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1.
Int J Mol Sci ; 23(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35682700

RESUMO

Platelets play a variety of roles in vascular biology and are best recognized as primary hemostasis and thrombosis mediators. Platelets have a large number of receptors and secretory molecules that are required for platelet functionality. Upon activation, platelets release multiple substances that have the ability to influence both physiological and pathophysiological processes including inflammation, tissue regeneration and repair, cancer progression, and spreading. The involvement of platelets in the progression and seriousness of a variety of disorders other than thrombosis is still being discovered, especially in the areas of inflammation and the immunological response. This review represents an integrated summary of recent advances on the function of platelets in pathophysiology that connects hemostasis, inflammation, and immunological response in health and disease and suggests that antiplatelet treatment might be used for more than only thrombosis.


Assuntos
Hemostasia , Trombose , Plaquetas/fisiologia , Hemostasia/fisiologia , Humanos , Inflamação , Ativação Plaquetária , Testes de Função Plaquetária
2.
Zhonghua Gan Zang Bing Za Zhi ; 30(3): 285-289, 2022 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-35462484

RESUMO

Objective: To study the diagnostic value of immediate color Doppler ultrasonography on traumatic hepatic hemorrhage after tissue sampling with ultrasound-guided liver biopsy and the clinical effect of its-directed local compression hemostasis at puncture-site. Methods: 132 hospitalized patients with various liver diseases underwent ultrasound-guided hepatic puncture-biopsies, including 61 cases with diffuse parenchymal and 71 cases with focal liver lesions. Immediate postoperative color Doppler ultrasonography was performed following liver biopsy. Abnormal blood flow signal was observed at hepatic puncture biopsy site, and if there were hemorrhagic signals, ultrasound-directed local compression hemostasis was performed until the bleeding signal disappeared. F-test and Chi-square test were used for statistical analysis. Results: Immediate color Doppler ultrasonography showed traumatic hemorrhage in 36.1% (22/61) and 40.8% (29/71) cases of diffuse liver disease and focal liver disease group, respectively. All hemorrhagic signals were eventually disappeared after ultrasound-directed local compression hemostasis. The median hemostasis time was 2 min in both groups, and there was no statistically significant difference in bleeding rate and hemostasis time between the two groups (P>0.05). There were no serious complications and deaths. Conclusion: Traumatic hepatic hemorrhage along the needle puncture tract is a common accompanying condition during liver biopsy. Immediate postoperative color Doppler ultrasonography can trace bleeding signals in timely manner and direct effective compression hemostasis, so it should be used routinely to help avoid occurrence of severe hemorrhagic complications.


Assuntos
Hemostasia , Hepatopatias , Biópsia , Hemorragia/etiologia , Hemostasia/fisiologia , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Hepatopatias/patologia , Ultrassonografia , Ultrassonografia Doppler em Cores/efeitos adversos
3.
Clin Appl Thromb Hemost ; 28: 10760296211064898, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35043658

RESUMO

INTRODUCTION: The pathophysiology of pulmonary embolism (PE) represents complex, multifactorial processes involving blood cells, vascular endothelium, and the activation of inflammatory pathways. Platelet (P), endothelial (E), and leukocyte (L)-selectin molecules may play an important role in PE pathophysiology. We aimed to profile the biomarkers of inflammation, including selectins in PE patients, and compare them to healthy individuals. MATERIALS AND METHODS: 100 acute PE patients and 50 controls were included in this case control study. ELISA methods were used to quantify levels of selectins, inflammatory, and hemostatic biomarkers. RESULTS: In PE patients, levels of selectin molecules as compared to controls convey increased P-selectin levels (95 ng/mL vs 40 ng/mL, p < .0001) and decreased L-selectin levels (1468 ng/mL vs 1934 ng/mL, p < .0001). Significant correlations were found between selectins and Plasminogen Activating Inhibitor-1 (PAI-1), Tumor Necrosis Factor-a (TNFa), and D-dimer. Fold change between selectins and controls is compared to other biomarkers, illustrating degrees of change comparable to TNFa, alpha-2-antiplasmin, and microparticles. L-selectin levels are inversely associated with all-cause-mortality in PE patients, (p = .040). CONCLUSION: These studies suggest that various thrombo-inflammatory biomarkers are elevated in PE patients. Furthermore, L-selectin levels are inversely associated with mortality outcomes.


