RARE DISEASE
Thrombotic microangiopathy
Thrombotic microangiopathy
Thrombotic microangiopathy
Synonyms: TMA
Synonyms: TMA
Synonyms: TMA
Drug discovery
4
drugs
With orphan designations
Overview
Thrombotic microangiopathy (TMA) is a group of life-threatening disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis causing ischemic organ damage. Etiologies include primary conditions like thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS), as well as secondary causes (e.g., malignancies, infections, pregnancy). Diagnosis hinges on lab findings of schistocytes, elevated LDH, and organ dysfunction. Prompt plasma exchange and targeted therapies (e.g., complement inhibitors for aHUS) are critical to reduce mortality [1][6][12].
Population
Annual incidence of 3–4 cases/million for TTP and aHUS, with 94% of TMAs being secondary to triggers like sepsis, cancer, or autoimmune conditions [2][9][16]
Higher prevalence in women, Black individuals, and those with comorbidities (e.g., hypertension, malignancies) [9][14]
Pediatric cases linked to Shiga toxin-producing E. coli (STEC-HUS), while adults more frequently develop TTP or chemotherapy-associated TMA [12][13]
Burden
Mortality rates reach 23–40% in secondary TMA and 8–25% in primary TMA, with HSCT-associated TMA showing 40% 1-year mortality [4][7][9]
50–62% require ICU care; 20–30% develop renal failure requiring dialysis [2][7][13]
Long-term sequelae include chronic kidney disease (30%), thromboembolic events (30%), and relapse rates >30% in TTP [9][11][13]
Therapies
TTP: Plasma exchange (PEX), corticosteroids, rituximab, and caplacizumab (anti-vWF therapy) [8][17]
aHUS: Complement inhibitors (eculizumab/ravulizumab) and PEX [13][17]
Secondary TMA: Address underlying cause (e.g., discontinue nephrotoxic drugs, treat infections) ± supportive care (dialysis, transfusions) [3][6]
Categories: rare renal diseases
Research Papers
2,465 drug discovery papers about Thrombotic microangiopathy, with 6 first-in-class and 17 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,465 drug discovery papers about Thrombotic microangiopathy, with 6 first-in-class and 17 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | Scleroderma Renal Crisis-Associated Thrombotic Microangiopathy Preceding Skin Sclerosis in Diffuse Cutaneous Systemic Sclerosis: A Case Report.
A prompt and accurate diagnosis is essential because the management of thrombotic microangiopathy (TMA) depends on its underlying etiology. We report a case of diffuse cutaneous systemic sclerosis (dcSSc) in which scleroderma renal crisis-associated TMA preceded the development of overt skin sclerosis. A 53-year-old woman presented with TMA and severe renal dysfunction. She tested positive for anti-RNA polymerase III antibodies and subsequently developed skin sclerosis, leading to a diagnosis of dcSSc. Angiotensin-converting enzyme inhibitor therapy resulted in a clinical improvement in the patient. Therefore, systemic sclerosis should be considered in the differential diagnosis of TMA, even in the absence of skin manifestations at presentation.
2026-09-16 | Conversion from calcineurin inhibitor to ruxolitinib as GVHD prophylaxis during patients with transplant-associated thrombotic microangiopathy.
Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with multifactorial etiology. Existing clinical guidelines recommend discontinuation or tapering of calcineurin inhibitors (CNIs) as the primary intervention after the initial TMA diagnosis; however, data on the options for immunosuppression manipulation (ISM) are limited. Ruxolitinib is an effective option in treatment of steroid refractory graft-versus-host disease (SR-GVHD), which seems promising to replace CNIs as a prophylactic agent with better GVHD control in patients with TA-TMA. We retrospectively analyzed the outcomes of 48 TA-TMA patients who received ISM with steroids (steroid group) or ruxolitinib (ruxolitinib group) as CNI substitutes. The primary endpoint was not met: the ORR at 4 weeks did not differ significantly between the ruxolitinib and steroid groups (65.2% vs. 80.0%, P = 0.250). However, in exploratory secondary analyses, more patients in the ruxolitinib group achieved complete response (CR) than in the steroid group (40% vs. 13%, P=0.036), and first remission was achieved more rapidly (13.5 vs. 25 days, P=0.046). Additionally, the ruxolitinib group demonstrated faster normalization of lactate dehydrogenase (LDH) levels and significantly better overall survival (HR 0.32, 95% CI 0.12-0.84, p=0.025) and relapse-free survival (HR 0.41, 95% CI 0.17-0.99, p=0.048) than the steroid group. Although hematologic recovery was slower in the ruxolitinib group than in the steroid group, we attribute this to ruxolitinib-induced myelosuppression. Infection was a significant risk factor in the ruxolitinib group (P=0.0426). However, there were no significant differences in the incidence of infection following treatment with steroid or ruxolitinib: pneumonia (26.1% vs. 16%, P=0.487), sepsis (17.4% vs. 12%, P=0.696), Epstein-Barr virus (EBV) reactivation (47.8% vs. 36%, P=0.406), or Cytomegalovirus (CMV) reactivation (56.5% vs. 52%, P=0.753). In this pilot study, the primary endpoint (ORR) was not met. Exploratory secondary analyses suggest that replacing CNIs with ruxolitinib during TA-TMA is feasible and may be associated with more rapid LDH normalization and CR, at the cost of slower peripheral count recovery; these observations are hypothesis-generating and require confirmation in adequately powered, prospective, multicenter studies.
2026-09-13 | Complete recovery of thrombotic microangiopathy with severe acute kidney injury due to intravenous use of modified release oxycodone.
Since the introduction of the tamper-resistant oral formulation of modified-release oxycodone (OxyContin®), cases of thrombotic microangiopathy (TMA) have been reported following intravenous injection of the drug. Previous reports have suggested that withdrawal of the offending agent alone may be sufficient to reverse the condition; however, the associated acute kidney injury (AKI) in these cases was only mild to moderate in severity. We report the first case of OxyContin®-associated TMA presenting with anuric AKI requiring dialysis, followed by complete renal recovery after cessation of intravenous OxyContin® use. This case demonstrates that withdrawal of the causative agent may be sufficient to achieve resolution of TMA even in severe presentations. Accordingly, supportive management without the need for invasive and costly interventions may be appropriate in selected cases. Awareness of the association between intravenous OxyContin® use and TMA is essential for timely diagnosis, as identification often depends on direct inquiry regarding drug exposure.
2026-09-10 | Thrombotic Microangiopathy Presenting With Multisystem Involvement and Acute Neurologic Deficits in a 61-Year-Old Female: A Case of Acquired Thrombotic Thrombocytopenic Purpura.
Thrombotic microangiopathy (TMA) is a rare, life-threatening hematologic syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ dysfunction. Among TMAs, thrombotic thrombocytopenic purpura (TTP), an emergent subtype caused by severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13), requires urgent recognition and prompt treatment. We present a 61-year-old woman who initially presented with abdominal pain and hematuria and was treated for a presumed urinary tract infection. She later developed chest pain, unilateral weakness, melena, and petechiae. Laboratory evaluation revealed severe anemia, thrombocytopenia, acute kidney injury, elevated lactate dehydrogenase, and schistocytes on peripheral smear, consistent with microangiopathic hemolysis. Urgent hematologic evaluation raised concern for TTP versus hemolytic uremic syndrome. Her PLASMIC score was high risk, prompting empiric initiation of plasma exchange and corticosteroids prior to confirmatory testing. Brain magnetic resonance imaging (MRI) demonstrated punctate acute infarcts in the right parietal lobe. ADAMTS13 activity returned <10%, confirming acquired TTP. The patient improved with plasma exchange, corticosteroids, and rituximab, and was discharged in stable condition with outpatient follow-up. This case highlights the importance of early recognition, use of clinical prediction tools, and prompt treatment of TTP in patients with multisystem involvement and neurologic deficits to reduce morbidity and mortality.
2026-08-27 | Safety and Efficacy of Ponatinib for Pulmonary Tumor Thrombotic Microangiopathy
Background: We evaluated the safety and efficacy of ponatinib, a multi-target tyrosine kinase inhibitor, for pulmonary tumor thrombotic microangiopathy (PTTM).
cell therapies
2026-09-03 | Porcine kidney xenotransplantation as a bridge to allotransplantation: a first-in-human study.
