Materiały źródłowe

• #1 Hemolytic Uremic Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556038/

  Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. HUS is most commonly caused by Shiga toxin (typical HUS) or, less commonly, infections or genetic abnormalities activating the alternative complement pathway (atypical HUS). […] In addition to cytotoxic effects, Shiga toxin is capable of activating the complement system by inhibiting complement factor H. Upon entering the bloodstream, Shiga toxin persists in binding to cells via the Gb3 receptor, with the highest prevalence found in the glomerular microvasculature. Endothelial damage is caused by 1) direct cytotoxicity of Shiga toxin, 2) disturbance of the hemostatic pathway, 3) increased cytokine release, and 4) alternative pathway activation.

• #2 Hemolytic-Uremic Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/779218-overview

  Damage to endothelial cells is the primary event in the pathogenesis of hemolytic-uremic syndrome (HUS). The cardinal lesion is composed of arteriolar and capillary microthrombi (thrombotic microangiopathy [TMA]) and red blood cell (RBC) fragmentation. […] HUS is classified into two main categories, depending on whether it is associated with Shiga toxin (Stx) or not. […] Typical HUS (Shiga toxin-associated HUS [Stx-HUS]) is the classic, primary or epidemic, form of HUS. […] Acute kidney injury occurs in 55-70% of patients, but they have a favorable prognosis, and as many as 70-85% of patients recover kidney function. […] Data from some studies have suggested that Stx favors leukocyte-dependent inflammation by altering endothelial cell-adhesion properties and metabolism, ultimately resulting in microvascular thrombosis.

• #2 Hemolytic-Uremic Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/779218-overview

  Non-Stx-HUS, or atypical HUS, is less common than Stx-HUS and accounts for 5-10% of all cases. […] Atypical HUS is a complement-mediated thrombotic microangiopathy. […] Overall, patients with non-Stx-HUS have a poor outcome, with as many as 50% progressing to end-stage renal disease (ESRD) or irreversible brain damage. […] The pathogenesis in these cases appears to have several mechanisms. […] Data suggest that familial non-Stx-HUS results from genetic abnormalities in the complement regulatory proteins, including C3, factor H, factor B, factor I, and CD46 (membrane cofactor protein, MCP). […] Factor H appears to be particularly important. […] Suboptimal HF1 activity is often enough to protect the patient from complement activation in physiologic conditions. However, activation of complement pathways results in higher-than-normal concentration of C3b, and its deposition on vascular endothelial cells cannot be prevented because of the inability of mutant HF1 to bind to polyanion proteoglycans.

• #3 Hemolytic-Uremic Syndrome (HUS) – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/thrombocytopenia-and-platelet-dysfunction/hemolytic-uremic-syndrome-hus

  Hemolytic-uremic syndrome, like thrombotic thrombocytopenic purpura (TTP), involves nonimmunologic platelet destruction. Endothelial damage is common. Loose strands of platelets and fibrin are deposited in multiple small vessels and damage passing platelets and red blood cells (RBCs), causing significant thrombocytopenia and anemia (microangiopathic hemolytic anemia). Platelets are also consumed within multiple small thrombi, contributing to the thrombocytopenia. […] Multiple organs develop platelet von Willebrand factor (VWF) thrombi localized primarily to arteriocapillary junctions, described as thrombotic microangiopathy. The brain, heart, and kidneys are particularly likely to be affected. The microthrombi do not include RBCs or fibrin (unlike thrombi in disseminated intravascular coagulation) and do not manifest the vessel wall granulocytic infiltration characteristic of vasculitis. Large-vessel thrombi are uncommon.

• #4 Hemolytic–uremic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hemolytic%E2%80%93uremic_syndrome

  HUS is caused by ingestion of bacteria that produce Shiga toxins, with Shiga-toxin producing E. coli (STEC) being the most common type. E. coli can produce shigatoxin-1, shigatoxin-2, or both; with shigatoxin-2 producing organisms being more virulent and being much more likely to cause HUS. […] Once ingested, the bacteria move to the intestines where they produce the Shiga toxins. The bacteria and toxins damage the mucosal lining of the intestines, and thus are able to gain entry into the circulation. […] Shiga toxin enters the mesenteric microvasculature lining the intestines where it releases inflammatory cytokines including IL-6, IL-8, TNF, and IL-1. […] These inflammatory mediators lead to inflammation and vascular injury with microthrombi that are seen with HUS. It also further damages the intestinal barrier leading to diarrhea (usually bloody) and further entry of Shiga toxin from the intestines to the bloodstream as the intestinal barrier is compromised.

• #5 Hemolytic uremic syndrome (HUS) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hemolytic-uremic-syndrome/symptoms-causes/syc-20352399

  Hemolytic uremic syndrome (HUS) is a condition that can occur when small blood vessels become damaged and inflamed. This damage can cause clots to form in the vessels all through the body. The clots can damage the kidneys and other organs. Hemolytic uremic syndrome can lead to kidney failure, which can be life-threatening. […] All forms of hemolytic uremic syndrome damage blood vessels. This damage causes red blood cells to break down, called anemia. The condition also causes blood clots to form in the blood vessels and, in turn, damage the kidneys. […] The most common cause of hemolytic uremic syndrome is infection with certain strains of E. coli bacteria. This is especially true for children under age 5. Some of the E. coli strains make a toxin called Shiga toxin. These strains are called Shiga toxin-producing E. coli (STEC).

• #6 Hemolytic Uremic Syndrome (HUS): Pearls and Pitfalls – emDocs

  https://www.emdocs.net/hus-pearls-and-pitfalls/

  The main culprit in STEC HUS is the Shiga toxin. The Shiga toxins are AB5 toxins that halt protein synthesis within the host cell, leading to apoptosis. HUS is thought to occur from damage to renal glomerular endothelial cells by Shiga toxin. The pathogenesis of STEC begins with oral ingestion. STEC reaches the human gut and adheres to the epithelial cells of the GI mucosa. Once it reaches systemic circulation, it is carried by polymorphonuclear cells to the kidneys. The toxin causes cell lysis, leading to detachment of the glomerular endothelial cells from the basement membrane while at the same time activating various cytokines, platelets, and the coagulation cascade. As thrombi form in smaller vessels, red blood cells are damaged leading to microangiopathic hemolysis. Unfortunately the toxin can deposit in any organ. Renal insufficiency is thought to occur due to fibrin thrombi formation at three levels in the kidney: glomerular, arterial, and cortical.