Assuntos
Hemostasia/fisiologia , Inflamação/sangue , Embolia Pulmonar/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Endotélio Vascular/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
4.
Adv Sci (Weinh) ; 9(7): e2103228, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35023301

RESUMO

Conventional antiplatelet agents indiscriminately inhibit both thrombosis and hemostasis, and the increased bleeding risk thus hampers their use at more aggressive dosages to achieve adequate effect. Blocking integrin αIIbß3 outside-in signaling by separating the ß3/Src interaction, yet to be proven in vivo, may nonetheless resolve this dilemma. Identification of a specific druggable target for this strategy remains a fundamental challenge as Src SH3 is known to be responsible for binding to not only integrin ß3 but also the proteins containing the PXXP motif. In vitro and in vivo mutational analyses show that the residues, especially E97, in the RT loop of Src SH3 are critical for interacting with ß3. DCDBS84, a small molecule resulting from structure-based virtual screening, is structurally validated to be directed toward the projected target. It specifically disrupts ß3/Src interaction without affecting canonical PXXP binding and thus inhibits the outside-in signaling-regulated platelet functions. Treatment of mice with DCDBS84 causes a profound inhibition of thrombosis, equivalent to that induced by extremely high doses of αIIbß3 antagonist, but does not compromise primary hemostasis. Specific targets are revealed for a preferential inhibition of thrombosis that may lead to new classes of potent antithrombotics without hemorrhagic side effects.


Assuntos
Plaquetas , Trombose , Animais , Plaquetas/metabolismo , Hemostasia/fisiologia , Integrina beta3/química , Integrina beta3/metabolismo , Camundongos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/química , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Trombose/metabolismo , Trombose/prevenção & controle
5.
Sci Transl Med ; 14(629): eabb8975, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-35080915

RESUMO

Treatment of bleeding disorders using transfusion of donor-derived platelets faces logistical challenges due to their limited availability, high risk of contamination, and short (5 to 7 days) shelf life. These challenges could be potentially addressed by designing platelet mimetics that emulate the adhesion, aggregation, and procoagulant functions of platelets. To this end, we created liposome-based platelet-mimicking procoagulant nanoparticles (PPNs) that can expose the phospholipid phosphatidylserine on their surface in response to plasmin. First, we tested PPNs in vitro using human plasma and demonstrated plasmin-triggered exposure of phosphatidylserine and the resultant assembly of coagulation factors on the PPN surface. We also showed that this phosphatidylserine exposed on the PPN surface could restore and enhance thrombin generation and fibrin formation in human plasma depleted of platelets. In human plasma and whole blood in vitro, PPNs improved fibrin stability and clot robustness in a fibrinolytic environment. We then tested PPNs in vivo in a mouse model of thrombocytopenia where treatment with PPNs reduced blood loss in a manner comparable to treatment with syngeneic platelets. Furthermore, in rat and mouse models of traumatic hemorrhage, treatment with PPNs substantially reduced bleeding and improved survival. No sign of systemic or off-target thrombotic risks was observed in the animal studies. These findings demonstrate the potential of PPNs as a platelet surrogate that should be further investigated for the management of bleeding.


Assuntos
Plaquetas , Nanopartículas , Animais , Hemorragia , Hemostasia/fisiologia , Camundongos , Modelos Animais , Ratos
6.
Circulation ; 145(3): 170-183, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34738828

