[Coagulation and complement crosstalk: molecular mechanisms of complement-mediated diseases].

The complement and coagulation systems are ancestrally related mechanisms of serine protease-induced protein activation. Recent studies have shown that the complement system enhances platelet aggregation by activating platelets and vascular endothelial cells. This system is also involved in the expression of tissue factor, which induces the coagulation reaction. Activated platelets and coagulation factors are also known to activate the complement system. In diseases involving the complement system, such as paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, and atypical hemolytic uremic syndrome, excessive activation of this system contributes to complement-mediated thrombosis. The anti-C5 antibody eculizumab has shown a remarkable thromboprophylactic effect in these complement diseases. The recent surge in development of new anti-complement agents has raised expectations for the advancement of treatments and preventive measures for thrombosis associated with complement disorders. This review outlines the crosstalk between these two systems, and describes the mechanisms of several diseases featuring both thrombosis and complement activation.

An Atypical Case of Hemolytic Uremic Syndrome Caused by Shiga Toxin Produced by Aeromonas spp.

Hemolytic uremic syndrome (HUS), traditionally recognized in pediatric populations, is characterized by renal insufficiency, hemolytic anemia, and thrombocytopenia, often linked to Shiga-like toxin (SLT) exposure. While typically associated with enteric pathogens like Escherichia coli (E. coli) and Shigella, Aeromonas spp. has also been identified as potential SLT producers, posing a new challenge. This study presents an exceptional case of HUS in a 77-year-old female, implicating Aeromonas hydrophila as the causative agent. The patient's clinical trajectory, marked by acute kidney injury post-consumption of raw oysters, underscores the unorthodox manifestation of HUS in adults. Diagnostic confirmation via stool antigen testing and blood culture revealed the presence of SLT and Aeromonas hydrophila, respectively. This case underscores the evolving landscape of HUS etiology, stressing the importance of heightened clinical awareness to expedite therapeutic intervention and mitigate long-term renal complications.

Atypical hemolytic uremic syndrome during induction chemotherapy in neuroblastoma, a rare phenomenon or common congenital predisposition?

Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H (CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.

Atypical hemolytic-uremic syndrome after COVID-19 vaccine: A case report.

BACKGROUND: The emergence of new SARS-CoV-2 variants and the global COVID-19 pandemic spurred urgent vaccine development. While common vaccine side effects are well-documented, rare adverse events necessitate post-marketing surveillance. Recent research linked messenger RNA vaccines to thrombotic microangiopathy (TMA), a group of syndromes characterized by microvascular hemolytic anemia and thrombocytopenia. This report describes a new-onset atypical hemolytic-uremic syndrome (aHUS) occurring after COVID-19 vaccination and complements recent literature. CASE PRESENTATION: A previously healthy 25-year-old woman developed malaise, nausea, edema, and renal dysfunction 60 days postvaccination. Laboratory findings confirmed TMA diagnosis. Genetic testing for complement system mutations was negative. Kidney biopsy supported the diagnosis, and the patient required hemodialysis. CONCLUSION: This case illustrates the rare occurrence of aHUS following COVID-19 vaccination, with unique characteristics compared to previous reports. Despite the critical role of vaccination in pandemic control, emerging adverse events, such as vaccine-related TMA, must be recognized and investigated. Additional clinical trials are imperative to comprehend the clinical features and pathophysiological mechanisms underlying TMA associated with COVID-19 vaccination.

Eculizumab for Shiga-toxin-induced hemolytic uremic syndrome in adults with neurological involvement.

The role of eculizumab in treating Shiga-toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) patients with neurological involvement remains unclear. We describe two distinctly different STEC-HUS patients with neurologic involvement successfully managed with eculizumab, and perform a literature review of all published cases. Both patients had complete resolution of neurological symptoms after initiation of eculizumab. Eighty patients with STEC-HUS treated with eculizumab were identified in the literature, 68.7% had complete resolution of neurological symptoms. Based on our experience and literature review, three prevailing themes were noted: 1) Early eculizumab administration optimized neurological outcomes, 2) Symptom resolution may not be immediate, neurological symptoms may initially worsen before improvement, and 3) Plasma exchange yielded no benefit. Early administration of eculizumab may reverse neurotoxicity in patients with STEC-HUS.

Clinical efficacy and safety of switching from eculizumab to ravulizumab in adult patients with aHUS- real-world data.

