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.

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Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: Clinically differentiating the thrombotic microangiopathies

European Journal of Internal Medicine ◽

10.1016/j.ejim.2013.05.007 ◽

2013 ◽

Vol 24 (6) ◽

pp. 486-491 ◽

Cited By ~ 33

Author(s):

Spero R. Cataland ◽

Haifeng M. Wu

Keyword(s):

Hemolytic Uremic Syndrome ◽

Thrombotic Thrombocytopenic Purpura ◽

Atypical Hemolytic Uremic Syndrome ◽

Thrombotic Microangiopathies ◽

Thrombocytopenic Purpura ◽

Uremic Syndrome

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C3 glomerulopathy and atypical hemolytic uremic syndrome: an updated review of the literature on alternative complement pathway disorders

International Urology and Nephrology ◽

10.1007/s11255-020-02729-y ◽

2021 ◽

Author(s):

Kultigin Turkmen ◽

Ismail Baloglu ◽

Hakan Ozer

Keyword(s):

Hemolytic Uremic Syndrome ◽

Atypical Hemolytic Uremic Syndrome ◽

Alternative Complement Pathway ◽

C3 Glomerulopathy ◽

Review Of The Literature ◽

Complement Pathway ◽

Alternative Complement ◽

Uremic Syndrome

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The experience of using the Russian biosimilar of the original drug eculizumab for the treatment of patients with atypical hemolytic-uremic syndrome

Terapevticheskii arkhiv ◽

10.26442/00403660.2020.06.000649 ◽

2020 ◽

Vol 92 (6) ◽

pp. 76-80

Author(s):

Yulia V. Lavrishcheva ◽

Alexander A. Yakovenko ◽

Dmitrii A. Kudlai

Keyword(s):

Hemolytic Uremic Syndrome ◽

Thrombotic Microangiopathy ◽

High Efficiency ◽

Systemic Disease ◽

Atypical Hemolytic Uremic Syndrome ◽

Adult Patients ◽

Alternative Complement Pathway ◽

Complement Pathway ◽

Alternative Complement ◽

Uremic Syndrome

Atypical hemolytic-uremic syndrome (aHUS) is a chronic systemic disease of a genetic nature, which is based on uncontrolled activation of the alternative complement pathway, leading to generalized thrombosis in the vessels of the microvasculature (complement-mediated thrombotic microangiopathy). To date, therapy with eculizumab is the most effective and pathogenetically substantiated method of treating patients with ASH. Using the example of three clinical cases of patients with a verified diagnosis of aHUS, the high efficiency and safety of the worlds first bioanalogue of eculizumab in the treatment of adult patients with aHUS (complement-mediated thrombotic microangiopathy) was demonstrated.

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Mutation of complement factor B causing massive fluid-phase dysregulation of the alternative complement pathway can result in atypical hemolytic uremic syndrome

Kidney International ◽

10.1016/j.kint.2020.05.028 ◽

2020 ◽

Vol 98 (5) ◽

pp. 1265-1274 ◽

Cited By ~ 1

Author(s):

Yuzhou Zhang ◽

Robin A. Kremsdorf ◽

C. John Sperati ◽

Kammi J. Henriksen ◽

Mari Mori ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

Atypical Hemolytic Uremic Syndrome ◽

Fluid Phase ◽

Complement Factor ◽

Complement Pathway ◽

Factor B ◽

Complement Factor B ◽

Alternative Complement ◽

Uremic Syndrome ◽

Massive Fluid

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ADAMTS13 Variants in Atypical Hemolytic Uremic Syndrome

Blood ◽

10.1182/blood.v120.21.490.490 ◽

2012 ◽

Vol 120 (21) ◽

pp. 490-490

Author(s):

Shuju Feng ◽

Stephen J. Eyler ◽

Yuzhou Zhang ◽

Tara K. Maga ◽

Michael H. Kroll ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

Genetic Variants ◽

Functional Activity ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Alternative Complement Pathway ◽

