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Thrombotic Thrombocytopenic Purpura (TTP) is rare and potentially life-threatening thrombotic microangiopathy (TMA) caused by acquired immune-mediated or congenital deficiency of the von Willebrand factor regulatory enzyme, a Disintegrin And Metalloproteinase with a Thrombospondin Type 1 motif, member 13 (ADAMTS13) which cause microthrombi to form and occlude the microvasculature. The occurrence of acute kidney injury (AKI) in TTP is rare and often underestimated due to confusion with hemolytic uremic syndrome (HUS). A 23-year-old Mestizo male patient presented with altered mental status, hemolytic anemia, thrombocytopenia, intermittent fever, laboratory tests suggestive of thrombotic microangiopathy, and clinical findings consistent with acute kidney injury. Predictive values of the platelet count, lactate dehydrogenase, absent active cancer, schistocytes, mean corpuscular volume, international normalized ratio, creatinine (PLASMIC) score, were used to assess the likelihood of ADAMTS13 deficiency, were employed, and enzymatic activity testing confirmed severe protein deficiency. Honduras' lack of advanced diagnostic capabilities is underscored, emphasizing the urgent need to invest in precision medical technology. ADAMTS13 testing allows for a more precise diagnosis of TTP, which is crucial for early diagnosis and timely treatment.

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The case report by Dwyre et al. shows that vitamin B12 deficiency may be misdiagnosed as acute thrombotic thrombocytopenic purpura. Together with similar observations, this underlines that acquired vitamin B12 deficiency-besides the inherited disorder of intracellular cobalamin metabolism, cbl C disease-should be listed as a separate entity of the thrombotic microangiopathies. Commentary on: Dwyre et al. Microangiopathic thrombocytopenia caused by vitamin B12 deficiency responding to plasma exchange. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19625.

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

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

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INTRODUCTION: Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal hematological disorder that requires urgent treatment. Once the diagnosis has been made, plasma exchange (PE) must be started immediately and until a response is obtained. AIM: Evaluate PE in terms of responses and complications in the treatment of TTP. METHODS: This was a monocentric, descriptive, retrospective study including patients in whom TTP was diagnosed and treated with plasmapheresis in the clinical hematology department at Aziza Othmana Hospital, between January 2010 and December 2020. RESULTS: Our study included 26 patients. PE was initiated within a median of 1 day. The rhythm of exchanges was daily in 22 patients. Twenty PE-related complications were noted, hypocalcemia being the most frequent (30%). CR was achieved in 15 patients after PE alone. Nine patients were refractory, and six received 2nd-line treatment, with CR achieved in five patients. Relapse was noted in six patients (40%). They were treated by PE and only one patient received rituximab. Four patients had a response. The overall response rate was 69% and overall mortality was 30%. OS at 2 years was 68,3% and RFS was 84,4%. Factors associated with the achievement of CR were the fall in LDH at D5 of treatment (p=0,027,OR=0,59 ;IC 95%[0,32-1,08]) and the daily rhythm of PE (p=0,005, OR=0,35; IC 95%[0,14-0,91]). CONCLUSION: Our results were comparable to those of the literature, but the rate of refractory disease was higher. Rituximab may enhance our results.

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BACKGROUND: Thrombotic microangiopathies (TMA) are a group of disorders with overlapping clinical features that require urgent intervention. Treatment is based on the recognition of the TMA type, which is often challenging. The aim of this study was to identify specific HLA associations with different TMA types to aid rapid diagnosis and appropriate treatment, since the HLA assay can be completed within five hours. METHODS: All 86 consecutive patients who presented to the University of Arkansas for Medical Sciences between May 2013 and January 2021 with a presumptive diagnosis of TMA were included in this study. HLA typing was performed and correlated with other clinical and laboratory studies. RESULTS: In comparison with other types of TMA, patients with acquired thrombotic thrombocytopenic purpura (aTTP) showed increased frequencies of HLA-DRB1*11, HLA-DQB1*03:01/19, HLA-DRB1*08 and HLA-DRB3. Combining the presence of these HLA associations with a PLASMIC score of 6 or more achieved a higher positive predictive value (90%) for identifying aTTP than the PLASMIC score alone (69%). In comparison with other TMA types, patients with aTTP showed decreased frequencies of HLA-DRB4, HLA-DRB1*07, HLA-DQB1*02. The HLA-DRB1*07/DQB1*02 was not observed in any aTTP patients (negative predictive value: 100%), and thus the presence of this haplotype essentially rules out aTTP. Further, HLA-DRB1*11/DQB1*03:01/19 was absent in atypical hemolytic uremic syndrome patients. CONCLUSION: HLA alleles can be used as an adjunct for the rapid assessment of TMA and can help to differentiate it from other primary and secondary forms of TMA, allowing for earlier definitive therapy.

