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Platelets assume a pivotal role in the pathogenesis of cardiovascular diseases (CVDs), emphasizing their significance in disease progression. Consequently, addressing CVDs necessitates a targeted approach focused on mitigating platelet activation. Eugenol, predominantly derived from clove oil, is recognized for its antibacterial, anticancer, and anti-inflammatory properties, rendering it a valuable medicinal agent. This investigation delves into the intricate mechanisms through which eugenol influences human platelets. At a low concentration of 2 μM, eugenol demonstrates inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Notably, thrombin and U46619 remain unaffected by eugenol. Its modulatory effects extend to ATP release, P-selectin expression, and intracellular calcium levels ([Ca2+]i). Eugenol significantly inhibits various signaling cascades, including phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3β, mitogen-activated protein kinases, and cytosolic phospholipase A2 (cPLA2)/thromboxane A2 (TxA2) formation induced by collagen. Eugenol selectively inhibited cPLA2/TxA2 phosphorylation induced by AA, not affecting p38 MAPK. In ADP-treated mice, eugenol reduced occluded lung vessels by platelet thrombi without extending bleeding time. In conclusion, eugenol exerts a potent inhibitory effect on platelet activation, achieved through the inhibition of the PLCγ2–PKC and cPLA2-TxA2 cascade, consequently suppressing platelet aggregation. These findings underscore the potential therapeutic applications of eugenol in CVDs. [ABSTRACT FROM AUTHOR]

Changquan Fang,1 Limin Xu2 1Department of Pulmonary and Critical Care Medicine, Huizhou Central People’s Hospital, Huizhou, Guangdong Province, Peoples’ Republic of China; 2Department of Geriatrics, Huizhou First People’s Hospital, Huizhou, Guangdong Province, People’s Republic of ChinaCorrespondence: Limin Xu, Department of Geriatrics, Huizhou First People’s Hospital, No. 20 Sanxin South Road, Huicheng District, Huizhou City, Guangdong Province, 516000, People’s Republic of China, Tel +86 136-3199-9563, Email 837899883@qq.comAbstract: Chlamydia psittaci pneumonia frequently leads to various extrapulmonary complications; however, reports of C. psittaci-pneumonia complicated by pulmonary thrombosis are uncommon. We report a case of severe C. psittaci pneumonia in a patient with a history of poultry contact and clinical manifestations including hyperpyrexia, dyspnea, and respiratory failure, which necessitated tracheal intubation for assisted ventilation. C. psittaci in bronchoalveolar lavage fluid was detected with metagenomic next-generation sequencing. Following targeted antibiotic therapy, the fever subsided, although dyspnea persisted without significant improvement, and chest pain developed. Compared to previous measurements, the D-dimer level increased, and CT pulmonary angiography revealed thromboses in the pulmonary artery trunk and left pulmonary artery. The symptoms improved after anticoagulant treatment, and the patient was discharged subsequently. This study suggests that C. psittaci infection may be associated with the formation of pulmonary thrombosis. Additional clinical data are required to support this inference. Following targeted antibiotic therapy, if persistent dyspnea, chest pain, and increased D-dimer level are present, pulmonary thrombosis should be considered, and pulmonary artery angiography can confirm the diagnosis.Keywords: Chlamydia psittaci, pneumonia, pulmonary thrombosis, metagenomic next-generation sequencing

The rate of thrombotic complications in COVID-19 patients is high and could be associated with the risk of unfavourable outcomes. Moreover, pulmonary thrombotic events can occur even in patients already on anticoagulant treatment. We present the case of a patient with severe COVID-19 pneumonia, without traditional risk factors for thrombosis, who developed massive pulmonary thrombosis (PT) despite therapeutic anticoagulation. The diagnosis was challenging, and the case raised concerns about the protective role of conventional anticoagulant treatment in COVID-19 pneumonia. Thus, we searched for literature reports on COVID-19 patients who developed PT despite being under anticoagulation therapy. We identified 13 cohort studies including 4058 patients of which 346 (8.5%) developed PT and nine case reports/series enrolling 14 patients. Four cohorts were further analysed, which reported data on risk factors for thrombosis, outcomes and biological characteristics. We found that there were no differences between patients with and without PT regarding the classical risk factors for thrombosis. PT occurred regardless of the anticoagulation regimen, and the risk factor identified was severe COVID-19 pneumonia and a stay in an intensive care unit (ICU). Pulmonary thrombotic events in patients with COVID-19 are rather inflammation-related than correlated with traditional thromboembolic risk factors, and the therapeutic approach must take into consideration this aspect. [ABSTRACT FROM AUTHOR]

Carolina Hungaro Cunha,1 Debora Yuri Sato,1 Jose Maria Pereira de Godoy,2 Gleison Juliano da Silva Russeff,1 Desirée Franccini Del Frari Silva,1 Henrique Jose Pereira de Godoy,3 Mariana Orate Menezes da Silva,4 Henrique Amorim Santos,4 Maria de Fatima Guerreiro Godoy5 1Ecography Service in Hospital de Base-FUNFARME/FAMERP, Sao Jose do Rio Preto, Brazil; 2Cardiology and Cardiovascular Surgery Department Sao Jose do Rio Preto School Medicine-FAMERP, Sao Jose do Rio Preto, Brazil; 3General Surgery Department São Jose do Rio Preto School Medicine-FAMERP, Sao Jose do Rio Preto, Brazil; 4Vascular Surgery Service São Jose do Rio Preto School Medicine-FAMERP, Sao Jose do Rio Preto, Brazil; 5Post-Graduate Program São José do Rio Preto-FAMERP, Sao Jose do Rio Preto School Medicine-FAMERP, Sao Jose do Rio Preto, BrazilCorrespondence: Jose Maria Pereira de Godoy, Cardiology and Cardiovascular Surgery Department São Jose do Rio Preto School Medicine-FAMERP, Rua Floriano Peixoto, São Jose do Rio Preto, SP, 2950, Brazil, Tel/Fax +551732326362, Email godoyjmp@gmail.comPurpose: The SARS-CoV-2 disease predisposes infected individuals to thrombosis, the underlying mechanisms of which are not fully understood. The balance between pro-coagulant factors and natural coagulation inhibitors in critically ill patients with Covid-19 is fundamental to the prevention and treatment of complications. The aim of the present study was to investigate the pulmonary injury patterns in Covid-19 having higher mortality in the presence of deep vein thrombosis in comparison to patients without venous thrombosis and determine the Gamma variant.Methods: A retrospective study was conducted involving the evaluation of 200 medical records of patients with Covid-19 and a clinical suspicion of deep vein thrombosis (DVT) at the intensive care unit of a public hospital. The sample was divided into two groups of patients were formed – those positive and those negative for DVT. Statistical analysis involved the use of Fisher’s exact test, the paired t-test and chi-square test.Results: Patients with DVT had more severe lung injuries (greater than 70%) compared to those without DVT (p = 0.003). Lesions affecting 50% to 70% of the lung area occurred in little more half of the group with DVT and just under half in the group without DVT (p = 0.5). Pulmonary lesions affecting less than 50% of the lung occurred more in patients without DVT (p = 0.0001). The Gamma variant increased prevalence of the both DVT and mortality (p=0.0001).Conclusion: Deep vein thrombosis is an aggravating factor of mortality in patients with SARS-CoV-2, and the Gamma variant is an aggravating factor of both thrombotic events and mortality.Keywords: Covid-19, deep vein thrombosis, pulmonary thrombosis, mortality

