Blood Hypercoagulability Research Articles

Revisiting Virchow’s triad: exploring the cellular and molecular alterations in cerebral venous congestion

BackgroundCerebral venous thrombosis (CVT) is a rare but serious condition that can lead to significant morbidity and mortality. Virchow’s triad elucidates the role of blood hypercoagulability, blood flow dynamics, and endothelial damage in the pathogenesis of CVT. Cerebral venous congestion (CVC) increases the risk of cerebral venous sinus thrombosis and can lead to recurrent episodes and residual symptoms. However, the precise mechanism by which blood congestion leads to thrombosis remains unclear. Our objective was to investigate the cellular and molecular alterations linked to CVC through analysis of the pathological morphology of venous sinus endothelial cells and transcriptomic profiling.ResultsThis study demonstrated a remarkable correlation between CVC and the phenotypic transformation of endothelial cells from an anticoagulant to a procoagulant state. The findings revealed that cerebral venous stasis results in tortuous dilatation of the venous sinuses, with slow blood flow and elevated pressure in the sinuses and damaged endothelial cells of the retroglenoid and internal jugular vein ligation (JVL) rat model. Mechanistically, analysis of transcriptomic results of cerebral venous sinus endothelial cells showed significant activation of platelet activation, complement and coagulation cascades pathway in the JVL rats. Furthermore, the expression of von Willebrand factor (vWF) and coagulation factor VIII (F8) in the complement and coagulation cascades and Fgg and F2 in the platelet activation was increased in the cerebral venous sinuses of JVL rats than in sham rats, suggesting that endothelial cell injury in the venous sinus induced by CVC has a prothrombotic effect. In addition, endothelial cell damage accelerates coagulation and promotes platelet activation. Significantly, the concentrations of vWF, F2 and F8 in venous sinus blood of patients with internal jugular vein stenosis were higher than in their peripheral blood.ConclusionCollectively, our data suggest that CVC can induce endothelial cell damage, which then exhibits a procoagulant phenotype and ultimately increases the risk of CVT. This research contributes to our understanding of the pathophysiology of CVC associated with procoagulant factors and reexamines the components of Virchow’s triad in the context of CVC.

COVID-19-induced extracorporeal circulation coagulation during continuous renal replacement therapy: A cross-sectional study.

After the control policies of the COVID-19 epidemic were lifted in China from December 5th, 2022, there was an increase in the demand for hemodialysis and continuous renal replacement therapy (CRRT) at our center, and patients experienced hypercoagulable blood states more frequently. This study aimed to investigate the effect of COVID-19 on extracorporeal coagulation during CRRT. All CRRT records were gathered from the Hemodialysis Center at our hospital from December 5th, 2022 to February 4th, 2023, and analyzed the incidence and risk factors associated with extracorporeal coagulation. COVID-19 substantially increased the likelihood of extracorporeal coagulation during CRRT. Venous pressure and transmembrane pressure were proportional to the severity of extracorporeal coagulation. Additionally, non-tunnel type conduit vascular access, and acute kidney injury had a positive correlation with the severity of coagulation. Blood tests demonstrated that COVID-19 altered 4 coagulation indices. Moreover, mitigation of coagulation can be achieved through increasing the dosage of low molecular weight heparin and administering regional citrate anticoagulation. Patients who fail anticoagulation may be switched to peritoneal dialysis. In conclusion, COVID-19 poses a heightened risk of extracorporeal coagulation during CRRT. This study underscores the importance of anticoagulant treatment in CRRT for infected patients with kidney failure and holds significant implications for clinical practice. In future, the epidemics of COVID-19 or any other pandemic, the metrics in this study can be referenced to determine coagulation risk, as well as relevant therapeutic practices may be considered.

Impact of Tibetan ethnicity and residence altitude on complications during total knee arthroplasty and difficulties of measurement of perioperative blood loss.

