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Initiation of complement cascade begins with activation of C3. Activation occurs via the 'tickover' process of the alternative pathway, the classical pathway and lectin pathway. Enzymatic cleavage of CFB bound to C3(H20) or C3b by complement Factor D results in activation of CFB to C3(H20)Bb or C3bBb, and Ba (a marker of proximal complement activation). C3bBb is stabilized by Properdin protein.
Source publication
Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) originally understood to be limited to renal and hematopoietic involvement. Whereas aberrations in complement regulatory proteins (CRPs), C3 or complement factor B (CFB) are detected in ∼60% of patients, a complement-derived pathogenesis that reflects dysregulation of t...
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Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) deficiency (activity <10%). Urgent intervention based on the timely evaluation of ADAMTS13 level is crucial to guide optimal therapy. The recently developed PLASMIC scor...
Citations
... 3 However, meta-analysis has shown no effect on mortality, dialysis dependence, blood product support or incidence of CKD. 3 As access and cost of complement inhibitors improves, this group of drugs will likely be explored as a therapeutic option; eculizumab has been demonstrated in case reports to be effective in treating other TMA syndromes confirmed not to be atypical haemolytic uraemic syndrome. 4 Currently, early administration of antivenom following envenomation along with supportive therapy, including dialysis, represents the best care. ...
... Historically, many forms of TMA with unknown or unclear etiology or pathophysiology have been classified as forms of aHUS [5]. More recently, the utility of the term ''aHUS'' has been questioned as other forms of TMA have begun to be recognized clinically. ...
Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a common complication occurring post-HSCT and is associated with substantial morbidity and mortality if not promptly identified and treated. Emerging evidence suggests a central role for the complement system in the pathogenesis of HSCT-TMA. The complement system has also been shown to interact with other pathways and processes including coagulation and inflammation, all of which are activated following HSCT. Three endothelial cell-damaging "hits" are required for HSCT-TMA genesis: a genetic predisposition or existing damage, an endothelial cell-damaging conditioning regimen, and additional damaging insults. Numerous risk factors for the development of HSCT-TMA have been identified (including primary diagnosis, graft type, and conditioning regimen) and validated lists of relatively simple diagnostic signs and symptoms exist, many utilizing routine clinical and laboratory assessments. Despite the relative ease with which HSCT-TMA can be screened for, it is often overlooked or masked by other common post-transplant conditions. Recent evidence that patients with HSCT-TMA may also concurrently present with these differential diagnoses only serve to further confound its identification and treatment. HSCT-TMA may be treated, or even prevented, by removing or ameliorating triggering "hits", and recent studies have also shown substantial utility of complement-targeted therapies in this patient population. Further investigation into optimal management and treatment strategies is needed. Greater awareness of TMA post-HSCT is urgently needed to improve patient outcomes; the objective of this article is to clarify current understanding, explain underlying complement biology and provide simple tools to aid the early recognition, management, and monitoring of HSCT-TMA.
... Classic clinical findings of both subtypes are hematuria and proteinuria (26). aHUS is a form of complement-mediated thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and multisystem end organ involvement primarily affecting the kidney (27). In aHUS, dysregulated complement activity primarily occurs on cell surfaces, leading to local prothrombotic states, especially in the kidney. ...
C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) are two rare diseases caused by dysregulated activity of the alternative pathway of complement secondary to the presence of genetic and/or acquired factors. Complement factor I (FI) is a serine protease that downregulates complement activity in the fluid phase and/or on cell surfaces in conjunction with one of its cofactors, factor H (FH), complement receptor 1 (CR1/CD35), C4 binding protein (C4BP) or membrane cofactor protein (MCP/CD46). Because altered FI activity is causally related to the pathogenesis of C3G and aHUS, we sought to test functional activity of select CFI missense variants in these two patient cohorts. We identified 65 patients (16, C3G; 48, aHUS; 1 with both) with at least one rare variant in CFI (defined as a MAF < 0.1%). Eight C3G and eleven aHUS patients also carried rare variants in either another complement gene, ADAMTS13 or THBD. We performed comprehensive complement analyses including biomarker profiling, pathway activity and autoantibody testing, and developed a novel FI functional assay, which we completed on 40 patients. Seventy-eight percent of rare CFI variants (31/40) were associated with FI protein levels below the 25th percentile; in 22 cases, FI levels were below the lower limit of normal (type 1 variants). Of the remaining nine variants, which associated with normal FI levels, two variants reduced FI activity (type 2 variants). No patients carried currently known autoantibodies (including FH autoantibodies and nephritic factors). We noted that while rare variants in CFI predispose to complement-mediated diseases, phenotypes are strongly contingent on the associated genetic background. As a general rule, in isolation, a rare CFI variant most frequently leads to aHUS, with the co-inheritance of a CD46 loss-of-function variant driving the onset of aHUS to the younger age group. In comparison, co-inheritance of a gain-of-function variant in C3 alters the phenotype to C3G. Defects in CFH (variants or fusion genes) are seen with both C3G and aHUS. This variability underscores the complexity and multifactorial nature of these two complement-mediated renal diseases.
