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1.
Clin Ter ; 172(4): 256-259, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34247205

RESUMO

Abstract: Phlegmasia Cerulea Dolens (PCD) is a severe and rare form of venous thrombosis of the lower extremities, caused by a subtotal or complete occlusion of venous outflow by a thrombus. PCD should be considered a real medical emergency; complications include necrosis and gangrene of the affected limb, amputation, massive pulmonary embolism and, in extreme cases, the death of the patient. Case Report. A 63-years-old man was admitted to the Emergency room with localized pain on the right calf, hyperthermia, cold sweating and vomiting episodes. Five days prior he developed flu-like symptoms, joint pain and cold sensation unresponsive to treatment. Ultrasound examination showed a deep venous thrombosis of the lower right limb with partial occlusion of common iliac and femoral veins. The patient was treated with low molecular weight heparin given twice daily. He began to develop severe hypotension and metabolic acidosis, with tachycardia and atrial fibrillation. Despite the treatment, there was no improvement and he developed severe sinus node dysfunction. He failed to respond to all resuscitative efforts and died. Family members complained Authority, assuming it was a medical error. The clinical-forensic investigation is essential to determine the causes and manner of death and to assess medical responsibility and liability.


Assuntos
Veia Femoral/fisiopatologia , Heparina/uso terapêutico , Veia Ilíaca/fisiopatologia , Responsabilidade Legal , Imperícia/legislação & jurisprudência , Trombose Venosa/tratamento farmacológico , Trombose Venosa/mortalidade , Trombose Venosa/fisiopatologia , Autopsia , Evolução Fatal , Humanos , Perna (Membro)/irrigação sanguínea , Masculino , Pessoa de Meia-Idade
3.
Lancet ; 397(10291): 2253-2263, 2021 06 12.
Artigo em Inglês | MEDLINE | ID: covidwho-1253771

RESUMO

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. FUNDING: Coalition COVID-19 Brazil, Bayer SA.


Assuntos
Anticoagulantes/uso terapêutico , COVID-19/sangue , COVID-19/tratamento farmacológico , Enoxaparina/uso terapêutico , Heparina/uso terapêutico , Rivaroxabana/efeitos adversos , Rivaroxabana/uso terapêutico , Adulto , Idoso , Coagulação Sanguínea/efeitos dos fármacos , Brasil/epidemiologia , Determinação de Ponto Final , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio , Hemorragia/induzido quimicamente , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , SARS-CoV-2 , Resultado do Tratamento
4.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: covidwho-1256613

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) global pandemic. The first step of viral infection is cell attachment, which is mediated by the binding of the SARS-CoV-2 receptor binding domain (RBD), part of the virus spike protein, to human angiotensin-converting enzyme 2 (ACE2). Therefore, drug repurposing to discover RBD-ACE2 binding inhibitors may provide a rapid and safe approach for COVID-19 therapy. Here, we describe the development of an in vitro RBD-ACE2 binding assay and its application to identify inhibitors of the interaction of the SARS-CoV-2 RBD to ACE2 by the high-throughput screening of two compound libraries (LOPAC®1280 and DiscoveryProbeTM). Three compounds, heparin sodium, aurintricarboxylic acid (ATA), and ellagic acid, were found to exert an effective binding inhibition, with IC50 values ranging from 0.6 to 5.5 µg/mL. A plaque reduction assay in Vero E6 cells infected with a SARS-CoV-2 surrogate virus confirmed the inhibition efficacy of heparin sodium and ATA. Molecular docking analysis located potential binding sites of these compounds in the RBD. In light of these findings, the screening system described herein can be applied to other drug libraries to discover potent SARS-CoV-2 inhibitors.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Descoberta de Drogas , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/genética , Animais , Antivirais/uso terapêutico , Ácido Aurintricarboxílico/farmacologia , Ácido Aurintricarboxílico/uso terapêutico , COVID-19/virologia , Chlorocebus aethiops , Ácido Elágico/farmacologia , Ácido Elágico/uso terapêutico , Heparina/farmacologia , Heparina/uso terapêutico , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Domínios Proteicos/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Internalização do Vírus/efeitos dos fármacos
5.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(5): 621-625, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34112306

