Microangiopathic Hemolytic Anemia Research Articles

The Role of the Complement System in the Pathogenesis of Infectious Forms of Hemolytic Uremic Syndrome.

Hemolytic uremic syndrome (HUS) is an acute disease and the most common cause of childhood acute renal failure. HUS is characterized by a triad of symptoms: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In most of the cases, HUS occurs as a result of infection caused by Shiga toxin-producing microbes: hemorrhagic Escherichia coli and Shigella dysenteriae type 1. They account for up to 90% of all cases of HUS. The remaining 10% of cases grouped under the general term atypical HUS represent a heterogeneous group of diseases with similar clinical signs. Emerging evidence suggests that in addition to E. coli and S. dysenteriae type 1, a variety of bacterial and viral infections can cause the development of HUS. In particular, infectious diseases act as the main cause of aHUS recurrence. The pathogenesis of most cases of atypical HUS is based on congenital or acquired defects of complement system. This review presents summarized data from recent studies, suggesting that complement dysregulation is a key pathogenetic factor in various types of infection-induced HUS. Separate links in the complement system are considered, the damage of which during bacterial and viral infections can lead to complement hyperactivation following by microvascular endothelial injury and development of acute renal failure.

Cancer-associated thrombotic microangiopathy; a review article

Cancer-associated thrombotic microangiopathy (TMA) is a rare but is a serious complication that can occur in individuals with malignancy. It is characterized by widespread small blood vessel thrombosis (formation of blood clots) in various organs of the body, leading to organ damage and dysfunction. The exact mechanisms underlying cancer-associated TMA are not fully understood. However, several factors may contribute to its development. Cancer cells can release procoagulant substances that promote blood clot formation, since some tumors can directly invade blood vessels, leading to endothelial cell damage and activation of the coagulation system. Additionally, certain chemotherapeutic agents used in cancer treatment can have adverse effects on the endothelium, further increasing the risk of TMA. Clinically, cancer-associated TMA presents with a range of symptoms depending on the organs affected. Common manifestations include microangiopathic hemolytic anemia, thrombocytopenia, and organ-specific symptoms such as neurological deficits, renal dysfunction, or cardiac abnormalities.

Complement Blockade, a New Therapeutic Approach in Malignant Hypertension

Abstract Atypical hemolytic uremic syndrome (aHUS) represents a major challenge due to its rare nature and severe impact on patients, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. This paper describes the case of a 41-year-old patient diagnosed with aHUS in the context of malignant arterial hypertension and severe renal impairment, manifested by anuria and significant azotemic retention syndrome. The complex management of the case, including the use of Eculizumab, a complement inhibitor, highlighted significant therapeutic benefits, especially in improving hematological parameters. Despite a positive response, challenges related to dosing, monitoring treatment efficacy, and maintaining remission without relapses emphasize the need for adapted therapeutic strategies and a deeper understanding of the disease mechanisms. This case also highlights the importance of individualized approaches and consideration of the possible benefits of dose adjustments based on specific clinical and pharmacological parameters, as well as continuous evaluation of treatment efficacy and safety, in the context of such a variable and potentially devastating syndrome as aHUS.

Clinical Evaluation and Management of Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) refers to a diverse group of diseases that share clinical and histopathologic features. TMA is clinically characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and organ injury that stems from endothelial damage and vascular occlusion. There are several disease states with distinct pathophysiological mechanisms that manifest as TMA. These conditions are associated with significant morbidity and mortality and require urgent recognition and treatment. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are traditionally considered to be primary forms of TMA, but TMA more commonly occurs in association with a coexisting condition such as infection, pregnancy, autoimmune disease, or malignant hypertension, among others. Determining the cause of TMA is a diagnostic challenge because of limited availability of disease-specific testing. However, identifying the underlying etiology is imperative as treatment strategies differ. Our understanding of the conditions that cause TMA is evolving. Recent advances have led to improved comprehension of the varying pathogenic mechanisms that drive TMA. Development of targeted therapeutics has resulted in significant improvements in patient outcomes. In this article, we review the pathogenesis and clinical features of the different TMA-causing conditions. We outline a practical approach to diagnosis and management and discuss empiric and disease-specific treatment strategies.

Low ADAMTS13 Activity in Patients with Liver Disease- Thrombotic Thrombocytopenic Purpura or Not?

