Yogendra Kanthi

BACKGROUND: Antiphospholipid antibodies (aPL) are associated with an increased risk of thrombosis. However, individual studies have reported conflicting findings regarding the prevalence of aPL in patients with ischemic stroke and their association with first or recurrent events. METHODS: Systematic searches of PubMed and Embase through May 13, 2025 were conducted to identify case-control, cohort, or cross-sectional studies investigating 3 questions related to aPL seropositivity (defined as positivity for either immunoglobulin G/immunoglobulin M anticardiolipin antibody, immunoglobulin G/immunoglobulin M anti-β2 glycoprotein I antibody, or a lupus anticoagulant): (1) the prevalence of aPL seropositivity among individuals with ischemic stroke; (2) the association between aPL seropositivity and the risk of first ischemic stroke; and (3) the association between aPL seropositivity and the risk of recurrent ischemic stroke. Random-effects models with inverse weighting were used to calculate pooled prevalences and odds ratios (OR) with 95% CIs. Risk of bias was assessed using the ROBINS-I tool. RESULTS: A total of 52 studies were included (40 case-control, 12 cohort). The pooled prevalence of seropositivity for any aPL among patients with ischemic stroke (51 studies, 9438 patients) was 19.1% (95% CI, 15.4%–23.0%; I ² =95.8%). aPL seropositivity was associated with higher odds of first ischemic stroke (43 studies, 19 097 patients; OR, 2.93 [95% CI, 2.31–3.73]; I ² =68.7%). The strongest associations were for lupus anticoagulant (OR, 6.69 [95% CI, 2.94–15.2]; I ² =92.6%) and immunoglobulin G anticardiolipin antibody (OR, 2.56 [95% CI, 1.96–3.35]; I ² =92.5%). The odds of recurrent ischemic stroke among patients with versus without any aPL seropositivity were not significantly different (OR, 1.20 [95% CI, 0.87–1.67]; 9 studies, 2873 patients, I ² =11.4%). CONCLUSIONS: Seropositivity for any aPL was present in nearly 1-in-5 patients with ischemic stroke and was associated with increased odds of ischemic stroke at presentation.

Brain metastasis (BrM) is a devastating complication of triple-negative breast cancer (TNBC), yet how host macroenvironmental conditions influence brain metastatic susceptibility remains poorly understood. Here, we investigated the impact of deep vein thrombosis (DVT), a common complication in patients with cancer, on TNBC brain metastasis. Analysis of a large clinical cohort identified DVT as an independent risk factor for BrM in patients with metastatic breast cancer. Using two syngeneic TNBC models, we demonstrated that DVT selectively enhanced brain metastasis without significantly affecting primary tumor growth or lung metastasis. Mechanistically, DVT increased neutrophil accumulation in the brain metastatic microenvironment, and neutrophil depletion completely abrogated the metastasis-promoting effect of DVT. Single-cell RNA sequencing of CD45+ cells in peripheral blood revealed that DVT reprogrammed circulating neutrophils toward migratory and inflammatory transcriptomic profiles characterized by neutrophil extracellular trap (NET) formation. DVT increased CXCR2 expression on circulating neutrophils and enhanced neutrophil recruitment in brain. Moreover, DVT significantly increased circulating NETs. Collectively, our findings identify DVT as a systemic driver of TNBC brain metastasis and reveal that DVT primes circulating neutrophils toward enhanced vascular recruitment and NET formation, providing a mechanistic link between cancer-associated thrombosis and brain metastatic susceptibility.

Antiphospholipid antibodies (aPL) are directed against phospholipids and phospholipid-binding proteins. Laboratory assays used to detect aPL include serological tests for aPL against β₂-glycoprotein 1, cardiolipin and other molecules, as well as functional assays for lupus anticoagulant. The presence of aPL can lead to endothelial dysfunction or a hypercoagulable state through prothrombotic and antifibrinolytic mechanisms. These processes, often in conjunction with a ‘second hit’, such as trauma, surgery, or other causes of hypercoagulability or stasis, can lead to venous or arterial thrombosis. The thrombotic risk associated with aPL is best recognized in thrombotic antiphospholipid syndrome, characterized by a persistently positive test for lupus anticoagulant or seropositivity for aPL associated with venous, arterial or microvascular thrombosis. However, aPL seropositivity and its clinical effect on thrombotic events have been increasingly recognized in a broader group of individuals who do not meet traditional research criteria for thrombotic antiphospholipid syndrome. In this Review, we provide an overview of the evidence related to aPL seropositivity in individuals with or without previous thrombosis and the clinical relevance of aPL seropositivity in predicting the risk of thrombotic cardiovascular events. We discuss potential management strategies and identify key knowledge gaps that warrant further research.

Near-infrared spectroscopy with vascular occlusion testing (NIRS-VOT) offers a non-invasive approach for real-time assessment of tissue oxygenation and vascular function. However, its clinical application remains limited, in part due to substantial inter-individual variability in anatomical and physiological characteristics. To identify potential sources of variability, we explored whether incorporating conduit artery size—specifically baseline brachial artery diameter (BrAD)—into the NIRS-VOT data analysis could enhance physiological interpretation and reduce measurement error. We analyzed NIRS-VOT responses from 16 healthy participants recruited to the NIH Clinical Center (NCT06552767 and NCT03538639), incorporating individual BrAD measurements as a covariate. Strong to moderate Spearman’s rank-order correlations were observed between BrAD and dynamic perfusion parameters, including the desaturation rate ( ρ = 0.77, p = 0.0005) and resaturation rate ( ρ = 0.79, p = 0.0003). These findings suggest that larger brachial arteries are associated with greater oxygen extraction during occlusion and faster reoxygenation during reperfusion. Across parameters, BrAD explained a substantial proportion of the variance in NIRS-VOT outcomes. When BrAD was included as a covariate, the unexplained variability in the desaturation and resaturation rates was reduced to 28% and 34% of the total variance, respectively, indicating that accounting for conduit artery size substantially decreases residual variability and enhances the interpretability of these dynamic responses. Visual comparison also indicated that incorporating BrAD helped clarify response patterns and reclassify outliers. By reducing inter-individual variability and explaining a greater share of the physiological response, the BrAD-informed analysis enhances the interpretability and consistency of NIRS-VOT measurements. Integrating vascular anatomy into NIRS-VOT analysis may improve the detection of subtle vascular dysfunction and strengthen its diagnostic utility. Future research involving larger and more diverse cohorts, and additional vascular territories are needed to validate and expand these findings.

