Form Of Thrombotic Microangiopathy Research Articles

Генетически-фенотипический профиль детей с атипичным гемолитико-уремическим синдромом

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease caused by dysregulation of the alternative complement pathway as a result of mutations in complement genes or the formation of antibodies (AB) to some of the complement factors. Identification of the gene mutations incidence and the corresponding phenotypic features in pediatric patients with aHUS in Russia is aimed at improving the diagnosis and prognosis of the disease as well as treatment tactics planning for patient management. The purpose of this research was to determine the patterns of progression, prognosis and outcomes of aHUS in children depending on their genetic profile. Materials and methods used: the Article represents data from a retro- and prospective analyses of the characteristics of the course of aHUS in 172 children depending on their genetic profile performed in Jan. 2012-Feb. 2022. The sporadic form of aHUS was diagnosed after exclusion of the other forms of thrombotic microangiopathy (TMA), the familial form (in cases with the familial records), the acquired (CFH-Ab HUS) in cases with AB increase to factor H. AutoAb against factor H was determined by enzyme-linked immunosorbent assay (ELISA-VIDITEST anti-complement factor H). The search for mutations (n=167) was carried out using Next-generation Sequencing (NGS) and Sanger sequencing methods. Results: the sporadic form of aHUS was diagnosed in 96.9% of cases, familial in 3.1% and CFH-Ab HUS in 23.8%. The genetic nature of aHUS was confirmed in 53.4% of cases. Pathogenic mutations were detected in 8.6% of cases, probably pathogenic in 42.8% and those with unclear clinical significance in 46.8%. The complement genes mutations were detected in 88.5% of cases and mutations of genes not related to the complement system (ADAMTS13, DGKE, INF2) in 11.5%. The most frequently identified mutations were in the CFH (17.1%), C3 (12.9%) and CD46 (12.9%) genes and less frequently in CFI (7.1%), THBD (5.7%), CFHR5 (5.7%) and CFB (1.4%). In children with CFH-Ab HUS, the CFHR1/CFHR3 deletion was detected in 87.8% of cases, including in 19.4% in combination with mutations of unknown clinical significance. Multiple organ failure syndrome had developed in 77.8% of cases in children with pathogenic/probably pathogenic mutations, in 85.3% in patients with mutations of unknown clinical significance, in 91.8% in patients without mutations and in 83.3% in patients with CFHR1/CFHR3 deletion. Chronic kidney disease (CKD) stages 3 to 5 in sporadic/familial aHUS, regardless of genetic profile, had counted for 14.5% and 16.7% in CFH-Ab HUS. Lethal outcome occurred in 4.3% of cases in the presence of mutations, in 4.9% in the absence of mutations and in 2.8% in cases of CFHR1/CFHR3 deletion. Relapses of aHUS prior to the Eculizumab treatment had developed more often in the presence of CFHR1/CFHR3 mutations and deletion in comparison with children without mutations (31.4% v. 13.1%, p=0.0313 and 44.4% v. 13.1%, p= 0.004). Relapse of aHUS after discontinuation of the Eculizumab therapy had developed in 16.4% of cases. Risk factors for the relapse of aHUS were as follows: patient’s age above 12 months old at the time of the development of aHUS, severe arterial hypertension in the acute period, the use of Eculizumab at the fourth week after the onset of the disease and/or later, recurrent course of aHUS and the presence of CKD prior to the start of the Eculizumab therapy. Conclusion: The genetic profile of patients does not determine the severity and outcome of aHUS though it does affect the relapse rate. The prognosis and survival of patients with aHUS are determined by the severity of the acute period and the timeliness of the complement blocking therapy management.

Thrombotic microangiopathy (TMA) associated with pregnancy: role of the clinical laboratory in differential diagnosis.

Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia, microangiopathic hemolytic anemia and target organ damage. Pregnancy is associated with several forms of TMA, including preeclampsia (PE), HELLP syndrome, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). When HUS is secondary to a deregulation of the alternative complement pathway, it is known as atypical HUS (aHUS). Differential diagnosis is challenging, as these forms share clinical characteristics. However, early diagnosis is crucial for a specific treatment to be established and improve prognosis. We present the case of a 43 year-old primiparous woman admitted to hospital for an urgent C-section at 33 gestational weeks due to a diagnosis of severe preeclampsia and fetal distress. In the immediate postpartum, the patient developed acute liver failure and anuric renal failure in the context of the HELLP syndrome, anemia, thrombocytopenia, arterial hypertension (HTN) and neurological deficit. TMA study and differential diagnosis confirmed pregnancy-associated aHUS. Treatment with eculizumab was initiated, with good response and progressive improvement of clinical and analytical parameters. aHUS is a rare multifactorial disease that used to be associated with high mortality rates before the advent of eculizumab. Due to challenging diagnosis, the clinical laboratory plays a major role in the differential diagnosis and management of the disease.

Clinical case of recurrent aHUS after allogeneic cadaveric kidney transplantation

Introduction. Atypical hemolytic uremic syndrome (aHUS) is a systemic orphan disease that reproduces as an uncontrolled activation of the alternative pathway of the complement system and is expressed as systemic thrombotic microangiopathy (TMA). The classical triad of aHUS symptoms are hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). Currently, diagnosis of aHUS is a diagnosis of exclusion and has no pathognomonic features. It is established based on the clinical presentation of the disease after excluding other forms of TMA, Objective: to increase physicians’ awareness of this rare disease, the diagnosis and treatment of aHUS using a clinical case study.Conclusion. Early diagnosis of aHUS is extremely important, as timely targeted therapy can significantly improve or completely restore the functions of the affected organ.

АКТУАЛЬНЫЕ ВОПРОСЫ ДИАГНОСТИКИ И ЛЕЧЕНИЯ АТИПИЧНОГО ГЕМОЛИТИКО-УРЕМИЧЕСКОГО СИНДРОМА: ОПЫТ ВЕДЕНИЯ ПАЦИЕНТОВ В ЧЕЛЯБИНСКОЙ ОБЛАСТИ

Atypical hemolytic-uremic syndrome (aHUS) is a rare systemic life-threatening disorder with an unfavorable prognosis and progressive course and is based on chronic uncontrolled overactivation of the alternative complement pathway of hereditary (gene mutations with loss of function of complement regulators/activators) or acquired nature (antibodies to factor H), which leads to the development of a systemic complement-mediated form of thrombotic microangiopathy (TMA). The pathomorphological essence of TMA is the development of endotheliosis, which in its turn triggers the activation of the coagulation cascade with the formation of platelet-fibrin thrombi, partially or completely occluding the lumen of the vessels of the microvasculature (small arteries and arterioles). The therapeutic approach to aHUS has been improved with the introduction of eculizumab, a humanized monoclonal antibody, into clinical practice. Eculizumab has a high affinity for the C5 component of complement and, by binding to it, completely blocks the splitting of C5 into C5a and C5b. As a result, the formation of pro-inflammatory cytokines is inhibited by blocking the formation of C5a and the membrane attack complex (MAC) by blocking the formation of C5b. This therapy improves the prognosis of the disease and reduces the risk for development of the life-threatening conditions, including end-stage chronic kidney disease (CKD). The Article represents the analysis of the Authors’ own clinical experience with aHUS in the region of the Chelyabinsk Oblast of Russia. The diagnosis of aHUS was based on a combination of microangiopathic non-immune hemolytic anemia, thrombocytopenia, and acute kidney injury, after excluding other forms of TMA. Most often, aHUS in the form of clinical manifestations of TMA was diagnosed in pediatric patients during the first 3 years of life (67%). Both pathogenic and possibly-pathogenic mutations associated with the development of aHUS were detected in 56% of cases. These included mutations in the CFH, CFI, C3 genes, heterozygous deletion of CFHR1/CFHR3. Eculizumab had demonstrated its high efficiency accompanied by the restoration of diuresis, a decrease in the severity of arterial hypertension, a rapid suppression of hemolysis activity and the signs of active TMA. Throughout the course of treatment, all patients maintained hematological remission coupled with the absence of necessity for continuing extracorporeal therapy. Conclusion: the onset of remission of aHUS against the background of complement blocking therapy with eculizumab confirmed the correctness of the established diagnosis and the chosen treatment tactics.