RESUMO

BACKGROUND: Transcatheter aortic valve replacement is an established treatment option for patients with severe symptomatic aortic stenosis and is most commonly performed through the transfemoral access route. Percutaneous access site closure can be achieved using dedicated plug-based or suture-based vascular closure device (VCD) strategies, but randomized comparative studies are scarce. METHODS: The CHOICE-CLOSURE trial (Randomized Comparison of Catheter-based Strategies for Interventional Access Site Closure during Transfemoral Transcatheter Aortic Valve Implantation) is an investigator-initiated, multicenter study, in which patients undergoing transfemoral transcatheter aortic valve replacement were randomly assigned to vascular access site closure using either a pure plug-based technique (MANTA, Teleflex) with no additional VCDs or a primary suture-based technique (ProGlide, Abbott Vascular) potentially complemented by a small plug. The primary end point consisted of access site- or access-related major and minor vascular complications during index hospitalization, defined according to the Valve Academic Research Consortium-2 criteria. Secondary end points included the rate of access site- or access-related bleeding, VCD failure, and time to hemostasis. RESULTS: A total of 516 patients were included and randomly assigned. The mean age of the study population was 80.5±6.1 years, 55.4% were male, 7.6% of patients had peripheral vascular disease, and the mean Society of Thoracic Surgeons score was 4.1±2.9%. The primary end point occurred in 19.4% (50/258) of the pure plug-based group and 12.0% (31/258) of the primary suture-based group (relative risk, 1.61 [95% CI, 1.07-2.44], P=0.029). Access site- or access-related bleeding occurred in 11.6% versus 7.4% (relative risk, 1.58 [95%CI: 0.91-2.73], P=0.133) and device failure in 4.7% versus 5.4% (relative risk, 0.86, [95% CI, 0.40-1.82], P=0.841) in the respective groups. Time to hemostasis was significantly shorter in the pure plug-based group (80 [32-180] versus 240 [174-316] seconds, P<0.001). CONCLUSIONS: Among patients treated with transfemoral transcatheter aortic valve replacement, a pure plug-based vascular closure technique using the MANTA VCD is associated with a higher rate of access site- or access-related vascular complications but a shorter time to hemostasis compared with a primary suture-based technique using the ProGlide VCD. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04459208.


Assuntos
Estenose da Valva Aórtica/cirurgia , Doenças Vasculares Periféricas/cirurgia , Substituição da Valva Aórtica Transcateter , Dispositivos de Oclusão Vascular , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/cirurgia , Artéria Femoral/cirurgia , Hemorragia/etiologia , Hemostasia/fisiologia , Humanos , Masculino , Suturas/efeitos adversos , Substituição da Valva Aórtica Transcateter/efeitos adversos , Resultado do Tratamento , Dispositivos de Oclusão Vascular/efeitos adversos
7.
Cell Tissue Res ; 387(3): 391-398, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34014399

RESUMO

Endothelial cells form a monolayer, which lines blood vessels. They are crucially involved in maintaining blood fluidity and providing controlled vascular hemostasis at sites of injury. Thereby endothelial cells facilitate multiple mechanisms, including both procoagulant and anticoagulant, which must be kept in balance. Under physiological conditions, endothelial cells constitute a nonadhesive surface preventing activation of platelets and the coagulation cascade. Multiple fibrinolytic and antithrombotic properties act on their cell surface contributing to the maintenance of blood fluidity. These include platelet inhibition, the heparin-antithrombin III system, tissue factor pathway inhibition, thrombomodulin/protein C system, and fibrinolytic qualities. At sites of vascular damage, platelets react immediately by adhering to the exposed extracellular matrix, followed by platelet-platelet interactions to form a clot that effectively seals the injured vessel wall to prevent excessive blood loss. For solid thrombus formation, functional platelets are essential. In this process, endothelial cells serve as a support surface for formation of procoagulant complexes and clotting. This review gives an overview about the central role of the endothelium as a dynamic lining which controls the complex interplay of the coagulation system with the surrounding cells.


Assuntos
Células Endoteliais , Trombose , Plaquetas , Endotélio/fisiologia , Hemostasia/fisiologia , Humanos
8.
Drug Discov Today ; 27(1): 102-116, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34311113

