Fibrinolytic therapy in patients with COVID-19 and ARDS: protocol for a systematic review and meta-analysis.

INTRODUCTION: In COVID-19-related acute respiratory distress syndrome (ARDS), the clot play a role in gas exchange abnormalities. Fibrinolytic therapy can improve alveolar ventilation by restoring blood flow. In this systematic review and meta-analysis protocol, we aim to assess the safety and efficacy of fibrinolytic therapy in such a population. METHODS: We will perform a systematic search in MEDLINE, EMBASE, Cochrane CENTRAL and LILACS databases without language restrictions for relevant randomised controlled trials (RCTs) and quasi-RCTs. Two review authors will independently perform data extraction and quality assessments of data from included studies. In case of divergence, a third author will be contacted. The Cochrane handbook will be used for guidance. If the results are not appropriate for a meta-analysis, a descriptive analysis will be performed. DISCUSSION: This systematic review and meta-analysis protocol will provide current evidence about the safety and efficacy of fibrinolytic therapy in patients with COVID-19 and ARDS. These findings will provide if fibrinolytic therapy might be an option for a desperate clinical setting, where all medical efforts have been used. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020187482. ETHICS AND DISSEMINATION: Ethics committee approval is not necessary. We intend to update the public registry, report any protocol amendments and publish the results in a widely accessible journal.

Thromboelastometry early identifies thrombotic complications related to COVID-19: A case report.

COVID-19 is a contagious infectious disease, which quickly spreads worldwide, whose clinical presentation includes from mild flu-like symptoms to pneumonia and severe acute respiratory syndrome. The severe presentation of the disease can affect different organs and systems. Coagulopathy has been associated with a worse clinical outcome, with manifestations such as pulmonary embolism and systemic arterial thrombosis. Thromboelastometry has been used to identify hypercoagulability in early stages of disease. We report the case of a 59-year-old woman with COVID-19 infection complicated by pulmonary embolism and acute arterial thrombosis associated with critical lower limb ischemia requiring amputation. This report showed a case of thrombotic complication in patient with infection caused by novel coronavirus 2019 whose thromboelastometry allowed the early identification of hypercoagulability pattern. This is a single case report and the use of thromboelastometry should be further evaluated in large prospective cohort studies.

Farmacogenética da varfarina como ferramenta de apoio na decisão terapêutica para prevenção de eventos tromboembólicos em idoso frágil com fibrilação atrial / Warfarin pharmacogenetics as a therapeutic decision support tool for the prevention of thromboembolic events in frail elderly patients with atrial fibrillation

INTRODUÇÃO: Fibrilação atrial (FA) é a taquiarritmia sustentada mais frequente em idosos. Acidente vascular cerebral (AVC) é uma das principais complicações relacionadas à FA, com risco crescente com a idade. Assim, a anticoagulação oral (ACO) é medida importante para reduzir o risco de AVC. Varfarina continua sendo muito utilizada, apesar do advento de anticoagulantes orais diretos. Há grande diferença individual na dose necessária de varfarina. A farmacogenética possui impacto no ajuste da dosagem e tem sido alternativa para sua quantificação. Quando há contraindicação para ACO ou presença de eventos embólicos na vigência de ACO efetiva, pode-se indicar oclusão do apêndice atrial esquerdo, capaz de reduzir eventos em mais de 90%. OBJETIVO: Descrever a importância do perfil farmacogenético da varfarina como suporte na decisão da terapia mais adequada para prevenção de eventos tromboembólicos em idoso frágil com FA. RELATO DE CASO: Paciente N.A.P.D, 78 anos, admitida com dispneia aos moderados esforços. Antecedente de FA, HAS e insuficiência cardíaca. CHA2 DS2 -VASc= 3 e HASBLED= 2. Iniciado ACO com varfarina. Evolui com necessidade progressiva de aumento da dose de varfarina (37,5mg/sem), labilidade de INR (TTR=43,77%) e dificuldade social para comparecer às consultas de controle, devido fratura de fêmur após queda e fragilidade. O perfil farmacogênico revelou padrão homozigoto para o gene CYP4F2, implicando em necessidade de aumento da dose de varfarina para alcance da meta. Entretanto, pela fragilidade, dificuldade de manter ACO e risco de aumento na dose, optou-se por oclusão do apêndice atrial esquerdo. DISCUSSÃO: A farmacogenética da resposta a varfarina é ferramenta importante para acompanhamento da ACO. A variação genética mostra impacto clinicamente importante na dose estável de varfarina. A associação entre CYP2C9, VKORC1 e dose de varfarina foi investigada em vários estudos e sua influência confirmada. O CYP4F2 controla a biodisponibilidade da vitamina K, cofator necessário para a coagulação. Variações no gene CYP4F2 afetam a biodisponibilidade da vitamina K e a dosagem de antagonistas da vitamina K, como varfarina, causando resistência e necessidade de maior dose de ACO. Assim a farmacogenética tem sido uma alternativa para a quantificação da dose da varfarina. CONCLUSÃO: Este relato enfatiza a importância do perfil farmacogenético da varfarina na decisão terapêutica para prevenção de eventos tromboembólicos em idosos, corroborando para a escolha da terapêutica mais adequada para esta população.