Introduction: Patients with liver injury have hemostatic defects including reduced ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13). Severe deficiency of ADAMTS13 (ADMS13) activity (< 10%) is pathognomonic for thrombotic thrombocytopenic purpura (TTP), a rare thrombotic microangiopathy (TMA). Differentiating TTP from severe liver injury is complex for multiple reasons including 1) low baseline ADMS13 2) concomitant coagulopathies complicating differentiation from disseminated intravascular coagulation (DIC) 3) ADMS13 activity (ADMS13:AC) assay interference (hyperbilirubinemia (>30mg/dL) can cause artifactual reduction of ADMS13:AC). Here we sought to characterize the clinical presentation, management, and outcomes of patients with liver injury presenting with thrombocytopenia (TCP), microangiopathic hemolytic anemia (MAHA) and low ADMS13:AC at our institution. Methods: In this retrospective study, after IRB approval, electronic medical records (EMR) of institutional patients who had ADMS13:AC and inhibitor profile performed in our special coagulation laboratory between 2018 and July 17, 2023, were reviewed. Eligible patients had ADMS13:AC ≤20% were ≥ 18 years and had evidence of liver injury at time of ADMS13. Liver injury was defined as ALT or AST elevations greater than two times the upper level of normal within one month prior to ADMS13:AC testing, history of end stage liver disease or cirrhosis, or liver transplant with evidence of graft dysfunction. Details regarding clinical presentation, management and outcomes were extracted from the EMR. PLASMIC and ISTH DIC scores were retrospectively calculated. Results: 70 patients had at least one ADMS13:AC < 20% during the study period. 28/70 patients met liver injury inclusion criteria and 20/28 had TCP and MAHA. Of those 20 patients, median age at initial ADMS13:AC was 56.5 years (29-85). Most patients (n=14) had ADMS13:AC of 10-20%. ADMS13:AC was < 5% and 5-10% in 3 patients each. Eleven patients had a positive inhibitor with a median Bethesda titer of 1.85 BU (0.5-3.9). Etiology of liver included: ischemic hepatopathy (n=8), liver graft failure (n=4), liver metastasis (n=3), cirrhosis (n=2), alcoholic hepatitis (n=1), unknown (n=2). Median hemoglobin and platelet (plt) count at time of ADMS13 was 7 g/dL (6.4-13.2) and 30 x10 9/L (3-98), respectively. 7/20 patients had a PLASMIC score of ≥5; PLASMIC score was ≥5, in 2/6 patients with ADMS13:AC <10%. 16/18 patients had an ISTH DIC score ≥5. 18/20 patients had a creatinine > 2 mg/dL or were receiving renal replacement therapy the time of ADMS13: AC. 7/20 patients had total or direct bilirubin of >30mg/dL. Eight/20 patients were treated with plasma exchange (PEX) for a median duration of 7 days (2-13). 66.7% of pts with ADMS13:AC <10% received PEX. Glucocorticoids and Rituximab were used with the intent to treat TTP in 7 and 3 patients, respectively. Caplacizumab was used in 2 patients. 3/8 (37.5%) patients receiving PEX demonstrated normalization of MAHA. One of these patients demonstrated improvement but not normalization of plts (Table 1B, case 5). All patients had recurrence of hematologic abnormalities after PEX was stopped. One patient was treated with plasma infusion with stabilization in plt count. There were 13 and 15 deaths within 1 and 6 months of first ADMTS13:AC, respectively. One death was potentially attributable to management of TTP (Table 1B, case 1). There was no difference in time to death or mortality with the use of PEX. Repeat ADMS13:AC remote from PEX, TCP and MAHA was available for 1/5 surviving patients. This patient (Table1, case 2) had normalization of ADMS:AC after undergoing liver transplant. Conclusion: The differential diagnosis of TCP and MAHA in patients with liver injury includes hepatic dysfunction, DIC and TMA. In the current cohort, 89% of evaluable patients met criteria for overt DIC per ISTH criteria. Due to a low ADMTS13:AC, 40% of patients underwent a trial of PEX with 37.5% demonstrating improvement in MAHA that was not sustained upon discontinuation of PEX due to persistent liver dysfunction. Six-month mortality was 75% and use of PEX did not affect mortality. Given the high mortality, further studies evaluating which patients with TMA and liver injury are more likely to benefit from therapies typically used to treat TTP are necessary.