• #7 Treatment of enterohemorrhagic Escherichia coli (EHEC) infection and hemolytic uremic syndrome (HUS) | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-10-12

  Verotoxigenic Escherichia coli (VTEC) are a specialized group of E. coli that can cause severe colonic disease and renal failure. Their pathogenicity derives from virulence factors that enable the bacteria to colonize the colon and deliver extremely powerful toxins known as verotoxins (VT) or Shiga toxins (Stx) to the systemic circulation. […] The pathogenesis of HUS disease remains incompletely understood; remarkably, during HUS serum Stx is undetectable. It seems polymorphonuclear leukocytes (PMN) are key players in delivering Stx to critical sites such as the kidneys. The extent of renal damage in children with STEC-associated HUS may relate to the concentration of Stx present on circulating PMN. […] The microvasculature plays an important role in pathogenesis: D+HUS is associated with platelet thrombi in the microvasculature of almost all vascular beds.

• #8 The Epidemiology of Hemolytic Uremic Syndrome: Clinical Presentation, Laboratory Findings, Management and Outcomes

  https://symbiosisonlinepublishing.com/hematology/hematology19.php

  Hemolytic-uremic syndrome (HUS) is a disease that has been initially identified in 1955 and described as a triad of sudden drop of hemoglobulin (hemolytic anemia), thrombocytopenia and kidney dysfunction. There are two types of HUS. Typical HUS that follows infection like E. coli OH157:H7, Shiga toxin and others. Atypical HUS (aHUS) defined as non-Shigatoxin- HUS that results from dysregulation of the complement alternative pathway and has a less favorable outcome. HUS and thrombotic thrombocytopenic purpura (TTP) are the two main variants of thrombotic microangiopathies (TMA) and related disorders. The important role of leukocytes in the pathogenesis of HUS and its endothelial dysfunction leading to HUS was also noted to be of vital role. In vitro experiments, STEC binds to leukocytes and is transferred by them to endothelial cells. Accordingly, STEC also has been detected on the surface of circulating leukocytes of patients with HUS, and in a murine HUS model, STEC 2 induced neutrophilia and neutrophil activation.

• #9 Hemolytic Uremic Syndrome: New Developments in Pathogenesis and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3159990/

  Hemolytic uremic syndrome is defined by the characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. […] Shiga toxin-(Stx-) mediated injury to vascular endothelial cells in the kidney, brain, and other organs underlies the pathogenesis of HUS caused by EHEC. […] Gb3 is a sphingolipid receptor expressed on endothelial cells, podocytes, and proximal tubular cells in human. […] Stx binding to Gb3 leads to Stx internalization by receptor-mediated endocytosis and its retrograde transport to the endoplasmic reticulum. […] This triggers a cascade of signalling events, involving NF-B activation, which induces apoptosis and the binding of leukocytes to endothelial cells. […] Stx-activated endothelial cells become thrombogenic by a complex mechanism not yet fully unravelled.

• #10 Hemolytic–uremic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hemolytic%E2%80%93uremic_syndrome

  Once Shiga toxin enters the circulation it can travel throughout the body and cause the wide array of end organ damage and the multitude of symptoms seen with HUS. […] Shiga toxin gains entry to cells by binding to globotriaosylceramide (Gb3) which is a globoside found on cell membranes, it is found throughout the body including the surface of the glomerular endothelium of the kidney. […] Shiga toxin gains entry to the cell via Gb3 and endocytosis, it then is transported to the Golgi apparatus where furin cleaves the A subunit of the Shiga toxin. […] It is then transported to the endoplasmic reticulum where it is further cleaved, leaving the A1 subunit of Shiga toxin free. The A1 subunit of Shiga toxin inhibits the 28s subunit of the ribosomal rRNA, this leads to inhibited protein production by the ribosomes.

• #11 Pathogenesis of Shiga Toxin-Associated Hemolytic Uremic Syndrome | Pediatric Research

  https://www.nature.com/articles/pr2001160

  A hypothetical sequence of events from ingestion of the bacteria to the development of full-blown hemolytic uremic syndrome is proposed. […] The histopathologic features observed in HUS have been termed thrombotic microangiopathy, a term that also encompasses other conditions such as HUS not associated with a diarrheal prodrome (D HUS) and thrombotic thrombocytopenic purpura. […] Endothelial cell damage is the hallmark of thrombotic microangiopathy found in D+ HUS. […] The histopathologic findings in D HUS and thrombotic thrombocytopenic purpura are different from those in D+ HUS. […] Strains of STEC that can cause hemorrhagic colitis and HUS have been termed EHEC. […] Human isolates of STEC may express Stx1 or Stx2 encoded on a bacteriophage. […] The A subunit has N-glycosidase activity, which leads to cell death by inhibition of protein synthesis at the level of 28S ribosomal RNA.

• #12 Hemolytic Uremic Syndrome: New Developments in Pathogenesis and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3159990/

  It has been demonstrated that Stxs modulate the expression of endothelial cell adhesive molecules such as 3-integrin subunit, vitronectin receptor, PECAM-1, and P-selectin on the microvasculature and induce the release of cytokines and chemokines by endothelial cells, implicated in platelet activation. […] An in vitro study showed that in addition to directly damaging the kidney, Stxs also activate complement and delay the function of its inhibitor, factor H, on the cell surface, leading to indirect kidney damage. […] These mutations result in dysregulation of the complement system that leads to excessive complement activation and in endothelial damage. […] The gene that is affected determines the clinical presentation and outcome. […] For example, patients with mutations of the gene for factor H (CFH) often progress to ESRD within the first year of presentation.

