Sepsis-associated coagulopathy refers to extensive coagulation activation accompanied by a high risk of bleeding and organ failure. In severe cases, it is manifested as disseminated intravascular coagulation (DIC) and leads to multiple organ dysfunction syndrome (MODS). Complement is an important component of the innate immune system and plays an important role in defending against invasion of pathogenic microorganisms. The early pathological process of sepsis involves excessive activation of the complement system, which forms an extremely complex network through interactions with the coagulation, kinin and fibrinolytic system, amplifying and exacerbating the systemic inflammatory response. In recent years, it has been suggested that uncontrolled complement activation system can exacerbate sepsis-associated coagulation dysfunction or even DIC, indicating the potential value of intervening in the complement system in the treatment of septic DIC, and related research progress is reviewed in this article in order to provide new ideas for the discovery of sepsis-associated coagulopathy therapy drugs.
Humans ; Blood Coagulation Disorders ; Complement Activation ; Blood Coagulation ; Multiple Organ Failure ; Sepsis

CD55 Antigens ; Complement Activation ; Humans ; Membrane Cofactor Protein ; Pemphigoid, Bullous ; Recombinant Fusion Proteins

C3 glomerulopathy is a renal disorder involving dysregulation of alternative pathway complement activation. In most instances, a membranoproliferative pattern of glomerular injury with a prevalence of C3 deposition is observed by immunofluorescence microscopy. Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are subclasses of C3 glomerulopathy that are distinguishable by electron microscopy. Highly electron-dense transformation of glomerular basement membrane is characteristic of DDD. C3GN should be differentiated from post-infectious glomerulonephritis and other immune complex-mediated glomerulonephritides showing C3 deposits.
Complement Activation ; Complement Pathway, Alternative ; Dichlorodiphenyldichloroethane ; Glomerular Basement Membrane ; Glomerulonephritis ; Glomerulonephritis, Membranoproliferative ; Microscopy, Electron ; Microscopy, Fluorescence ; Pathology ; Prevalence

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) involves dysregulation of the complement system, but whether this also occurs in thrombotic thrombocytopenic purpura (TTP) remains unclear. Although these conditions are difficult to differentiate clinically, TTP can be distinguished by low (<10%) ADAMTS13 activity. The aim was to identify the differences in complement activation products between TTP and aHUS and investigate ADAMTS13 activity as a prognostic factor in aHUS. METHODS: We analyzed patients with thrombotic microangiopathy diagnosed as TTP (N=48) or aHUS (N=50), selected from a Korean registry (N=551). Complement activation products in the plasma samples collected from the patients prior to treatment and in 40 healthy controls were measured by ELISA. RESULTS: The levels of generalized (C3a), alternate (factor Bb), and terminal (C5a and C5b-9) markers were significantly higher (all P<0.01) in the patients than in the healthy controls. Only the factor Bb levels significantly differed (P=0.008) between the two disease groups. In aHUS patients, high normal ADAMTS13 activity (≥77%) was associated with improved treatment response (OR, 6.769; 95% CI, 1.605–28.542; P=0.005), remission (OR, 6.000; 95% CI, 1.693–21.262; P=0.004), exacerbation (OR, 0.242; 95% CI, 0.064–0.916; P=0.031), and disease-associated mortality rates (OR, 0.155; 95% CI, 0.029–0.813; P=0.017). CONCLUSION: These data suggest that complement biomarkers, except factor Bb, are similarly activated in TTP and aHUS patients, and ADAMTS13 activity can predict the treatment response and outcome in aHUS patients.
Atypical Hemolytic Uremic Syndrome ; Biomarkers ; Complement Activation ; Complement System Proteins ; Enzyme-Linked Immunosorbent Assay ; Humans ; Mortality ; Plasma ; Purpura, Thrombotic Thrombocytopenic ; Thrombotic Microangiopathies