Isolated arterial mucoid intimal thickening lesion in early post-transplant kidney allograft biopsies.

Thrombotic microangiopathy (TMA) on kidney biopsy shows a variable combination of features: arterial mucoid intimal thickening, acellular closure of glomerular capillary loops, fragmented red blood cells, fibrin thrombi, and arterial fibrinoid necrosis. However, some early post-transplant kidney biopsies show only arterial mucoid intimal thickening. We aimed to elucidate the importance of this finding. We identified 19 biopsies showing isolated arterial mucoid intimal thickening and compared them with 22 bona fide TMA biopsies identified based on the pathological findings (excluding rejection) (2011-2020). Additionally, delayed graft function (DGF) (n=237), and no DGF (control, n=1314) groups were included for survival analysis. Seven of 19 cases with isolated arterial mucoid intimal thickening showed peripheral blood schistocytes but no other systemic features of TMA. Eight patients underwent adjustments in maintenance immunosuppression (mainly calcineurin inhibitors). None of the cases progressed to full-blown TMA on consecutive biopsies. The overall and death-censored graft survival rates in this group were comparable to the DGF group, but significantly better than the TMA group (P=.005 and .04, respectively). Isolated arterial mucoid intimal thickening in early post-transplant biopsies may be an early/mild form of TMA, probably requiring adjustment in immunosuppressive regimen. Careful exclusion of known causes of TMA, and donor-derived arterial injury are important.

A decade of improved outcomes in aHUS: insights on complement inhibition and special populations

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) characterized by microangiopathic anemia with red blood cell fragmentation, thrombocytopenia, and acute kidney injury. Over the longer term, thrombotic damage to the kidney can lead to end-stage renal disease and the need for transplantation. Although aHUS is rare, it is important for clinicians to understand how to distinguish it from other forms of TMA and initiate the appropriate management. At the recent annual congress of the European Renal Association (ERA), more than a dozen poster presentations and a sponsored symposium discussed the latest insights into the diagnosis and management of aHUS; this report will focus on new data about the impact of the C5 inhibitors eculizumab and ravulizumab on aHUS management, and on special considerations for aHUS in pregnancy and pediatric patients.

КОМПЛЕКСНЫЙ ПОДХОД К ДИАГНОСТИКЕ И ТАКТИКА ЛЕЧЕНИЯ АТИПИЧНОГО ГЕМОЛИТИКО-УРЕМИЧЕСКОГО СИНДРОМА, АССОЦИИРОВАННОГО С МУТАЦИЕЙ В ГЕНЕ CFH: КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ

The atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease with a genetically determined dysregulation of the alternative complement pathway, which leads to the development of thrombotic microangiopathy. The application of the targeted therapy in Russia has changed the natural course of the disease since 2012: from death of a patient to achieving a long-term remission of the aHUS. The authors report the clinical case of the aHUS associated with a heterozygous mutation in CFH gene c.2850G>T (p.Gln950His) in a 2 years and 2 months old pediatric patient. The difficulty in diagnosing of the aHUS was the lack of specific laboratory criteria confirming the diagnosis as well as the presence of a diarrheal prodrome at the onset. The diagnosis has been made on the basis of the development of microangiopathic hemolytic anemia, thrombocytopenia, acute kidney injury and the exclusion of other forms of thrombotic microangiopathy. The treatment of the patient in accordance with the clinical guidelines for the management of patients with this nosology proved to be effective and led to a stable remission of the aHUS, which also confirmed the correctness of the diagnosis. The described clinical case observation is of interest to pediatrician physicians and nephrologists. The important factors in the management of such patients are the timely diagnosis of the aHUS along with the initiation of complement-inhibiting Eculizumab therapy.

