RARE DISEASE
Genetic thrombotic microangiopathy
Genetic thrombotic microangiopathy
Genetic thrombotic microangiopathy
Drug discovery
687
papers
On emerging therapies
Overview
Genetic thrombotic microangiopathy (TMA) encompasses rare inherited disorders characterized by microvascular thrombosis, thrombocytopenia, and organ injury due to mutations in genes regulating complement pathways (e.g., CFH, CFI, CD46, C3, CFB), ADAMTS13 (cTTP), or metabolic pathways (MMACHC, DGKE). These mutations drive endothelial damage, leading to conditions like atypical hemolytic uremic syndrome (aHUS) and congenital TTP, often triggered by environmental factors [1][2][7].
Categories: rare genetic diseases
Research Papers
687 drug discovery papers about Genetic thrombotic microangiopathy, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
687 drug discovery papers about Genetic thrombotic microangiopathy, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-09-29 | Clinical Practice Guideline: The Diagnosis, Treatment, and Follow-Up Management of Thrombotic Thrombocytopenic Purpura.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy. The global incidence of immune-mediated TTP (iTTP) is 1-6 cases per million people per year. The new (S3-level) clinical practice guideline is the first in the German-speaking world to compile evidence- and consensus-based recommendations on the diagnosis, treatment, follow-up management, and care of patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) and congenital thrombotic thrombocytopenic purpura (cTTP). This clinical practice guideline was developed under the aegis of the Society for Thrombosis and Hemostatsis Research (Gesellschaft für Thrombose- und Hämostaseforschung, GTH) according to the criteria for S3-level guidelines issued by the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). It is based on information from publications retrieved through systematic literature searches and a structured assessment of the evidence using the GRADE scheme (Grading of Recommendations, Assessment, Development, and Evaluation), with a formal consensus process. Early diagnosis of TTP is essential. Measurement of ADAMTS13 activity is the diagnostic gold standard. In case of clinical suspicion of acute iTTP, treatment with plasma exchange, corticosteroids, and caplacizumab should be initiated at once. In a randomized trial with an active control group, plasma exchange lowered mortality at the end of the first treatment cycle from 15.7% to 3.9%. In a cohort study, standard treatment with plasma exchange, corticosteroids, caplacizumab, and rituximab was associated with a mortality of 2.2%, compared to 12.2% in a historical control cohort. Further management consists of regular clinical follow-up, ADAMTS13 monitoring, and the detection and treatment of late sequelae. For pregnancy in female TTP patients, monitoring and recurrence prophylaxis are recommended. The purpose of the clinical practice guideline is to improve the acute care and interdisciplinary management of TTP. Further research is needed on the use of recombinant ADAMTS13 and on the definition of uTTP (TTP in the absence of causative antibodies or genetic mutations).
2026-09-15 | Atypical hemolytic uremic syndrome in kidney transplantation.
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder that affects individuals of any age. It is caused by genetic abnormalities of the alternative complement pathway, arising from inherited or de novo mutations, or from acquired factors such as autoantibodies against complement proteins, including complement factor H. Clinically, aHUS is characterized by the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. However, its clinical presentation may be difficult to distinguish from typical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. aHUS is driven by uncontrolled activation of the alternative complement pathway, leading to endothelial injury and microvascular thrombosis. Atypical HUS may also occur after kidney transplantation, either as recurrence of the native disease or as de novo post-transplant thrombotic microangiopathy. The diagnosis of post-transplant aHUS relies on the presence of the above-mentioned classic triad and the exclusion of secondary causes such as thrombotic thrombocytopenic purpura and Shiga toxin-associated HUS. The pathophysiology is similar, involving either genetic mutations affecting complement proteins or acquired dysregulation due to autoantibodies. Historically, plasma exchange was used to replace dysfunctional complement regulators and remove circulating autoantibodies, with variable success. After transplantation, the disorder may either recur or develop de novo. In the past, plasmapheresis was considered beneficial. More recently, the availability of eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement activation, has become the treatment of choice, either as monotherapy or with plasma exchange. However, uncertainties remain regarding the optimal duration and dosing of long-term therapy, particularly in transplant recipients.
2026-08-26 | Recurrent Postpartum Atypical Hemolytic Uremic Syndrome Caused by a C3 Pathogenic Variant: A Case Report.
Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy (TMA) driven by uncontrolled activation of the complement alternative pathway. Pregnancy and postpartum period are well-recognized triggers for aHUS. In recent years, the prognosis of aHUS has substantially improved with the use of complement-targeted therapies. However, timely recognition, accurate classification, and prompt treatment initiation remain critical. This report describes a case of postpartum aHUS caused by a C3 gene mutation that achieved complete clinical and laboratory remission following a treatment strategy that included early eculizumab, plasma infusion, and renal replacement therapy. Drawing on the literature, we discuss key diagnostic and therapeutic considerations as well as clinical implications to provide guidance for clinical practice. We present a 35-year-old multiparous woman (gravida 3, para 3) who developed acute kidney injury, microangiopathic hemolytic anemia, and severe thrombocytopenia 2 days after cesarean section. She had a history of similar TMA episode 8 years postpartum. Laboratory investigations showed normal ADAMTS13 activity, negative autoimmune antibodies, reduced serum complement C3 and factor I levels, and elevated sC5b-9. Whole-exome sequencing identified a heterozygous pathogenic mutation in the C3 gene: c.1774C>T (p.R592W). Eculizumab was initiated within 24 hours of clinical suspicion, combined with plasma infusion and renal replacement therapy. The patient achieved complete clinical and laboratory remission: renal function, platelet count, hemoglobin, and lactate dehydrogenase returned to normal within 4 weeks. She remained stable during long-term follow-up on maintenance eculizumab. This case is particularly instructive because the patient had a prior TMA episode that was retrospectively suggestive of aHUS following genetic confirmation; however, definitive reclassification could not be established with certainty due to the lack of genetic testing at that time. This case highlights that C3 variant-mediated aHUS can be repeatedly triggered by pregnancy. Early recognition, prompt initiation of C5 inhibition, and multidisciplinary care are critical for renal recovery and favorable outcomes. Clinicians should distinguish postpartum aHUS from preeclampsia, HELLP syndrome, and TTP to prevent treatment delay.
2026-07-23 | Biallelic pathogenic variants in EXOSC3 mediate renal thrombotic microangiopathy of the kidney.
Thrombotic microangiopathy (TMA) is characterized by the classical triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Complement inhibition with eculizumab is highly efficacious in TMA secondary to complement dysregulation. However, a growing number of eculizumab-nonresponsive TMAs are reported. Recently, a syndromic form of TMA due to recessive variants in RNA exosome components (EXOSC3 and EXOSC5) has been identified. The underlying pathogenesis remains unclear. We identified 34 children across Europe with pontocerebellar hypoplasia 1b (PCH1b) due to EXOSC3 rare variants and reviewed their clinical history for signs of TMA. To further examine the pathogenesis, a tamoxifen-inducible whole-body Exosc3 conditional knockout mouse model (Exosc3KO) was used. Thirteen (eight male, five female) cases of EXOSC3-TMA were identified. In the United Kingdom, the incidence of EXOSC3-TMA was 0.004/million/year. Three children received long-term eculizumab therapy: one child failed to respond and two relapsed on treatment. Exosc3KO demonstrated cell-cycle arrest and apoptosis resulting in death in a median of eight days, with sequelae noted in actively dividing cells in the bone marrow and large intestine. In this timeframe, no kidney pathology was identified. EXOSC3-TMA is a severe, early-onset, C5 inhibitor-resistant TMA. EXOSC3-TMA should be considered in eculizumab-resistant pediatric TMA, particularly in the context of neurodevelopmental disease.
2026-07-09 | [Atypical hemolytic uremic syndrome: key points in differential diagnosis and recent advances in treatment].
Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by endothelial injury resulting from dysregulated activation of the alternative complement pathway. Clinical outcomes have markedly improved since the anti-complement agent eculizumab, an anti-C5 monoclonal antibody, became available in 2013. However, no established diagnostic method directly assesses complement activation for definitive diagnosis. In practice, diagnosis relies on the evaluation of pathogenic variants in complement-related genes as predisposing factors and on the exclusion of other diseases that can cause TMA. Consequently, distinguishing aHUS from secondary TMA can sometimes be clinically challenging. In particular, secondary TMA associated with hypertensive emergencies or pregnancy may overlap with aHUS, requiring careful diagnostic consideration. In recent years, several novel anti-complement agents have been developed. In addition to therapies targeting the terminal complement pathway downstream of C5, agents that act on the proximal complement cascade are also under development, and further clinical evidence on these strategies is awaited.
small molecules
2026-09-02 | Comprehensive review of thrombotic microangiopathy: classification, genetics, and management.
Thrombotic microangiopathy (TMA) comprises syndromes characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury, most commonly affecting the kidneys and brain. Recent advances have reframed TMAs from classical clinical labels (thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome, secondary TMA) toward a pathway‑based view centered on complement dysregulation, severe ADAMTS13 deficiency, and secondary endothelial injury. This review integrates current data on genetics, environmental "triggers," and clinical presentation to support a two‑hit model in which germline or acquired susceptibility is unmasked by infection, pregnancy, drugs, transplantation, or malignant hypertension. Building on this framework, we propose a stepwise diagnostic approach that combines ADAMTS13 testing, targeted evaluation for secondary causes, and rational use of complement and genetic testing, with the goal of assigning each patient to a dominant pathogenic pathway. Finally, we discuss mechanism‑based treatment strategies-including plasma exchange and immunosuppression for ADAMTS13‑mediated TTP, complement inhibition for complement‑mediated TMA, and trigger‑directed management in secondary forms-and outline key uncertainties regarding treatment duration, relapse prediction, and access to advanced therapies.
2026-05-14 | A review of genetic and epigenetic biomarkers involved in the occurrence of atypical hemolytic uremic syndrome and its therapeutic strategies.