RESUMO

Hemophilia A is an X-linked hereditary disorder that results from deficient coagulation factor VIII (FVIII) activity, leading to spontaneous bleeding episodes, particularly in joints and muscles. FVIII deficiency has been associated with altered bone remodeling, dysregulated macrophage polarization, and inflammatory processes that are associated with the neoformation of abnormal blood vessels. Treatment based on FVIII replacement can lead to the development of inhibitors that render FVIII concentrate infusion ineffective. In this context, hemophilia has entered a new therapeutic era with the development of new drugs, such as emicizumab, that seek to restore the hemostatic balance by bypassing pathologically acquired antibodies. We discuss the potential extrahemostatic functions of FVIII that may be crucial for defining future therapies in hemophilia.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Remodelação Óssea/efeitos dos fármacos , Fator VIII , Imunidade/efeitos dos fármacos , Descoberta de Drogas/métodos , Fator VIII/imunologia , Fator VIII/metabolismo , Hemofilia A/tratamento farmacológico , Hemofilia A/metabolismo , Hemostasia/efeitos dos fármacos , Hemostasia/fisiologia , Humanos
9.
Platelets ; 33(3): 416-424, 2022 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-34115551

RESUMO

Platelet function assays and global haemostasis assays are essential in diagnosing bleeding tendencies, with light transmission aggregometry (LTA) as golden standard. The Multiple Electrode Aggregation (Multiplate), platelet function assay (PFA) and rotational thromboelastometry (ROTEM) are mostly used as whole-blood screening tests. Currently, patients have to travel to specialized laboratories to undergo these tests, since specific expertise is required. Pre-analytical variables, like storage time and temperature during transport, are still considered to be the most vulnerable part of the process and may lead to discrepancies in the test results. We aim to give a first impression on the stability of blood samples from healthy volunteers during storage and investigate the effect of storage time (1, 3, 6 and 24 hours) and temperature (4°C, room temperature and 37°C) on the Multiplate, PFA, ROTEM and LTA test results. Our data indicated that, for the PFA, whole blood can be stored for 3 hours at room temperature. Whole blood used for the Multiplate and ROTEM can be stored for 6 hours of storage. For LTA, PRP and whole blood were stable up to 3 hours at 4°C or room temperature and 6 hours at room temperature, respectively.


Assuntos
Bioensaio/métodos , Hemostasia/fisiologia , Armazenamento e Recuperação da Informação/métodos , Testes de Função Plaquetária/métodos , Adulto , Feminino , Humanos , Masculino , Temperatura , Adulto Jovem
10.
Shock ; 57(1): 1-6, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34172612

RESUMO

BACKGROUND: The pathomechanisms of hypoxemia and treatment strategies for type H and type L acute respiratory distress syndrome (ARDS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) have not been elucidated. MAIN TEXT: SARS-CoV-2 mainly targets the lungs and blood, leading to ARDS, and systemic thrombosis or bleeding. Angiotensin II-induced coagulopathy, SARS-CoV-2-induced hyperfibrin(ogen)olysis, and pulmonary and/or disseminated intravascular coagulation due to immunothrombosis contribute to COVID-19-associated coagulopathy. Type H ARDS is associated with hypoxemia due to diffuse alveolar damage-induced high right-to-left shunts. Immunothrombosis occurs at the site of infection due to innate immune inflammatory and coagulofibrinolytic responses to SARS-CoV-2, resulting in microvascular occlusion with hypoperfusion of the lungs. Lung immunothrombosis in type L ARDS results from neutrophil extracellular traps containing platelets and fibrin in the lung microvasculature, leading to hypoxemia due to impaired blood flow and a high ventilation/perfusion (VA/Q) ratio. COVID-19-associated ARDS is more vascular centric than the other types of ARDS. D-dimer levels have been monitored for the progression of microvascular thrombosis in COVID-19 patients. Early anticoagulation therapy in critical patients with high D-dimer levels may improve prognosis, including the prevention and/or alleviation of ARDS. CONCLUSIONS: Right-to-left shunts and high VA/Q ratios caused by lung microvascular thrombosis contribute to hypoxemia in type H and L ARDS, respectively. D-dimer monitoring-based anticoagulation therapy may prevent the progression to and/or worsening of ARDS in COVID-19 patients.