Drug Induced Thrombotic Microangiopathy Secondary to Quetiapine; The Second Reportable Case in Medical Literature

INTRODUCTION Thrombotic microangiopathy (TMA) describes a group of disorders that are often related to microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. A common etiology is from exposure to certain drugs. Hereby, we present the second reportable case in medical literature of TMA secondary to quetiapine exposure. CASE PRESENTATION A 27 years old male patient with past medical history of schizoaffective disorder and depression, was admitted for altered mental status. Patient was completely disoriented with noncoherent speech. Home medications included quetiapine 775mg and valproate 750mg. Labs on admission were significant for Hb 7.6, Platelets 16, Wbc 8.1, Na 139, K 4.7, Hco3 23, Cr 14.5. Patient received 1 PRBC unit on admission. Hb was 7.9 on day 2, and his home medication quetiapine was resumed on that evening. Within 24hrs of receiving quetiapine, Hb and platelets reached a low point of 6.6 and 11 respectively. And within 48hrs, 3 PRBCs and 1 platelet units were transfused, resulting in Hb 6.7 and platelets 45 at the end of that 48hrs period. Clinically, patient was restless and agitated. His speech became slurred. Patient also had severe AKI with oliguria requiring hemodialysis. Further workup showed undetectable haptoglobin, elevated LDH, total bilirubin 3.22 and direct bilirubin 0.72, reticulocytes 12%, schistocytes on peripheral smear, INR 1.1, normal B12 level, valproic acid level of 52.7 (within normal reference range), negative HIV and syphilis, negative Coombs test, negative ANA/ANCA panel, negative platelet antibody, AdamTS13 level 99.1% (prior to plasma exchange), negative CFH antibody. Progression of laboratory findings and treatments received are shown in the accompanying figures (Figure 1, 2). In total, patient received 7 PRBC units, 1 single donor platelets unit, methylprednisolone followed by prednisone course, 5 plasma exchange sessions, 2 Rituximab infusions. During his hospital stay, patient gradually recovered, lab values demonstrated stability, and was discharged on day 15. DISCUSSION Drug induced thrombotic microangiopathy (DITMA) is part of a larger entity called thrombotic microangiopathies (TMA), which is often observed with MAHA and thrombocytopenia. DITMA is subdivided into an immune mechanism with prior or ongoing exposure to a drug thereby generating antibodies, and a nonimmune mechanism usually occurring after chronic exposure to a drug resulting in accumulation or can occur with acute exposure. The clinical presentation in immune mediated DITMA usually has a severe and sudden onset, with lab findings of MAHA, thrombocytopenia, severe acute kidney injury, along with normal or mildly decreased AdamTS13 activity (above 10%). However, DITMA is a diagnosis of exclusion, therefore other differentials have to be ruled out including thrombotic thrombocytopenic purpura (TTP) that is associated with an AdamTS13 level less than 10%, complement mediated TMA that can be evaluated with CFH antibody, hemolytic uremic syndrome (HUS) that typically presents in children with diarrhea, metabolism mediated TMA that is often related to vitamin B12 deficiency. Once the diagnosis is made, management involves discontinuation of the inciting drug. However, when the diagnosis is uncertain, therapies utilized in other forms of TMA may be used. Patients with DITMA should avoid re-exposure to the implicated drug in the future. The Oklahoma registry and the blood center of Wisconsin developed a criteria to evaluate patients with evidence of TMA and a suspected drug etiology. In our case, it meets the criteria for definite immune-mediated association with quetiapine, where other causes of TMA were excluded, quetiapine was the only drug taken during hospitalization, patient was taking this drug prior to hospitalization and subsequent exposure lead to manifestations of TMA within 24 hours. Literature review for similar reports revealed as few as 3 cases of quetiapine associated TMA, but AdamTS13 was noted to be either <10% or not documented. However, a case report published in 2021 shows quetiapine associated TMA with normal AdamTS13 level. Therefore, our case report would be the second reportable case in medical literature of quetiapine associated DITMA with normal ADAMTS13 levels. CONCLUSION It is of vital importance to raise awareness on how a commonly prescribed psychiatric medication such as quetiapine can cause an immune mediated TMA that is life-threatening. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MAC Plus Study: A Retrospective Study Correlating DNA Variants, Clinical Course and Outcomes from 187 Patients Who Underwent Testing Using an Atypical Hemolytic Uremic Syndrome and Thrombotic Microangiopathy Genetic Sequencing Panel