BACKGROUND: The complement factor 5 (C5)-inhibitor eculizumab has been established as standard-of-care for the treatment of atypical hemolytic uremic syndrome (aHUS). In 2021, the long-acting C5-inhibitor ravulizumab was approved, extending intervals of intravenous treatment from two to eight weeks resulting in improvement of quality of life for patients and lowering direct and indirect therapy associated costs. METHODS: This multicenter, retrospective data analysis of 32 adult patients with aHUS (including 10 kidney transplant recipients) treated with eculizumab for at least three months and switched to ravulizumab aims to evaluate the safety and efficacy of switching medication in the real-world setting. Hematologic parameters, kidney function, concurrent therapy and aHUS associated events were evaluated three months before and until up to 12 months after switching to ravulizumab. RESULTS: Mean age (range) at ravulizumab initiation was 41 years (19-78 years) and 59% of the patients were female. Genetic analysis was available for all patients with 72% showing a pathogenic variant. Median time (range) on eculizumab before switching was 20 months (3-120 months). No new events of TMA or worsening of renal function were reported during up to 12 months of follow-up during ravulizumab treatment. CONCLUSIONS: This is the largest, non-industry derived, multi-center retrospective analysis of adult patients with aHUS switching C5-inhibitor treatment from eculizumab to ravulizumab in the real-world setting. Switching to ravulizumab was safe and efficient resulting in sustained hematological stability and preservation of renal function.

Plasma Exchange in Postpartum Hemorrhage (PPH)-Associated Thrombotic Microangiopathy (TMA): A Case Report.

Thrombotic microangiopathy (TMA) is a rare yet potentially life-threatening condition. The diagnosis is difficult as there are other conditions presenting with features akin to TMA during the peripartum period such as eclampsia, preeclampsia, hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, and antiphospholipid syndrome. A 28-year-old woman with no significant past medical history developed TMA following a massive hemorrhage after an emergency cesarean section at 41 weeks of gestation. This case was finally diagnosed as postpartum hemorrhage (PPH)-associated TMA. The patient fully recovered after plasma exchange therapy. We posit the value of accumulating case reports, given that the documentation on the efficacy of plasma exchange in PPH-associated TMA is limited.

Clinical presentation and management of atypical hemolytic uremic syndrome in Latin America: a narrative review of the literature.

INTRODUCTION: Comprehensive information about atypical hemolytic uremic syndrome (aHUS) is relatively scarce outside of Europe and North America. This narrative review assembles available published data about the clinical presentation and management of aHUS in Latin America. AREAS COVERED: A search conducted in February 2023 of the MEDLINE (from inception), Embase (from inception), and LILACS/IBECS (1950 to 2023) databases using search terms 'atypical hemolytic uremic syndrome' and 'Latin America' and their variations retrieved 51 records (full papers and conference abstracts) published in English, Spanish, or Portuguese. After de-duplication, manual screening of titles/abstracts and addition of author-known articles, 25 articles were included of which 17 (68%) are full papers. All articles were published during the years 2013-2022. Articles include cohort studies, a registry analysis, and case reports from Argentina, Brazil, Chile and Columbia. Overall, Latin American patients with aHUS present the classic epidemiological, clinical, and genetic characteristics associated with this condition as described in other world regions. Depending on the country and time of reporting, aHUS in Latin America was treated mainly with plasma therapy and/or eculizumab. Where reported, eculizumab substantially improved aHUS-related outcomes in almost all adult and pediatric patients. EXPERT OPINION: Eculizumab has dramatically altered the natural course of aHUS, improving prognosis and patient outcomes. Addressing economic challenges and investing in healthcare infrastructure will be essential to implement strategies for timely detection and early treatment of aHUS in Latin America.

