A carregar...
Publicação
Fibrinogen concentrate safety for the correction of hypofibrinogenemia on coagulopathic surgical patients
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 8.82 MB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
RESUMO: O fibrinogénio plasmático é um fator da coagulação que desempenha um papel crítico na hemostase primária e secundária, uma vez que constitui a base do coágulo sanguíneo, após lesão de um vaso. Trata-se de uma molécula grande, estruturalmente intrincada e que circula em altas concentrações no plasma. A hemorragia leva à perda, diluição e consumo de fibrinogénio, enquanto que a hipotermia e a acidose alteram a sua capacidade funcional. Em qualquer doente que apresente uma hemorragia aguda, os níveis de fibrinogénio dependem de um equilíbrio delicado entre a sua síntese, consumo e degradação. Os procedimentos cirúrgicos, em particular as cirurgias major, estão frequentemente associadas a hemorragia, e esse facto pode representar um desafio para a hemostase. Um número crescente de estudos sustenta o facto de que a reposição de fibrinogénio ajuda a melhorar a coagulopatia adquirida e minimizar a necessidade de transfusão sanguínea, que não é inócua, além do sangue ser um bem escasso, nem sempre disponível e indiscutivelmente caro. Dada a sua importância e papel único na manutenção da hemostase, a sua rápida suplementação torna-se essencial para alcançar o controlo das perdas sanguíneas, uma vez que o aumento da síntese de fibrinogénio, pode não ser suficiente para compensar o seu consumo. Existem três possibilidades de suplementação de fibrinogénio: plasma, crioprecipitado e concentrado de fibrinogénio. O plasma e o crioprecipitado não são a fonte ideal para reposição de fibrinogénio, enquanto que o concentrado de fibrinogénio tem a vantagem de possuir uma quantidade fixa de fibrinogénio num pequeno volume, ser submetido a pasteurização e inativação viral e estar rapidamente disponível. No entanto, as evidências disponíveis sobre a relação benefício/risco do uso de concentrado de fibrinogénio para diminuir a hemorragia e complicações relacionadas, em diferentes situações clínicas, não são amplamente aceites. A maioria dos ensaios clínicos randomizados disponíveis e outros estudos clínicos concluem que o concentrado de fibrinogénio mostra eficácia e parece ser seguro, mas persistem dúvidas e resultados discrepantes. Várias décadas de farmacovigilância evidenciam poucos relatos de eventos adversos, mas devemos considerar que, além do facto de o concentrado de fibrinogénio ser um pró-coagulante, ele é administrado a doentes com coagulopatias e com outros fatores de risco cumulativos para o desenvolvimento de eventos trombóticos/tromboembólicos. O objetivo deste projeto foi avaliar a segurança do concentrado de fibrinogénio em doentes com coagulopatias adquiridas aos quais foi administrado concentrado de fibrinogénio, para correção de hipofibrinogenémia, tendo como foco a mortalidade e eventos trombóticos/tromboembólicos diagnosticados por métodos clínicos, laboratoriais e radiológicos. Esta tese foi baseada em dois estudos: uma revisão sistemática com meta-análise sobre a segurança do concentrado de fibrinogénio em doentes adultos durante o período peri operatório, e um estudo observacional prospetivo realizado num só centro, que incluiu todos os doentes xiv adultos submetidos a cirurgia programada ou de emergência com coagulopatia hemorrágica associada a administração de concentrado de fibrinogénio, dentro dos limites terapêuticos para este efeito, com a intenção de corrigir a hipofibrinogenémia. No primeiro estudo, foi realizada uma pesquisa bibliográfica extensa no PubMed/Medline, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews e Cochrane Central Register of Controlled Trials. Dois revisores administraram o processo de forma independente, examinando meticulosamente os estudos recuperados, extraindo dados e avaliando a integridade metodológica. Um terceiro revisor resolveu qualquer desacordo entre eles. O segundo estudo foi realizado no Hospital da Luz Lisboa, com o objetivo de reproduzir no mundo real, a abordagem à hemorragia associada à hipofibrinogenémia, tendo os doentes sido acompanhados até à data da alta hospitalar. Os dados colhidos foram abrangentes, incluindo idade, sexo, tipo