Atypical hemolytic uremic syndrome (aHUS) is a rare, potentially fatal disease that is often difficult to diagnose. The clinical presentation and pathogenesis of aHUS can overlap with several other rare, serious diseases (e.g., inherited thrombotic thrombocytopenia (TTP), shiga-toxin hemolytic uremic syndrome (STEC-HUS), and C3 glomerulopathy (C3G)). In many cases, a positive genetic finding can help clarify the diagnosis, guide treatment decisions, and inform prognosis. We have sequenced >2000 patients with a genetic panel targeting a collection of rare thrombotic microangiopathy (TMA) diseases and here we report the clinical course and outcomes for a subset (n=187). We cataloged all of the rare variants detected from sequencing ADAMTS13, C2, C3, C3AR1, CD46 (MCP), CFB, CFD, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, DGKE, MASP2, MMACHC, THBD, PLG, WT1 and the variant in C5 causing eculizumab resistance (p.Arg885). We collected data including clinical lab values, potential triggers, diagnoses, treatments, and outcomes. Our cohort here is distinct in that it is not a collection of patients clinically diagnosed with a specific disease (e.g., aHUS); instead, this cohort comprises real-world cases where the physicians sought out genetic testing for their patients as a part of the diagnostic picture. Physicians may be especially likely to seek out genetics when the diagnosis is especially murky. Patients treated with eculizumab responded well (52 responded, 7 did not respond, 8 unknown). Among patients who initiated eculizumab therapy, 34/67 discontinued its use and zero reported disease relapse. Of the 34 discontinuing eculizumab, 8 had a non-aHUS, non-TMA diagnosis while the 33 patients continuing therapy had only 1 with a non-aHUS, non-TMA diagnosis. In this cohort, 38% (71/187) ended up with a diagnosis of aHUS, 14% (27/187) were diagnosed with C3G/C3G-TMA, and 21% (40/187) were diagnosed with some other form of thrombotic microangiopathy (e.g., hypertension-TMA). Only 19 patients had a clear-cut positive genetic finding with 13 of those being the large, homozygous deletion of CFHR1 that is associated with CFH autoantibodies. 52 cases were negative for genetics while 86 had one or more rare variants of unknown significance. The difficulty in interpreting rare variants in the context of very rare, partially penetrant diseases like aHUS underscores the need for more genetic and clinical data to be made publicly available. The collection of data here will be a valuable resource for clinicians and scientists actively conducting research on these rare diseases and perhaps even more valuable for the clinical scientists and genetic counselors seeking context and comparisons for their own patients' variants, where the biggest problem currently is that most rare variants for these diseases are unfortunately variants of unknown significance.

Coronavirus Disease 2019-Associated Thrombotic Microangiopathy: Literature Review.

Coronavirus disease 2019 (COVID-19) can lead to clinically significant multisystem disorders that also affect the kidney. According to recent data, renal injury in the form of thrombotic microangiopathy (TMA) in native kidneys ranks third in frequency. Our review of global literature revealed 46 cases of TMA in association with COVID-19. Among identified cases, 18 patients presented as thrombotic thrombocytopenic purpura (TTP) and 28 cases presented as atypical hemolytic uremic syndrome (aHUS). Altogether, seven patients with aHUS had previously proven pathogenic or likely pathogenic genetic complement abnormalities. TMA occurred at the time of viremia or even after viral clearance. Infection with COVID-19 resulted in almost no or only mild respiratory symptoms in the majority of patients, while digestive symptoms occurred in almost one-third of patients. Regarding the clinical presentation of COVID-19-associated TMA, the cases showed no major deviations from the known presentation. Patients with TTP were treated with plasma exchange (88.9%) or fresh frozen plasma (11.1%), corticosteroids (88.9%), rituximab (38.9%), and caplacizumab (11.1%). Furthermore, 53.6% of patients with aHUS underwent plasma exchange with or without steroid as initial therapy, and 57.1% of patients received a C5 complement inhibitor. Mortality in the studied cohort was 16.7% for patients with TTP and 10.7% for patients with aHUS. The exact role of COVID-19 in the setting of COVID-19-associated TMA remains unclear. COVID-19 likely represents a second hit of aHUS or TTP that manifests in genetically predisposed individuals. Early identification of the TMA subtype and appropriate prompt and specific treatment could lead to good outcomes comparable to survival and recovery statistics for TMA of all causes.