Kidney xenotransplantation offers a potential solution to the organ shortage, but questions remain regarding durability, zoonotic infection risk, and whether the immunological response to the xenograft elicits sensitisation that could complicate subsequent allotransplantation. We report outcomes from a porcine kidney xenograft in a living recipient followed by human allotransplantation. A patient with end-stage kidney disease, a prolonged anticipated waiting time for deceased donor transplantation, and with no suitable living donor underwent transplantation at Massachusetts General Hospital (Boston, MA, USA) with a gene-edited porcine kidney (EGEN-2784; eGenesis [Cambridge, MA, USA]) incorporating the deletion of major glycan xenoantigens, inactivation of porcine endogenous retroviruses, and insertion of seven human transgenes. The recipient received costimulation blockade-based immunosuppression with complement inhibition. Monitoring included renal function, flow cytometric crossmatch, anti-HLA antibodies, and porcine microbial surveillance, including metagenomic sequencing. This report describes the first recipient in a planned three-patient study conducted under a US Food and Drug Administration Expanded Access Investigational New Drug application. The xenograft functioned immediately after transplantation on Jan 25, 2025, and sustained dialysis independence for 271 days. A biopsy on day 14 showed T-cell-mediated rejection, which resolved with treatment. Graft function remained stable for approximately 6 months until immunosuppression was reduced in the setting of non-zoonotic bacterial infection. Microvascular inflammation with endothelial injury subsequently emerged, progressing to thrombotic microangiopathy despite persistently negative donor-specific crossmatch, leading to graft failure and nephrectomy. Tissue analysis showed a macrophage and natural-killer-cell-predominant infiltrate with minimal T-cell involvement. No porcine pathogen transmission was detected. Anti-HLA antibodies remained unchanged. 82 days after explantation, the patient underwent human kidney allotransplantation with immediate graft function and no evidence of sensitisation during 231 days of follow-up. This case shows that porcine kidney xenotransplantation can provide prolonged renal support and be discontinued without clinically significant allosensitisation or zoonotic infection. Early cellular rejection resolved with treatment, whereas later graft failure was associated with microvascular injury progressing to thrombotic microangiopathy despite a negative donor-specific crossmatch, supporting the possibility that mechanisms beyond conventional antibody-mediated rejection contributed to late graft injury. Kidney xenotransplantation has the potential to provide prolonged dialysis-free support while also serving as a bridge to subsequent human allotransplantation. Massachusetts General Hospital and eGenesis.
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.
2026-09-01 | Long-term outcome of pediatric anti-complement factor H antibody-associated atypical hemolytic uremic syndrome receiving abbreviated plasma exchange: a retrospective study from a single center.
Anti-complement factor H antibody- (anti-CFH Ab) associated atypical hemolytic uremic syndrome (aHUS) is a known cause of pediatric complement-mediated thrombotic microangiopathy. In our center, plasma exchange (PEX) until remission paired with immunosuppression continues to be the mainstay of therapy, due to limited access to eculizumab. We wanted to study the long-term outcome of this cohort. We conducted a retrospective cohort study of children (<12 years) with Anti-CFH Ab-associated aHUS admitted between January 2017 and December 2024 at our center. Clinical, laboratory, treatment, and outcome data were retrieved from medical records. The primary outcome was renal recovery, defined as eGFR >90 mL/min/1.73 m2 with normal blood pressure, no significant proteinuria, and absence of hematuria at last follow-up or at 5 years. Of 66 records screened, 40 children were eligible. Median age at presentation was 7 years (interquartile range [IQR] 5,8). Median anti-CFH Ab titer was 306 AU/mL (IQR 214-426). Low C3 was noted in 55% of subjects. All patients received PEX (median 11 cycles; IQR 7.25, 20) and immunosuppression. Median follow-up was 24 months (IQR 7-53). At last follow-up, 21 (52.5%) achieved complete renal recovery, while 19 (47.5%) had CKD stage 2-4. Relapse incidence was 7.1 per 100 person-years, usually within 6 months of onset. No baseline clinical, laboratory, or treatment variable except duration of dialysis independently predicted renal recovery. Persistent proteinuria was observed up to 6 months but subsequently improved. PEX paired with immunosuppression remains effective for anti-CFH Ab-associated aHUS, but further studies are needed to refine protocols and evaluate complement inhibitors for improved long-term outcomes.
2026-08-07 | Delayed Recognition of Thrombotic Thrombocytopenic Purpura Following Platelet Transfusion: A Clinical Pitfall.
Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 deficiency, usually due to autoantibody-mediated inhibition. Its presentation is heterogeneous and often lacks the classic pentad, leading to diagnostic delays. Neurological symptoms may predominate, masking the underlying hematologic emergency. In our case, a 37-year-old previously healthy woman presented with acute headache, speech disturbance, and altered mental status. Despite normal neuroimaging, laboratory tests revealed severe thrombocytopenia and normocytic anemia. Lack of response to erythrocyte and platelet transfusions prompted further evaluation, revealing microangiopathic hemolytic anemia with elevated lactate dehydrogenase, undetectable haptoglobin, indirect hyperbilirubinemia, reticulocytosis, and normal coagulation parameters. A PLASMIC score of 6/7 indicated a high probability of severe ADAMTS13 deficiency. Treatment with high-dose corticosteroids was initiated immediately, followed by plasma exchange and rituximab. ADAMTS13 activity confirmed severe deficiency at 0.3%, supporting the diagnosis of acquired TTP in the clinical context. The patient achieved rapid remission and complete neurological recovery. This case highlights the importance of early recognition of microangiopathic hemolysis and prompt treatment without waiting for confirmatory ADAMTS13 results to reduce morbidity and mortality.
2026-07-10 | Secondary thrombotic thrombocytopenic purpura with features of Evans syndrome in a patient with SLE.
A female in her early 40s with systemic lupus erythematosus (SLE) and prior immune thrombocytopenic purpura presented with dizziness, dyspnoea, haematuria and fatigue. Investigations revealed a life-threatening thrombotic microangiopathy triad (platelets 3000/µL, microangiopathic haemolytic anaemia, acute kidney injury) and the strongly positive Coombs test with haemolysis markers supported autoimmune haemolysis in addition to microangiopathic haemolysis. Together with her prior history of immune thrombocytopenia, these findings are consistent with an Evans syndrome overlap, though consumptive thrombocytopenia from thrombotic thrombocytopenic purpura (TTP) could not be excluded. There was evidence of SLE vasculitis. Despite diagnostic overlap obscuring TTP, empiric plasma exchange (PLEX), steroids and rituximab induced rapid haematologic and clinical recovery. Days later, severe ADAMTS13 deficiency (<0.03 IU/mL) confirmed SLE-associated secondary TTP. This case highlights the critical need for empiric PLEX in suspected TTP when possible Evans syndrome complicates SLE and the efficacy of combined immunomodulation targeting both entities.
antibodies
2026-09-28 | Bilateral postpartum renal cortical necrosis complicated by peripartum cardiomyopathy after postpartum hemorrhage: a case report.
A 36-year-old woman developed postpartum haemorrhage after an uncomplicated vaginal delivery, followed by disseminated intravascular coagulation, thrombotic microangiopathy, and persistent anuric kidney failure. Contrast-enhanced computed tomography showed bilateral reversal of corticomedullary enhancement, consistent with renal cortical necrosis. Despite kidney replacement therapy and 13 litres of ultrafiltration, she remained oxygen-dependent, prompting cardiac evaluation on postpartum day 11, which revealed severe left ventricular systolic dysfunction (ejection fraction 25%) consistent with peripartum cardiomyopathy. Cardiac function recovered with medical therapy, whereas kidney function remained irreversible, requiring dialysis and transplantation. Renal cortical necrosis and peripartum cardiomyopathy are linked to endothelial dysfunction, yet their coexistence has rarely been reported. Cardiac dysfunction emerged only after substantial fluid removal, arguing against volume overload alone and suggesting a shared postpartum endotheliopathy. Persistent oxygen requirement despite adequate decongestion should prompt early cardiac assessment rather than being attributed to fluid overload alone.