Tibetan patients undergoing total knee arthroplasty (TKA) have greater fluctuations in perioperative haemoglobin levels and blood hypercoagulability. This study was to investigate whether ethnicity and altitude affect perioperative blood loss and the risk of complications after TKA. We retrospectively enrolled 1,116 patients undergoing TKA for knee osteoarthritis at our hospital between January 2016 and September 2021. We divided patients into four groups according to whether they were of Tibetan or Han ethnicity and whether they lived above or below 2500m above sea level. Primary outcomes were total, intraoperative, and hidden blood losses, while secondary outcomes were complications and homologous transfusion. Factors associated with increased blood loss were analyzed by multivariate regression. Total blood loss was higher among patients residing at high altitude compared with lower altitude, whether they were of Han (794.6 mL vs. 667.2 mL, P = 0.020) or Tibetan (904.4 mL vs. 663.8 mL, P < 0.001). Total blood loss was similar between the two ethnic groups at the same altitude. Altitude, but not Tibetan ethnicity, remained associated with increased blood loss after being analyzed by multivariate regression. Complications among the four groups were generally similar, although the frequency of calf muscular venous thrombosis was higher among Tibetan patients, while the frequency of blood transfusion was higher among Han subjects. Our findings indicate that residence at high altitude, but not ethnicity, may contribute to increased total blood loss during TKA. Thrombotic complications were more frequent among Tibetan than Han patients.

VALIDAÇÃO DE WEBSITE PARA IMPLANTAÇÃO DO PROTOCOLO PERIOPERATÓRIO NA PROFILAXIA DE TROMBOEMBOLISMO VENOSO

Introduction: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the leading cause of preventable postoperative deaths. Identifying risk factors based on Virchow’s Triad (blood stasis, hypercoagulability, and endothelial injury) is crucial. Approximately 20% of surgical patients develop VTE, with 7% resulting in fatal PE. The Caprini risk score, used to assess VTE risk, is complex and has limited adherence despite its validation across various specialties. Methodology: The applied research developed the application of a perioperative protocol for VTE prophylaxis in the Vascular Surgery ward of the Hospital Municipal de Marabá. The descriptive and quantitative study was structured via website. The 2013 version of the Caprini score was adopted for risk stratification. Validation of the tool involved 16 experts with inclusion criteria focused on doctors and nurses with experience in the area, where everyone responded to the Likert scale that evaluated 2 major domains of the tool: usability and functionality. Results: Among the 16 evaluators, 56,3% were male and 43,8% female, with an average age of 32,4 years and 7,6 years of experience. The system’s functionality received 97,5% approval, 96,3% of reliability, and 91,3% regarding interface and usability. The utility was well-rated, with 98,8% approving the professional facilitation. Chi-square tests indicated that functionality perception did not vary between physicians and nurses, but utility was significantly influenced by profession. Cronbach’s alpha coefficients indicated high internal consistency: 0,85 for functionality and 0,77 for utility. Discussion: The diverse profiles of the evaluators enriched the website’s validation. Functionality was consistently positively rated, while utility varied by professional role. High internal consistency suggests that the questionnaire is reliable for measuring website performance perceptions. Conclusion: The inclusion of the Caprini protocol in the Tupan Health website demonstrated good performance and high reliability among professionals, facilitating protocol adherence and the prevention of perioperative complications.

Specificities of primary and secondary prevention of lower extremity artery disease in patients with diabetes mellitus.

Diabetes mellitus (DM) is a major risk factor for lower extremity arterial disease (LEAD) and about 20% of symptomatic patients with LEAD have DM. In subjects with DM, LEAD is a cause of morbidity and mortality. DM typically causes complications in the form of macro- and microangiopathy. In these patients, macroangiopathy manifests as atherosclerosis like in non-diabetic patients. However, its course is accelerated due to accompanying risk factors like hyperlipidemia and hypertension, with cumulative effects. Other factors are also relevant such as inflammation, endothelial dysfunction, platelet activation, blood rheological properties, hypercoagulability, and factors stimulating vascular smooth muscle cell proliferation. Additionally, DM is a risk factor for restenosis and amputation. DM is strongly associated with femoral-popliteal and tibial LEAD, which manifests earlier in patients with DM and may progress more rapidly to critical limb ischemia. Diabetic microangiopathy is characterized by arteriolosclerosis and interstitial fibrosis which additionally affects progression and outcomes of angiopathy of lower limbs. Glycemic control particularly decreases microangiopathic complications, while prevention of macrovascular complications requires treatment of accompanying risk factors like hypertension and dyslipidemia.

Hypercoagulable state and effect of low-molecular-weight heparin prophylaxis on coagulation after lung cancer resection: results from thrombo-elastography.