Hek293 Cells ◽

Complement Pathway ◽

Alternative Complement ◽

Uremic Syndrome

Abstract Abstract 490 Atypical hemolytic uremic syndrome (aHUS) is a clinically defined thrombotic microangiopathic anemia (TMA) characterized by the symptom triad of renal failure, thrombocytopenia and microangiopathic hemolytic anemia in the absence of Shiga-toxin-producing bacteria as a triggering factor. Its pathogenesis is linked to dysregulation of the alternative pathway of the complement cascade, with loss-of-function mutations reported in complement regulators like factor H (CFH), membrane cofactor protein (MCP), factor I (CHI) and thrombomodulin (THBD), and gain-of-function mutations in complement activators like factor B (CFB) and complement component 3 (C3). In nearly 40% of patients, however, mutations are not identified in these genes raising the possibility of unrecognized contributory genetic causes. Genetic variants in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs) have been causally related to thrombotic thrombocytopenic purpura (TTP), another TMA characterized by the pentad of neurologic symptoms, fever, kidney failure, thrombocytopenia and microangiopathichemolytic anemia. The phenotypic similarities between aHUS and TTP can at times lead to difficulty in their clinical distinction. On this basis, we hypothesized that partial deficiency in ADAMTS13 function may coexist with abnormalities in the alternative complement pathway in patients with aHUS. To test this hypothesis, we measured ADAMTS13 functional activity in 26 patients with aHUS by fluorescence resonance energy transfer substrate-von Willebrandfactor 73mer (FRETS-VWF73) and recombinant VWF A2 domain cleavage assay. We also genotyped all patients for ADAMTS13 and alternative complement pathway genes. We transiently expressed 10 different ADAMTS13 missense variants in HEK293 cells to analyze activity and secretion of each recombinant protein. The ADAMTS13 functional activity was partially reduced (< 60%) in serum from 20 patients (77%) as measured by FRETS-VWF73 and recombinant VWF A2 cleavage assays. Genetic variants in ADAMTS13 were identified in 21 patients (81%) and included R386C, Q448E, A900V, V832M, R1060W, R7W/Q448E, A900V/Q448E, R1096H/A747V, R7W/A1033T, R7W/P618A/Q448E, R7W/P618A/A900V/Q448E, R7W/P618A/A732V/Q448E. The coexistence of both ADAMTS13 deficiency and excessive complement functional activity was present in 13 patients (50%). Activity of recombinant ADAMTS13 proteins containing the following variants was normal: R386C, Q448E, P618A, A732V, A747V, V832M, A900V, A1033T and R1060H. The R1096H variant of ADAMTS13 was associated with a reduction in functional activity by 50%. The secretion of recombinant proteins with the following variants was severely reduced: P618A, R1060H (<1%), R386C, R1096H (<10%), and A1033T (<50%) (Figures 1 and 2). This study implicates ADAMTS13 in the pathogenesis of aHUS and mandates the evaluation of ADAMTS13 in aHUS patients. Defining the role of ADAMTS13 in aHUS may aid in the development of new treatments and/or assist in clarifying whether long-term treatment with currently available anti-complement therapy is required for this disease. Disclosures: Kroll: Aplagon: Membership on an entity's Board of Directors or advisory committees; Optimer: Consultancy; Leo: Honoraria, Travel Expenses, Travel Expenses Other.

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Efficacy and safety of the long-acting C5 inhibitor ravulizumab in patients with atypical hemolytic uremic syndrome triggered by pregnancy: a subgroup analysis

BMC Nephrology ◽

10.1186/s12882-020-02190-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Anja Gäckler ◽