Prospective Clinical and Biomarker Validation of the ASTCT Consensus Definition for Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

Introduction: Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications post-hematopoietic cell transplantation (HCT). Diagnosing TA-TMA is challenging due to non-standardized criteria. The American Society for Transplantation and Cellular Therapy (ASTCT) has proposed new consensus diagnostic criteria for standard risk (ASTCT-SR) and high risk (ASTCT-HR) but their correlation with older criteria based on microangiopathic hemolytic anemia (MAHA) or diagnostic complement biomarkers used in previous TA-TMA studies, such as levels of the terminal complement activation product sC5b-9 and the alternative complement pathway activation product Factor Ba, is unknown. Using data and samples from an ongoing prospective pediatric cohort study, we compared the two definitions and their associations with biomarkers. Methods: Patients aged 0 to 18 years who underwent first allogeneic HCT 2021-2023 at Texas Children's Hospital were included in the clinical and biomarker study. Those who did not have at least 100-day post-HCT event-free follow-up were excluded. Two different definitions for TA-TMA were applied. Clinical TMA (cTMA) was diagnosed if a patient 1) met 4/4 concurrent criteria of MAHA (schistocytosis, thrombocytopenia, anemia, and elevated lactate dehydrogenase (LDH)) at least twice in 14 days and 2) clinically adjudicated to exclude known mimics or alternative causes of TMA. In contrast, ASTCT-HR TMA was diagnosed if a patient 1) met 4/7 non-concurrent criteria (schistocytosis, thrombocytopenia, anemia, elevated LDH, elevated blood pressure, elevated urinary protein excretion, and elevated sC5b9) at least twice in 14 days and 2) had evidence of LDH >2x normal, proteinuria ≥1 mg/mg, elevated sC5b9, acute graft-versus-host disease, active bacterial/viral infection, or end-organ damage. Cumulative incidence of TA-TMA was assessed by the competing risk method. Overall survival was compared by the Kaplan Meier estimator and log-rank test. Biomarker levels for samples collected at day 15 (+/- 14 days) were compared using the t-test. Results: A total of 32 patients met the inclusion criteria. The median age was 5.7 years (range 1.1-18.8) and most were White (68.8%) and Hispanic (56.2%). Malignant disease was the indication for HCT in 50% of patients. While the classic MAHA-based cTMA definition had an incidence of 12.7%, the newly proposed ASTCT-HR definition doubled it to 28.5% by day-100 (Figure 1). In contrast to patients with concordant TA-TMA diagnosis (+/+) who had significantly worse post-transplant survival (p=0.0047) compared with those with concordant non-TMA (-/-), those reclassified as TA-TMA by the new definition only (-/+) had an unexpectedly good prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Longitudinal biomarker analysis was conducted on 29 patients. The highest average plasma levels of sC5b-9 and Ba during the first 100 days were observed in patients meeting both cTMA and ASTCT-HR criteria (+/+). When focused on early biomarkers measured around day 15, sC5b-9 (P=0.041) and Ba (P=0.004) were significantly elevated in the doubly positive TMA group (+/+) vs. non-TMA group (-/-) (Figure 2). We did not observe significant differences for ASTCT-HR singly positive (-/+) vs. non-TMA group (-/-). Conclusions: In the current prospective clinical and biomarker study, the recently proposed ASTCT-HR definition was more sensitive but less prognostic than the traditional cTMA definition for TA-TMA. Patients who solely met the ASTCT-HR diagnostic criteria but not the cTMA criteria had benign complement biomarker profiles and excellent survival prognosis without TMA-directed therapy. While clinicians need to be vigilant for this infrequent yet potentially severe complications, it is crucial that diagnostic criteria accurately identify affected patients given the expense and potential complications of treatment. We recommend ongoing validations of the new consensus diagnostic criteria from other prospective cohort studies with larger sample sizes and extended follow-up.

