Thrombotic Thrombocytopenic Purpura: 100 Years of Research on Moschcowitz's Syndrome.

In the 100 years since Dr. Eli Moschcowitz reported the first case of thrombotic thrombocytopenic purpura (TTP), there has been remarkable awareness and progress in the diagnosis and management of this rare blood disorder. This progress initially was the result of careful clinical observations followed by well thought-out therapeutic interventions, with dual goals of both improving outcomes and discerning the pathophysiology of TTP. The discovery of the ADAMTS13 protease set in motion efforts to more accurately define the specific etiologies of thrombotic microangiopathies (TMA) based on objective, scientific data rather than clinical characterizations alone. This accurate differentiation led to better and more revealing clinical trials and advancements in the treatment of TTP and other TMA. Further advances followed and included improvements in immune suppressive therapy and targeted therapies of immune-mediated TTP (iTTP) (caplacizumab) and congenital TTP (cTTP) (recombinant ADAMTS13). The longitudinal study of TTP patients revealed the unexpected risk for long-term complications in both iTTP and cTTP patients in remission. Ongoing studies aim to further understand the prevalence, mechanisms, and appropriate screening for these mood disorders, neurocognitive deficits, and cardiovascular complications that develop at remarkably high rates, and are associated with a decreased life expectancy. These discoveries are a result of the collaborative efforts of investigators worldwide that have been fostered by the frequent interactions of investigators via the International TTP Working Group meetings and TMA workshops held regularly at international meetings. These efforts will support the rapid pace of discovery and improved understanding of this rare disease.

Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known. METHODS: In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment. RESULTS: A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy. CONCLUSIONS: During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.).

A machine learning approach to predict mortality due to immune-mediated thrombotic thrombocytopenic purpura.

Background: Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models. Objectives: To validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index. Methods: We analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm. Results: In our cohort (n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively. Conclusion: The USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare.

The latest insights into rare blood disorders: Diagnosis and treatment strategies.

Please visit https://bit.ly/AJHpodcast to complete the accredited learning activity and receive CME credit or NCPD contact hours. Because immune-mediated rare blood disorders are uncommon, healthcare providers often lack the knowledge and experience necessary to identify, diagnose, and treat them in accordance with best practices. As a result, there are significant gaps in care, including delays in diagnosis and suboptimal treatment. To ensure that more patients with these rare disorders are offered quality, evidence-based care, it is essential that healthcare providers possess up-to-date information about best practices and new developments in this area of medicine. In this activity, composed of three podcasts, an expert moderator will interview three expert faculty members about evidence-based guidelines for the diagnosis and treatment of acquired thrombotic thrombocytopenic purpura; developments in the diagnosis and treatment of cold agglutinin disease; and the challenges of achieving enduring remission in patients with immune thrombocytopenia.

Thrombotic Complications in Immune Thrombocytopenia Patients Treated with Avatrombopag.

Avatrombopag is a novel oral non-peptide thrombopoietin receptor agonist (TPO-RA) that was approved by the FDA as a second-line therapy for chronic immune thrombocytopenia (cITP). Avatrombopag has shown promising results in regards to efficacy and tolerability, but to our knowledge, there are no reports of thrombotic complications associated with avatrombopag. We present two patients with chronic ITP who suffered thromboembolic events shortly after starting treatment with avatrombopag. The first case is that of a 30-year-old female with refractory cITP who failed multiple lines of ITP therapy and was hospitalized with an intracranial bleed. The patient eventually recovered after an emergent splenectomy but subsequently developed a right lower lobe pulmonary embolism three weeks after starting treatment with avatrombopag. The second case is that of a 58-year-old female with a prolonged history of ITP, and no prior history of peripheral vascular disease, who suffered from both arterial and venous thrombotic events four weeks after starting avatrombopag. Given the new arterial and venous thrombotic complications, avatrombopag was stopped. She was challenged with avatrombopag again and developed yet another thrombotic complication.