Neonatal venous thrombosis is a rare condition that can be iatrogenic or occur due to viral infections or genetic mutations. Thromboembolic complications are also commonly observed as a result of SARS-CoV-2 infections. They can affect pediatric patients, especially the ones suffering from multisystem inflammatory syndrome in children (MIS-C) or multisystem inflammatory syndrome in neonates (MIS-N). The question remains whether the maternal SARS-CoV-2 infection during pregnancy can lead to thromboembolic complications in fetuses and neonates. We report on a patient born with an embolism in the arterial duct, left pulmonary artery, and pulmonary trunk, who presented several characteristic features of MIS-N, suspecting that the cause might have been the maternal SARS-CoV2 infection in late pregnancy. Multiple genetic and laboratory tests were performed. The neonate presented only with a positive result of IgG antibodies against SARS-CoV-2. He was treated with low molecular weight heparin. Subsequent echocardiographic tests showed that the embolism dissolved. More research is necessary to evaluate the possible neonatal complications of maternal SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Platelets assume a pivotal role in the pathogenesis of cardiovascular diseases (CVDs), emphasizing their significance in disease progression. Consequently, addressing CVDs necessitates a targeted approach focused on mitigating platelet activation. Eugenol, predominantly derived from clove oil, is recognized for its antibacterial, anticancer, and anti-inflammatory properties, rendering it a valuable medicinal agent. This investigation delves into the intricate mechanisms through which eugenol influences human platelets. At a low concentration of 2 μM, eugenol demonstrates inhibition of collagen and arachidonic acid (AA)-induced platelet aggregation. Notably, thrombin and U46619 remain unaffected by eugenol. Its modulatory effects extend to ATP release, P-selectin expression, and intracellular calcium levels ([Ca2+]i). Eugenol significantly inhibits various signaling cascades, including phospholipase Cγ2 (PLCγ2)/protein kinase C (PKC), phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3β, mitogen-activated protein kinases, and cytosolic phospholipase A2 (cPLA2)/thromboxane A2 (TxA2) formation induced by collagen. Eugenol selectively inhibited cPLA2/TxA2 phosphorylation induced by AA, not affecting p38 MAPK. In ADP-treated mice, eugenol reduced occluded lung vessels by platelet thrombi without extending bleeding time. In conclusion, eugenol exerts a potent inhibitory effect on platelet activation, achieved through the inhibition of the PLCγ2–PKC and cPLA2-TxA2 cascade, consequently suppressing platelet aggregation. These findings underscore the potential therapeutic applications of eugenol in CVDs.

Pulmonary thrombosis (PT) is a frequent complication of COVID-19. However, the risk factors, predictive scores, and precise diagnostic guidelines on indications for CT pulmonary angiography (CTPA) are still lacking. This study aimed to analyze the clinical and laboratory characteristics associated with PT in patients with COVID-19. We conducted a cohort study of consecutively hospitalized adult patients with COVID-19 who underwent CTPA at the University Hospital for Infectious Diseases in Zagreb, Croatia between 1 April and 31 December 2021. Of 2078 hospitalized patients, 575 (27.6%) underwent CTPA. PT was diagnosed in 178 (30.9%) patients (69.6% males, median age of 61, IQR 50–69 years). The PT group had a higher CRP, LDH, D-dimer, platelets, and CHOD score. PT was more frequent in patients requiring ≥15 L O2/min (25.0% vs. 39.7%). In multivariable analysis, only D-dimer ≥ 1.0 mg/L (OR 1.78, 95%CI 1.12–2.75) and O2 ≥ 15 L (OR 1.89, 95%CI 1.26–2.84) were associated with PT. PT was not associated with in-hospital mortality. In conclusion, our data confirmed a high incidence of PT in hospitalized patients with COVID-19, however, no correlation with traditional risk factors and mortality was found. CTPA should be performed in patients requiring high-flow supplemental oxygen or those with increased D-dimer levels. [ABSTRACT FROM AUTHOR]

Abstract Background Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by a necrotizing vasculitis with tissue and peripheral blood eosinophilia affecting small and medium-sized arteries, capillaries, and veins. Venous thromboembolic events are uncommon in EGPA. Moreover, there are only a few reported cases of EGPA complicated by pulmonary embolism or infarction. Case presentation We report the case of a 43-year-old woman with eosinophilic granulomatosis with polyangiitis and acute respiratory and heart failure due to bilateral pulmonary artery thrombosis and left femoral vein thrombosis 12 years after disease onset. She also had cardiac involvement (myocarditis, pericardial effusion, and diastolic dysfunction), gastrointestinal symptoms, and peripheral neuropathy. The condition was refractory to treatment with systemic corticosteroids, intravenous cyclophosphamide, and mepolizumab, but the thrombosis and associated acute cardiac failure, as well as the cardiac and gastrointestinal symptoms and multiple polyneuropathy, improved after a switch to rituximab. However, the heart failure did not improve sufficiently and the patient continued to need inhaled oxygen at 1 L/min and asthma exacerbations occurred. We then swapped the patient’s mepolizumab treatment for dupilumab. Not only did she have no further asthma attacks after switching to dupilumab, but also her vasculitis symptoms improved. Oxygen therapy was discontinued as the heart failure improved 5 months after starting the dupilumab. Conclusions This may be the first case report of the successful treatment by rituximab of pulmonary thromboembolism associated with EGPA. In addition, in this patient, treatment with dupilumab was effective not only for the asthma symptoms but also for the symptoms of vasculitis and heart failure.

Purpose: The SARS-CoV-2 disease predisposes infected individuals to thrombosis, the underlying mechanisms of which are not fully understood. The balance between pro-coagulant factors and natural coagulation inhibitors in critically ill patients with Covid-19 is fundamental to the prevention and treatment of complications. The aim of the present study was to investigate the pulmonary injury patterns in Covid-19 having higher mortality in the presence of deep vein thrombosis in comparison to patients without venous thrombosis and determine the Gamma variant. Methods: A retrospective study was conducted involving the evaluation of 200 medical records of patients with Covid-19 and a clinical suspicion of deep vein thrombosis (DVT) at the intensive care unit of a public hospital. The sample was divided into two groups of patients were formed – those positive and those negative for DVT. Statistical analysis involved the use of Fisher's exact test, the paired t-test and chi-square test. Results: Patients with DVT had more severe lung injuries (greater than 70%) compared to those without DVT (p = 0.003). Lesions affecting 50% to 70% of the lung area occurred in little more half of the group with DVT and just under half in the group without DVT (p = 0.5). Pulmonary lesions affecting less than 50% of the lung occurred more in patients without DVT (p = 0.0001). The Gamma variant increased prevalence of the both DVT and mortality (p=0.0001). Conclusion: Deep vein thrombosis is an aggravating factor of mortality in patients with SARS-CoV-2, and the Gamma variant is an aggravating factor of both thrombotic events and mortality. [ABSTRACT FROM AUTHOR]

