Secondary Thrombotic Microangiopathy Research Articles

Epidemiology and Administration outcomes of Thrombotic Thrombocytopenic Purpura (TTP): Review article

Background: Fever, thrombocytopenia, hemolysis, pentad failing kidneys, anaemia, and neurological impairment has historically been used to describe bleeding as the blood syndrome “thrombotic thrombocytopenic purpura” (TTP), a type of hemolytic anaemia caused by microangiopathy. TTP is an uncommon condition, and it is unclear exactly how often it is? According to studies, incidence per million depends on where individuals live. TTP can occur in youth with congenital forms, however it mostly strikes adults over the age of 40. The two organ systems most frequently impacted by TTP are the nerve system of the body (CNS) and kidneys. Because TTP is a serious medical condition with a 90% fatality grad if untreated, prompt diagnosis is crucial. Initial therapy is effective in around 80% of patients, and post-treatment mortality is between 10% and 15%. Objectives: The study aimed to summarize current evidences regarding epidemiology and outcomes of Thrombotic Thrombocytopenic Purpura therapy (TTP). Methods: For article selection, the PubMed database and EBSCO Information Services were used. All articles relevant with our topic and other articles were used in our review. Other articles that were not related to this field were excluded. The data was extracted in a specific format that was reviewed by the group members. Conclusion: Older patients had longer Immune thrombotic thrombocytopenic purpura (iTTP) episodes and died at higher rates than younger patients. iTTP patients have a considerable increase in chance of illness and demise, while receiving TPE and immunosuppressants, which necessitate the need for more potent treatments. Moreover, they are more likely to have secondary thrombotic microangiopathies than primary microangiopathies due to several causes. Depending on the origin of thrombotic microangiopathies, there are different risks associated with dialysis, neurologic and cardiac issues, and mortality. Mortality rate are low for patients who received hospital care with low rate of complications.

It's Probably the Lupus: A Case of Secondary Thrombotic Microangiopathy

It's Probably the Lupus: A Case of Secondary Thrombotic Microangiopathy

POS-035 A PHASE 3 STUDY TO SUPPORT IPTACOPAN REGISTRATION IN ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS): OVERVIEW OF APPELHUS STUDY DESIGN CONSIDERATIONS

POS-035 A PHASE 3 STUDY TO SUPPORT IPTACOPAN REGISTRATION IN ATYPICAL HEMOLYTIC UREMIC SYNDROME (aHUS): OVERVIEW OF APPELHUS STUDY DESIGN CONSIDERATIONS

POS-036 A YOUNG FEMALE WITH RENAL CORTICAL NECROSIS TREATED WITH INTRAVENOUS IMMUNOGLOBULIN IN A RESOURCE POOR SETTING: CASE REPORT

Renal cortical necrosis is a rare cause of acute kidney injury (AKI) characterized by diffuse or patchy ischemic coagulation necrosis of the cortex. One of the important causes is acute Thrombotic Microangiopathy (TMA).Thrombotic microangiopathy (TMA) is one of the most important causes of Renal cortical necrosis and Rapidly progressive renal failure (RPRF). It can be classified into Primary (hereditary or acquired) & secondary TMA. It is very crucial to diagnose & treat Renal cortical necrosis & TMA early to avoid morbidity & mortality.

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.

Eculizumab for paediatric patients with atypical haemolytic uraemic syndrome: full dataset analysis of post-marketing surveillance in Japan.

Eculizumab was approved for atypical haemolytic uraemic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in a real-world setting. Paediatric patients in the PMS cohort who were <18 years of age at the first administration of eculizumab and diagnosed with aHUS [excluding Shiga toxin-producing Escherichia coli HUS, thrombotic thrombocytopaenic purpura and secondary thrombotic microangiopathy (TMA)] were included in the effectiveness and safety analysis. Clinical endpoints of effectiveness [complete TMA response, TMA event-free status, platelet (PLT) count and lactate dehydrogenase (LDH) normalization, serum creatinine (sCr) decrease and estimated glomerular filtration rate (eGFR) improvement] were analysed in patients treated with at least one dose of eculizumab. Serious adverse events (SAEs) were also evaluated. A total of 40 paediatric patients (median age 5 years) were included. The median eculizumab treatment duration was 66 weeks. PLT count, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3% and 77.5% of patients, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation and 5 patients, including 1 patient with aHUS relapse, continued the treatment but extended the treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan.