Pregnancy and Immune Mediated Thrombotic Thrombocytopenic Purpura (iTTP); A Descriptive Analysis from the U.S. Thrombotic Microangiopathy (USTMA) Registry

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is defined by thrombocytopenia and microangiopathic hemolytic anemia without an alternative explanation, confirmed by severely deficient ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) to <10%. It is caused by autoantibodies against the ADAMTS13 protease. Pregnancy can precipitate iTTP, but the diagnosis and treatment are challenging, since it is often difficult to differentiate from other TMAs associated with pregnancy The aim of this study was to describe the clinical presentation, treatment, and outcomes of pregnancy related iTTP. Methods: Data was obtained from the USTMA retrospective database, including 15 large USTMA referral centers. Patients were identified based on the diagnosis of iTTP provoked by pregnancy between 9/6/1990 and 6/18/2018. The study cohort included participants with a clinical diagnosis of iTTP, confirmed by ADAMTS13 activity <10% who had a pregnancy or recent delivery within 30 days of presenting with iTTP. For participants diagnosed before the ADAMTS13 assay was developed (2006), the iTTP diagnosis was based on the clinical course and absence of alternative causes. iTTP exacerbation was defined as clinical disease recurrence within 30 days of PLEX (plasma exchange) discontinuation, and clinical relapse was defined as disease recurrence after 30 days of last PLEX. Maternal and fetal outcomes were additionally collected from 7/15 sites. Results: 42 patients had 55 iTTP episodes provoked by pregnancy. Median age for patients was 29. Sixteen (38.1%) were white, 20 (47.6%) were black. The most common presenting symptoms were headache and fatigue in 11/55 (20%) episodes. Thirty nine (70.9%) episodes had a platelet count <30 x10 9/L, and 46 (83.6%) had laboratory findings concerning for hemolysis as evidenced by elevated lactate dehydrogenase (LDH) and/or schistocytes present on peripheral smear. Only 5 (9%) episodes presented with a creatinine >2 mg/dL. ADAMTS13 activity was documented in 33 (60%) episodes and was <10% in 30 (90.9%) (Table 1). Treatment with PLEX was described in 30 (54.5%) episodes with a median duration of 6 days (2-26 days). Further immunosuppression included prednisone in 38 (69.1%) episodes and rituximab in 11 (20%), of which 7 (63.6%) had no future exacerbations or relapses during the study period.Seventeen (40.5%) patients had a prior diagnosis of iTTP. There were 10 exacerbations in 8 patients (19%), and 34 relapses in 13 (30%) patients after the 55-pregnancy provoked iTTP episodes. Five of those relapses were triggered again by pregnancy. Pregnancy related outcomes were obtained in 16 patients. Twenty five percent (4/16) of patients had a prior history of iTTP; median time of last iTTP to current presentation was 34 months (10-108). Of 16 patients, iTTP occurred with first pregnancy in 8 patients. Of the remaining eight patients, iTTP occurred in the eleventh (n=1), ninth (n=1), sixth (n=1), fifth (n=1), fourth (n=2), and unknown (n=2) pregnancy. Only 13 of 16 patients had further pregnancy specific outcomes available (Table 2). Preeclampsia was noted in 3 patients. Seven and 1 patients, presented with iTTP within 30 days postpartum or after miscarriage, respectively. The remaining patients (n=5) developed iTTP during the antepartum period. Of these, 2 pregnancies were terminated due to iTTP (second trimester and third trimester). One of the three remaining pregnancies resulted in fetal demise at 24 weeks. The latter two patients delivered healthy infants. There were no maternal deaths in our cohort. Conclusions: This is first multicenter descriptive analysis of pregnancy related iTTP from the USTMA registry. The clinical presentation of this cohort is consistent with iTTP triggered by other causes, and the low rate of acute kidney injury is helpful in identifying iTTP from other TMAs in pregnancy. We observed that pregnancy is a risk not only for acute episodes of iTTP in first pregnancy, but also in subsequent pregnancies and in the relapse setting of those with previous diagnosis of iTTP. While there was a 20% and 30% exacerbation and relapse rate respectively, maternal mortality was not observed. Rituximab did not affect maternal mortality. Fetal mortality was affected by iTTP in the antepartum period. These findings will serve as bases of prospective USTMA study for standardize management of this population.