RESUMO

Sepsis is caused by the imbalance of the host body's response to infection, which causes life-threatening organ dysfunction. Disorders of blood coagulation play a very important role in the development of sepsis. In sepsis, the body's coagulation system is activated, leading to hypercoagulability, while the anticoagulation mechanism is significantly inhibited, causing a large number of microthrombi to form, and disseminated intravascular coagulation (DIC) may occur. Although there are obvious controversies about the anticoagulation treatment of sepsis at home and abroad, we cannot deny the significance of anticoagulation treatment in sepsis. Only appropriate anticoagulation can effectively reduce the mortality in septic DIC, septic shock and high-risk population, and ultimately effectively reduce the occurrence of multiple organ dysfunction syndrome. The sepsis-induced coagulation dysfunction (SIC) score is currently used internationally to guide anticoagulation. SIC score is optimized based on the International Society on Thrombosis and Haemostasis (ISTH) overt DIC score and Sepsis-3, including platelet, international normalized ratio (INR) and sequential organ failure assessment (SOFA). The SIC score can sensitively monitor sepsis-induced coagulation dysfunction. When the SIC score is ≥ 4, it is the best timing to initiate anticoagulation therapy. At present, the internationally recommended anticoagulant drugs include antithrombin (AT), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), heparin, etc., while the domestically recommended anticoagulant drugs are only unfractionated heparin and low molecular weight heparin. Before using anticoagulant drugs, it is necessary to evaluate the possibility of bleeding and thrombosis in the patients. At the same time, it is necessary to pay attention to the patient's primary disease. Try to adopt the treatment strategy of transitioning from unfractionated heparin to low molecular weight heparin without obvious anticoagulation contraindications.


Assuntos
Coagulação Intravascular Disseminada , Sepse , Anticoagulantes/uso terapêutico , Coagulação Intravascular Disseminada/tratamento farmacológico , Heparina/uso terapêutico , Humanos , Insuficiência de Múltiplos Órgãos , Sepse/tratamento farmacológico
6.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072087

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) global pandemic. The first step of viral infection is cell attachment, which is mediated by the binding of the SARS-CoV-2 receptor binding domain (RBD), part of the virus spike protein, to human angiotensin-converting enzyme 2 (ACE2). Therefore, drug repurposing to discover RBD-ACE2 binding inhibitors may provide a rapid and safe approach for COVID-19 therapy. Here, we describe the development of an in vitro RBD-ACE2 binding assay and its application to identify inhibitors of the interaction of the SARS-CoV-2 RBD to ACE2 by the high-throughput screening of two compound libraries (LOPAC®1280 and DiscoveryProbeTM). Three compounds, heparin sodium, aurintricarboxylic acid (ATA), and ellagic acid, were found to exert an effective binding inhibition, with IC50 values ranging from 0.6 to 5.5 µg/mL. A plaque reduction assay in Vero E6 cells infected with a SARS-CoV-2 surrogate virus confirmed the inhibition efficacy of heparin sodium and ATA. Molecular docking analysis located potential binding sites of these compounds in the RBD. In light of these findings, the screening system described herein can be applied to other drug libraries to discover potent SARS-CoV-2 inhibitors.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Descoberta de Drogas , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/genética , Animais , Antivirais/uso terapêutico , Ácido Aurintricarboxílico/farmacologia , Ácido Aurintricarboxílico/uso terapêutico , COVID-19/virologia , Chlorocebus aethiops , Ácido Elágico/farmacologia , Ácido Elágico/uso terapêutico , Heparina/farmacologia , Heparina/uso terapêutico , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Domínios Proteicos/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Internalização do Vírus/efeitos dos fármacos
7.
Lancet ; 397(10291): 2253-2263, 2021 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-34097856

RESUMO

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. FUNDING: Coalition COVID-19 Brazil, Bayer SA.


Assuntos
Anticoagulantes/uso terapêutico , COVID-19/sangue , COVID-19/tratamento farmacológico , Enoxaparina/uso terapêutico , Heparina/uso terapêutico , Rivaroxabana/efeitos adversos , Rivaroxabana/uso terapêutico , Adulto , Idoso , Coagulação Sanguínea/efeitos dos fármacos , Brasil/epidemiologia , Determinação de Ponto Final , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio , Hemorragia/induzido quimicamente , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , SARS-CoV-2 , Resultado do Tratamento
8.
S D Med ; 74(2): 70-74, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34161687