Assuntos
COVID-19/fisiopatologia , Hemostasia/fisiologia , Hipóxia/fisiopatologia , Síndrome do Desconforto Respiratório/fisiopatologia , Trombose/fisiopatologia , Anticoagulantes/uso terapêutico , Biomarcadores/sangue , Plaquetas/metabolismo , COVID-19/tratamento farmacológico , Armadilhas Extracelulares/metabolismo , Fibrina/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinólise , Humanos , Pulmão/irrigação sanguínea , Microvasos/fisiopatologia , Fenótipo , Síndrome do Desconforto Respiratório/tratamento farmacológico , SARS-CoV-2 , Trombose/tratamento farmacológico
11.
PLoS One ; 16(12): e0261429, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34910783

RESUMO

BACKGROUND: Coagulation system is heavily involved into the process of infective endocarditis (IE) vegetation formation and can facilitate further embolization. In this study we aimed to assess the coagulation and platelet state in IE implementing a wide range of standard and global laboratory assays. We also aim to determine whether prothrombotic genetic polymorphisms play any role in embolization and mortality in IE patients. METHODS: 37 patients with IE were enrolled into the study. Coagulation was assessed using standard coagulation assays (activated partial thromboplastin time (APTT), prothrombin, fibrinogen, D-dimer concentrations) and integral assays (thromboelastography (TEG) and thrombodynamics (TD)). Platelet functional activity was estimated by flow cytometry. Single nuclear polymorphisms of coagulation system genes were studied. RESULTS: Fibrinogen concentration and fibrinogen-dependent parameters of TEG and TD were increased in patients indicating systemic inflammation. In majority of patients clot growth rate in thrombodynamics was significantly shifted towards hypercoagulation in consistency with D-dimers elevation. However, in some patients prothrombin, thromboelastography and thrombodynamics were shifted towards hypocoagulation. Resting platelets were characterized by glycoprotein IIb-IIIa activation and degranulation. In patients with fatal IE, we observed a significant decrease in fibrinogen and thrombodynamics. In patients with embolism, we observed a significant decrease in the TEG R parameter. No association of embolism or mortality with genetic polymorphisms was found in our cohort. CONCLUSIONS: Our findings suggest that coagulation in patients with infective endocarditis is characterized by general hypercoagulability and platelet pre-activation. Some patients, however, have hypocoagulant coagulation profile, which presumably can indicate progressing of hypercoagulation into consumption coagulopathy.


Assuntos
Endocardite/patologia , Ativação Plaquetária/genética , Ativação Plaquetária/fisiologia , Trombofilia/genética , Trombofilia/patologia , Adulto , Idoso , Plaquetas/fisiologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Hemostasia/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial/métodos , Polimorfismo de Nucleotídeo Único/genética , Protrombina/análise , Tromboelastografia/métodos
12.
Heart Surg Forum ; 24(5): E833-E841, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34623250

RESUMO

BACKGROUND: Chitin is a nitrogen-containing polysaccharide that can promote wound healing and stop bleeding. This paper investigates the effects of the addition of a chitin hemostatic patch on the time to arterial hemostasis, bleeding time, and reduction of the risk of bleeding and hematoma in patients undergoing cardiac catheterization. METHODS: Databases were searched for published clinical studies. The subjects were patients who received cardiac catheterization and had a chitin hemostatic patch added at the site of arterial puncture, while the control group received routine hemostatic treatment. The research quality was evaluated using the Cochrane risk-of-bias tool, version 2.0, and the meta-analysis was carried out using RevMan software. RESULTS: After searching literature databases, five randomized controlled trials were retrieved and included in the meta-analysis. The results showed that adding a chitin hemostatic patch could shorten the time to arterial hemostasis in patients, who received cardiac catheterization (Std. Mean Difference, -0.58; P < .001). In the subgroup analysis, the grouped effect of the chitin hemostatic patch on the bleeding time showed that the bleeding time was not significantly shortened after adding a chitin hemostatic patch in patients in the experimental group (RR, 0.78). At the same time, this measure did not significantly reduce the risk of arterial bleeding (RR, 0.49) or hematoma (RR, 0.73). CONCLUSIONS: The results of the meta-analysis showed that adding a chitin hemostatic patch at the site of arterial puncture in patients undergoing cardiac catheterization significantly reduced the time to hemostasis, but did not significantly reduce the incidence of bleeding and hematoma.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Cateterismo Cardíaco/efeitos adversos , Quitosana/administração & dosagem , Hemostasia/fisiologia , Hemorragia Pós-Operatória/prevenção & controle , Hemostasia/efeitos dos fármacos , Hemostáticos/administração & dosagem , Humanos , Hemorragia Pós-Operatória/sangue
13.
Br J Radiol ; 94(1128): 20210353, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34538063