Atypical hemolytic uremic syndrome (aHUS) is a rare, chronic, and life-threatening thrombotic microangiopathy (TMA). The disease is most frequently linked to genetic or acquired dysregulation of the alternative complement pathway and affects both children and adults. The paucity of a gold standard for diagnostic testing and the variety of clinical manifestations are the primary reasons for the challenge in accurately diagnosing aHUS, which can have an impact on patient care. This is due to the fact that the more prevalent autoinflammatory diseases are multifactorial in nature, with both genetic and non-genetic factors playing critical roles. Until the last decade, treatment options were limited to plasma therapy and, in selected cases, liver transplantation, neither of which directly addressed the underlying pathophysiology and both of which carried substantial risks. Since its introduction in 2011, the anti-C5 monoclonal antibody eculizumab has significantly improved outcomes and transformed disease management. Trials on novel complement inhibitors, regenerative medicine, targeted therapy, and stem cell therapy may also improve future treatment options. The primary objectives of this investigation are to identify the genetic and epigenetic causes of aHUS, as well as the limitations and debates surrounding its management. Due to the prevalence and significance of this type of illness, researchers have investigated effective therapeutic methods and more recent approaches.
2026-02-06 | RTX-family toxin EhxA drives morphological remodeling and thrombogenesis in RBCs during enterohemorrhagic Escherichia coli infection.
Enterohemorrhagic Escherichia coli (EHEC) causes thrombotic microangiopathy, yet the red blood cell (RBC)-centered mechanism has remained unclear. We identify the RTX-family hemolysin EhxA as the driver of RBC-mediated thrombogenesis. Deletion of ehxA abolishes Ca2+ influx, phosphatidylserine (PS) exposure, progression from discocyte to echinocyte to spherocyte, thrombin generation, RBC-endothelium adhesion, and RBC aggregation. Genetic complementation restores these readouts to wild type, and purified EhxA in bacteria-free assays recapitulates them while localizing to intact RBC membranes. By contrast, Δstx2 mutants do not elicit these RBC phenotypes, distinguishing this pathway from Shiga toxin-dependent effects. Multiple regression quantifies the link between PS exposure, morphology, and procoagulant outputs. In rats, infection with wild type increased RBC remodeling and venous thrombosis, whereas infection with ΔehxA did not. Together, the data define an EhxA-Ca2+-PS pathway that drives RBC structural remodeling and procoagulant activation during EHEC infection and nominate RTX toxins as targets for preventing toxin-induced coagulopathies.
2025-11-03 | Efficacy of iptacopan in treatment of transplant-associated thrombotic microangiopathy (TA-TMA) post-allogeneic hematopoietic stem cell transplantation: A case series analysis
Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is pivotal for treating blood disorders but is complicated by graft-versus-host disease (GVHD), infections, and transplant-associated thrombotic microangiopathy (TA-TMA). This case series evaluates the clinical utility of novel agents (Iptacopan, Vedolizumab, Ruxolitinib) in managing these complications. Case Summaries Methods -Interventions: Novel agents combined with standard therapies (immunosuppressants, antivirals). -Monitoring: Serial blood counts, liver/kidney function, viral load (CMV/EBV DNA), and coagulation profiles. Results Symptom Improvement: GVHD: Reduced diarrhea frequency (Case 2) and abdominal pain severity (Case 3) with vedolizumab.TA-TMA: Stabilized blood pressure and improved renal function using Iptacopan. Lab Trends: Blood Counts: Platelet recovery in Case 2 (19→44×10⁹/L).Liver Function: Declined ALT/AST (Case 3: ALT 35→25 U/L).Viral Load: EBV DNA turned negative in Cases 2 and 3. Safety: Infections: EBV/Enterococcus faecium reactivation (Case 3).Organ Toxicity: Transient liver enzyme elevation (Case 1). Discussion - Efficacy: Novel agents demonstrated targeted efficacy in GVHD/TA-TMA with improved lab parameters.Safety: Increased infection risk and transient organ toxicity necessitate vigilant monitoring.Personalization: Tailored dosing based on genetic/clinical factors may optimize outcomes. Conclusion: Iptacopan, Vedolizumab and Ruxolitinib show promise in managing post-allo-HSCT complications. Balancing efficacy with safety through personalized regimens and long-term follow-up is critical. Keywords: Allo-HSCT, GVHD, TA-TMA, Novel agents, Iptacopan, Vedolizumab, Ruxolitinib Table: Baseline Characteristics vs. Post-Treatment Lab Trends Case Diagnosis Complications Key Novel Agents Used 1 Severe Aplastic Anemia (SAA) Intestinal GVHD, TA-TMA, Cytomegalovirus (CMV) viremia Iptacopan, Vedolizumab 2 Myelodysplastic Syndrome (MDS)-EB-2 Intestinal GVHD, TA-TMA, Epstein-Barr Virus (EBV) infection Iptacopan 3 MDS-LB Liver/Intestinal GVHD, TA-TMA, EBV viremia Iptacopan, Vedolizumab, Ruxolitinib Parameter Case I (41F, SAA) Case II (53F, MDS-EB-2) Case III (28M, MDS-LB) Baseline Characteristics Diagnosis Severe Aplastic Anemia (SAA) Myelodysplastic Syndrome with Excess Blasts-2 (MDS-EB-2) Myelodysplastic Syndrome-Low Blast (MDS-LB) Pre-Treatment Labs - WBC: ↓ (2.13×10⁹/L)- HGB: 65g/L↓- PLT: 4×10⁹/L↓↓- ALT/AST: ↑ (44.56/50.96 U/L) - WBC: ↓ (3.73×10⁹/L)- HGB: 44g/L↓↓- PLT: 19×10⁹/L↓- PT/INR: ↑ (24.8s/2.17) - WBC: ↑ (15.42×10⁹/L)- HGB: 105g/L↓- ALT/AST: ↑ (35.49/47.32 U/L)- D-dimer: 3.56 mg/L↑ Complications CMV viremia, TA-TMA, intestinal GVHD, heart failure EBV infection, TA-TMA, intestinal GVHD EBV viremia, liver GVHD, intestinal GVHD, TA-TMA New Drugs Used Iptacopan, Vedolizumab Iptacopan Iptacopan, Vedolizumab, Ruxolitinib Post-Treatment Trends Blood Routine - WBC/HGB/PLT: Continued fluctuations (no stabilization) - PLT: ↑ (improvement)- WBC/HGB: Partial stabilization - WBC: Stabilized- HGB/PLT: Gradual improvement Liver Function - ALT/AST: Persistent fluctuations (disease/drug-related) - Bilirubin: Improved with supportive care - ALT/AST: ↓ (improved with ruxolitinib)- Bilirubin: Stabilized Kidney Function - Creatinine: Fluctuations - Urea/Creatinine: Partial improvement - Creatinine: Stabilized Coagulation - PT/INR/D-dimer: Persistent abnormalities - PT/INR: Partial improvement - D-dimer: ↓ (3.56 → lower)- Fibrinogen: Remained low Viral Load - CMV DNA: Controlled (↓ with ganciclovir/foscarnet) - EBV DNA: Turned negative - EBV DNA: Significant ↓ Other - Heart failure: Improved with cardiac drugs - Brain lesions: Stabilized with adjusted treatment -Hypokalemia/Hyponatremia: Corrected
2025-10-31 | Plasminogen mutation-associated thrombotic microangiopathy and role of anticoagulation: a single institution case series.
Knowledge gaps exist regarding the role of coagulation pathway mutations such as those in the plasminogen (PLG) gene in the pathogenesis of thrombotic microangiopathy (TMA) and treatment outcomes. This study aims to describe the unique phenotypic features of patients with PLG mutations and perform structural mapping of the variants to enhance variant interpretation. This was a single-center retrospective study of patients with TMA in whom genetic testing was performed between 2011 and 2023. Data were collected regarding demographics, clinical features at their first presentation, renal outcomes, genetic mutations, and recurrence for those who were found to have a PLG mutation. Structural mapping of the PLG variants was performed using X-ray structural data. Over the 12-year study period, we identified 6 individuals in our TMA cohort with PLG mutations. Median age at the time of first TMA event was 45.5 years (range: 5-57 years). Nearly all were female (n = 5, 83%). Half of the cohort (n = 3, 50%) had recurrent TMA, with 1 having recurrent episodes while on long-term complement blockade therapy. Three patients are now on long-term anticoagulation with no further TMA recurrences observed. Structural mapping of the variants revealed that the mutations could be categorized into 3 groups. Among these, group 2 variants (residues K38 in the PAN-apple domain and residue R523 in kringle-5) had a more severe phenotype with severe thrombocytopenia at presentation and a recurrent TMA course. Patients with PLG mutation-associated TMAs appear to have a poor response to complement blockade therapy, suggesting that pathways in addition to or independent of complement dysregulation may be involved in some patients. Future studies are warranted to explore the role of anticoagulation in preventing recurrence in patients with PLG mutations.
proteins
2026-05-27 | Mutation Spectrum of ADAMTS13 Gene in Patients with Upshaw-Schulman Syndrome (USS) in Russia.
Upshaw-Schulman syndrome (USS) is a rare inherited autosomal recessive thrombotic microangiopathy affecting less than 1/1,000,000 individuals. It is a congenital form of thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 protease deficiency because of mutations in the ADAMTS13 gene. USS is characterized by the formation of platelet thrombi in the microcirculation, accompanied by hemolytic anemia, thrombocytopenia, and clinical and laboratory signs of renal and neurological failure. The aim of this study was to describe the ADAMTS13 gene mutation spectrum in the Russian population. We analyzed the ADAMTS13 gene in 45 unrelated patients with TTP of unknown origin. DNA was extracted from blood cells using the phenol-chlorophorm method, and all exons of the gene were investigated using Sanger sequencing. In 15 out of 45 patients, we identified 20 different variants associated with USS, including two frameshift, two variants affecting the splice site, one nonsense and fifteen missense mutations. Eight out of those mutations were previously undescribed. Tree variants were revealed more than once: p.Arg1060Trp (7 patients), p.Glu1326ArgfsTer6 (7 patients) and p.Cys1067SerfsTer30 (3 patients). Variants (p.Arg1060Trp) and p.Glu1326ArgfsTer6 prevailed in the global population; however, p.Cys1067SerfsTer30 was not previously described in the European population. Our results expand the existing knowledge of the molecular basis of USS and may contribute to improved genetic diagnostics in Russia.
