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1.
Thromb Res ; 213: 179-194, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35397313

RESUMO

Platelet-leukocyte crosstalk is commonly manifested by reciprocal links between thrombosis and inflammation. Platelet thrombus acts as a reactive matrix that recruits leukocytes to the injury site where their massive accumulation, activation and migration promote thrombotic events while triggering inflammatory responses. As a life-threatening condition with the associations between inflammation and thrombosis, COVID-19 presents diffuse alveolar damage due to exaggerated macrophage activity and cytokine storms. These events, together with direct intracellular virus invasion lead to pulmonary vascular endothelialitis, cell membranes disruption, severe endothelial injury, and thrombosis. The developing pre-alveolar thrombus provides a hyper-reactive milieu that recruits circulating leukocytes to the injury site where their activation contributes to thrombus stabilization and thrombosis propagation, primarily through the formation of Neutrophil extracellular trap (NET). NET fragments can also circulate and deposit in further distance where they may disseminate intravascular thrombosis in severe cases of disease. Thrombi may also facilitate leukocytes migration into alveoli where their accumulation and activation exacerbate cytokine storms and tissue damage, further complicating the disease. Based on these mechanisms, whether an effective anti-inflammatory protocol can prevent thrombotic events, or on the other hand; efficient antiplatelet or anticoagulant regimens may be associated with reduced cytokine storms and tissue damage, is now of interests for several ongoing researches. Thus shedding more light on platelet-leukocyte crosstalk, the review presented here discusses the detailed mechanisms by which platelets may contribute to the pathogenesis of COVID-19, especially in severe cases where their interaction with leukocytes can intensify both inflammatory state and thrombosis in a reciprocal manner.


Assuntos
COVID-19 , Trombose , Plaquetas/metabolismo , COVID-19/complicações , Síndrome da Liberação de Citocina , Humanos , Inflamação/metabolismo , Leucócitos/metabolismo , Prognóstico , Trombose/patologia
2.
Int J Mol Sci ; 23(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35409226

RESUMO

There is accumulating evidence that platelets play roles beyond their traditional functions in thrombosis and hemostasis, e.g., in inflammatory processes, infection and cancer, and that they interact, stimulate and regulate cells of the innate immune system such as neutrophils, monocytes and macrophages. In this review, we will focus on platelet activation in hemostatic and inflammatory processes, as well as platelet interactions with neutrophils and monocytes/macrophages. We take a closer look at the contributions of major platelet receptors GPIb, αIIbß3, TLT-1, CLEC-2 and Toll-like receptors (TLRs) as well as secretions from platelet granules on platelet-neutrophil aggregate and neutrophil extracellular trap (NET) formation in atherosclerosis, transfusion-related acute lung injury (TRALI) and COVID-19. Further, we will address platelet-monocyte and macrophage interactions during cancer metastasis, infection, sepsis and platelet clearance.


Assuntos
COVID-19 , Trombose , Plaquetas/patologia , Hemostasia , Humanos , Imunidade Inata , Inflamação/patologia , Neutrófilos/patologia , Ativação Plaquetária , Trombose/patologia
3.
Sci Rep ; 12(1): 5725, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35388064

RESUMO

Transarterial chemoembolization (TACE) combined with apatinib has been used for advanced hepatocellular carcinoma (HCC), and the efficacy is good. The study was conducted to compare the efficacy and safety of drug-eluting bead TACE plus apatinib (D-TACE-A) with conventional TACE plus apatinib (C-TACE-A) in the treatment of HCC with portal vein tumor thrombus (PVTT). A total of 130 continuous patients who received D-TACE-A or C-TACE-A were included in the study from January 2017 to June 2020. Propensity score matching (PSM) was used to reduce potential selection bias. Before PSM, the median overall survival (mOS) (14 months) and median progression-free survival (mPFS) (7 months) in the C-TACE-A group were longer than the mOS (9 months; P = 0.001) and mPFS (4 months; P = 0.001) in the D-TACE-A group. After PSM, the mOS (14 months vs 9 months; P = 0.039) and mPFS (7 months vs 5 months; P = 0.009) in the C-TACE-A group were longer than those in the D-TACE-A group. In the multivariate regression analysis, C-TACE-A reduced the mortality rate and tumor progression rate compared with D-TACE-A. For the subgroup analysis, patients with VP1-2, without extrahepatic metastases, and with multiple TACE sessions who received C-TACE-A had a lower death risk and tumor progression risk than patients who received D-TACE-A. Before PSM, there was no statistically significant difference in any grade or grade III/IV adverse events (all P > 0.05). C-TACE-A could prolong mOS and mPFS in patients with PVTT, especially for patients with VP1-2 stage PVTT, no extrahepatic tumor metastases, and multiple TACE sessions.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Trombose , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/efeitos adversos , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/terapia , Veia Porta/patologia , Piridinas , Estudos Retrospectivos , Trombose/etiologia , Trombose/patologia , Trombose/terapia , Resultado do Tratamento
4.
Front Immunol ; 13: 861245, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35359975