Atypical hemolytic uremic syndrome (aHUS), a rare form of thrombotic microangiopathy, is distinguished from the typical form by the absence of a preceding verotoxin-producing Escherichia coli infection. Notably, aHUS occurs in association with genetic or acquired disorders causing dysregulation of the alternative complement pathway. Patients with aHUS may show the presence of anti-complement factor H (CFH) autoantibodies. This acquired form of aHUS (anti-CFH-aHUS) primarily affects children aged 9–13 years. We report a case of a 13-year-old Lao girl with clinical features of aHUS (most likely anti-CFH-aHUS). The initial presentation of the patient met the classical clinical triad of thrombotic microangiopathy (microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury) without preceding diarrheal illness. Low serum levels of complement 3 and normal levels of complement 4 indicated abnormal activation of the alternative complement pathway. Plasma infusion and high-dose corticosteroid therapy resulted in improvement of the renal function and hematological profile, although the patient subsequently died of infectious complications. This is the first case report that describes aHUS (possibly anti-CFH-aHUS) in Laos.
Adolescent ; Anemia, Hemolytic ; Atypical Hemolytic Uremic Syndrome ; Autoantibodies ; Child ; Complement C3 ; Complement C4 ; Complement Factor H ; Complement Pathway, Alternative ; Female ; Humans ; Immunosuppression ; Kidney ; Laos ; Plasma ; Shiga-Toxigenic Escherichia coli ; Thrombocytopenia ; Thrombotic Microangiopathies

Ehlers-Danlos syndrome (EDS) VIII is an autosomal dominant inherited connective tissue disorder characterized by intractable periodontal inflammation, absence of gingiva, pretibial plaques, skin hyperextensibility, joint hypermobility, and tissue fragility with onset in the childhood or adolescence. In a recent report, heterozygous variants of the C1R or C1S related to the classical complement pathway were identified in families with history of EDS VIII. The current report describes a Korean 34-year-old female carrying a novel missense variant of C1R c.925T>G (p.Cys309Gly) and exhibiting early severe periodontitis, skin fragility, and joint hypermobility. The patient also had frontal, parietal, and temporal white matter brain lesions without definite vascular abnormalities on brain magnetic resonance imaging, which have not been surveyed meticulously in EDS VIII. Considering the genetic alteration of classic complement pathways in this condition, it is necessary to carefully observe multisystemic inflammation processes such as changes in brain white matter.
Adolescent ; Adult ; Brain ; Complement C1r ; Complement Pathway, Classical ; Complement System Proteins ; Connective Tissue ; Ehlers-Danlos Syndrome ; Female ; Gingiva ; Humans ; Inflammation ; Joint Instability ; Magnetic Resonance Imaging ; Periodontitis ; Rabeprazole ; Skin ; White Matter

Glial cells are receiving much attention since they have been recognized as important regulators of many aspects of brain function and disease. Recent evidence has revealed that two different glial cells, astrocytes and microglia, control synapse elimination under normal and pathological conditions via phagocytosis. Astrocytes use the MEGF10 and MERTK phagocytic pathways, and microglia use the classical complement pathway to recognize and eliminate unwanted synapses. Notably, glial phagocytosis also contributes to the clearance of disease-specific protein aggregates, such as β-amyloid, huntingtin, and α-synuclein. Here we reivew recent findings showing that glial cells are active regulators in brain functions through phagocytosis and that changes in glial phagocytosis contribute to the pathogenesis of various neurodegenerative diseases. A better understanding of the cellular and molecular mechanisms of glial phagocytosis in healthy and diseased brains will greatly improve our current approach in treating these diseases.
Astrocytes ; Brain* ; Complement Pathway, Classical ; Microglia ; Neurodegenerative Diseases ; Neuroglia* ; Phagocytosis ; Protein Aggregates ; Synapses