2026-03-28 | ADAMTS-13 R1206K variant exhibits an open conformation and an enhanced proteolytic activity toward von Willebrand factor.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by severe deficiency of ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, 13), a plasma metalloprotease that cleaves von Willebrand factor (VWF). Recombinant ADAMTS-13 has been developed for treatment of TTP, but it requires a high dose and frequent administrations to achieve therapeutic efficacy. The present study aims to identify more efficacious ADAMTS-13 variants for potential management of TTP. Site-directed mutagenesis, recombinant protein production and purification, enzyme kinetic and binding assays, and microfluidic thrombus formation were all used in the study. ADAMTS-13 R1206K variant exhibits a significantly increased activity compared with wild-type ADAMTS-13 for proteolytic cleavage of multimeric VWF and its surrogate peptide. Additionally, the R1206K is significantly more efficacious for inhibiting platelet adhesion and aggregation on a collagen-coated surface under arterial flow. Biolayer interferometry assay reveals a faster association kinetics (ka) between R1206K and VWF73L1603A substrate but a reduced binding affinity between R1206K and autoantibodies against ADAMTS-13, derived from immune-mediated TTP. Consistent with these results, the fluorescent energy transfers (FRETS)-VWF73 assay reveals a higher IC50 for autoantibodies (IgG4 4-16 and 4-20) to inhibit the R1206K than wild-type ADAMTS-13. These results demonstrate that ADAMTS-13 R1206K variant has an enhanced enzymatic activity, resulting from the disruption of autoinhibition that leads to an open conformation, which increases its substrate binding but reduces its autoantibody inhibition. This gain-of-function ADAMTS-13 variant may be further explored for the management of TTP and perhaps other inflammatory thrombotic disorders.
2026-03-02 | Thrombotic thrombocytopenic purpura: celebrating 25 years of ADAMTS13.
Thrombotic thrombocytopenic purpura (TTP) was first described just over a century ago, and it is now 25 years since the identification of ADAMTS13 as the enzyme deficient in both antibody-mediated immune TTP (iTTP) and congenital TTP (cTTP). The discovery of ADAMTS13 has been fundamental to the vast improvement seen in TTP outcomes. Understanding the interaction between ADAMTS13, platelets, and von Willebrand factor led to the development of clinical ADAMTS13 assays, and therefore quicker and accurate diagnosis, but also, critically, to novel therapies and monitoring of treatment. Landmark additions to iTTP therapy have included anti-CD20 treatment with rituximab, in both the acute and elective settings, and the use of the nanobody caplacizumab in acute TTP. In cTTP, the use of ADAMTS13 replacement is playing a role in reducing end-organ damage and morbidity, with recombinant ADAMTS13 (rADAMTS13) now representing the gold standard for cTTP. The ability to measure response to treatment by monitoring ADAMTS13 activity has underpinned these treatment advances, and allowed clinicians to tailor immunosuppressive treatment for iTTP and rADAMTS13 dosing in cTTP. Looking forward, there are many avenues for future development, with potential expansion of rADAMTS13 to treat iTTP, new, quicker assays to improve diagnosis, monitoring, and immunomodulatory therapeutic advancement, all underpinned by ADAMTS13. Future endeavors for the role of ADAMTS13 in other thrombotic indications open further exciting opportunities.
2026-02-16 | Genetics of Thrombotic Thrombocytopenic Purpura (TTP): Systematic Review in Immune and Congenital TTP.
Thrombotic Thrombocytopenic Purpura (TTP) is a thrombotic microangiopathy, caused by severe deficiency of the metalloprotease ADAMTS13. TTP has two subtypes: immune (iTTP) and congenital (cTTP). Autoimmune mechanisms underlie iTTP, however the genetic factors influencing disease risk, relapse risk and response to treatment are incompletely understood. In cTTP, although variants are described throughout the ADAMTS13 gene, the effect of many of these variants is uncertain. We conducted a comprehensive literature review of both iTTP and cTTP, incorporating findings from genome-wide association studies (GWAS), case-control studies, registry publications and population-level databases. In iTTP, nine studies have investigated the effect of HLA alleles, with HLA-DRB1*11 most consistently associated with an increased risk, and HLA DRB1*04 with protection. However, effect sizes varied across ancestral populations, as we highlight in a meta-analysis of available studies. Beyond the HLA locus, a GWAS in iTTP patients with European ancestry identified a locus on chromosome 3 (rs9884090) associated with a reduced iTTP risk. In cTTP, we identified 364 variants within the literature, the majority (199, 54.7%) being missense variants within coding regions. Although variants are located across the gene, the highest density of variants was observed within exon 7 (32 variants, 8.8% of the total), corresponding to the metalloprotease domain. Finally, analysis of population-level constraint data from gnomAD offered additional insight into the tolerance of ADAMTS13 to variation. Together, these findings highlight the complexity of the genetic factors influencing TTP, and the value of combining clinical information and population data to increase understanding of the disease.
2026-02-05 | Optimizing the management of congenital thrombotic thrombocytopenic purpura.
Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare, life-threatening thrombotic microangiopathy caused by genetic mutations in the ADAMTS-13 gene, leading to severe enzyme deficiency. This results in the accumulation of ultralarge von Willebrand factor multimers, which trigger platelet aggregation, microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. cTTP episodes are often triggered by physiological stressors and have a bimodal age of presentation. To summarize the clinical course, complications, and advances in treatment of cTTP, highlighting the role of recombinant ADAMTS-13 (rADAMTS-13). A review of registry data, clinical studies, and expert guidelines was conducted to assess cTTP pathophysiology, presentation, and therapeutic approaches. Acute cTTP episodes manifest variably, often requiring a "second hit," such as infection or pregnancy, for disease induction. Chronic complications include cardiovascular disease, chronic kidney disease, and neurocognitive impairments, contributing to increased morbidity and mortality. Plasma infusions are effective but are associated with logistical challenges and adverse events. rADAMTS-13, a novel therapy approved in 2023, demonstrated superior efficacy in preventing acute episodes and reducing treatment burden, with fewer adverse events compared with standard plasma therapy. cTTP management necessitates individualized care by a multidisciplinary team. Treatment of cTTP relies on ADAMTS-13 replacement, which may be more effectively delivered with rADAMTS-13 than with plasma infusions. Further studies are needed to evaluate its long-term safety, particularly during pregnancy, and to optimize treatment strategies.
cell therapies
2026-07-01 | Adult-Onset Hereditary Thrombotic Thrombocytopenic Purpura Presenting as Kidney Failure: A Heterozygous ADAMTS13 Variant and Possible Modifying Polymorphisms.
Hereditary thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive disorder caused by ADAMTS13 deficiency, typically presenting in childhood or early adulthood. We describe an atypical presentation of hereditary TTP in a 55-year-old man presenting with acute kidney injury on a background of diabetic kidney disease, without prior suggestive history or identifiable triggers. Initial evaluation revealed features of thrombotic microangiopathy, including haemolysis, thrombocytopenia, with preserved coagulation parameters. Presumptive complement-mediated thrombotic microangiopathy was treated with eculizumab; however, the patient progressed to dialysis dependence and developed transient neurological symptoms. ADAMTS13 activity was reduced (8 U/dL) without a detectable inhibitor, prompting treatment with fresh frozen plasma (FFP), which resulted in haematologic and neurological improvement. Kidney biopsy demonstrated acute thrombotic microangiopathy superimposed on advanced diabetic and vascular disease. Genetic testing identified a heterozygous pathogenic ADAMTS13 variant (c.587C>T; p.Thr196Ile) without a second pathogenic allele. Additional long-read sequencing detected polymorphisms that may be associated with reduced ADAMTS13 activity, however current evidence suggests that these are variants of unknown significance (VUS). Although these variants have been associated with variation in ADAMTS13 levels in population or functional studies, the contribution of the additional variants remains uncertain. Functional response to FFP with transient correction of ADAMTS13 levels supported a diagnosis of hereditary TTP. The patient was commenced on regular FFP infusions and has been stable without further haematological or neurological events. He remains dialysis-dependent, awaiting kidney transplantation. This case highlights a late-onset, atypical presentation of hereditary TTP and raises important questions regarding the pathogenicity of heterozygous variants and modifying polymorphisms. It underscores the need to consider ADAMTS13 deficiency in unexplained thrombotic microangiopathy and kidney failure, even in the absence of classic features or biallelic mutations.
2026-01-06 | Functional Xenogeneic Liver Support in a Living Human: Promise, Lessons, and Next Steps.
Genetically engineered porcine organs are redefining the boundaries of clinical xenotransplantation. Zhang et al. now report the first functional pig-to-human liver xenotransplantation in a living patient, demonstrating that a 10-gene-edited auxiliary porcine liver can engraft, produce bile, and synthesize metabolic and coagulation factors in vivo. The xenograft supported a high-risk hepatectomy with borderline remnant volume and contributed to early postoperative stability, although xenotransplant-associated thrombotic microangiopathy ultimately required graft removal. The case highlights both the promise of xenogeneic hepatic support and the physiologic limits that currently preclude durable therapy, including thrombocytopenia, complement-coagulation incompatibility, portal-flow competition, and challenges in assessing dual-graft function. These results establish proof-of-concept for temporary porcine liver support in humans and outline key priorities for next-generation designs: optimized thromboregulation, mitigation of xTMA, improved immunomodulation, and strategies for controlled transition to native-liver autonomy.
2025-11-25 | Navigating Pediatric Atypical Hemolytic Uremic Syndrome: A Two-Year Case Series From Eastern India.
Background Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare form of thrombotic microangiopathy that results from complement system activation. It represents a significant etiology of acute kidney injury among children. In India, aHUS is predominantly associated with anti-factor H antibodies, presenting unique diagnostic and therapeutic challenges. This study aims to delineate the clinical characteristics, immunological profile, management strategies, and outcomes of pediatric aHUS cases from a tertiary center in Eastern India. Methodology We conducted a retrospective, observational, case series at a tertiary care hospital in Eastern India, including seven pediatric patients diagnosed with aHUS between January 2023 and December 2024. Diagnosis was based on a clinical triad (acute kidney injury, microangiopathic anemia, thrombocytopenia), exclusion of Shiga toxin-associated cases and secondary causes, confirmation with complement/anti-factor H antibody testing, and, where feasible, genetic analysis. Patients received plasma exchange, immunomodulators, and supportive care. Data were analyzed using descriptive statistics. Results A total of seven children (median age = 7 years, six females) were treated for aHUS. CFHR1-CFHR3 deletions and anti-factor H antibodies were each identified in 43% of patients. Plasma exchange and steroids formed the therapeutic mainstay. Hematological remission was achieved in 71% of cases within one week, and 43% attained full renal recovery. However, 29% progressed to chronic kidney disease or remained dialysis-dependent, and the remaining 29% showed only limited renal improvement. Early initiation of plasmapheresis and immunosuppression was associated with better renal outcomes, while lack of access to eculizumab and genetic testing remained significant barriers. Conclusions Pediatric aHUS in Eastern India demonstrates a high burden of anti-factor H antibody-mediated disease and genetic complement abnormalities. Early plasmapheresis and immunomodulator use result in improved hematological and renal outcomes. There is a critical need for enhanced access to complement inhibitors and diagnostic tools to optimize management and prognosis in resource-constrained settings.
2025-10-07 | Generation of a transgenic pluripotent stem cell line expressing MMACHC protein harbouring the renal 2 thrombotic microangiopapathy-causing mutation (p.Q27R).
Mutations in the MMACHC (metabolism of cobalamin associated C) gene are associated with cobalamin C disorder and have been reported in infants with renal thrombotic microangiopaopathy (TMA). The pathophysiology underlying these mutations and their role in causing endothelial damage remains elusive. We generated a transgenic pluripotent stem cell (iPSC) line expressing MMACHC protein harbouring the renal 2 thrombotic microangiopapathy-causing mutation (p.Q27R). The iPSC exhibits a typical stem cell morphology, expresses pluripotency markers, and displays a normal karyotype. The iPSC line provides a valuable platform for exploring the pathogenesis of endothelial injury induced by metabolism-mediated TMA and for screening drugs to reduce endothelial damage.
2025-10-06 | Zebrafish model reveals developmental and hematopoietic functions of ADAMTS13.
ADAMTS13 is a metalloprotease that cleaves the von Willebrand factor and prevents pathological thrombosis. Severe genetic deficiency of ADAMTS13 causes congenital thrombotic thrombocytopenic purpura, a life-threatening thrombotic microangiopathy. Increasing evidence suggests that ADAMTS13 contributes to physiological processes beyond hemostasis, including vascular development and tissue homeostasis, but these functions remain poorly understood. To address this gap, we generated a transparent, multitransgenic adamts13i5 zebrafish model and began investigating the developmental and disease-related roles of ADAMTS13 in vivo. The adamts13i5 mutants recapitulated hallmark features of congenital thrombotic thrombocytopenic purpura, including erythrocyte fragmentation and schistocyte formation in adults. In larvae, ADAMTS13 loss unveiled a prothrombotic response to vascular injury, a phenotype masked in patients by thrombocytopenia. Mechanistically, ADAMTS13 deficiency impaired developmental vascular patterning, suppressed vegfa expression, and reduced macrophage number, accompanied by diminished inflammatory and pro-angiogenic signaling. ADAMTS13 loss disrupted hematopoietic homeostasis in adulthood, with myeloid expansion and lymphoid depletion in the kidney marrow. These findings establish ADAMTS13 as a multifaceted regulator of thrombosis, vascular development, inflammation, and hematopoietic lineage specification. The adamts13i5 Zebrafish provides a powerful vertebrate model for dissecting the mechanisms of thrombotic thrombocytopenic purpura pathogenesis and identifying therapeutic strategies extending beyond hemostasis.
other
2026-06-12 | Safety of Adeno-Associated Viral Vectors in Gene Therapy: Mechanisms of Toxicity, Clinical Risks, and Strategies for Their Minimization.
Adeno-associated viral (AAV) vectors have established themselves as a promising platform for genetic material delivery in clinical practice, evidenced by regulatory approval of multiple therapeutics. Despite proven therapeutic efficacy, safety concerns remain a critical limitation requiring systematic analysis. This review analyzes clinical data to identify mechanisms of toxicity, clinical risks, and strategies for their minimization in AAV gene therapy. The study examines dose-dependent toxicity, immune responses, and organ-specific burdens associated with systemic and local administration routes. Analysis reveals a clear correlation between systemic delivery efficacy and dose-dependent toxicity, with principal mechanisms including capsid-directed immune responses, hepatic burden, and complement system activation leading to thrombotic microangiopathy. Key determinants of the safety profile include pre-existing neutralizing antibodies, vector dose, serotype selection, and patient baseline conditions. Contemporary strategies for toxicity minimization are evolving from reactive management toward proactive risk mitigation, including prophylactic immunosuppressive regimens, vector engineering to alter tropism or reduce immunogenicity, and rigorous post-infusion monitoring. Integration of improved vector constructs, rational immunosuppressive regimens, and rigorous post-infusion surveillance has the potential to expand the therapeutic window of AAV-based gene therapy, achieving an optimal balance between efficacy and safety for a broader patient population.
2026-04-14 | Immune Toxicities in AAV Gene Therapy: Overview for Clinicians.
Gene therapy using recombinant adeno-associated virus (rAAV) vectors has emerged as a transformative therapeutic modality for genetic disorders, demonstrating high transduction efficiency and a generally favorable safety profile during pre-clinical development. However, serious adverse events, including thrombotic microangiopathy, acute respiratory distress syndrome, hepatotoxicity, myocarditis, cytokine storm, and hemophagocytic lymphohistiocytosis, have been observed across multiple gene therapy clinical trials. Significant efforts have been made to understand the toxicities that cause these adverse events and clinical care for patients receiving gene therapies has evolved to mitigate their effects. These toxicities arise from a complex interplay between the innate and adaptive immune responses directed against the viral capsid and transgene products and are often compounded by pre-existing anti-AAV immunity. Immunomodulatory strategies have been developed to combat these responses to improve the long-term success of gene therapies, and this review provides clinicians managing gene therapy patients with an overview of mechanisms underlying AAV-associated immunotoxicities and a discussion of syndromes and mitigation strategies that have been reported in the clinical care of patients.
2026-01-23 | Translational importance of non-human primates for the study of the immune response in gene therapy procedures involving in vivo administration of rAAV vectors
In vivo gene therapies based on viral vectors, particularly recombinant adeno-associated viruses (rAAV), have become a promising approach for the treatment of various genetic diseases. However, the immune response against these vectors is still a major obstacle, affecting their efficacy and safety. This review examines the importance of non-human primates (NHPs) as translational models for the study of immune responses against rAAVs. After an overview of the characteristics of AAV vectors and the challenges posed by the translatability of animal models, we analyze the innate and adaptive immune responses to these vectors, highlighting the role of neutralizing antibodies and cytotoxic cells. We also discuss the severe adverse events observed in clinical trials, such as liver toxicity, thrombotic microangiopathy and neurotoxicity, and their correlation with preclinical studies on NHPs. Finally, we discuss strategies to improve the safety and efficacy of rAAV-based therapies, including immune modulation and optimization of preclinical models. All of these elements highlight the need to improve the translatability of preclinical results for better predictability of side effects and optimization of therapeutic protocols.
2024-09-12 | Emerging Thrombotic Disorders Associated with Virus-Based Innovative Therapies: From VITT to AAV Gene Therapy-Related Thrombotic Microangiopathy.
Gene therapy is a promising therapeutic approach for treating life-threatening disorders. Despite the clinical improvements observed with gene therapy, immune responses either innate or adaptive against the vector used for gene delivery, can affect treatment efficacy and lead to adverse reactions. Thrombotic microangiopathy (TMA) is a thrombosis with thrombocytopenia syndrome (TTS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and small vessel occlusion known to be elicited by several drugs, that has been recently reported as an adverse event of adeno-associated virus (AAV)-based gene therapy. TMA encompasses a heterogenous group of disorders, its classification and underlining mechanisms are still uncertain, and still lacks validated biomarkers. The identification of predictors of TMA, such as vector dose and patient characteristics, is a pressing need to recognize patients at risk before and after AAV-based gene therapy administration. This review aims to explore the literature on TMA associated with AAV-based gene therapy in the larger context of TMA (i.e., hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and other drug-related TMAs). Considering the wide attention recently gained by another TTS associated with a non-gene therapy viral platform (adenovirus, AV COVID-19 vaccine), namely vaccine-induced immune thrombocytopenia and thrombosis (VITT), AAV gene therapy-related TMA mechanisms will be discussed and differentiated from those of VITT to avoid recency bias and favor a correct positioning of these two recently emerged syndromes within the heterogenous group of drug-related TTS. Finally, the review will discuss strategies for enhancing the safety and optimize the management of AAV-based gene therapy that is emerging as an efficacious therapeutic option for disparate, severe, and often orphan conditions.
2024-06-26 | Novel mechanisms of action of emerging therapies of hereditary thrombotic thrombocytopenic purpura.
Hereditary thrombotic thrombocytopenic purpura (hTTP) is caused by deficiency of plasma ADAMTS13 activity, resulting from ADAMTS13 mutations. ADAMTS13 cleaves ultra large von Willebrand factor (VWF), thus reducing its multimer sizes. Hereditary deficiency of plasma ADAMTS13 activity leads to the formation of excessive platelet-VWF aggregates in small arterioles and capillaries, resulting in hTTP. PubMed search from 1956 to 2024 using thrombotic thrombocytopenic purpura and therapy identified 3,675 articles. Only the articles relevant to the topic were selected for discussion, which focuses on pathophysiology, clinical presentations, and mechanisms of action of emerging therapeutics for hTTP. Current therapies include infusion of plasma, or coagulation factor VIII, or recombinant ADAMTS13. Emerging therapies include anti-VWF A1 aptamers or nanobody and gene therapies with adeno-associated viral vector or self-inactivated lentiviral vector or a sleeping beauty transposon system for a long-term expression of a functional ADAMTS13 enzyme. Frequent plasma infusion remains to be the standard of care in most parts of the world, while recombinant ADAMTS13 has become the treatment of choice for hTTP in some of the Western countries. The success of gene therapies in preclinical models may hold a promise for future development of these novel approaches for a cure of hTTP.
antibodies
2026-09-29 | Clinical Practice Guideline: The Diagnosis, Treatment, and Follow-Up Management of Thrombotic Thrombocytopenic Purpura.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy. The global incidence of immune-mediated TTP (iTTP) is 1-6 cases per million people per year. The new (S3-level) clinical practice guideline is the first in the German-speaking world to compile evidence- and consensus-based recommendations on the diagnosis, treatment, follow-up management, and care of patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) and congenital thrombotic thrombocytopenic purpura (cTTP). This clinical practice guideline was developed under the aegis of the Society for Thrombosis and Hemostatsis Research (Gesellschaft für Thrombose- und Hämostaseforschung, GTH) according to the criteria for S3-level guidelines issued by the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). It is based on information from publications retrieved through systematic literature searches and a structured assessment of the evidence using the GRADE scheme (Grading of Recommendations, Assessment, Development, and Evaluation), with a formal consensus process. Early diagnosis of TTP is essential. Measurement of ADAMTS13 activity is the diagnostic gold standard. In case of clinical suspicion of acute iTTP, treatment with plasma exchange, corticosteroids, and caplacizumab should be initiated at once. In a randomized trial with an active control group, plasma exchange lowered mortality at the end of the first treatment cycle from 15.7% to 3.9%. In a cohort study, standard treatment with plasma exchange, corticosteroids, caplacizumab, and rituximab was associated with a mortality of 2.2%, compared to 12.2% in a historical control cohort. Further management consists of regular clinical follow-up, ADAMTS13 monitoring, and the detection and treatment of late sequelae. For pregnancy in female TTP patients, monitoring and recurrence prophylaxis are recommended. The purpose of the clinical practice guideline is to improve the acute care and interdisciplinary management of TTP. Further research is needed on the use of recombinant ADAMTS13 and on the definition of uTTP (TTP in the absence of causative antibodies or genetic mutations).
2026-09-15 | Atypical hemolytic uremic syndrome in kidney transplantation.
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder that affects individuals of any age. It is caused by genetic abnormalities of the alternative complement pathway, arising from inherited or de novo mutations, or from acquired factors such as autoantibodies against complement proteins, including complement factor H. Clinically, aHUS is characterized by the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. However, its clinical presentation may be difficult to distinguish from typical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. aHUS is driven by uncontrolled activation of the alternative complement pathway, leading to endothelial injury and microvascular thrombosis. Atypical HUS may also occur after kidney transplantation, either as recurrence of the native disease or as de novo post-transplant thrombotic microangiopathy. The diagnosis of post-transplant aHUS relies on the presence of the above-mentioned classic triad and the exclusion of secondary causes such as thrombotic thrombocytopenic purpura and Shiga toxin-associated HUS. The pathophysiology is similar, involving either genetic mutations affecting complement proteins or acquired dysregulation due to autoantibodies. Historically, plasma exchange was used to replace dysfunctional complement regulators and remove circulating autoantibodies, with variable success. After transplantation, the disorder may either recur or develop de novo. In the past, plasmapheresis was considered beneficial. More recently, the availability of eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement activation, has become the treatment of choice, either as monotherapy or with plasma exchange. However, uncertainties remain regarding the optimal duration and dosing of long-term therapy, particularly in transplant recipients.
2026-08-26 | Recurrent Postpartum Atypical Hemolytic Uremic Syndrome Caused by a C3 Pathogenic Variant: A Case Report.
Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy (TMA) driven by uncontrolled activation of the complement alternative pathway. Pregnancy and postpartum period are well-recognized triggers for aHUS. In recent years, the prognosis of aHUS has substantially improved with the use of complement-targeted therapies. However, timely recognition, accurate classification, and prompt treatment initiation remain critical. This report describes a case of postpartum aHUS caused by a C3 gene mutation that achieved complete clinical and laboratory remission following a treatment strategy that included early eculizumab, plasma infusion, and renal replacement therapy. Drawing on the literature, we discuss key diagnostic and therapeutic considerations as well as clinical implications to provide guidance for clinical practice. We present a 35-year-old multiparous woman (gravida 3, para 3) who developed acute kidney injury, microangiopathic hemolytic anemia, and severe thrombocytopenia 2 days after cesarean section. She had a history of similar TMA episode 8 years postpartum. Laboratory investigations showed normal ADAMTS13 activity, negative autoimmune antibodies, reduced serum complement C3 and factor I levels, and elevated sC5b-9. Whole-exome sequencing identified a heterozygous pathogenic mutation in the C3 gene: c.1774C>T (p.R592W). Eculizumab was initiated within 24 hours of clinical suspicion, combined with plasma infusion and renal replacement therapy. The patient achieved complete clinical and laboratory remission: renal function, platelet count, hemoglobin, and lactate dehydrogenase returned to normal within 4 weeks. She remained stable during long-term follow-up on maintenance eculizumab. This case is particularly instructive because the patient had a prior TMA episode that was retrospectively suggestive of aHUS following genetic confirmation; however, definitive reclassification could not be established with certainty due to the lack of genetic testing at that time. This case highlights that C3 variant-mediated aHUS can be repeatedly triggered by pregnancy. Early recognition, prompt initiation of C5 inhibition, and multidisciplinary care are critical for renal recovery and favorable outcomes. Clinicians should distinguish postpartum aHUS from preeclampsia, HELLP syndrome, and TTP to prevent treatment delay.
2026-07-23 | Biallelic pathogenic variants in EXOSC3 mediate renal thrombotic microangiopathy of the kidney.
Thrombotic microangiopathy (TMA) is characterized by the classical triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Complement inhibition with eculizumab is highly efficacious in TMA secondary to complement dysregulation. However, a growing number of eculizumab-nonresponsive TMAs are reported. Recently, a syndromic form of TMA due to recessive variants in RNA exosome components (EXOSC3 and EXOSC5) has been identified. The underlying pathogenesis remains unclear. We identified 34 children across Europe with pontocerebellar hypoplasia 1b (PCH1b) due to EXOSC3 rare variants and reviewed their clinical history for signs of TMA. To further examine the pathogenesis, a tamoxifen-inducible whole-body Exosc3 conditional knockout mouse model (Exosc3KO) was used. Thirteen (eight male, five female) cases of EXOSC3-TMA were identified. In the United Kingdom, the incidence of EXOSC3-TMA was 0.004/million/year. Three children received long-term eculizumab therapy: one child failed to respond and two relapsed on treatment. Exosc3KO demonstrated cell-cycle arrest and apoptosis resulting in death in a median of eight days, with sequelae noted in actively dividing cells in the bone marrow and large intestine. In this timeframe, no kidney pathology was identified. EXOSC3-TMA is a severe, early-onset, C5 inhibitor-resistant TMA. EXOSC3-TMA should be considered in eculizumab-resistant pediatric TMA, particularly in the context of neurodevelopmental disease.
2026-07-09 | [Atypical hemolytic uremic syndrome: key points in differential diagnosis and recent advances in treatment].
Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by endothelial injury resulting from dysregulated activation of the alternative complement pathway. Clinical outcomes have markedly improved since the anti-complement agent eculizumab, an anti-C5 monoclonal antibody, became available in 2013. However, no established diagnostic method directly assesses complement activation for definitive diagnosis. In practice, diagnosis relies on the evaluation of pathogenic variants in complement-related genes as predisposing factors and on the exclusion of other diseases that can cause TMA. Consequently, distinguishing aHUS from secondary TMA can sometimes be clinically challenging. In particular, secondary TMA associated with hypertensive emergencies or pregnancy may overlap with aHUS, requiring careful diagnostic consideration. In recent years, several novel anti-complement agents have been developed. In addition to therapies targeting the terminal complement pathway downstream of C5, agents that act on the proximal complement cascade are also under development, and further clinical evidence on these strategies is awaited.
small molecules
2026-09-02 | Comprehensive review of thrombotic microangiopathy: classification, genetics, and management.
Thrombotic microangiopathy (TMA) comprises syndromes characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury, most commonly affecting the kidneys and brain. Recent advances have reframed TMAs from classical clinical labels (thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome, secondary TMA) toward a pathway‑based view centered on complement dysregulation, severe ADAMTS13 deficiency, and secondary endothelial injury. This review integrates current data on genetics, environmental "triggers," and clinical presentation to support a two‑hit model in which germline or acquired susceptibility is unmasked by infection, pregnancy, drugs, transplantation, or malignant hypertension. Building on this framework, we propose a stepwise diagnostic approach that combines ADAMTS13 testing, targeted evaluation for secondary causes, and rational use of complement and genetic testing, with the goal of assigning each patient to a dominant pathogenic pathway. Finally, we discuss mechanism‑based treatment strategies-including plasma exchange and immunosuppression for ADAMTS13‑mediated TTP, complement inhibition for complement‑mediated TMA, and trigger‑directed management in secondary forms-and outline key uncertainties regarding treatment duration, relapse prediction, and access to advanced therapies.
2026-05-14 | A review of genetic and epigenetic biomarkers involved in the occurrence of atypical hemolytic uremic syndrome and its therapeutic strategies.
Atypical hemolytic uremic syndrome (aHUS) is a rare, chronic, and life-threatening thrombotic microangiopathy (TMA). The disease is most frequently linked to genetic or acquired dysregulation of the alternative complement pathway and affects both children and adults. The paucity of a gold standard for diagnostic testing and the variety of clinical manifestations are the primary reasons for the challenge in accurately diagnosing aHUS, which can have an impact on patient care. This is due to the fact that the more prevalent autoinflammatory diseases are multifactorial in nature, with both genetic and non-genetic factors playing critical roles. Until the last decade, treatment options were limited to plasma therapy and, in selected cases, liver transplantation, neither of which directly addressed the underlying pathophysiology and both of which carried substantial risks. Since its introduction in 2011, the anti-C5 monoclonal antibody eculizumab has significantly improved outcomes and transformed disease management. Trials on novel complement inhibitors, regenerative medicine, targeted therapy, and stem cell therapy may also improve future treatment options. The primary objectives of this investigation are to identify the genetic and epigenetic causes of aHUS, as well as the limitations and debates surrounding its management. Due to the prevalence and significance of this type of illness, researchers have investigated effective therapeutic methods and more recent approaches.