RESUMO

Pregnancy can be defined a vascular event upon endocrine control. In the human hemo-chorial placentation the chorionic villi penetrate the wall of the uterine spiral arteries, to provide increasing amounts of nutrients and oxygen for optimal fetal growth. In any physiological pregnancy the natural maternal response is of a Th1 inflammatory type, aimed at avoiding blood loss through the arteriolar wall openings. The control of the vascular function, during gestation as in any other condition, is achieved through the action of two main types of prostanoids: prostaglandin E2 and thromboxane on the one hand (for vasoconstriction and coagulation), prostacyclin on the other (for vasodilation and blood fluidification). The control of the maternal immune response is upon the responsibility of the fetus itself. Indeed, the chorionic villi are able to counteract the natural maternal response, thus changing the inflammatory Th1 type into the anti-inflammatory Th2. Clinical and experimental research in the past half century address to inflammation as the leading cause of abortion, pregnancy loss, premature delivery and related pulmonary, cerebral, intestinal fetal syndromes. Increased level of Interleukin 6, Interleukin 1-beta, Tumor Necrosis Factor-alfa, Interferon-gamma, are some among the well-known markers of gestational inflammation. On the other side, COVID-19 pneumonia is a result of extensive inflammation induced by viral replication within the cells of the respiratory tract. As it may happen in the uterine arteries in the absence of an effective fetal control, viral pneumonia triggers pulmonary vascular coagulation. The cytokines involved in the process are the same as those in gestational inflammation. As the fetus breathes throughout the placenta, fetal death from placental thrombosis is similar to adult death from pulmonary thrombosis. Preventing and counteracting inflammation is mandatory in both conditions. The most relevant literature dealing with the above-mentioned concepts is reviewed in the present article.


Assuntos
Aborto Espontâneo , COVID-19 , Trombose , Aborto Espontâneo/patologia , Adulto , Citocinas , Feminino , Humanos , Inflamação/patologia , Placenta/patologia , Gravidez , Trombose/patologia
5.
BMC Neurol ; 22(1): 130, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35382802

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) affects the occurrence and prognosis of acute ischemic stroke (AIS). However, the impact of diabetes on thrombus characteristics is unclear. The relationship between the composition and ultrastructure of clots and DM with admission hyperglycemia was investigated. METHODS: Consecutive patients with AIS who underwent endovascular thrombus retrieval between June 2017 and May 2021 were recruited. The thrombus composition and ultrastructure were evaluated using Martius scarlet blue stain and scanning electron microscopy. Clot perviousness was evaluated via thrombus attenuation increase on computed tomography angiography (CTA) versus non-contrast CT. Patients with admission hyperglycemia DM (ahDM) and those without DM (nonDM) were compared in terms of thrombus composition, ultrastructure, and perviousness. RESULTS: On admission, higher NIHSS scores (17 vs. 12, respectively, p = 0.015) was evident in ahDM patients. After the 90-day follow-up, the rates of excellent outcomes (mRS 0-1) were lower in patients with ahDM (16.6%, p = 0.038), but functional independence (mRS 0-2) and handicapped (mRS 3-5) were comparable between patients with ahDM and nonDM. The outcome of mortality was higher in patients with ahDM (33.3%, p = 0.046) than in nonDM patients. Clots in patients with ahDM had more fibrin (39.4% vs. 25.0%, respectively, p = 0.007), fewer erythrocyte components (21.2% vs. 41.5%, respectively, p = 0.043), equivalent platelet fraction (27.7% vs. 24.6%, respectively, p = 0.587), and higher WBC counts (4.6% vs. 3.3%, respectively, p = 0.004) than in nonDM patients. The percentage of polyhedral erythrocytes in thrombi was significantly higher in ahDM patients than in nonDM patients (68.9% vs. 45.6%, respectively, p = 0.007). The proportion of pervious clots was higher in patients nonDM than in patients with ahDM (82.61% vs. 40%, respectively, p = 0.026). CONCLUSION: Patients with ahDM presented with greater stroke severity on admission and poorer functional outcomes after 3 months. Clots in patients with ahDM had more fibrin, leucocytes, and fewer erythrocyte components than in patients nonDM. The content of polyhedral erythrocytes and impervious clots proportion were significantly higher in thrombi of patients with AIS and ahDM. Further research is required to validate these findings.