2026-09-15 | Therapeutic Plasma Exchange in Immune-Mediated Thrombotic Thrombocytopenic Purpura: From Cornerstone to Contextualized Therapy.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 deficiency due to anti-ADAMTS13 autoantibodies. The resulting persistence of ultra-large von Willebrand factor (VWF) multimers promotes uncontrolled platelet adhesion and aggregation in the microcirculation, leading to thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ injury. Therapeutic plasma exchange (TPE) has transformed the prognosis of iTTP by removing circulating autoantibodies and replenishing functional ADAMTS13, and it remains a life-saving intervention in acute disease. However, TPE is invasive, resource-intensive, dependent on central venous access and plasma availability, and associated with catheter-related, hemodynamic, metabolic, infectious, and plasma-related adverse events. The therapeutic landscape has changed substantially with the incorporation of immunosuppression and the anti-VWF nanobody caplacizumab. Caplacizumab rapidly blocks VWF-platelet interactions at the effector level, whereas corticosteroids and B-cell-directed therapy target the autoimmune basis of iTTP. Triple therapy with TPE, immunosuppression, and caplacizumab accelerates platelet recovery and reduces unfavorable outcomes. At the same time, accumulating observational evidence and early prospective data suggest that selected patients may achieve remission with caplacizumab plus immunosuppression without routine first-line TPE. This perspective review critically re-evaluates the role of TPE in contemporary iTTP management. We propose that TPE should no longer be viewed exclusively as an obligatory universal first-line intervention, but rather as a contextualized component of individualized, response-adapted care. TPE remains indispensable for severe, unstable, or refractory disease and must be immediately available when TPE-free treatment is attempted. Safe implementation of TPE-free strategies requires experienced centers, rapid ADAMTS13 testing, immediate access to caplacizumab and immunosuppression, careful patient selection, and close clinical and laboratory monitoring. Defining which patients can be treated safely without TPE is a central challenge for future trials and guideline development.
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.
2026-09-08 | Evidence for the use of anti-CD20 therapeutic antibodies in immune thrombotic thrombocytopenic purpura management: a review.
Immune thrombotic thrombocytopenic purpura (iTTP) is an autoimmune thrombotic microangiopathy caused by antibody-mediated deficiency of the plasma metalloprotease ADAMTS13. Therapeutic antibodies that target antibody-producing B-cells via the CD20 surface receptor protein to prevent disease exacerbation and relapse have become part of the standard of care of patients with iTTP. However, clinical trial data regarding the use of anti-CD20 agents is limited to mostly phase II studies; no universally agreed-upon standardized protocol for the use of CD20-targeting antibodies for iTTP regarding choice of agent, dosage, or duration of treatment exists; refractoriness or lack of response to anti-CD20 antibodies can occur; and several agents and biosimilars are now available for the treatment of iTTP patients, which complicates the decision tree for clinicians caring for these patients. In this review, we explore the current landscape of anti-CD20 therapeutics used to treat iTTP, focusing on agents currently available for clinical use. We describe the pharmacokinetic and pharmacodynamic properties of CD20-targeting antibodies; available data regarding dosage and duration of treatment; anti-CD20 antibody therapy refractoriness or lack of response; and the evolving role of anti-CD20 biosimilars. This review will shed light on the state-of-the-art in CD20-targeting antibodies used to treat iTTP patients with an eye toward identifying areas in need of further study to aid in the care of patients with this rare and often devastating disease.
2026-08-22 | Real-world evolution of therapeutic strategies and outcomes in acquired thrombotic thrombocytopenic purpura: a 14-year referral center experience.
Acquired or immune thrombotic thrombocytopenic purpura (iTTP) is a rare thrombotic microangiopathy caused by autoantibodies against ADAMTS13. The aim of this study was to evaluate the efficacy and safety of caplacizumab (CPZ) and rituximab (RTX) added to standard therapy in a real-world cohort. A single-center retrospective observational study of all adult patients with iTTP treated at Hospital Universitari de Bellvitge (2010-2024). Efficacy and safety variables were compared between patients treated with CPZ added to standard therapy versus those who were not, between patients who received RTX versus those who did not, and finally between quadruple therapy (corticosteroids [CS] + plasma exchange [PEX] + CPZ + RTX) and dual therapy (CS + PEX). Thirty patients were included (46 acute episodes). CPZ was significantly associated with a shorter time to clinical response (5 vs. 9days; P=.023), shorter time to remission (24.8 vs. 40.6days; P<.001), and fewer plasma exchange sessions (5.5 vs. 9.5 sessions; P<.001). Early administration (<72hours) was associated with a shorter hospital stay (11 vs. 19.5days; P=.012). RTX showed a reduction in the number of relapses (13.3% vs. 50%; P=.085), without reaching statistical significance. Both drugs showed favorable safety profiles. Quadruple therapy resulted in a shorter time to clinical remission (26.1±9.9 vs. 40.3±7days; P<.001) and a lower number of PEX sessions (6 [4-7] vs. 8 [7-15.8]; P=.034). In iTTP, CPZ improves short-term outcomes, particularly when administered early. RTX is associated with a trend toward greater relapse-free survival. Quadruple therapy reduces the time to clinical remission and the number of plasma exchange sessions. In iTTP, the incorporation of targeted and personalized therapeutic advances into clinical practice is associated with an improvement in clinical outcomes.
proteins
2026-09-30 | Current standards and novel concepts in thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a rare and rapidly life-threatening thrombotic microangiopathy. Disseminated microvascular thrombosis and resulting ischemia are the critical events determining outcome, if left untreated. The pathogenic hallmark is a severe deficiency of the plasma metalloprotease ADAMTS13, resulting in impaired cleavage of ultra-large von Willebrand factor (vWF) multimers leading to platelet aggregation. The vast majority of TTP cases are acquired and immune-mediated, depleting ADAMTS13 through autoantibodies. In contrast, congenital deficiency of ADAMTS13 affects a minority of patients. Measurement of ADAMTS13 activity is the cornerstone for diagnosis and implementation of treatment. However, clinical prediction scores support early therapeutic decision-making when results are pending. Plasma exchange, immunosuppression and more recently, the anti-vWF nanobody caplacizumab, are the central pillars for treatment of immune-mediated TTP. Caplacizumab prevents microvascular thrombosis during the acute episode but does not address the autoimmune-mediated ADAMTS13 depletion, underscoring the importance of plasma exchange and immunosuppression. Congenital TTP was previously treated using ADAMTS13 replacement through regular plasma infusions, but provision of recombinant ADAMTS13 has recently transformed treatment in these patients. Despite major advances, relapse remains a persistent threat for patients, making structured, long-term follow-up necessary. Diagnostic advances may help improve relapse prediction and corresponding therapeutic management. This review summarizes current concepts in the pathophysiology, diagnosis, clinical management of TTP and highlights recent therapeutic advancements and future challenges.
2026-09-21 | Hereditary TTP and Hemolytic Anemia in Newborns.
Hereditary thrombotic thrombocytopenic purpura (hTTP) is a thrombotic microangiopathy due to severe ADAMTS13 deficiency. hTTP typically presents in adulthood with thrombocytopenia, hemolytic anemia, and/or neurologic abnormalities. However, nearly half of the patients with hTTP are symptomatic at birth, most commonly presenting as severe jaundice secondary to hemolysis. Turbulent blood flow during birth puts neonates at high risk for thrombotic events and subsequent hemolytic anemia. We present a case series of 3 siblings with ADAMTS13 loss-of-function variants, all of whom required neonatal exchange transfusion. These siblings are now in their 30s and were diagnosed with hTTP between the ages of 13 and 18. One sibling experienced a neonatal stroke, while another sibling required a leukemia workup in her childhood because of hTTP. They remain in good health as adults. Two of them receive recombinant ADAMTS13 treatment for their deficiency. A recent report found that only 5% of patients with hTTP were correctly diagnosed at birth-underscoring the importance of having a high index of suspicion in the neonatal period for the anemic and thrombocytopenic newborn with nonimmune hemolytic anemia. With newly Food and Drug Administration-approved recombinant ADAMTS13 therapy and rapid diagnostic testing for ADAMTS13 levels, it is imperative that pediatricians and neonatologists recognize this rare but treatable form of recalcitrant jaundice. We propose a diagnostic algorithm to assist clinicians in neonatal diagnosis of hTTP in hopes of mitigating the need for exchange transfusions and extensive hematologic workups later in life. Timely diagnosis would prompt targeted treatment, which can prevent long-term neurologic and renal sequelae.