Veno-venous extracorporeal membrane oxygenation in managing acute respiratory distress syndrome associated with hemolytic uremic syndrome and septic shock: a case report.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is a rescue therapy for severe respiratory failure in which conventional mechanical ventilation therapy is unsuccessful. Hemolysis during VV-ECMO support arises from multiple factors associated with organ damage and poor outcomes. Therefore, close and prompt monitoring is needed. Hemolytic uremic syndrome (HUS) is characterized by hemolysis, acute renal failure, and thrombocytopenia. Hemolytic features of the disease may complicate VV-ECMO management. A 26-year-old man with a history of cerebral palsy underwent VV-ECMO for acute respiratory distress syndrome (ARDS) due to septic shock caused by bacterial translocation during treatment for HUS. He showed features of hemolysis, with elevated lactate dehydrogenase (LDH), fragmented red blood cells, and low haptoglobin levels. Plasma free hemoglobin was measured daily throughout the whole course of ECMO with levels higher than 10 mg/dL but not exceeding 50 mg/dL. The extracorporeal membrane oxygenation (ECMO) circuit pressures were carefully monitored to ensure the pump generated no excessive negative pressure. The patient was weaned off ECMO on the eleventh day. There have been several cases of VA-ECMO in patients with HUS; however, there is limited literature on VV-ECMO. As the days on VV-ECMO tend to be longer than those on VA-ECMO, features of hemolysis may complicate management. Although HUS did not directly influence the clinical course in the present case, features of hemolysis were continuously observed. This case highlighted the importance of standard ECMO monitoring, especially daily measurement of plasma free hemoglobin.

[When a Headache Is Not Just Hypertension: A Case of Atypical Hemolytic Uremic Syndrome in a Young Patient].

Thrombotic microangiopathies represent a group of particularly serious pathologies that can cause a rapid worsening of renal function, especially in young subjects. Through the clinical case described, we will focus our attention on the clinical and laboratory manifestations of the pathology, on the diagnostics and on the therapies to be used. Recent therapeutic innovations for the treatment of this pathology will also be analysed.

Comprehensive functional characterization of complement factor I rare variant genotypes identified in the SCOPE geographic atrophy cohort.

Rare variants (RVs) in the gene encoding the regulatory enzyme complement factor I (CFI; FI) that reduce protein function or levels increase age-related macular degeneration risk. A total of 3357 subjects underwent screening in the SCOPE natural history study for geographic atrophy secondary to age-related macular degeneration, including CFI sequencing and serum FI measurement. Eleven CFI RV genotypes that were challenging to categorize as type I (low serum level) or type II (normal serum level, reduced enzymatic function) were characterized in the context of pure FI protein in C3b and C4b fluid phase cleavage assays and a novel bead-based functional assay (BBFA) of C3b cleavage. Four variants predicted or previously characterized as benign were analyzed by BBFA for comparison. In all, three variants (W51S, C67R, and I370T) resulted in low expression. Furthermore, four variants (P64L, R339Q, G527V, and P528T) were identified as being highly deleterious with IC50s for C3b breakdown >1 log increased versus the WT protein, while two variants (K476E and R474Q) were ∼1 log reduced in function. Meanwhile, six variants (P50A, T203I, K441R, E548Q, P553S, and S570T) had IC50s similar to WT. Odds ratios and BBFA IC50s were positively correlated (r = 0.76, p < 0.01), while odds ratios versus combined annotation dependent depletion (CADD) scores were not (r = 0.43, p = 0.16). Overall, 15 CFI RVs were functionally characterized which may aid future patient stratification for complement-targeted therapies. Pure protein in vitro analysis remains the gold standard for determining the functional consequence of CFI RVs.

Anti-factor H Autoantibody-Associated Hemolytic Uremic Syndrome: A Rare Entity in a Pediatric Patient.

An 11-year-old patient presented with the primary complaint of hematuria and vomiting. On further investigation and a series of diagnostic tests, including a biopsy and thrombotic microangiopathy (TMA) profile, the patient was diagnosed with thrombotic microangiopathy. TMA is a pathological process involving endothelial cell injury, leading to thrombocytopenia and microangiopathic hemolytic anemia. This case highlights the importance of considering TMA in pediatric patients presenting with nonspecific symptoms, such as loss of appetite. Further research is needed to understand the pathophysiology and optimal management strategies for pediatric TMA. This case adds to the growing body of literature on pediatric TMA and underscores the need for a high index of suspicion in similar clinical scenarios.

Thrombotic Microangiopathy Post-COVID-19 Vaccination.