Thromboelastometry identifies coagulopathy associated with liver failure and disseminated intravascular coagulation caused by yellow fever, guiding specific hemostatic therapy: a case report. / A tromboelastometria identifica coagulopatia associada à insuficiência hepática e coagulação intravascular disseminada causadas por febre amarela, orientando a terapia hemostática específica: um relato de caso.

This case report a severe case of yellow fever complicated by liver failure and disseminated intravascular coagulation. Thromboelastometry was capable of identifying clotting disorders and guiding hemostatic therapy. We report the case of a 23-year-old male admitted to the Intensive Care Unit with sudden onset of fever, generalized muscle pain associated with liver failure, and disseminated intravascular coagulation. The results of conventional laboratory tests showed thrombocytopenia, whereas thromboelastometry suggested coagulopathy with slight hypofibrinogenemia, clotting factor consumption, and, consequently, an increased risk of bleeding. Unlike conventional laboratory tests, thromboelastometry identified the specific coagulation disorder and thereby guided hemostatic therapy. Both fibrinogen concentrates and vitamin K were administered, and no blood component transfusion was required, even in the presence of thrombocytopenia. Administration of hemostatic drugs, including fibrinogen concentrate and vitamin K, improved thromboelastometric parameters, correcting the complex coagulation disorder. Blood component transfusion was not performed, and there was no bleeding.

Este relato de caso detalha um caso grave de febre amarela complicada por insuficiência hepática e coagulação intravascular disseminada. A tromboelastometria foi capaz de identificar os distúrbios da coagulação e orientar o tratamento hemostático. Relatamos o caso de um homem com 23 anos de idade admitido na unidade de terapia intensiva com quadro com início abrupto de febre e dor muscular generalizada associados a insuficiência hepática e coagulação intravascular disseminada. Os resultados dos exames laboratoriais convencionais revelaram trombocitopenia, enquanto a tromboelastometria sugeriu coagulopatia com discreta hipofibrinogenemia, consumo de fatores de coagulação e, consequentemente, aumento do risco de sangramento. Diferentemente dos exames laboratoriais convencionais, a tromboelastometria identificou o distúrbio de coagulação específico e, assim, orientou o tratamento hemostático. Administraram-se concentrados de fibrinogênio e vitamina K, não sendo necessária a transfusão de qualquer componente do sangue, mesmo na presença de trombocitopenia. A tromboelastometria permitiu a identificação precoce da coagulopatia e ajudou a orientar a terapêutica hemostática. A administração de fármacos hemostáticos, incluindo concentrados de fibrinogênio e vitamina K, melhorou os parâmetros tromboelastométricos, com correção do transtorno da coagulação. Não se realizou transfusão de hemocomponentes, e não ocorreu qualquer sangramento.

A tromboelastometria identifica coagulopatia associada à insuficiência hepática e coagulação intravascular disseminada causadas por febre amarela, orientando a terapia hemostática específica: um relato de caso / Thromboelastometry identifies coagulopathy associated with liver failure and disseminated intravascular coagulation caused by yellow fever, guiding specific hemostatic therapy: a case report

