Immature Platelet Fraction and Thrombin Generation: Preeclampsia Biomarkers / Fração de plaquetas imaturas e geração de trombina: Biomarcadores da pré-eclâmpsia

Abstract Preeclampsia, a human pregnancy syndrome, is characterized by elevated blood pressure and proteinuria after the 20th week of gestation. Its etiology remains unknown, and its pathophysiological mechanisms are related to placental hypoperfusion, endothelial dysfunction, inflammation, and coagulation cascade activation. Recently, the role of the complement system has been considered. This syndrome is one of the main causes of maternal and fetal mortality and morbidity. This article discusses the hypothesis of preeclampsia being triggered by the occurrence of inadequate implantation of the syncytiotrophoblast, associated with bleeding during the first stage of pregnancy and with augmented thrombin generation. Thrombin activates platelets, increasing the release of antiangiogenic factors and activating the complement system, inducing the membrane attack complex (C5b9). Immature platelet fraction and thrombin generation may be possible blood biomarkers to help the early diagnosis of preeclampsia.

Resumo A pré-eclâmpsia, uma síndrome da gestação humana, é caracterizada por elevação da pressão arterial e proteinúria patológica após a 20ª semana de gestação. Sua etiologia permanece desconhecida, e seus mecanismos fisiopatológicos estão relacionados à hipoperfusão placentária, disfunção endotelial, inflamação, e ativação da cascata de coagulação. Recentemente, o papel do sistema do complemento foi considerado. Essa síndrome é uma das principais causas de morbidade e mortalidade materna e fetal. Este artigo discute a hipótese de a pré-eclâmpsia ser desencadeada pela ocorrência da implantação inadequada do sinciciotrofoblasto, associada ao sangramento durante o primeiro trimestre da gravidez com aumento da geração de trombina. A trombina ativa plaquetas, aumentando a liberação de fatores antiangiogênicos na circulação e ativando o sistema do complemento, especialmente o complexo de ataque de membrana (C5b9). Portanto, a fração de plaquetas imaturas e a geração de trombina podem ser possíveis biomarcadores sanguíneos para auxílio no diagnóstico precoce da pré-eclâmpsia.

The application of complement-targeted therapies in autoimmune diseases of nervous system / 中华神经科杂志

Complement is an important element of immune system playing vital roles in immune surveillance and tissue homeostasis. Increasing evidence shows that complement activations not only protect the body, but contribute to the occurrence and development of autoimmune diseases. Inappropriate activations of complement may also lead to or aggravate various neuro-immunological diseases, including neuromyelitis optica spectrum disease, myasthenia gravis and Guillain-Barré syndrome. Several complement-targeted therapeutics have emerged in recent years, established themselves as popular clinical research topics associated with various autoimmune diseases. Following that note, this review introduces mechanisms of complements participating in autoimmune diseases of the nervous system and the latest development of complement-targeted therapeutics, with the view to contributing to the development of this emerging therapeutic field.

Nephrotic syndrome associated with primary atypical hemolytic uremic syndrome / Síndrome nefrótica associada à síndrome hemolítico-urêmica atípica primária

Abstract Primary atypical hemolytic-uremic syndrome is a rare disease characterized by non-immune microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction; it is related to alterations in the regulation of the alternative pathway of complement due to genetic mutations. The association with nephrotic syndrome is unusual. We present here a pediatric patient diagnosed with primary atypical hemolytic-uremic syndrome associated with nephrotic syndrome who responded to eculizumab treatment.

Resumo A síndrome hemolítico-urêmica atípica primária é uma doença rara, caracterizada por anemia hemolítica microangiopática não-imune, trombocitopenia e disfunção renal; está relacionado a alterações na regulação da via alternativa do complemento devido a mutações genéticas. A associação com a síndrome nefrótica é incomum. Apresentamos aqui um paciente pediátrico com diagnóstico de síndrome hemolítico-urêmica atípica primária associada à síndrome nefrótica que respondeu ao tratamento com eculizumab.