2026-09-07 | ADAMTS-13 fusion constructs with dual activity against von Willebrand factor: a novel strategy for immune-mediated thrombotic thrombocytopenic purpura.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy. iTTP pathophysiology stems from severe a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS-13) deficiency caused by autoantibodies, leading to accumulation of ultralarge von Willebrand factor (VWF) multimers and microvascular thrombosis. Engineered ADAMTS-13 variants reduce autoantibody binding. However, some show impaired VWF-cleaving activity, whereas others, such as glycan-engineered variants, retain proteolytic function. To investigate the AU/VWFa-11 (aVWF) single-domain antibody (sdAb) targeting the A1 domain of VWF in its active conformation, and 2 dual-action fusion constructs linking the sdAb to either a truncated ADAMTS-13 (Metalloprotease, Disintegrin, Thrombospondin type 1 repeat, Cysteine-rich and Spacer domains [MDTCS]; MDTCS-aVWF) or an autoantibody-resistant mutant (MDTCSm; MDTCSm-aVWF). Binding of aVWF to active VWF and the VWF A1 domain was assessed by enzyme-linked immunosorbent assays. Proteolytic activity was assessed using fluorescence resonance energy transfer substrate (FRETS)-VWF73, VWF multimer, and beads-on-a-string assays. VWF-platelet interactions were measured by light transmission aggregometry and flow cytometry. Autoantibody resistance was evaluated using FRETS-VWF73 assays in the presence of plasma from iTTP patients. aVWF sdAb selectively bound active VWF and inhibited platelet-VWF interactions in solution without impairing platelet adhesion to collagen-bound VWF. Both MDTCS-aVWF and MDTCSm-aVWF retained high proteolytic activity against VWF and reduced platelet-VWF interactions. Notably, MDTCSm-aVWF showed enhanced proteolytic activity and greater resistance to iTTP autoantibodies. The fusion construct MDTCSm-aVWF, which combines an enzymatically active, autoantibody-resistant ADAMTS-13 variant with a VWF conformation-specific inhibitory sdAb, offers a novel alternative therapeutic approach for iTTP.
2026-08-24 | Cobalamin E deficiency complicated with thrombotic microangiopathy: a case report
Cobalamin E (cblE) defect, caused by pathogenic variants in MTRR encoding methionine synthase reductase, is a rare remethylation disorder typically documented in small case series. While common features include failure to thrive, cognitive impairment, and macrocytic anemia, renal thrombotic microangiopathy (TMA) is uncommon and remains under-recognized. An 8-year-old, previously healthy Thai boy presented with a 4-day history of fever and fatigue. Initial investigation revealed bicytopenia with megaloblastic anemia and renal dysfunction. Chronic TMA was diagnosed by renal pathology which demonstrated double contours of the glomerular basement membrane without mesangial or endocapillary hypercellularity. Given the combination of megaloblastic anemia, TMA, and renal impairment, an inborn error of cobalamin metabolism was suspected. A serum total homocysteine test revealed markedly elevated levels with undetectable urine methylmalonic acid, suggesting a remethylation defect. Singleton whole exome sequencing (WES) was carried out, followed by Sanger sequencing of the supposed variant. The result indicated a compound heterozygous MTRR mutation, c.309dup (p.Phe104Leufs*9) and c.1770-5T>G, confirming cblE defect. After parenteral hydroxocobalamin was given, the patient demonstrated gradual improvement in TMA and renal function, accompanied by a decline in homocysteine levels. This case underscores that cblE defects can present in late childhood with chronic TMA and megaloblastic anemia. Prompt recognition of remethylation disorders and early institution of hydroxocobalamin therapy can mitigate microangiopathic injury and prevent progression to kidney failure. Genetic confirmation remains essential to guide long-term management and family counseling.
2026-08-14 | Thrombotic Microangiopathy-Like Phenotype in Patients With Infection-Associated Disseminated Intravascular Coagulation Treated With Thrombomodulin Alfa.
Despite disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) sharing features of thrombocytopenia, organ dysfunction, and bleeding, the relationship between these two conditions remains unclear. We therefore conducted a post hoc analysis of post-marketing surveillance data from Japan to evaluate the clinical characteristics of 2362 patients with DIC (TMA-like phenotype DIC, n = 217; and non-TMA-like phenotype DIC, n = 2145) who received thrombomodulin alfa (TM-α). TMA-like phenotype DIC was defined as platelet count < 15 × 104/μL, hemoglobin < 10 g/dL and lactate dehydrogenase > 500 IU/L. Approximately 9% of the registered infection-associated cases of DIC were TMA-like phenotype DIC. Patients with TMA-like phenotype were younger and had more renal dysfunction and liver dysfunction than those with non-TMA-like phenotype. Regarding the hemostatic examinations, fibrin/fibrinogen degradation products, D-dimer, and thrombin-antithrombin complex levels were higher in patients with TMA-like phenotype than in those with non-TMA-like phenotype. Patients with TMA-like phenotype had worse resolution of DIC and 28-day survival rates than those with non-TMA-like phenotype; however, the coagulation and fibrinolysis parameters in both groups showed improvement after TM-α administration. These findings describe a clinically severe subgroup of infection-associated DIC and should be interpreted as exploratory given that confirmatory TMA testing was unavailable.
other
2026-09-07 | Beyond immune rejection: integrative genetic engineering strategies for overcoming coagulopathy in xenotransplantation.
The four-decade evolution of genetically engineered (GE) pigs from the first α-1,3-galactosyltransferase knockout in 2003 to today's 10-gene and 69-edit donors has progressively dismantled the immunologic barriers to xenotransplantation. Hyperacute and acute humoral rejection have been largely overcome through triple knockout of xenoreactive carbohydrate antigens and transgenic expression of human complement regulators. Yet a less appreciated barrier now dominates long-term graft survival: pig-to-human coagulation dysregulation. Molecular incompatibility between porcine endothelial regulators of hemostasis, particularly thrombomodulin, endothelial protein C receptor, and the CD39 axis, and the primate coagulation cascade drives thrombotic microangiopathy and consumptive coagulopathy that erode graft function after immunologic control is achieved. The six reported human cases (Cases 1-6, numbered chronologically) confirm this transition. Notably, the 10-gene configuration now used in most clinical xenotransplants reflects the proprietary design of a single industrial source, not a biologically derived optimum. This review traces the historical development of GE pigs, synthesizes the rationale for integrative endothelial humanization, and argues that scientific progress requires diverse new gene combinations and, ultimately, organ-tailored donor pigs.
2026-08-18 | Genetic susceptibility to thrombotic microangiopathy in a 10-month-old patient with SMA type 1: a caveat for gene therapy eligibility.
Gene therapy with onasemnogene abeparvovec (OA) has dramatically improved the prognosis of spinal muscular atrophy (SMA) since its approval. Thrombotic microangiopathies (TMA), including atypical complement-mediated hemolytic uremic syndrome (aHUS), represent rare but potentially life-threatening complications associated with OA. Complement activation and immune response against the viral vector capsid are considered the main pathogenic mechanisms. We report a 10-month-old girl with SMA type 1 and three SMN2 gene copies, initially eligible for OA. Baseline assessment revealed persistently undetectable Complement Component 3 (C3) levels (<0.29 g/L) and multiple concurrent infections. Next-generation sequencing identified likely pathogenic heterozygous C3 (c.3489+1G>A) and heterozygous CFI gene variants of uncertain significance (c.148C>G, p.Pro50Ala), both associated with increased risk of aHUS. The multidisciplinary team considered the patient at high risk and OA was withheld to prevent a potentially fatal TMA event. This case highlights how systematic complement screening prior to gene therapy may help identify high-risk individuals.