• #13 Hemolytic–uremic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hemolytic%E2%80%93uremic_syndrome

  With the cell’s protein synthesis inhibited by Shiga toxin, the cell is destroyed. […] This leads to vascular injury (including in the kidneys where Gb3 is concentrated). The vascular injury facilitates the formation of vascular microthrombi which are characteristic of TTP. […] The TTP leads to platelet trapping (and thrombocytopenia), red blood cell destruction (and anemia), and end organ damage that is characteristically seen with HUS and TTP. […] HUS is one of the thrombotic microangiopathies, a category of disorders that includes STEC-HUS, aHUS, and thrombotic thrombocytopenic purpura (TTP). The release of cytokines and chemokines (IL-6, IL-8, TNF-, IL-1) that are commonly released by Shiga toxin are implicated in platelet activation and TTP. […] The presence of schistocytes is a key finding that helps to diagnose HUS.

• #14 Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review

  https://www.mdpi.com/2072-6651/12/2/67

  Shiga toxins induce a profound remodeling of the gene expression repertoire of endothelial cells rather than prompting cell death, provided that vascular cells are subjected to sublethal concentrations of Shiga toxin. […] The net effect is that endothelial cells adopt a prothrombogenic phenotype by expressing increased levels of tissue factor (TF), releasing augmented levels of von Willebrand factor, and activating platelets via the CXCR4/CXCR7/SDF-1 pathway. […] Shiga toxins activate multiple stress signaling and apoptotic pathways, and it is responsible for the production of inflammatory cytokines by target cells. […] Evidence has also been garnered suggesting the participation of an alternative pathway in STEC-HUS. […] Plasma levels of Bb and C5b-9, two complement pathway products, and C3-bearing microparticles from platelets and monocytes, were found to be elevated in patients suffering from STEC-HUS. […] The absence of C4d or C5b9 by immunochemistry in biopsies from patients during the O104:H4 outbreak is also a source of concern. […] The pathophysiology of Shiga toxin trafficking and intracellular action is schematized in Figure 3.

• #15 Hemolytic–uremic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hemolytic%E2%80%93uremic_syndrome

  Shiga-toxin directly activates the alternative complement pathway and also interferes with complement regulation by binding to complement factor H, an inhibitor of the complement cascade. […] Shiga-toxin causes complement-mediated platelet, leukocyte, and endothelial cell activation, resulting in systemic hemolysis, inflammation and thrombosis. […] Severe clinical complications of TMA have been reported in patients from 2 weeks to more than 44 days after presentation with STEC-HUS, with improvements in clinical condition extending beyond this time frame, suggesting that complement activation persists beyond the acute clinical presentation and for at least 4 months. […] The consumption of platelets as they adhere to the thrombi lodged in the small vessels typically leads to mild or moderate thrombocytopenia with a platelet count of less than 60,000 per microliter.

• #16 Shiga Toxin Associated Hemolytic Uremic Syndrome | Oncohema Key

  https://oncohemakey.com/shiga-toxin-associated-hemolytic-uremic-syndrome/

  Stx can bind to and inhibit the complement regulatory function of complement factor H (CFH) and CFH-related protein 1, which may make cells vulnerable to complement-mediated damage. […] Stx can directly activate complement predominately via the alternative pathway. […] In this murine model of Stx HUS, alternative pathway blockade through genetic knockout was protective.

• #17 The Role of the Complement System in the Pathogenesis of Infectious Forms of Hemolytic Uremic Syndrome

  https://www.mdpi.com/2218-273X/14/1/39

  Dysregulation of the activity of these systems and the pathways of interaction between them can lead to the development of severe complications, including complement-associated thrombotic microangiopathies. […] The complement system is in close relationship with the blood coagulation system and the result of the development of HUS is thrombosis. […] The complement system is also involved in the pathogenesis of STEC-HUS. […] The activation of the complement system may be mediated by P-selectin. […] The mechanisms of lectin pathway activation are unclear. […] The data presented in the literature allow us to identify several possible pathways of activation of the complement system in STEC-HUS. […] The activation of the complement system is accompanied by the cleavage of native factors with the formation of complexes with specific activities.

• #18 Delayed Hemolytic Uremic Syndrome Presenting as Diffuse Alveolar Hemorrhage

  https://www.accjournal.org/journal/view.php?number=156

  Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical intravascular hemolytic anemia with schistocytosis, thrombocytopenia and acute renal failure. […] The distinction of pathogenesis is blurred because Shiga toxin can also mediate alternative complement pathway activation and acquired complement dysfunction in typical HUS. […] The current hypothesis about alveolar hemorrhage in HUS is that endothelial damage, the landmark of thrombotic microangiopathy, results in alveolar wall necrosis, loss of capillary integrity and alveolar hemorrhage. […] It is remarkable that renal insufficiency, alveolar hemorrhage, and myocarditis could be preceding manifestations prior to the development of typical features such as hemolytic anemia or thrombocytopenia. […] In atypical HUS, plasmapheresis with infusions of fresh frozen plasma is the first treatment option. […] The complement blocker, eculizumab (humanized monoclonal anti-C5 immunoglobulin G) should be considered for HUS patients who are resistant to plasma exchange.

• #19 Atypical hemolytic uremic syndrome | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-6-60

  Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and renal impairment. […] Atypical HUS represents 5 -10% of HUS in children, but the majority of HUS in adults. […] Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20-30%, 5-15%, 4-10% and 3-5% of patients respectively, and mutations in the genes of C3 convertase proteins, C3 and factor B, in 2-10% and 1-4%. […] Diagnosis of aHUS relies on 1) No associated disease 2) No criteria for Shigatoxin-HUS (stool culture and PCR for Shiga-toxins; serology for anti-lipopolysaccharides antibodies) 3) No criteria for thrombotic thrombocytopenic purpura (serum ADAMTS 13 activity 10%).