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Pregnancy and the postpartum period represent phases of heightened vulnerability to thrombotic microangiopathies (TMAs), as evidenced by distinct patterns of pregnancy-specific TMAs (e.g., preeclampsia, HELLP syndrome), as well as a higher incidence of nonspecific TMAs, such as thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, during pregnancy. Significant strides have been taken in understanding the underlying mechanisms of these disorders in the past 40 years. This progress has involved the identification of pivotal factors contributing to TMAs, such as the complement system, ADAMTS13, and the soluble VEGF receptor Flt1. Regardless of the specific causal factor (which is not generally unique in relation to the usual multifactorial origin of TMAs), the endothelial cell stands as a central player in the pathophysiology of TMAs. Pregnancy has a major impact on the physiology of the endothelium. Besides to the development of placenta and its vascular consequences, pregnancy modifies the characteristics of the women's microvascular endothelium and tends to render it more prone to thrombosis. This review aims to delineate the distinct features of pregnancy-related TMAs and explore the contributing mechanisms that lead to this increased susceptibility, particularly influenced by the "gravid endothelium." Furthermore, we will discuss the potential contribution of histopathological studies in facilitating the etiological diagnosis of pregnancy-related TMAs.

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Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

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Background: A disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS-13) is the specific von Willebrand factor-cleaving protease and circulates in a closed and latent conformation due to a spacer/CUB1 domain interaction. ADAMTS-13 is allosterically activated after binding of its substrate or antibodies, inducing an open conformation. Recently, we suggested a potential role of plasmin (fibrinolysin) in hemostasis disorders reported in most patients with hemophagocytic lymphohistiocytosis (HLH), a rare and life-threatening condition related to a severe systemic inflammatory state. Most patients with HLH had a partial ADAMTS-13 deficiency, and plasmin could induce a truncation of the C-terminal part of ADAMTS-13 and thus an open conformation. Objectives: To understand the effect of plasmin on ADAMTS-13, our study aimed to investigate ADAMTS-13 conformation in patients with HLH. Methods: Forty-five critically ill patients with HLH were prospectively enrolled between April 2015 and December 2018. ADAMTS-13 activity was measured by fluorescent resonance energy transfer-VWF73 assay, ADAMTS-13 antigen, and conformation with our homemade 3H9-enzyme-linked immunosorbent assay and 1C4-enzyme-linked immunosorbent assay. Results: ADAMTS-13 activity ranged from <10 to 65 IU/dL, and 41 of the 45 patients had a quantitative deficiency in ADAMTS-13 (activity <50 IU/dL). Twenty patients had a severe ADAMTS-13 deficiency (activity <20 IU/dL). ADAMTS-13 conformation was folded in all patients under normal conditions. Surprisingly, the switch of ADAMTS-13 conformation expected with the monoclonal antibody 17G2 (anti-CUB1) was disturbed in 6 patients (activity <20 IU/dL). Conclusion: Our study reported that ADAMTS-13 conformation is closed in HLH and provides an indirect proof that plasmin is not able to massively degrade ADAMTS-13. Further studies on glycosylation and citrullination profiles of ADAMTS-13 are needed to understand their role in HLH.

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Atypical hemolytic uremic syndrome, a rare thrombotic microangiopathy, necessitates early diagnosis and comprehensive care due to its potential severity, emphasizing the importance of a multidisciplinary approach to improve outcomes.

