of ACE2, HBMECs were modified with an ACE2-carrying pseudovirus. SARS-CoV-2 replication was confirmed by RNA, protein expression, and infectious particles release. Infection upregulated cytokines and endothelial permeability, enhancing viral and leukocyte transmigration. Additionally, viral replication impaired ACE2 function in HBMECs, amplifying the response to DABK, increasing nitric oxide (NO) production, and further disrupting endothelial integrity. Our findings reveal a mechanism by which SARS-CoV-2 impacts the BBB and highlights the ACE2/KKS/B1R axis as a potential contributor to long COVID-19 neurological symptoms. Full article

Interleukin-6 (IL-6) is a pleiotropic cytokine with critical roles in immune regulation, inflammation, and haematopoiesis. While its functions in host defence and tissue repair are well established, accumulating evidence suggests that IL-6 also can directly and indirectly modulate megakaryocyte and platelet biology. This review examines the mechanistic basis supporting IL-6-mediated platelet hyper-responsiveness, in addition to its effect on megakaryopoiesis and thrombopoiesis in thromboinflammatory disease states. We discuss how IL-6-mediated trans-signalling may sensitizes platelets to activation, and that this may be exclusive to glycoprotein VI (GPVI) stimulation due to Janus kinase (JAK)–signal transducer 2 crosstalk, in addition to other mechanisms that may contribute to priming platelets. We further highlight clinical evidence linking IL-6 to thrombotic complications in cardiovascular disease and infection (e.g., COVID-19 and sepsis). Given the emerging interest in IL-6-targeting therapies as anti-inflammatory and anti-thrombotic agents, a thorough understanding of how IL-6 can drive platelet responsiveness is crucial. Full article

Patients hospitalized due to coronavirus disease 2019 (COVID-19) usually present with severe or critical intensity of symptoms, accompanied by a marked systemic inflammatory response. Classical inflammatory biomarkers, C-reactive protein (CRP), albumin, and red blood cell distribution width (RDW) have previously been reported to be prognostic in hospitalized COVID-19 patients. We performed a retrospective analysis of two large cohorts (2305 and 2328 patients, respectively) of consecutive hospitalized COVID-19 patients with mostly severe and critical symptoms admitted to the tertiary referral center to develop and validate a prognostic score for 30-day mortality based on CRP-to-Albumin-Ratio (CAR), RDW, and age (termed CARRA-VID score). We identified 6 prognostic categories: very low, low, intermediate-1, intermediate-2, high, and very high risk, with corresponding 30-day mortality rates of 2.7%, 10.7%, 30.9%, 47.1%, 61.9%, and 89.7%, respectively. Effective risk stratification was validated in an independent cohort of patients and remained independent of the World Health Organization-defined disease severity and other commonly utilized risk scores. Additional analyses evaluated the score across different time periods dominated by distinct viral variants. We also present a simplified 3-tiered version of the score. A Microsoft Excel Workbook containing the score calculator is provided. Full article