Transplant Associated Thrombotic Microangiopathy: Acomprehensive Review and Local Experience

Introduction Thrombotic Microangiopathy (TMA) is a rare, life-threatening severe condition characterized by microangiopathic hemolytic anemia, thrombocytopenia and microthrombi in the walls of small blood vessels leading to ischemic organ dysfunction. Transplant-associated TMA (TA-TMA) can occur as a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The mechanism of TA-TMA is not fully understood, and conventional treatment options are based on targeting the identified risk factors and hypothesized pathophysiology. This review aimed to compile the information to date about TA-TMA and possible treatment strategies and report successful cases at the National Center for Cancer Care and Research (NCCCR). Methods Scientific databases were scoped for reviews on TA-TMA, its pathophysiology, risk factors and therapeutic strategies. Results were compiled to formulate an understanding of TA-TMA. Local cases of TA-TMA at NCCCR were also reported. Results TA-TMA pathophysiology and risk factors are described in Figure 1 and Table 1, respectively. Due to the complexity of the patient cases under investigation, TA-TMA diagnosis is clinical. Proposed diagnostic criteria include anemia, thrombocytopenia, elevated LDH, presence of schistocytes, hypertension, proteinuria, and elevated sC5b-9. Therapeutic approaches start the management of modifiable risk factors such as withdrawal or decreasing the dosage of calcineurin inhibitors (CNIs), control of hypertension and AKI, treatment of active infections and management of graft versus host disease (GvHD). Therapeutic plasma exchange (TPE) may benefit some patients who are positive for factor H autoantibodies. eculizumab, a humanized antibody against complement protein, can be highly effective in patients with TA-TMA. It is recommended for patients with high-risk features such as elevated sC5b-9 and proteinuria and can also be used for patients with organ damage or disseminated disease. Other available treatment options include rituximab and defibrotide. Other therapeutic agents are under clinical trials such as ravulizumab (C5 inhibitor), nomacopan (C5 and leukotriene B4 inhibitor) and narsoplimab (mannan-binding lectin-associated serine protease-2 [MASP-2] inhibitor). Four cases were diagnosed with TA-TMA at NCCCR between September 2017 and February 2023, as described in Figure 2. All cases recovered; however, the challenge remains in the choice of therapy. Thus far, the choice is to individualize therapy according to comorbidities, severity of clinical presentation and availability of the treatment options. Conclusion TA-TMA remains a significant clinical challenge for transplant physicians, and more research is needed to improve our understanding of its pathogenesis, diagnosis, and management, particularly in guiding the choice of therapy.

Patient Characteristics and Diagnostic Journey of Thrombotic Microangiopathy Associated with a Trigger: A Real-World, Retrospective, Multi-National Study

Introduction Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia, microangiopathic hemolytic anemia and microthrombi leading to ischemic tissue injury and organ damage. Disease emergence is unpredictable and in some cases TMA manifests in relation to a trigger, including autoimmune disease, infection, malignant hypertension, pregnancy, transplantation and drugs. In this study, we characterized the patient diagnostic journey of TMA associated with a trigger using real-world data. Methods Data were drawn from the Adelphi aHUS Disease Specific Programme, a cross-sectional survey of physicians and their patients with TMA associated with a trigger (data collected August-December 2022) from Australia, France, Germany, Italy, Spain, the UK and the USA. This analysis included physician-reported patient data and all patients had TMA associated with a trigger diagnosed by a physician. Analyses were conducted with all triggers combined, and by trigger type. Results Overall, 321 patients with TMA associated with a trigger were included; the top 5 most frequent triggers were infection (19.0%), drug (15.0%), autoimmune disease (14.6%), malignancy (13.7%) and solid organ transplantation (10.6%). Demographics, clinical characteristics and route to diagnosis are provided for all patients in the Table.At the point of survey, 53.6% of patients were female and the median age (interquartile range [IQR]) was 47.0 (33.5-59.0) years. Overall, 7/312 (2.2%) and 16/309 (5.2%) patients had a family history of TMA or kidney disease, respectively, although these proportions were higher in patients with TMA triggered postpartum (2/18 [11.1%] and 4/18 [22.2%]). The most common ethnicity was White/Caucasian (199/280 [71.1%]), however this varied across triggers; lowest in malignant severe hypertension (12/24 [50.0%]) and highest in bone marrow transplantation (21/25 [84.0%]). At first presentation to a healthcare professional (HCP), the most common symptom/complication was hemolytic anemia (208/312 [66.7%]), yet other common symptoms/complications varied across triggers (e.g. 24/45 [53.3%] patients with TMA triggered by an autoimmune disease presented with fatigue, and 17/29 [58.6%] and 14/29 [48.3%] patients with TMA triggered by malignant hypertension presented with kidney damage and proteinuria, respectively). At first diagnosis of TMA associated with a trigger, 125/315 (39.7%) and 44/315 (14.0%) patients had severe or life-threatening TMA, respectively; further, 260/277 (93.9%) patients had a platelet count outside the normal range, 101/115 (87.8%) patients had a lactate dehydrogenase level > 1.5 × the upper limit of normal, and the median (IQR) serum creatinine level among all patients was 2.9 mg/dL (1.8-4.0). Across all triggers, the first consulting HCP at symptom onset was most often a nephrologist (23.4%), general practitioner (GP; 21.8%) or emergency room (ER)/intensive care unit (ICU) physician (21.2%), while the first diagnosing HCP of TMA associated with a trigger was most often a nephrologist (38.6%), hematologist (24.9%), or hematologist-oncologist (22.4%). In 249 patients with available data, the median duration from symptom onset to TMA diagnosis was 6.0 days (IQR, 0-30.0 days). Conclusion In this study, severe or life-threatening TMA associated with a trigger was reported at the point of diagnosis for over half of the patients. An increased awareness of the clinical characteristics, symptoms and complications of TMA associated with a trigger by HCPs, particularly GPs who were frequently the first consulting HCP, is key to facilitating early diagnosis and timely referral to TMA experts/multi-disciplinary teams and optimizing patient management. Study/medical writing support funder: Alexion, AstraZeneca Rare Disease, Boston, MA, USA.