POS-001 A NOVEL CFHR5 COPY NUMBER VARIATION ASSOCIATED WITH POST-PARTUM ATYPICAL HUS SUPERIMPOSED TO HELLP SYNDROME

Pregnancy and postpartum are triggers for various forms of thrombotic microangiopathy (TMA), a lesion characterized by endothelial injury and thrombosis in the microcirculation of various organs. These forms include thrombotic thrombocytopenic purpura (TTP), caused by ADAMTS13 deficiency, and atypical hemolytic uremic syndrome (aHUS), most often associated with genetically determined dysregulation of complement system. HUS is the most common form of TMA in the post-partum period. The diagnosis of pregnancy-associated HUS can be difficult because preeclampsia and HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome may present with clinical and laboratory features of TMA that however commonly resolve spontaneously after delivery.Here, we report the biochemical and genetic characterization of a 22 years old primigravida of African origin who presented at 38 weeks of gestation with severe hypertension, nephrotic syndrome (NS) and elevated liver enzymes, consistent with a diagnosis of HELLP.

MO316: Eculizumab for Adult Patients With Atypical Haemolytic-Uremic Syndrome: Full Dataset Analysis of Post-Marketing Surveillance in Japan

Abstract BACKGROUND AND AIMS Atypical haemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) associated with dysregulation of the alternative complement pathway [1]. It is characterized by microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury [1]. In the USA, two adults per million develop aHUS each year, whereas 1 to 2 patients per million are estimated in Japan [2, 3]. Eculizumab has been approved for aHUS in Japan since 2013. A regulatory-mandated post-marketing surveillance (PMS) was conducted in a real-world setting from September 2013 to July 2018, for which an interim analysis has been published [3]. Here, we report the findings from the full data set analysis of the data from the PMS. METHOD The PMS enrolled adult patients diagnosed with aHUS and treated with at least one dose of eculizumab. The patients without underlying diseases, i.e. autoimmune diseases, drugs, infection, malignant tumours, metabolic disorders or transplantation, were evaluated for serious adverse events (SAE) and clinical effectiveness endpoints, i.e. haematologic normalization, platelet count (PLT) normalization, lactic dehydrogenase (LDH) normalization, a decrease of ≥ 25% in serum creatinine (sCr) levels, TMA event-free status and a complete TMA response (haematologic normalization and a ≥ 25% decrease in sCr that persisted for ≥ 4 weeks during eculizumab treatment). In addition, the difference of baseline (i.e. at treatment initiation of eculizumab) patient characteristics between patients who met and did not meet effectiveness endpoints was evaluated. RESULTS In this analysis, 79 adult patients were included; the median age was 54.0 years. Median eculizumab treatment duration was 30 weeks. The total exposure time of eculizumab was 75.51 person-years and 94 SAEs (1.24 per person-years) were reported in 39 patients. No unexpected safety signals were identified in this population by the end of observation. No meningococcal infection was reported throughout the observation period. Mean PLT (P &amp;lt; .001), LDH (P &amp;lt; .05) and estimated glomerular filtration rate (P &amp;lt; .01) were significantly improved after 7 days. Complete TMA response, haematologic normalization, PLT normalization, LDH normalization, improvement of sCr levels, and TMA event-free status were met by 35.3%, 40.4%, 49.2%, 50.0%, 51.3% and 50.0% of patients, respectively. Median treatment duration was shorter in patients who did not meet complete TMA response than in patients who met (6 weeks versus 114 weeks; P &amp;lt; .001). Multivariate analysis suggested that the time from most recent TMA to eculizumab treatment (OR 0.899; P = .007) and the days of plasma therapy (OR 0.807; P = .008) were negatively associated with improvement of sCr levels. CONCLUSION The percentages of patients who met effectiveness endpoints were similar to the interim analysis [3], yet the percentages of patients who met complete TMA responses were lower than in clinical trials [4]; the disparity in these outcomes could be attributed to the differences between clinical and real-world studies. This PMS analysis further demonstrated the safety and effectiveness of eculizumab in Japanese patients with aHUS in a real-world setting.