Assuntos
Isquemia Encefálica , Diabetes Mellitus Tipo 2 , Hiperglicemia , AVC Isquêmico , Acidente Vascular Cerebral , Trombose , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Diabetes Mellitus Tipo 2/complicações , Humanos , Hiperglicemia/complicações , Acidente Vascular Cerebral/etiologia , Trombectomia/métodos , Trombose/complicações , Trombose/patologia
6.
Front Immunol ; 13: 834562, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35251025

RESUMO

Thrombus components are dynamically influenced by local blood flow and blood immune cells. After a large-vessel occlusion stroke, changes in the cerebral thrombus are unclear. Here we assessed a total of 206 cerebral thrombi from patients with ischemic stroke undergoing endovascular thrombectomy. The thrombi were categorized by time to reperfusion of <4 h (T4), 4-8 h (T4-8), and >8 h (T8). The cellular compositions in thrombus were analyzed, and relevant clinical features were compared. Both white blood cells and neutrophils were increased and then decreased in thrombus with time to reperfusion, which were positively correlated with those in peripheral blood. The neutrophil extracellular trap (NET) content in thrombus was correlated with the degree of neurological impairment of patients. Moreover, with prolonged time to reperfusion, the patients showed a trend of better collateral grade, which was associated with a lower NET content in the thrombus. In conclusion, the present results reveal the relationship between time-related endovascular immune response and clinical symptoms post-stroke from the perspective of thrombus and peripheral blood. The time-related pathological changes of cerebral thrombus may not be the direct cause for the difficulty in thrombolysis and thrombectomy. A low NET content in thrombi indicates excellent collateral flow, which suggests that treatments targeting NETs in thrombi might be beneficial for early neurological protection.


Assuntos
Trombose Intracraniana , AVC Isquêmico , Acidente Vascular Cerebral , Trombose , Humanos , Trombose Intracraniana/etiologia , Trombose Intracraniana/patologia , Leucócitos/patologia , Acidente Vascular Cerebral/patologia , Trombectomia/métodos , Trombose/patologia
7.
Sci Rep ; 12(1): 5012, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35322079

RESUMO

The lymphatic vasculature is critical for lung function, but defects in lymphatic function in the pathogenesis of lung disease is understudied. In mice, lymphatic dysfunction alone is sufficient to cause lung injury that resembles human emphysema. Whether lymphatic function is disrupted in cigarette smoke (CS)-induced emphysema is unknown. In this study, we investigated the effect of CS on lung lymphatic function. Analysis of human lung tissue revealed significant lung lymphatic thrombosis in patients with emphysema compared to control smokers that increased with disease severity. In a mouse model, CS exposure led to lung lymphatic thrombosis, decreased lymphatic drainage, and impaired leukocyte trafficking that all preceded the development of emphysema. Proteomic analysis demonstrated an increased abundance of coagulation factors in the lymph draining from the lungs of CS-exposed mice compared to control mice. In addition, in vitro assays demonstrated a direct effect of CS on lymphatic endothelial cell integrity. These data show that CS exposure results in lung lymphatic dysfunction and a shift in thoracic lymph towards a prothrombic state. Furthermore, our data suggest that lymphatic dysfunction is due to effects of CS on the lymphatic vasculature that precede emphysema. These studies demonstrate a novel component of CS-induced lung injury that occurs early in the pathogenesis of emphysema.