The emergence of COVID-19 has caused a wide spectrum of symptoms, ranging from asymptomatic to devastating symptoms, leading to death. One of the most serious complications of COVID-19 is the thromboembolic phenomenon, which has led to increased morbidity and mortality. Several vaccines were developed to protect against this infection and used widely across the globe. However, thromboembolic events were observed in the vaccinated population and were certainly the most commonly reported events following the COVID-19 vaccination. Although the thrombotic complications of COVID-19 were poorly understood, hyper-inflammatory responses were thought to be one of the main explanations for this infection sequel. In the setting of COVID-19 vaccines, there is still no clear understanding of the thrombosis pathophysiology, and, again, exaggerated pro-inflammatory and immune-mediated processes seem to be leading causes. Definitely, with the rise in reported cases of serious complications and increased awareness of these phenomena, we learn new theories and explanations that help us understand and manage those patients. We report the case report of two patients we managed over the last three years who presented with thrombotic microangiopathy following the COVID-19 vaccination.

A 26-year-old man with multiple organ failure caused by Aeromonas dhakensis infection: a case report and literature review.

Background: Infections in humans are mainly caused by Aeromonas hydrophila, Aeromonas caviae, and Aeromonas veronii. In recent years, Aeromonas dhakensis has been recognized as widely distributed in the environment, with strong virulence. However, this bacterial infection usually does not appear in patients with pneumonia as the first symptom. Case report: We report a 26-year-old man who was admitted to the hospital with community-acquired pneumonia as the first symptom and developed serious conditions such as hemolytic uremic syndrome, multiple organ dysfunction, and hemorrhagic shock within a short period. He died after 13 h of admission, and the subsequent metagenomic-next generation sequencing test confirmed the finally identified pathogen of infection as A. dhakensis. Conclusion: Aeromonas is a rare pathogen identified in the diagnosis of community-acquired pneumonia. Hence, doctors need to develop their experience in identifying the difference between infections caused by pathogenic microorganisms. Medical attention is essential during the occurrence of respiratory symptoms that could be controlled by empirical drugs, such as cephalosporins or quinolones. When patients with community-acquired pneumonia present hemoptysis and multiple organ dysfunction in clinical treatment, an unusual pathogen infection should be considered, and the underlying etiology should be clarified at the earliest for timely treatment.

Recurrent complement-mediated Hemolytic uremic syndrome after kidney transplantation.

Hereditary forms of hemolytic uremic syndrome (HUS), formerly known as atypical HUS, typically involve mutations in genes encoding for components of the alternative pathway of complement, therefore they are often referred to as complement-mediated HUS (cHUS). This condition has a high risk of recurrence in the transplanted kidney, leading to accelerated graft loss. The availability of anti-complement component C5 antibody eculizumab has enabled successful transplantation with a notably reduced recurrence rate and improved prognosis. Open questions are related to the potential for complement inhibitor discontinuation, ideal timing of treatment withdrawal, and patient selection based on genetic abnormalities. Our review delves into the pathophysiology, classification, genetic predispositions, and management strategies for cHUS in the native and transplant kidneys.

Adolescence-onset atypical hemolytic uremic syndrome: is it different from infant-onset?

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, mostly complement-mediated thrombotic microangiopathy. The majority of patients are infants. In contrast to infantile-onset aHUS, the clinical and genetic characteristics of adolescence-onset aHUS have not been sufficiently addressed to date. METHODS: A total of 28 patients (21 girls, 7 boys) who were diagnosed as aHUS between the ages of ≥10 years and <18 years were included in this study. All available data in the Turkish Pediatric aHUS registry were collected and analyzed. RESULTS: The mean age at diagnosis was 12.8±2.3 years. Extra-renal involvement was noted in 13 patients (46.4%); neurological involvement was the most common (32%). A total of 21 patients (75%) required kidney replacement therapy. Five patients (17.8%) received only plasma therapy and 23 (82%) of the patients received eculizumab. Hematologic remission and renal remission were achieved in 25 (89.3%) and 17 (60.7%) of the patients, respectively. Compared with the infantile-onset aHUS patients, adolescent patients had a lower complete remission rate during the first episode (p = 0.002). Genetic analyses were performed in all and a genetic variant was detected in 39.3% of the patients. The mean follow-up duration was 4.9±2.6 years. At the last visit, adolescent patients had lower eGFR levels (p = 0.03) and higher rates of chronic kidney disease stage 5 when compared to infantile-onset aHUS patients (p = 0.04). CONCLUSIONS: Adolescence-onset aHUS is a rare disease but tends to cause more permanent renal dysfunction than infantile-onset aHUS. These results may modify the management approaches in these patients.