RESUMO

INTRODUCTION: Pulmonary embolism (PE) is a significant disease process that affects an estimated 117 cases per 100,000 person-years. Chronic pulmonary hypertension (CPH) is a long-term complication associated with acute PE which has a significant cost to treat, ranging from $98,000-117,000. METHODS: A retrospective chart review of 341 patients from January 2011 to November 2018 who presented with massive or submassive PE and were treated with either systemic heparin therapy or catheter directed thrombolysis (CDT). The results of the short-term cost analysis and pulmonary hypertension rates from data collected was then used in a long-term cost model using a standardized 100 patient model. RESULTS: Treatment with CDT resulted in fewer bleeding complications (4.2 percent vs. 13.8 percent, p=0.005), a shorter length of stay, a greater percentage of patients returning to their prior living conditions (89.0 percent vs. 79.3 percent, p=0.042), and a lower rate of chronic pulmonary hypertension at 12 months (6.3 percent vs. 15.9 percent, p=0.030) than those treated with systemic heparin. The expense of treatment utilizing CDT was greater than those undergoing systemic heparin treatment with a difference of approximately $31,000 (p=0.001) though our cost model showed the heparin group to have a higher cost over time. CONCLUSIONS: For patients with massive or submassive PE, this study demonstrated a significant long-term cost savings and improved outcomes for patients treated with catheter directed thrombolysis when compared to systemic heparin administration.


Assuntos
Hipertensão Pulmonar , Embolia Pulmonar , Cateteres , Custos e Análise de Custo , Heparina/uso terapêutico , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Embolia Pulmonar/tratamento farmacológico , Estudos Retrospectivos , Terapia Trombolítica , Resultado do Tratamento
9.
Diabetes Metab Syndr ; 15(3): 1039-1045, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1235878

RESUMO

BACKGROUND AND AIMS: Initially, novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was considered primarily a respiratory pathogen. However, with time it has behaved as a virus with the potential to cause multi-system involvement, including neurological manifestations. Cerebral venous sinus thrombosis (CVT) has increasingly been reported in association with coronavirus infectious disease of 2019 (COVID-19). Here, we have shed light upon CVT and its possible mechanisms in the backdrop of the ongoing COVID-19 pandemic. METHODS: In this review, data were collected from PubMed, EMBASE and Web of Science, until March 30, 2021, using pre-specified searching strategies. The search strategy consisted of a variation of keywords of relevant medical subject headings and keywords, including "COVID-19", "SARS-CoV-2", "coronavirus", and "cerebral venous sinus thrombosis". RESULTS: COVID-19 has a causal association with a plethora of neurological, neuropsychiatric and psychological effects. CVT has gained particular importance in this regard. The known hypercoagulable state in SARS-CoV-2 infection is thought to be the main mechanism in COVID-19 related CVT. Other plausible mechanisms may include vascular endothelial dysfunction and altered flow dynamics. CONCLUSIONS: Although there are no specific clinical characteristics, insidious or acute onset headache, seizures, stroke-like, or encephalopathy symptoms in a patient with, or who has suffered COVID-19, should prompt the attending physician to investigate for CVT. The treatment of COVID-19 associated CVT does not differ radically from the therapy of CVT without the infection, i.e. urgent initiation of parenteral unfractionated heparin or low molecular weight heparin followed by conventional or mostly newer oral anticoagulants.


Assuntos
COVID-19/complicações , COVID-19/terapia , Trombose Intracraniana/etiologia , Trombose Intracraniana/terapia , Anticoagulantes/uso terapêutico , COVID-19/epidemiologia , Serviços Médicos de Emergência/métodos , Heparina/uso terapêutico , Humanos , Trombose Intracraniana/epidemiologia , Pandemias , SARS-CoV-2/fisiologia
10.
Eur Rev Med Pharmacol Sci ; 25(9): 3594-3606, 2021 May.
Artigo em Inglês | MEDLINE | ID: covidwho-1232731

RESUMO

OBJECTIVE: Patients with 2019-nCoV infection have a high risk to develop venous thrombotic events. Several guidelines recommend the use of either unfractionated heparin or low molecular weight heparins in preventing thrombotic events in these patients. However, results from clinical studies, so far published, reached controversial conclusions on heparin efficacy in this kind of patients since the incidence of venous thromboembolism remains high despite prophylaxis. This narrative review aims to provide an overview of the antiviral and anti-inflammatory properties of heparins and their efficacy and safety in SARS-CoV-2 medical ward-patients. Moreover, anatomical findings and ongoing trials are also reported. Finally, this narrative review tries to explain why heparins fail to prevent venous thrombosis. MATERIALS AND METHODS: We searched for the most relevant published studies on heparins and 2019-nCoV infected patients using the MEDLINE electronic database in the period between January and December 2020. Articles were preliminarily defined as eligible if they: a) were in English language, b) enrolled 250 or more medical ward-patients and 100 or more ICU-patients, c) reported results on patients treated with heparins in a percentage of at least 70% and d) performed an objectively confirmed diagnosis of VTE. RESULTS: Data from medium to large scientific studies show that the incidence of venous thrombotic events in medical ward-patients with SARS-CoV-2 vary between 0% and 8.3%, while this rate is higher, from 6.2% to 49%, in Intensive Care Unit-patients. However, heparins reduce the mortality rate in these patients of about 50%. Histological findings show that thrombosis could affect capillaries, main and small-mid-sized vessels, and it is associated with diffuse alveolar damage. CONCLUSIONS: Heparins have anti-inflammatory and anti-viral properties, which may be of help in reducing mortality in SARS-CoV-2 patients. Failure of heparins at prophylactic dosages in preventing VTE, especially in ICU-patients, could be due to the severity of the disease. Data on the use of heparins in an early phase of the 2019-nCoV infection are still lacking.