de cirurgia, comorbidades associadas, terapia anticoagulante e/ou antiagregante e número de componentes sanguíneos transfundidos. Os dados laboratoriais sobre concentração plasmática de fibrinogénio, resultados de testes viscoelásticos, hemoglobina e contagem de plaquetas antes e após a cirurgia também foram colhidos. Os objetivos primários foram a taxa de mortalidade à data de alta e quaisquer eventos trombóticos ou tromboembólicos relatados, incluindo trombose venosa profunda, embolia pulmonar e enfarte do miocárdio até a alta hospitalar. No início do estudo, fatores de risco adicionais para eventos trombóticos/tromboembólicos, como: obesidade, tabagismo, história familiar e pessoal pregressa de eventos tromboembólicos, trombofilia hereditária, imobilidade, dias de repouso no leito e medicamentos, como anticoncecionais orais, terapia de reposição hormonal e glicocorticoides, também foram colhidos. Uma vez que estes podem representar variáveis confundentes, esses dados permitiram uma análise de estratificação estatística posterior. A revisão sistemática com meta-análise englobou dez estudos envolvendo 1391 pacientes. Verificou-se uma diminuição do risco de eventos tromboembólicos totais em doentes tratados com fibrinogénio em comparação com o grupo controlo (OR 0,65; IC 95% 0,43 a 0,98, I2 = 0%). Além disso, quando o fibrinogénio foi usado profilaticamente, resultou em menor tempo de permanência na Unidade de Cuidados Intensivos (MD -1,50; IC 95% -2,64 a -0,36), quando comparado ao seu uso terapêutico. No entanto estes resultados devem ser analisados com alguma cautela. A análise de sensibilidade em estudos de cirurgia cardiovascular não revelou diferenças estatisticamente significativas. O segundo estudo, que abrangeu 91 doentes cirúrgicos, e onde se verificou a morte de oito doentes, não revelou nenhuma associação percetível entre a administração de concentrado de fibrinogénio e mortalidade. Da mesma forma, oito doentes apresentaram eventos tromboembólicos após a cirurgia, mas todos se encontravam vivos à data da alta hospitalar. Ao contrário de outros relatos, houve uma distribuição igualitária de sexos entre esses doentes. xv Variáveis confundentes, como doenças concomitantes e história pessoal ou familiar de doença trombótica, podem fornecer explicações alternativas para esses eventos tromboembólicos. Desses oito doentes, apenas um não apresentava comorbidades associadas. Entre os sete restantes, cinco tinham história pessoal de eventos tromboembólicos e um tinha história familiar positiva. Estes doentes também apresentaram diversas situações clínicas, como infeção por COVID-19, neoplasias e fibrilhação auricular. Os doentes que sofreram eventos tromboembólicos durante a fase de acompanhamento, também tiveram tempos de internamento hospitalares mais longos e receberam mais unidades de concentrado eritrócitário. Os nossos dados indicam que a idade, a incidência de eventos tromboembólicos prévios e as cirurgias de emergência, se associaram a uma maior necessidade de transfusão de componentes sanguíneos e períodos de internamento hospitalar mais longos. Embora o uso de concentrado de fibrinogénio não pareça aumentar o risco de eventos tromboembólicos, os doentes que necessitaram de doses mais altas de concentrado de fibrinogênio também receberam mais unidades de eritrócitos. Esse achado está alinhado com uma revisão sistemática que analisou a adminstração de concentrado de fibrinogénio para controlo da hemorragia em situações de emergência. Os resultados de ambos os estudos estão alinhados e parecem reforçar as mesmas conclusões. Por um lado, os resultados da revisão sistemática com meta-análise indicam que o uso de concentrado de fibrinogénio no período peri operatório de doentes adultos sem coagulopatia traumática e não obstétricos, pode levar a benefícios potenciais. Por outro lado, os resultados do estudo prospetivo indicam um perfil de segurança favorável para o concentrado de fibrinogénio em doentes cirúrgicos, demonstrado por uma baixa incidência de óbitos e eventos tromboembólicos, atribuídos a outros fatores. No entanto, pesquisas futuras devem priorizar a minimização de viés e o aumento da robustez estatística para esclarecer de forma mais eficaz as medidas de segurança do doente, que possam ser clinicamente significativas.