The rate of thrombotic complications in COVID-19 patients is high and could be associated with the risk of unfavourable outcomes. Moreover, pulmonary thrombotic events can occur even in patients already on anticoagulant treatment. We present the case of a patient with severe COVID-19 pneumonia, without traditional risk factors for thrombosis, who developed massive pulmonary thrombosis (PT) despite therapeutic anticoagulation. The diagnosis was challenging, and the case raised concerns about the protective role of conventional anticoagulant treatment in COVID-19 pneumonia. Thus, we searched for literature reports on COVID-19 patients who developed PT despite being under anticoagulation therapy. We identified 13 cohort studies including 4058 patients of which 346 (8.5%) developed PT and nine case reports/series enrolling 14 patients. Four cohorts were further analysed, which reported data on risk factors for thrombosis, outcomes and biological characteristics. We found that there were no differences between patients with and without PT regarding the classical risk factors for thrombosis. PT occurred regardless of the anticoagulation regimen, and the risk factor identified was severe COVID-19 pneumonia and a stay in an intensive care unit (ICU). Pulmonary thrombotic events in patients with COVID-19 are rather inflammation-related than correlated with traditional thromboembolic risk factors, and the therapeutic approach must take into consideration this aspect.

Metformin is widely used as first-line medication for type 2 diabetes (T2D), the main disease comorbid with kidney disease, cardiovascular diseases (CVDs), and retinopathy. Platelets are crucial in platelet-dependent arterial thrombosis, which causes CVDs and cerebrovascular diseases. Research indicates that metformin may improve these diseases; metformin reportedly reduced platelet activation in rats. However, no reports have included human platelets. We investigated the mechanisms underlying metformin's effects on platelet activation by using human platelets and evaluated its in vivo effectiveness in experimental mice. Metformin inhibited platelet aggregation stimulated by collagen but not by arachidonic acid, U46619, or thrombin. Metformin suppressed ATP release, [Ca2+]i mobilization, and P-selectin expression, as well as phospholipase C (PLC)γ2/protein kinase C (PKC), p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation. Metformin did not affect vasodilator-stimulated phosphoprotein (VASP) phosphorylation. In the animal studies, metformin reduced acute pulmonary thromboembolism mortality without increasing bleeding times. These results provide insights into the role and mechanisms of metformin in human platelet activation. Metformin decreased platelet activation by interfering with the PLCγ2/PKC, PI3K/Akt/GSK3β, and p38 MAPK pathways through a VASP-independent mechanism. Metformin demonstrates promise as a new class of antiplatelet agent that can inhibit platelet activation. [ABSTRACT FROM AUTHOR]

Cold agglutinin disease is a rare cause of arterial thrombosis leading to stroke, commonly encountered against a background of mycoplasma pneumonia infections. A 22-year-old patient presented with acute-onset left hemiplegia preceded by a short history of fever and cough. Magnetic resonance imaging (MRI) showed a right middle cerebral artery infarct. Serially repeated hemoglobin levels showed a progressive drop and peripheral smear showed evidence of hemolysis. Blood drawn for investigations would rapidly clot, suggesting a possibility of cold agglutinin-induced hemolysis. The patient was then worked up for all the possible causes of hemolytic anemia including secondary causes which were all negative except for significant immunoglobulin M mycoplasma levels with elevated cold antibody titers. The patient was then initiated on pulse steroids with azithromycin and doxycycline and hemoglobin levels stabilized. The patient also developed pulmonary thromboembolism which was managed with anticoagulation. The patient made a steady improvement, was discharged, and is on follow-up. Here, we present a unique case of mycoplasma associated cold agglutinin disease causing arterial thrombosis. [ABSTRACT FROM AUTHOR]

Abstract Background The incidence of pulmonary thromboembolism is high in SARS-CoV-2 patients admitted to the Intensive Care. Elevated biomarkers of coagulation (fibrinogen and D-dimer) and inflammation (c-reactive protein (CRP) and ferritin) are associated with poor outcome in SARS-CoV-2. Whether the time-course of fibrinogen, D-dimer, CRP and ferritin is associated with the occurrence of pulmonary thromboembolism in SARS-CoV-2 patients is unknown. We hypothesise that patients on mechanical ventilation with SARS-CoV-2 infection and clinical pulmonary thromboembolism have lower concentrations of fibrinogen and higher D-dimer, CRP, and ferritin concentrations over time compared to patients without a clinical pulmonary thromboembolism. Methods In a prospective study, fibrinogen, D-dimer, CRP and ferritin were measured daily. Clinical suspected pulmonary thromboembolism was either confirmed or excluded based on computed tomography pulmonary angiography (CTPA) or by transthoracic ultrasound (TTU) (i.e., right-sided cardiac thrombus). In addition, patients who received therapy with recombinant tissue plasminogen activator were included when clinical instability in suspected pulmonary thromboembolism did not allow CTPA. Serial data were analysed using a mixed-effects linear regression model, and models were adjusted for known risk factors (age, sex, APACHE-II score, body mass index), biomarkers of coagulation and inflammation, and anticoagulants. Results Thirty-one patients were considered to suffer from pulmonary thromboembolism ((positive CTPA (n = 27), TTU positive (n = 1), therapy with recombinant tissue plasminogen activator (n = 3)), and eight patients with negative CTPA were included. After adjustment for known risk factors and anticoagulants, patients with, compared to those without, clinical pulmonary thromboembolism had lower average fibrinogen concentration of − 0.9 g/L (95% CI: − 1.6 – − 0.1) and lower average ferritin concentration of − 1045 μg/L (95% CI: − 1983 – − 106) over time. D-dimer and CRP average concentration did not significantly differ, 561 μg/L (− 6212–7334) and 27 mg/L (− 32–86) respectively. Ferritin lost statistical significance, both in sensitivity analysis and after adjustment for fibrinogen and D-dimer. Conclusion Lower average concentrations of fibrinogen over time were associated with the presence of clinical pulmonary thromboembolism in patients at the Intensive Care, whereas D-dimer, CRP and ferritin were not. Lower concentrations over time may indicate the consumption of fibrinogen related to thrombus formation in the pulmonary vessels.

Neonatal venous thrombosis is a rare condition that can be iatrogenic or occur due to viral infections or genetic mutations. Thromboembolic complications are also commonly observed as a result of SARS-CoV-2 infections. They can affect pediatric patients, especially the ones suffering from multisystem inflammatory syndrome in children (MIS-C) or multisystem inflammatory syndrome in neonates (MIS-N). The question remains whether the maternal SARS-CoV-2 infection during pregnancy can lead to thromboembolic complications in fetuses and neonates. We report on a patient born with an embolism in the arterial duct, left pulmonary artery, and pulmonary trunk, who presented several characteristic features of MIS-N, suspecting that the cause might have been the maternal SARS-CoV2 infection in late pregnancy. Multiple genetic and laboratory tests were performed. The neonate presented only with a positive result of IgG antibodies against SARS-CoV-2. He was treated with low molecular weight heparin. Subsequent echocardiographic tests showed that the embolism dissolved. More research is necessary to evaluate the possible neonatal complications of maternal SARS-CoV-2 infection.