Assuntos
Anticoagulantes/uso terapêutico , COVID-19/tratamento farmacológico , Heparina/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , COVID-19/epidemiologia , COVID-19/imunologia , Humanos , Mortalidade/tendências , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/imunologia
11.
J Med Case Rep ; 15(1): 260, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33941263

RESUMO

BACKGROUND: Although life-threatening hemorrhage is a usual manifestation of acute promyelocytic leukemia (APL), thrombotic events seem to be more common in APL compared to other subtypes of acute leukemia. The treatment and prophylaxis of thrombosis are controversial due to the high risk of bleeding caused by disseminated intravascular coagulation (DIC) and thrombocytopenia. To the best of our knowledge we report the first case of APL in a patient with prosthetic heart valves successfully treated with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). We hope this case report helps clinicians to manage different spectra of coagulopathy in APL successfully. CASE PRESENTATION: A 38-year-old Asian man presented with diagnosis of APL confirmed by bone marrow biopsy. He was on warfarin due to prosthetic mitral and aortic valves. He was at risk of both hemorrhagic events due to DIC and life-threatening valve thrombosis. Our management regimen included unfractionated heparin adjusted according to the platelet count to prevent both valve thrombosis and bleeding events. The patient tolerated treatment well without any hemorrhagic or thrombotic events, and complete molecular remission was achieved by ATRA and ATO without the need for chemotherapeutic agents. CONCLUSION: Although this case is exceptional, a precise evaluation may be needed to select the appropriate dose and type of anticoagulant to treat a patient with APL.


Assuntos
Leucemia Promielocítica Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Trióxido de Arsênio/uso terapêutico , Valvas Cardíacas , Heparina/uso terapêutico , Humanos , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Tretinoína/uso terapêutico
12.
Eur Rev Med Pharmacol Sci ; 25(9): 3594-3606, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34002834

RESUMO

OBJECTIVE: Patients with 2019-nCoV infection have a high risk to develop venous thrombotic events. Several guidelines recommend the use of either unfractionated heparin or low molecular weight heparins in preventing thrombotic events in these patients. However, results from clinical studies, so far published, reached controversial conclusions on heparin efficacy in this kind of patients since the incidence of venous thromboembolism remains high despite prophylaxis. This narrative review aims to provide an overview of the antiviral and anti-inflammatory properties of heparins and their efficacy and safety in SARS-CoV-2 medical ward-patients. Moreover, anatomical findings and ongoing trials are also reported. Finally, this narrative review tries to explain why heparins fail to prevent venous thrombosis. MATERIALS AND METHODS: We searched for the most relevant published studies on heparins and 2019-nCoV infected patients using the MEDLINE electronic database in the period between January and December 2020. Articles were preliminarily defined as eligible if they: a) were in English language, b) enrolled 250 or more medical ward-patients and 100 or more ICU-patients, c) reported results on patients treated with heparins in a percentage of at least 70% and d) performed an objectively confirmed diagnosis of VTE. RESULTS: Data from medium to large scientific studies show that the incidence of venous thrombotic events in medical ward-patients with SARS-CoV-2 vary between 0% and 8.3%, while this rate is higher, from 6.2% to 49%, in Intensive Care Unit-patients. However, heparins reduce the mortality rate in these patients of about 50%. Histological findings show that thrombosis could affect capillaries, main and small-mid-sized vessels, and it is associated with diffuse alveolar damage. CONCLUSIONS: Heparins have anti-inflammatory and anti-viral properties, which may be of help in reducing mortality in SARS-CoV-2 patients. Failure of heparins at prophylactic dosages in preventing VTE, especially in ICU-patients, could be due to the severity of the disease. Data on the use of heparins in an early phase of the 2019-nCoV infection are still lacking.