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Objective:To investigate the effectiveness and safety of plasma exchange for thrombotic microangiopathy and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which require renal replacement therapy.Methods:This is a retrospective study. The clinical data of four patients who underwent plasma exchange at the Blood Purification Center, North Branch of the First Affiliated Hospital of Anhui Medical University, from June 2021 to February 2022 were collected and analyzed. The records included a total of 19 treatments performed, including 15 treatments with a single plasma exchange regimen used in 3 patients and 4 treatments with double filtration plasmapheresis used in 1 patient. Changes in condition before and after treatment, as well as corresponding biochemical test results, were recorded.Results:In four patients, clinical symptoms and biochemical indicators improved. Three patients required maintenance hemodialysis, while one patient showed remarkable clinical efficacy. After treatment, hemoglobin level increased from 76 g/L to 83 g/L, blood creatinine level decreased from 703.6 μmol/L to 526.2 μmol/L, anti-SM antibody decreased from > 400 RU/mL to < 2 RU/mL, anti-myeloperoxidase antibody decreased from 255.49 RU/mL to 15.64 RU/mL, and perinuclear anti-neutrophil cytoplasmic antibody turned negative. During treatment, there were two cases of allergic reactions, which were significantly alleviated after treatment.Conclusion:Plasma exchange is safe and effective against thrombotic microangiopathy and anti-neutrophil cytoplasmic antibody-associated vasculitis, which require renal replacement therapy.

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ABSTRACT Objective: To report a pediatric case of drug-induced thrombotic microangiopathy caused by cocaine Case description: We report a nine-month-old patient who developed thrombotic microangiopathies after extreme cocaine intoxication, multiple organ dysfunction syndrome with hemodynamic dysfunction, anuric renal failure, liver failure, encephalopathy, and myocardial injury, corresponding phenotypically to thrombocytopenia-associated multiple organ failure. The patient received continuous venous hemofiltration and therapeutic plasma exchange, recovering satisfactorily. She was discharged after 30 days of hospitalization under the guidance of the childcare service, and was healthy after one year of follow-up. Toxicological samples confirmed high levels of cocaine and derivatives in blood, urine and hair. Comments: To our knowledge, this is the first reported pediatric case. There are particularities of cocaine intoxication pathophysiology that can trigger thrombotic microangiopathies because of vasoconstriction, direct endothelial injury, platelet activation, and increasing von Willebrand factor and fibrinogen levels. All of which results in a prothrombotic state, inflammatory dysregulation, and microvascular thrombi. The increasing use of cocaine, especially among young adults, puts children at high risk of toxicity, either by passive unintentional exposure, or abuse due to the increased availability in homes.

RESUMO Objetivo: Relatar um caso pediátrico de microangiopatia trombótica induzida por drogas causada por cocaína Descrição do caso: Relatamos uma paciente de nove meses de idade que desenvolveu microangiopatia trombótica após intoxicação extrema por cocaína, síndrome de disfunção de múltiplos órgãos com disfunção hemodinâmica, insuficiência renal anúrica, insuficiência hepática, encefalopatia e lesão miocárdica, correspondendo fenotipicamente à falência múltipla de órgãos associada à trombocitopenia. A paciente recebeu hemofiltração venosa contínua e plasmaférese terapêutica, recuperando-se satisfatoriamente. Recebeu alta após 30 dias de internação sob orientação do serviço de puericultura e estava saudável após um ano de seguimento. Amostras toxicológicas confirmaram altos níveis de cocaína e derivados no sangue, urina e cabelos. Comentários: Até onde sabemos, este é o primeiro caso pediátrico relatado. Existem particularidades da fisiopatologia da intoxicação por cocaína que podem desencadear a microangiopatia trombótica devido à vasoconstrição, lesão endotelial direta, ativação plaquetária e aumento do fator de von Willebrand e dos níveis de fibrinogênio. Tudo isso resulta em um estado pró-trombótico, desregulação inflamatória e trombos microvasculares. O uso crescente de cocaína, principalmente entre adultos jovens, coloca as crianças em alto risco de toxicidade, seja por exposição passiva não intencional ou abuso devido à maior disponibilidade nas residências.