Background Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with systemic changes in immune response, which might be associated with coronavirus disease 2019 (COVID-19) severity. The aim of this study was to investigate the impact of NAFLD on COVID-19 severity and outcomes. Methods A prospective observational study included consecutively hospitalized adult patients, hospitalized between March and June 2021, with severe COVID-19. Patients were screened for fatty liver by ultrasound and subsequently diagnosed with NAFLD. Patients were daily followed until discharge, and demographic, clinical, and laboratory data were collected and correlated to clinical outcomes. Results Of the 216 patients included, 120 (55.5%) had NAFLD. The NAFLD group had higher C-reactive protein (interquartile range [IQR]) (84.7 [38.6–129.8] mg/L vs 66.9 [32.2–97.3] mg/L; P  = .0340), interleukin-6 (49.19 [22.66–92.04] ng/L vs 13.22 [5.29–39.75] ng/L; P  < .0001), aspartate aminotransferase (58 [40–81] IU/L vs 46 [29–82] IU/L; P  = .0123), alanine aminotransferase (51 [32–73] IU/L vs 40 [23–69] IU/L; P  = .0345), and lactate dehydrogenase (391 [285–483] IU/L vs 324 [247–411] IU/L; P  = .0027). The patients with NAFLD had higher disease severity assessed by 7-category ordinal scale, more frequently required high-flow nasal cannula or noninvasive ventilation (26, 21.66%, vs 10, 10.42%; P  = .0289), had longer duration of hospitalization (IQR) (10 [8–15] days vs 9 [6–12] days; P  = .0018), and more frequently had pulmonary thromboembolism (26.66% vs 13.54%; P  = .0191). On multivariable analyses, NAFLD was negatively associated with time to recovery (hazard ratio, 0.64; 95% CI, 0.48 to 0.86) and was identified as a risk factor for pulmonary thrombosis (odds ratio, 2.15; 95% CI, 1.04 to 4.46). Conclusions NAFLD is associated with higher COVID-19 severity, more adverse outcomes, and more frequent pulmonary thrombosis. [ABSTRACT FROM AUTHOR]

Abstract Background Pulmonary involvement in COVID-19 is characterized pathologically by diffuse alveolar damage (DAD) and thrombosis, leading to the clinical picture of Acute Respiratory Distress Syndrome. The direct action of SARS-CoV-2 in lung cells and the dysregulated immuno-coagulative pathways activated in ARDS influence pulmonary involvement in severe COVID, that might be modulated by disease duration and individual factors. In this study we assessed the proportions of different lung pathology patterns in severe COVID-19 patients along the disease evolution and individual characteristics. Methods We analysed lung tissue from 41 COVID-19 patients that died in the period March–June 2020 and were submitted to a minimally invasive autopsy. Eight pulmonary regions were sampled. Pulmonary pathologists analysed the H&E stained slides, performing semiquantitative scores on the following parameters: exudative, intermediate or advanced DAD, bronchopneumonia, alveolar haemorrhage, infarct (%), arteriolar (number) or capillary thrombosis (yes/no). Histopathological data were correlated with demographic-clinical variables and periods of symptoms-hospital stay. Results Patient´s age varied from 22 to 88 years (18f/23 m), with hospital admission varying from 0 to 40 days. All patients had different proportions of DAD in their biopsies. Ninety percent of the patients presented pulmonary microthrombosis. The proportion of exudative DAD was higher in the period 0–8 days of hospital admission till death, whereas advanced DAD was higher after 17 days of hospital admission. In the group of patients that died within eight days of hospital admission, elderly patients had less proportion of the exudative pattern and increased proportions of the intermediate patterns. Obese patients had lower proportion of advanced DAD pattern in their biopsies, and lower than patients with overweight. Clustering analysis showed that patterns of vascular lesions (microthrombosis, infarction) clustered together, but not the other patterns. The vascular pattern was not influenced by demographic or clinical parameters, including time of disease progression. Conclusion Patients with severe COVID-19 present different proportions of DAD patterns over time, with advanced DAD being more prevalent after 17 days, which seems to be influenced by age and weight. Vascular involvement is present in a large proportion of patients, occurs early in disease progression, and does not change over time.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by a necrotizing vasculitis with tissue and peripheral blood eosinophilia affecting small and medium-sized arteries, capillaries, and veins. Venous thromboembolic events are uncommon in EGPA. Moreover, there are only a few reported cases of EGPA complicated by pulmonary embolism or infarction. Case presentation: We report the case of a 43-year-old woman with eosinophilic granulomatosis with polyangiitis and acute respiratory and heart failure due to bilateral pulmonary artery thrombosis and left femoral vein thrombosis 12 years after disease onset. She also had cardiac involvement (myocarditis, pericardial effusion, and diastolic dysfunction), gastrointestinal symptoms, and peripheral neuropathy. The condition was refractory to treatment with systemic corticosteroids, intravenous cyclophosphamide, and mepolizumab, but the thrombosis and associated acute cardiac failure, as well as the cardiac and gastrointestinal symptoms and multiple polyneuropathy, improved after a switch to rituximab. However, the heart failure did not improve sufficiently and the patient continued to need inhaled oxygen at 1 L/min and asthma exacerbations occurred. We then swapped the patient's mepolizumab treatment for dupilumab. Not only did she have no further asthma attacks after switching to dupilumab, but also her vasculitis symptoms improved. Oxygen therapy was discontinued as the heart failure improved 5 months after starting the dupilumab. Conclusions: This may be the first case report of the successful treatment by rituximab of pulmonary thromboembolism associated with EGPA. In addition, in this patient, treatment with dupilumab was effective not only for the asthma symptoms but also for the symptoms of vasculitis and heart failure. [ABSTRACT FROM AUTHOR]

We report a case of pulmonary thrombosis in a teenager during a hypercoagulable state associated with COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). A condition rare in children and adolescents, pulmonary thrombosis underdiagnosis likely increases morbidity and mortality. A pulmonary thrombosis diagnosis requires a high level of suspicion and relies on the combination of clinical presentation, D-dimer elevation, and computed tomography (CT) pulmonary angiography or ventilation/perfusion scans, imaging techniques that are difficult to perform. Electrical impedance tomography (EIT) has gained attention, as it provides real-time ventilation distribution analysis. In addition, lung pulsatility images can be obtained through this technique using electrocardiogram gating to filter out ventilation. In this case report, the reduced EIT pulsatility corresponded to the perfusion defect found on the CT scan, information that was obtained at the bedside without radiation or contrast exposure. [ABSTRACT FROM AUTHOR]