• #20 Hemolytic Uremic Syndrome (HUS): Symptoms, Treatment, Causes, Prognosis

  https://www.medicinenet.com/hemolytic_uremic_syndrome/article.htm

  Only the diarrheal form of HUS is considered to be typical HUS and is usually a disease of infants and children younger than 3 years of age. The others are classified as atypical HUS and also include the familial form of the disease in which a gene mutation affects the blood clotting mechanism. […] In typical HUS, gastroenteritis occurs with abdominal cramping, vomiting and profuse bloody, watery diarrhea, as a symptom up to a week before the onset of HUS. This may cause significant dehydration, weakness and lethargy, as well as electrolyte imbalances because of the loss of sodium, potassium, and chloride in the vomit and diarrhea. These symptoms may resolve before the onset of anemia and the kidney failure symptoms of HUS. […] The anemia and uremia usually present with weakness, lethargy, and sleepiness. Seizures may occur. Purpura or small areas of bleeding in the skin may be seen because of low platelet counts (thrombocytopenia).

• #21 Hemolytic Uremic Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556038/

  In aHUS, the alternative complement pathway is activated as described above, with particular emphasis on regulatory Factor H that stabilizes C3 and inactivates C3b. aHUS is usually associated with a genetic abnormality affecting the regulation in the alternative complement system coupled with an inciting stress such as infection. Secondary HUS generally follows the same pathophysiology pattern as aHUS.

• #22 Hemolytic Uremic Syndrome: New Developments in Pathogenesis and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3159990/

  The association between aHUS and mutations in CFH was first described by Warwicker et al. […] It was subsequently found that it is the most frequent genetic abnormality in patients with aHUS, accounting for 25 to 30% of cases. […] Factor H, a serum complement regulatory protease, acts as a cofactor for factor I-mediated inactivation of C3b, competes with factor B for C3b binding, and accelerates C3 convertase decay. […] Most mutations affect the short consensus repeats 19 and 20 of the protein. […] Most of them are missense mutations, which do not affect the levels of factor H and C3 but affect the C-terminal region, which is important for binding to C3b and anionic surfaces.

• #23 Atypical hemolytic-uremic syndrome: improving outcomes | JMDH

  https://www.dovepress.com/atypical-hemolytic-uremic-syndrome-genetic-basis-clinical-manifestatio-peer-reviewed-fulltext-article-JMDH

  Nearly half of aHUS patients with an identified genetic cause carry a pathogenic variant in the CFH gene, residing in the regulators of complement activation (RCA) cluster on chromosome 1. […] The gene encodes Factor H (FH), a serum protein that binds to glycan structures on host cells and blocks complement activation. […] Most CFH mutations are loss-of-function; gain-of-function variants affect activating factors such as C3 and complement factor B (FB), a key mediator of C3 convertase function. […] Mutations affecting FB and C3 are found in less than 10% of aHUS patients. C3 mutations reduce the binding affinity of C3b to FH, decreasing the degradation of C3b to iC3b. CFB mutations increase the affinity of FB to C3b, resulting in a more stable C3 convertase. […] Both C3 and CFB mutations result in a state of complement hyperactivation. Mutant C3 and FB are associated with aggressive aHUS disease progression. Amongst all patients with aHUS, those with CFH-aHUS have the highest risk of developing kidney failure, usually within one year of diagnosis.

• #24

  https://www.omim.org/entry/235400

  Autoantibodies in aHUS […] Dragon-Durey et al. (2005) identified serum anti-CFH IgG autoantibodies in 3 (6%) of 48 children with recurrent aHUS. Plasma CFH activity was decreased, whereas plasma CFH antigen levels were normal and CFH gene analysis was normal, indicating an acquired functional CFH deficiency. The findings indicated that aHUS may occur in the context of an autoimmune disease, and suggested that plasma exchange or immunosuppression may be a beneficial treatment. […] Of 147 patients with aHUS, 121 of whom had previously been reported by Zipfel et al. (2007), Jozsi et al. (2008) identified serum anti-CFH autoantibodies in 16 (11%); 14 lacked CFHR1/CFHR3 completely and 2 showed extremely low CFHR1/CFHR3 plasma levels. These observations suggested that CFHR1/CFHR3 deficiency represents a risk factor for CFH autoantibody formation. Unaffected family members with decreased CFHR1/CFHR3 did not have CFH autoantibodies. The binding epitopes of all autoantibodies were localized to the C-terminal recognition region of factor H, which represents a hotspot for aHUS mutations. The authors thus defined a subgroup of aHUS, which they termed DEAP HUS (deficiency of CFHR proteins and CFH autoantibody positive), that is characterized by a combination of genetic and acquired factors. The findings illustrated a new combination of 2 susceptibility factors for the development of aHUS.

• #25 Atypical hemolytic-uremic syndrome: improving outcomes | JMDH

  https://www.dovepress.com/atypical-hemolytic-uremic-syndrome-genetic-basis-clinical-manifestatio-peer-reviewed-fulltext-article-JMDH

  The complement system has three pathways: classical, alternative, and lectin-binding. These pathways have different initial steps but converge on forming C3 convertase to propagate complement activity and destroy pathogens. […] Without tight control of the alternative complement pathway, extensive damage is inflicted with endothelial damage and activation of the coagulation cascade including platelets. In aHUS, the innate immune system loses its ability to regulate the pathway, resulting in uncontrolled complement activation. This is most commonly caused by mutations in genes encoding alternative complement pathway initiators (eg, C3, Factor B), regulatory proteins (eg, Factor H, Factor I, Membrane Cofactor Protein), and autoantibodies against Factor H. […] Causal variants in alternative complement pathway proteins are detected in up to 60% of aHUS cases; mutations may also be found in coagulation proteins and enzymes that indirectly contribute to the coagulation cascade.