Clinical features and outcomes of four atypical hemolytic uremic syndrome cases at a single institution in Miyazaki Prefecture from 2015 to 2019

BackgroundAlthough atypical hemolytic uremic syndrome (aHUS) is a life-threatening clinical entity that was characterized by thrombotic microangiopathy (TMA) with the activation of the complement system and the efficient treatment of eculizumab, the clinical features of aHUS have been unclear because of the rare incidence.Case presentationWe retrospectively analyzed 4 aHUS cases at a single institution during 2015–2019. Here, we presented 4 aHUS cases with renal transplantation (one case), influenza/acute interstitial pneumonia/disseminated intravascular coagulation (two cases), and severe fever with thrombocytopenia syndrome (one case), respectively. Initial clinical symptoms were microangiopathic hemolytic anemia (four cases), renal dysfunction (four cases), thrombocytopenia (four cases), and pulmonary hemorrhage (three cases) consisted with TMA features. Subsequent further examinations ruled out thrombotic thrombocytopenic purpura, Shiga toxin-producing E.coli-induced hemolytic uremic syndrome, and secondary TMA. Taken these findings together, we made the clinical diagnosis of aHUS. Furthermore, all cases also presented the high levels of plasma soluble C5b-9 (871.1 ng/ml, 1144.3 ng/ml, 929.2 ng/ml, and 337.5 ng/ml), suggesting persistent activation of complementary system. Regarding the treatment, plasma exchange (PE) (four cases) and eculizumab (two cases) therapy were administered for aHUS cases. Consequently, case 2 and case 4 were still alive with 768 days and 235 days, respectively. The other two cases were dead at 34 days and 13 days, respectively. Finally, although the previous reported genetic pathogenetic mutations were not detected in our cases, multiple genetic variants of complement factors were detected as CFH (H402Y, E936D), and THBD (A473V) in case 1, CFH (V62I, H402Y, V837I) in case 2, and CFH (H402Y, E 936D) and THBD (A473V) in case 3, CFH (V62I, H402Y, E936D) and THBD (473V) in case 4, respectively.ConclusionsBecause of still high mortality in our study, an urgent diagnosis of aHUS and subsequent immediate treatment including PE and eculizumab should be essential in clinical practice. Furthermore, the multiple genetic variants and the triggers may be related to one of the pathogenesis of aHUS. Thus, we assume that such a case-oriented study would be highly useful to the physicians who directly care for aHUS cases in clinical practice.

Application of C5 inhibitors in glomerular diseases in 2021.

The complement pathway is an essential mechanism in innate immunity, but it is also involved in multiple pathologies. For kidney diseases, strong evidence of a dysregulation in the alternative pathway in atypical hemolytic uremic syndrome (aHUS) led to the use of eculizumab, the first anti-C5 inhibitor available in clinical practice. Intensive fundamental research resulted in the development of subsequent new drugs, such as long-acting C5 inhibitors, oral medications, or antagonists of C5aR, the receptor for C5a. New data in the domain of C5-inhibition in glomerular diseases are still limited and mainly focus on 1) the efficacy of ravulizumab, a long-acting C5 inhibitor in aHUS, and 2) the use of avacopan, a C5aR antagonist, in antineutrophil cytoplasmic antibody vasculitis. Several new studies ongoing or planned for the next few years will evaluate the efficacy of C5 inhibition in secondary thrombotic microangiopathy, C3 glomerulopathy, membranous nephropathy, or immunoglobulin A nephropathy.