... More recently, eculizumab was shown efficacious in aHUS by interrupting further uncontrolled complement activation through endothelial injury. This resulted in normalized platelet counts and hematologic values, no thrombotic microangiopathic events during treatment, and improved kidney function reflected, among others, as being dialysis-free in a significantly larger proportion of patients compared to previous treatment options (94,95). ...
The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.
... Given a high index of suspicion, early involvement of a hematology team and prompt initiation of plasmapheresis along with hemodialysis, if indicated, are lifesaving. Furthermore, eculizumab approval from the Food and Drug Administration for treatment of aHUS has revolutionized its management [6]. ...
Patient: Female, 67-year-old
Final Diagnosis: Atypical hemolytic uremic syndrome
Symptoms: Anemia • renal failure • thrombocytopenia
Medication: —
Clinical Procedure: —
Specialty: Hematology • General and Internal Medicine • Pathology
Objective
Unusual clinical course
Background
Hemolytic uremic syndrome (HUS) develops from uncontrolled complement activation leading to intravascular hemolysis and thrombotic microangiopathy. Atypical HUS is diagnosed by excluding a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13 deficiency, and infection-associated HUS. Patients with atypical HUS may respond to eculizumab. We present a case of a 67-year-old woman who developed atypical HUS with hemolytic anemia, renal failure, and thrombocytopenia following an elective hip arthroplasty.
Case Report
An otherwise healthy 67-year-old woman was admitted to our hospital after an elective right total hip arthroplasty. In the postoperative course, she developed vomiting and acute renal failure that was initially attributed to a prerenal cause. She continued to have worsened renal failure in spite of intravenous hydration, and she also developed mild thrombocytopenia. A peripheral blood smear was performed and showed the presence of schistocytes (red blood cell fragments) consistent with microangiopathic hemolytic anemia. In the context of anemia, thrombocytopenia, and renal failure, this finding led to a prompt and early referral to a tertiary care center and a timely diagnosis of atypical HUS. The patient underwent treatment with plasmapheresis, hemo-dialysis, and eculizumab.
Conclusions
This report highlights the importance of examination of the peripheral blood smear in the diagnosis of thrombotic microangiopathy. As shown in our case, the presence of schistocytes indicates the need for prompt clinical management.
... The activation of both classical and lectin pathways needs specific initiator, but the AP is "always on" at low level by the hydrolysis of complement factor C3. It allows the constant formation of a C3 convertase (called "tick-over"), ensuing a rapid response to pathogens (Fig. 2). C3 convertase facilitates formation of C5b-9 (MAC) that forms a transmembrane channel, causing cell lysis [14]. The complement system is exquisitely controlled by the complement regulatory proteins (CRPs): complement factor H (CFH), complement factor I (CFI), and membrane cofactor protein (MCP or CD46). ...
Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and multisystem end organ involvement, most commonly affecting the kidney. Diagnosis is clinical, after exclusion of other TMA causes. Primary aHUS arises from genetic abnormalities, resulting in uncontrolled complement activity, while a variety of clinical scenarios cause secondary aHUS, including infection, pregnancy, malignancy, autoimmune disease, and medications. They can also induce a temporary complement deregulation with an overlap between both scenarios, which can make differential diagnosis difficult. Primary aHUS can be sporadic or familial and is associated with a high rate of progression to ESRD. Many aHUS patients relapse in the native or transplanted kidneys, leading to kidney failure. The introduction of eculizumab has changed the prognosis of aHUS, by inducing hematologic remission, improving or stabilizing kidney functions, and preventing graft failure. The early institution of appropriate therapy can prevent multiorgan damage, so is essential to recognize and differentiate the TMA syndromes. Eculizumab is considered now the first-line treatment, and it is recommended lifelong therapy. However, the high cost of therapy has led to make efforts to develop precise complement functional and genetic studies that help physicians to determine the appropriate duration of eculizumab therapy. Nowadays, more studies are needed to select candidates to adjustment of therapy.
... The negative genetic findings in aHUS, more than anything, may reflect the present diagnostic limitations in detecting all existing complement pathway mutations. More research is needed in this area [14], and our case report also highlights a similar need. ...
Atypical hemolytic uremic syndrome (aHUS) is a rare but life-threatening pediatric disease caused by uncontrolled activation of the alternative complement pathway related to genetic mutations and carries a worse prognosis. In the last decade, a monoclonal antibody against complement C5, eculizumab, has dramatically improved the disease outcomes. The complement mutations in aHUS are detected only in 60%-70% of cases in previous studies. We report a severe presentation of aHUS diagnosed in a two-month-old child who presented with seizures, renal failure with anuria, and microangiopathic hemolytic anemia and required peritoneal dialysis soon after admission. The patient was clinically diagnosed having aHUS and was started on eculizumab on day 4 of hospital admission. The genetic study for major known complement mutations causing aHUS was reported negative. He had a major episode of disease relapse associated with seizures four weeks after eculizumab therapy and required prolonged peritoneal dialysis over more than two months at the time of initial admission. He developed dilated cardiomyopathy and oro-motor dysfunction as complications of aHUS. At five-year follow-up, the patient has stage 3 chronic kidney disease (CKD), proteinuria, hypertension, and required G-tube for feeds. This report discussed the long-term outcome of an infant diagnosed with aHUS and tested negative for common complement mutations on eculizumab therapy. More research is needed to identify novel genes and antibodies contributing to aHUS. While the eculizumab is expensive, and the duration of treatment is not definite, the clinical severity of the disease, relapses, and presence of long-term renal complications are essential factors to decide treatment continuation.