Complement Mediated Endothelial Damage in Thrombotic Microangiopathies.

Thrombotic microangiopathies (TMA) constitute a group of different disorders that have a common underlying mechanism: the endothelial damage. These disorders may exhibit different mechanisms of endothelial injury depending on the pathological trigger. However, over the last decades, the potential role of the complement system (CS) has gained prominence in their pathogenesis. This is partly due to the great efficacy of complement-inhibitors in atypical hemolytic syndrome (aHUS), a TMA form where the primary defect is an alternative complement pathway dysregulation over endothelial cells (genetic and/or adquired). Complement involvement has also been demonstrated in other forms of TMA, such as thrombotic thrombocytopenic purpura (TTP) and in Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), as well as in secondary TMAs, in which complement activation occurs in the context of other diseases. However, at present, there is scarce evidence about the efficacy of complement-targeted therapies in these entities. The relationship between complement dysregulation and endothelial damage as the main causes of TMA will be reviewed here. Moreover, the different clinical trials evaluating the use of complement-inhibitors for the treatment of patients suffering from different TMA-associated disorders are summarized, as a clear example of the entry into a new era of personalized medicine in its management.

Regorafenib-induced renal-limited thrombotic microangiopathy: a case report and review of literatures

BackgroundRegorafenib belongs to a sub-group of small-molecule multi-targeted tyrosine kinase inhibitors(TKIs). In various studies with respect to the side-effect of regorafenib, drug-associated proteinuria standardly qualified to be defined as nephrotic syndrome was rarely reported as well as the relation of regorafenib with the occurrence and development of thrombotic microangiopathy (TMA).Case presentationIn this case report and literature review, we presented a 62-year-old patient receiving regorafenib for metastatic colon cancer, manifesting abundant proteinuria, in which TMA was also diagnosed through renal biopsy. As far as we were concerned, this was the first reported in terms of regorafenib-induced TMA confirmed by renal biopsy.ConclusionThis case indicates that regorafenib, a kind of TKIs may result in TMA, which is a rare but life-threatening complication of cancer treatment drug. Insights from this case might help physicians diagnose rare forms of TMA and adjust treatment for patients in a timely manner.

Updates on aHUS: Latest Insights into Triggers, Diagnosis, and Management Outcomes

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) that primarily affects the kidney but has a wide variability in its triggers and clinical presentation. In spite of its ultra-rare status, aHUS was a topic of interest at Kidney Week, the flagship conference of the American Society of Nephrology. Nineteen posters and four publication-only abstracts covered various facets of aHUS, using case studies and larger-scale analyses from clinical trials and the Global aHUS Registry to deepen our understanding of aHUS triggers and diagnosis, and to give us new perspectives on the long-term clinical outcomes with complement C5 inhibitor medications.

Atypical hemolytic-uremic syndrome - A case series from a tertiary care hospital from Eastern India

Atypical hemolytic–uremic syndrome (aHUS) is a form of thrombotic microangiopathy that occurs due to dysregulation of alternate pathway of complement system, which progressively causes systemic complications, end-stage renal disease, and death. As prognosis is poor compared to typical hemolytic–uremic syndrome, early diagnosis and treatment is crucial for favorable outcome. We came across seven patients of aHUS in our pediatric intensive care unit in the last 5 years. Plasma exchange (PE) along with immunosupressives was used for treatment. First child who did not receive PE died. Rest six patients underwent PE and attained hematological remission; however, one later on progressed to chronic kidney disease and expired. All others are on regular follow-up and doing well. A high index of suspicion is required to diagnose aHUS. Early PE can give a better prognosis.