2026-02-06 | RTX-family toxin EhxA drives morphological remodeling and thrombogenesis in RBCs during enterohemorrhagic Escherichia coli infection.
Enterohemorrhagic Escherichia coli (EHEC) causes thrombotic microangiopathy, yet the red blood cell (RBC)-centered mechanism has remained unclear. We identify the RTX-family hemolysin EhxA as the driver of RBC-mediated thrombogenesis. Deletion of ehxA abolishes Ca2+ influx, phosphatidylserine (PS) exposure, progression from discocyte to echinocyte to spherocyte, thrombin generation, RBC-endothelium adhesion, and RBC aggregation. Genetic complementation restores these readouts to wild type, and purified EhxA in bacteria-free assays recapitulates them while localizing to intact RBC membranes. By contrast, Δstx2 mutants do not elicit these RBC phenotypes, distinguishing this pathway from Shiga toxin-dependent effects. Multiple regression quantifies the link between PS exposure, morphology, and procoagulant outputs. In rats, infection with wild type increased RBC remodeling and venous thrombosis, whereas infection with ΔehxA did not. Together, the data define an EhxA-Ca2+-PS pathway that drives RBC structural remodeling and procoagulant activation during EHEC infection and nominate RTX toxins as targets for preventing toxin-induced coagulopathies.
2025-11-03 | Efficacy of iptacopan in treatment of transplant-associated thrombotic microangiopathy (TA-TMA) post-allogeneic hematopoietic stem cell transplantation: A case series analysis
Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is pivotal for treating blood disorders but is complicated by graft-versus-host disease (GVHD), infections, and transplant-associated thrombotic microangiopathy (TA-TMA). This case series evaluates the clinical utility of novel agents (Iptacopan, Vedolizumab, Ruxolitinib) in managing these complications. Case Summaries Methods -Interventions: Novel agents combined with standard therapies (immunosuppressants, antivirals). -Monitoring: Serial blood counts, liver/kidney function, viral load (CMV/EBV DNA), and coagulation profiles. Results Symptom Improvement: GVHD: Reduced diarrhea frequency (Case 2) and abdominal pain severity (Case 3) with vedolizumab.TA-TMA: Stabilized blood pressure and improved renal function using Iptacopan. Lab Trends: Blood Counts: Platelet recovery in Case 2 (19→44×10⁹/L).Liver Function: Declined ALT/AST (Case 3: ALT 35→25 U/L).Viral Load: EBV DNA turned negative in Cases 2 and 3. Safety: Infections: EBV/Enterococcus faecium reactivation (Case 3).Organ Toxicity: Transient liver enzyme elevation (Case 1). Discussion - Efficacy: Novel agents demonstrated targeted efficacy in GVHD/TA-TMA with improved lab parameters.Safety: Increased infection risk and transient organ toxicity necessitate vigilant monitoring.Personalization: Tailored dosing based on genetic/clinical factors may optimize outcomes. Conclusion: Iptacopan, Vedolizumab and Ruxolitinib show promise in managing post-allo-HSCT complications. Balancing efficacy with safety through personalized regimens and long-term follow-up is critical. Keywords: Allo-HSCT, GVHD, TA-TMA, Novel agents, Iptacopan, Vedolizumab, Ruxolitinib Table: Baseline Characteristics vs. Post-Treatment Lab Trends Case Diagnosis Complications Key Novel Agents Used 1 Severe Aplastic Anemia (SAA) Intestinal GVHD, TA-TMA, Cytomegalovirus (CMV) viremia Iptacopan, Vedolizumab 2 Myelodysplastic Syndrome (MDS)-EB-2 Intestinal GVHD, TA-TMA, Epstein-Barr Virus (EBV) infection Iptacopan 3 MDS-LB Liver/Intestinal GVHD, TA-TMA, EBV viremia Iptacopan, Vedolizumab, Ruxolitinib Parameter Case I (41F, SAA) Case II (53F, MDS-EB-2) Case III (28M, MDS-LB) Baseline Characteristics Diagnosis Severe Aplastic Anemia (SAA) Myelodysplastic Syndrome with Excess Blasts-2 (MDS-EB-2) Myelodysplastic Syndrome-Low Blast (MDS-LB) Pre-Treatment Labs - WBC: ↓ (2.13×10⁹/L)- HGB: 65g/L↓- PLT: 4×10⁹/L↓↓- ALT/AST: ↑ (44.56/50.96 U/L) - WBC: ↓ (3.73×10⁹/L)- HGB: 44g/L↓↓- PLT: 19×10⁹/L↓- PT/INR: ↑ (24.8s/2.17) - WBC: ↑ (15.42×10⁹/L)- HGB: 105g/L↓- ALT/AST: ↑ (35.49/47.32 U/L)- D-dimer: 3.56 mg/L↑ Complications CMV viremia, TA-TMA, intestinal GVHD, heart failure EBV infection, TA-TMA, intestinal GVHD EBV viremia, liver GVHD, intestinal GVHD, TA-TMA New Drugs Used Iptacopan, Vedolizumab Iptacopan Iptacopan, Vedolizumab, Ruxolitinib Post-Treatment Trends Blood Routine - WBC/HGB/PLT: Continued fluctuations (no stabilization) - PLT: ↑ (improvement)- WBC/HGB: Partial stabilization - WBC: Stabilized- HGB/PLT: Gradual improvement Liver Function - ALT/AST: Persistent fluctuations (disease/drug-related) - Bilirubin: Improved with supportive care - ALT/AST: ↓ (improved with ruxolitinib)- Bilirubin: Stabilized Kidney Function - Creatinine: Fluctuations - Urea/Creatinine: Partial improvement - Creatinine: Stabilized Coagulation - PT/INR/D-dimer: Persistent abnormalities - PT/INR: Partial improvement - D-dimer: ↓ (3.56 → lower)- Fibrinogen: Remained low Viral Load - CMV DNA: Controlled (↓ with ganciclovir/foscarnet) - EBV DNA: Turned negative - EBV DNA: Significant ↓ Other - Heart failure: Improved with cardiac drugs - Brain lesions: Stabilized with adjusted treatment -Hypokalemia/Hyponatremia: Corrected
2025-10-31 | Plasminogen mutation-associated thrombotic microangiopathy and role of anticoagulation: a single institution case series.
Knowledge gaps exist regarding the role of coagulation pathway mutations such as those in the plasminogen (PLG) gene in the pathogenesis of thrombotic microangiopathy (TMA) and treatment outcomes. This study aims to describe the unique phenotypic features of patients with PLG mutations and perform structural mapping of the variants to enhance variant interpretation. This was a single-center retrospective study of patients with TMA in whom genetic testing was performed between 2011 and 2023. Data were collected regarding demographics, clinical features at their first presentation, renal outcomes, genetic mutations, and recurrence for those who were found to have a PLG mutation. Structural mapping of the PLG variants was performed using X-ray structural data. Over the 12-year study period, we identified 6 individuals in our TMA cohort with PLG mutations. Median age at the time of first TMA event was 45.5 years (range: 5-57 years). Nearly all were female (n = 5, 83%). Half of the cohort (n = 3, 50%) had recurrent TMA, with 1 having recurrent episodes while on long-term complement blockade therapy. Three patients are now on long-term anticoagulation with no further TMA recurrences observed. Structural mapping of the variants revealed that the mutations could be categorized into 3 groups. Among these, group 2 variants (residues K38 in the PAN-apple domain and residue R523 in kringle-5) had a more severe phenotype with severe thrombocytopenia at presentation and a recurrent TMA course. Patients with PLG mutation-associated TMAs appear to have a poor response to complement blockade therapy, suggesting that pathways in addition to or independent of complement dysregulation may be involved in some patients. Future studies are warranted to explore the role of anticoagulation in preventing recurrence in patients with PLG mutations.
proteins
2026-05-27 | Mutation Spectrum of ADAMTS13 Gene in Patients with Upshaw-Schulman Syndrome (USS) in Russia.
Upshaw-Schulman syndrome (USS) is a rare inherited autosomal recessive thrombotic microangiopathy affecting less than 1/1,000,000 individuals. It is a congenital form of thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 protease deficiency because of mutations in the ADAMTS13 gene. USS is characterized by the formation of platelet thrombi in the microcirculation, accompanied by hemolytic anemia, thrombocytopenia, and clinical and laboratory signs of renal and neurological failure. The aim of this study was to describe the ADAMTS13 gene mutation spectrum in the Russian population. We analyzed the ADAMTS13 gene in 45 unrelated patients with TTP of unknown origin. DNA was extracted from blood cells using the phenol-chlorophorm method, and all exons of the gene were investigated using Sanger sequencing. In 15 out of 45 patients, we identified 20 different variants associated with USS, including two frameshift, two variants affecting the splice site, one nonsense and fifteen missense mutations. Eight out of those mutations were previously undescribed. Tree variants were revealed more than once: p.Arg1060Trp (7 patients), p.Glu1326ArgfsTer6 (7 patients) and p.Cys1067SerfsTer30 (3 patients). Variants (p.Arg1060Trp) and p.Glu1326ArgfsTer6 prevailed in the global population; however, p.Cys1067SerfsTer30 was not previously described in the European population. Our results expand the existing knowledge of the molecular basis of USS and may contribute to improved genetic diagnostics in Russia.