Assuntos
Anticoagulantes/uso terapêutico , COVID-19/tratamento farmacológico , Heparina/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , COVID-19/epidemiologia , COVID-19/imunologia , Humanos , Mortalidade/tendências , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/imunologia
13.
Diabetes Metab Syndr ; 15(3): 1039-1045, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34015627

RESUMO

BACKGROUND AND AIMS: Initially, novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was considered primarily a respiratory pathogen. However, with time it has behaved as a virus with the potential to cause multi-system involvement, including neurological manifestations. Cerebral venous sinus thrombosis (CVT) has increasingly been reported in association with coronavirus infectious disease of 2019 (COVID-19). Here, we have shed light upon CVT and its possible mechanisms in the backdrop of the ongoing COVID-19 pandemic. METHODS: In this review, data were collected from PubMed, EMBASE and Web of Science, until March 30, 2021, using pre-specified searching strategies. The search strategy consisted of a variation of keywords of relevant medical subject headings and keywords, including "COVID-19", "SARS-CoV-2", "coronavirus", and "cerebral venous sinus thrombosis". RESULTS: COVID-19 has a causal association with a plethora of neurological, neuropsychiatric and psychological effects. CVT has gained particular importance in this regard. The known hypercoagulable state in SARS-CoV-2 infection is thought to be the main mechanism in COVID-19 related CVT. Other plausible mechanisms may include vascular endothelial dysfunction and altered flow dynamics. CONCLUSIONS: Although there are no specific clinical characteristics, insidious or acute onset headache, seizures, stroke-like, or encephalopathy symptoms in a patient with, or who has suffered COVID-19, should prompt the attending physician to investigate for CVT. The treatment of COVID-19 associated CVT does not differ radically from the therapy of CVT without the infection, i.e. urgent initiation of parenteral unfractionated heparin or low molecular weight heparin followed by conventional or mostly newer oral anticoagulants.


Assuntos
COVID-19/complicações , COVID-19/terapia , Trombose Intracraniana/etiologia , Trombose Intracraniana/terapia , Anticoagulantes/uso terapêutico , COVID-19/epidemiologia , Serviços Médicos de Emergência/métodos , Heparina/uso terapêutico , Humanos , Trombose Intracraniana/epidemiologia , Pandemias , SARS-CoV-2/fisiologia
14.
BMJ Case Rep ; 14(4)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795268

RESUMO

A 77-year-old male patient presented with a 5-day history of abdominal pain, coffee ground vomiting and blood-stained diarrhoea. CT scan of the abdomen and pelvis demonstrated a long segment thrombotic occlusion of the superior mesenteric vein (SMV) extending up to the proximal portion of the portal vein causing significant acute small bowel ischaemia. Patient's deteriorating clinical condition warranted surgical management. Successful surgical management required multidisciplinary teamwork between emergency, vascular surgeons, anaesthetists and intensivists. Emergency laparotomy revealed gangrene of an estimated 120 cm of small bowel segment starting from duodenojejunal junction and a long segment thrombotic occlusion of the SMV extending up to the portal confluence. Resection of gangrenous small bowel without anastomosis and thrombo-embolectomy of SMV along with laparostomy was done at the initial operation. Patient was admitted in the intensive care unit on systemic heparinisation through intravenous administration of unfractionated heparin. Second relook exploration was done after 48 hours followed by anastomosis of the small bowel and closure of the abdomen. Patient made a good recovery following anticoagulation therapy and was discharged on postoperative day 10.


Assuntos
Isquemia Mesentérica , Oclusão Vascular Mesentérica , Trombose , Idoso , Heparina/uso terapêutico , Humanos , Masculino , Isquemia Mesentérica/diagnóstico por imagem , Isquemia Mesentérica/etiologia , Isquemia Mesentérica/cirurgia , Oclusão Vascular Mesentérica/diagnóstico por imagem , Oclusão Vascular Mesentérica/etiologia , Oclusão Vascular Mesentérica/cirurgia , Veias Mesentéricas/diagnóstico por imagem , Veias Mesentéricas/cirurgia , Veia Porta/diagnóstico por imagem , Veia Porta/cirurgia , Trombose/complicações , Trombose/diagnóstico por imagem
15.
Biomed Pharmacother ; 139: 111561, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33848775

RESUMO

Heparin is the earliest and most widely used anticoagulant and antithrombotic drug that is still used in a variety of clinical indications. Since it was discovered in 1916, after more than a century of repeated exploration, heparin has not been replaced by other drugs, but a great progress has been made in its basic research and clinical application. Besides anticoagulant and antithrombotic effects, heparin also has antitumor, anti-inflammatory, antiviral, and other pharmacological activities. It is widely used clinically in cardiovascular and cerebrovascular diseases, lung diseases, kidney diseases, cancer, etc., as the first anticoagulant medicine in COVID-19 exerts anticoagulant, anti-inflammatory and antiviral effects. At the same time, however, it also leads to a lot of adverse reactions, such as bleeding, thrombocytopenia, elevated transaminase, allergic reactions, and others. This article comprehensively reviews the modern research progress of heparin compounds; discusses the structure, preparation, and adverse reactions of heparin; emphasizes the pharmacological activity and clinical application of heparin; reveals the possible mechanism of the therapeutic effect of heparin in related clinical applications; provides evidence support for the clinical application of heparin; and hints on the significance of exploring the wider application fields of heparin.