Síndrome hemolítico urémico en una mujer adulta mayor: reporte de caso y revisión de la literatura

El síndrome hemolítico urémico (SHU) típico en adultos es una patología infrecuente. En la literatura se encuentran pocos reportes, y se ha documentado principalmente en la población pediátrica. Esta entidad se caracteriza por ser una microangiopatía trombótica (MAT) que compromete de manera característica los riñones. Es causada usualmente por la infección por Escherichia coli productora de toxina Shiga (STEC), específicamente el serotipo O157:H7. En Colombia no existen casos reportados sobre esta condición en adultos, lo cual llama la atención, pero puede deberse en parte a las dificultades en su diagnóstico, al no tenerse fácil acceso a algunas de las pruebas que orientan hacia esta enfermedad y confirman el diagnóstico. Se reporta el caso de una mujer adulta mayor colombiana, quien consultó por deposiciones diarreicas y hematoquecia, con el posterior desarrollo de trombocitopenia severa, lesión renal aguda, y evidencia de equinocitos y esquistocitos en extendido de sangre periférica, lo que llevó a sospechar una MAT. Se le solicitó FilmArray gastrointestinal, el cual fue positivo para STEC, confirmando así el diagnóstico de un SHU típico. Se presenta también una breve revisión del tema, de una entidad que requiere un diagnóstico temprano y certero que permita brindar un tratamiento eficaz y oportuno.

The use of eculizumab in Capnocytophaga canimorsus associated thrombotic microangiopathy: a case report

BackgroundThe use of complement inhibition is well established for complement mediated thrombotic microangiopathy, but its role in secondary forms of thrombotic microangiopathy is debated. We here present a case of thrombotic microangiopathy triggered by Capnocytophaga canimorsus, illustrating the diagnostic difficulties in discriminating between different thrombotic microangiopathies, and the dilemmas regarding how to treat this disease entity.Case presentationA previously healthy 56-year-old woman presented with fever and confusion. She was diagnosed with sepsis from Capnocytophaga canimorsus and thrombotic microangiopathy. Marked activation of both T-cells, endothelium and complement were documented. She was successfully treated with antimicrobial therapy, the complement inhibitor eculizumab and splenectomy. After several weeks, a heterozygote variant in complement factor B was localized, potentially implying the diagnosis of a complement mediated TMA over an isolated infection related TMA.ConclusionsWe discuss the possible interactions between complement activation and other findings in severe infection and argue that complement inhibition proved beneficial to this patient’s rapid recovery.

Clinicopathological features of cutaneous and renal glomerular vasculopathy in 178 dogs.

One hundred seventy-eight dogs with cutaneous and renal glomerular vasculopathy (CRGV) were evaluated to further the understanding of the natural course of CRGV. CRGV, a form of thrombotic microangiopathy, can cause skin lesions and potentially acute kidney injury (AKI) with a high mortality rate. Cases were submitted from multiple practices from 2012 until June 2019. Clinical histories and laboratory data were reviewed to describe the features of CRGV. Most cases (91%) occurred between November and May. Fifteen dogs (8.4%) with CRGV were in contact with another dog that developed skin lesions +/- AKI. Limb lesions were present on 144 dogs (80.9%) at presentation. Median time from appearance of a lesion to AKI was 3 days (range -4-45 days). Neurological signs occurred in 33 dogs (18.6%) including at presentation in 2 (1.1%). Systemic signs were present in 13 dogs prior to a skin lesion (7.3%). Non-steroidal anti-inflammatory drugs were prescribed prior to AKI identification in 92 of 170 dogs (54.1%). Thrombocytopenia was present in 115 of 137 (83.9%) of dogs. The timeframe over which AKI may develop is longer than previously reported, neurological signs can be identified at presentation or during hospitalisation, and thrombocytopenia is even more common than previously reported.

Making the Correct Diagnosis in Thrombotic Microangiopathy: A Narrative Review.

Purpose of review:Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli–induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment.Sources of information:Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors.Methods:This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies.Key findings:Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli–induced hemolytic uremic syndrome, also known as “typical” HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA.Limitations:The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach.