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Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. Methods In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. Discussion In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. Trial registration The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

This review examines the intricate relationship between obesity and venous thromboembolism (VTE), highlighting the underlying pathophysiological mechanisms and clinical implications. Obesity is an established independent risk factor for VTE, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). The risk of VTE escalates with increasing body mass index (BMI) and is particularly associated with abdominal adiposity. Dysfunctional adipose tissue (AT) in obesity promotes a pro-thrombotic state through chronic low-grade inflammation and impaired fibrinolysis. This inflammation is driven by stress within hypertrophied adipocytes, which leads to localized hypoxia, cellular dysfunction, and ultimately, cell death. This inflammation is driven by adipocyte stress and the infiltration of immune cells. The adipokine leptin exemplifies the complex link between obesity and VTE. While leptin has pro-thrombotic effects, low leptin levels are paradoxically associated with an increased morbidity and mortality in patients with acute PE, a phenomenon termed the “obesity paradox”. Furthermore, metabolic syndrome significantly increases the risk of recurrent VTE, with the risk growing with each additional metabolic component. Ultimately, a deeper understanding of the molecular and cellular links between obesity and VTE is essential for developing targeted strategies to reduce risk and improve outcomes in this vulnerable population.

Hyperhomocysteinemia/Homocysteinuria is characterized by an increased level of toxic homocysteine in the plasma. The plasma concentration of homocysteine is 5–15 μmol/L in healthy individuals, while in hyperhomocysteinemic patients, it can be as high as 500 μmol/L. While increased homocysteine levels can cause symptoms such as osteoporosis and eye lens dislocation, high homocysteine levels are most closely associated with cardiovascular complications. Recent advances have shown that increased plasma Hcy is also a fundamental cause of neurodegenerative diseases (including Alzheimer’s disease, Parkinson’s disease, and dementia), diabetes, Down syndrome, and megaloblastic anemia, among others. In recent years, increased plasma homocysteine has also been shown to be closely related to cancer. In this review, we discuss the relation between elevated plasma Hcy levels and cancer, and we conclude that disturbed homocysteine metabolism is associated with cancer. Future clinical perspectives are also discussed. Cancer: Links with homocysteine Cancer can be added to the wide range of diseases known to be associated with elevated blood levels of the small amino acid homocysteine. Abnormally high levels of this compound are already known to contribute to conditions including cardiovascular problems, neurodegenerative diseases, neural tube defects, Down’s syndrome, diabetes and megaloblastic anemia. This review, by Laishram R. Singh and colleagues at the University of Delhi, India, concludes that disturbed homocysteine metabolism is associated with many forms of human cancer. The authors discuss a range of genetic, epigenetic and environmental factors that may be involved in the cause and effect relationships between homocysteine metabolism and cancer. It is particularly interesting that low folate (vitamin B9) levels result in high homocysteine levels, and vice versa. Further research may yield insights leading to new forms of cancer treatment and diagnosis.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality, with risk heightened in premenopausal women with obesity or use estrogen-based oral contraceptives. When both risk factors are present, the thrombosis risk increases substantially. Protein S (PS), an essential anticoagulant cofactor, is downregulated by both estrogen and obesity, but the molecular basis for this suppression remains poorly defined. We investigated the effect of estrogen and obesity on PS expression using plasma samples from 157 women stratified by BMI and contraceptive use, alongside 40 mice categorized as lean or obese with or without estrogen pellet treatment. The levels of PS were reduced by either estrogen or obesity alone, and the combined effect increased thrombin generation. In HepG2 hepatocytes, hypoxic conditions (1%–10% O 2 ) mimicking obesity, with or without 17 β-estradiol, suppressed PROS1 transcription and promoter activity. ChIP confirmed direct binding of hypoxia-inducible factor 1α (HIF1α) to the PROS1 promoter, repressing gene expression. These findings define a mechanistic pathway through which estrogen and obesity converge to suppress PS synthesis, providing insight into the elevated thrombosis risk observed in women with obesity using estrogen-based contraceptives.