C3 glomerulopathy (C3G) is a recently defined pathological entity characterized by C3 accumulation with absent or scant immunoglobulin deposition, leading to variable glomerular inflammation. The clinical presentation of patients with C3G is highly variable, as they may present with symptoms ranging from microscopic or mild proteinuria to full-blown nephrotic syndrome, with or without renal impairment. However, there is no consensus recommendation for specific treatment in children with C3G. Recently, new therapies have been suggested to target complement pathways, owing to an improvement in the understanding of the pathogenesis of C3G. C3G complement blockade with eculizumab, a monoclonal antibody targeted against complement C5, inhibits activation of the alternative complement pathway. We could not use eculizumab owing to its high price; thus, we administered oral prednisolone and mycophenolate mofetil (MMF). MMF was replaced with cyclosporine because proteinuria persisted, with a consistently low serum C3 level; we tapered off the prednisolone because of a Cushingoid appearance and amenorrhea. Thereafter, proteinuria improved, and the serum C3 level returned to normal. Thus, we report the effectiveness of cyclosporine in a patient with C3G and an inadequate response to prednisolone and MMF, who was detected via school urinary screening.
Amenorrhea ; Child* ; Complement C5 ; Complement Pathway, Alternative ; Complement System Proteins ; Consensus ; Cyclosporine* ; Female* ; Humans ; Immunoglobulins ; Inflammation ; Mass Screening ; Nephrotic Syndrome ; Prednisolone ; Proteinuria

The complement system is an innate immune defense machinery comprising components that deploy rapid immune responses and provide efficient protection against foreign invaders and unwanted host elements. The complement system is activated upon recognition of pathogenic microorganisms or altered self-cells by exclusive pattern recognition molecules (PRMs), such as collectins, ficolins and pentraxins. Recent accumulating evidence shows that the different classes of effector PRMs build up a co-operative network and exert synergistic effects on complement activation. In this review, we describe our updated view of the crosstalk between previously unlinked PRMs in complement activation and the potential pathogenic effects during infection and inflammation.
Collectins ; Complement Activation* ; Complement System Proteins* ; Inflammation

OBJECTIVETo investigate the action of Shen-Fu Injection (SFI) in regulating the expression of the serum complements and inflammatory cytokines synthesized and released in response to the stress of global ischemia accompanying cardiac arrest (CA) and resuscitation.

METHODSThirty pigs were randomly divided into the sham (n=6) and 3 returns of spontaneous circulation (ROSC) groups (n=24). After 8-min untreated ventricular fibrillation and 2-min basic life support, 24 pigs of the ROSC groups were randomized into three groups (n=8 per group), which received central venous injection of SFI (SFI group), epinephrine (EP group), or saline (SA group). Hemodynamic status and blood samples were obtained at 0, 0.5, 1, 2, 4, 6, 12, and 24 h after ROSC.

RESULTSSerum concentrations of specific activation markers of the complement system C3, C4 and C5b-9 were increased during cardiopulmonary resuscitation through 24 h after ROSC. There were intense changes of various pro-inflammatory cytokines and anti-inflammatory cytokines as early as 0.5 h after CA. Compared with the EP and SA groups, SFI treatment reduced the proinflammatory cytokines levels of interleukin (IL)-6, IL-8 and tumor necrosis factor α (TNF-α, P<0.05), and increased the anti-inflammatory cytokine levels of IL-4 and IL-10 (P<0.05). Further, SFI treatment decreased the values of C3, C4 and C5b-9 compared with the EP and SA groups.

CONCLUSIONSSFI, derived from the ancient Chinese medicine, has significant effects in attenuating post-resuscitation immune dysfunction by modulating the expression of complements and cytokines levels. The current study provided an experimental basis for the clinical application of a potential pharmacologic target for post resuscitation immune dysfunction.

Aconitine ; chemistry ; pharmacology ; Animals ; Cardiopulmonary Resuscitation ; Complement Activation ; drug effects ; Complement System Proteins ; metabolism ; Cytokines ; blood ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Ginsenosides ; chemistry ; pharmacology ; Hemodynamics ; drug effects ; Inflammation Mediators ; metabolism ; Injections ; Male ; Models, Animal ; Oxygen ; metabolism ; Survival Analysis ; Sus scrofa