Five years of caplacizumab - lessons learned and remaining controversies in immune-mediated thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare hematologic disease caused by autoantibodies against ADAMTS-13 that trigger microangiopathic hemolytic anemia. Therapeutic plasma exchange and glucocorticoids have been the mainstay of treatment for the past 30 years. In 2019, caplacizumab was approved as an addition to this regimen for the acute treatment of iTTP. Randomized controlled trials and real-world evidence have shown that caplacizumab reduces the time to platelet count normalization, refractoriness, and exacerbations of the disease, with an acceptable safety profile. In the past 5 years, there have been arguments against the upfront use of caplacizumab in all patients with iTTP, particularly related to the perceived lack of clinical benefit, safety concerns related to bleeding risk, and high costs. This perspective aimed to address these concerns in the context of the experience of expert centers that have used the drug for >5 years.

Race, rituximab, and relapse in TTP.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.

How I treat immune-mediated thrombotic thrombocytopenic purpura after hospital discharge.

Immune-mediated thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy characterized by an acquired ADAMTS13 deficiency as a result of the presence of an antibody inhibitor of ADAMTS13 leading to the formation of ultralarge von Willebrand multimers. Treatment of iTTP includes plasma exchange, high-dose glucocorticoids, rituximab, and, more recently, caplacizumab, to prevent the development of exacerbations. There is the risk of both relapse and long-term complications that include neurocognitive deficits and cardiovascular events that occur in patients in remission after recovery from an acute iTTP episode. Data on the risk factors for the development of these complications, the appropriate screening, and treatment are limited due to the paucity of research. This article is a review of the current understanding on the risk factors for exacerbation, relapse, and long-term complications of iTTP and discusses an approach to observing patients with iTTP after hospital discharge and during the long-term follow-up in the outpatient setting.

Clinical relapse of immune-mediated thrombotic thrombocytopenic purpura following COVID-19 vaccination.

De novo and relapsed immune-mediated thrombotic thrombocytopenic purpura (iTTP) have been documented to have occurred following severe acute respiratory syndrome coronavirus 2 (COVID-19) vaccination. Here, we present a case of a 28-year-old woman who received the tozinameran (BNT162b2, Pfizer-BioNtech) vaccine for COVID-19 and experienced an iTTP relapse during longitudinal follow-up. She received the vaccine 30 months after her initial diagnosis, while she was in clinical remission. She was not in complete ADAMTS-13 remission, as she had undetectable ADAMTS-13 activity during follow-up except for one isolated measurement of 48%. Shortly after vaccination, she developed complaints of bruising, petechiae, ataxia, and an episode of slurred speech. Laboratory testing demonstrated thrombocytopenia, schistocytes, and eventually undetectable ADAMTS-13 activity. She was successfully treated with caplacizumab, rituximab, and corticosteroids without plasma exchange. She achieved complete clinical and ADAMTS-13 remission after treatment. We recommend caution in the administration of COVID-19 vaccines for survivors of iTTP in remission with severely deficient ADAMTS-13 activity.

Cardiovascular disease is a leading cause of mortality among TTP survivors in clinical remission.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors experience high rates of adverse health sequelae and increased mortality over long-term follow-up. We conducted this multicenter cohort study to evaluate long-term mortality and causes of death in iTTP survivors. Between 2003 and 2020, 222 patients were enrolled in the Ohio State University and Johns Hopkins TTP registries and followed for a median of 4.5 (interquartile range [IQR], 75 0.4-11.5) years. Nine patients died during their first iTTP episode, and 29 patients died during follow-up. Mortality rate was 1.8 times higher than expected from an age-, sex-, and race-adjusted reference population. Cardiovascular disease was a leading primary cause of death (27.6%) tied with relapsed iTTP (27.6%), followed by malignancy (20.7%), infection (13.8%), and other causes (10.3%). Male sex (hazard ratio [HR], 3.74; 95% confidence interval [CI], 1.65-8.48), increasing age (HR, 1.04; 95% CI, 1.01-1.07), and number of iTTP episodes (HR, 1.10; 95% CI, 1.01-1.20) were associated with mortality in a model adjusted for African American race (HR, 0.70; 95% CI, 0.30-1.65), hypertension (HR, 0.47; 95% CI, 0.20-1.08), chronic kidney disease (HR 1.46; 95% CI, 0.65-3.30), and site (HR, 1.46; 95% CI, 0.64-3.30). There was a trend toward shorter survival in patients with lower ADAMTS13 activity during remission (P = .078). Our study highlights the need for survivorship care and investigation focused on cardiovascular disease and early mortality in TTP survivors.

Major adverse cardiovascular events in survivors of immune-mediated thrombotic thrombocytopenic purpura.