Assuntos
Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Medicamentos Essenciais , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Heparina/farmacologia , Heparina/uso terapêutico , Animais , COVID-19/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/tratamento farmacológico , Humanos , Nefropatias/tratamento farmacológico , Lesão Pulmonar/tratamento farmacológico
16.
Cochrane Database Syst Rev ; 4: CD004437, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33857326

RESUMO

BACKGROUND: Thrombolytic therapy is usually reserved for people with clinically serious or massive pulmonary embolism (PE). Evidence suggests that thrombolytic agents may dissolve blood clots more rapidly than heparin and may reduce the death rate associated with PE. However, there are still concerns about the possible risk of adverse effects of thrombolytic therapy, such as major or minor haemorrhage. This is the fourth update of the Cochrane review first published in 2006. OBJECTIVES: To assess the effects of thrombolytic therapy for acute pulmonary embolism. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 17 August 2020. We undertook reference checking to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared thrombolytic therapy followed by heparin versus heparin alone, heparin plus placebo, or surgical intervention for people with acute PE (massive/submassive). We did not include trials comparing two different thrombolytic agents or different doses of the same thrombolytic drug. DATA COLLECTION AND ANALYSIS: Two review authors (ZZ, QH) assessed the eligibility and risk of bias of trials and extracted data. We calculated effect estimates using the odds ratio (OR) with a 95% confidence interval (CI) or the mean difference (MD) with a 95% CI. The primary outcomes of interest were death, recurrence of PE and haemorrhagic events. We assessed the certainty of the evidence using GRADE criteria. MAIN RESULTS: We identified three new studies for inclusion in this update. We included 21 trials in the review, with a total of 2401 participants. No studies compared thrombolytics versus surgical intervention. We were not able to include one study in the meta-analysis because it provided no extractable data. Most studies carried a high or unclear risk of bias related to randomisation and blinding. Meta-analysis showed that, compared to control (heparin alone or heparin plus placebo), thrombolytics plus heparin probably reduce both the odds of death (OR 0.58, 95% CI 0.38 to 0.88; 19 studies, 2319 participants; low-certainty evidence), and recurrence of PE (OR 0.54, 95% CI 0.32 to 0.91; 12 studies, 2050 participants; low-certainty evidence). Effects on mortality weakened when six studies at high risk of bias were excluded from analysis (OR 0.71, 95% CI 0.45 to 1.13; 13 studies, 2046 participants) and in the analysis of submassive PE participants (OR 0.61, 95% CI 0.37 to 1.02; 1993 participants). Effects on recurrence of PE also weakened after removing one study at high risk of bias for sensitivity analysis (OR 0.60, 95% CI 0.35 to 1.04; 11 studies, 1949 participants). We downgraded the certainty of evidence to low because of 'Risk of bias' concerns. Major haemorrhagic events were probably more common in the thrombolytics group than in the control group (OR 2.84, 95% CI 1.92 to 4.20; 15 studies, 2101 participants; moderate-certainty evidence), as were minor haemorrhagic events (OR 2.97, 95% CI 1.66 to 5.30; 13 studies,1757 participants; low-certainty evidence). We downgraded the certainty of the evidence to moderate or low because of 'Risk of bias' concerns and inconsistency. Haemorrhagic stroke may occur more often in the thrombolytics group than in the control group (OR 7.59, 95% CI 1.38 to 41.72; 2 studies, 1091 participants). Limited data indicated that thrombolytics may benefit haemodynamic outcomes, perfusion lung scanning, pulmonary angiogram assessment, echocardiograms, pulmonary hypertension, coagulation parameters, composite clinical outcomes, need for escalation and survival time to a greater extent than heparin alone. However, the heterogeneity of the studies and the small number of participants involved warrant caution when interpreting results. The length of hospital stay was shorter in the thrombolytics group than in the control group (mean difference (MD) -1.40 days, 95% CI -2.69 to -0.11; 5 studies, 368 participants). Haemodynamic decompensation may occur less in the thrombolytics group than in the control group (OR 0.36, 95% CI 0.20 to 0.66; 3 studies, 1157 participants). Quality of life was similar between the two treatment groups. None of the included studies provided data on post-thrombotic syndrome or on cost comparison. AUTHORS' CONCLUSIONS: Low-certainty evidence suggests that thrombolytics may reduce death following acute pulmonary embolism compared with heparin (the effectiveness was mainly driven by one trial with massive PE). Thrombolytic therapy may be helpful in reducing the recurrence of pulmonary emboli but may cause more major and minor haemorrhagic events, including haemorrhagic stroke. More studies of high methodological quality are needed to assess safety and cost effectiveness of thrombolytic therapy for people with pulmonary embolism.