Complement activation in a mouse model of cisplatin-induced renal interstitial fibrosis / 中华肾脏病杂志

Objective:To explore the mechanism of cisplatin-induced renal interstitial fibrosis and provide a new idea for the prevention and treatment of renal interstitial fibrosis.Methods:Eight-week-old male C57BL/6 mice (specific pathogen-free) were used to carry out the experiment. The mice were divided into cisplatin group (10 mg/kg, n=6) and saline group ( n=6) with intraperitoneal injection on day 0, 7 and 21, and sacrificed on day 28. The kidney tissues were collected for RNA Illumina high-throughput sequencing, real-time PCR, Western blotting, Masson staining and bioinformatics analysis. Results:Through real-time PCR, Western blotting and Masson staining, a mouse model with cisplatin-induced renal interstitial fibrosis was successfully established. Through RNA Illumina high-throughput sequencing, 387 long noncoding RNA (lncRNA) and 2 427 mRNA were differently expressed between cisplatin group and saline group. The expression of the top two lncRNA was confirmed by real-time PCR with the same tendency as RNA sequencing. Complement C3 was found to be at the top among the different expressed mRNA by RNA sequencing. Several terms related to immunity were found to be within the top 20 terms through Gene Ontology (GO) enrichment analysis. Systemic lupus erythematous pathway (ko05322, Q=3.4E-17), including the complement cascade pathway, was found to be the top pathway through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The mRNA expression levels of C1q, C2, C3 and C4 were up-regulated remarkably in the cisplatin group by RNA sequencing than those in saline group (all P<0.05) and confirmed by real-time PCR. Conclusions:Renal interstitial fibrosis can be induced by intraperitoneal injection of cisplatin periodically in mice, with complement cascade pathway activation in the diseased kidney.

Progress of the role of complement system in lymphoma / 白血病·淋巴瘤

The complement system is a protein response system with a precise regulation mechanism, and an important part of the body's innate and adaptive immunity. Abnormal complement components, excessive activation and other functional disorders are closely related to the development and progression of lymphoma and immune escape. In addition, the complement system has a certain relevance to clinical treatment, especially immunotherapy. This paper reviews the role of complement system in the occurrence and treatment of lymphoma.

Níveis inatos de C3 e C4 em pacientes curados para a leishmaniose visceral e associação com os aspectos clínico-laboratoriais / Innate levels of C3 and C4 in patients cured for visceral leishmaniasis and association with clinical and laboratory aspects

Introdução: assim que inoculada pelo flebotomíneo, a Leishmania entra em contato com o sistema complemento, sendo que poucos estudos têm avaliado os níveis inatos dos componentes iniciais C3 e C4. Objetivo: avaliar os níveis inatos dos componentes C3 e C4 do sistema complemento em pacientes curados de leishmaniose visceral (LV) e sua associação com aspectos clínico-laboratoriais no momento de diagnóstico da doença. Metodologia: foram estudados 29 pacientes com LV curada. Os níveis de C3 e C4 séricos foram dosados pela técnica de imunodifusão radial simples, após um tempo médio de 59,48 meses pós-tratamento, formados os grupos: C3: baixo (< 84 mg/dl; n=10), normal (84 a 193 mg/dl; n=14) e elevado (> 193 mg/dl; n=5); C4: muito baixo (< 20 mg/dl; n=10), baixo (20 a 40 mg/dl; n=15) e normal (> 40 mg/dl; n=4). Os dados clínicos e laboratoriais empregados para as análises foram coletados por levantamento dos prontuários, considerando o período de diagnóstico da doença de cada paciente. Resultados: foi observada uma correlação positiva fraca entre os níveis de C3 e C4 (rho=0,46; p=0,01). Verificou-se que a maioria dos pacientes sintomáticos no momento do diagnóstico apresentavam níveis inatos normais de C3 e baixos de C4. Pacientes com C3 baixo apresentaram maiores níveis do hematócrito em relação ao grupo C3 normal (p=0,0406). Conclusão: conclui-se que o componente C3 do sistema complemento está associado às alterações do hematócrito, sugerindo o acompanhamento dos seus níveis em pacientes com LV.