Cardiovascular disease is a leading cause of death in survivors of immune-mediated thrombotic thrombocytopenic purpura (iTTP), but the epidemiology of major adverse cardiovascular events (MACE) in iTTP survivors is unknown. We evaluated the prevalence and risk factors for MACE, defined as the composite of non-fatal or fatal myocardial infarction (MI), stroke, and cardiac revascularization, during clinical remission in two large iTTP cohorts (Johns Hopkins University and Ohio State University). Of 181 patients followed for ≥ 3 months after recovery from acute iTTP, 28.6% had a MACE event over a median follow up of 7.6 years. Stroke was the most common type of MACE (18.2%), followed by non-fatal MI (6.6%), cardiac revascularization (4.9%) and fatal MI (0.6%). Compared to the general United States population, iTTP survivors were younger at first stroke in remission (males [56.5 years vs. 68.6 years, p = 0.031], females [49.7 years vs. 72.9 years, p < 0.001]) or MI in remission (males [56.5 years vs. 65.6 years, p < 0.001] and females [53.1 years vs. 72.0 years, p < 0.001]). Age (HR 1.03 [95% CI 1.002-1.054]), race (Black/Other vs. White) (HR 2.32 [95% CI 1.12-4.82]), and diabetes mellitus (HR 2.37 [95% CI 1.09-0.03]) were associated with MACE in a Cox regression model also adjusted for sex, hypertension, obesity, hyperlipidemia, chronic kidney disease, atrial fibrillation, autoimmune disease, and relapsing iTTP. Remission ADAMTS13 activity was not significantly associated with MACE. In conclusion, iTTP survivors experience high rates of MACE and may benefit from aggressively screening for and managing cardiovascular risk factors.

Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management.

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic end organ injury due to microvascular platelet-rich thrombi. TTP results from a severe deficiency of the specific von Willebrand factor (VWF)-cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). ADAMTS13 deficiency is most commonly acquired due to anti-ADAMTS13 autoantibodies. It can also be inherited in the congenital form as a result of biallelic mutations in the ADAMTS13 gene. In adults, the condition is most often immune-mediated (iTTP) whereas congenital TTP (cTTP) is often detected in childhood or during pregnancy. iTTP occurs more often in women and is potentially lethal without prompt recognition and treatment. Front-line therapy includes daily plasma exchange with fresh frozen plasma replacement and immunosuppression with corticosteroids. Immunosuppression targeting ADAMTS13 autoantibodies with the humanized anti-CD20 monoclonal antibody rituximab is frequently added to the initial therapy. If available, anti-VWF therapy with caplacizumab is also added to the front-line setting. While it is hypothesized that refractory TTP will be less common in the era of caplacizumab, in relapsed or refractory cases cyclosporine A, N-acetylcysteine, bortezomib, cyclophosphamide, vincristine, or splenectomy can be considered. Novel agents, such as recombinant ADAMTS13, are also currently under investigation and show promise for the treatment of TTP. Long-term follow-up after the acute episode is critical to monitor for relapse and to diagnose and manage chronic sequelae of this disease.

Redefining outcomes in immune TTP: an international working group consensus report.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission, and relapse were initially proposed in 2003 and modified by the International Working Group for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects on the platelet count of caplacizumab, a novel anti-von Willebrand factor (VWF) nanobody. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy, by using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE but also that of anti-VWF therapy. Retrospective validation of the revised definitions is described, although they have yet to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided to highlight their clinical relevance.

ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.

BACKGROUND: Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its appropriate treatment. METHODS: In June 2018, the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to immune-mediated TTP (iTTP) and hereditary or congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations. RESULTS: The panel agreed on 11 recommendations based on evidence ranging from very low to moderate certainty. For first acute episode and relapses of iTTP, the panel made a strong recommendation for adding corticosteroids to therapeutic plasma exchange (TPE) and a conditional recommendation for adding rituximab and caplacizumab. For asymptomatic iTTP with low plasma ADAMTS13 activity, the panel made a conditional recommendation for the use of rituximab outside of pregnancy, but prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, and a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy. CONCLUSIONS: The panel's recommendations are based on all the available evidence for the effects of an individual component of various treatment approaches, including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing the formation of ADAMTS13 autoantibody. There was insufficient evidence for further comparing different treatment approaches (eg, TPE, corticosteroids, rituximab, and caplacizumab, etc.), for which high quality studies are needed.