Thrombosis is a common complication in cancer patients, with a substantial impact on morbidity and mortality. Diffuse large B-cell lymphoma (DLBCL) and other aggressive lymphomas carry a high venous thromboembolism (VTE) risk. Extracellular vesicles (EVs) have gained attention in recent research as a new potential biomarker for VTE development. To determine the profile and association of EVs with VTE in patients with DLBCL, we conducted a prospective cohort study on 62 patients diagnosed with DLBCL. A total of 11 patients (17.7%) developed VTE. The concentrations of platelet-derived EVs (PEVs), E-selectin+ EVs, P-selectin+ EVs, tissue factor (TF)-positive/CD20+ EVs, TF−/CD19+ EVs, TF−/CD45+ EVs, and TF−/CD20+ EVs were significantly higher in DLBCL patients compared to healthy controls. In contrast, the concentration of TF− PEVs was significantly lower in DLBCL patients compared to healthy controls. No statistically significant differences were observed in the concentrations of the EV profiles among the DLBCL patients with and without VTE. Using Cox regression analysis, we found that none of the observed EV populations demonstrated an association with overall survival (OS). In conclusion, patients with DLBCL have elevated concentrations of distinct EV populations—in particular, PEVs, E-selectin EVs, P-selectin EVs, TF+/CD20+ EVs, and TF− DLBCL/B-cell EVs (CD19, CD20, CD45)—compared to healthy controls. DLBCL patients exhibit a specific EV profile, which is not significantly related to the risk of VTE and OS outcomes. Our data provide an intriguing insight into EV profiles in patients with DLBCL. Additional research is needed to elucidate these findings further.

The Finkel‐Biskis‐Jinkins Osteosarcoma (c‐Fos; encoded by FOS) plays an important role in several cardiovascular diseases, including atherosclerosis and stroke. However, the relationship between FOS and venous thromboembolism (VTE) remains unknown. We identified differentially expressed genes in Gene Expression Omnibus dataset, GSE48000, comprising VTE patients and healthy individuals, and analysed them using CIBERSORT and weighted co‐expression network analysis (WGCNA). FOS and CD46 expressions were significantly downregulated (FOS p = 2.26E‐05, CD64 p = 8.83E‐05) and strongly linked to neutrophil activity in VTE. We used GSE19151 and performed PCR to confirm that FOS and CD46 had diagnostic potential for VTE; however, only FOS showed differential expression by PCR and ELISA in whole blood samples. Moreover, we found that hsa‐miR‐144 which regulates FOS expression was significantly upregulated in VTE. Furthermore, FOS expression was significantly downregulated in neutrophils of VTE patients (p = 0.03). RNA sequencing performed on whole blood samples of VTE patients showed that FOS exerted its effects in VTE via the leptin‐mediated adipokine signalling pathway. Our results suggest that FOS and related genes or proteins can outperform traditional clinical markers and may be used as diagnostic biomarkers for VTE.

Venous thromboembolism is a life-threatening vascular event with high prevalence and genetic determinants. PWAS has become a popular strategy to identify therapeutic targets of complex diseases. However, the current PWAS model only considers the linear relationship between protein and disease. Here, we propose a novel non-linear PWAS pipeline and identify 43 proteins exhibiting non-linear associations with venous thromboembolism in the UK Biobank, of which eight proteins cannot be captured by linear PWAS. We further conduct prospective cohort replication in the UK Biobank Pharma Proteomics Project, and replicate eight proteins with similar non-linear trends, including ULBP2, IL18BP, MAN1A2, CCL25, ICAM2, LGALS4, VSIG2 and ABO. Pathway enrichment analysis suggests that the identified non-linear proteins are involved in endothelium development, fluid shear stress and atherosclerosis pathways. In summary, we develop a novel non-linear PWAS analysis pipeline, and identify 43 non-linear proteins with venous thromboembolism, highlighting the importance of incorporating non-linear analysis in PWAS. Venous thromboembolism is a serious condition influenced by genetics, but current protein-based analyses often miss complex patterns. Here, the authors show that a new non-linear analysis method reveals 43 associated proteins, including eight missed by traditional models, offering deeper insight into disease mechanisms.