ABSTRACT: Fibrinogen, a clotting factor, plays a critical role in both primary and secondary hemostasis, forming the basis of the clot. This structurally intricate, large molecule circulates at high concentrations. Bleeding can lead to fibrinogen loss, dilution, and consumption, while hypothermia and acidosis impair its function. The fibrinogen levels in any patient presenting with an acute hemorrhage are dependent on a delicate balance between synthesis, consumption, and degradation. Surgery is often associated with bleeding, which can pose a challenge to hemostasis. An increasing number of studies support the concept that fibrinogen replacement can improve acquired coagulopathy and reduce the need for blood transfusions. These transfusions are not innocuous and, due to their scarcity and significant cost, may not always be available. Given its importance and unique role in maintaining hemostasis, rapid fibrinogen supplementation becomes essential to achieve blood loss control, since an increase in synthesis alone may not compensate for consumption. There are three possibilities for fibrinogen supplementation: plasma, cryoprecipitate, and fibrinogen concentrate. Plasma and cryoprecipitate have not been proven to be the ideal sources for fibrinogen replacement. Meanwhile, fibrinogen concentrate appears to have advantages as it has a fixed amount of fibrinogen in a small volume, undergoes pasteurization and viral inactivation, and is rapidly available. However, the existing evidence on the benefit/risk ratio of using fibrinogen concentrate to decrease bleeding and related complications in different clinical situations is not widely accepted. The majority of available randomized clinical trials and other clinical studies conclude that fibrinogen concentrate is effective and appears safe, but there are some conflicting data. Several decades of pharmacovigilance have reported relatively few adverse events. However, we must take into account that fibrinogen concentrate is a procoagulant that is administered to coagulopathic patients, who often have other accumulated risk factors for developing a thrombotic/thromboembolic event. The goal of this project was to evaluate the safety of fibrinogen concentrate in coagulopathic patients who received it to rectify hypofibrinogenemia. The focus was on studying mortality and thrombotic/thromboembolic events diagnosed by clinical, laboratory, and radiological methods. This thesis was based on two studies: a systematic review with a meta-analysis on the safety of fibrinogen concentrate in non-trauma, non-obstetric adult patients during the perioperative period, and a single-center, prospective observational study. The latter included all adult patients undergoing scheduled or emergency surgery, presenting with bleeding coagulopathy, and receiving administration of fibrinogen concentrate within therapeutic ranges for the correction of hypofibrinogenemia. xviii In the initial study, an exhaustive online search was performed on PubMed/Medline, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials. Two reviewers independently undertook the process, carefully screening the retrieved studies, extracting data, and assessing methodological integrity. Any discrepancies between them were resolved by a third-party reviewer. The second study was conducted at Hospital da Luz Lisboa, to encapsulate a real-world approach to bleeding related to hypofibrinogenemia. Patients were followed until their discharge from the institution. Comprehensive data were collected, which included age, sex, type of surgery, associated comorbidities, anticoagulant and/or anti-aggregating therapy, and the number of blood transfusions. Laboratory data – such as plasmatic fibrinogen concentration, point-of-care results, hemoglobin, and platelet count before and after surgery – were also collected. The primary outcomes were the mortality rate at discharge and any reported thrombotic or thromboembolic events, including deep vein thrombosis, pulmonary embolism, and myocardial infarction until the point of hospital discharge. At baseline, additional risk factors for thrombotic/thromboembolic events, such as obesity, smoking, family and past personal history of venous thromboembolism(VTE), inherited thrombophilia, immobility, days of bed rest, and drugs like oral contraceptives, hormone replacement therapy, and glucocorticoids, were also collected. Given that these could be confounding variables, this data set allowed for further statistical stratification analysis. The systematic review, which included a meta-analysis, covered ten studies involving 1,391 patients. It revealed a decreased risk of total thromboembolic events in patients treated with fibrinogen, compared to the control group (OR 0.65, 95% CI from 0.43 to 0.98, with I2 at 0%). Additionally, when fibrinogen was used prophylactically, it led to reduced lengths of intensive care unit (ICU) stays (MD -1.50, 95% CI from -2.64 to -0.36) compared to its therapeutic use. A sensitivity analysis focusing on