2026-07-09 | Update in treatment options for congenital and immune thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy resulting either from congenital deficiency (cTTP) or acquired (immune) deficiency (iTTP) of A Disintegrin and Metalloprotease with ThromboSpondin-type 1 motif, member 13 (ADAMTS13). Deficiency of ADAMTS13 leads to disseminated platelet thrombosis and organ dysfunction. High mortality of cTTP is prevented by plasma infusion to replace the deficient protease, or more recently by infusion of recombinant ADAMTS13. Standard treatment of iTTP includes steroids, plasma exchange, and rituximab, with or without caplacizumab. Although standard treatment of iTTP improves mortality, refractory cases persist, indicating the need for additional treatment options. This review summarizes the status of novel treatment options for cTTP and iTTP, including additional recombinant ADAMTS13 products, ADAMTS13 gene therapies, plasma cell-directed therapies (bortezomib, daratumumab) as well as novel inhibitors of von Willebrand factor activity.
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.
small molecules
2026-09-30 | Scleroderma Renal Crisis-Associated Thrombotic Microangiopathy Preceding Skin Sclerosis in Diffuse Cutaneous Systemic Sclerosis: A Case Report.
A prompt and accurate diagnosis is essential because the management of thrombotic microangiopathy (TMA) depends on its underlying etiology. We report a case of diffuse cutaneous systemic sclerosis (dcSSc) in which scleroderma renal crisis-associated TMA preceded the development of overt skin sclerosis. A 53-year-old woman presented with TMA and severe renal dysfunction. She tested positive for anti-RNA polymerase III antibodies and subsequently developed skin sclerosis, leading to a diagnosis of dcSSc. Angiotensin-converting enzyme inhibitor therapy resulted in a clinical improvement in the patient. Therefore, systemic sclerosis should be considered in the differential diagnosis of TMA, even in the absence of skin manifestations at presentation.
2026-09-16 | Conversion from calcineurin inhibitor to ruxolitinib as GVHD prophylaxis during patients with transplant-associated thrombotic microangiopathy.
Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with multifactorial etiology. Existing clinical guidelines recommend discontinuation or tapering of calcineurin inhibitors (CNIs) as the primary intervention after the initial TMA diagnosis; however, data on the options for immunosuppression manipulation (ISM) are limited. Ruxolitinib is an effective option in treatment of steroid refractory graft-versus-host disease (SR-GVHD), which seems promising to replace CNIs as a prophylactic agent with better GVHD control in patients with TA-TMA. We retrospectively analyzed the outcomes of 48 TA-TMA patients who received ISM with steroids (steroid group) or ruxolitinib (ruxolitinib group) as CNI substitutes. The primary endpoint was not met: the ORR at 4 weeks did not differ significantly between the ruxolitinib and steroid groups (65.2% vs. 80.0%, P = 0.250). However, in exploratory secondary analyses, more patients in the ruxolitinib group achieved complete response (CR) than in the steroid group (40% vs. 13%, P=0.036), and first remission was achieved more rapidly (13.5 vs. 25 days, P=0.046). Additionally, the ruxolitinib group demonstrated faster normalization of lactate dehydrogenase (LDH) levels and significantly better overall survival (HR 0.32, 95% CI 0.12-0.84, p=0.025) and relapse-free survival (HR 0.41, 95% CI 0.17-0.99, p=0.048) than the steroid group. Although hematologic recovery was slower in the ruxolitinib group than in the steroid group, we attribute this to ruxolitinib-induced myelosuppression. Infection was a significant risk factor in the ruxolitinib group (P=0.0426). However, there were no significant differences in the incidence of infection following treatment with steroid or ruxolitinib: pneumonia (26.1% vs. 16%, P=0.487), sepsis (17.4% vs. 12%, P=0.696), Epstein-Barr virus (EBV) reactivation (47.8% vs. 36%, P=0.406), or Cytomegalovirus (CMV) reactivation (56.5% vs. 52%, P=0.753). In this pilot study, the primary endpoint (ORR) was not met. Exploratory secondary analyses suggest that replacing CNIs with ruxolitinib during TA-TMA is feasible and may be associated with more rapid LDH normalization and CR, at the cost of slower peripheral count recovery; these observations are hypothesis-generating and require confirmation in adequately powered, prospective, multicenter studies.
2026-09-13 | Complete recovery of thrombotic microangiopathy with severe acute kidney injury due to intravenous use of modified release oxycodone.
Since the introduction of the tamper-resistant oral formulation of modified-release oxycodone (OxyContin®), cases of thrombotic microangiopathy (TMA) have been reported following intravenous injection of the drug. Previous reports have suggested that withdrawal of the offending agent alone may be sufficient to reverse the condition; however, the associated acute kidney injury (AKI) in these cases was only mild to moderate in severity. We report the first case of OxyContin®-associated TMA presenting with anuric AKI requiring dialysis, followed by complete renal recovery after cessation of intravenous OxyContin® use. This case demonstrates that withdrawal of the causative agent may be sufficient to achieve resolution of TMA even in severe presentations. Accordingly, supportive management without the need for invasive and costly interventions may be appropriate in selected cases. Awareness of the association between intravenous OxyContin® use and TMA is essential for timely diagnosis, as identification often depends on direct inquiry regarding drug exposure.
2026-09-10 | Thrombotic Microangiopathy Presenting With Multisystem Involvement and Acute Neurologic Deficits in a 61-Year-Old Female: A Case of Acquired Thrombotic Thrombocytopenic Purpura.
Thrombotic microangiopathy (TMA) is a rare, life-threatening hematologic syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ dysfunction. Among TMAs, thrombotic thrombocytopenic purpura (TTP), an emergent subtype caused by severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13), requires urgent recognition and prompt treatment. We present a 61-year-old woman who initially presented with abdominal pain and hematuria and was treated for a presumed urinary tract infection. She later developed chest pain, unilateral weakness, melena, and petechiae. Laboratory evaluation revealed severe anemia, thrombocytopenia, acute kidney injury, elevated lactate dehydrogenase, and schistocytes on peripheral smear, consistent with microangiopathic hemolysis. Urgent hematologic evaluation raised concern for TTP versus hemolytic uremic syndrome. Her PLASMIC score was high risk, prompting empiric initiation of plasma exchange and corticosteroids prior to confirmatory testing. Brain magnetic resonance imaging (MRI) demonstrated punctate acute infarcts in the right parietal lobe. ADAMTS13 activity returned <10%, confirming acquired TTP. The patient improved with plasma exchange, corticosteroids, and rituximab, and was discharged in stable condition with outpatient follow-up. This case highlights the importance of early recognition, use of clinical prediction tools, and prompt treatment of TTP in patients with multisystem involvement and neurologic deficits to reduce morbidity and mortality.
2026-08-27 | Safety and Efficacy of Ponatinib for Pulmonary Tumor Thrombotic Microangiopathy
Background: We evaluated the safety and efficacy of ponatinib, a multi-target tyrosine kinase inhibitor, for pulmonary tumor thrombotic microangiopathy (PTTM).
cell therapies
2026-09-03 | Porcine kidney xenotransplantation as a bridge to allotransplantation: a first-in-human study.
Kidney xenotransplantation offers a potential solution to the organ shortage, but questions remain regarding durability, zoonotic infection risk, and whether the immunological response to the xenograft elicits sensitisation that could complicate subsequent allotransplantation. We report outcomes from a porcine kidney xenograft in a living recipient followed by human allotransplantation. A patient with end-stage kidney disease, a prolonged anticipated waiting time for deceased donor transplantation, and with no suitable living donor underwent transplantation at Massachusetts General Hospital (Boston, MA, USA) with a gene-edited porcine kidney (EGEN-2784; eGenesis [Cambridge, MA, USA]) incorporating the deletion of major glycan xenoantigens, inactivation of porcine endogenous retroviruses, and insertion of seven human transgenes. The recipient received costimulation blockade-based immunosuppression with complement inhibition. Monitoring included renal function, flow cytometric crossmatch, anti-HLA antibodies, and porcine microbial surveillance, including metagenomic sequencing. This report describes the first recipient in a planned three-patient study conducted under a US Food and Drug Administration Expanded Access Investigational New Drug application. The xenograft functioned immediately after transplantation on Jan 25, 2025, and sustained dialysis independence for 271 days. A biopsy on day 14 showed T-cell-mediated rejection, which resolved with treatment. Graft function remained stable for approximately 6 months until immunosuppression was reduced in the setting of non-zoonotic bacterial infection. Microvascular inflammation with endothelial injury subsequently emerged, progressing to thrombotic microangiopathy despite persistently negative donor-specific crossmatch, leading to graft failure and nephrectomy. Tissue analysis showed a macrophage and natural-killer-cell-predominant infiltrate with minimal T-cell involvement. No porcine pathogen transmission was detected. Anti-HLA antibodies remained unchanged. 82 days after explantation, the patient underwent human kidney allotransplantation with immediate graft function and no evidence of sensitisation during 231 days of follow-up. This case shows that porcine kidney xenotransplantation can provide prolonged renal support and be discontinued without clinically significant allosensitisation or zoonotic infection. Early cellular rejection resolved with treatment, whereas later graft failure was associated with microvascular injury progressing to thrombotic microangiopathy despite a negative donor-specific crossmatch, supporting the possibility that mechanisms beyond conventional antibody-mediated rejection contributed to late graft injury. Kidney xenotransplantation has the potential to provide prolonged dialysis-free support while also serving as a bridge to subsequent human allotransplantation. Massachusetts General Hospital and eGenesis.