Introduction: once inoculated by the sand fly, Leishmania comes into contact with the complement system, and few studies have evaluated the innate levels of the initial components C3 and C4. Objective: to evaluate the innate levels of the C3 and C4 components of the complement system in patients cured of visceral leishmaniasis (VL) and its association with clinical and laboratory aspects at the time of diagnosis of the disease. Methodology: twenty-nine patients with cured VL were studied. Serum C3 and C4 levels were measured by simple radial immunodiffusion technique, after an average time of 59.48 months post-treatment, forming the groups: C3: low (< 84 mg/dl; n=10), normal (84 to 193 mg/dl; n=14) and high (> 193 mg/dl; n=5); C4: very low (< 20 mg/dl; n=10), low (20 to 40 mg/dl; n=15) and normal (> 40 mg/dl; n=4). The clinical and laboratory data used for the analyzes were collected by surveying the medical records, considering the period of diagnosis of the disease of each patient. Results: a weak positive correlation was observed between C3 and C4 levels (rho=0.46; p=0.01). Most symptomatic patients at the time of diagnosis were found to have normal C3 and low C4 levels. Low C3 patients had higher levels of hematocrit compared to the normal C3 group (p=0.0406). Conclusion: in conclusion, the C3 component of the complement system is associated with changes in the hematocrit, suggesting the monitoring of its levels in patients with VL.

Nefropatía por C1q: una rara variedad de síndrome nefrótico: caso clínico / C1q nephropathy: report of one case

C1q nephropathy is a rare glomerulopathy characterized by mesangial deposition of the complement component C1q. These deposits can be isolated or associated with immunoglobulins or complement fractions, which are observed by immunofluorescence or immunohistochemical microscopy. In ultramicroscopy, dense mesangial deposits and alterations of the podocyte are observed. Clinically it presents as a nephrotic syndrome (NS) or by alterations of the urinalysis such as proteinuria and/or hematuria in children and young adults. In light microscopy, it is expressed with a morphological pattern of minimal change disease (MCD), mesangial proliferative glomerulonephritis or focal segmental glomerulosclerosis (FSGS). The NS during its evolution usually evolve in steroid resistance or steroid dependency, often requiring the association of immunosuppressants to obtain remission. We report a 14 years old male with a history of NS and its evolution under various treatments during a 12-year follow-up.

Doenças associadas à deficiência do sistema complemento / Diseases associated with the deficiency of the complement system

Introdução: O sistema complemento é composto por diversas proteínas plasmáticas e é um importante mecanismo de defesa da imunidade inata e adquirida, que exerce funções homeostáticas e fisiológicas, como a remoção de células apoptóticas e complexos imunes. A deficiência neste mecanismo pode ser hereditária ou adquirida, e leva ao aumento da susceptibilidade a doenças infecciosas e não infecciosas, raras e fatais. Objetivo: Descrever as principais causas e consequências da deficiência do sistema complemento e relacioná-las com múltiplas patologias. Material e Métodos: Trata-se de uma revisão bibliográfica narrativa, tendo como base de dados, artigos publicados no Scientific Electronic Library Online (SciELO), National Library of Medicine (PubMed), Medical Literature Analysis and retrieval System Online (MEDLINE), nos últimos 5 anos. Resultados: A associação do complemento e doenças foram observadas em situações de deficiência do sistema complemento, anormalidades na regulação e nas inflamações. Mutações genéticas ou aumento do consumo do complemento levam à ativação imprópria ou excessiva do complemento, podendo conduzir a consequências lesivas e ao desenvolvimento de diversas doenças, como, lúpus eritematoso sistêmico, síndrome urêmica hemolítica atípica, glomerulopatia C3, hemoglobinúria paroxística noturna, glomerulonefrite pós-infecciosas, artrite reumatoide, dentre outras. Conclusão: É evidente a participação do sistema complemento na patogênese e patogenia de diversas doenças. O investimento em pesquisas, que visem ampliar o entendimento do papel do mecanismo do sistema complemento, pode contribuir para o desenvolvimento de intervenções terapêuticas paliativas e ou de cura de diversas doenças, com a consequente melhoria da qualidade de vida dos indivíduos acometidos.

Introduction: The complement system is composed of several plasma proteins and is an important defense mechanism of innate and acquired immunity, which exerts homeostatic and physiological functions, such as the removal of apoptotic cells and immune complexes. Deficiency in this mechanism may be hereditary or acquired, and leads to increased susceptibility to infectious and non-infectious, rare and fatal diseases. Objective: To describe the main causes and consequences of the deficiency of the complement system and to relate them to multiple pathologies. Material and Methods: This is a bibliographical narrative review, based on data published in SciELO (Scientific Electronic Library Online), PubMed (National Library of Medicine), MEDLINE (Medical Literature Analysis and retrieval System Online), last five years. Results:The associations of complement and diseases were observed in situations of deficiency of the complement system, abnormalities in regulation and inflammation. Genetic mutations lead to inappropriate or excessive activation of the complement, as well as increased the consumption of the complement. This can lead to harmful consequences and the development of several diseases, such as systemic lupus erythematosus, atypical hemolytic uremic syndrome, C3 glomerulopathy, nocturnal paroxysmal hemoglobinuria, postpartum glomerulonephritis, infectious diseases, rheumatoid arthritis, among others. Conclusion: The participation of the complement system in the pathogenesis and pathogenesis of several diseases is evident. Investing in research, aimed at broadening the understanding of the role of the complement system mechanism, may contribute to the development of palliative therapeutic interventions and or cure of various diseases, with the consequent improvement in the quality of life of affected individuals.