RESUMO

OBJECTIVE: To evaluate the hemostatic efficacy of re-radiofrequency ablation (re-RFA) for hepatic tract bleeding after ultrasound-guided RFA of hepatic tumors. METHODS: A total of 4679 percutaneous ultrasound-guided RFA procedures were performed for hepatic tumors at Samsung Medical Center between January 2012 and December 2020. We identified patients who had hepatic tract bleeding after RFA by reviewing radiologic reports and ultrasound images and investigated the measures taken to control the bleeding and their outcomes. We also identified patients who had a significant peritoneal hematoma on immediate post-RFA CT or underwent transarterial embolization to control hepatic bleeding after RFA of hepatic tumors. RESULTS: In total, 91 patients with tract bleeding after RFA were identified. As initial measures to control the bleeding, external compression, re-RFA, and observation were performed in 71 (78%), 17 (19%), and 3 (3%) patients, respectively. Hemostasis using re-RFA was attempted to control tract bleeding in 40 patients as an initial measure or an additional measure after other initial efforts. In all 40 patients, the bleeding stopped after re-RFA on Doppler ultrasound, and there was no active bleeding on the immediate follow-up CT. During the study period, in the years when re-RFA was performed frequently, the number of transarterial embolizations to control tract bleeding and significant peritoneal hematoma formation tended to be low. CONCLUSION: Hemostasis using re-RFA of the needle tract is effective in controlling tract bleeding after ultrasound-guided RFA of hepatic tumors. ADVANCES IN KNOWLEDGE: Re-RFA is a simple, safe, and effective method to control tract bleeding.


Assuntos
Hemorragia/etiologia , Hemorragia/cirurgia , Hemostasia/fisiologia , Neoplasias Hepáticas/cirurgia , Ablação por Radiofrequência/efeitos adversos , Ablação por Radiofrequência/métodos , Ultrassonografia de Intervenção/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hemorragia/fisiopatologia , Humanos , Fígado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Retratamento , Estudos Retrospectivos , Resultado do Tratamento
14.
Int J Mol Sci ; 22(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34502548

RESUMO

Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A2 and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood.


Assuntos
Transtornos da Coagulação Sanguínea/fisiopatologia , Venenos de Crotalídeos/metabolismo , Hemorragia/fisiopatologia , Hemostasia/fisiologia , Trombose/fisiopatologia , Animais , Antivenenos/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Venenos de Crotalídeos/antagonistas & inibidores , Humanos
15.
Cells ; 10(9)2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34572000

RESUMO

The plasma glycoprotein von Willebrand factor (VWF) is exclusively synthesized in endothelial cells (ECs) and megakaryocytes, the precursor cells of platelets. Its primary function lies in hemostasis. However, VWF is much more than just a "fishing hook" for platelets and a transporter for coagulation factor VIII. VWF is a true multitasker when it comes to its many roles in cellular processes. In ECs, VWF coordinates the formation of Weibel-Palade bodies and guides several cargo proteins to these storage organelles, which control the release of hemostatic, inflammatory and angiogenic factors. Leukocytes employ VWF to assist their rolling on, adhesion to and passage through the endothelium. Vascular smooth muscle cell proliferation is supported by VWF, and it regulates angiogenesis. The life cycle of platelets is accompanied by VWF from their budding from megakaryocytes to adhesion, activation and aggregation until the end in apoptosis. Some tumor cells acquire the ability to produce VWF to promote metastasis and hide in a shell of VWF and platelets, and even the maturation of osteoclasts is regulated by VWF. This review summarizes the current knowledge on VWF's versatile cellular functions and the resulting pathophysiological consequences of their dysregulation.