Patients with coronavirus disease 2019 (COVID-19) pneumonia are prone to intrapulmonary thrombosis owing to excessive inflammation and platelet activation. Myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with ring sideroblasts and thrombocytosis (RS-T) is a rare disease in MDS/MPN overlap entities. Patients with MDS/MPN RS-T are known to be at a high risk of thrombosis, and platelet count control with drug therapy does not necessarily reduce this risk. Here, we report the autopsy case of an older male patient with MDS/MPN RS-T and severe COVID-19 pneumonia complicated by intrapulmonary thrombosis. His platelet count had been controlled in the normal range after treatment with hydroxyurea and 5-aza-2'-deoxycytidine. On admission day, he rapidly developed respiratory distress and tested positive on a polymerase chain reaction test for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). After admission, he received supplemental oxygen and was administered remdesivir and dexamethasone; however, his respiratory and circulatory status did not improve. The patient died on day 4 of illness. Autopsy findings revealed massive thrombi within blood vessels and diffuse alveolar damage in both lungs, which were determined to be the cause of death. In patients with MDS/MPN RS-T combined with COVID-19 pneumonia, clinicians may need to pay close attention to the risk of pulmonary thrombosis., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Harada et al.)

Recent reports have shown that thrombotic complications occur rather frequently among patients who have the novel coronavirus disease 2019 (COVID-19). Clinical presentation of pulmonary thrombosis is usually in association with moderate to severe symptoms of COVID-19 and manifests with worsening symptoms and features of atypical pneumonia on imaging. We report an unusual case of extensive pulmonary thrombosis in a young otherwise healthy adult without any typical COVID-19 symptom nor features of atypical pneumonia on imaging.

Metformin is widely used as first-line medication for type 2 diabetes (T2D), the main disease comorbid with kidney disease, cardiovascular diseases (CVDs), and retinopathy. Platelets are crucial in platelet-dependent arterial thrombosis, which causes CVDs and cerebrovascular diseases. Research indicates that metformin may improve these diseases; metformin reportedly reduced platelet activation in rats. However, no reports have included human platelets. We investigated the mechanisms underlying metformin’s effects on platelet activation by using human platelets and evaluated its in vivo effectiveness in experimental mice. Metformin inhibited platelet aggregation stimulated by collagen but not by arachidonic acid, U46619, or thrombin. Metformin suppressed ATP release, [Ca2+]i mobilization, and P-selectin expression, as well as phospholipase C (PLC)γ2/protein kinase C (PKC), p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation. Metformin did not affect vasodilator-stimulated phosphoprotein (VASP) phosphorylation. In the animal studies, metformin reduced acute pulmonary thromboembolism mortality without increasing bleeding times. These results provide insights into the role and mechanisms of metformin in human platelet activation. Metformin decreased platelet activation by interfering with the PLCγ2/PKC, PI3K/Akt/GSK3β, and p38 MAPK pathways through a VASP-independent mechanism. Metformin demonstrates promise as a new class of antiplatelet agent that can inhibit platelet activation.

Background: Coronavirus disease of 2019 (COVID-19) is associated with a prothrombotic state and a high incidence of thrombotic event(s) (TE).Objectives: To study platelet reactivity in hospitalized COVID-19 patients and determine a possible association with the clinical outcomes thrombosis and all-cause mortality.Methods: Seventy nine hospitalized COVID-19 patients were enrolled in this retrospective cohort study and provided blood samples in which platelet reactivity in response to stimulation with ADP and TRAP-6 was determined using flow cytometry. Clinical outcomes included thrombotic events, and all-cause mortality.Results: The incidence of TE in this study was 28% and all-cause mortality 16%. Patients that developed a TE were younger than patients that did not develop a TE [median age of 55 vs. 70 years; adjusted odds ratio (AOR) = 0.96 per 1 year of age, 95% confidence interval (CI) 0.92–1.00; p = 0.041]. Furthermore, patients using preexisting thromboprophylaxis were less likely to develop a thrombotic complication than patients that were not (18 vs. 54%; AOR = 0.19, 95% CI 0.04–0.84; p = 0.029). Conversely, having asthma strongly increased the risk on TE development (AOR = 6.2, 95% CI 1.15–33.7; p = 0.034). No significant differences in baseline P-selectin expression or platelet reactivity were observed between the COVID-19 positive patients (n = 79) and COVID-19 negative hospitalized control patients (n = 21), nor between COVID-19 positive survivors or non-survivors. However, patients showed decreased platelet reactivity in response to TRAP-6 following TE development.Conclusion: We observed an association between the use of preexisting thromboprophylaxis and a decreased risk of TE during COVID-19. This suggests that these therapies are beneficial for coping with COVID-19 associated hypercoagulability. This highlights the importance of patient therapy adherence. We observed lowered platelet reactivity after the development of TE, which might be attributed to platelet desensitization during thromboinflammation.

Background: The incidence of pulmonary thromboembolism is high in SARS-CoV-2 patients admitted to the Intensive Care. Elevated biomarkers of coagulation (fibrinogen and D-dimer) and inflammation (c-reactive protein (CRP) and ferritin) are associated with poor outcome in SARS-CoV-2. Whether the time-course of fibrinogen, D-dimer, CRP and ferritin is associated with the occurrence of pulmonary thromboembolism in SARS-CoV-2 patients is unknown. We hypothesise that patients on mechanical ventilation with SARS-CoV-2 infection and clinical pulmonary thromboembolism have lower concentrations of fibrinogen and higher D-dimer, CRP, and ferritin concentrations over time compared to patients without a clinical pulmonary thromboembolism. Methods: In a prospective study, fibrinogen, D-dimer, CRP and ferritin were measured daily. Clinical suspected pulmonary thromboembolism was either confirmed or excluded based on computed tomography pulmonary angiography (CTPA) or by transthoracic ultrasound (TTU) (i.e., right-sided cardiac thrombus). In addition, patients who received therapy with recombinant tissue plasminogen activator were included when clinical instability in suspected pulmonary thromboembolism did not allow CTPA. Serial data were analysed using a mixed-effects linear regression model, and models were adjusted for known risk factors (age, sex, APACHE-II score, body mass index), biomarkers of coagulation and inflammation, and anticoagulants. Results: Thirty-one patients were considered to suffer from pulmonary thromboembolism ((positive CTPA (n = 27), TTU positive (n = 1), therapy with recombinant tissue plasminogen activator (n = 3)), and eight patients with negative CTPA were included. After adjustment for known risk factors and anticoagulants, patients with, compared to those without, clinical pulmonary thromboembolism had lower average fibrinogen concentration of − 0.9 g/L (95% CI: − 1.6 – − 0.1) and lower average ferritin concentration of − 1045 μg/L (95% CI: − 1983 – − 106) over time. D-dimer and CRP average concentration did not significantly differ, 561 μg/L (− 6212–7334) and 27 mg/L (− 32–86) respectively. Ferritin lost statistical significance, both in sensitivity analysis and after adjustment for fibrinogen and D-dimer. Conclusion: Lower average concentrations of fibrinogen over time were associated with the presence of clinical pulmonary thromboembolism in patients at the Intensive Care, whereas D-dimer, CRP and ferritin were not. Lower concentrations over time may indicate the consumption of fibrinogen related to thrombus formation in the pulmonary vessels. [ABSTRACT FROM AUTHOR]