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Introduction: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy associated with severe ADAMTS13 deficiency that can be potentially fatal if not treated in a timely manner. Case report: A 49-year-old previously healthy woman was admitted with a 3-month history of thoracoabdominal pain and headache associated with loss of appetite, emesis, nocturnal diaphoresis, and unintentional loss of 10 kg. On admission she presented anemia, thrombocytopenia, schistocytes in peripheral blood smear, and ADAMTS13 in 1.4%. Due to laboratory findings a diagnosis of TTP was established, and plasma exchange therapy and steroid pulses were started, with resolution of hematological alterations. Within the studies to determine etiology of TTP, pulmonary tuberculosis (TB) was found, neoplastic and autoimmune pathologies were excluded. The tetraconjugated treatment was initiated with optimal tolerance. Conclusions: Upon clinical suspicion of TTP, plasma exchange therapy should be initiated urgently; infectious, neoplastic, or autoimmune pathologies can be triggers; in this case, pulmonary TB was confirmed.

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Thrombotic Thrombocytopenic Purpura (TTP) is a subtype of thrombotic microangiopathy (TMA) resulting in thrombocytopenia, anemia, fever, renal and neurological deficits. Although many drugs have been associated with drug-induced TTP, ceftriaxone has never been reported. Our case reports a patient who was started on ceftriaxone and developed TTP. Peripheral smear showed schistocytes and thrombocytopenia. Surprisingly, antibody formation against the metalloproteinase (ADAMTS13) levels were low-normal. The patient was treated with plasmapheresis and eczulimab, leading to platelet recovery and symptom resolution. TTP is a rare disorder and can be acquired or idiopathic. TTP can be diagnosed with normal ADAMTS13 as well. Further research is required to assess the mechanism by which ceftriaxone causes TTP. Physicians should consider the possibility of TTP in patients with similar presentations following ceftriaxone therapy and use it for timely diagnosis and treatment. Early diagnosis and treatment of ceftriaxone-induced TTP can prevent devastating consequences.

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Hereditary thrombotic thrombocytopenic purpura (hTTP), also known as Upshaw-Schulman syndrome, is a rare genetic disorder caused by mutations in the ADAMTS13 gene that leads to decreased or absent production of the plasma von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13. The result is circulating ultra-large multimers of VWF that can cause microthrombi, intravascular occlusion and organ damage, especially at times of turbulent circulation. Patients with hTTP may have many overt or clinically silent manifestations, and a high index of suspicion is required for diagnosis. For the treatment of hTTP, the goal is simply replacement of ADAMTS13. The primary treatment is prophylaxis with plasma infusions or plasma-derived factor VIII products, providing sufficient ADAMTS13 to prevent acute episodes. When acute episodes occur, prophylaxis is intensified. Recombinant ADAMTS13, which is near to approval, will immediately be the most effective and also the most convenient treatment. In this review, we discuss the possible clinical manifestations of this rare disease and the relevant differential diagnoses in different age groups. An extensive discussion on prophylaxis and treatment strategies is also presented. Unique real patient cases have been added to highlight critical aspects of hTTP manifestations, diagnosis and treatment.

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La púrpura trombótica trombocitopénica es una entidad poco frecuente en pediatría, pero de alta mortalidad sin tratamiento adecuado y oportuno. Se caracteriza por presentar anemia hemolítica microangiopática asociada a signos y síntomas neurológicos, cardíacos, abdominales y menos frecuentemente renales; puede estar acompañada de fiebre. En niños, el diagnóstico se basa en los hallazgos clínicos y de laboratorio. La actividad de ADAMTS13 <10 % apoya, pero no confirma el diagnóstico y, dada la gravedad de la patología, el resultado no debe retrasar el inicio del tratamiento. Se presenta una paciente de 15 años, previamente sana, con signos neurológicos asociados a anemia hemolítica y trombocitopenia. Durante su internación, se arribó al diagnóstico de púrpura trombótica trombocitopénica adquirida.