Assuntos
Enfisema , Lesão Pulmonar , Enfisema Pulmonar , Fumaça , Trombose , Poluição por Fumaça de Tabaco , Animais , Enfisema/patologia , Humanos , Pulmão/patologia , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteômica , Enfisema Pulmonar/patologia , Fumaça/efeitos adversos , Lesão por Inalação de Fumaça , Trombose/patologia , Tabaco/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos
8.
J Am Heart Assoc ; 11(6): e023274, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35229617

RESUMO

Background Inflammation of the perivascular adipose tissue (PvAT) may be related to atherosclerosis; however, the association of polarized macrophages in the pericoronary PvAT with measurements of atherosclerosis components in humans has not been fully investigated. Methods and Results Coronary arteries were dissected with surrounding PvAT. We evaluated the percentage of arterial obstruction, intima-media thickness, fibrous cap thickness, plaque components, and the number of vasa vasorum. The number of proinflammatory (M1) and anti-inflammatory (M2) macrophages in the periplaque and control PvAT were evaluated using immunohistochemistry. Regression models adjusted for sociodemographic and clinical variables were used. In 319 segments from 82 individuals, we found a correlation of the M1/M2 macrophage density ratio with an increase in arterial obstruction (P=0.02) and lipid content (P=0.01), and a decrease in smooth muscle cells (P=0.02). M1 and the ratio of M1/M2 macrophages were associated with an increased risk of thrombosis (P=0.03). In plaques with thrombosis, M1 macrophages were correlated with a decrease in fibrous cap thickness (P=0.006), an increase in lipid content (P=0.008), and the number of vasa vasorum in the adventitia layer (P=0.001). M2 macrophages were correlated with increased arterial obstruction (P=0.01), calcification (P=0.02), necrosis (P=0.03) only in plaques without thrombosis, and decrease of the number of vasa vasorum in plaques with thrombosis (P=0.003). Conclusions M1 macrophages in the periplaque PvAT were associated with a higher risk of coronary thrombosis and were correlated with histological components of plaque progression and destabilization. M2 macrophages were correlated with plaque size, calcification, necrotic content, and a decrease in the number of vasa vasorum in the adventitia layer.


Assuntos
Aterosclerose , Calcinose , Doença da Artéria Coronariana , Placa Aterosclerótica , Trombose , Tecido Adiposo/patologia , Aterosclerose/patologia , Calcinose/patologia , Espessura Intima-Media Carotídea , Doença da Artéria Coronariana/patologia , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Humanos , Lipídeos , Macrófagos/patologia , Placa Aterosclerótica/patologia , Trombose/patologia
9.
Oxid Med Cell Longev ; 2022: 4845264, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35281464

RESUMO

Background: The continuous development of endovascular treatment technology provides more opportunities for the histological study of thrombus. According to Trial of Org 10 172 in Acute Stroke Treatment (TOAST), clinicians take different strategies in anticoagulant or antiplatelet therapy. There are some patients still suffering from recurrent stroke while they took anticoagulant or antiplatelet drugs regularly for secondary prevention. In view of that, we found that histological analysis of thrombus can provide guidance for secondary prevention. Aim: Exploring the histological characteristics differences between large atherosclerotic and cardiogenic embolic thrombosis in order to guide clinical secondary prevention of the two stroke subtypes. Methods: A total of 54 patients with acute ischemic stroke were collected from December 2019 to April 2021. Identify stroke subtypes according to TOAST classification. Stain thrombus specimens with hematoxylin-eosin staining, and perform statistical analysis on the components (red blood cells and fibrin/platelets) of thrombus. Results: In cardiogenic thrombi, the composition of RBCs was dominant (51.38 ± 18.463%) compared to that of fibrin/platelets (48.62 ± 18.463%). Similarly, among the thrombi of large artery atherosclerotic, RBCs (50.40 ± 20.100%) compared to fibrin/platelets (49.60 ± 20.100%). There was no statistical difference in RBCs or fibrin/platelet composition of both cardiogenic and atherosclerotic thrombi (P = 0.89). Conclusions: The histologic composition of thrombi in cardiogenic and atherosclerotic had no statistical difference. These thrombi are all mixed thrombus, which are rich in RBCs, fibrinogen, and platelets. Anticoagulation combined with antiplatelet may be a more effective secondary prevention strategy.