Ulf Schönermarck ◽

Vladimir Dobronravov ◽

Gaetano La Manna ◽

Andrew Denker ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

Atypical Hemolytic Uremic Syndrome ◽

Multicenter Trial ◽

Efficacy And Safety ◽

Meningococcal Infections ◽

Phase 3 ◽

Alternative Complement ◽

Uremic Syndrome ◽

Long Acting ◽

Inhibitor Treatment

Abstract Background Atypical hemolytic uremic syndrome (aHUS) triggered by pregnancy is a rare disease caused by dysregulation of the alternative complement pathway that occurs in approximately 1 in 25,000 pregnancies. The 311 phase 3 trial (NCT02949128) showed that ravulizumab, a long-acting C5 inhibitor obtained through selective modifications to eculizumab, is efficacious in inhibiting complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. In this analysis, we report outcomes in a subgroup of patients from the 311 study who developed TMA postpartum. Methods This was a phase 3, multicenter trial evaluating efficacy and safety of ravulizumab in adults (≥18 years of age) with aHUS naïve to complement inhibitor treatment. The primary endpoint was complete TMA response (simultaneous platelet count normalization [≥150 × 109/L], lactate dehydrogenase normalization [≤246 U/L] and 25% improvement in serum creatinine) through the 183-day initial evaluation period. Additional efficacy endpoints included time to complete TMA response, hematologic normalization, and dialysis requirement status. Results Eight patients presenting with TMA postpartum (median age of 37.7 [range; 22.1–45.2] years) were diagnosed with aHUS and received ≥1 dose of ravulizumab. Five patients (63%) were on dialysis at baseline. Complete TMA response was achieved in 7/8 patients (87.5%) in a median time of 31.5 days. Hematologic normalization was observed in all patients. All patients on dialysis at baseline discontinued dialysis within 21 days after treatment with ravulizumab. All patients showed continued improvements in the estimated glomerular filtration rate from baseline to Day 183. Three possible treatment-related adverse events were observed in 2 patients (arthralgia and nasopharyngitis [both non-severe]; urinary tract infection). No deaths or meningococcal infections occurred. Conclusions Treatment with ravulizumab provided immediate and complete C5 inhibition, resulting in rapid clinical and laboratory improvements and complete TMA response through 183 days in patients with aHUS triggered by pregnancy. The safety profile observed in this subset of patients analysed is consistent with the 311 study investigating ravulizumab in patients with aHUS naïve to complement treatment. Trial registration Clinical trial identifier:NCT02949128.

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Clinical Practice Guidelines for the Management of Atypical Hemolytic Uremic Syndrome in Korea

Journal of Korean Medical Science ◽

10.3346/jkms.2016.31.10.1516 ◽

2016 ◽

Vol 31 (10) ◽

pp. 1516 ◽

Cited By ~ 11

Author(s):

Hae Il Cheong ◽

Sang Kyung Jo ◽

Sung-Soo Yoon ◽

Heeyeon Cho ◽

Jin Seok Kim ◽

...

Keyword(s):

Clinical Practice ◽

Hemolytic Uremic Syndrome ◽

Clinical Practice Guidelines ◽

Practice Guidelines ◽

Atypical Hemolytic Uremic Syndrome ◽

Uremic Syndrome

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Case Report: Lipoprotein Glomerulopathy Complicated by Atypical Hemolytic Uremic Syndrome

Frontiers in Medicine ◽

10.3389/fmed.2021.679048 ◽

2021 ◽

Vol 8 ◽

Author(s):

Lara Kollbrunner ◽

Patricia Hirt-Minkowski ◽

Javier Sanz ◽

Elena Bresin ◽

Thomas J. Neuhaus ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Complement Factor ◽

Inherited Disease ◽

Lipoprotein Glomerulopathy ◽

Gene Encoding ◽

Alternative Complement ◽

Uremic Syndrome ◽

The Complement System

Lipoprotein glomerulopathy (LPG) is a rare inherited disease caused by mutations in the APOE gene, encoding apolipoprotein E (apoE). Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by overactivation of the alternative complement pathway. Here we report the case of a 21-year-old man with LPG who developed aHUS. A functional complement assay demonstrated an overactivation of the complement system. Complementary genetic analysis revealed a homozygous aHUS risk allele for complement factor-H related 1 (CFHR1), CFHR1*B. To the best of our knowledge, this is the first report of an aHUS in a patient with LPG.

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Desafios Diagnósticos e Terapêuticos na Síndrome Hemolítica Urémica Atípica: A Propósito de Um Caso Clínico

Acta Médica Portuguesa ◽

10.20344/amp.10021 ◽

2019 ◽

Vol 32 (10) ◽

pp. 673

Author(s):

Sofia Reis ◽

Daniela Ramos ◽

Carolina Cordinhã ◽

Clara Gomes

Keyword(s):

Differential Diagnosis ◽

Hemolytic Uremic Syndrome ◽

Shiga Toxin ◽

Atypical Hemolytic Uremic Syndrome ◽

Specific Treatment ◽

Neurological Involvement ◽

Thrombocytopenic Purpura ◽

Alternate Pathway ◽

Uremic Syndrome ◽

Deficient Activity

The atypical hemolytic uremic syndrome comprises a thrombotic microangiopathy resulting from the complement alternate pathway hyperactivation. Its severity requires early diagnosis and treatment. The differential diagnosis includes typical hemolytic uremic syndrome (associated with Shiga toxin) and thrombotic thrombocytopenic purpura (associated with deficient activity of ADAMTS13). The only specific treatment currently available for atypical hemolytic uremic syndrome is eculizumab. We describe the case of a child with atypical hemolytic uremic syndrome diagnosed in the context of bloody diarrhea, complicated by neurological involvement that posed several diagnostic and therapeutic challenges.

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