Assuntos
Fator de von Willebrand/metabolismo , Animais , Apoptose/fisiologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Hemostasia/fisiologia , Humanos , Leucócitos/metabolismo , Miócitos de Músculo Liso/metabolismo , Corpos de Weibel-Palade/metabolismo
16.
Hepatol Commun ; 5(12): 1987-2000, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34558850

RESUMO

In patients with cirrhosis, particularly those with hepatocellular carcinoma (HCC), hypercoagulability may be associated with purported increased risks of portal vein thrombosis and cirrhosis progression. In this study, we extensively investigated hemostatic alterations potentially responsible for the thrombotic tendency in HCC, and evaluated whether such alterations were predictive of hepatic decompensation. Patients with cirrhosis at all stages were prospectively recruited and underwent an extensive hemostatic assessment, including all procoagulant factors and inhibitors, thrombin generation with and without thrombomodulin (TG), profibrinolytic and antifibrinolytic factors, and plasmin-antiplasmin complex. In study part 1 (case control), we compared alterations of coagulation and fibrinolysis in patients with cirrhosis with versus without HCC. In study part 2 (prospective), the subgroup of patients with decompensated cirrhosis was followed for development of further decompensation, and predictors of outcome were assessed by multivariate analysis. One-hundred patients were recruited (50 each with and without HCC). Severity of cirrhosis was comparable between groups. Median HCC volume was 9 cm3 (range: 5-16). Compared with controls, patients with HCC demonstrated a significantly more prothrombotic hemostatic profile due to increased TG and reduced activation of fibrinolysis, independent of cirrhosis stage. During a median follow-up of 175 days, 20 patients with decompensated cirrhosis developed further episodes of decompensation that were predicted by low FVII and high plasminogen activator inhibitor-1 levels, independent of Model for End-Stage Liver Disease score. Conclusion: Patients with cirrhosis with HCC have profound hyper-coagulable changes that can account for their increased thrombotic tendency. In contrast, hypercoagulability in patients with decompensated cirrhosis is more likely a consequence of chronic liver disease rather than a driver for cirrhosis progression.


Assuntos
Carcinoma Hepatocelular/sangue , Hemostáticos/sangue , Cirrose Hepática/sangue , Neoplasias Hepáticas/sangue , Trombofilia/sangue , Idoso , Coagulação Sanguínea/fisiologia , Carcinoma Hepatocelular/complicações , Estudos de Casos e Controles , Progressão da Doença , Feminino , Fibrinólise/fisiologia , Hemostasia/fisiologia , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/complicações , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gravidade do Paciente , Veia Porta/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Trombofilia/etiologia , Trombose Venosa/sangue , Trombose Venosa/etiologia
17.
Commun Biol ; 4(1): 1090, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531522

RESUMO

Primary hemostasis results in a platelet-rich thrombus that has long been assumed to form a solid plug. Unexpectedly, our 3-dimensional (3D) electron microscopy of mouse jugular vein puncture wounds revealed that the resulting thrombi were structured about localized, nucleated platelet aggregates, pedestals and columns, that produced a vaulted thrombus capped by extravascular platelet adherence. Pedestal and column surfaces were lined by procoagulant platelets. Furthermore, early steps in thrombus assembly were sensitive to P2Y12 inhibition and late steps to thrombin inhibition. Based on these results, we propose a Cap and Build, puncture wound paradigm that should have translational implications for bleeding control and hemostasis.


Assuntos
Plaquetas/fisiologia , Hemostasia/fisiologia , Punções/efeitos adversos , Trombose/fisiopatologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Trombose/etiologia
18.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445665

RESUMO

Mast cell disease is an epigenetically and genetically determined disease entity with very diverse clinical manifestations in potentially every system and tissue due to inap pro priate release of variable subsets of mast cell mediators together with accumulation of either morphologically normal or altered mast cells. Easy bruising, excessive bleeding, and aberrancies of erythropoiesis can frequently be observed in patients with mast cell disease. A thorough history, including a family history, will guide the appropriate work-up, and laboratory evaluations may provide clues to diagnosis. In recent years, our understanding of the involvement of coagulation and anticoagulant pathways, the fibrinolytic system, and erythropoiesis in the pathophysiology of mast cell disease has increased considerably. This review summarizes current knowledge of the impact of the disturbed hemostatic and erythropoietic balance in patients with mast cell disease and describes options of treatment.