Complement Activation and Thrombotic Microangiopathy Associated With Monoclonal Gammopathy: A National French Case Series

Hemolytic uremic syndrome (HUS), a thrombotic microangiopathy (TMA) with kidney involvement, is a rare condition in patients with monoclonal gammopathy. In the absence of known causes of TMA, the role of complement activation in endothelial injury in patients with monoclonal gammopathy remains unknown and was the focus of this investigation. Case series. We studied the 24 patients in the French national registry of HUS between 2000 and 2020 who had monoclonal gammopathy without other causes of secondary TMA. We provide the clinical histories and complement studies of these patients. Monoclonal gammopathy-associated TMA with kidney involvement is estimated to be 10 times less frequent than adult atypical HUS (aHUS) in the French national registry. It is characterized by severe clinical features, with 17 of 24 patients requiring dialysis at disease onset, and with median renal survival of only 20 months. TMA-mediated extrarenal manifestations, particularly cutaneous and neurological involvement, were common and associated with poor overall prognosis. Complement studies identified low C3, normal C4, and high soluble C5b-9 levels in 33%, 100%, and 77% of tested patients, respectively, indicating a contribution of the alternative and terminal complement pathways in the pathophysiology of the disease. Genetic abnormalities in complement genes known to be associated with aHUS were found in only 3 of 17 (17%) who were tested. Retrospective study without comparison group; limited number of patients, limited available blood samples. Within the spectrum of TMA, TMA associated with monoclonal gammopathy represents a distinct subset. Our findings suggest that HUS associated with monoclonal immunoglobulin is a complement-mediated disease akin to aHUS.

POS-023 SECONDARY THROMBOTIC MICROANGIOPATHY – CLINICAL PROFILE AND OUTCOME

Secondary thrombotic microangiopathy (TMA) can present in the setting of drug intake, pregnancy, snake bite, malignant hypertension, pancreatitis and underlying autoimmune disease. Several of these patients have underlying genetic defect in complement pathway. The risk of progression to ESRD (End Stage Renal Disease) in TMA is high and it is known to recur post-transplant.

POS-148 COEXISTENCE OF HEMOLYTIC UREMIC SYNDROME WITH ACUTE PANCREATITIS: "THE DILEMMA OF DOUBLE TROUBLE"- AN ANALYSIS OF FOUR CASES AND REVIEW OF LITERATURE2021-A-WCN22-0482(101164299908)

Thrombotic microangiopathy (TMA) is a pathological description which presents clinically as microangiopathic anemia, thrombocytopenia and organ damage. TMA can be classified on the basis of the underlying etiology like ADAMTS13 deficiency (TTP),complement dysregulation (aHUS), secondary TMAs and infection associated TMAs.

What is the impact of blood pressure on neurological symptoms and the risk of ESKD in primary and secondary thrombotic microangiopathies based on clinical presentation: a retrospective study

BackgroundThe impact of blood pressure on neurological symptoms and risk of end-stage kidney disease (ESKD) is unknown in primary and secondary thrombotic microangiopathies (TMAs).MethodsWe measured baseline systolic (SBP) and diastolic (DBP) BP in consecutive 563 patients with adjudicated primary and secondary TMAs, and assessed its association with the risk of ESKD.ResultsNormal BP, grade 1, 2 and 3 hypertension were present in 243 (43.1%), 132 (23.4%), 101 (17.9%) and 88 (15.6%), respectively.Significant BP differences were noted in relation to the cause of TMA: highest BP values were found in patients with atypical hemolytic-uremic syndrome (aHUS), pregnancy, transplantation and auto-immune-related TMAs. Normal BP or grade 1 hypertension was found in 17/18 (94.4%) patients with thrombotic thrombocytopenic patients (only 1/18 (5.6%) had a SBP value>150 mmHg). In contrast, BP values could not differentiate isolated “essential” malignant hypertension (MH) from MH associated with aHUS (isolated MH (n=15): BP (median (IQR)): 220 (182-249)/132 (101-150) mmHg; MH with aHUS (n=5): BP: 223 (196-245)/131 (111-144) mmHg).The risk of vigilance disturbances (6.9%, 15.0%, 25.0%, respectively), epileptic seizures (1.5%, 4.0%, 12.5%, respectively) and posterior reversible encephalopathy syndrome (0.76%, 2.97%, 6.82%, respectively) increased with increasing baseline BP values from grade 1 to grade 3 hypertension.ESKD occurred in 35/563 (6.2%) patients (1.23%, 2.27%, 11.9% and 19.3% of patients with normal BP, grade 1, 2 and 3 hypertension, respectively). As compared to patients with normal BP (<120/139 mmHg), grade 1, grade 2 and grade 3 hypertension were associated with a greater risk of ESKD in univariate (OR: 1.91 [0.83-4.40], 13.2 [3.56-48.9] and 34.8 [9.31-130], respectively) and multivariate (OR: 0.89 [0.30-2.69], 7.00 [1.57-31.3] and 19.7 [4.53-85.2], respectively) analyses. The association between BP and the risk of ESRD was unchanged after adjustment on eculizumab use (OR: 3.46 [1.41-8.49], 17.7 [4.44-70.0] and 70.6 [8.61-579], respectively). Patients with MH, regardless of its cause, had a greater risk of ESKD (OR: 26.4 [10.0-69.8] vs other patients).ConclusionsBaseline BP differs in primary and secondary TMAs. High BP reduces the neurological tolerance of TMAs and is a powerful independent risk factor of ESKD, even after adjustment on TMA’s cause.