The soluble variant of the ectopeptidase CD13 (sCD13), released from the cell surface by matrix metalloproteinase 14 (MMP14), is a potent pro-inflammatory mediator, displaying chemotactic, angiogenic, and arthritogenic properties through bradykinin receptor B1 (B1R). We revealed a link between sCD13 and amplified neutrophil-mediated inflammatory responses in SARS-CoV-2 infection. sCD13 was markedly elevated in patients with COVID-19 and correlated with disease severity and variants, ethnicity, inflammation markers, and neutrophil extracellular trap formation (NETosis). Neutrophils treated with sCD13 showed heightened NETosis and chemotaxis, which were inhibited by sCD13 receptor blockade. Meanwhile sCD13 did not induce platelet aggregation. Single-cell analysis of COVID-19 lungs revealed coexpression of CD13 and MMP14 by various cell types, and higher CD13 expression compared with controls. Neutrophils with high CD13 mRNA were enriched for genes associated with immaturity, though CD13 protein expression was lower. Histological examination of COVID-19 lungs revealed CD13-positive leukocytes trapped in vessels with fibrin thrombi. Flow cytometry verified the presence of B1R and a second sCD13 receptor, protease-activated receptor 4, on monocytes and neutrophils. These findings identify sCD13 as a potential instigator of COVID-19–associated NETosis, potentiating vascular stress and thromboembolic complications. The potent pro-inflammatory effects of sCD13 may contribute to severe COVID-19, suggesting that sCD13 and its receptors might be therapeutic targets.

Neutrophils can contribute to inflammatory disease propagation via innate mechanisms intended for inflammation resolution. For example, neutrophil extracellular traps (NETs) are necessary for trapping pathogens but can contribute to clot formation and blood flow restriction, that is, ischemia. Currently, no therapeutics in the clinic directly target NETs despite the known involvement of NETs contributing to mortality and increased disease severity. Vascular‐deployed particle‐based therapeutics are a novel and robust alternative to traditional small‐molecule drugs by enhancing drug delivery to cells of interest. This work designs a high‐throughput assay to investigate the immunomodulatory behavior and functionality of salicylic acid‐based polymer‐based particle therapeutics against NETosis in human neutrophils. Briefly, this work finds that polymeric composition plays a role, and particle size can also influence rates of NETosis. Salicylate‐based polymeric (Poly‐SA) particles are found to functionally inhibit NETosis depending on the particle size and concentration exposed to neutrophils. This work demonstrates the high throughput method can help fast‐track particle‐based therapeutic optimization and design, more efficiently preparing this innovative therapeutics for the clinic.

Risk of severe disease and death due to COVID-19 is increased in certain patient demographic groups, including those of advanced age, male sex, and obese body mass index. Investigations of the biological variations that contribute to this risk have been hampered by heterogeneous severity, with immunologic features of critical disease potentially obscuring differences between risk groups. To examine immune heterogeneity related to demographic risk factors, we enrolled 38 patients hospitalized with clinically homogeneous COVID-19 pneumonia — defined as oxygen saturation less than 94% on room air without respiratory failure, septic shock, or multiple organ dysfunction — and performed single-cell RNA-Seq of leukocytes collected at admission. Examination of individual risk factors identified strong shifts within neutrophil and monocyte/dendritic cell (Mo/DC) compartments, revealing altered immune cell type–specific responses in higher risk COVID-19 patient subgroups. Specifically, we found transcriptional evidence of altered neutrophil maturation in aged versus young patients and enhanced cytokine responses in Mo/DCs of male versus female patients. Such innate immune cell alterations may contribute to outcome differences linked to these risk factors. They also highlight the importance of diverse patient cohorts in studies of therapies targeting the immune response in COVID-19.

Spleen tyrosine kinase (SYK) is a previously unidentified therapeutic target that inhibits neutrophil and macrophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, a SYK inhibitor, was studied in a phase 2 placebo-controlled randomized clinical trial and was associated with improvements in many secondary end points related to efficacy. Here, we used a multiomic approach to evaluate cellular and soluble immune mediator responses of patients enrolled in this trial. We demonstrated that SYK inhibition was associated with reduced neutrophil activation, increased circulation of mature neutrophils (CD10 ⁺ CD33 ⁻ ), and decreased circulation of low-density granulocytes and polymorphonuclear myeloid-derived suppressor cells (HLA-DR ⁻ CD33 ⁺ CD11b ⁻ ). SYK inhibition was also associated with normalization of transcriptional activity in circulating monocytes relative to healthy controls, an increase in frequency of circulating nonclassical and HLA-DR ^hi classical monocyte populations, and restoration of interferon responses. Together, these data suggest that SYK inhibition may mitigate proinflammatory myeloid cellular and soluble mediator responses thought to contribute to immunopathogenesis of severe COVID-19.