RARE DISEASE
Genetic thrombotic microangiopathy
Genetic thrombotic microangiopathy
Genetic thrombotic microangiopathy
Drug discovery
0
drugs
With orphan designations
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
682 drug discovery papers about Genetic thrombotic microangiopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
682 drug discovery papers about Genetic thrombotic microangiopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
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.
2026-07-07 | A case report of atypical hemolytic uremic syndrome with a CFH mutation complicated by recurrent posterior reversible encephalopathy syndrome.
Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction, particularly affecting the kidneys and the central nervous system. It is caused by genetic variants or autoantibodies involved in dysregulation of the complement system. Pathogenic variants of the complement factor H (CFH) gene are associated with severe disease and may lead to life-threatening multiorgan failure during the acute phase. We report a case of CFH mutation-positive aHUS complicated by recurrent posterior reversible encephalopathy syndrome (PRES) during the course of treatment. A 32-year-old woman presented with progressive fatigue and acute dyspnea. Laboratory tests revealed hemolytic anemia, thrombocytopenia, and severe acute kidney injury. A peripheral blood smear revealed schistocytes, consistent with TMA. On hospital day 1, she developed generalized tonic-clonic seizures followed by respiratory arrest that required mechanical ventilation. Continuous hemodialysis was initiated for severe renal failure. After the exclusion of thrombotic thrombocytopenic purpura, typical hemolytic uremic syndrome, and secondary causes of TMA, a clinical diagnosis of aHUS was made. Genetic testing later revealed a pathogenic heterozygous CFH variant (c.3572C>T, p.Ser1191Leu), confirming the diagnosis of aHUS. Anti-C5 monoclonal antibody (eculizumab) was initiated based on the clinical diagnosis of aHUS. Intensive care management, including mechanical ventilation, renal replacement therapy, plasma exchange, and strict blood pressure control, was also provided. During the course of the disease, she developed severe cardiomyopathy and recurrent PRES. Early initiation of complement inhibition combined with intensive care management resulted in complete neurological recovery, and the patient was discharged home without any sequelae. This case highlights that CFH mutation-positive aHUS can be complicated by severe multiorgan dysfunction, including cardiomyopathy and recurrent PRES. Early clinical recognition and prompt initiation of complement inhibition were central to the favorable outcome, while intensive blood pressure control and comprehensive supportive care may have contributed to neurological recovery.
2026-07-05 | Clinical Pig Organ Transplantation: What Have We Learned So Far?
Since January 2022, eleven clinical xenotransplants into living patients involving gene-edited pig hearts (n = 2) or kidneys (n = 9) have provided initial data on patient selection, organ sourcing, and immunosuppression. Lessons from cardiac cases indicate that (i) patient selection must prioritize candidates with a realistic recovery potential from preexisting debility, (ii) immunosuppressive regimens should be initiated 5-7 days pretransplant to ensure therapeutic blood levels, (iii) the administration of products that potentially contain anti-pig antibodies should be avoided, and (iv) highly sensitive assays are essential to ensure the graft is free of pathogenic microorganisms. In renal cases, evidence suggests that (i) pig organs with multiple gene edits may provide superior protection against the human immune response, and (ii) while immunosuppression targeting the CD40/CD154 co-stimulation pathway effectively prevents the adaptive immune response, it currently fails to eliminate the development of thrombotic microangiopathy or proteinuria. It remains to be determined whether the current gene editing and immunosuppressive protocols are sufficient to enable truly long-term survival of patients and grafts.
2026-07-03 | Complement mediated thrombotic microangiopathy after liver transplantation in combination with a novel C6 variant of uncertain significance.
Thrombotic microangiopathies (TMAs) encompass a spectrum of severe pathological conditions mostly characterized by hemolytic anemia, microvascular thrombosis with organ failure, and thrombocytopenia. The etiological spectrum of TMA is diverse, with a notable association in transplant recipients, particularly linked to the administration of calcineurin inhibitors (CNI) and due to perioperative stress factors. The clinical case presented concerns the occurrence of complement-mediated TMA (cTMA) in a recipient following liver transplantation (LT) who had previously been diagnosed with autoimmune hepatitis (AIH). The patient received total plasma exchange, followed by treatment with the anti-complement factor C5 antibody ravulizumab shortly after diagnosis. Significant improvement in the patient's clinical condition and a decline in renal impairment was observed. Subsequently, dialysis therapy could be discontinued. In addition, an enhancement in liver functionality was detected. The diagnosis of cTMA was undoubtedly attributable to a multifactorial cause. Genetic testing identified variants involving complement factor H-related protein 5 (CFHR5) and complement component 6 (C6). The identified C6 variant was classified as a variant of uncertain significance (VUS), and its pathogenic relevance in complement-mediated TMA remains unclear. Notably, a sustained clinical response was documented six months after starting ravulizumab treatment, highlighting the complexities of managing complement-mediated disorders and the potential for durable responses using the therapy at the earliest possible time.