Thrombotic thrombocytopenic purpura is a rare disease in pediatrics, but it has a high mortality if not managed in an adequate and timely manner. It is characterized by microangiopathic hemolytic anemia associated with neurological, cardiac, abdominal, and less frequently, renal signs and symptoms; it may be accompanied by fever. In children, diagnosis is based on clinical and laboratory findings. ADAMTS13 activity < 10% supports the diagnosis but does not confirm it and, given its severity, the result should not delay treatment initiation. Here we describe the case of a previously healthy 15-year-old female patient with neurological signs associated with hemolytic anemia and thrombocytopenia. During hospitalization, she was diagnosed with acquired thrombotic thrombocytopenic purpura.

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Radiation nephropathy is a rare complication following total body irradiation (TBI) and peptide receptor radionuclide therapy (PRRT). Yttrium 90-DOTATOC (Y90) is a somatostatin analogue labelled with Y90 used for somatostatin-positive neuroendocrine tumours. Y90 is renally excreted and has a cumulative effect in the renal parenchyma Despite fractionation and co-administration of renoprotective intravenous amino acids, targeted radionuclide therapy can still be nephrotoxic. Rising adoption of PRRT has led to the re-emergence of radiation nephropathy. We report on three recent cases of insidious onset of progressive kidney dysfunction and biopsy-proven thrombotic microangiopathy following PRRT and TBI.

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AIM: Although perinatal thrombotic microangiopathy has become increasingly understood, the racial characteristics of patients with this condition remain unclear. Herein, we report the characteristics of patients with perinatal thrombotic microangiopathy at a single institution in Japan. METHODS: We conducted a retrospective study over a 5-year period from January 1, 2017, to December 31, 2021, using the electronic medical records of pregnant women who delivered at the perinatal center of our hospital. We extracted the data of those who developed perinatal thrombotic microangiopathy and evaluated their characteristics at the time of disease onset, final diagnosis, and maternal and fetal outcomes. RESULTS: Of the 10 224 deliveries that occurred during the 5-year period, only seven patients (0.06%) had perinatal thrombotic microangiopathy. The median pre-pregnant body mass index was 18.65 kg/m2 (minimum 17.3 kg/m2 , maximum 20.7 kg/m2 ). More than half of the patients were conceived by in-vitro fertilization, and 42% these had twin deliveries. Four patients had a history of rheumatic disease. The other three patients without underlying diseases developed thrombotic microangiopathy with HELLP syndrome, and one patient transitioned to atypical hemolytic uremic syndrome. CONCLUSIONS: Based on low body mass index and in-vitro fertilization, which are characteristic of Japanese women, medical complications and twin pregnancies may be a risk for thrombotic microangiopathy. Additionally, depending on the cause of thrombotic microangiopathy, its timing and onset differed.

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Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications after allogeneic hematopoietic cell transplantation (allo-HCT). Diagnosing TA-TMA is challenging because of the lack of standardized criteria. In this study, we aimed to evaluate the new TA-TMA consensus definition from the American Society for Transplantation and Cellular Therapy (ASTCT) panel as part of an ongoing prospective pediatric cohort study, and also to compare the impact and outcomes of using the current definition of clinical TMA (cTMA) versus the new consensus definition. We included patients age 0 to 18 years who underwent their first allo-HCT between May 2021 and January 2023 at Texas Children's Hospital. We compared the incidence, biomarkers, and outcomes of TA-TMA applying the previous and recently proposed screening algorithms and definitions. Whereas use of the classic microangiopathic hemolytic anemia (MAHA)-based cTMA definition led to an incidence of 12.7% by day 100 post-transplantation, the ASTCT-HR definition doubled the incidence to 28.5% by day 100. In contrast to patients with a concordant diagnosis (+/+), who had significantly worse post-transplantation survival, those reclassified as TA-TMA only by the new definition (-/+) had a significantly different prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Furthermore, biomarkers of the terminal and alternative complement pathways (sC5b9 and Ba, respectively) were significantly elevated compared with non-TMA patients around day 15 in the concordant group (+/+) but not in the discordant group (-/+). The recently proposed ASTCT consensus TA-TMA diagnosis is more sensitive and allows earlier recognition of manifestation that requires closer clinical monitoring but risks overdiagnosis and overtreatment. We recommend additional prospective validation.

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