Procarboxypeptidase U (proCPU, TAFI, proCPB2) is a basic carboxypeptidase zymogen that is converted by thrombin(-thrombomodulin) or plasmin into the active carboxypeptidase U (CPU, TAFIa, CPB2), a potent attenuator of fibrinolysis. As CPU forms a molecular link between coagulation and fibrinolysis, the development of CPU inhibitors as profibrinolytic agents constitutes an attractive new concept to improve endogenous fibrinolysis or to increase the efficacy of thrombolytic therapy in thromboembolic diseases. Furthermore, extensive research has been conducted on the in vivo role of CPU in (the acute phase of) thromboembolic disease, as well as on the hypothesis that high proCPU levels and the Thr/Ile325 polymorphism may cause a thrombotic predisposition. In this paper, an overview is given of the methods available for measuring proCPU, CPU, and inactivated CPU (CPUi), together with a summary of the clinical data generated so far, ranging from the current knowledge on proCPU concentrations and polymorphisms as potential thromboembolic risk factors to the positioning of different CPU forms (proCPU, CPU, and CPUi) as diagnostic markers for thromboembolic disease, and the potential benefit of pharmacological inhibition of the CPU pathway.

Abstract Thromboembolic complications remain a major risk of endovascular neurosurgery during the treatment of intracranial aneurysms, despite the use of therapeutic heparinization and oral antiplatelet therapy when indicated. Glycoprotein (GP) IIb/IIIa inhibitors target a nonredundant pathway of platelet aggregation following adhesion and activation. Initially established and implemented in the cardiovascular arena, this drug class has provided a new tool in the neurovascular armamentarium as well. Numerous case reports, case series, and retrospective reviews have evaluated the safety and efficacy of abciximab, eptifibatide, and tirofiban in the treatment of acute thromboembolic complications during the endovascular treatment of intracranial aneurysms. The use of this drug class has also been found to be beneficial as a prophylactic agent, providing ischemia protection during the placement of intracranial stents, flow diverters, and thrombogenic coils in the setting of subarachnoid hemorrhage and during elective aneurysmal embolization. While the current published literature clearly establishes efficacy and safety of GP IIb/IIIa inhibitors in the prevention of thromboembolic complications, there does not yet exist an established protocol for their administration in endovascular neurosurgery. This review provides a comprehensive evaluation of the current published literature pertaining to the use of all available GP IIb/IIIa inhibitors for thromboembolic complications, providing recommendations for dosing and administration of abciximab, eptifibatide, and tirofiban based on previously published rates of efficacy and intracranial hemorrhage.

The propensity towards platelet-rich thrombus formation increases substantially during normal ageing, and this trend is mediated by decreases in platelet responsiveness to the anti-aggregatory nitric oxide (NO) and prostacyclin (PGI2) pathways. The impairment of soluble guanylate cyclase and adenylate cyclase-based signalling that is associated with oxidative stress represents the major mechanism of this loss of anti-aggregatory reactivity. Platelet desensitization to these autacoids represents an adverse prognostic marker in patients with ischemic heart disease and may contribute to increased thrombo-embolic risk in patients with heart failure. Patients with platelet resistance to PGI2 also are unresponsive to ADP receptor antagonist therapy. Apart from ischemia, diabetes and aortic valve disease are also associated with impaired anti-aggregatory homeostasis. This review examines the association of impaired platelet cyclic nucleotide (i.e., cGMP and cAMP) signalling with the emerging evidence of thromboembolic risk in cardiovascular diseases, and discusses the potential therapeutic strategies targeting this abnormality.