• #26 Atypical Hemolytic-Uremic Syndrome: When to Suspect and What to Do

  https://www.medscape.org/viewarticle/751917

  A rare but unique form of HUS can be caused by Streptococcus pneumoniae infection. This form of HUS usually develops 3-13 days (peak, 7-9 days) after the onset of infection. The mechanism of cellular damage is thought to be connected to the exposure of the normally hidden Thomson-Friedenreich (T) antigen. Neuraminidase, an enzyme secreted by S pneumoniae, cleaves N-acetyl-neuraminic acid (sialic acid) residues from the T antigen, which results in the exposure of the T-antigen as neoepitope. Preexisting, naturally occurring IgM antibodies bind to the newly exposed T-antigen, which is found on erythrocytes, endothelial cells, and platelets, resulting in cellular damage and platelet aggregation. […] aHUS pathology is intimately linked to activation and regulation of the complement system, particularly the AP. Unlike the classic (CP) and mannan binding lectin (MBL) complement activation pathways, which require specific initiation triggers, the AP is constitutively active. Complement C3 contains a thioester bond that is easily hydrolyzed by H2O, yielding C3H2O („tick over”). This hydrolysis induces a conformational change in the protein, which allows C3H2O to interact with factor B (CFB) and factor D (CFD), forming a C3 convertase complex in blood (C3H2OBb). This C3 convertase efficiently generates C3b molecules, which can serve as nuclei for more C3 convertase complexes (ie, C3 conversion drives an amplification loop).

• #27 Atypical hemolytic uremic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Atypical_hemolytic_uremic_syndrome

  Atypical hemolytic uremic syndrome (aHUS), also known as complement-mediated hemolytic uremic syndrome, is an extremely rare, life-threatening, progressive disease that frequently has a genetic component. In most cases, it can be effectively controlled by interruption of the complement cascade. aHUS is usually caused by chronic, uncontrolled activation of the complement system, a branch of the body’s immune system that destroys and removes foreign particles. […] The complement system activation may be due to mutations in the complement regulatory proteins (factor H, factor I, or membrane cofactor protein (CD46)), or occasionally due to acquired neutralizing autoantibody inhibitors of these complement system components (e.g. antifactor H antibodies). […] In healthy individuals, complement is used to attack foreign substances, and the complement system is highly regulated to prevent it from damaging healthy tissues and organs. However, in most patients with aHUS, it has been demonstrated that chronic, uncontrolled, and excessive activation of complement can result from production of anti-factor H autoantibodies or from genetic mutations in any of several complement regulatory proteins (e.g., factor H, factor HR1 or HR3, membrane cofactor protein, factor I, factor B, complement C3, and thrombomodulin). This results in platelet activation, damage to endothelial cells, and white blood cell activation, leading to systemic TMA, which manifests as decreased platelet count, hemolysis, damage to multiple organs, and often, death.

• #28 Atypical Hemolytic-Uremic Syndrome: When to Suspect and What to Do

  https://www.medscape.org/viewarticle/751917

  If not stopped at this point, the complement cascade continues activating downstream components, eventually resulting in the formation of the membrane attack complex (MAC, C5b-9), cell lysis, inflammation, and activation of the coagulation cascade. While the default setting of the AP is attack, specificity — or differentiation between self (host cells) and non-self (bacteria, viruses) — is achieved by a multilayered system of plasma and surface-anchored complement regulators preventing complement-mediated damage to self-tissue. Loss of AP regulation (eg, caused by mutations) results in tissue damage, especially of the glomerular endothelium, and eventually causes aHUS. […] In summary, the familial form aHUS is characterized by impaired AP control. Massive and unregulated AP activation leads to the formation of C3a, C5a, and MAC (C5b-9), resulting in direct (MAC, C5b-9) or indirect (C3a/C5a) damage of the endothelium.

• #29 Atypical hemolytic uremic syndrome: genetically-based insights into pathogenesis through an analysis of the complement regulator CD46 – Wu – Annals of Blood

  https://aob.amegroups.org/article/view/7737/html

  Reduced control of complement activation (specifically CA) on the cell membrane is the essential pathogenetic mechanism of aHUS. […] Mutations of membrane regulator CD46 or serum protease CFI contribute to inadequate regulation of complement activation on the cell membrane. […] These observations indicate that the lack of effective catabolism of C3b on endothelial cells plays a key role in the pathogenesis of aHUS.

• #30

  https://www.omim.org/entry/235400

  Using in vitro expression studies, Manuelian et al. (2003) demonstrated that pathogenic mutations in the CFH gene (134370.0001; 134370.0017-134370.0018) resulted in mutant proteins with decreased binding to heparin, C3b/C3d, and human endothelial cells. The findings suggested that reduced interaction with the surface of endothelial cells is central to the pathophysiology of aHUS and that normal factor H has a protective role during tissue injury. […] Stahl et al. (2008) demonstrated that aHUS-associated mutant factor H (see, e.g., 134370.0022) exhibited decreased binding to normal platelets compared to wildtype factor H. Addition of patient serum containing mutant factor H to control platelets resulted in complement activation, deposition of C3 and C9, release of platelet-derived microparticles, and platelet aggregation, indicating platelet activation. Similar findings were obtained with other aHUS-associated CFH mutations. Preincubation of normal platelets with factor H reduced these effects. The findings indicated that mutant CFH results in complement activation on the surface of platelets and platelet activation, which may contribute to thrombocytopenia.

• #31 The Role of the Complement System in the Pathogenesis of Infectious Forms of Hemolytic Uremic Syndrome

  https://www.mdpi.com/2218-273X/14/1/39

  The presence of mutations in the genes of complement factors does not in itself trigger the pathological process. […] The complement system plays an important role in the body’s humoral defenses, enabling pathogen detection and elimination. […] The role of dysregulation of the alternative complement pathway in endothelial cell damage and the development of TMA was first considered in 1998, when abnormalities in the CFH gene, encoding complement factor H, were discovered in patients with HUS. […] The complement system is also regulated by other systems, including the blood coagulation system. […] The complement system and the blood coagulation system have a common evolutionary origin, which led to the presence of common activators and inhibitors and synergy in their work, which is extremely important for the body’s fight against pathogens.

• #32 Hemolytic-Uremic Syndrome (HUS) – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/thrombocytopenia-and-platelet-dysfunction/hemolytic-uremic-syndrome-hus

  Activation of the complement system is common in children with HUS caused by acute infection. […] A small minority of cases are unrelated to infection and involve mutations of the complement system: These mutations involve genes controlling complement proteins or complement factors but sometimes from acquired autoantibodies to certain complement factors. Congenital complement disorders may also increase the risk of HUS after an infection. […] HUS due to complement-factor mutations do not usually have an infectious prodrome but may be exacerbated by an infection. […] In patients with HUS caused by complement dysregulation (including most children), complement inhibition with eculizumab, ravulizumab, or pegcetacoplan can often reverse the kidney failure. […] HUS due to complement factor mutations/deficiency may respond to complement inhibition using eculizumab, ravulizumab.