Disordered coagulation, endothelial dysfunction, dehydration and immobility contribute to a substantially elevated risk of deep venous thrombosis, pulmonary embolism (PE) and systemic thrombosis in coronavirus disease 2019 (Covid-19). We evaluated the prevalence of pulmonary thrombosis and reported RV (right ventricular) dilatation/dysfunction associated with Covid-19 in a tertiary referral Covid-19 centre. Of 370 patients, positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 39 patients (mean age 62.3 ± 15 years, 56% male) underwent computed tomography pulmonary angiography (CTPA), due to increasing oxygen requirements or refractory hypoxia, not improving on oxygen, very elevated D-dimer or tachycardia disproportionate to clinical condition. Thrombosis in the pulmonary vasculature was found in 18 (46.2%) patients. However, pulmonary thrombosis did not predict survival (46.2% survivors vs 41.7% non-survivors, p = 0.796), but RV dilatation was less frequent among survivors (11.5% survivors vs 58.3% non-survivors, p = 0.002). Over the following month, we observed four Covid-19 patients, who were admitted with high and intermediate-high risk PE, and we treated them with UACTD (ultrasound-assisted catheter-directed thrombolysis), and four further patients, who were admitted with PE up to 4 weeks after recovery from Covid-19. Finally, we observed a case of RV dysfunction and pre-capillary pulmonary hypertension, associated with Covid-19 extensive lung disease. We demonstrated that pulmonary thrombosis is common in association with Covid-19. Also, the thrombotic risk in the pulmonary vasculature is present before and during hospital admission, and continues at least up to four weeks after discharge, and we present UACTD for high and intermediate-high risk PE management in Covid-19 patients. [ABSTRACT FROM AUTHOR]

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Background: Pulmonary involvement in COVID-19 is characterized pathologically by diffuse alveolar damage (DAD) and thrombosis, leading to the clinical picture of Acute Respiratory Distress Syndrome. The direct action of SARSCoV-2 in lung cells and the dysregulated immuno-coagulative pathways activated in ARDS influence pulmonary involvement in severe COVID, that might be modulated by disease duration and individual factors. In this study we assessed the proportions of different lung pathology patterns in severe COVID-19 patients along the disease evolution and individual characteristics. Methods: We analysed lung tissue from 41 COVID-19 patients that died in the period March-June 2020 and were submitted to a minimally invasive autopsy. Eight pulmonary regions were sampled. Pulmonary pathologists analysed the H&E stained slides, performing semiquantitative scores on the following parameters: exudative, intermediate or advanced DAD, bronchopneumonia, alveolar haemorrhage, infarct (%), arteriolar (number) or capillary thrombosis (yes/no). Histopathological data were correlated with demographic-clinical variables and periods of symptoms-hospital stay. Results: Patient's age varied from 22 to 88 years (18f/23 m), with hospital admission varying from 0 to 40 days. All patients had different proportions of DAD in their biopsies. Ninety percent of the patients presented pulmonary microthrombosis. The proportion of exudative DAD was higher in the period 0-8 days of hospital admission till death, whereas advanced DAD was higher after 17 days of hospital admission. In the group of patients that died within eight days of hospital admission, elderly patients had less proportion of the exudative pattern and increased proportions of the intermediate patterns. Obese patients had lower proportion of advanced DAD pattern in their biopsies, and lower than patients with overweight. Clustering analysis showed that patterns of vascular lesions (microthrombosis, infarction) clustered together, but not the other patterns. The vascular pattern was not influenced by demographic or clinical parameters, including time of disease progression. Conclusion: Patients with severe COVID-19 present different proportions of DAD patterns over time, with advanced DAD being more prevalent after 17 days, which seems to be influenced by age and weight. Vascular involvement is present in a large proportion of patients, occurs early in disease progression, and does not change over time. [ABSTRACT FROM AUTHOR]

A middle-aged woman with unrepaired congenital heart disease died suddenly from asphyxia due to hemoptysis. Postmortem computed tomography, autopsy, and histological examinations revealed the presence of an aneurysm and dissection of the right main pulmonary artery with intraluminal thrombus. The observed congenital heart diseases included patent ductus arteriosus, ventricular septal defect, and right-sided aorta. These anomalies predisposed her to left to right shunt, resulting not only in pulmonary artery hypertension and right ventricular hypertrophy, but also pulmonary artery aneurysm and dissection. Histological examinations confirmed the presence of medial degeneration and elastic fiber disruption, as well as muscular hyperplasia of the vasa vasorum and follicular infiltration of the lymphocytes and plasma cells in the main pulmonary artery. These changes may have contributed to the pathogenesis of the aneurysm and dissection through the induction of arterial wall fragility. Histology demonstrated, in addition to findings of pulmonary hypertension, such as plexiform lesions, medial-intimal hyperplasia, and veno-occlusive lesion, unique findings related to multiple dissections of the intra-pulmonary elastic arteries, which may have caused the lethal hemoptysis.

Objective: We set out to analyze the incidence and predictive factors of pulmonary embolism (PE) in hospitalized patients with Covid-19.Methods: We prospectively collected data from all consecutive patients with laboratory-confirmed Covid-19 admitted to the Hospital de la Santa Creu i Sant Pau, a university hospital in Barcelona, between March 9 and April 15, 2020. Patients with suspected PE, according to standardized guidelines, underwent CT pulmonary angiography (CTPA).Results: A total of 1,275 patients with Covid-19 were admitted to hospital. CTPA was performed on 76 inpatients, and a diagnosis of PE was made in 32 (2.6% [95%CI 1.7–3.5%]). Patients with PE were older, and they exhibited lower PaO2:FiO2 ratios and higher levels of D-dimer and C-reactive protein (CRP). They more often required admission to ICU and mechanical ventilation, and they often had longer hospital stays, although in-hospital mortality was no greater than in patients without PE. High CRP and D-dimer levels at admission (≥150 mg/L and ≥1,000 ng/ml, respectively) and a peak D-dimer ≥6,000 ng/ml during hospital stay were independent factors associated with PE. Prophylactic low molecular weight heparin did not appear to prevent PE. Increased CRP levels correlated with increased D-dimer levels and both correlated with a lower PaO2:FiO2.Conclusions: The 2.6% incidence of PE in Covid-19 hospitalized patients is clearly high. Higher doses of thromboprophylaxis may be required to prevent PE, particularly in patients at increased risk, such as those with high levels of CRP and D-dimer at admission. These findings should be validated in future studies.