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.
2026-09-01 | Long-term outcome of pediatric anti-complement factor H antibody-associated atypical hemolytic uremic syndrome receiving abbreviated plasma exchange: a retrospective study from a single center.
Anti-complement factor H antibody- (anti-CFH Ab) associated atypical hemolytic uremic syndrome (aHUS) is a known cause of pediatric complement-mediated thrombotic microangiopathy. In our center, plasma exchange (PEX) until remission paired with immunosuppression continues to be the mainstay of therapy, due to limited access to eculizumab. We wanted to study the long-term outcome of this cohort. We conducted a retrospective cohort study of children (<12 years) with Anti-CFH Ab-associated aHUS admitted between January 2017 and December 2024 at our center. Clinical, laboratory, treatment, and outcome data were retrieved from medical records. The primary outcome was renal recovery, defined as eGFR >90 mL/min/1.73 m2 with normal blood pressure, no significant proteinuria, and absence of hematuria at last follow-up or at 5 years. Of 66 records screened, 40 children were eligible. Median age at presentation was 7 years (interquartile range [IQR] 5,8). Median anti-CFH Ab titer was 306 AU/mL (IQR 214-426). Low C3 was noted in 55% of subjects. All patients received PEX (median 11 cycles; IQR 7.25, 20) and immunosuppression. Median follow-up was 24 months (IQR 7-53). At last follow-up, 21 (52.5%) achieved complete renal recovery, while 19 (47.5%) had CKD stage 2-4. Relapse incidence was 7.1 per 100 person-years, usually within 6 months of onset. No baseline clinical, laboratory, or treatment variable except duration of dialysis independently predicted renal recovery. Persistent proteinuria was observed up to 6 months but subsequently improved. PEX paired with immunosuppression remains effective for anti-CFH Ab-associated aHUS, but further studies are needed to refine protocols and evaluate complement inhibitors for improved long-term outcomes.
2026-08-07 | Delayed Recognition of Thrombotic Thrombocytopenic Purpura Following Platelet Transfusion: A Clinical Pitfall.
Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 deficiency, usually due to autoantibody-mediated inhibition. Its presentation is heterogeneous and often lacks the classic pentad, leading to diagnostic delays. Neurological symptoms may predominate, masking the underlying hematologic emergency. In our case, a 37-year-old previously healthy woman presented with acute headache, speech disturbance, and altered mental status. Despite normal neuroimaging, laboratory tests revealed severe thrombocytopenia and normocytic anemia. Lack of response to erythrocyte and platelet transfusions prompted further evaluation, revealing microangiopathic hemolytic anemia with elevated lactate dehydrogenase, undetectable haptoglobin, indirect hyperbilirubinemia, reticulocytosis, and normal coagulation parameters. A PLASMIC score of 6/7 indicated a high probability of severe ADAMTS13 deficiency. Treatment with high-dose corticosteroids was initiated immediately, followed by plasma exchange and rituximab. ADAMTS13 activity confirmed severe deficiency at 0.3%, supporting the diagnosis of acquired TTP in the clinical context. The patient achieved rapid remission and complete neurological recovery. This case highlights the importance of early recognition of microangiopathic hemolysis and prompt treatment without waiting for confirmatory ADAMTS13 results to reduce morbidity and mortality.
2026-07-10 | Secondary thrombotic thrombocytopenic purpura with features of Evans syndrome in a patient with SLE.
A female in her early 40s with systemic lupus erythematosus (SLE) and prior immune thrombocytopenic purpura presented with dizziness, dyspnoea, haematuria and fatigue. Investigations revealed a life-threatening thrombotic microangiopathy triad (platelets 3000/µL, microangiopathic haemolytic anaemia, acute kidney injury) and the strongly positive Coombs test with haemolysis markers supported autoimmune haemolysis in addition to microangiopathic haemolysis. Together with her prior history of immune thrombocytopenia, these findings are consistent with an Evans syndrome overlap, though consumptive thrombocytopenia from thrombotic thrombocytopenic purpura (TTP) could not be excluded. There was evidence of SLE vasculitis. Despite diagnostic overlap obscuring TTP, empiric plasma exchange (PLEX), steroids and rituximab induced rapid haematologic and clinical recovery. Days later, severe ADAMTS13 deficiency (<0.03 IU/mL) confirmed SLE-associated secondary TTP. This case highlights the critical need for empiric PLEX in suspected TTP when possible Evans syndrome complicates SLE and the efficacy of combined immunomodulation targeting both entities.
antibodies
2026-09-28 | Bilateral postpartum renal cortical necrosis complicated by peripartum cardiomyopathy after postpartum hemorrhage: a case report.
A 36-year-old woman developed postpartum haemorrhage after an uncomplicated vaginal delivery, followed by disseminated intravascular coagulation, thrombotic microangiopathy, and persistent anuric kidney failure. Contrast-enhanced computed tomography showed bilateral reversal of corticomedullary enhancement, consistent with renal cortical necrosis. Despite kidney replacement therapy and 13 litres of ultrafiltration, she remained oxygen-dependent, prompting cardiac evaluation on postpartum day 11, which revealed severe left ventricular systolic dysfunction (ejection fraction 25%) consistent with peripartum cardiomyopathy. Cardiac function recovered with medical therapy, whereas kidney function remained irreversible, requiring dialysis and transplantation. Renal cortical necrosis and peripartum cardiomyopathy are linked to endothelial dysfunction, yet their coexistence has rarely been reported. Cardiac dysfunction emerged only after substantial fluid removal, arguing against volume overload alone and suggesting a shared postpartum endotheliopathy. Persistent oxygen requirement despite adequate decongestion should prompt early cardiac assessment rather than being attributed to fluid overload alone.
2026-09-15 | Therapeutic Plasma Exchange in Immune-Mediated Thrombotic Thrombocytopenic Purpura: From Cornerstone to Contextualized Therapy.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 deficiency due to anti-ADAMTS13 autoantibodies. The resulting persistence of ultra-large von Willebrand factor (VWF) multimers promotes uncontrolled platelet adhesion and aggregation in the microcirculation, leading to thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ injury. Therapeutic plasma exchange (TPE) has transformed the prognosis of iTTP by removing circulating autoantibodies and replenishing functional ADAMTS13, and it remains a life-saving intervention in acute disease. However, TPE is invasive, resource-intensive, dependent on central venous access and plasma availability, and associated with catheter-related, hemodynamic, metabolic, infectious, and plasma-related adverse events. The therapeutic landscape has changed substantially with the incorporation of immunosuppression and the anti-VWF nanobody caplacizumab. Caplacizumab rapidly blocks VWF-platelet interactions at the effector level, whereas corticosteroids and B-cell-directed therapy target the autoimmune basis of iTTP. Triple therapy with TPE, immunosuppression, and caplacizumab accelerates platelet recovery and reduces unfavorable outcomes. At the same time, accumulating observational evidence and early prospective data suggest that selected patients may achieve remission with caplacizumab plus immunosuppression without routine first-line TPE. This perspective review critically re-evaluates the role of TPE in contemporary iTTP management. We propose that TPE should no longer be viewed exclusively as an obligatory universal first-line intervention, but rather as a contextualized component of individualized, response-adapted care. TPE remains indispensable for severe, unstable, or refractory disease and must be immediately available when TPE-free treatment is attempted. Safe implementation of TPE-free strategies requires experienced centers, rapid ADAMTS13 testing, immediate access to caplacizumab and immunosuppression, careful patient selection, and close clinical and laboratory monitoring. Defining which patients can be treated safely without TPE is a central challenge for future trials and guideline development.