Lung cancer patients undergoing surgery are at increased risk for Venous thromboembolism (VTE). We monitored changes in perioperative coagulation status through Thrombo-elastography (TEG), and monitored the anticoagulant effect of low molecular weight heparin through TEG for the first time. From July 2019 to January 2020, 207 patients receiving curative surgery were retrospectively screened. and 23 patients were excluded because they did not meet the inclusion criteria. Blood samples were required at three time points (prior to, the first and third day after surgery). Some patients were administrated nadroparin calcium daily from the first day after surgery. Repeated measures ANOVA and Chi-square test were used to analyze the coagulation states variation. To balance the confounders, propensity score matching (PSM) was used to determine the differences of coagulation states between patients with or without Low-molecular-weight heparin (LMWH) prophylaxis. In 184 patients, TEG parameters displayed significant procoagulant changes after lung surgery but conventional coagulation tests exhibited paradoxical trends. There were 6.5% (12/184) of patients identified as hypercoagulability before surgery. According to TEG results, the proportion of patients with hypercoagulability rose from 21.7% to 25% postoperatively, but more were classified into platelet or mixed hypercoagulability at third day compared with that at first day (3.8% vs 14.1%, P < 0.001). By PSM analysis, there were no significant differences in the proportion of hypercoagulable patients postoperatively between chemoprophylactic and nonprophylactic group. TEG was eligible to distinguish changing states of hypercoagulability postoperatively and indicate the role of platelet in blood hypercoagulability. Administration of postoperative LMWH prophylaxis showed little mitigation on hypercoagulable states.

Cardiovascular and non-renal complications of chronic kidney disease: Managing risk.

Chronic kidney disease (CKD) currently affects approximately 850 million people globally and is continuing to increase in prevalence as well as in importance as a cause of death. The excess mortality related to CKD is mostly caused by an increase in cardiovascular disease. This includes atherosclerotic cardiovascular disease as many promoters of atherosclerosis, such as blood pressure, lipid levels and hypercoagulation, are increased in people with CKD. Diabetes is a leading cause of CKD contributing to the risk of CVD, and obesity is also increasingly prevalent. Management of these risk factors is therefore very important in CKD, and to reduce risk of CKD progression. Heart failure is also more prevalent in CKD and, again, many risk factors are shared. The concept of foundational pillars in the management of heart failure has been adapted to the treatment of CKD, with many organ-protective interventions, such renin-angiotensin system blockade, sodium-glucose cotransporter-2 inhibition and mineralocorticoid receptor antagonism, reducing the risk for mortality in heart failure with reduced ejection fraction, but also for progression of CKD. Atrial fibrillation is also more common with CKD and affects the management of the former. In this review these non-renal complications of CKD are discussed, along with how the risk of these complications should be managed. Many new opportunities have demonstrated heart and kidney organ protection, but implementation is a challenge.

The impact of left atrial morphology on thrombosis risk in atrial fibrillation

Atrial fibrillation (AF) is an arrhythmia disease that can disrupt the movement of the left atrium (LA), which will facilitate thromboembolism in LA and further exacerbate the stroke risk. The left atrial appendage (LAA) is a vital site for thrombus formation. The morphology of the LAA is believed to have a profound effect on thrombosis. However, due to the limitation of observation and monitoring methods, the mechanism of this effect is still unrevealed. Virchow's triad is a theory of thrombogenic mechanisms, stating that endothelial injury, blood hypercoagulability, and blood stasis are the three main factors involved in thrombus formation. In this study, we conducted personalized simulation analyses for 12 AF patients and discussed simulation results from the perspective of Virchow's triad. The simulation results indicate the effectiveness of Virchow's triad in elucidating the thrombosis mechanism within the LAA. The LAA is more prone to thrombosis than the other region of LA, because of the lower blood flow velocity and significantly higher endothelial cell activation potential values there, which indicates a higher risk of blood stasis and endothelial injury, respectively. Furthermore, a comprehensive score is proposed to assess the performance of Virchow's triad in the LAA. The morphology of LA has a significant influence on the performance of the three factors in Virchow's triad. Hence, for a quickly assessment of LAA thrombosis risk in AF patients through the lens of Virchow's triad, we need a more refined shape scoring system that can better reflect patient-specific morphological features of the entire LA.