Value of complement system in the diagnosis of systemic lupus erythematosus / 中华检验医学杂志

The complement system plays a major role in systemic lupus erythematosus (SLE). At present, complement component 3(C3) and component 4(C4) are the diagnostic markers in the internationally recognized standard of SLE classification. Complement C3 and C4 can play a role in the diagnosis of SLE patients, but they are not very specific diagnostic markers. Therefore, it is important to find more better biomarkers of SLE. In this review, the latest findings in complement-focused research in SLE were explored. Complement level, cell-bound complement activation products and membrane-bound complement regulatory proteins are associated with the pathogenesis of SLE. They may become SLE biomarkers and aid the diagnosis and monitoring of patients with this disease.

The role of complement system in thrombotic microangiopathy and its research progress / 中华检验医学杂志

Thrombotic microangiopathy (TMA) is a group of acute clinical pathological syndromes with common pathological features, which include hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura syndrome. They have many similarities in etiology and clinical presentation. The role of abnormal activation of complement bypass pathway in the genesis and development of HUS has been recognized. More than 100 kinds of complement regulatory factors or gene mutations of complement itself were found to be associated with the development of HUS, which resulted in the decrease of negative complement regulatory protein activity or the increase of complement activation protein function. Abnormal activation of complement system resulted in endothelial injury and thrombosis. Loss of ADAMTS13 activity (<10%) is the most important pathogenesis of TTP. However, there are more and more evidence that complement bypassing pathway is over-regulated and over-activated in the formation of TTP. At present, the research of TMA is focused on finding specific complement-activated biomarkers in patients with various forms of TMA and developing new targeted therapeutic drugs for the disease.

Progress of complement system in Alzheimer′s disease / 中华检验医学杂志

Alzheimer′s disease (AD) is a growing global health concern with huge implications for individuals and society. In this review, current understanding of the pathogenesis of complement system in Alzheimer′s disease is outlined and current clinical laboratory diagnostic methods are discussed. Some theoretical basis and new ideas for seeking the biomarkers of AD and its treatment are also provided.

The role and progress of complement activation in antiphospholipid syndrome / 中华检验医学杂志

Antiphospholipid syndrome(APS) is a non-inflammatory autoimmune disease caused by anti-phospholipid antibodies. In recent years, it has been found that over-activation of complement is the key factor leading to the formation of thrombosis and pathological pregnancy in APS. With more understanding of the role of complement activation in the pathogenesis of APS, methods of complement inhibition therapy have emerged one after another. Therefore, the detection of complement components is of great significance for the early diagnosis, treatment and monitoring of APS.

Clinical value of complements detection in pregnancy related thrombotic microangiopathy / 中华检验医学杂志

Thrombotic microangiopathy (TMA) is an acute clinico-pathological syndrome with varied reasons. Pregnancy related-TMA includes pregnancy associated thrombotic thrombocytopenic purpura (TTP), postpartum hemolytic-uremic syndrome (pHUS), severe preeclampsia (SPE) and Hemolysis, Elevated Liver enzymes and Low Platelet syndrome (HELLP syndrome) and the outcomes are severe. Aberrant activation of complement system plays an important role in the pathogenesis of these diseases. Although these diseases have similar clinical appearance, their pathogenesis, diagnostic and therapeutic methods are different. Precision diagnosis of these diseases to select targeted treatment will greatly improve the prognosis of these patients. Herein, the value of complement system components in the diagnosis and treatment of pregnancy-related TMA are introduced.