Platelets play a critical role in arterial thrombosis. Rutaecarpine (RUT) was purified from Tetradium ruticarpum, a well-known Chinese medicine. This study examined the relative activity of RUT with NF-κB inhibitors in human platelets. BAY11-7082 (an inhibitor of IκB kinase [IKK]), Ro106-9920 (an inhibitor of proteasomes), and RUT concentration-dependently (1–6 μM) inhibited platelet aggregation and P-selectin expression. RUT was found to have a similar effect to that of BAY11-7082; however, it exhibits more effectiveness than Ro106-9920. RUT suppresses the NF-κB pathway as it inhibits IKK, IκBα, and p65 phosphorylation and reverses IκBα degradation in activated platelets. This study also investigated the role of p38 and NF-κB in cell signaling events and found that SB203580 (an inhibitor of p38) markedly reduced p38, IKK, and p65 phosphorylation and reversed IκBα degradation as well as p65 activation in a confocal microscope, whereas BAY11-7082 had no effects in p38 phosphorylation. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay shows that RUT and BAY11-7082 did not exhibit free radical scavenging activity. In the in vivo study, compared with BAY11-7082, RUT more effectively reduced mortality in adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism without affecting the bleeding time. In conclusion, a distinctive pathway of p38-mediated NF-κB activation may involve RUT-mediated antiplatelet activation, and RUT could act as a strong prophylactic or therapeutic drug for cardiovascular diseases.

Epidemiological evidence shows that smoking causes a thrombophilic milieu that may play a role in the pathophysiology of chronic obstructive pulmonary disease (COPD) as well as pulmonary thromboembolism. The increased nicotine level induces a prothrombotic status and abnormal blood coagulation in smokers. Since several anticoagulants increase bleeding risk, alternative therapies need to be identified to protect against thrombosis without affecting hemostasis. Astragalin is a flavonoid present in persimmon leaves and green tea seeds and exhibits diverse activities of antioxidant and anti-inflammation. The current study investigated that astragalin attenuated smoking-induced pulmonary thrombosis and alveolar inflammation. In addition, it was explored that molecular links between thrombosis and inflammation entailed protease-activated receptor (PAR) activation and oxidative stress-responsive mitogen-activated protein kinase (MAPK)-signaling. BALB/c mice were orally administrated with 10–20 mg/kg astragalin and exposed to cigarette smoke for 8 weeks. For the in vitro study, 10 U/mL thrombin was added to alveolar epithelial A549 cells in the presence of 1–20 µM astragalin. The cigarette smoking-induced the expression of PAR-1 and PAR-2 in lung tissues, which was attenuated by the administration of ≥10 mg/kg astragalin. The oral supplementation of ≥10 mg/kg astragalin to cigarette smoke-challenged mice attenuated the protein induction of urokinase plasminogen activator, plasminogen activator inhibitor-1and tissue factor, and instead enhanced the induction of tissue plasminogen activator in lung tissues. The astragalin treatment alleviated cigarette smoke-induced lung emphysema and pulmonary thrombosis. Astragalin caused lymphocytosis and neutrophilia in bronchoalveolar lavage fluid due to cigarette smoke but curtailed infiltration of neutrophils and macrophages in airways. Furthermore, this compound retarded thrombin-induced activation of PAR proteins and expression of inflammatory mediators in alveolar cells. Treating astragalin interrupted PAR proteins-activated reactive oxygen species production and MAPK signaling leading to alveolar inflammation. Accordingly, astragalin may interrupt the smoking-induced oxidative stress–MAPK signaling–inflammation axis via disconnection between alveolar PAR activation and pulmonary thromboembolism.

Since Virchow's autopsy studies in the mid-1800s, it has generally been believed that pulmonary embolism (PE) originated from the embolization of fibrin fragments from a deep venous thrombosis (DVT). However, a DVT is often not found in patients with PE (up to 50% of cases). Could fibrin form in the pulmonary vessels without coming from the periphery? In this review, the authors will try to support the hypothesis that a pulmonary thrombosis (PT) may develop. They will do so through different clinical models related to some pathological conditions such as pneumonia, chronic obstructive pulmonary disease (COPD), and asthma, all of which show a close relationship between local inflammation and activation of blood coagulation, two defensive systems that may lead to fibrin deposition in the lungs, thus recognizing the possibility that PT may be a newly recognized entity. An increased risk for PE has been demonstrated in these conditions. Sickle cell disease and assisted reproductive technologies are other very different conditions in which an increased risk for PE has been found. Gaucher's disease is a rare hereditary condition in which the hemostatic system could have a role in the pathogenesis of pulmonary hypertension, which complicates the course of the disease. In particular, the increased risk for PT, common to all these conditions, deserves attention when a patient presents with sudden dyspnea, an unexpected COPD exacerbation, or severe sudden asthmatic dyspnea. As a consequence, prediction scores for venous thromboembolism could be revised. [ABSTRACT FROM AUTHOR]

• Among TXA recipients, 12.5% developed VTE with 5.6% mortality. • TXA was not clearly identified as an independent risk factor for VTE, but the risk of VTE among trauma patients receiving TXA remains high (12.5%). • Based on the high rates of DVT in those receiving TXA, we recommend early initiation of DVT prophylaxis in this high-risk group. The early use of tranexamic acid (TXA) has demonstrated benefit among some trauma patients in hemorrhagic shock. The association between TXA administration and thromboembolic events (including deep vein thrombosis (DVT), pulmonary embolism (PE) and pulmonary thrombosis (PT)) remains unclear. We aimed to characterize the risk of venous thromboembolism (VTE) subtypes among trauma patients receiving TXA and to determine whether TXA is associated with VTE risk and mortality. We analyzed a prospective, observational, multicenter cohort data from the Consortium of Leaders in the Study of Traumatic Thromboembolism (CLOTT) study group. The study was conducted across 17 US level I trauma centers between January 1, 2018, and December 31,2020. We studied trauma patients ages 18–40 years, admitted for at least 48 h with a minimum of 1 VTE risk factor and followed until hospital discharge or 30 days. We compared TXA recipients to non-recipients for VTE and mortality using inverse probability weighted Cox models. The primary outcome was the presence of documented venous thromboembolism (VTE). The secondary outcome was mortality. VTE was defined as DVT, PE, or PT. Among the 7,331 trauma patients analyzed, 466 (6.4%) received TXA. Patients in the TXA group were more severely injured than patients in the non-TXA group (ISS 16+: 69.1% vs. 48.5%, p < 0.001) and a higher percentage underwent a major surgical procedure (85.8% vs. 73.6%, p < 0.001). Among TXA recipients, 12.5% developed VTE (1.3% PT, 2.4% PE, 8.8% DVT) with 5.6% mortality. In the non-TXA group, 4.6% developed VTE (1.1% PT, 0.5% PE, 3.0% DVT) with 1.7% mortality. In analyses adjusting for patient demographic and clinical characteristics, TXA administration was not significantly associated with VTE (aHR 1.00, 95%CI: 0.69–1.46, p = 0.99) but was significantly associated with increased mortality (aHR 2.01, 95%CI: 1.46–2.77, p < 0.001). TXA was not clearly identified as an independent risk factor for VTE in adjusted analyses, but the risk of VTE among trauma patients receiving TXA remains high (12.5%). This supports the judicious use of TXA in resuscitation, with consideration of early initiation of DVT prophylaxis in this high-risk group. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Chronic thromboembolic pulmonary hypertension is one of the most prevalent forms of pulmonary hypertension and is a major complication of acute pulmonary embolism. One mainstay of chronic thromboembolic pulmonary hypertension treatment is lifelong anticoagulation. The recent advent of direct oral anticoagulants for acute pulmonary embolism treatment has provided a viable and effective alternative for treating this condition. However, little is known about the efficacy of this new class of drugs for treating chronic thromboembolic pulmonary hypertension. We aimed to evaluate the safety and efficacy of direct oral anticoagulants in the treatment of chronic thromboembolic pulmonary hypertension. METHODS: A cohort of chronic thromboembolic pulmonary hypertension patients who initiated treatment with direct oral anticoagulants between June 2015 and November 2016 were enrolled in this study. RESULTS: Sixteen patients used rivaroxaban, three used dabigatran and one used apixaban for a mean follow-up of 20.9 months. The mean age was 51 years, and eighteen patients were classified as functional class II/III. Eight patients underwent a pulmonary endarterectomy and exhibited clinical, hemodynamic and functional improvement and currently continue to use direct oral anticoagulants. No episode of venous thromboembolism recurrence was identified during the follow-up period, but there was one episode of major bleeding after a traumatic fall. CONCLUSIONS: Although direct oral anticoagulants appear to be a safe and effective alternative for treating chronic thromboembolic pulmonary hypertension, larger studies are needed to support their routine use.