Incidence of Thrombotic Microangiopathies in Quebec: An 8-Year Overview from a Laboratory Centralizing Adamts-13 Testing

Primary and secondary thrombotic microangiopathies (TMA) constitute a group of life-threatening diseases of different aetiologies characterized by similar symptoms. The comprehensive compilation of data related to TMA is challenging due to their rare occurrence. The objective of this study was to provide an overview of the incidence of thrombotic thrombocytopenia (TTP) and non-TTP TMAs in the Province of Quebec (PQ) (8.485 Million inhabitants in 2019) by taking advantage of the centralized ADAMTS-13 activity and antibody testing for PQ since 2013 at the CHU Sainte-Justine (CHUSJ)All ADAMTS-13 activity and antibody titration were performed locally at CHUSJ. ADAMTS-13 results and patient demographic characteristics from April 2012 to December 2019 were extracted from the Laboratory Information System of CHUSJ and used in an anonymized database. Information on previous TMA episodes was obtained from a standardized clinical assessment form accompanying each plasma sample. Statistical analyses were performed with IBM SPSS version 26.0. The annual incidence rates were calculated based on the number of patients with a first-time recorded diagnosis of TMA using the Quebec mid-year (yr) estimated population of the years at stake. Patients with suspected TMA were further divided into two categories: individuals with TTP, defined by either an ADAMTS-13 activity ≤10% or a positive anti-ADAMTS-13 antibody titration, and patients with a suspected TMA other than TTP (non-TTP TMA) with a result of ADAMTS-13 activity >10%. The study was approved by the Research Ethics Committee of CHUSJ.A progressive increase in the annual requests for ADAMTS13 activity was observed over the study period. The number of new patients increased from 2012 to 2016 but plateaued after 2016 at an average number of 170 new patients per year. The number of confirmed TTP cases in Quebec was higher from 2014 to 2018 compared to in 2012, 2013 and 2019 (Figure 1). A total of 2081 requests for ADAMTS13 activity testing were received during the study period, representing 846 subjects with a suspected TMA. 147 subjects (17%) had a confirmed TTP and 699 (83%) had a suspected non-TTP TMA.TMAs were suspected more often in females (59%), both in confirmed TTP (62%) and non-TTP TMA (58%).The mean annual incidence rate (MAIR) of TTP was 1.91 case/million/yr (95%CI: 1.46-2.35). This was higher in females (2.36 cases/million/yr; 95%CI: 1.34-3.37) compared to males (1.42 case/million/yr; 95%CI: 0.57-1.44; p=0.001). The MAIR of non-TTP TMA was 9.97 cases/million/yr (95%CI:5.85-14.09), 11.52 for females (95%CI:6.71-16.33) versus 8.41 for males (95% CI: 4.81-12.02; p=0.001).In non-TPP TMA, the MAIR for males ranged from 3.9 to 7.2 cases per million prior to 60 year of age and increased after up to 24.5 at ages 80-89. For females, a first peak MAIR above 10 cases per million was observed during their thirties and a second peak was observed during their seventies (Figure 2).In TPP, peaks incidences in females were observed from ages 20 to 49. It dipped from ages 50 to 69 and then increased again. In males, a highest MAIR was observed between ages 40 to 79.In conclusion, the provincial centralization of ADAMTS-13 testing has enabled us to depict comprehensive picture of TTP and other suspected non-TPP TMA, thereby providing valuable information for caregivers and health authorities into these rare diseases. Sex and age related incidences observed in this study are comparable to those obtained through other registries and aggregated studies. Further analyses on clinical presentation of TMAs and patient follow up are now possible using the identification of this large cohort. [Display omitted] DisclosuresLapeyraque: Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rivard: Bayer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma Inc: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees; CSL Behring Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bonnefoy: Sanofi Genzyme Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Withdrawn: Prospective registry of adult patients receiving therapeutic plasma exchange with presumptive diagnosis of thrombotic microangiopathy (TMA): The Turkish hematology research and education group (ThREG)-TMA02 study