• #33 Overview of hemolytic uremic syndrome in children – UpToDate

  https://www.uptodate.com/contents/overview-of-hemolytic-uremic-syndrome-in-children

  The hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. It is one of the main causes of acute kidney injury in children. Although all pediatric cases exhibit the classic triad of findings that define HUS, there are a number of various etiologies of HUS that result in differences in presentation, management, and outcome. […] Thrombotic microangiopathy describes a specific pathologic lesion in which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis. It includes several primary disorders including thrombotic thrombocytopenic purpura, Shiga toxin-mediated HUS and complement-mediated HUS or TMA. […] Ongoing research has provided a better understanding of the underlying causes of HUS, especially those due to genetic mutations in the alternative pathway of complement.

• #34 Hemolytic uremic syndrome – Symptoms, diagnosis and treatment | BMJ Best Practice US

  https://bestpractice.bmj.com/topics/en-us/470

  Hemolytic uremic syndrome (HUS) is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. […] Most cases of HUS occur in children and are diarrhea-associated (D+ HUS). Diarrhea-associated HUS is usually caused by Shiga toxin-producing Escherichia coli. […] Atypical HUS occurs due to abnormalities in the alternative complement regulatory pathway, resulting in endothelial cell damage and causing microvascular thrombosis. […] HUS can also occur as a secondary phenomenon due to medications, cancer, and other systemic diseases.

• #35 Hemolytic Uremic Syndrome – itjem

  https://www.itjem.org/2019/05/15/hemolytic-uremic-syndrome/

  Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy defined by thrombocytopenia, non immune microangiopathic hemolytic anemia and acute renal failure. […] Early diagnosis and identification of underlying pathogenic mechanism allow instating specific support measures and therapies. […] The typical microvascular lesions of HUS, defined as Thrombotic microangiopathy consist of a thickening of the wall of small vessels (specially capillaries and arterioles) with swelling and detachment of endothelial cells from basal membrane. […] The pathogenesis of aHUS may result from several mechanisms, ranging from infectious processes (Streptococcus pneumonia, HIV), systemic diseases, drug administration (e.g. some chemotherapeutics, antibiotics and oral contraceptives), organ transplantation (in liver, kidney, heart and bone marrow transplantation, the cause of HUS is the use of calcineurin inhibitors), autoimmune syndromes (Lupus Erythematosus, Rheumatoid arthritis, rheumatoid spondylitis) and in particular abnormalities of the complement pathway.

• #36 Hemolytic Uremic Syndrome | 5-Minute Pediatric Consult

  https://peds.unboundmedicine.com/pedscentral/view/5-Minute-Pediatric-Consult/617794/all/Hemolytic_Uremic_Syndrome?q=Stroke

  Hemolytic uremic syndrome (HUS) is characterized by the triad of acute kidney injury, thrombocytopenia, and hemolytic anemia with fragmentation of erythrocytes (schistocytes noted on peripheral smear). […] Vascular endothelial cell injury is central to the pathogenesis of all forms of HUS. […] STEC colonize colonic mucosa, adhere to mucosal villi, and release Shiga toxin (Stx). […] Stx enters the systemic circulation, where it causes endothelial cell injury via inflammation, upregulation of chemokine and cytokine production, and by binding to endothelial cell surface receptors (Gb3) and interrupting protein synthesis. […] Endothelial cell injury exposes the thrombogenic basement membrane, causing platelet activation and local intravascular thrombosis. […] In vitro studies show that glomerular endothelial cells and proximal tubular epithelial cells have receptors with very high affinity for Stx. […] aHUS is caused by dysregulation of the alternate complement pathway.

• #37 Haemolytic uremic syndrome | PPT

  https://www.slideshare.net/slideshow/haemolytic-uremic-syndrome-125169222/125169222

  Hemolytic Uremic Syndrome (HUS) is a clinical syndrome characterized by microangiopathic hemolytic anemia, acute kidney injury, and thrombocytopenia. It is caused by Shiga toxin-producing bacteria like E. coli O157:H7 or by complement dysregulation. […] Shiga-like toxin affects endothelial cells and initiates intravascular thrombo-genesis. After entering the circulation via the gastrointestinal mucosa, the toxin preferentially localizes to the kidneys, inhibiting protein synthesis and eventually leading to cell necrosis or apoptosis. Endothelial cell damage subsequently potentiates renal microvascular thrombosis by promoting activation of the blood coagulation cascade. Platelet aggregation results in a consumptive thrombocytopenia. Microangiopathic hemolytic anemia results from mechanical damage to red blood cells circulating through partially occluded microcirculation.

• #38 Hemolytic–uremic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hemolytic%E2%80%93uremic_syndrome

  As in the related condition TTP, reduced blood flow through the narrowed blood vessels of the microvasculature leads to reduced blood flow to vital organs, and ischemia may develop. […] The kidneys and the central nervous system (brain and spinal cord) are the parts of the body most critically dependent on high blood flow, and are thus the most likely organs to be affected. However, in comparison to TTP, the kidneys tend to be more severely affected in HUS, and the central nervous system is less commonly affected. […] In contrast with typical disseminated intravascular coagulation seen with other causes of sepsis and occasionally with advanced cancer, coagulation factors are not consumed in HUS (or TTP) and the coagulation screen, fibrinogen level, and assays for fibrin degradation products such as „D-Dimers”, are generally normal despite the low platelet count (thrombocytopenia).

• #39 Treatment of enterohemorrhagic Escherichia coli (EHEC) infection and hemolytic uremic syndrome (HUS) | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-10-12

  Two key events are involved in the pathogenesis of D+HUS: altered Von Willebrand factor (VWF) activity (for example, as seen with 'a disintegrin and metalloproteinase with thrombospondin motif-13′ (ADAMTS13) deficiency) and site-specific activation and/or apoptosis of microvascular endothelial cells. […] Targeting the interruption of these processes gives hope for potential novel treatment modalities.