Case report: NSCLC with pulmonary embolism after treatment with almonertinib

Rationale: Almonertinib is the first independently developed third generation epidermal growth factor receptor tyrosine kinase inhibitors in China. It can be used not only for epidermal growth factor receptor (EGFR) sensitive mutation patients but also for T790M (+) resistant patients, and has better safety and survivability compared to the first and second generation EGFR-TKIs. The previous literature and case studies have reported significant treatment-related adverse reactions in non-small cell lung cancers patients treated with almonertinib, including elevated blood creatine phosphatase, prolonged cardiac QT interval, altered myocardial contractility, interstitial lung disease, eye disease, and hematological events. But there are few individual reports of pulmonary embolism events. Patient concerns: A 55-year-old female with no history of smoking visited a local hospital with mild cough and lower sacrococcygeal pain without obvious cause. Diagnosis: She was diagnosed with right lung adenocarcinoma with multiple bone metastases (T2bN1M1c, stage IVB) after image and histological examination, with EGFR 21 exon L858R sensitive mutation. Interventions: She initially underwent surgical treatment due to the discovery of a sacral tumor, and the pathology of the surgery indicated metastatic lung adenocarcinoma. Genetic testing results showed EGFR 21 exon L858R sensitive mutation. Combined with positron emission tomography/computed tomography imaging results and sacral tumor surgical pathology results, it was considered that the patient had lung adenocarcinoma with multiple bone metastases. Treatment plan: targeted treatment with almonertinib which is the third-generation EGFR-TKIs. After only 1 month of targeted treatment, chest enhanced computed tomography revealed pulmonary embolism imaging, combined with coagulation indicators, considering pulmonary embolism. As the thromboembolic site is located at the end of the pulmonary artery branch and imaging shows that tumor lesions are stable. Consider continuing targeted treatment with almonertinib and adjuvant oral anticoagulant therapy with rivaroxaban for treatment. Outcomes: Two months later, the patient’s condition was followed up and it was found that the imaging manifestations of pulmonary embolism disappeared, but the coagulation indicators remained in a hypercoagulable state. The patient’s treatment plan remained unchanged, and the patient was hospitalized for follow-up every 6 to 8 weeks to closely observe changes in the condition. Lessons: There are many reasons for the occurrence of hypercoagulable blood in tumor patients, and there are very few reports of treatment-related pulmonary embolism events in patients who are treated with almonertinib targeted therapy. It is particularly important to determine whether the hypercoagulable blood in such patients is related to targeted therapy drugs in clinical practice, as this will affect the clinical benefits of patients in epidermal growth factor receptor tyrosine kinase inhibitors treatment and the clinical indicators which need to pay more attention in follow-up observation, to avoid serious pulmonary embolism events and thus affect the patient’s survival status and quality of life.

Combining KRAS gene status with preoperative D‑dimer levels as a predictive marker of venous thromboembolism risk in patients with resectable colorectal cancer: A prospective cohort study.

Colorectal cancer (CRC), one of the most prevalent types of cancer, is accompanied by a notably high incidence of thrombotic complications. The present study aimed to elucidate the association between KRAS mutations and hypercoagulability in operable CRC. The prognostic value of preoperative D-dimer levels was also investigated, thus providing novel insights into the development of therapeutic strategies to enhance patient survival and diminish morbidity. Therefore, a prospective analysis of 333 CRC cases post-surgery at Yan'an Hospital Affiliated to Kunming Medical University, between May 2019 and October 2022 was performed. Data on demographics, tumor characteristics and D-dimer levels were compiled from the electronic health records. Venous thromboembolism (VTE) was diagnosed by doppler or computed tomography angiography, with D-dimer thresholds set at 550 and 1,650 µg/l. KRAS mutations at codons 12 and 13 were assessed in a subset of 56 cases. Subsequently, the factors affecting the hypercoagulable state in these patients were prospectively analyzed, focusing on the pivotal role of KRAS. The results showed that KRAS mutations were associated with elevated preoperative D-dimer levels, with 1,076 µg/l compared with 485 µg/l in the wild-type cohort, indicative of a hypercoagulable state. Increased D-dimer levels were also associated with vascular invasion, distant metastases and a heightened risk of postoperative VTE. Furthermore, multivariate analyses identified KRAS mutations, distant metastases and vascular invasion as independent predictors of elevated D-dimer levels, with relative risk values of 2.912, 1.884 and 1.525, respectively. Conversely, sex, age, tumor location, differentiation grade, Ki67 index and tumor stage could not significantly affect D-dimer levels, thus indicating a complex interplay between tumor genetics and coagulation dysfunction in CRC. The current study suggested that the KRAS mutation status, distant metastasis and vascular invasion could be considered as independent risk factors of blood hypercoagulability in patients with CRC, potentially serving as prognostic factors for VTE risk.

Effect of Zhishenyuanhu Anticoagulant Formula on Hypercoagulability in Rats with Qi Stagnation and Blood Stasis and Arterial and Venous Thrombosis in Rats

Background: Tumor patients present with hypercoagulable blood and are at risk of venous thromboembolism (VTE). We explored the effect of Zhishenyuanhu anticoagulant formula（ZSYH）on hypercoagulability in rats with qi stagnation and blood stasis and thrombosis in rats.Methods: Part I. Epinephrine (0.6 mg/kg, hypodermic injection, h.i.) was administered every day for 7 days. Six groups were gavaged with saline, saline, rivaroxaban, low-dose, medium-dose, and high-dose ZSYH every day. We collected rats’ daily body weight, food intake, clotting time (CT), coagulation and hemorheology results. Part II. Six groups of rats were given the same drugs as in part I for 7 days. Half of rats in each group were used to construct a common carotid artery thrombusis model, while the other half were used to construct an inferior vena cava thrombusis model. Results: ZSYH caused decreases in FIB, shear rate 1, whole blood low shear relative index, and RE. The high dose of ZSYH caused decreases in wet and dry weight of arterial and venous thrombosis.Conclusion: ZSYH is effective in treating hypercoagulability in rats with qi stagnation and blood stasis. The high dose of ZSYH prevent the development of arterial thrombosis and venous thrombosis.

Ultrasound blood flow characteristics changes in fetal umbilical artery thrombosis: A retrospective analysis.

Umbilical artery thrombosis (UAT) is extremely uncommon and leads to adverse perinatal outcomes. Hypercoagulation of blood in pregnant women is suspected to be an important risk for UAT. Ultrasound is an effective way to detect thrombosis. The mother can monitor her own fetal health using ultrasound, which enables her to take preventative action in case of emergency. To investigate ultrasonic blood signal after UAT in the umbilical artery, and evaluate the relationship between hypercoagulability and UAT. We described a case of a newly formed UAT with markedly altered ultrasonic indices of umbilical artery blood flow, and retrospectively studied it with 18 UAT patients confirmed by histopathology from October 2019 and March 2023 in Xiamen Women and Children's Hospital. Patients' information was collected from medical archives, including maternal clinical data, neonatal outcomes, pathological findings and ultrasonic indices of umbilical artery blood flow, such as systolic-diastolic duration ratio (S/D), resistance index (RI), pulsatility index (PI) and peak systolic velocity (PSV). Ultrasound and coagulation indices were analyzed with matched samples t-test and Wilcoxon rank sum test using the statistical packages in R (version 4.2.1) including car (version 3.1-0) and stats (version 4.2.1), and visualized by ggplot2 package (version 3.3.6). A patient with normal findings in second and third-trimester routine ultrasound scan developed UAT with severe changes in ultrasonic indices of umbilical artery blood flow (within 2.5th of reference ranges) in a short period of time. Statistical analysis of umbilical artery blood flow ultrasound indices for 19 patients with UAT showed that the decrease in S/D, RI, and PI and increase of PSV during the disease process was greater than that of non-UAT. All 18 patients delivered in our hospital showed characteristic manifestations of UAT on histological examination after delivery, most of which (16/18) showed umbilical cord abnormalities, with 15 umbilical cord torsion and 1 pseudoknot. Coagulation parameters were not significantly changed in UAT patients compared with normal pregnancy women. Significant changes in ultrasound indicators after UAT were demonstrated. PSV can play important roles in the diagnosis of UAT. Hypercoagulability alone is not sufficient for the occurrence of UAT.

Application of the (fr)AGILE scale in the evaluation of multidimensional frailty in elderly inpatients from internal medicine wards: a cross-sectional observational study.

With the rapid growth of an aging global population and proportion, the prevalence of frailty is constantly increasing. Therefore, finding a frailty assessment tool suitable for clinical application by physicians has become the primary link in the comprehensive management of frailty in elderly patients. This study used the (fr)AGILE scale to investigate the frailty status of elderly patients from internal medicine wards and identified relevant factors that affect the severity of frailty. In this study, 408 elderly inpatients in internal medicine departments of Qilu Hospital of Shandong University from May 2021 to August 2022 were enrolled as research subjects, and a cross-sectional observational study was conducted. Researchers evaluated the frailty based on the (fr)AGILE scale score. The general condition, past medical history, physical examination, laboratory examination, nutrition control score, intervention and treatment measures and other elderly patient information was collected. Logistic regression analysis was used to analyze the relevant factors that affect the severity of frailty and hospitalization costs. According to the (fr)AGILE scale score, the elderly patients were divided into groups to determine whether they were frail and the severity of the frailty. Among them, 164 patients were in the prefrailty stage, which accounted for 40.2%. There were 188 cases of mild frailty that accounted for 46.1%, and 56 cases of moderate to severe frailty that accounted for 13.7%. Decreased grip strength, elevated white blood cell levels, and low sodium and potassium are independent risk factors affecting the severity of frailty. As the severity of frailty increases, the proportion of sodium, potassium, albumin supplementation as well as anti-infection gradually increases. Frailty is a common elderly syndrome with a high incidence among elderly patients in internal medicine departments. The main manifestations of frailty vary with different severity levels. Inflammation, anemia, and poor nutritional status can lead to an increase in the severity of frailty as well as blood hypercoagulability, myocardial damage, and additional supportive interventions. This ultimately leads to prolonged hospitalization and increased hospitalization costs.