Epidemiological Characteristics of Shiga Toxin-Producing Escherichia coli Responsible for Infections in the Polish Pediatric Population.

Shiga toxin-producing Escherichia coli (STEC) are zoonotic pathogens causing hemorrhagic colitis and hemolytic uremic syndrome (HUS) in children and the elderly. Stool samples were collected from 180 children hospitalized in five pediatric centers in Poland in 2018-2022. Direct stx1/stx2 gene detection by PCR in feces and E. coli isolates was performed. Antibiotic susceptibility was tested according to EUCAST v.12. Randomly selected isolates were serotyped with O157 antiserum and genotyped by pulsed-field gel electrophoresis (PFGE). A total of 44 E. coli isolates were confirmed as STEC by PCR. Among them, 84.4% were positive for stx2, and equally 6,8% for only stx1 and both stx1 and stx2 genes. The stx1 gene was also found in one Citrobacter freundii isolate. E. coli serotype O157 was present in 97.6% of the isolates. STEC infections most often occurred between June-October with a peak in July and August (51%). The highest, 77.8% of STEC isolates were found in the 1-5 years old group. No extended-spectrum ß-lactamases (ESBL) were found. Resistance only to amoxicillin/clavulanic acid (24.4%), piperacillin/tazobactam (3%), cefotaxime (6%), gentamicin (6%), ciprofloxacin (3%), azithromycin (3%), trimethoprim/sulfamethoxazole (24,2%) was detected. PFGE analysis showed 18 PFGE types with no clonal distribution. Eight isolates with A, B, and C PFGE types showed genetic relatedness in the type with no detection of transmission way of distribution. STEC strains pose a serious threat to human health, therefore demographic and epidemiological characteristics are crucial for their surveillance.

Pregnancy-associated atypical hemolytic uremic syndrome. Case report.

Pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) is a rare disease. There are only few reports in the literature, and most are in the puerperium period. It is a thrombotic microangiopathy (TMA) characterized for microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. We report the case of a pregnant patient at 26.3 gestation weeks, who developed clinical features of TMA, neurological alterations, and septic shock; then after fetus and placental delivery, no clinical improvement was observed; a diagnostic protocol was performed due to suspicion of P-aHUS, showing improvement after the plasma exchange sessions and eculizumab. We present here a brief review of the case since it is an entity that needs to be suspected during pregnancy when TMA features and requires an immediate diagnosis to provide timely treatment.

How We Interpret Thrombosis with Thrombocytopenia Syndrome?

Platelets play an important role in hemostasis, and a low platelet count usually increases the risk of bleeding. Conditions in which thrombosis occurs despite low platelet counts are referred to as thrombosis with thrombocytopenia syndrome, including heparin-induced thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia, paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, thrombotic microangiopathy (TMA), and disseminated intravascular coagulation. TMA includes thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (HUS), and atypical HUS. Patients with these pathologies present with thrombosis and consumptive thrombocytopenia associated with the activation of platelets and the coagulation system. Treatment varies from disease to disease, and many diseases have direct impacts on mortality and organ prognosis if therapeutic interventions are not promptly implemented. Underlying diseases and the results of physical examinations and general laboratory tests as part of a thorough workup for patients should promptly lead to therapeutic intervention before definitive diagnosis. For some diseases, the diagnosis and initial treatment must proceed in parallel. Utilization of not only laboratory tests but also various scoring systems is important for validating therapeutic interventions based on clinical information.

A Rare Case of Atypical Hemolytic Uremic Syndrome (aHUS) Precipitated by Dengue and the Treatment Landscape in Singapore.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by uncontrolled complement activation due to complement dysregulation. It is often triggered by precipitating events such as infections, inflammation, pregnancy, or medications. Dengue, an endemic viral infection in Southeast Asia, can activate the complement pathway, thereby triggering aHUS in genetically susceptible individuals. Here, we present the case of a 33-year-old male who presented with Dengue fever and subsequently developed aHUS. Plasma exchange (PLEX) successfully normalized his neurological status and hematological parameters. Although his renal function improved, it failed to normalize. Eculizumab, a monoclonal antibody that inhibits C5, was administered for a total of six months. The treatment was successfully discontinued without evidence of relapse after six months of follow-up. This case report demonstrates the safety of discontinuing eculizumab in patients who do not possess pathogenic mutations or variants in complement factors.