• #40 The Role of the Complement System in the Pathogenesis of Infectious Forms of Hemolytic Uremic Syndrome

  https://www.mdpi.com/2218-273X/14/1/39

  The terminal stage of the complement activation cascade is triggered by the formation of C5 convertase. […] The combined activity of thrombin and C5 convertase leads to the formation of cleavage products C5a and C5b(T). […] The complement system plays an important role in the pathogenesis of STEC-HUS.

• #41 The Role of the Complement System in the Pathogenesis of Infectious Forms of Hemolytic Uremic Syndrome

  https://www.mdpi.com/2218-273X/14/1/39

  Dysregulation of the activity of these systems and the pathways of interaction between them can lead to the development of severe complications, including complement-associated thrombotic microangiopathies. […] The complement system is in close relationship with the blood coagulation system and the result of the development of HUS is thrombosis. […] The complement system is also involved in the pathogenesis of STEC-HUS. […] The activation of the complement system may be mediated by P-selectin. […] The mechanisms of lectin pathway activation are unclear. […] The data presented in the literature allow us to identify several possible pathways of activation of the complement system in STEC-HUS. […] The activation of the complement system is accompanied by the cleavage of native factors with the formation of complexes with specific activities.

• #42 Hemolytic–uremic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hemolytic%E2%80%93uremic_syndrome

  HUS occurs after 37% of all sporadic E. coli O157:H7 infections and up to approximately 20% or more of epidemic infections. […] Children and adolescents are commonly affected. […] One reason could be that children have more Gb3 receptors than adults which may be why children are more susceptible to HUS. […] Cattle, swine, deer, and other mammals do not have GB3 receptors, but can be asymptomatic carriers of Shiga toxin-producing bacteria. Some humans can also be asymptomatic carriers. […] Once the bacteria colonizes, diarrhea followed by bloody diarrhea, hemorrhagic colitis, typically follows. Other serotypes of STEC also cause disease, including HUS, as occurred with E. coli O104:H4, which triggered a 2011 epidemic of STEC-HUS in Germany. […] Grossly, the kidneys may show patchy or diffuse renal cortical necrosis. Histologically, the glomeruli show thickened and sometimes split capillary walls due largely to endothelial swelling. […] Large deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the mesangium are also found along with mesangiolysis. Interlobular and afferent arterioles show fibrinoid necrosis and intimal hyperplasia and are often occluded by thrombi.

• #43

  https://journals.lww.com/md-journal/fulltext/2018/02160/haemolytic_uremic_syndrome_due_to_infection_with.35.aspx

  The risk factors for the progression into HUS are the age of more the 5 years old, different etiologies from STEC, persistent oligoanuria, central nervous system, and glomerular impairment (80%). […] Hemolytic uremic syndrome is responsible for 7% of cases of hypertension in infants, being the leading factor in chronic renal dysfunction in children, and an important cause of significant kidney damage in adults. […] Although the most common etiology of HUS remains STEC, other etiologies like viral etiologies should not be neglected, keeping in mind the fact that they might be responsible for severe enteric infection with progression into HUS.

• #44 Hemolytic Uremic Syndrome (HUS)

  https://www.health.ny.gov/diseases/communicable/e_coli/fact_sheet.htm

  Hemolytic Uremic Syndrome (HUS) is a rare but serious disease that affects the kidneys and blood clotting functions of infected people. Infection with HUS causes destruction of red blood cells, which can then cause kidney failure. HUS occurs as a complication of a diarrheal infection (usually E.coli O157:H7 infection). The disease occurs more commonly in children under 5 years of age than in other age groups. […] Anyone infected with E. coli O57:H7 or another Shiga toxin-producing E. coli(STEC) strain can get HUS. Children who are less than 5 years old, people with weakened immune systems (such as those with cancer, HIV/AIDS, or a transplant), or persons with a family history of HUS are more at risk to develop the disease. Only a small fraction of people diagnosed with E.coli O57:H7 (or STEC) infection develop HUS.

• #45 Pathogenesis of Shiga Toxin-Associated Hemolytic Uremic Syndrome | Pediatric Research

  https://www.nature.com/articles/pr2001160

  Several observations suggest that Stx2 may be more virulent in human disease than Stx1. […] The presence of Gb3 or galabiosyl ceramide receptors on cells has been found to determine the localization of tissue damage in rabbits, mice, and humans. […] Stx is cytotoxic for human endothelial cells and may also induce apoptosis. […] Stx may directly lead to endothelial cell activation with perturbed expression of endothelial-derived vasomediators. […] In addition to endothelial cells, Stx has been shown to have a cytotoxic effect on various other cells, including renal glomerular and tubular epithelial cells. […] Stx-induced apoptosis may contribute to the renal injury during HUS. […] The mechanisms of intestinal adhesion have been characterized. […] The toxin has been found to be both stimulatory and cytotoxic and may circulate bound to polymorphonuclear cells from which it will transfer to endothelial cells. […] These advances will hopefully enable the development of toxin binding, neutralizing, and removal therapies in the future.

• #46 Postpartum hemolytic uremic syndrome with multiple organ involvement in a severe case | Nefrología

  https://revistanefrologia.com/en-postpartum-hemolytic-uremic-syndrome-with-articulo-X2013251412001109

  The renal pathology in HUS is characterized by glomerular capillary subendothelial expansion, arteriolar fibrinoid necrosis, arterial edematous intimal expansion and vascular thrombosis. […] Our case showed typical subendothelial edematous expansion and renal arteriolar intimal expansion with fibrin exudation which supported renal microangiopathy, but without diffused thrombi and fibrinoid necrosis in renal tissue which seemed to be inconsistent with the following development of multiple organ complications and the progression to CRF. […] In conclusion, pancreatic necrosis, CRAO and DIC were observed in PHUS. Although renal replacement therapy and PE with FFP infusion have improved the survival of PHUS significantly, multiple organ complications such as pancreatic necrosis, CRAO and DIC may cause severe sequelae and lead to a poor prognosis of PHUS.