Thrombotic microangiopathy(TMA) is a pathological diagnosis characterized by abnormalities of small vessels leading to microvascular thrombosis of arterioles and capillaries. The current prospective, non-interventional, multicenter (n:18) study aimed to define distribution of different TMA forms in adult Turkish patients who were referred for therapeutic plasma exchange (TPE) for a presumptive diagnosis of TMA. Patients with serum ADAMTS13 activity <5% were diagnosed as acquired thrombotic thrombocytopenic purpura (aTTP). Patients presenting with ADAMTS13 activity 6-10 % / normal renal function and patients with ADAMTS13 activity >10 %, normal renal function and no secondary TMA were treated as unclassified TMA. The study included a total of 97 patients (female: 60; male: 30) with a median age of 48 (18-74). Detailed evaluation at 1 month after hospital admission revealed aTTP, secondary TMA, infection/complement-associated hemolytic uremic syndrome and unclassified TMA in 32 (33 %), 33 (34 %), 26 (27 %) and 6 (6%) patients respectively. As subclassification of various TMAs will dictate specific therapy, proper diagnosis in a timely manner is of utmost clinical significance.

Increased VWF and Decreased ADAMTS-13 in COVID-19: Creating a Milieu for (Micro)Thrombosis.

von Willebrand factor (VWF) is a large adhesive multimeric protein involved in hemostasis. The larger the size (or number of VWF multimers), the greater the functionality of the protein. A deficiency or defect of VWF can lead to von Willebrand disease (VWD) and cause bleeding. Conversely, an increase in VWF may create an environment that promotes thrombosis. ADAMS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), sometimes called VWF-cleaving protease, is primarily responsible for controlling the size of VWF. The most severe deficiency (<10% of normal levels) of ADAMTS-13 arises in thrombotic thrombocytopenic purpura, a condition characterized by the presence of ultralarge VWF and clinically resulting in enhanced risk of thrombosis. However, ADAMTS-13 deficiency may result from other pathological processes. Of relevance is the recent finding that COVID-19 (coronavirus disease 2019) is associated with both increased levels and activity of VWF as well as generally decreased (or occasionally normal) activity levels of ADAMTS-13. Thus, in COVID-19 there is an alteration in the VWF/ADAMTS-13 axis, most often described by increased VWF/ADAMTS-13 ratio (or reduced ADAMTS-13/VWF ratio). COVID-19 is also associated with high prothrombotic risk. Thus, the imbalance of VWF and ADAMTS-13 in COVID-19 may be providing a milieu that promotes (micro)thrombosis, in a clinical picture resembling a secondary thrombotic microangiopathy in some patients. This review therefore assesses the literature on VWF, ADAMTS-13, and COVID-19. Whenever reported in COVID-19, VWF has always been identified as raised (compared with normal reference ranges or control populations). Reports have included VWF level (i.e., VWF antigen) and in some cases one or more VWF "activity" (e.g., collagen binding; platelet glycoprotein Ib [GPIb] binding, using ristocetin cofactor or more modern versions including VWF:GPIbR [recombinant] and VWF:GPIbM [mutant]). Whenever reported, ADAMTS-13 has been reported as "normal" or reduced; however, it should be recognized that "normal" levels may still identify a relative reduction in individual cases. Some reports also discuss the raised VWF/ADAMTS-13 (or reduced ADAMTS-13/VWF) ratio, but very few provide actual numerical data.