Assuntos
Fibrinolíticos/uso terapêutico , Heparina/uso terapêutico , Embolia Pulmonar/tratamento farmacológico , Terapia Trombolítica/métodos , Doença Aguda , Viés , Causas de Morte , Fibrinolíticos/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Heparina/efeitos adversos , Humanos , Embolia Pulmonar/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Terapia Trombolítica/efeitos adversos
17.
Biomed Pharmacother ; 139: 111561, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: covidwho-1174103

RESUMO

Heparin is the earliest and most widely used anticoagulant and antithrombotic drug that is still used in a variety of clinical indications. Since it was discovered in 1916, after more than a century of repeated exploration, heparin has not been replaced by other drugs, but a great progress has been made in its basic research and clinical application. Besides anticoagulant and antithrombotic effects, heparin also has antitumor, anti-inflammatory, antiviral, and other pharmacological activities. It is widely used clinically in cardiovascular and cerebrovascular diseases, lung diseases, kidney diseases, cancer, etc., as the first anticoagulant medicine in COVID-19 exerts anticoagulant, anti-inflammatory and antiviral effects. At the same time, however, it also leads to a lot of adverse reactions, such as bleeding, thrombocytopenia, elevated transaminase, allergic reactions, and others. This article comprehensively reviews the modern research progress of heparin compounds; discusses the structure, preparation, and adverse reactions of heparin; emphasizes the pharmacological activity and clinical application of heparin; reveals the possible mechanism of the therapeutic effect of heparin in related clinical applications; provides evidence support for the clinical application of heparin; and hints on the significance of exploring the wider application fields of heparin.


Assuntos
Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Medicamentos Essenciais , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Heparina/farmacologia , Heparina/uso terapêutico , Animais , COVID-19/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/tratamento farmacológico , Humanos , Nefropatias/tratamento farmacológico , Lesão Pulmonar/tratamento farmacológico
18.
BMC Nephrol ; 22(1): 141, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: covidwho-1195914

RESUMO

BACKGROUND: Coronavirus Disease 2019 (COVID-19) infection has been associated with a hypercoagulable state with increased reports of thrombotic events. Acute kidney injury requiring dialysis is common in critically ill patients and circuit clotting compromises efficacy of treatment. This study aims to analyze the circuit life and circuit clotting during continuous kidney replacement therapy (CKRT) and intermittent hemodialysis in patients with and without COVID-19. METHODS: This is a single-center, retrospective cohort study in critically ill patients undergoing CKRT or intermittent hemodialysis between 1 February 2020 to 22 May 2020. Patients in the intensive care unit (ICU) with COVID-19 infection and contemporary controls who tested negative were included. Co-primary outcomes were functional circuit life for patients on CKRT and all circuit clotting events for patients on CKRT and/or intermittent hemodialysis. RESULTS: Seventy CKRT circuits and 32 intermittent hemodialysis sessions for 12 COVID-19 cases and 22 CKRT circuits and 18 intermittent hemodialysis sessions for 15 controls were analyzed. CKRT circuit clotting was more common in the COVID-19 group compared to the control group (64% vs 36%, p = 0.02), despite higher anticoagulation use in the COVID-19 group (41% vs 14%, p = 0.02). Functional CKRT circuit life was similar in COVID-19 patients and controls (median 11 vs 12 h, p = 0.69). On Cox regression analysis, circuit clotting was similar with hazard ratio (HR) 1.90 [95% confidence interval (CI): 0.89-4.04]; however, clotting was increased in COVID-19 patients after adjustment for anticoagulation use (HR: 3.31 [95% CI 1.49-7.33]). In patients with COVID-19, CKRT circuits with anticoagulation had a longer circuit life compared to CKRT circuits without anticoagulation (median 22 versus 7 h respectively, p <  0.001). Circuit clotting was similar in both groups undergoing intermittent hemodialysis. CONCLUSION: Dialysis clotting amongst COVID-19 patients is increased despite more anticoagulation use and the hazard for clotting is greater especially after adjusting for anticoagulation use. Circuit life was suboptimal in COVID-19 patients on circuits without anticoagulation and therefore routine use of anticoagulation amongst COVID-19 patients should be considered whenever possible.