cardiovascular surgery studies found no statistically significant variation. The second study, which included 91 surgical patients, revealed no conspicuous associations between the administration of fibrinogen concentrate and mortality among the eight patients who died. Likewise, eight patients encountered thromboembolic events after surgery, but all were alive at the time of hospital discharge. In contrast to other reports, the distribution of genders among these patients was evenly balanced. Confounding variables, such as concurrent illnesses and personal or familial history of thrombotic disease, could provide alternate explanations for these thromboembolic events. Among these eight patients, only one had no associated comorbidities. Of the remaining seven, one had a positive family history of thrombotic disease. These patients also presented with varied conditions, which included prior thromboembolic events in two cases, a history of COVID-19 infection, cancer, and atrial fibrillation in the others. Patients who experienced thromboembolic xix events during the follow-up phase also had longer hospital stays and received more units of red blood cells (RBCs). Our findings suggest that factors such as age, the incidence of thromboembolic events, and emergency surgeries were associated with a greater need for blood transfusions and extended hospital stays. Although the application of fibrinogen concentrate did not appear to increase the risk of thromboembolic events, patients who required higher doses of fibrinogen concentrate also received a greater quantity of RBC units. This observation is consistent with a systematic review that investigated the employment of fibrinogen concentrate in addressing hemorrhaging during emergencies. The results from both studies are aligned and seem to strengthen the same conclusions. On the one hand, the systematic review with meta-analysis indicates that the use of fibrinogen concentrate in the perioperative care of non-trauma and non-obstetric adult patients may lead to potential benefits. On the other hand, the prospective study demonstrates a favorable safety profile for fibrinogen concentrate in surgical patients, as indicated by a low incidence of deaths and thromboembolic events, primarily attributed to other factors. However, future research should prioritize minimizing bias and enhancing statistical robustness to more effectively highlight clinically significant patient safety measures
ABSTRACT: Fibrinogen, a clotting factor, plays a critical role in both primary and secondary hemostasis, forming the basis of the clot. This structurally intricate, large molecule circulates at high concentrations. Bleeding can lead to fibrinogen loss, dilution, and consumption, while hypothermia and acidosis impair its function. The fibrinogen levels in any patient presenting with an acute hemorrhage are dependent on a delicate balance between synthesis, consumption, and degradation. Surgery is often associated with bleeding, which can pose a challenge to hemostasis. An increasing number of studies support the concept that fibrinogen replacement can improve acquired coagulopathy and reduce the need for blood transfusions. These transfusions are not innocuous and, due to their scarcity and significant cost, may not always be available. Given its importance and unique role in maintaining hemostasis, rapid fibrinogen supplementation becomes essential to achieve blood loss control, since an increase in synthesis alone may not compensate for consumption. There are three possibilities for fibrinogen supplementation: plasma, cryoprecipitate, and fibrinogen concentrate. Plasma and cryoprecipitate have not been proven to be the ideal sources for fibrinogen replacement. Meanwhile, fibrinogen concentrate appears to have advantages as it has a fixed amount of fibrinogen in a small volume, undergoes pasteurization and viral inactivation, and is rapidly available. However, the existing evidence on the benefit/risk ratio of using fibrinogen concentrate to decrease bleeding and related complications in different clinical situations is not widely accepted. The majority of available randomized clinical trials and other clinical studies conclude that fibrinogen concentrate is effective and appears safe, but there are some conflicting data. Several decades of pharmacovigilance have reported relatively few adverse events. However, we must take into account that fibrinogen concentrate is a procoagulant that is administered to coagulopathic patients, who often have other accumulated risk factors for developing a thrombotic/thromboembolic event. The goal of this project was to evaluate the safety of fibrinogen concentrate in coagulopathic patients who received it to rectify hypofibrinogenemia. The focus was on studying mortality and thrombotic/thromboembolic events diagnosed by clinical, laboratory, and radiological methods. This thesis was based on two studies: a systematic review with a meta-analysis on the safety of fibrinogen concentrate in