• #47 Hong Kong Journal of Paediatrics [HK J Paediatr (New Series) 2001;6:57-62]

  https://www.hkjpaed.org/details.asp?id=191&show=1234

  Haemolytic uraemic syndrome is characterized by the triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure. […] The neuraminidase exposes the T (or Thomsen-Friedenreich) antigen in the cell membrane of erythrocytes, platelets and glomerular endothelial cells. Anti-T IgM in normal sera will react with the exposed T-antigen, resulting in agglutination and haemolysis of red blood cells, thrombocytopenia and thrombotic renal microangiopathy. […] The proposed pathogenic cascade starts from the ingestion of EHEC and binding to the intestinal epithelial cells. The toxins produced most probably damage the microvasculature of the intestinal wall resulting in the haemorrhagic and ulcerative intestinal lesions. The toxins then enter the circulation through the damaged gut-blood barrier. Direct toxin invasion to the glomerular and arteriolar endothelial cells is believed to be the primary event of renal damage. Swelling of the injured endothelial cells promotes fibrin and platelet deposition resulting in a „localized” intravascular coagulopathy. Glomerular capillary lumens are occluded by the swollen cells and microthrombi, with subsequent reduction in glomerular filtration, fragmentation of red cells and the classical microangiopathic haemolytic anaemia.

• #48 Atypical hemolytic uremic syndrome | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-6-60

  Eculizumab is a recombinant, humanized, monoclonal immunoglobulin G antibody that targets C5. […] Eculizumab blocks the cleavage of C5 to C5b, ultimately preventing the generation of the proinflammatory peptide C5b and the cytotoxic membrane attack complex C5b-9. […] Overall, these results demonstrate the potential for eculizumab treatment as the new standard of care for patients with aHUS.

• #49 Hemolytic Uremic Syndrome (HUS): Symptoms, Treatment, Causes, Prognosis

  https://www.medicinenet.com/hemolytic_uremic_syndrome/article.htm

  Typical HUS in children tends to be self-limiting, and supportive care is often all that is needed. This may include intravenous fluids for rehydration and rebalancing of electrolytes like sodium and potassium, which can be lost with the diarrhea. Blood transfusions are only used for the most severe cases of anemia in which the hemoglobin falls below 6 or 7 g/dL (depending on age, the normal value is 11-16). Kidney failure may be managed expectantly (by observation and supportive care), and dialysis is not often required. Adults with atypical HUS tend to become more ill and need more aggressive therapy than children with the condition. In addition to the supportive care discussed above, plasmapheresis or plasma exchange may be required. Since it is thought there is an abnormal chemical in the plasma stimulating the abnormal clot formation, removing the plasma and replacing it with donor plasma is helpful in treating adult HUS. Dialysis may be needed while awaiting recovery of the kidneys from the illness. Eculizumab (Soliris) has been approved by the FDA for the treatment of atypical HUS. It is a monoclonal antibody that decreases the blood clotting in the capillary blood vessels, decreasing the potential destruction of cells. This type of therapy decreases the body’s immune capabilities, and the risk of infection increases. […] Patients with HUS not related to a diarrheal illness have a worse prognosis than those whose illness is due to gastrointestinal infection. In those patients with genetically caused HUS, relapsing illness is common as are kidney failure requiring dialysis and death.

• #50 Haemolytic uraemic syndrome | Nature Reviews Nephrology

  https://www.nature.com/subjects/haemolytic-uremic-syndrome/nrneph

  Effective treatments for atypical haemolytic uraemic syndrome (aHUS) have long been lacking, but the discovery that complement dysregulation is a major risk factor for this disease and the availability of the complement inhibitor eculizumab have improved the clinical picture. […] Improved understanding of the mechanisms by which atypical HUS occurs after transplantation should result in the improved management of affected patients. […] Intensive research over the past several years has revealed dysregulation of the complement system to be the main underlying cause of the syndrome, making this system the target of promising novel diagnostic and treatment strategies.

• #51 Hemolytic Uremic Syndrome – itjem

  https://www.itjem.org/2019/05/15/hemolytic-uremic-syndrome/

  Eculizumab should be started in patients with no response to PE/PI within a few days or in those cases in which the presumptive diagnosis of aHUS is more certain. […] This combinant humanized monoclonal antibody blocks cleavage of complement factor C5 and the formation of the complement membrane attack complex C5b.

• #52 Hemolytic Uremic Syndrome – itjem

  https://www.itjem.org/2019/05/15/hemolytic-uremic-syndrome/

  Complement-mediated hemolytic uremic syndrome are due to gene mutation of complement factors (factor H, I, B, THBD, C3, CD46) or secondary to antibodies to complement protein. […] Recently some groups identified mutations in DGKE gene (encoding diacyilglyicerol kinasi) in children with aHUS. […] Although the pathogenesis of the disease is similar to that of secondary forms to infection of E. coli O157, the disease is generally more severe with a mortality rate in the 15th percentile and over 40% of patients develop end-stage renal disease (ESRD). […] The efficacy of plasma therapy is presumed to be related to its ability to deliver normal levels of complement proteins and, when plasma is exchanged by apheresis, to remove mutant regulators, anti-CFH antibodies, and hyperfunctional complement components.

• #53 Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review

  https://www.mdpi.com/2072-6651/12/2/67

  Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) belongs to the body of thrombotic microangiopathies, a heterogeneous group of diseases characterized by a triad of features: thrombocytopenia, mechanical hemolytic anemia with schistocytosis, and ischemic organ damage. […] Herein, we review the current knowledge of STEC virulence, how societies organize the prevention of human disease, and how physicians treat (and, hopefully, will treat) its potentially fatal complications. In particular, we focus on STEC-induced hemolytic and uremic syndrome (HUS), where the intrusion of toxins inside endothelial cells results in massive cell death, activation of the coagulation within capillaries, and eventually organ failure. […] Recent progress in the understanding of HUS mechanisms has highlighted the role of the complement pathway in endothelial damage and gone a long way in deciphering the intracellular trafficking of Shiga toxin.

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