Retrospective and Systematic Analysis of Causes and Outcomes of Thrombotic Microangiopathies in Routine Clinical Practice: An 11-Year Study.

Background: Thrombotic microangiopathies (TMAs) are highly suspected in patients showing mechanical hemolytic anemia, thrombocytopenia, and haptoglobin consumption. Primary [thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome] and secondary TMA are considered. Even if ADAMTS13 measurements and alternative complement pathway explorations have greatly improved the ability to identify primary TMA, their diagnosis remains difficult, and their frequency relative to that of secondary TMA is undetermined. The objectives of the present study were, therefore, to describe the etiologies, management, and the outcomes of patients presenting with TMA in real-life clinical practice.Methods: We conducted a retrospective study between 01/01/2008 and 31/12/2018 that included all consecutive patients presenting with biological TMA syndrome at admission or developing during hospitalization. Patients were identified from the laboratory databases, and their medical files were reviewed to confirm TMA diagnosis, to determine etiology, and to analyze their therapeutic management and outcomes.Results: During this period, 239 patients with a full TMA biological syndrome were identified, and the TMA diagnosis was finally confirmed in 216 (90.4%) after the cases were reviewed. Primary TMAs (thrombotic thrombocytopenic purpura or atypical hemolytic uremic syndrome) were diagnosed in 20 of 216 patients (9.3%). Typical HUS was diagnosed in eight patients (3.7%), and the most frequent secondary TMAs were HELLP syndrome (79/216, 36.6%) and active malignancies (30/219, 13.9%). ADAMTS13 measurements and alternative complement pathway analyses were performed in a minority of patients. Multiple factors identified as TMA triggers were present in most patients, in 55% of patients with primary TMA, vs. 44.7% of patients with secondary TMA (p = 0.377). Death occurred in 57 patients (23.4%) during follow-up, and dialysis was required in 51 patients (23.6%). Active malignancies [odds ratio (OR) 13.7], transplantation (OR 4.43), male sex (OR 2.89), and older age (OR 1.07) were significantly associated with death.Conclusion: Secondary TMAs represent many TMA causes in patients presenting a full TMA biological syndrome during routine clinical practice. Multiple factors favoring TMA are present in about half of primary or secondary TMA. ADAMTS13 and complement pathway were poorly explored in our cohort. The risk of death is particularly high in patients with malignancies as compared with patients with other TMA.

Childhood\u2010onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report

BackgroundSystemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.Case presentationA 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.ConclusionsAn additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.

Серия случаев вторичной тромботической микроангиопатии при мультисистемном воспалительном синдроме у детей, ассоциированном с COVID-19

Thrombotic microangiopathy (TMA) is one of the main links in the pathogenesis of multisystem inflammatory syndrome in children (MIS-C) associated with a new coronavirus infection caused by SARS-Cov-2 (COVID-19). In the setting of an increasing number of patients with hemolytic uremic syndrome (HUS) during the COVID-19 pandemic, 5 out of 7 cases of HUS (according to the Khimki Regional Hospital) in children revealed the association between acute kidney injury (AKI) and history of COVID-19. Also, there were recorded laboratory markers of systemic inflammation, the relevant criteria for the diagnosis of MIS-C associated with SARS-CoV-2. The article presents a clinical analysis of the case series concerning HUS, during which a comparison with the world literature data was conducted. It was proposed to consider this pathology in children as secondary thrombotic microangiopathy (TMA) in the setting of new coronavirus infection, similar to secondary TMA, developed due to exposure to HIV. During the COVID-19 pandemic, it is extremely important to establish the association between the TMA and the experienced COVID-19 in children for the therapy correction and further follow-up of patients after discharge from the hospital. KEYWORDS: new coronavirus infection, SARS-CoV-2, COVID-19, multisystem inflammatory syndrome, secondary thrombotic microangiopathy, hemolytic-uremic syndrome, acute kidney injury. FOR CITATION: Novikov D.V., Sabinina T.S., Shalbarova T.V. et al. Case series of secondary thrombotic microangiopathy in children with multisystem inflammatory syndrome associated with COVID-19. Russian Medical Inquiry. 2021;5(11):773–777 (in Russ.). DOI: 10.32364/2587-6821-2021-5-11-773-777.