Acute Pulmonary Embolism and Immunity in Animal Models.

Venous thromboembolism, encompassing acute pulmonary embolism (APE) and deep vein thrombosis (DVT), is a potentially fatal disease with complex pathophysiology. Traditionally, the Virchow triad provided a framework for understanding the pathogenic contributors to thrombus formation, which include endothelial dysfunction, alterations in blood flow and blood hypercoagulability. In the last years, it has become apparent that immunity plays a central role in thrombosis, interacting with classical prothrombotic mechanisms, oxidative stress and vascular factors. Thrombosis amplifies inflammation, and exaggerated inflammatory processes can trigger thrombosis mainly due to the activation of leukocytes, platelets, and endothelial cells. APE-related endothelium injury is a major trigger for immune system activation. Endothelium is also a key component mediating inflammatory reaction and it is relevant to maintain vascular permeability. Exaggerated right ventricular wall stress and overload, with coexisting systemic hypotension and hypoxemia, result in myocardial injury and necrosis. Hypoxia, tissue factor activation and cytokine storm are engaged in the thrombo-inflammatory processes. Thrombus development is characterized by inflammatory state vascular wall caused mainly by an early extravasation of leukocytes and intense selectins and cytokines production. Nevertheless, immunity of DVT is well described, little is known about potential chemokine and cellular differences between thrombus that develops in the vein and thrombus that detaches and lodges in the pulmonary circulation being a cause of APE. There is a paucity of data considering inflammatory state in the pulmonary artery wall during an acute episode of pulmonary embolism. The main aim of this review is to summarize the knowledge of immunity in acute phase of pulmonary embolism in experimental models.

High salt diet accelerates skin aging in wistar rats: an 8-week investigation of cell cycle inhibitors, SASP markers, and oxidative stress.

Recent studies have shown that the high salt diet (HSD) is linked to increased dermal pro-inflammatory status and reduced extracellular matrix (ECM) expression in inflamed skin of mice. Decreased ECM content is a known aging phenotype of the skin, and alterations in ECM composition and organization significantly contribute to skin aging. This study aimed to determine whether a high salt diet accelerates skin aging and to identify the time point at which this effect becomes apparent. Wistar rats were randomly divided into normal diet and high salt diet groups and fed continuously for 8weeks. Skin samples were collected at weeks 7 and week 8. Skin pathological sections were evaluated and levels of cell cycle inhibitors, senescence-associated secretory phenotype (SASP), oxidative stress and vascular regulatory factors (VRFs) were examined. Correlation analyses were performed to reveal the effect of a high salt diet as an extrinsic factor on skin aging and to analyse the correlation between a high salt diet and intrinsic aging and blood flow status. At week 8, HSD rats exhibited thickened epidermis, thinned dermis, and atrophied hair follicles. The expression of cell cycle inhibitors and oxidative stress levels were significantly elevated in the skin of HSD rats at both week 7 and week 8. At week 7, some SASPs, including TGF-β and PAI-1, were elevated, but others (IL-1, IL-6, IL-8, NO) were not significantly changed. By week 8, inflammatory molecules (IL-1, IL-6, TGF-β), chemokines (IL-8), proteases (PAI-1), and non-protein molecules (NO) were significantly increased. Notably, despite elevated PAI-1 levels suggesting possible blood hypercoagulation, the ET-1/NO ratio was reduced in the HSD group at week 8. The data suggest that a high salt diet causes skin aging by week 8. The effect of a high salt diet on skin aging is related to the level of oxidative stress and the expression of cell cycle inhibitors. Additionally, a potential protective mechanism may be at play, as evidenced by the reduced ET-1/NO ratio, which could help counteract the hypercoagulable state and support nutrient delivery to aging skin.