... La evidencia sugiere que después de la fase de iniciación, el tiempo medio para alcanzar la normalización del recuento plaquetario y los niveles séricos de LDH fue de 7 y 28 días, respectivamente; asimismo, el 75% de los pacientes alcanzaron un ascenso en las cifras de hemoglobina por encima de 10 g/dL en la semana 26 de terapia, y un 80% de los que requirieron terapia de reemplazo renal y que iniciaron manejo con eculizumab en el primer mes posterior al diagnóstico fueron capaces de suspender hemodiálisis, con una mejoría media en la tasa de filtración glomerular (TFG) mayor a 30 ml/min/1.73 m 2 a la semana 27 (14,15). Para nuestro caso en particular, se logró hacia los primeros 30 días de tratamiento un incremento en la TFG hasta 27.7 ml/min/1.73 ...
El síndrome hemolítico urémico atípico (SHUa) constituye un diagnóstico de exclusión que debe plantearse ante la presencia de anemia hemolítica microangiopática, trombocitopenia y lesión renal aguda. Está asociado con mutaciones que provocan una disregulación del sistema del complemento e implica un pronóstico adverso y alto riesgo de progresión a enfermedad renal crónica. A continuación, presentamos el caso de un paciente con SHUa resaltando el efecto e importancia de la terapia biológica con el anticuerpo monoclonal eculizumab.
... This review mainly deals with diagnostic aspects of MAHA and TMAs. A number of clinical problems await solutions in TMA, such as the positioning of rituximab in the treatment sequence of primary TTP, management of ST-producing Escherichia coli-HUS complicated by encephalopathy, the efficacy and longterm safety of eculizumab in atypical HUS, and elucidation of the pathogenesis of secondary TMA [28,29,30]. ...
Thrombotic microangiopathies (TMAs) are multiple disease entities with different etiopathogeneses, characterized by thrombocytopenia, microangiopathic hemolytic anemia (MAHA) with schistocytosis, variable symptoms including fever, and multi-organ failure such as mild renal impairment and neurological deficits. The two paradigms of TMAs are represented on one hand by acquired thrombotic thrombocytopenic purpura (TTP) and on the other by hemolytic uremic syndrome (HUS). The differential diagnosis between these two paradigmatic forms of TMA is based on the presence of either frank renal failure in HUS or a severe deficiency (10% could rule out the presence of a TTP form. However, it is often difficult to differentiate either a TTP or HUS clinical scenario presenting with typical symptoms of TMA. There are in fact several additional diagnoses that should be considered in patients with ADAMTS13 activity of >10%. Widespread inflammation with endothelial damage and adverse reactions to drugs play a central role in the pathogenesis of several forms of TMA, and in these cases, the differential diagnosis should be directed at the underlying disease. Hence, a correct etiologic diagnosis of TMA should involve a critical illness, cancer-associated TMA, drug-induced TMA, and hematopoietic transplant-associated TMA. A complete assessment of all the possible etiologies for TMA symptoms, including acquired or congenital TTP, will allow for a more accurate diagnosis and application of a more appropriate treatment.
... In his article 'Atypical hemolytic uremic syndrome: a syndrome in need of clarity', Berger [10] recognizes thrombotic thrombocytopenic purpura (TTP) and Shiga-like toxin-producing Escherichia coli (STEC)-haemolytic uraemic syndrome (HUS) as distinct disease entities. However, all other TMA syndromes are summarized as atypical HUS (aHUS), either primary or secondary. ...
Conditions presenting with signs of thrombotic microangiopathies (TMAs) comprise a wide spectrum of different diseases. While pathological hallmarks are thrombosis of arterioles and capillaries, clinical signs are mechanical haemolysis, thrombocytopenia and acute renal injury or neurological manifestations. The current classification of various syndromes of TMA is heterogeneous and often does not take the underlying pathophysiology into consideration. Therefore we propose a simplified classification based on the aetiology of different syndromes leading to TMA. We propose to categorize different TMA syndromes in hereditary and acquired forms and classify them based on the genetic background or underlying conditions. Of course, this classification is not always distinctly applicable in each case and from time to time reassessment of the established diagnosis is strongly recommended. The recommended treatment of TMA in the past was plasma exchange (PE). However, recently, the terminal complement inhibitor eculizumab became commercially available and has shown promising results in different open-label studies and case series. In our centre, first-line therapy is PE; however, patients are instantly switched to complement inhibitory therapy in case of treatment failure or intolerance.