Assuntos
Aterosclerose/patologia , Trombose/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Curr Opin Organ Transplant ; 27(2): 144-147, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35143434

RESUMO

PURPOSE OF REVIEW: Portomesenteric thrombosis (PMT) is a serious condition encountered mainly in cirrhotic patients awaiting liver transplantation. More recently, this potentially fatal complication has been described after bariatric surgery and inflammatory bowel disease. Several consensus guidelines have been published over the past few years and this mini review was conducted to discuss updated nontransplant treatment options based on currently available evidence. RECENT FINDINGS: Anticoagulation is the mainstay of treatment for PMT involving <50% of the main portal vein. Transjugular intrahepatic portosystemic shunt are usually preserved for patients with more extensive disease or those with clinically significant portal hypertension that are treatment refractory. SUMMARY: The extent of PMT, response to therapy, and complications related with PMT are the determinants of therapy.


Assuntos
Hipertensão Portal , Transplante de Fígado , Derivação Portossistêmica Transjugular Intra-Hepática , Trombose , Humanos , Hipertensão Portal/etiologia , Hipertensão Portal/cirurgia , Cirrose Hepática/complicações , Transplante de Fígado/efeitos adversos , Veia Porta/diagnóstico por imagem , Veia Porta/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Trombose/complicações , Trombose/patologia , Resultado do Tratamento
12.
Int J Legal Med ; 136(3): 705-711, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35147733

RESUMO

The timing of umbilical cord and placental thrombosis in the third trimester intrauterine fetal death (TT-IUFD) may be fundamental for medico-legal purposes, when it undergoes medical litigation due to the absence of risk factors. Authors apply to human TT-IUFD cases a protocol, which includes histochemistry and immunohistochemistry (IHC) for the assessment of thrombi's chronology. A total of 35 thrombi of umbilical cord and/or placenta were assessed: 2 in umbilical artery, 6 in umbilical vein, 15 in insertion, 10 in chorionic vessels, 1 in fetal renal vein, 1 in fetal brachiocephalic vein. Thrombi's features were evaluated with hematoxylin-eosin, Picro-Mallory, Von Kossa, Perls, and immunohistochemistry for CD15, CD68, CD31, CD61, and Smooth Muscle Actin. The estimation of the age of the thrombi was established by applying neutrophils/macrophages ratio taking into consideration, according to literature, the presence of hemosiderophagi, calcium deposition, and angiogenesis. To estimate an approximate age of fresh thrombi (< 1 day), a non-linear regression model was tested. Results were compared to maternal risk factors, fetal time of death estimated at autopsy, mechanism, and cause of death. Our study confirms that the maternal risk factors for fetal intrauterine death and the pathologies of the cord, followed by those of the placental parenchyma, are the conditions that are most frequently associated with the presence of thrombi. Results obtained with histological stainings document that the neutrophile/macrophage ratio is a useful tool for determining placental thrombi's age. Age estimation of thrombi on the first day is very challenging; therefore, the study presented suggests the N/M ratio as a parameter to be used, together with others, i.e., hemosiderophagi, calcium deposition, and angiogenesis, for thrombi's age determination, and hypothesizes that its usefulness regards particularly the first days when all other parameters are negative.


Assuntos
Cálcio , Trombose , Feminino , Morte Fetal/etiologia , Humanos , Placenta/patologia , Gravidez , Terceiro Trimestre da Gravidez , Natimorto , Trombose/patologia , Cordão Umbilical/irrigação sanguínea , Cordão Umbilical/patologia
13.
Int J Mol Sci ; 23(3)2022 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-35163333