COVID-19 shed light on Virchow's law of thrombosis.

Virchow's law of thrombosis states that thrombosis in a vessel occurs as a combination of the following: (i) injury to the vessel wall, (ii) stasis of blood flow, and (iii) blood hypercoagulability. Injury to the wall includes infection/inflammation and/or injury to the resident cells of the wall. We postulate that in COVID-19, the SARS-CoV-2 virus directly infects the alveolar type II cell or directly or indirectly infects/injures the pericyte, promoting inflammation and interaction with endothelial cells, thereby causing a cascade of events leading to our observation that thrombosis occurred within the walls of the pulmonary vessels and not in the lumen of the vascular circulation.

Clinical efficacy and safety of Panax notoginseng saponins in treating chronic obstructive pulmonary disease with blood hypercoagulability: A meta-analysis of randomized controlled trials

BackgroundPanax notoginseng saponins (PNS) are the primary active components of an ancient Chinese herb Panax notoginseng. Hypercoagulable state of blood (HCS) is an independent risk factor and a cause of death in chronic obstructive pulmonary disease (COPD). Several vivo studies have demonstrated the use of PNS preparations for treating COPD with HCS. PurposeThis study aimed to systematically evaluate the clinical efficacy and safety of PNS preparations in treating COPD with HCS. Study DesignMeta-analysis of the randomized controlled trials (RCTs) was conducted to review data. MethodsRCTs on the treatment of COPD with HCS and PNS preparations were searched from PubMed, Cochrane Library, Embase, Web of Science, Chinese National Knowledge Infrastructure, Vip Information Database, Wanfang data, and Chinese Biomedical Literature Database. Relevant data were extracted from the included studies and methodological quality evaluation was performed. R language (version 4.2.3) was applied for the meta-analysis. ResultsTwenty RCTs involving 1831 patients were analyzed. The results revealed that PNS preparations considerably increased the total clinical efficiency, improved forced expiratory volume in one second percent of predicted, and forced expiratory volume/forced vital capacity ratio. Further, PNS preparations improved fibrinogen, plasma d-dimer, whole blood viscosity at high cut, whole blood viscosity at low cut, and plasma viscosity levels. The results obtained for activated partial thromboplastin and prothrombin times were not statistically significant. Finally, PNS preparations increased partial pressure of oxygen and decreased carbon dioxide pressure. ConclusionThis is the first relatively comprehensive systematic review of the clinical efficacy and safety of PNS preparations for treating COPD with HCS. The study revealed that PNS preparations considerably improve lung function, hypoxia, and blood hypercoagulability in patients with COPD and HCS without increasing the risk of hemorrhage and has a good safety profile; therefore, it can be used as a new modulating agent and anticoagulant.

Deep and infratentorial cerebral microbleeds are related to wake-up stroke by large-artery atherosclerosis and cardioembolism

Background and aimsCircadian variability of blood pressure (BP) and hypercoagulation in the morning have been proposed as underlying mechanisms of wake-up stroke (WUS). The aim was to determine the impact of cerebral microbleeds (CMBs), showing BP fluctuation and background hypercoagulability, on WUS. MethodsConsecutive patients with acute ischemic stroke onset-to-door time within one week were screened. WUS was defined as an ischemic stroke that occurred during sleep at night. CMBs were categorized into three: “strictly Lobar”, “strictly Deep (D) and/or Infratentorial (I)”, and “Mixed”. Moderate to severe CMBs were defined as having more than three in total. First, whether CMBs are associated with WUS was examined. Second, the same analysis was performed according to the stroke subtype classified as large-artery atherosclerosis (LAA), cardioembolism (CE), and small-vessel occlusion (SVO). ResultsA total of 1477 patients (1059 [72%] male, median age 69 years) were included, and WUS was observed in 363 (25%) patients. On Poisson regression analysis with a robust variance estimator in the total cohort, moderate to severe strictly D and/or I CMBs (PR 1.505, 95% CI 1.154–1.962, p = 0.003) were associated with WUS. From the perspective of stroke subtype, the same result was confirmed in LAA (PR 2.223, 95% CI 1.036–4.768, p = 0.040) and CE (PR 1.668, 95% CI 1.027–2.709, p = 0.039), not SVO. ConclusionsThe presence of moderate to severe strictly D and/or I CMBs might be associated with the development of WUS. By stroke subtype, the same result was confirmed in LAA and CE.