2026-03-28 | ADAMTS-13 R1206K variant exhibits an open conformation and an enhanced proteolytic activity toward von Willebrand factor.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by severe deficiency of ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, 13), a plasma metalloprotease that cleaves von Willebrand factor (VWF). Recombinant ADAMTS-13 has been developed for treatment of TTP, but it requires a high dose and frequent administrations to achieve therapeutic efficacy. The present study aims to identify more efficacious ADAMTS-13 variants for potential management of TTP. Site-directed mutagenesis, recombinant protein production and purification, enzyme kinetic and binding assays, and microfluidic thrombus formation were all used in the study. ADAMTS-13 R1206K variant exhibits a significantly increased activity compared with wild-type ADAMTS-13 for proteolytic cleavage of multimeric VWF and its surrogate peptide. Additionally, the R1206K is significantly more efficacious for inhibiting platelet adhesion and aggregation on a collagen-coated surface under arterial flow. Biolayer interferometry assay reveals a faster association kinetics (ka) between R1206K and VWF73L1603A substrate but a reduced binding affinity between R1206K and autoantibodies against ADAMTS-13, derived from immune-mediated TTP. Consistent with these results, the fluorescent energy transfers (FRETS)-VWF73 assay reveals a higher IC50 for autoantibodies (IgG4 4-16 and 4-20) to inhibit the R1206K than wild-type ADAMTS-13. These results demonstrate that ADAMTS-13 R1206K variant has an enhanced enzymatic activity, resulting from the disruption of autoinhibition that leads to an open conformation, which increases its substrate binding but reduces its autoantibody inhibition. This gain-of-function ADAMTS-13 variant may be further explored for the management of TTP and perhaps other inflammatory thrombotic disorders.
2026-03-02 | Thrombotic thrombocytopenic purpura: celebrating 25 years of ADAMTS13.
Thrombotic thrombocytopenic purpura (TTP) was first described just over a century ago, and it is now 25 years since the identification of ADAMTS13 as the enzyme deficient in both antibody-mediated immune TTP (iTTP) and congenital TTP (cTTP). The discovery of ADAMTS13 has been fundamental to the vast improvement seen in TTP outcomes. Understanding the interaction between ADAMTS13, platelets, and von Willebrand factor led to the development of clinical ADAMTS13 assays, and therefore quicker and accurate diagnosis, but also, critically, to novel therapies and monitoring of treatment. Landmark additions to iTTP therapy have included anti-CD20 treatment with rituximab, in both the acute and elective settings, and the use of the nanobody caplacizumab in acute TTP. In cTTP, the use of ADAMTS13 replacement is playing a role in reducing end-organ damage and morbidity, with recombinant ADAMTS13 (rADAMTS13) now representing the gold standard for cTTP. The ability to measure response to treatment by monitoring ADAMTS13 activity has underpinned these treatment advances, and allowed clinicians to tailor immunosuppressive treatment for iTTP and rADAMTS13 dosing in cTTP. Looking forward, there are many avenues for future development, with potential expansion of rADAMTS13 to treat iTTP, new, quicker assays to improve diagnosis, monitoring, and immunomodulatory therapeutic advancement, all underpinned by ADAMTS13. Future endeavors for the role of ADAMTS13 in other thrombotic indications open further exciting opportunities.
2026-02-16 | Genetics of Thrombotic Thrombocytopenic Purpura (TTP): Systematic Review in Immune and Congenital TTP.
Thrombotic Thrombocytopenic Purpura (TTP) is a thrombotic microangiopathy, caused by severe deficiency of the metalloprotease ADAMTS13. TTP has two subtypes: immune (iTTP) and congenital (cTTP). Autoimmune mechanisms underlie iTTP, however the genetic factors influencing disease risk, relapse risk and response to treatment are incompletely understood. In cTTP, although variants are described throughout the ADAMTS13 gene, the effect of many of these variants is uncertain. We conducted a comprehensive literature review of both iTTP and cTTP, incorporating findings from genome-wide association studies (GWAS), case-control studies, registry publications and population-level databases. In iTTP, nine studies have investigated the effect of HLA alleles, with HLA-DRB1*11 most consistently associated with an increased risk, and HLA DRB1*04 with protection. However, effect sizes varied across ancestral populations, as we highlight in a meta-analysis of available studies. Beyond the HLA locus, a GWAS in iTTP patients with European ancestry identified a locus on chromosome 3 (rs9884090) associated with a reduced iTTP risk. In cTTP, we identified 364 variants within the literature, the majority (199, 54.7%) being missense variants within coding regions. Although variants are located across the gene, the highest density of variants was observed within exon 7 (32 variants, 8.8% of the total), corresponding to the metalloprotease domain. Finally, analysis of population-level constraint data from gnomAD offered additional insight into the tolerance of ADAMTS13 to variation. Together, these findings highlight the complexity of the genetic factors influencing TTP, and the value of combining clinical information and population data to increase understanding of the disease.
2026-02-05 | Optimizing the management of congenital thrombotic thrombocytopenic purpura.
Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare, life-threatening thrombotic microangiopathy caused by genetic mutations in the ADAMTS-13 gene, leading to severe enzyme deficiency. This results in the accumulation of ultralarge von Willebrand factor multimers, which trigger platelet aggregation, microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. cTTP episodes are often triggered by physiological stressors and have a bimodal age of presentation. To summarize the clinical course, complications, and advances in treatment of cTTP, highlighting the role of recombinant ADAMTS-13 (rADAMTS-13). A review of registry data, clinical studies, and expert guidelines was conducted to assess cTTP pathophysiology, presentation, and therapeutic approaches. Acute cTTP episodes manifest variably, often requiring a "second hit," such as infection or pregnancy, for disease induction. Chronic complications include cardiovascular disease, chronic kidney disease, and neurocognitive impairments, contributing to increased morbidity and mortality. Plasma infusions are effective but are associated with logistical challenges and adverse events. rADAMTS-13, a novel therapy approved in 2023, demonstrated superior efficacy in preventing acute episodes and reducing treatment burden, with fewer adverse events compared with standard plasma therapy. cTTP management necessitates individualized care by a multidisciplinary team. Treatment of cTTP relies on ADAMTS-13 replacement, which may be more effectively delivered with rADAMTS-13 than with plasma infusions. Further studies are needed to evaluate its long-term safety, particularly during pregnancy, and to optimize treatment strategies.
cell therapies
2026-07-01 | Adult-Onset Hereditary Thrombotic Thrombocytopenic Purpura Presenting as Kidney Failure: A Heterozygous ADAMTS13 Variant and Possible Modifying Polymorphisms.
Hereditary thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive disorder caused by ADAMTS13 deficiency, typically presenting in childhood or early adulthood. We describe an atypical presentation of hereditary TTP in a 55-year-old man presenting with acute kidney injury on a background of diabetic kidney disease, without prior suggestive history or identifiable triggers. Initial evaluation revealed features of thrombotic microangiopathy, including haemolysis, thrombocytopenia, with preserved coagulation parameters. Presumptive complement-mediated thrombotic microangiopathy was treated with eculizumab; however, the patient progressed to dialysis dependence and developed transient neurological symptoms. ADAMTS13 activity was reduced (8 U/dL) without a detectable inhibitor, prompting treatment with fresh frozen plasma (FFP), which resulted in haematologic and neurological improvement. Kidney biopsy demonstrated acute thrombotic microangiopathy superimposed on advanced diabetic and vascular disease. Genetic testing identified a heterozygous pathogenic ADAMTS13 variant (c.587C>T; p.Thr196Ile) without a second pathogenic allele. Additional long-read sequencing detected polymorphisms that may be associated with reduced ADAMTS13 activity, however current evidence suggests that these are variants of unknown significance (VUS). Although these variants have been associated with variation in ADAMTS13 levels in population or functional studies, the contribution of the additional variants remains uncertain. Functional response to FFP with transient correction of ADAMTS13 levels supported a diagnosis of hereditary TTP. The patient was commenced on regular FFP infusions and has been stable without further haematological or neurological events. He remains dialysis-dependent, awaiting kidney transplantation. This case highlights a late-onset, atypical presentation of hereditary TTP and raises important questions regarding the pathogenicity of heterozygous variants and modifying polymorphisms. It underscores the need to consider ADAMTS13 deficiency in unexplained thrombotic microangiopathy and kidney failure, even in the absence of classic features or biallelic mutations.
2026-01-06 | Functional Xenogeneic Liver Support in a Living Human: Promise, Lessons, and Next Steps.
Genetically engineered porcine organs are redefining the boundaries of clinical xenotransplantation. Zhang et al. now report the first functional pig-to-human liver xenotransplantation in a living patient, demonstrating that a 10-gene-edited auxiliary porcine liver can engraft, produce bile, and synthesize metabolic and coagulation factors in vivo. The xenograft supported a high-risk hepatectomy with borderline remnant volume and contributed to early postoperative stability, although xenotransplant-associated thrombotic microangiopathy ultimately required graft removal. The case highlights both the promise of xenogeneic hepatic support and the physiologic limits that currently preclude durable therapy, including thrombocytopenia, complement-coagulation incompatibility, portal-flow competition, and challenges in assessing dual-graft function. These results establish proof-of-concept for temporary porcine liver support in humans and outline key priorities for next-generation designs: optimized thromboregulation, mitigation of xTMA, improved immunomodulation, and strategies for controlled transition to native-liver autonomy.
2025-11-25 | Navigating Pediatric Atypical Hemolytic Uremic Syndrome: A Two-Year Case Series From Eastern India.