Eisenmenger syndrome is a late complication of untreated congenital heart disease associated with left to right shunt, that can prompt in situ pulmonary thrombosis. Herein the case of a 41 year old man with suspected pulmonary embolism, where an atrial septal defect lead to Eisenmenger Syndrome, is presented. Only lung transplantation and surgical defect closure revealed to be the optimal treatment.

In this work, we examined the hemodynamic responses to Lachesis muta (South American bushmaster) venom in anesthetized male Wistar rats. Venom (1.5 mg/kg, i.v.) caused immediate hypotension that was followed by a gradual return towards baseline over 60 min; there were no significant changes in heart rate, ECG parameters and respiratory rate. A higher dose (3 mg/kg, i.v.) caused sustained hypotension, variable bradycardia, respiratory depression and fluctuations in ECG; death occurred within 10–60 min. Venom injected intramuscularly (15 mg/kg) produced a smaller decrease in blood pressure that was more persistent than with 1.5 mg/kg (i.v.). Pre-treatment with atenolol (selective β 1 -adrenergic receptor antagonist) potentiated the response to venom (1.5 mg/kg, i.v.) and resulted in a hemodynamic profile similar to that seen with 3 mg/kg (i.v.). Macroscopically, systemic hemorrhage was seen only in the ileum, whereas histological analysis revealed extensive pulmonary hemorrhage; the heart, liver and kidney were generally unaffected. Intravascular pulmonary thrombosis occurred with venom given i.v. and i.m., but was less marked with the latter route. In rat isolated perfused hearts, venom caused a persistent decrease in left ventricular developed pressure but no change in heart rate, coronary flow or ECG; there was tissue necrosis and release of CK-MB that were abolished by pre-treating venom with the PLA 2 inhibitor p -bromophenacyl bromide. These results show that in rats L. muta venom causes hypotension, bradycardia and respiratory depression, depending on the dose and route of administration. The hemodynamic responses apparently do not involve direct cardiotoxicity and are modulated by the adrenergic system. [ABSTRACT FROM AUTHOR]

In this work, we examined some mechanisms involved in the hypotension caused by Lachesis muta (South American bushmaster) venom in anesthetized rats. Venom (1.5 mg/kg, i.v.) caused immediate hypotension that was maximal after 5 min and gradually returned to baseline over 60 min. Pretreatment of rats with the non-selective nitric oxide synthase (NOS) inhibitor N ω -nitro-L-arginine methyl ester (L-NAME) did not attenuate the early phase of venom-induced hypotension, but abolished the recovery phase and resulted in rapid death; a similar effect was observed with the soluble guanylate cyclase (sGC) inhibitor ODQ. In contrast, the hemodynamic responses to venom were not attenuated by the non-selective NOS inhibitor N G -monomethyl-L-arginine, the inducible NOS inhibitor aminoguanidine, the phosphodiesterase 5 inhibitor sildenafil, the adenylate cyclase (AC) inhibitor SQ-22.536, the non-selective muscarinic receptor antagonist atropine, the bradykinin B2 receptor antagonist HOE-140 and the non-selective cyclooxygenase inhibitor indomethacin. Preincubation of venom with the PLA 2 inhibitor p BPB had no effect on the immediate hypotension but tended to improve the recovery phase. Neither AEBSF (a serine proteinase inhibitor) nor EDTA (a metalloproteinase inhibitor) prevented the venom-induced hypotension, but AEBSF and not EDTA protected against the lethality of a high dose (3.0 mg/kg, i.v.). There were no marked changes in the ECG parameters with the various treatments, except with L-NAME and ODQ that increased the RR interval. Pulmonary thrombus formation was markedly enhanced by L-NAME and ODQ, and to a lesser extent by p BPB, especially in small vessels, whereas AEBSF and EDTA inhibited thrombus formation. Venom relaxed phenylephrine-precontracted thoracic aorta and pulmonary artery in vitro, with the latter being more sensitive. The relaxation was endothelium-dependent and was inhibited by ODQ but not by H-89, a protein kinase A (PKA) inhibitor. Together, these findings indicate involvement of the NO/sGC/cGMP, but not the AC/cAMP/PKA signaling pathway, in the hemodynamic responses to L. muta venom in rats. Muscarinic mechanisms, kinins and arachidonic acid metabolites are apparently not involved. [ABSTRACT FROM AUTHOR]

The current report describes the use of a molecular technique to identify immature Fascioloides magna. An 18-month-old Brangus heifer was found dead in the field without any prior clinical signs. The cause of death was exsanguination into the thoracic cavity associated with pulmonary embolization and infection by immature Fascioloides magna resulting in 2 large foci of pulmonary necrosis and focal arteriolar and lung rupture. The liver had a few random migratory tracts with typical iron and porphyrin fluke exhaust, but no identified fluke larvae. A single immature fluke was found in the lungs, and species level identification as F. magna was confirmed by DNA sequence analysis of the ribosomal internal transcribed spacer regions (ITS1 region, 5.8S rRNA gene, and ITS2) and of partial 28S rRNA gene sequence. This is one of only a few pulmonary fascioloidiasis cases associated with hemothorax in the veterinary literature. [ABSTRACT FROM AUTHOR]

To study bacterial co-infection following 1918 H1N1 influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by Streptococcus pneumoniae ( SP) 72 h later. Co-infected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in co-infected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed extensive expression of tissue factor ( F3) and prominent deposition of neutrophil elastase on endothelial and epithelial cells in co-infected mice. Lung sections of SP-positive 1918 autopsy cases showed extensive thrombi and prominent staining for F3 in alveolar macrophages, monocytes, neutrophils, endothelial and epithelial cells, in contrast to co-infection-positive 2009 pandemic H1N1 autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and SP co-infection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]