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.
2026-09-08 | Evidence for the use of anti-CD20 therapeutic antibodies in immune thrombotic thrombocytopenic purpura management: a review.
Immune thrombotic thrombocytopenic purpura (iTTP) is an autoimmune thrombotic microangiopathy caused by antibody-mediated deficiency of the plasma metalloprotease ADAMTS13. Therapeutic antibodies that target antibody-producing B-cells via the CD20 surface receptor protein to prevent disease exacerbation and relapse have become part of the standard of care of patients with iTTP. However, clinical trial data regarding the use of anti-CD20 agents is limited to mostly phase II studies; no universally agreed-upon standardized protocol for the use of CD20-targeting antibodies for iTTP regarding choice of agent, dosage, or duration of treatment exists; refractoriness or lack of response to anti-CD20 antibodies can occur; and several agents and biosimilars are now available for the treatment of iTTP patients, which complicates the decision tree for clinicians caring for these patients. In this review, we explore the current landscape of anti-CD20 therapeutics used to treat iTTP, focusing on agents currently available for clinical use. We describe the pharmacokinetic and pharmacodynamic properties of CD20-targeting antibodies; available data regarding dosage and duration of treatment; anti-CD20 antibody therapy refractoriness or lack of response; and the evolving role of anti-CD20 biosimilars. This review will shed light on the state-of-the-art in CD20-targeting antibodies used to treat iTTP patients with an eye toward identifying areas in need of further study to aid in the care of patients with this rare and often devastating disease.
2026-08-22 | Real-world evolution of therapeutic strategies and outcomes in acquired thrombotic thrombocytopenic purpura: a 14-year referral center experience.
Acquired or immune thrombotic thrombocytopenic purpura (iTTP) is a rare thrombotic microangiopathy caused by autoantibodies against ADAMTS13. The aim of this study was to evaluate the efficacy and safety of caplacizumab (CPZ) and rituximab (RTX) added to standard therapy in a real-world cohort. A single-center retrospective observational study of all adult patients with iTTP treated at Hospital Universitari de Bellvitge (2010-2024). Efficacy and safety variables were compared between patients treated with CPZ added to standard therapy versus those who were not, between patients who received RTX versus those who did not, and finally between quadruple therapy (corticosteroids [CS] + plasma exchange [PEX] + CPZ + RTX) and dual therapy (CS + PEX). Thirty patients were included (46 acute episodes). CPZ was significantly associated with a shorter time to clinical response (5 vs. 9days; P=.023), shorter time to remission (24.8 vs. 40.6days; P<.001), and fewer plasma exchange sessions (5.5 vs. 9.5 sessions; P<.001). Early administration (<72hours) was associated with a shorter hospital stay (11 vs. 19.5days; P=.012). RTX showed a reduction in the number of relapses (13.3% vs. 50%; P=.085), without reaching statistical significance. Both drugs showed favorable safety profiles. Quadruple therapy resulted in a shorter time to clinical remission (26.1±9.9 vs. 40.3±7days; P<.001) and a lower number of PEX sessions (6 [4-7] vs. 8 [7-15.8]; P=.034). In iTTP, CPZ improves short-term outcomes, particularly when administered early. RTX is associated with a trend toward greater relapse-free survival. Quadruple therapy reduces the time to clinical remission and the number of plasma exchange sessions. In iTTP, the incorporation of targeted and personalized therapeutic advances into clinical practice is associated with an improvement in clinical outcomes.
proteins
2026-09-30 | Current standards and novel concepts in thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a rare and rapidly life-threatening thrombotic microangiopathy. Disseminated microvascular thrombosis and resulting ischemia are the critical events determining outcome, if left untreated. The pathogenic hallmark is a severe deficiency of the plasma metalloprotease ADAMTS13, resulting in impaired cleavage of ultra-large von Willebrand factor (vWF) multimers leading to platelet aggregation. The vast majority of TTP cases are acquired and immune-mediated, depleting ADAMTS13 through autoantibodies. In contrast, congenital deficiency of ADAMTS13 affects a minority of patients. Measurement of ADAMTS13 activity is the cornerstone for diagnosis and implementation of treatment. However, clinical prediction scores support early therapeutic decision-making when results are pending. Plasma exchange, immunosuppression and more recently, the anti-vWF nanobody caplacizumab, are the central pillars for treatment of immune-mediated TTP. Caplacizumab prevents microvascular thrombosis during the acute episode but does not address the autoimmune-mediated ADAMTS13 depletion, underscoring the importance of plasma exchange and immunosuppression. Congenital TTP was previously treated using ADAMTS13 replacement through regular plasma infusions, but provision of recombinant ADAMTS13 has recently transformed treatment in these patients. Despite major advances, relapse remains a persistent threat for patients, making structured, long-term follow-up necessary. Diagnostic advances may help improve relapse prediction and corresponding therapeutic management. This review summarizes current concepts in the pathophysiology, diagnosis, clinical management of TTP and highlights recent therapeutic advancements and future challenges.
2026-09-21 | Hereditary TTP and Hemolytic Anemia in Newborns.
Hereditary thrombotic thrombocytopenic purpura (hTTP) is a thrombotic microangiopathy due to severe ADAMTS13 deficiency. hTTP typically presents in adulthood with thrombocytopenia, hemolytic anemia, and/or neurologic abnormalities. However, nearly half of the patients with hTTP are symptomatic at birth, most commonly presenting as severe jaundice secondary to hemolysis. Turbulent blood flow during birth puts neonates at high risk for thrombotic events and subsequent hemolytic anemia. We present a case series of 3 siblings with ADAMTS13 loss-of-function variants, all of whom required neonatal exchange transfusion. These siblings are now in their 30s and were diagnosed with hTTP between the ages of 13 and 18. One sibling experienced a neonatal stroke, while another sibling required a leukemia workup in her childhood because of hTTP. They remain in good health as adults. Two of them receive recombinant ADAMTS13 treatment for their deficiency. A recent report found that only 5% of patients with hTTP were correctly diagnosed at birth-underscoring the importance of having a high index of suspicion in the neonatal period for the anemic and thrombocytopenic newborn with nonimmune hemolytic anemia. With newly Food and Drug Administration-approved recombinant ADAMTS13 therapy and rapid diagnostic testing for ADAMTS13 levels, it is imperative that pediatricians and neonatologists recognize this rare but treatable form of recalcitrant jaundice. We propose a diagnostic algorithm to assist clinicians in neonatal diagnosis of hTTP in hopes of mitigating the need for exchange transfusions and extensive hematologic workups later in life. Timely diagnosis would prompt targeted treatment, which can prevent long-term neurologic and renal sequelae.