Good practice statements (GPS) for the clinical care of patients with thrombotic thrombocytopenic purpura.

BACKGROUND: Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its management. METHODS: In June 2018, the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to both immune-mediated TTP (iTTP) and hereditary/congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations. RESULTS: The panel agreed on eleven recommendations based on evidence ranging from very low to moderate certainty. For first episode and relapses of acute iTTP, the panel made a strong recommendation for the addition of corticosteroids to therapeutic plasma exchange (TPE), and a conditional recommendation for addition of rituximab and caplacizumab. For asymptomatic iTTP with low ADAMTS13, the panel made a conditional recommendation for rituximab outside of pregnancy, and for prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, but a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy. CONCLUSIONS: The panel's recommendations are based on all the available evidence for the treatment effects of various approaches including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing ADAMTS13 antibody production. There was insufficient evidence for further comparison of different treatment approaches, for which future high-quality studies in iTTP (e.g., rituximab, corticosteroids, recombinant ADAMTS13, and caplacizumab) and in cTTP (eg, recombinant ADAMTS13) are needed.

ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.

BACKGROUND: Despite an increase in our understandings of pathogenesis of thrombotic thrombocytopenic purpura (TTP), the approaches for initial diagnosis and management of TTP vary significantly. OBJECTIVE: The evidence-based guidelines of the International Society on Thrombosis and Haemostasis (ISTH) are intended to support patients, clinicians, and other health care professionals in their decisions about the initial diagnosis and management of acute TTP. METHODS: In June 2018, ISTH formed a multidisciplinary panel that included hematologists, an intensive care physician, nephrologist, clinical pathologist, biostatistician, and patient representatives, as well as a methodology team from McMaster University. The panel composition was designed to minimize the potential conflicts of interests. The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach and the Population, Intervention, Comparison, Outcome framework to develop and grade their recommendations. Public comments were sought and incorporated in the final document. RESULTS: The panel agreed on three recommendations covering the initial diagnosis with emphasis on the importance of ADAMTS13 testing (eg, activity, anti-ADAMTS13 IgG or inhibitor) and assessment of the pretest probability of TTP by clinical assessment and/or the risk assessment models like the PLASMIC or French score. The panel noted how availability and turnaround time of ADAMTS13 test results might affect early diagnosis and management, in particular the use of caplacizumab. CONCLUSIONS: There is a lack of high-quality evidence to support strong recommendations for the initial diagnosis and management of a suspected TTP. The panel emphasized the importance of obtaining ADAMTS13 testing in a proper clinical context. Future research should focus on how to monitor and act on ADAMTS13 levels during remission.

Atypical haemolytic uraemic syndrome: a case report of a rare cause of reversible cardiomyopathy.

BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is a life-threatening, genetic disease of complement-mediated thrombotic microangiopathy that typically presents as anaemia, thrombocytopenia, and renal failure. Cardiomyopathy is seen in up to 10% of aHUS cases, but the aetiology is not well-understood. CASE SUMMARY: A 63-year-old man recently was diagnosed with a thrombotic microangiopathy most consistent with aHUS by renal biopsy after presentation with acute renal failure requiring haemodialysis. He was started on therapy with complement inhibitor, eculizumab. Six weeks after diagnosis, he presented with progressive dyspnoea on exertion and chest pain. An echocardiogram demonstrated an acute drop in left ventricular ejection fraction to 20-25% with global hypokinesis. Left heart catheterization showed moderate, non-obstructive coronary artery disease. Cardiac magnetic resonance imaging demonstrated diffuse myocardial oedema. Endomyocardial biopsy revealed an arteriole with obliterative changes and a few possible fragmented red blood cells suggestive of thrombotic microangiopathy. There was no biopsy evidence of immune complex deposition or myocarditis. He was treated for heart failure and was maintained on eculizumab. On repeat echocardiogram 3 months later, the patient had complete recovery of his ejection fraction (60-65%). DISCUSSION: In this report, we describe complete recovery of aHUS-associated heart failure with eculizumab therapy and demonstrate for the first time that the aetiology of aHUS-associated heart failure is likely an acute thrombotic microangiopathy involving small intramyocardial arterioles, as demonstrated by cardiac biopsy.