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.
2026-07-07 | A case report of atypical hemolytic uremic syndrome with a CFH mutation complicated by recurrent posterior reversible encephalopathy syndrome.
Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction, particularly affecting the kidneys and the central nervous system. It is caused by genetic variants or autoantibodies involved in dysregulation of the complement system. Pathogenic variants of the complement factor H (CFH) gene are associated with severe disease and may lead to life-threatening multiorgan failure during the acute phase. We report a case of CFH mutation-positive aHUS complicated by recurrent posterior reversible encephalopathy syndrome (PRES) during the course of treatment. A 32-year-old woman presented with progressive fatigue and acute dyspnea. Laboratory tests revealed hemolytic anemia, thrombocytopenia, and severe acute kidney injury. A peripheral blood smear revealed schistocytes, consistent with TMA. On hospital day 1, she developed generalized tonic-clonic seizures followed by respiratory arrest that required mechanical ventilation. Continuous hemodialysis was initiated for severe renal failure. After the exclusion of thrombotic thrombocytopenic purpura, typical hemolytic uremic syndrome, and secondary causes of TMA, a clinical diagnosis of aHUS was made. Genetic testing later revealed a pathogenic heterozygous CFH variant (c.3572C>T, p.Ser1191Leu), confirming the diagnosis of aHUS. Anti-C5 monoclonal antibody (eculizumab) was initiated based on the clinical diagnosis of aHUS. Intensive care management, including mechanical ventilation, renal replacement therapy, plasma exchange, and strict blood pressure control, was also provided. During the course of the disease, she developed severe cardiomyopathy and recurrent PRES. Early initiation of complement inhibition combined with intensive care management resulted in complete neurological recovery, and the patient was discharged home without any sequelae. This case highlights that CFH mutation-positive aHUS can be complicated by severe multiorgan dysfunction, including cardiomyopathy and recurrent PRES. Early clinical recognition and prompt initiation of complement inhibition were central to the favorable outcome, while intensive blood pressure control and comprehensive supportive care may have contributed to neurological recovery.
2026-07-05 | Clinical Pig Organ Transplantation: What Have We Learned So Far?
Since January 2022, eleven clinical xenotransplants into living patients involving gene-edited pig hearts (n = 2) or kidneys (n = 9) have provided initial data on patient selection, organ sourcing, and immunosuppression. Lessons from cardiac cases indicate that (i) patient selection must prioritize candidates with a realistic recovery potential from preexisting debility, (ii) immunosuppressive regimens should be initiated 5-7 days pretransplant to ensure therapeutic blood levels, (iii) the administration of products that potentially contain anti-pig antibodies should be avoided, and (iv) highly sensitive assays are essential to ensure the graft is free of pathogenic microorganisms. In renal cases, evidence suggests that (i) pig organs with multiple gene edits may provide superior protection against the human immune response, and (ii) while immunosuppression targeting the CD40/CD154 co-stimulation pathway effectively prevents the adaptive immune response, it currently fails to eliminate the development of thrombotic microangiopathy or proteinuria. It remains to be determined whether the current gene editing and immunosuppressive protocols are sufficient to enable truly long-term survival of patients and grafts.
2026-07-03 | Complement mediated thrombotic microangiopathy after liver transplantation in combination with a novel C6 variant of uncertain significance.
Thrombotic microangiopathies (TMAs) encompass a spectrum of severe pathological conditions mostly characterized by hemolytic anemia, microvascular thrombosis with organ failure, and thrombocytopenia. The etiological spectrum of TMA is diverse, with a notable association in transplant recipients, particularly linked to the administration of calcineurin inhibitors (CNI) and due to perioperative stress factors. The clinical case presented concerns the occurrence of complement-mediated TMA (cTMA) in a recipient following liver transplantation (LT) who had previously been diagnosed with autoimmune hepatitis (AIH). The patient received total plasma exchange, followed by treatment with the anti-complement factor C5 antibody ravulizumab shortly after diagnosis. Significant improvement in the patient's clinical condition and a decline in renal impairment was observed. Subsequently, dialysis therapy could be discontinued. In addition, an enhancement in liver functionality was detected. The diagnosis of cTMA was undoubtedly attributable to a multifactorial cause. Genetic testing identified variants involving complement factor H-related protein 5 (CFHR5) and complement component 6 (C6). The identified C6 variant was classified as a variant of uncertain significance (VUS), and its pathogenic relevance in complement-mediated TMA remains unclear. Notably, a sustained clinical response was documented six months after starting ravulizumab treatment, highlighting the complexities of managing complement-mediated disorders and the potential for durable responses using the therapy at the earliest possible time.
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