RESUMO Este relato de caso detalha um caso grave de febre amarela complicada por insuficiência hepática e coagulação intravascular disseminada. A tromboelastometria foi capaz de identificar os distúrbios da coagulação e orientar o tratamento hemostático. Relatamos o caso de um homem com 23 anos de idade admitido na unidade de terapia intensiva com quadro com início abrupto de febre e dor muscular generalizada associados a insuficiência hepática e coagulação intravascular disseminada. Os resultados dos exames laboratoriais convencionais revelaram trombocitopenia, enquanto a tromboelastometria sugeriu coagulopatia com discreta hipofibrinogenemia, consumo de fatores de coagulação e, consequentemente, aumento do risco de sangramento. Diferentemente dos exames laboratoriais convencionais, a tromboelastometria identificou o distúrbio de coagulação específico e, assim, orientou o tratamento hemostático. Administraram-se concentrados de fibrinogênio e vitamina K, não sendo necessária a transfusão de qualquer componente do sangue, mesmo na presença de trombocitopenia. A tromboelastometria permitiu a identificação precoce da coagulopatia e ajudou a orientar a terapêutica hemostática. A administração de fármacos hemostáticos, incluindo concentrados de fibrinogênio e vitamina K, melhorou os parâmetros tromboelastométricos, com correção do transtorno da coagulação. Não se realizou transfusão de hemocomponentes, e não ocorreu qualquer sangramento.

Abstract This case report a severe case of yellow fever complicated by liver failure and disseminated intravascular coagulation. Thromboelastometry was capable of identifying clotting disorders and guiding hemostatic therapy. We report the case of a 23-year-old male admitted to the Intensive Care Unit with sudden onset of fever, generalized muscle pain associated with liver failure, and disseminated intravascular coagulation. The results of conventional laboratory tests showed thrombocytopenia, whereas thromboelastometry suggested coagulopathy with slight hypofibrinogenemia, clotting factor consumption, and, consequently, an increased risk of bleeding. Unlike conventional laboratory tests, thromboelastometry identified the specific coagulation disorder and thereby guided hemostatic therapy. Both fibrinogen concentrates and vitamin K were administered, and no blood component transfusion was required, even in the presence of thrombocytopenia. Administration of hemostatic drugs, including fibrinogen concentrate and vitamin K, improved thromboelastometric parameters, correcting the complex coagulation disorder. Blood component transfusion was not performed, and there was no bleeding.

Compensatory effect of fibrinogen in a patient with bone marrow aplasia, septic shock, and severe thrombocytopenia guided by thromboelastometry: a case report. / Efeito compensatório do fibrinogênio em paciente com aplasia de medula óssea, choque séptico e trombocitopenia grave guiado por tromboelastometria: relato de caso.

Platelet transfusion is a common practice to prevent spontaneous bleeding or bleeding due to invasive procedures. Transfusion of allogeneic blood components is associated with increased mortality and a worse clinical outcome. The clot strength is assessed by thromboelastometry and determined by the interaction between platelets and fibrinogen. The compensatory effect of high levels of fibrinogen on clot strength in patients with thrombocytopenia has been demonstrated in different clinical settings including sepsis. We report the case of a patient with severe thrombocytopenia whose thromboelastometry showed clot strength that was compensated for by the increase in plasma fibrinogen levels as an acute phase reactant of septic patients. Here, we report a case of a 62-year-old female diagnosed with bone marrow aplasia admitted in the intensive care unit with septic shock and severe thrombocytopenia. During the first 24 hours in the intensive care unit, she presented acute respiratory insufficiency and circulatory shock. The use of invasive mechanical ventilation and norepinephrine was required. Her chest X-ray showed bilateral lung injury. Thus, bronchoscopy with bronchoalveolar lavage was requested. Thromboelastometry was performed and resulted in a normal coagulable profile. Despite severe thrombocytopenia (1,000/mm3), fibrinogen levels were increased (1,050mg/dL) due to septic shock. Bronchoscopy was performed without any active or further bleeding. Here, we report the use of thromboelastometry in the diagnosis of coagulation disorders, preventing unnecessary prophylactic platelet transfusion.

A transfusão de concentrado de plaquetas é prática comum para prevenção de sangramento espontâneo ou decorrente de procedimentos invasivos; sabe-se que a transfusão de componentes alogênicos do sangue se associa a aumento da mortalidade e piora do desfecho clínico. A força do coágulo é avaliada por meio da tromboelastometria rotacional e determinada pela interação entre plaquetas e fibrinogênio. O efeito compensatório do incremento na concentração sérica de fibrinogênio na força do coágulo, em pacientes com trombocitopenia, tem sido demonstrado em diferentes contextos clínicos, incluindo sepse. Relatamos o caso de uma paciente com trombocitopenia grave, cujo resultado da tromboelastometria rotacional demonstrou efeito compensatório na força do coágulo determinada pelos níveis plasmáticos aumentados de fibrinogênio como reagente de fase aguda em pacientes sépticos. Relatamos o caso de uma paciente de 62 anos com diagnóstico de aplasia de medula óssea admitida a uma unidade de terapia intensiva com choque séptico e trombocitopenia grave. Nas primeiras 24 horas na unidade de terapia intensiva, ela apresentou quadro clínico de insuficiência respiratória aguda e choque. Foi necessário utilizar ventilação mecânica invasiva e fármaco vasoativo. A radiografia de tórax mostrou padrão de lesão pulmonar bilateral. Desta forma, foi solicitada broncoscopia com lavagem broncoalveolar para investigação diagnóstica. Conduziu-se uma tromboelastometria rotacional, e seu resultado mostrou perfil de coagulação normal. Apesar da trombocitopenia grave (1.000/mm3), os níveis de fibrinogênio aumentaram (1.050mg/dL) devido ao choque séptico. A broncoscopia foi realizada sem que subsequentemente ocorresse sangramento ativo. Este caso relata o uso da tromboelastometria como ferramenta diagnóstica em distúrbios da coagulação de pacientes graves, permitindo prevenir o uso desnecessário de transfusões profiláticas de concentrado de plaquetas.