Complement mediated tumor immune escape and its application in immune checkpoint inhibitors therapy / 中华检验医学杂志

The complement system is an important part of the innate immune system. More evidence showed that the function of complement was not only limited to the elimination of pathogens and other risk factors from the body but also affected the immune escape mechanism of the tumor through different activating pathways. Because of the complex and important role of complement in the tumor, this review expounds the mechanism of complement system participating in immune escape of the tumor from three aspects: complement inherent components, complement activation products and complement regulatory proteins. Additionally, these mechanisms are expected to provide a new application of complement in tumor immunotherapy with immune checkpoint inhibitors.

Value of complement system in the diagnosis of systemic lupus erythematosus / 中华检验医学杂志

The complement system plays a major role in systemic lupus erythematosus (SLE). At present, complement component 3(C3) and component 4(C4) are the diagnostic markers in the internationally recognized standard of SLE classification. Complement C3 and C4 can play a role in the diagnosis of SLE patients, but they are not very specific diagnostic markers. Therefore, it is important to find more better biomarkers of SLE. In this review, the latest findings in complement-focused research in SLE were explored. Complement level, cell-bound complement activation products and membrane-bound complement regulatory proteins are associated with the pathogenesis of SLE. They may become SLE biomarkers and aid the diagnosis and monitoring of patients with this disease.

The role of complement system in thrombotic microangiopathy and its research progress / 中华检验医学杂志

Thrombotic microangiopathy (TMA) is a group of acute clinical pathological syndromes with common pathological features, which include hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura syndrome. They have many similarities in etiology and clinical presentation. The role of abnormal activation of complement bypass pathway in the genesis and development of HUS has been recognized. More than 100 kinds of complement regulatory factors or gene mutations of complement itself were found to be associated with the development of HUS, which resulted in the decrease of negative complement regulatory protein activity or the increase of complement activation protein function . Abnormal activation of complement system resulted in endothelial injury and thrombosis. Loss of ADAMTS13 activity (<10％) is the most important pathogenesis of TTP. However, there are more and more evidence that complement bypassing pathway is over-regulated and over-activated in the formation of TTP. At present, the research of TMA is focused on finding specific complement-activated biomarkers in patients with various forms of TMA and developing new targeted therapeutic drugs for the disease.

Progress of complement system in Alzheimer's disease / 中华检验医学杂志

Alzheimer's disease (AD) is a growing global health concern with huge implications for individuals and society. In this review, current understanding of the pathogenesis of complement system in Alzheimer's disease is outlined and current clinical laboratory diagnostic methods are discussed. Some theoretical basis and new ideas for seeking the biomarkers of AD and its treatment are also provided.

The role and progress of complement activation in antiphospholipid syndrome / 中华检验医学杂志

Antiphospholipid syndrome(APS) is a non-inflammatory autoimmune disease caused by anti-phospholipid antibodies. In recent years, it has been found that over-activation of complement is the key factor leading to the formation of thrombosis and pathological pregnancy in APS. With more understanding of the role of complement activation in the pathogenesis of APS, methods of complement inhibition therapy have emerged one after another. Therefore, the detection of complement components is of great significance for the early diagnosis, treatment and monitoring of APS.

Clinical value of complements detection in pregnancy related thrombotic microangiopathy / 中华检验医学杂志

Thrombotic microangiopathy (TMA) is an acute clinico-pathological syndrome with varied reasons. Pregnancy related-TMA includes pregnancy associated thrombotic thrombocytopenic purpura (TTP), postpartum hemolytic-uremic syndrome (pHUS), severe preeclampsia (SPE) and Hemolysis, Elevated Liver enzymes and Low Platelet syndrome (HELLP syndrome) and the outcomes are severe. Aberrant activation of complement system plays an important role in the pathogenesis of these diseases. Although these diseases have similar clinical appearance, their pathogenesis, diagnostic and therapeutic methods are different. Precision diagnosis of these diseases to select targeted treatment will greatly improve the prognosis of these patients. Herein, the value of complement system components in the diagnosis and treatment of pregnancy-related TMA are introduced.

Complement mediated tumor immune escape and its application in immune checkpoint inhibitors therapy / 中华检验医学杂志

The complement system is an important part of the innate immune system. More evidence showed that the function of complement was not only limited to the elimination of pathogens and other risk factors from the body but also affected the immune escape mechanism of the tumor through different activating pathways. Because of the complex and important role of complement in the tumor, this review expounds the mechanism of complement system participating in immune escape of the tumor from three aspects:complement inherent components, complement activation products and complement regulatory proteins. Additionally, these mechanisms are expected to provide a new application of complement in tumor immunotherapy with immune checkpoint inhibitors.