This may explain why STEC-HUS, secondary HUS, and aHUS share clinical features although the processes start in various ways. THE CAUSE. Independent of the initiation point, the process may have similar features because of numerous feedback loops and powerful amplification under certain conditions. In secondary HUS, a coexisting disease such as autoimmunity, transplantation, or cancer, or an infection, normal pregnancy, or use of certain cytotoxic drugs is associated with disease manifestation.15  Pathogenesis of secondary HUS has not been intensively studied, but complement is involved in some cases. Finally, activation of the coagulation system leads to platelet activation via various mechanisms. Background: Patients negative for Shiga toxin-producing E. coli (STEC) are categorized as having atypical hemolytic uremic syndrome (HUS) and are associated with an increased risk for complement mutations and poorer prognosis compared with typical HUS. He… 1-3. Strictly speaking therefore, the presence of E. coli O157 should exclude this case as … 2013 Sep;24(6):496-502. doi: 10.1016/j.ejim.2013.05.009. Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. In aHUS, mutations have been reported in 5 central complement proteins. World J Hepatol. Schematic presentation of the main links between the complement and coagulation systems and platelets in formation of microthrombi in aHUS. Schematic model of the role of complement activation, cell damage, and thrombosis in various severe diseases or conditions with major thrombotic problems. Accordingly, it may be relevant for clinical hematologists to have insight into the role of complement in these diseases as well. The typical clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and organ damage can be explained in STEC-HUS by the cytotoxic effects of Shiga toxin and in secondary HUS and aHUS usually by complement-mediated processes. Accessibility 2012 Nov;8(11):622-33. doi: 10.1038/nrneph.2012.195. These phenomena lead to a procoagulative state, coagulation, and thrombosis-mediated tissue damage. In some of these diseases, such as PNH,134  sepsis syndrome,135  disseminated intravascular coagulation,3  or ischemia-reperfusion injury,84  the alternative pathway contributes to or is even fully responsible for initiating the complement activation. T. Sakari Jokiranta; HUS and atypical HUS. COVID-19 is an emerging, rapidly evolving situation. STEC-HUS is usually initiated a few days after clinical gastroenteritis caused by STEC (usually serotype O157:H7 or O104:H4), and the Shiga toxin is central in causing endothelial cell damage, thereby apparently initiating the disease process. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. Systematic Approach of Diagnosis Atypical HUS TTP Step 5 – TTP vs HUS Difficult to distinguish on clinical grounds only Differential diagnosis of aHUS is made on exclusion: • Of infections by STEC or neuraminidase - producing S.pneumoniae, • Of ADAMTS13 deficiency, • Of Systemic-associated diseases 5 Systematic Approach of Diagnosis 45. Unfortunately, there are many less typical patterns of TTP (secondary TTP) and HUS (aHUS) that occur in patients with another chronic medical condition, which may have acted as a trigger. In this model, the process is not linear but cyclical, and possibly all the processes happen simultaneously in vivo. Eur J Intern Med. Activation of the coagulation cascade leads to generation of active thrombin that is able to cleave not only fibrinogen but also complement C5, which thereby enables coagulation-enhanced complement activation. Those molecules include diacylglycerol kinase ε,10  plasminogen,11  and factor XII (although only in the presence of anti-factor H autoantibodies).9,12  In addition, some patients with aHUS are associated with mutations in thrombomodulin (CD141),13  which has a role in both coagulation and complement regulation.13,14. Recurrent Glomerulonephritis after Renal Transplantation: The Clinical Problem. In addition to infections, secondary HUS may be associated with transplantation (solid organ or bone marrow),25-28  autoimmune disease,29,30  cancer,31,32  pregnancy,33  and the use of certain cytotoxic drugs.34,35  The common feature for these coexisting diseases or conditions is that they may cause direct cell damage, promote activation of the complement system in general, or enhance activation of complement on self cells (Figure 1). Atypical-HUS is a rare and complicated disease caused by an uncontrolled complement system, which is part of the body’s immune system. Cells that are continuously exposed to complement alternative pathway activation include all cells in contact with plasma: red cells, platelets, leukocytes, and endothelial cells. Early recognition is critical, because of the potential to improve morbidity and mortality. CAPS, catastrophic antiphospholipid syndrome, DIC, disseminated intravascular coagulation; PLG, plasminogen; THBD, thrombomodulin. HUS usually occurs in children following an infection, typically with Shiga toxin–producing bacteria (eg, Escherichia coli O157:H7 ), … Infante B, Rossini M, Leo S, Troise D, Netti GS, Ranieri E, Gesualdo L, Castellano G, Stallone G. Int J Mol Sci. The remainder of cases are called atypical haemolytic uraemic syndrome (aHUS). Bianchi L, Gaiani F, Vincenzi F, Kayali S, Di Mario F, Leandro G, De' Angelis GL, Ruberto C. Acta Biomed. doi: https://doi.org/10.1182/blood-2016-11-709865. These common features indicate similarities in disease pathogenesis of these 3 forms of HUS. Epub 2012 Sep 18. Examples of such factors are cell exposure to nitric oxide, free hemoglobin, activated neutrophils and monocytes or released reactive oxygen species from these cells, C3a or C5a, proinflammatory cytokines, proinflammatory or procoagulant microparticles, or cellular hypoxia due to microthrombi. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Diacylglycerol kinase ε mutations are most frequently found in patients with disease manifestation within the first year of life (5%-27% in this population). In general, it is likely that HUS and aHUS are not the only diseases in which the feedback loop among cell damage, coagulation and thrombosis, hypoxia-mediated endothelial activation, and activation of complement form a vicious cycle. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Know your atypical-HUS. Clipboard, Search History, and several other advanced features are temporarily unavailable. Most of the links in this kind of self-amplifying process are evident, but the clinical importance of some others in human diseases remains to be shown. The simultaneous interaction of factor H with both C3b and cell surface sialic acids (or possibly glycosaminoglycans [GAGs]) is essential for proper regulation on self red cells, platelets, and endothelial cells. Research Programs Unit, Immunobiology, University of Helsinki, Helsinki University Central Hospital, and United Medix Laboratories, Helsinki, Finland. In the pathogenesis of aHUS, STEC-HUS, and at least some forms of secondary HUS, the interplay between complement, coagulation, and platelets seems to be essential. This results in a low number of covalently bound (via hydroxyl or amine groups) C3b depositions on practically all biological surfaces in contact with plasma,46,47  a phenomenon that can be compared with blind shooting. If the initial C3b deposit is rapidly inactivated, then activation fails to proceed and the surface is spared. This condition, which can occur at any age, causes abnormal blood clots (thrombi) to form in small blood vessels in the kidneys. Distinct from these is the alternative pathway of complement, which is based on constant and spontaneous low-level activation in plasma. It is important not to confuse “triggers” of atypical HUS with the root cause. The impact of complement in the pathogenesis of STEC-HUS and secondary HUS is still uncertain. The cellular or molecular consequences discussed above can be summarized as parallel or consecutive phenomena with regard to the various cells involved and the clinical signs typical for HUS and aHUS, thereby forming a model of HUS pathogenesis (Figure 4). STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Cureus. (Left) Activation of complement consists of continuous alternative pathway activation and occasional (or longer standing) physiological or pathological activation. Complement activation in diseases presenting with thrombotic microangiopathy. 2018 Dec 17;89(9-S):153-157. doi: 10.23750/abm.v89i9-S.7911. Secondary HUS is initiated by a coexisting disease or condition. D (+) HUS has also been labeled 'typical HUS' and D (-) HUS as 'atypical HUS'. aHUS can be inherited or acquired, and does not appear to vary by race, gender, or geographic area. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. However, atypical-HUS can be managed. It is logical that therapeutic complement inhibition is effective in aHUS. A pediatric prevalence of 3.3 cases per million population is documented in one publication of a European hemolytic uremic syndrome (HUS) registry involving 167 pediatric patients. 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Lessons from genotype-phenotype correlations, Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome, Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome, A case of atypical hemolytic uremic syndrome due to anti-factor H antibody in a patient presenting with a factor XII deficiency identified two novel mutations, Thrombomodulin mutations in atypical hemolytic-uremic syndrome, Thrombomodulin and its role in inflammation, An international consensus approach to the management of atypical hemolytic uremic syndrome in children, Manganese blocks intracellular trafficking of Shiga toxin and protects against Shiga toxicosis, Shiga toxin downregulates tissue factor pathway inhibitor, modulating an increase in the expression of functional tissue factor on endothelium, Role of complement in enterohemorrhagic Escherichia coli-Induced hemolytic uremic syndrome, Shiga toxin-induced complement-mediated hemolysis and release of complement-coated red blood cell-derived microvesicles in hemolytic uremic syndrome, Platelet activation in hemolytic uremic syndrome, Collaborators of the DGfN STEC-HUS registry, Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry, Action of shiga toxin type-2 and subtilase cytotoxin on human microvascular endothelial cells, The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome. Our recent study provided a novel possible explanation for why certain infections can lead to secondary HUS. Objective To determine the efficacy and safety of eculizumab for patients with atypical haemolytic uraemic syndrome (aHUS), compared with current treatment options. Streptococcus pneumonia-associated hemolytic uremic syndrome (HUS) (pneumococcal HUS) is an uncommon condition mainly observed in young children. In this global, phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial … Unable to load your collection due to an error, Unable to load your delegates due to an error. Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. In a number of aHUS patients, an infection (often an upper respiratory tract infection) precedes the clinical triad typical for TMAs.8  In aHUS, infections are usually considered as triggers, not as causes of the disease as such. The use of therapeutic complement inhibition beyond the current indications of eculizumab (aHUS and PNH) might demonstrate the relevance of complement in at least some of these disease processes. In our review we summarize the pathophysiology, clinical features, diagnostic difficulties and management of this potentially under-diagnosed condition. Although complement clearly contributes to disease pathogenesis in some patients with STEC-HUS,126  and some patients seem to benefit from early administration of eculizumab,127  most STEC-HUS patients do not respond clearly to this drug.21  TTP is also not generally considered to be an indication for eculizumab treatment,128,129  mainly because plasma therapy is usually effective. Atypical hemolytic-uremic syndrome is a disease that primarily affects kidney function. The impact of complement is seen most clearly in observing the effects of therapeutic complement inhibition on these diseases. As expected with an ultra-rare disease, data on the prevalence of aHUS are extremely limited. Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. Please enable it to take advantage of the complete set of features! The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In addition, autoantibodies against factor H can interfere with regulation in a manner similar to mutations.69  The common feature for the mutations and autoantibodies is impaired control of the complement alternative pathway on self-cell surfaces. (Right) Regulation consists of the role of the membrane regulators CD35, CD46, CD55, and CD59, and the plasma regulators factors H and I. The most important of these seems to be the activation of platelets by membrane attack complexes92  or C5a.102  The procoagulative effect of membrane attack complexes seems to be mediated by platelet prothrombinase,103  not by irreversible cell damage.104  Independent of the reason for the activation of platelets, it is well known that their activation and aggregation is closely linked to coagulation, thereby creating another bridge between activation of the complement and coagulation cascades. This has led to some oversimplification, in that atypical has become synonymous with poor outcome. Hemolytic Uremic Syndrome (HUS) • A thrombotic mircoangiopathy (TMA) characterized by: • Non-immune Microangiopathic Hemolytic Anemia (MAHA) • Elevated LD, low haptoglobin, schistocytes • Thrombocytopenia • Acute Kidney Injury • Can involve multiple organ systems (CNS, cardiac, pulmonary, liver, etc) 9. ULTOMIRIS is the first and only long-acting complement inhibitor for atypical-HUS that provides immediate and complete C5 inhibition sustained for up to 8 weeks. Some disturb recognition of C3b by factor H,56,60  factor I,61  or CD4662 ; some disturb recognition of self-cell surface molecules, such as sialic acid or glycosaminoglycans, by factor H.55,59  Some mutations in C3 or factor B prolong the C3 convertase half-life or prevent its elimination.63,64  The frequencies of mutations observed in aHUS are shown in Table 1. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. Despite this, eculizumab has been beneficial in some TTP cases that are refractory to conventional therapy.130,131  Eculizumab does not seem to be effective for the aHUS patients in whom a DGKε mutation is found10,113,132  or in those with cobalamin C deficiency in adulthood133 ; however, this treatment has been attempted in only a limited number of patients. Pandemic H1N1 influenza A infection and (atypical) HUS--more than just another trigger? There are also links between complement and platelets. Endothelial cells and leukocytes can remove complement deposits and membrane attack complexes more efficiently than red cells, either by internalization or by shedding from the plasma membrane in microvesicles.78,79  In addition, these cells may also repair membrane damage. The more important of these is promotion of phagocytosis via opsonization with C3b and its fragments, as well as phagocyte attraction via release of powerful chemotactic and anaphylatoxic peptides such as C5a.42  These phenomena lead to rapid opsonophagocytosis of the target by neutrophils and macrophages (Figure 2A). Does dysregulated complement activation contribute to haemolytic uraemic syndrome secondary to Streptococcus pneumoniae? Regulation is compromised by mutations in complement regulators, autoantibodies against factor H, or potentially some infections in which microbes remove sialic acids from the surface of self cells. Excess complement activation on endothelial cell, platelet, and red cell surfaces leads to C5a release and membrane attack complex (MAC) formation. Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome. © 2017 by The American Society of Hematology. Rinsho Ketsueki. Combined liver-kidney transplantation for rare diseases. 2020 Sep 11;12(9):e10392. 2020 Sep 3;5(36):23070-23080. doi: 10.1021/acsomega.0c02833. Most of these mutations lead to impaired regulation of alternative pathway activation. Induction of circular C9 polymerization by the C5b-8 assembly, C3d of complement as a molecular adjuvant: bridging innate and acquired immunity, Initiation of the alternative complement pathway due to spontaneous hydrolysis of the thioester of C3, Covalent binding and hemolytic activity of complement proteins, Factor H mediated cell surface protection from complement is critical for the survival of PNH erythrocytes, Formation of the initial C3 convertase of the alternative complement pathway. (B) Alternative pathway activation is based on continuous, low-level covalent deposition of C3b molecules onto practically all surfaces in contact with plasma. However, some shedding of the complement membrane attack complexes on these cells can occur,70  but contribution of this phenomenon to the protection of red cells from complement lysis has not been proven. The process of pathogenesis in typical HUS or STEC-HUS is apparently initiated when the Shiga toxin (or Shiga-like toxin), a known potent cytotoxin, binds to cell membrane glycolipid Gb3 (via domain B). Studies on the pathogenesis of aHUS have revealed a central role of factor H in discriminating between self cells and microbes (ie, whether a target should be spared or destroyed).55,56  If factor H binds to C3b deposited onto a surface, activation is efficiently inhibited. Complement activation may also contribute to pathogenesis in some patients with STEC-HUS and secondary HUS, either by regulation defects or by triggers that lead to enhanced complement activation. has received lecture honoraria or consultation fees from AbbVie, Alexion Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Medac Pharma, Merck Sharp & Dohme, Pfizer, Roche, and Takeda Pharmaceuticals. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGKε mutation, and some patients with STEC-HUS or secondary HUS. There are several feedback loops in this process. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Common for the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. The level of complement activation can be increased by mutations in complement proteins C3 or factor B, infections, iatrogenic phenomena (eg, transplantation, plasma exchange, or certain drugs), pregnancy, or malignancy. The impact of complement activation on the pathogenesis of STEC-HUS, aHUS, and secondary HUS seems to be variable, apparently because of the biological phenomena linked to the pathogenesis. Second, complement activation leads to release of C5a or formation of soluble C5b-9 complexes that can induce endothelial cell activation and expression of procoagulative tissue factor.95-97  In addition, numerous molecular interactions between complement and coagulation proteins have been described.98,99  The physiological relevance of most of these interactions has not been proven. Blood 2017; 129 (21): 2847–2856. While children are more commonly affected, adults may have worse outcomes. This provides an explanation for the observed increase in complement hemolytic activity during the acute phase.109  Increased plasma concentrations of these proteins do not trigger complement activation as such but could promote activation upon complement-activating circumstances caused by the microbe itself or damaged host tissues. Atypical hemolytic uremic syndrome (aHUS) is a rare variant of TMA that is caused by abnormalities of the alternative complement pathway resulting in endothelial cell dysfunction and formation of microvascular thrombi. Description. Atypical-HUS is a rare disease that affects 1 to 2 people out of every 1 million Americans. * *Starting 2 weeks after the initial loading dose, maintenance doses are administered once … National Library of Medicine Article No 393. Thrombosis can lead to further tissue damage and increasing complement activation. Correspondence: T. Sakari Jokiranta, Research Programs Unit, Immunobiology, Haartmaninkatu 3, FIN-00014, University of Helsinki, Helsinki, Finland; e-mail: sakari.jokiranta@helsinki.fi. (A) The complement system can be activated via 3 pathways: classical, lectin, and alternative. Hemolytic-uremic syndrome (HUS) is an acute, fulminant disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. We observed that sialic acid in in vitro assays is the main ligand for factor H on red cells and also on platelets and endothelial cells.59  Pneumococci23  and influenza A virus,24  most often seen in secondary HUS associated with infections, possess very active neuraminidases specialized in removing sialic acid from self cell surfaces.110,111  It is therefore possible that microbial enzymes could make self blood cells more vulnerable to the complement alternative pathway.112, The course of STEC-HUS is usually self-limiting, although acute kidney injury and systemic involvement can complicate and prolong the disease. Endothelial cell damage is evident in histologic analysis of biopsies taken from HUS patients during the acute stage.80  The reason for endothelial cell damage in STEC-HUS is linked to Shiga toxin, whereas damage in aHUS has been attributed to lytic or sublytic complement attack.60,81  However, several other mechanisms affecting endothelial cells can cause or contribute to the damage. However, there are no specific biomarkers for the diagnosis of DIC. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. The primary point of process initiation could be in complement-mediated cell damage, direct activation of platelets, initiation of a procoagulative state in the endothelium, dysregulation of the coagulation or thrombolytic pathways, or direct complement-independent cell damage. Although complement is involved in each of these diseases, its impact needs to be clarified in clinical studies. There are two main mechanistic explanations underlying hemolysis and the appearance of red cell fragments and schistocytes in the peripheral blood in aHUS (ie, signs of microangiopathic hemolysis characteristic for TMAs).72,73  The first and traditional explanation is mechanical hemolysis as a result of narrowed microvasculature caused by microthrombi. Such a cycle could be formed between complement-mediated cell damage (to endothelial cells, platelets, and red cells), formation of fibrin or platelet thrombi (or both), tissue hypoxia as a result of vascular occlusion, further tissue damage, and damage-induced secondary complement overactivation (Figure 5). Hemolytic uremic syndrome (HUS) is a condition that can occur when the small blood vessels in your kidneys become damaged and inflamed. Atypical hemolytic uremic syndrome (aHUS) is a disease that causes abnormal blood clots to form in small blood vessels in the kidneys. Complement is activated via 3 pathways: classical, lectin, and alternative. Some interactions, such as cleavage of C5 by thrombin, may be clinically relevant.100,101. The process can enhance itself via positive feedback loops and form a vicious cycle. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice. Atypical HUS & #Nephrology #SoMe. Epub 2016 Oct 7. Activation of complement can occur via the alternative pathway (in the absence of antibodies) or the classical pathway (in the presence of target-bound antibodies). In this review, the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed with an emphasis on the role of complement in the disease processes and the similarities and differences between STEC-HUS and aHUS, also considering the possible role of complement in secondary HUS. Complement as a Therapeutic Target in Systemic Autoimmune Diseases. HUS is usually categorized as typical, caused by Shiga toxin-producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. eCollection 2020 Sep 15. Nevertheless, at least some patients seem to benefit from therapeutic complement inhibition, indicating that complement may also be involved in these diseases. Epub 2013 Jun 4. In many cases, HUS is caused by infection with certain strains of Escherichia coli (E. coli) bacteria. Understanding the central differences in pathogenesis between aHUS and STEC-HUS began with the discovery of the association between aHUS and mutations in the gene coding for the key complement regulator in plasma, complement factor H (CFH).7  Thereafter, mutations in several other complement regulators and other complement proteins, such as C3, factor B, factor I, and CD46, have been identified.8  Many patients have more than 1 mutation or rare polymorphisms affecting the complement system.9, In addition to mutations in complement proteins, some patients with aHUS have mutations also in or only in molecules not directly linked to the complement system. Taking action and learning about the disease is a great place to start. Platelets may, however, be involved, either primarily or secondarily, in pathogenesis of this disease because thrombocytopenia is a typical feature of TMAs,89  and the thrombi in capillaries and arterioles contain platelets90  in addition to red cells.91  Platelets are easily activated by complement attack92  via the formation of membrane attack complex on the platelet membrane,93  but some internalization or shedding of the complement membrane attack complexes can occur.40  Although platelets are normally protected from complement attack by the concerted action of factor H and membrane regulators,94  this protection is impaired in aHUS.20  We have recently shown that protection of platelets from complement attack by factor H requires sialic acids on the cell membrane in vitro.59  Therefore, impaired alternative pathway regulation is a logical explanation for thrombocytopenia and could also contribute to formation of platelet-rich microvascular thrombi.72,73, The common conclusion from the numerous studies linking complement and coagulation is that complement activation leads to initiation or enhancement of coagulation.
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