Assuntos
Eritropoese/fisiologia , Hemostasia/fisiologia , Mastocitose/sangue , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Eritropoese/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Fibrinolíticos/farmacologia , Hemostasia/efeitos dos fármacos , Heparina/farmacologia , Humanos , Mastocitose/imunologia , Mastocitose/fisiopatologia
19.
Anesthesiology ; 135(4): 673-685, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34370811

RESUMO

BACKGROUND: Life-threatening bleeding requires prompt reversal of the anticoagulant effects of factor Xa inhibitors. This study investigated the effectiveness of four-factor prothrombin complex concentrate in treating trauma-related hemorrhage with rivaroxaban-anticoagulation in a pig polytrauma model. This study also tested the hypothesis that the combined use of a low dose of prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate could improve its subtherapeutic effects. METHODS: Trauma (blunt liver injury and bilateral femur fractures) was induced in 48 anesthetized male pigs after 30 min of rivaroxaban infusion (1 mg/kg). Animals in the first part of the study received prothrombin complex concentrate (12.5, 25, and 50 U/kg). In the second part, animals were treated with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid or plus tranexamic acid and fibrinogen concentrate. The primary endpoint was total blood loss postinjury. The secondary endpoints (panel of coagulation parameters and thrombin generation) were monitored for 240 min posttrauma or until death. RESULTS: The first part of the study showed that blood loss was significantly lower in the 25 U/kg prothrombin complex concentrate (1,541 ± 269 ml) and 50 U/kg prothrombin complex concentrate (1,464 ± 108 ml) compared with control (3,313 ± 634 ml), and 12.5 U/kg prothrombin complex concentrate (2,671 ± 334 ml, all P < 0.0001). In the second part of the study, blood loss was significantly less in the 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate (1,836 ± 556 ml, P < 0.001) compared with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid (2,910 ± 856 ml), and there were no early deaths in the 25 U/kg prothrombin complex concentrate, 50 U/kg prothrombin complex concentrate, and 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate groups. Histopathologic analyses postmortem showed no adverse events. CONCLUSIONS: Prothrombin complex concentrate effectively reduced blood loss, restored hemostasis, and balanced thrombin generation. A multimodal hemostatic approach using tranexamic acid plus fibrinogen concentrate enhanced the effect of low doses of prothrombin complex concentrate, potentially reducing the prothrombin complex concentrate doses required for effective bleeding control.


Assuntos
Anticoagulantes/toxicidade , Modelos Animais de Doenças , Inibidores do Fator Xa/toxicidade , Hemostasia/efeitos dos fármacos , Traumatismo Múltiplo/tratamento farmacológico , Rivaroxabana/toxicidade , Animais , Fatores de Coagulação Sanguínea/farmacologia , Fatores de Coagulação Sanguínea/uso terapêutico , Terapia Combinada/métodos , Relação Dose-Resposta a Droga , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemorragia/fisiopatologia , Hemostasia/fisiologia , Masculino , Traumatismo Múltiplo/induzido quimicamente , Traumatismo Múltiplo/fisiopatologia , Suínos
20.
J Am Coll Cardiol ; 78(6): 625-631, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34353538

RESUMO

Hemostasis and thrombosis are believed to be so intricately linked that any strategies that reduce thrombosis will have an inevitable impact on hemostasis. Consequently, bleeding is viewed as an unavoidable side effect of anticoagulant therapy. Emerging evidence suggests that factor XI is important for thrombosis but has a minor role in hemostasis. This information raises the possibility that anticoagulants that target factor XI will be safer than currently available agents. The authors provide a visual representation of the coagulation pathways that distinguishes between the steps involved in thrombosis and hemostasis to explain why factor XI inhibitors may serve as hemostasis-sparing anticoagulants. A safer class of anticoagulants would provide opportunities for treatment of a wider range of patients, including those at high risk for bleeding. Ongoing clinical studies will determine the extent to which factor XI inhibitors attenuate thrombosis without disruption of hemostasis.


Assuntos
Inibidores do Fator Xa/farmacologia , Hemostasia , Trombose , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Hemostasia/efeitos dos fármacos , Hemostasia/fisiologia , Humanos , Trombose/sangue , Trombose/tratamento farmacológico
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