2026-09-07 | ADAMTS-13 fusion constructs with dual activity against von Willebrand factor: a novel strategy for immune-mediated thrombotic thrombocytopenic purpura.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy. iTTP pathophysiology stems from severe a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS-13) deficiency caused by autoantibodies, leading to accumulation of ultralarge von Willebrand factor (VWF) multimers and microvascular thrombosis. Engineered ADAMTS-13 variants reduce autoantibody binding. However, some show impaired VWF-cleaving activity, whereas others, such as glycan-engineered variants, retain proteolytic function. To investigate the AU/VWFa-11 (aVWF) single-domain antibody (sdAb) targeting the A1 domain of VWF in its active conformation, and 2 dual-action fusion constructs linking the sdAb to either a truncated ADAMTS-13 (Metalloprotease, Disintegrin, Thrombospondin type 1 repeat, Cysteine-rich and Spacer domains [MDTCS]; MDTCS-aVWF) or an autoantibody-resistant mutant (MDTCSm; MDTCSm-aVWF). Binding of aVWF to active VWF and the VWF A1 domain was assessed by enzyme-linked immunosorbent assays. Proteolytic activity was assessed using fluorescence resonance energy transfer substrate (FRETS)-VWF73, VWF multimer, and beads-on-a-string assays. VWF-platelet interactions were measured by light transmission aggregometry and flow cytometry. Autoantibody resistance was evaluated using FRETS-VWF73 assays in the presence of plasma from iTTP patients. aVWF sdAb selectively bound active VWF and inhibited platelet-VWF interactions in solution without impairing platelet adhesion to collagen-bound VWF. Both MDTCS-aVWF and MDTCSm-aVWF retained high proteolytic activity against VWF and reduced platelet-VWF interactions. Notably, MDTCSm-aVWF showed enhanced proteolytic activity and greater resistance to iTTP autoantibodies. The fusion construct MDTCSm-aVWF, which combines an enzymatically active, autoantibody-resistant ADAMTS-13 variant with a VWF conformation-specific inhibitory sdAb, offers a novel alternative therapeutic approach for iTTP.
2026-08-24 | Cobalamin E deficiency complicated with thrombotic microangiopathy: a case report
Cobalamin E (cblE) defect, caused by pathogenic variants in MTRR encoding methionine synthase reductase, is a rare remethylation disorder typically documented in small case series. While common features include failure to thrive, cognitive impairment, and macrocytic anemia, renal thrombotic microangiopathy (TMA) is uncommon and remains under-recognized. An 8-year-old, previously healthy Thai boy presented with a 4-day history of fever and fatigue. Initial investigation revealed bicytopenia with megaloblastic anemia and renal dysfunction. Chronic TMA was diagnosed by renal pathology which demonstrated double contours of the glomerular basement membrane without mesangial or endocapillary hypercellularity. Given the combination of megaloblastic anemia, TMA, and renal impairment, an inborn error of cobalamin metabolism was suspected. A serum total homocysteine test revealed markedly elevated levels with undetectable urine methylmalonic acid, suggesting a remethylation defect. Singleton whole exome sequencing (WES) was carried out, followed by Sanger sequencing of the supposed variant. The result indicated a compound heterozygous MTRR mutation, c.309dup (p.Phe104Leufs*9) and c.1770-5T>G, confirming cblE defect. After parenteral hydroxocobalamin was given, the patient demonstrated gradual improvement in TMA and renal function, accompanied by a decline in homocysteine levels. This case underscores that cblE defects can present in late childhood with chronic TMA and megaloblastic anemia. Prompt recognition of remethylation disorders and early institution of hydroxocobalamin therapy can mitigate microangiopathic injury and prevent progression to kidney failure. Genetic confirmation remains essential to guide long-term management and family counseling.
2026-08-14 | Thrombotic Microangiopathy-Like Phenotype in Patients With Infection-Associated Disseminated Intravascular Coagulation Treated With Thrombomodulin Alfa.
Despite disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) sharing features of thrombocytopenia, organ dysfunction, and bleeding, the relationship between these two conditions remains unclear. We therefore conducted a post hoc analysis of post-marketing surveillance data from Japan to evaluate the clinical characteristics of 2362 patients with DIC (TMA-like phenotype DIC, n = 217; and non-TMA-like phenotype DIC, n = 2145) who received thrombomodulin alfa (TM-α). TMA-like phenotype DIC was defined as platelet count < 15 × 104/μL, hemoglobin < 10 g/dL and lactate dehydrogenase > 500 IU/L. Approximately 9% of the registered infection-associated cases of DIC were TMA-like phenotype DIC. Patients with TMA-like phenotype were younger and had more renal dysfunction and liver dysfunction than those with non-TMA-like phenotype. Regarding the hemostatic examinations, fibrin/fibrinogen degradation products, D-dimer, and thrombin-antithrombin complex levels were higher in patients with TMA-like phenotype than in those with non-TMA-like phenotype. Patients with TMA-like phenotype had worse resolution of DIC and 28-day survival rates than those with non-TMA-like phenotype; however, the coagulation and fibrinolysis parameters in both groups showed improvement after TM-α administration. These findings describe a clinically severe subgroup of infection-associated DIC and should be interpreted as exploratory given that confirmatory TMA testing was unavailable.
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2026-09-07 | Beyond immune rejection: integrative genetic engineering strategies for overcoming coagulopathy in xenotransplantation.
The four-decade evolution of genetically engineered (GE) pigs from the first α-1,3-galactosyltransferase knockout in 2003 to today's 10-gene and 69-edit donors has progressively dismantled the immunologic barriers to xenotransplantation. Hyperacute and acute humoral rejection have been largely overcome through triple knockout of xenoreactive carbohydrate antigens and transgenic expression of human complement regulators. Yet a less appreciated barrier now dominates long-term graft survival: pig-to-human coagulation dysregulation. Molecular incompatibility between porcine endothelial regulators of hemostasis, particularly thrombomodulin, endothelial protein C receptor, and the CD39 axis, and the primate coagulation cascade drives thrombotic microangiopathy and consumptive coagulopathy that erode graft function after immunologic control is achieved. The six reported human cases (Cases 1-6, numbered chronologically) confirm this transition. Notably, the 10-gene configuration now used in most clinical xenotransplants reflects the proprietary design of a single industrial source, not a biologically derived optimum. This review traces the historical development of GE pigs, synthesizes the rationale for integrative endothelial humanization, and argues that scientific progress requires diverse new gene combinations and, ultimately, organ-tailored donor pigs.
2026-08-18 | Genetic susceptibility to thrombotic microangiopathy in a 10-month-old patient with SMA type 1: a caveat for gene therapy eligibility.
Gene therapy with onasemnogene abeparvovec (OA) has dramatically improved the prognosis of spinal muscular atrophy (SMA) since its approval. Thrombotic microangiopathies (TMA), including atypical complement-mediated hemolytic uremic syndrome (aHUS), represent rare but potentially life-threatening complications associated with OA. Complement activation and immune response against the viral vector capsid are considered the main pathogenic mechanisms. We report a 10-month-old girl with SMA type 1 and three SMN2 gene copies, initially eligible for OA. Baseline assessment revealed persistently undetectable Complement Component 3 (C3) levels (<0.29 g/L) and multiple concurrent infections. Next-generation sequencing identified likely pathogenic heterozygous C3 (c.3489+1G>A) and heterozygous CFI gene variants of uncertain significance (c.148C>G, p.Pro50Ala), both associated with increased risk of aHUS. The multidisciplinary team considered the patient at high risk and OA was withheld to prevent a potentially fatal TMA event. This case highlights how systematic complement screening prior to gene therapy may help identify high-risk individuals.
2026-07-09 | Update in treatment options for congenital and immune thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy resulting either from congenital deficiency (cTTP) or acquired (immune) deficiency (iTTP) of A Disintegrin and Metalloprotease with ThromboSpondin-type 1 motif, member 13 (ADAMTS13). Deficiency of ADAMTS13 leads to disseminated platelet thrombosis and organ dysfunction. High mortality of cTTP is prevented by plasma infusion to replace the deficient protease, or more recently by infusion of recombinant ADAMTS13. Standard treatment of iTTP includes steroids, plasma exchange, and rituximab, with or without caplacizumab. Although standard treatment of iTTP improves mortality, refractory cases persist, indicating the need for additional treatment options. This review summarizes the status of novel treatment options for cTTP and iTTP, including additional recombinant ADAMTS13 products, ADAMTS13 gene therapies, plasma cell-directed therapies (bortezomib, daratumumab) as well as novel inhibitors of von Willebrand factor activity.
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.
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Drug Discovery Landscape
4 orphan drug designations for Thrombotic microangiopathy, including 1 approved therapy.
4 orphan drug designations for Thrombotic microangiopathy, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Ravulizumab | antibodies | FDA | Alexion Pharmaceuticals, Inc. | |
nomacopan | proteins | FDA | Akari Therapeutics Plc | |
narsoplimab-wuug [Yartemlea] | antibodies | FDA | Approved | Omeros Corporation |
Human monoclonal antibody inhibitor of mannan binding lectin-associated serine protease-2 (MASP-2) | antibodies | FDA | Omeros Corporation |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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