Gender and Racial Disparities in Risk and Outcomes of Thrombotic Thrombocytopenic Purpura Admissions: An Analysis of the National Inpatient Sample 2016-2019

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a rare disorder associated with severe deficiency in ADAMTS13 leading to microangiopathic hemolytic anemia, thrombocytopenia and end organ damage. The purpose of this study is to compare incidence and outcomes of TTP hospitalization between genders and races. Methods: We studied the National Inpatient Sample (NIS) from 2016 to 2019 for hospitalizations with the primary diagnosis of TTP. We fitted a multivariable logistic regression model to compare the risk of TTP amongst different races and genders. The model also accounted for age and comorbidities including solid or hematologic malignancies, history of thrombophilia, obesity, diabetes mellitus, hypertension, hyperlipidemia, chronic coronary artery disease, chronic liver disease, and chronic kidney disease. To compare mortality outcomes, we narrowed our analysis to TTP admissions only and fitted a multivariable logistic regression model with similar parameters. All reported confidence intervals were adjusted for multiplicity using the Bonferroni method. Results: A total of 7845 patients met the inclusion criteria of which 65.4% were female and 34.6% were males. The distribution of age and co-morbidities were different between the different racial groups. On adjusted analysis, females had higher rates of hospitalization due to TTP, with OR 1.32 (95% CI 1.24 to 1.41) compared to males, while there was no significant difference in mortality with OR 0.98 (95% CI 0.76 to 1.28). African American patients had significantly higher rates of hospitalization compared to Caucasian patients with OR of 3.62 (95% CI 3.38 to 3.88), followed by Asian and Hispanic patients respectively. Interestingly, the mortality in the African American patients was lower compared to Caucasian patients with OR of 0.74 (95% CI 0.55 to 0.98). There was no significant difference in mortality in other races. Conclusion: African American patients and females experienced significantly higher rates of hospitalization with TTP. However, African American patients experienced lower mortality. More research is needed to understand the cause behind these differences and modify our diagnostic and management to improve outcomes for patients with TTP.

A Long-Term Follow-Up Study in Immune-Mediated Thrombotic Thrombocytopenic Purpura: What Are the Outcomes?

Endothelium damage triggers the multimeric protein von Willebrand factor (VWF) release and subsequent binding to platelets, which are recruited at sites of vascular injury. A complex and fragile equilibrium between circulating levels of von Willebrand factor and its metalloprotease, ADAMTS13, is responsible for the hemostatic balance. However, the presence of autoantibodies targeting ADAMTS13 results in an increase in von Willebrand factor, mainly in its ultra-large multimers. The latter lead to platelet aggregation, the formation of thrombi and microangiopathic hemolytic anemia. This pathologic condition, known as immune-mediated thrombotic thrombocytopenic purpura (iTTP), occurs with high morbidity and a high rate of relapses. In this work, the long-term follow-up of 40 patients with iTTP is reported. We assessed ADAMTS13 activity, plasmatic VWF levels and the ADAMTS13/VWF ratio, comparing iTTP relapsing patients with remitting ones. A decrease in the ADAMTS13/VWF ratio, along with a reduced ADAMTS13 activity, could serve as predictive and sensitive biomarkers of incoming relapses.