non-trauma, non-obstetric adult patients during the perioperative period, and a single-center, prospective observational study. The latter included all adult patients undergoing scheduled or emergency surgery, presenting with bleeding coagulopathy, and receiving administration of fibrinogen concentrate within therapeutic ranges for the correction of hypofibrinogenemia. xviii In the initial study, an exhaustive online search was performed on PubMed/Medline, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials. Two reviewers independently undertook the process, carefully screening the retrieved studies, extracting data, and assessing methodological integrity. Any discrepancies between them were resolved by a third-party reviewer. The second study was conducted at Hospital da Luz Lisboa, to encapsulate a real-world approach to bleeding related to hypofibrinogenemia. Patients were followed until their discharge from the institution. Comprehensive data were collected, which included age, sex, type of surgery, associated comorbidities, anticoagulant and/or anti-aggregating therapy, and the number of blood transfusions. Laboratory data – such as plasmatic fibrinogen concentration, point-of-care results, hemoglobin, and platelet count before and after surgery – were also collected. The primary outcomes were the mortality rate at discharge and any reported thrombotic or thromboembolic events, including deep vein thrombosis, pulmonary embolism, and myocardial infarction until the point of hospital discharge. At baseline, additional risk factors for thrombotic/thromboembolic events, such as obesity, smoking, family and past personal history of venous thromboembolism(VTE), inherited thrombophilia, immobility, days of bed rest, and drugs like oral contraceptives, hormone replacement therapy, and glucocorticoids, were also collected. Given that these could be confounding variables, this data set allowed for further statistical stratification analysis. The systematic review, which included a meta-analysis, covered ten studies involving 1,391 patients. It revealed a decreased risk of total thromboembolic events in patients treated with fibrinogen, compared to the control group (OR 0.65, 95% CI from 0.43 to 0.98, with I2 at 0%). Additionally, when fibrinogen was used prophylactically, it led to reduced lengths of intensive care unit (ICU) stays (MD -1.50, 95% CI from -2.64 to -0.36) compared to its therapeutic use. A sensitivity analysis focusing on cardiovascular surgery studies found no statistically significant variation. The second study, which included 91 surgical patients, revealed no conspicuous associations between the administration of fibrinogen concentrate and mortality among the eight patients who died. Likewise, eight patients encountered thromboembolic events after surgery, but all were alive at the time of hospital discharge. In contrast to other reports, the distribution of genders among these patients was evenly balanced. Confounding variables, such as concurrent illnesses and personal or familial history of thrombotic disease, could provide alternate explanations for these thromboembolic events. Among these eight patients, only one had no associated comorbidities. Of the remaining seven, one had a positive family history of thrombotic disease. These patients also presented with varied conditions, which included prior thromboembolic events in two cases, a history of COVID-19 infection, cancer, and atrial fibrillation in the others. Patients who experienced thromboembolic xix events during the follow-up phase also had longer hospital stays and received more units of red blood cells (RBCs). Our findings suggest that factors such as age, the incidence of thromboembolic events, and emergency surgeries were associated with a greater need for blood transfusions and extended hospital stays. Although the application of fibrinogen concentrate did not appear to increase the risk of thromboembolic events, patients who required higher doses of fibrinogen concentrate also received a greater quantity of RBC units. This observation is consistent with a systematic review that investigated the employment of fibrinogen concentrate in addressing hemorrhaging during emergencies. The results from both studies are aligned and seem to strengthen the same conclusions. On the one hand, the systematic review with meta-analysis indicates that the use of fibrinogen concentrate in the perioperative care of non-trauma and non-obstetric adult patients may lead to potential benefits. On the other hand, the prospective study demonstrates a favorable safety profile for fibrinogen concentrate in surgical patients, as indicated by a low incidence of deaths and thromboembolic events, primarily attributed to other factors. However, future research should prioritize minimizing bias and enhancing statistical robustness to more effectively highlight clinically significant patient safety measures
Descrição
Palavras-chave
Fibrinogen concentrate safety Hypofibrinogenemia Coagulopathic surgical patients