Background Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare form of thrombotic microangiopathy that results from complement system activation. It represents a significant etiology of acute kidney injury among children. In India, aHUS is predominantly associated with anti-factor H antibodies, presenting unique diagnostic and therapeutic challenges. This study aims to delineate the clinical characteristics, immunological profile, management strategies, and outcomes of pediatric aHUS cases from a tertiary center in Eastern India. Methodology We conducted a retrospective, observational, case series at a tertiary care hospital in Eastern India, including seven pediatric patients diagnosed with aHUS between January 2023 and December 2024. Diagnosis was based on a clinical triad (acute kidney injury, microangiopathic anemia, thrombocytopenia), exclusion of Shiga toxin-associated cases and secondary causes, confirmation with complement/anti-factor H antibody testing, and, where feasible, genetic analysis. Patients received plasma exchange, immunomodulators, and supportive care. Data were analyzed using descriptive statistics. Results A total of seven children (median age = 7 years, six females) were treated for aHUS. CFHR1-CFHR3 deletions and anti-factor H antibodies were each identified in 43% of patients. Plasma exchange and steroids formed the therapeutic mainstay. Hematological remission was achieved in 71% of cases within one week, and 43% attained full renal recovery. However, 29% progressed to chronic kidney disease or remained dialysis-dependent, and the remaining 29% showed only limited renal improvement. Early initiation of plasmapheresis and immunosuppression was associated with better renal outcomes, while lack of access to eculizumab and genetic testing remained significant barriers. Conclusions Pediatric aHUS in Eastern India demonstrates a high burden of anti-factor H antibody-mediated disease and genetic complement abnormalities. Early plasmapheresis and immunomodulator use result in improved hematological and renal outcomes. There is a critical need for enhanced access to complement inhibitors and diagnostic tools to optimize management and prognosis in resource-constrained settings.
2025-10-07 | Generation of a transgenic pluripotent stem cell line expressing MMACHC protein harbouring the renal 2 thrombotic microangiopapathy-causing mutation (p.Q27R).
Mutations in the MMACHC (metabolism of cobalamin associated C) gene are associated with cobalamin C disorder and have been reported in infants with renal thrombotic microangiopaopathy (TMA). The pathophysiology underlying these mutations and their role in causing endothelial damage remains elusive. We generated a transgenic pluripotent stem cell (iPSC) line expressing MMACHC protein harbouring the renal 2 thrombotic microangiopapathy-causing mutation (p.Q27R). The iPSC exhibits a typical stem cell morphology, expresses pluripotency markers, and displays a normal karyotype. The iPSC line provides a valuable platform for exploring the pathogenesis of endothelial injury induced by metabolism-mediated TMA and for screening drugs to reduce endothelial damage.
2025-10-06 | Zebrafish model reveals developmental and hematopoietic functions of ADAMTS13.
ADAMTS13 is a metalloprotease that cleaves the von Willebrand factor and prevents pathological thrombosis. Severe genetic deficiency of ADAMTS13 causes congenital thrombotic thrombocytopenic purpura, a life-threatening thrombotic microangiopathy. Increasing evidence suggests that ADAMTS13 contributes to physiological processes beyond hemostasis, including vascular development and tissue homeostasis, but these functions remain poorly understood. To address this gap, we generated a transparent, multitransgenic adamts13i5 zebrafish model and began investigating the developmental and disease-related roles of ADAMTS13 in vivo. The adamts13i5 mutants recapitulated hallmark features of congenital thrombotic thrombocytopenic purpura, including erythrocyte fragmentation and schistocyte formation in adults. In larvae, ADAMTS13 loss unveiled a prothrombotic response to vascular injury, a phenotype masked in patients by thrombocytopenia. Mechanistically, ADAMTS13 deficiency impaired developmental vascular patterning, suppressed vegfa expression, and reduced macrophage number, accompanied by diminished inflammatory and pro-angiogenic signaling. ADAMTS13 loss disrupted hematopoietic homeostasis in adulthood, with myeloid expansion and lymphoid depletion in the kidney marrow. These findings establish ADAMTS13 as a multifaceted regulator of thrombosis, vascular development, inflammation, and hematopoietic lineage specification. The adamts13i5 Zebrafish provides a powerful vertebrate model for dissecting the mechanisms of thrombotic thrombocytopenic purpura pathogenesis and identifying therapeutic strategies extending beyond hemostasis.
other
2026-06-12 | Safety of Adeno-Associated Viral Vectors in Gene Therapy: Mechanisms of Toxicity, Clinical Risks, and Strategies for Their Minimization.
Adeno-associated viral (AAV) vectors have established themselves as a promising platform for genetic material delivery in clinical practice, evidenced by regulatory approval of multiple therapeutics. Despite proven therapeutic efficacy, safety concerns remain a critical limitation requiring systematic analysis. This review analyzes clinical data to identify mechanisms of toxicity, clinical risks, and strategies for their minimization in AAV gene therapy. The study examines dose-dependent toxicity, immune responses, and organ-specific burdens associated with systemic and local administration routes. Analysis reveals a clear correlation between systemic delivery efficacy and dose-dependent toxicity, with principal mechanisms including capsid-directed immune responses, hepatic burden, and complement system activation leading to thrombotic microangiopathy. Key determinants of the safety profile include pre-existing neutralizing antibodies, vector dose, serotype selection, and patient baseline conditions. Contemporary strategies for toxicity minimization are evolving from reactive management toward proactive risk mitigation, including prophylactic immunosuppressive regimens, vector engineering to alter tropism or reduce immunogenicity, and rigorous post-infusion monitoring. Integration of improved vector constructs, rational immunosuppressive regimens, and rigorous post-infusion surveillance has the potential to expand the therapeutic window of AAV-based gene therapy, achieving an optimal balance between efficacy and safety for a broader patient population.
2026-04-14 | Immune Toxicities in AAV Gene Therapy: Overview for Clinicians.
Gene therapy using recombinant adeno-associated virus (rAAV) vectors has emerged as a transformative therapeutic modality for genetic disorders, demonstrating high transduction efficiency and a generally favorable safety profile during pre-clinical development. However, serious adverse events, including thrombotic microangiopathy, acute respiratory distress syndrome, hepatotoxicity, myocarditis, cytokine storm, and hemophagocytic lymphohistiocytosis, have been observed across multiple gene therapy clinical trials. Significant efforts have been made to understand the toxicities that cause these adverse events and clinical care for patients receiving gene therapies has evolved to mitigate their effects. These toxicities arise from a complex interplay between the innate and adaptive immune responses directed against the viral capsid and transgene products and are often compounded by pre-existing anti-AAV immunity. Immunomodulatory strategies have been developed to combat these responses to improve the long-term success of gene therapies, and this review provides clinicians managing gene therapy patients with an overview of mechanisms underlying AAV-associated immunotoxicities and a discussion of syndromes and mitigation strategies that have been reported in the clinical care of patients.
2026-01-23 | Translational importance of non-human primates for the study of the immune response in gene therapy procedures involving in vivo administration of rAAV vectors
In vivo gene therapies based on viral vectors, particularly recombinant adeno-associated viruses (rAAV), have become a promising approach for the treatment of various genetic diseases. However, the immune response against these vectors is still a major obstacle, affecting their efficacy and safety. This review examines the importance of non-human primates (NHPs) as translational models for the study of immune responses against rAAVs. After an overview of the characteristics of AAV vectors and the challenges posed by the translatability of animal models, we analyze the innate and adaptive immune responses to these vectors, highlighting the role of neutralizing antibodies and cytotoxic cells. We also discuss the severe adverse events observed in clinical trials, such as liver toxicity, thrombotic microangiopathy and neurotoxicity, and their correlation with preclinical studies on NHPs. Finally, we discuss strategies to improve the safety and efficacy of rAAV-based therapies, including immune modulation and optimization of preclinical models. All of these elements highlight the need to improve the translatability of preclinical results for better predictability of side effects and optimization of therapeutic protocols.
2024-09-12 | Emerging Thrombotic Disorders Associated with Virus-Based Innovative Therapies: From VITT to AAV Gene Therapy-Related Thrombotic Microangiopathy.
Gene therapy is a promising therapeutic approach for treating life-threatening disorders. Despite the clinical improvements observed with gene therapy, immune responses either innate or adaptive against the vector used for gene delivery, can affect treatment efficacy and lead to adverse reactions. Thrombotic microangiopathy (TMA) is a thrombosis with thrombocytopenia syndrome (TTS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and small vessel occlusion known to be elicited by several drugs, that has been recently reported as an adverse event of adeno-associated virus (AAV)-based gene therapy. TMA encompasses a heterogenous group of disorders, its classification and underlining mechanisms are still uncertain, and still lacks validated biomarkers. The identification of predictors of TMA, such as vector dose and patient characteristics, is a pressing need to recognize patients at risk before and after AAV-based gene therapy administration. This review aims to explore the literature on TMA associated with AAV-based gene therapy in the larger context of TMA (i.e., hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and other drug-related TMAs). Considering the wide attention recently gained by another TTS associated with a non-gene therapy viral platform (adenovirus, AV COVID-19 vaccine), namely vaccine-induced immune thrombocytopenia and thrombosis (VITT), AAV gene therapy-related TMA mechanisms will be discussed and differentiated from those of VITT to avoid recency bias and favor a correct positioning of these two recently emerged syndromes within the heterogenous group of drug-related TTS. Finally, the review will discuss strategies for enhancing the safety and optimize the management of AAV-based gene therapy that is emerging as an efficacious therapeutic option for disparate, severe, and often orphan conditions.
2024-06-26 | Novel mechanisms of action of emerging therapies of hereditary thrombotic thrombocytopenic purpura.
Hereditary thrombotic thrombocytopenic purpura (hTTP) is caused by deficiency of plasma ADAMTS13 activity, resulting from ADAMTS13 mutations. ADAMTS13 cleaves ultra large von Willebrand factor (VWF), thus reducing its multimer sizes. Hereditary deficiency of plasma ADAMTS13 activity leads to the formation of excessive platelet-VWF aggregates in small arterioles and capillaries, resulting in hTTP. PubMed search from 1956 to 2024 using thrombotic thrombocytopenic purpura and therapy identified 3,675 articles. Only the articles relevant to the topic were selected for discussion, which focuses on pathophysiology, clinical presentations, and mechanisms of action of emerging therapeutics for hTTP. Current therapies include infusion of plasma, or coagulation factor VIII, or recombinant ADAMTS13. Emerging therapies include anti-VWF A1 aptamers or nanobody and gene therapies with adeno-associated viral vector or self-inactivated lentiviral vector or a sleeping beauty transposon system for a long-term expression of a functional ADAMTS13 enzyme. Frequent plasma infusion remains to be the standard of care in most parts of the world, while recombinant ADAMTS13 has become the treatment of choice for hTTP in some of the Western countries. The success of gene therapies in preclinical models may hold a promise for future development of these novel approaches for a cure of hTTP.
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