Thrombotic microangiopathy triggered by podocytopathy.

Thrombotic microangiopathy (TMA) is a rare group of diseases characterized by microangiopathic hemolytic anemia, thrombocytopenia, and target organ damage. It can be divided into primary and secondary TMA. Herein we report a case of TMA associated to a primary glomerular disease. We report the case of a 31-year-old Black male from Cape Verde admitted in March 2018 with nephrotic syndrome and upper gastrointestinal bleeding, the latter due to severe erythematous gastritis. He was discharged after clinical stabilization. The patient came to Portugal 8 months later. On admission, he presented with rapid deterioration of kidney function and hyperkalemia. The etiologic study revealed microangiopathic hemolytic anemia, nephrotic syndrome and microscopic hematuria. Immunologic study and viral serology were negative. ADAMTS13 activity and inhibitor testing were within normal range, genetic complement evaluation showed CFH-H3 in homozygosity, functional complement studies revealed decreased function of alternative pathway. Kidney biopsy was consistent with the diagnosis of TMA, and electron microscopy was compatible with minimal change disease. Patient underwent plasmapheresis with resolution of hemolysis, fluid overload and recovery of renal function. Two months later, he presented with nephrotic syndrome and started prednisolone with remission. Six months later, the nephrotic syndrome relapsed, and it became steroid-, MMF-, and rituximab-resistant. Tacrolimus was initiated, achieving partial remission. Atypical hemolytic uremic syndrome is an uncommon disease and is rarely reported as secondary to glomerular diseases. This case showcases the challenges regarding treatment options in a resistant glomerulopathy and the implications of therapeutic choices and kidney outcomes with the coexisting TMA.

ADAMTS13 activity to von Willebrand factor antigen ratio predicts acute kidney injury in patients with COVID-19: Evidence of SARS-CoV-2 induced secondary thrombotic microangiopathy.

IntroductionSevere COVID‐19 is often compounded by a prothrombotic state that is associated with poor outcomes. In this investigation, we aimed to evaluate ADAMTS13 activity, von Willebrand factor level (VWF:Ag), and the corresponding ADAMTS13 activity/VWF:Ag ratio, in patients with COVID‐19 and for associations with disease progression and acute kidney injury (AKI).MethodsPatients presenting to the emergency department (ED) with COVID‐19 were enrolled in this prospective, observational study. ADAMTS13 activity and VWF:Ag were measured at index ED visit. The primary endpoint was severe AKI defined by KDIGO stage 2 + 3 criteria, while the secondary endpoint was peak 30‐day COVID‐19 severity.ResultsA total of 52 adult COVID‐19 patients were enrolled. Overall, we observed that 23.1% of the cohort had a relative deficiency in ADAMTS13 activity, while 80.8% had elevated VWF:Ag. The ADAMTS13 activity/VWF:Ag ratio was significantly lower in patients with severe AKI (P = .002) and those who developed the severe form of COVID‐19 (P = .020). The ADAMTS13 activity/VWF:Ag ratio was negatively correlated with age (P < .001) and LDH (P < .001), while positively correlated with hemoglobin (P = .041). After controlling for confounders, a one‐unit increase in ADAMTS13/VWF:Ag ratio was associated with 20% decreased odds of severe AKI.ConclusionA low ADAMTS13 activity:VWF:Ag ratio at ED presentation is associated with progression to severe COVID‐19 disease and severe AKI, with a pattern suggestive of a secondary microangiopathy. Further interventional studies should be conducted to assess the restoration of ADAMTS13:VWF:Ag ratio in hospitalized patients with COVID‐19.