Thromboelastometry Identified Alteration of Clot Stabilization and Factor XIII Supplementation Need in a Patient with Decompensated Liver Disease Undergoing Liver Biopsy.

Liver disease has been considered the prototype of hemorrhagic disease. Disorder in any component of coagulation system can lead to hemorrhage. Deficiency of factor XIII may impair clot strength and clot stabilization and can be accessed by thromboelastometry. We report a case of a patient with a rapid evolution of liver disease who underwent a liver biopsy. Thromboelastometry was performed, evidencing impairment of clot stability. This clotting disorder was corrected with factor XIII concentrate after unsuccessful administration of antifibrinolytic drugs and hepatic biopsy was performed without hemorrhagic complications. Case Presentation. We report the case of a previously healthy 38-year-old man, who presented to our emergency department with clinical signs of rapid progression of acute liver failure. The laboratory tests revealed platelets of 142x103/mm3, plasma fibrinogen concentration of 221 mg/dl, increased international nationalized ratio (INR 1.9), total bilirubin of 3.9mg/dl, direct bilirubin of 2.3mg/dl, ALT 751U/l, and AST 540U/l without acute bleeding. A liver biopsy was indicated. Based on the results of the thromboelastometry, Tranexamic Acid was administered to correct hyperfibrinolysis followed by factor XIII concentrate to correct factor XIII deficiency. Thromboelastometry was normal despite conventional coagulation tests were still altered. So, liver biopsy was performed with no signs of bleeding and without need of further transfusion. Conclusion. Thromboelastometry may be considered a useful, feasible, and safe tool to monitor and manage coagulopathy in patients with liver disease, with the potential advantage of helping avoid unnecessary transfusion in such patients.

Efeito compensatório do fibrinogênio em paciente com aplasia de medula óssea, choque séptico e trombocitopenia grave guiado por tromboelastometria: relato de caso / Compensatory effect of fibrinogen in a patient with bone marrow aplasia, septic shock, and severe thrombocytopenia guided by thromboelastometry: a case report

RESUMO A transfusão de concentrado de plaquetas é prática comum para prevenção de sangramento espontâneo ou decorrente de procedimentos invasivos; sabe-se que a transfusão de componentes alogênicos do sangue se associa a aumento da mortalidade e piora do desfecho clínico. A força do coágulo é avaliada por meio da tromboelastometria rotacional e determinada pela interação entre plaquetas e fibrinogênio. O efeito compensatório do incremento na concentração sérica de fibrinogênio na força do coágulo, em pacientes com trombocitopenia, tem sido demonstrado em diferentes contextos clínicos, incluindo sepse. Relatamos o caso de uma paciente com trombocitopenia grave, cujo resultado da tromboelastometria rotacional demonstrou efeito compensatório na força do coágulo determinada pelos níveis plasmáticos aumentados de fibrinogênio como reagente de fase aguda em pacientes sépticos. Relatamos o caso de uma paciente de 62 anos com diagnóstico de aplasia de medula óssea admitida a uma unidade de terapia intensiva com choque séptico e trombocitopenia grave. Nas primeiras 24 horas na unidade de terapia intensiva, ela apresentou quadro clínico de insuficiência respiratória aguda e choque. Foi necessário utilizar ventilação mecânica invasiva e fármaco vasoativo. A radiografia de tórax mostrou padrão de lesão pulmonar bilateral. Desta forma, foi solicitada broncoscopia com lavagem broncoalveolar para investigação diagnóstica. Conduziu-se uma tromboelastometria rotacional, e seu resultado mostrou perfil de coagulação normal. Apesar da trombocitopenia grave (1.000/mm3), os níveis de fibrinogênio aumentaram (1.050mg/dL) devido ao choque séptico. A broncoscopia foi realizada sem que subsequentemente ocorresse sangramento ativo. Este caso relata o uso da tromboelastometria como ferramenta diagnóstica em distúrbios da coagulação de pacientes graves, permitindo prevenir o uso desnecessário de transfusões profiláticas de concentrado de plaquetas.