RESUMO

Thrombosis is one of the major causes of mortality worldwide. Notably, it is not only implicated in cardiovascular diseases, such as myocardial infarction (MI), stroke, and pulmonary embolism (PE), but also in cancers. Understanding the cellular and molecular mechanisms involved in platelet thrombus formation is a major challenge for scientists today. For this purpose, new imaging technologies (such as confocal intravital microscopy, electron microscopy, holotomography, etc.) coupled with animal models of thrombosis (mouse, rat, rabbit, etc.) allow a better overview of this complex physiopathological process. Each of the cellular components is known to participate, including the subendothelial matrix, the endothelium, platelets, circulating cells, and, notably, neutrophils. Initially known as immune cells, neutrophils have been considered to be part of the landscape of thrombosis for more than a decade. They participate in this biological process through their expression of tissue factor (TF) and protein disulfide isomerase (PDI). Moreover, highly activated neutrophils are described as being able to release their DNA and thus form chromatin networks known as "neutrophil extracellular traps" (NETs). Initially, described as "dead sacrifices for a good cause" that prevent the dissemination of bacteria in the body, NETs have also been studied in several human pathologies, such as cardiovascular and respiratory diseases. Many articles suggest that they are involved in platelet thrombus formation and the activation of the coagulation cascade. This review presents the models of thrombosis in which neutrophils and NETs are involved and describes their mechanisms of action. We have even highlighted the medical diagnostic advances related to this research.


Assuntos
Armadilhas Extracelulares , Trombose , Animais , Plaquetas/metabolismo , Armadilhas Extracelulares/metabolismo , Camundongos , Modelos Animais , Neutrófilos/metabolismo , Coelhos , Ratos , Trombose/patologia
14.
Biomolecules ; 12(2)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35204706

RESUMO

Abdominal aortic aneurysm (AAA) is a potentially fatal vascular disease that involves complex multifactorial hemodynamic, thrombotic, inflammatory, and aortic wall remodeling processes. However, its mechanisms are incompletely understood. It has become increasingly clear that platelets are involved in pathological processes of vascular diseases beyond their role in hemostasis and thrombosis. Platelet activation with membrane receptors and secreted mediators promotes thrombus formation and the accumulation of inflammatory cells, which may play an important role in the development of AAA by destroying the structural integrity and stability of the vessel wall. Turbulent blood flow in aortic aneurysms promotes platelet activation and aggregation. Platelet count and heterogeneity are important predictive, diagnostic, and prognostic indicators of AAA. We summarize the relationship between platelet activation and AAA development and propose future research directions and possible clinical applications.


Assuntos
Aneurisma da Aorta Abdominal , Trombose , Aorta/patologia , Aneurisma da Aorta Abdominal/patologia , Plaquetas/patologia , Humanos , Ativação Plaquetária , Trombose/patologia
15.
Biomolecules ; 12(2)2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35204755

RESUMO

An intraluminal thrombus (ILT), which accumulates large numbers of neutrophils, plays a key role in abdominal aortic aneurysm (AAA) pathogenesis. This study aimed to compare levels of selected neutrophil inflammatory mediators in thick and thin ILT, plus adjacent AAA walls, to determine whether levels depend on ILT thickness. Neutrophil mediator levels were analysed by enzyme-linked immunosorbent assays in thick and thin segments of ILT, plus adjacent aneurysm wall sections, taken from one aneurysm sac each from 36 AAA patients. In aneurysmal walls covered by thick ILT, neutrophil elastase and TNF-a levels were significantly higher, as were concentrations of IL-6, in thick ILT compared to thin layers. Positive correlations of NGAL, MPO, and neutrophil elastase were observed between thick ILT and the adjacent wall and thin ILT and the adjacent wall, suggesting that these mediators probably infiltrate thick AAA compartments as well as thin. These observations might support the idea that neutrophil mediators and inflammatory cytokines differentially accumulate in AAA tissues according to ILT thickness. The increased levels of neutrophil mediators within thicker AAA segments might suggest the existence of an intensified proinflammatory state that in turn presumably might preferentially weaken the AAA wall at that region.