Assuntos
Injúria Renal Aguda/terapia , COVID-19/terapia , Falência Renal Crônica/terapia , Rins Artificiais , Trombose/epidemiologia , Injúria Renal Aguda/etiologia , Idoso , Anticoagulantes/uso terapêutico , COVID-19/sangue , COVID-19/complicações , Estudos de Casos e Controles , Ácido Cítrico/uso terapêutico , Estudos de Coortes , Terapia de Substituição Renal Contínua , Estado Terminal , Feminino , Heparina/uso terapêutico , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Diálise Renal , Estudos Retrospectivos , SARS-CoV-2 , Trombose/prevenção & controle
19.
Am J Case Rep ; 22: e931080, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1168169

RESUMO

BACKGROUND The novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), often manifests a coagulopathy in severely ill patients, which may cause hemorrhage and/or thrombosis of varying severity. This report comprises the cases of 3 patients with COVID-19-associated coagulopathy who were evaluated with thromboelastography (TEG) and activated partial thromboplastin time (aPTT) to enable personalized anticoagulant therapy. CASE REPORT Three patients presented with COVID-19 pneumonia, confirmed by reverse transcription-polymerase chain reaction, who developed thrombohemorrhagic coagulopathy.Case 1: A 72-year-old woman on long-term warfarin therapy for a history of venous thromboembolism developed a right upper lobe pulmonary embolus, despite an international normalized ratio of 6.4 and aPTT of 120.7 s. TEG enabled successful anticoagulation with heparin, and her pulmonary infarct was no longer present 2 weeks later.Case 2: A 55-year-old woman developed a rectus sheath hematoma while on heparin, and TEG demonstrated increased fibrinolysis despite COVID-19 patients more commonly undergoing fibrinolytic shutdown.Case 3: A 43-year-old woman had significant thrombus burden while severely hypocoagulable according to laboratory testing. As the venous thrombi enlarged in a disseminated intravascular coagulopathic-like state, the heparin dose was escalated to achieve a target aPTT of 70 to 80 s, resulting in a flat line TEG tracing. CONCLUSIONS These 3 cases of COVID-19 pneumonia with complex and varied clinical histories demonstrated the clinical value of TEG combined with the measurement of aPTT to facilitate personalized anticoagulation, resulting in good clinical outcomes.


Assuntos
Anticoagulantes/uso terapêutico , COVID-19/complicações , Hemorragia/tratamento farmacológico , Tromboelastografia , Terapia Trombolítica , Trombose/tratamento farmacológico , Adulto , Idoso , Feminino , Hemorragia/virologia , Heparina/uso terapêutico , Humanos , Pessoa de Meia-Idade , Trombose/virologia
20.
Int J Biol Macromol ; 183: 203-212, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33915212

RESUMO

The world is currently facing a novel coronavirus (SARS-CoV-2) pandemic. The greatest threat that is disrupting the normal functioning of society is the exceptionally high species independent transmission. Drug repurposing is understood to be the best strategy to immediately deploy well-characterized agents against new pathogens. Several repurposable drugs are already in evaluation for determining suitability to treat COVID-19. One such promising compound includes heparin, which is widely used in reducing thrombotic events associated with COVID-19 induced pathology. As part of identifying target-specific antiviral compounds among FDA and world-approved libraries using high-throughput virtual screening (HTVS), we previously evaluated top hits for anti-SARS-CoV-2 activity. Here, we report results of highly efficacious viral entry blocking properties of heparin (IC50 = 12.3 nM) in the complete virus assay, and further, propose ways to use it as a potential transmission blocker. Exploring further, our in-silico analysis indicated that the heparin interacts with post-translational glycoconjugates present on spike proteins. The patterns of accessible spike-glycoconjugates in open and closed states are completely contrasted by one another. Heparin-binding to the open conformation of spike structurally supports the state and may aid ACE2 binding as reported with cell surface-bound heparan sulfate. We also studied spike protein mutant variants' heparin interactions for possible resistance. Based on available data and optimal absorption properties by the skin, heparin could potentially be used to block SARS-CoV-2 transmission. Studies should be designed to exploit its nanomolar antiviral activity to formulate heparin as topical or inhalation-based formulations, particularly on exposed areas and sites of primary viremia e.g. ACE2 rich epithelia of the eye (conjunctiva/lids), nasal cavity, and mouth.


Assuntos
Reposicionamento de Medicamentos , Heparina/química , SARS-CoV-2/química , Glicoproteína da Espícula de Coronavírus/química , COVID-19/tratamento farmacológico , COVID-19/prevenção & controle , COVID-19/transmissão , Heparina/uso terapêutico , Humanos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética
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