ABSTRACT Platelet transfusion is a common practice to prevent spontaneous bleeding or bleeding due to invasive procedures. Transfusion of allogeneic blood components is associated with increased mortality and a worse clinical outcome. The clot strength is assessed by thromboelastometry and determined by the interaction between platelets and fibrinogen. The compensatory effect of high levels of fibrinogen on clot strength in patients with thrombocytopenia has been demonstrated in different clinical settings including sepsis. We report the case of a patient with severe thrombocytopenia whose thromboelastometry showed clot strength that was compensated for by the increase in plasma fibrinogen levels as an acute phase reactant of septic patients. Here, we report a case of a 62-year-old female diagnosed with bone marrow aplasia admitted in the intensive care unit with septic shock and severe thrombocytopenia. During the first 24 hours in the intensive care unit, she presented acute respiratory insufficiency and circulatory shock. The use of invasive mechanical ventilation and norepinephrine was required. Her chest X-ray showed bilateral lung injury. Thus, bronchoscopy with bronchoalveolar lavage was requested. Thromboelastometry was performed and resulted in a normal coagulable profile. Despite severe thrombocytopenia (1,000/mm3), fibrinogen levels were increased (1,050mg/dL) due to septic shock. Bronchoscopy was performed without any active or further bleeding. Here, we report the use of thromboelastometry in the diagnosis of coagulation disorders, preventing unnecessary prophylactic platelet transfusion.

Thromboelastometry-guided hemostatic therapy for hemorrhagic shock in the postoperative period of vascular surgery: a case report.

BACKGROUND: Hemorrhagic shock is a medical emergency that often complicates vascular surgery and can lead to death. Hemorrhagic shock is characterized by hypoperfusion and hemodynamic abnormalities leading to the collapse of homeostasis due to massive blood loss. Early diagnosis is critical for a favorable outcome. Thromboelastometry has been considered an effective tool for bleeding management in critically ill patients. Thromboelastometry can guide transfusion therapy quickly, reducing the need for blood products. Therefore, it could be an alternative test to guide hemostatic therapy in complex cases of hemorrhagic shock as a result of vascular surgeries. We report our successful experience with a case of hemorrhagic shock in postoperative care in vascular surgery, in which bleeding management was guided by thromboelastometry and bleeding control was achieved with hemostatic drugs and coagulation factor concentrates. CASE PRESENTATION: We report a case of an 82-year-old Afro-Brazilian man who presented to the intensive care unit with hemorrhagic shock in the postoperative period of vascular surgery. He underwent surgery for correction of iliac artery aneurysm with endoleak. His laboratory tests revealed severe anemia (hemoglobin 7.4 mg/dL), metabolic acidosis (bicarbonate 10 mEq/L, pH 7.11), acute kidney injury (creatinine 3.1 mg/dL), thrombocytopenia (platelets count 83 × 103/mm3), hypofibrinogenemia (70 mg/dL), international nationalized ratio 1.95, activated partial thromboplastin time 64.5 seconds, and lactate 87 mmol/L. There was active bleeding in surgical site. Bleeding management was guided by thromboelastometry. The first test showed fulminant hyperfibrinolysis, which was corrected with the administration of tranexamic acid. The second thromboelastometry test showed improvement of hyperfibrinolysis but severe hypocoagulability. Fibrinogen concentrate, platelet apheresis, cryoprecipitate, and prothrombin complex concentrate were sequentially administrated. Thromboelastometry was completely corrected after 2 hours. Arteriography to evaluate mechanical cause of bleeding was normal. No more bleeding was identified, and neither was any further transfusion needed. He was discharged from the intensive care unit from the ward 3 days after admission. CONCLUSIONS: Thromboelastometry may be considered a useful, feasible and safe tool to monitor and manage coagulopathy in patients with hemorrhagic shock. Moreover, it has the potential benefit of allowing rapid diagnosis,  goal-directed therapy with hemostatic drugs and coagulation factor concentrates and thus, avoiding unnecessary blood component transfusion.