Assuntos
Aneurisma da Aorta Abdominal , Trombose , Aneurisma da Aorta Abdominal/patologia , Humanos , Neutrófilos/patologia , Trombose/patologia
16.
Hamostaseologie ; 42(1): 65-72, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35196732

RESUMO

Blood coagulation is essential to maintain the integrity of a closed circulatory system (hemostasis), but also contributes to thromboembolic occlusion of vessels (thrombosis). Thrombosis may cause deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral artery disease, and ischemic stroke, collectively the most common causes of death and disability in the developed world. Treatment for the prevention of thromboembolic diseases using anticoagulants such as heparin, coumarins, thrombin inhibitors, or antiplatelet drugs increase the risk of bleeding and are associated with an increase in potentially life-threatening hemorrhage, partially offsetting the benefits of reduced coagulation. Thus, drug development aiming at novel targets is needed to provide efficient and safe anticoagulation. Within the last decade, experimental and preclinical data have shown that some coagulation mechanisms principally differ in thrombosis and hemostasis. The plasma contact system protein factors XII and XI, high-molecular-weight kininogen, and plasma kallikrein specifically contribute to thrombosis, however, have minor, if any, role in hemostatic coagulation mechanisms. Inherited deficiency in contact system proteins is not associated with increased bleeding in humans and animal models. Therefore, targeting contact system proteins provides the exciting opportunity to interfere specifically with thromboembolic diseases without increasing the bleeding risk. Recent studies that investigated pharmacologic inhibition of contact system proteins have shown that this approach provides efficient and safe thrombo-protection that in contrast to classical anticoagulants is not associated with increased bleeding risk. This review summarizes therapeutic and conceptual developments for selective interference with pathological thrombus formation, while sparing physiologic hemostasis, that enables safe anticoagulation treatment.


Assuntos
Coagulação Sanguínea , Trombose , Animais , Anticoagulantes/efeitos adversos , Fator XII/metabolismo , Fator XII/farmacologia , Fator XII/uso terapêutico , Hemostasia , Humanos , Trombose/tratamento farmacológico , Trombose/patologia , Trombose/prevenção & controle
17.
Int J Mol Sci ; 23(4)2022 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-35216363

RESUMO

Polycythemia vera (PV) is a Ph-negative myeloproliferative neoplasm (MPN) which is characterized by erythrocytosis and a high incidence of thrombotic complications, including stroke. The study aimed to evaluate red blood cell (RBC) morphodynamic properties in PV patients and their possible association with stroke. We enrolled 48 patients with PV in this cross-sectional study, 13 of which have a history of ischemic stroke. The control group consisted of 90 healthy subjects. RBC deformability and aggregation analysis were performed using a laser-assisted optical rotational red cell analyzer. The following parameters were calculated: aggregation amplitude (Amp), RBC rouleaux formation time constant (Tf), time of formation of three-dimensional aggregates (Ts), aggregation index (AI), rate of complete disaggregation (y-dis), and the maximal elongation of RBC (EImax). Statistical analysis was performed with the R programming language. There were significant differences in RBCs morphodynamics features between patients with PV and the control group. Lower EImax (0.47 (0.44; 0.51) vs. 0.51 (0.47; 0.54), p < 0.001) and γ-dis (100 (100; 140) vs. 140 (106; 188) s-1, p < 0.001) along with higher amplitude (10.1 (8.6; 12.2) vs. 7.7 (6.6; 9.2), p < 0.001) was seen in patients with PV compared with control. A statistically significant difference between PV patients with and without stroke in aggregation amplitude was found (p = 0.03). A logistic regression model for stroke was built based on RBC morphodynamics which performed reasonably well (p = 0.01). RBC alterations may be associated with overt cerebrovascular disease in PV, suggesting a possible link between erythrocyte morphodynamics and increased risk of stroke.


Assuntos
Eritrócitos/patologia , Policitemia Vera/sangue , Policitemia Vera/patologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/patologia , Adulto , Estudos Transversais , Agregação Eritrocítica/fisiologia , Deformação Eritrocítica/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/patologia , Trombose/sangue , Trombose/patologia
18.
Cell Rep ; 38(7): 110391, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35172156