Immune Checkpoint Blockade Promotes Thrombosis Via T-Cell and Neutrophil Activation, and Tumor-Cell Associated Tissue Factor (TF) in a Murine Model of Colorectal Cancer

Background: Immune checkpoint blockade (ICB) is a paradigm shift in cancer therapy. Despite clinical benefit, various adverse events are associated with ICB using immune checkpoint inhibitors (ICI). Venous thrombosis is an emerging clinical problem in cancer patients receiving ICI. Little is known about how ICI promotes thrombosis in cancer. To define the underlying mechanisms of ICI-associated thrombosis (IAT), we assessed the ICI impact on blood hypercoagulability and tumor TF expression using a mouse thrombosis model of colorectal cancer. Methods: We developed a CT26 mouse thrombosis model with ICI (aPD-1+aCTLA4) administration. Systemic hypercoagulability was assessed by measurement of circulating nucleosomes (Nu.Q H3.1 Immunoassay), neutrophil extracellular traps (NETs) (CitH3 immunofluorescence), circulating neutrophil-platelet aggregates (immunophenotyping), and levels of thrombin-antithrombin (TAT) complexes in ICI-treated mice. Tumor-associated TF and TF activity in circulating extracellular vesicles (EV) were assessed by western blotting and Factor Xa generation assays. To gain mechanistic insights into TF induction by ICI, tumor cytokines were also profiled (proteome profiler array). The role of cancer cell-derived TF in IAT was determined using mice implanted with CRISPR/Cas9-mediated TF knockout (TFKO) CT26 tumor cells. Results: ICI treated tumor-bearing mice developed larger thrombi than control mice and demonstrated elevated levels of circulating nucleosomes (114 vs 82 ng/ml), NET (15.8 vs 6.8%), platelet-neutrophil aggregates (44.8 vs 22.3%), and TAT complexes (12.6 vs 7.9 ng/ml) compared to IgG-treated mice. Tumor TF expression was increased in tumor extracts. Cytokine profiling suggested enhanced production of IFNɣ (2-fold) and TNFα (5-fold), as well as CXCL11 (6.8-fold), an effector T cell-recruiting chemokine. IFNɣ-increased TF expression in cultured CT26 cells, suggesting that T-cell derived IFNɣ may play a role in enhancing tumor TF expression in vivo. Circulating EV TF antigen and procoagulant activity were increased by ICI. CRISPR/Cas9-mediated TF KO in CT26 cells resulted in complete loss of TF expression, and mice bearing these cells showed reduced tumor and EV-associated TF (Fig. A), associated with a significant decrease in thrombus formation after ICI treatment (24.2 vs 20.5 mg, Fig. B). There was no significant difference in growth of wild-type and TF KO CT26 tumors. Conclusions: Our findings provide insights into cellular and molecular mechanisms associated with ICI-induced thrombosis, and suggest a role for neutrophil and granulocyte activation, and tumor-associated TF. Additional studies are ongoing to further define these pathways in the murine model and in patients.

Interatrial Block, Bayés Syndrome, Left Atrial Enlargement, and Atrial Failure

Interatrial block (IAB) is defined by the presence of a P-wave ≥120 ms. Advanced IAB is diagnosed when there is also a biphasic morphology in inferior leads. The cause of IAB is complete block of Bachmann’s bundle, resulting in retrograde depolarization of the left atrium from areas near the atrioventricular junction. The anatomic substrate of advanced IAB is fibrotic atrial cardiomyopathy. Dyssynchrony induced by advanced IAB is frequently a trigger and maintenance mechanism of atrial fibrillation (AF) and other atrial arrhythmias. Bayés syndrome is characterized by the association of advanced IAB with atrial arrhythmias. This syndrome is associated with an increased risk of stroke, dementia, and mortality. Advanced IAB frequently produces an alteration of the atrial architecture. This atrial remodeling may promote blood stasis and hypercoagulability, triggering the thrombogenic cascade, even in patients without AF. In addition, atrial remodeling may ultimately lead to mechanical dyssynchrony and enlargement. Atrial enlargement is usually the result of prolonged elevation of atrial pressure due to various underlying conditions such as IAB, diastolic dysfunction, left ventricular hypertrophy, valvular heart disease, hypertension, and athlete’s heart. Left atrial enlargement (LAE) may be considered present if left atrial volume indexed to body surface is &gt; 34 mL/m2; however, different cut-offs have been used. Finally, atrial failure is a global clinical entity that includes any atrial dysfunction that results in impaired cardiac performance, symptoms, and decreased quality of life or life expectancy.