RESUMO

The metabolism of activated macrophages relies on aerobic glycolysis, while mitochondrial oxidation is disrupted. In lipopolysaccharide-activated macrophages, the citrate carrier (CIC) exports citrate from mitochondria to enhance glycolytic genes through histone acetylation. CIC inhibition or Slc25a1 knockdown reduces the occupancy of H3K9ac to hypoxia-inducible factor-1α (HIF-1α) binding sites in promoters of glycolytic genes to restrain glycolysis. HIF-1α also transcriptionally upregulates immune-responsive gene 1 for itaconate production, which is inhibited by CIC blocking. Isotopic tracing of [U-13C6] glucose shows that CIC blockage prevents citrate accumulation and itaconate production by reducing glycolytic flux and facilitating metabolic flux in the TCA cycle. Isotopic tracing of [U-13C5] glutamine reveals that CIC inhibition reduces succinate accumulation from glutaminolysis and the gamma-aminobutyric acid shunt by enhancing mitochondrial oxidation. By restraining glycolysis, CIC inhibition increases NAD+ content to ensure mitochondrial biogenesis for oxidative phosphorylation. Furthermore, blockage of citrate export reduces cerebral thrombosis by inactivation of peripheral macrophages.


Assuntos
Ciclo do Ácido Cítrico , Ácido Cítrico/metabolismo , Hidroliases/metabolismo , Acetilação , Animais , Transporte Biológico , Proteínas de Transporte/metabolismo , Histonas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , NAD/metabolismo , Biogênese de Organelas , Oxirredução , Succinatos , Ácido Succínico/metabolismo , Trombose/patologia , Trombose/prevenção & controle , Transcrição Genética , Peixe-Zebra
19.
Blood Adv ; 6(9): 2872-2883, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35086138

RESUMO

The structure of occlusive arterial thrombi is described herein. Macroscopic thrombi were made from whole blood in a collagen-coated, large-scale stenosis model with high shear flow similar to an atherosclerotic artery. The millimeter-sized thrombi were harvested for histology and scanning electron microscopy. Histological images showed 3 distinctive structures of the thrombus. (1) The upstream region showed string-like platelet aggregates growing out from the wall that protrude into the central lumen, with red blood cells trapped between the strings. The strings were >10 times as long as they were wide and reached out to join the strings from the opposite wall. (2) Near the apex, the platelet strings coalesced into a dense mass with microchannels that effectively occluded the lumen. (3) In the expansion region, the thrombus ended abruptly with an annulus of free blood in the flow-separation zone. Scanning electron microscopy showed dense clusters of spherical platelets upstream and downstream, with amorphous platelets in the occluded throat consistent with prior activation. The total clot is estimated to contain 1.23 billion platelets with pores 10 to 100 µm in diameter. The results revealed a complex structure of arterial thrombi that grow from their tips under high shear stress to bridge the 2.5-mm lumen quickly with von Willebrand factor platelet strings. The occlusion leaves many microchannels that allow for some flow through the bulk of the thrombus. This architecture can create occlusion or hemostasis rapidly with minimal material, yet can remain porous for potential delivery of lytic agents to the core of the thrombus.


Assuntos
Plaquetas , Trombose , Hemostasia , Humanos , Estresse Mecânico , Trombose/patologia , Fator de von Willebrand
20.
Clin Hemorheol Microcirc ; 81(1): 81-96, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35034895

RESUMO

BACKGROUND: Almost 95% of the venous valves are micron scale found in veins smaller than 300µm diameter. The fluid dynamics of blood flow and transport through these micro venous valves and their contribution to thrombosis is not yet well understood or characterized due to difficulty in making direct measurements in murine models. OBJECTIVE: The unique flow patterns that may arise in physiological and pathological non-actuating micro venous valves are predicted. METHODS: Computational fluid and transport simulations are used to model blood flow and oxygen gradients in a microfluidic vein. RESULTS: The model successfully recreates the typical non-Newtonian vortical flow within the valve cusps seen in preclinical experimental models and in clinic. The analysis further reveals variation in the vortex strengths due to temporal changes in blood flow. The cusp oxygen is typically low from the main lumen, and it is regulated by systemic venous flow. CONCLUSIONS: The analysis leads to a clinically-relevant hypothesis that micro venous valves may not create a hypoxic environment needed for endothelial inflammation, which is one of the main causes of thrombosis. However, incompetent micro venous valves are still locations for complex fluid dynamics of blood leading to low shear regions that may contribute to thrombosis through other pathways.


Assuntos
Trombose , Válvulas Venosas , Animais , Hemodinâmica , Humanos , Camundongos , Modelos Cardiovasculares , Oxigênio , Trombose/patologia , Veias
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