Viral interactions with host factors (TIM-1, TAM -receptors, Glut-1) are related to the disruption of glucose and ascorbate transport and homeostasis, causing the haemorrhagic manifestations of viral haemorrhagic fevers.

The haemorrhagic features of viral haemorrhagic fevers may be caused by common patterns of metabolic disturbances of the glucose and ascorbate homeostasis. Haemorrhages and vasculature disfunctions are a clinical feature not only of viral haemorrhagic fevers, but also in scurvy, diabetes and thrombotic microangiopathic haemolytic anaemia. Interestingly, the expression of glucose and ascorbate transporter Glut-1 on the erythrocyte membrane is associated with the inability to synthesize ascorbate and is restricted to that very species that are susceptible to filoviruses (primates, humans and fruit bats). Glut-1 may play a pivotal role in haemorrhagic fever pathogenesis. TIM-1 and TAM receptors have been recognized to enhance entry of Ebola, Lassa and Dengue viruses and viral interferences with TIM-1 could disturb its function, disturbing the expression of Glut-1.In those species not able to synthesize ascorbate and expressing Glut-1 on erythrocytes virus could interact with Glut-1 or other functionally related protein, and the influx of glucose into the cells would be severely impaired. As a consequence, transient hyperglycemia and a marked oxidative stress coupled with the high levels of glucose in plasma would be established, and then promote the activation of NF–κB transcription, exacerbating a pro-inflammatory response mediated by cytokines and chemokines: The inability to synthesize ascorbate is an Achilles Heel when trying to counteract the oxidative stress.

Anti-factor H autoantibody-associated hemolytic uremic syndrome in an Argentine pediatric cohort

Aim: To describe the clinical characteristics and frequency of anti-factor H (FH) autoantibody-associated atypical hemolytic uremic syndrome (aHUS) in the first cohort of Argentine patients. Methods: The presence of anti-FH autoantibodies in 70 pediatric patients with suspected aHUS was investigated between 2013 and 2022. Clinical and laboratory parameters were collected and compared between patients who were positive and negative for anti-FH antibodies. Results: The 70 patients screened for anti-FH autoantibodies presented clinical features of non-immune microangiopathic hemolytic anemia, thrombocytopenia and renal injury. Positive titers were found in 14 children [mean: 1,938 arbitrary units per mL (AU/mL), range 179–8,500]. Due to missing clinical data, two patients who tested positive for anti-FH and 20 patients who tested negative for anti-FH were excluded from the data analysis. The laboratory features and clinical manifestations of anti-FH-positive aHUS cases (n = 12) were very similar to those of subjects with no autoantibodies detected (n = 36). Treatment administration was heterogeneous among the 12 patients analyzed. Dialysis was performed in six patients in total. Five children received plasmapheresis, while three patients were treated with plasma exchange followed by administration of eculizumab. Two patients received eculizumab only and one showed significant improvement solely through supportive care. Eight patients in total received immunosuppressive therapy. Follow-up of three patients showed a significant decrease of anti-FH autoantibody titers in 2/3 after treatment and during clinical remission. Conclusions: The cohort of 70 pediatric patients in this study demonstrated that the frequency of anti-FH autoantibody-associated aHUS in Argentina is 20%. The implementation of anti-FH testing in the country can potentially contribute to improved treatment and follow-up for patients with autoimmune aHUS.

Population Pharmacokinetics and Exposure-Response Analyses to Demonstrate the Link of Causality between ADAMTS13 and the Clinical Effects of Recombinant ADAMTS13 Compared to Plasma-Based Therapies

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening deficiency of ADAMTS13. TTP clinical manifestations include thrombocytopenia and microangiopathic hemolytic anemia (MAHA) but incomplete understanding of their relationship to ADAMTS13 exposure is a challenge for assessing the impact of ADAMTS13 supplementation. Integrated population pharmacokinetics (PopPK) analysis and exposure-response modeling were conducted to support the clinical benefit assessment of recombinant ADAMTS13 (rADAMTS13; Takeda Development Center Americas, Inc., Lexington, MA, USA) in patients with cTTP. Aims: To characterize ADAMTS13 activity following intravenous (IV) administration of rADAMTS13 or plasma-based therapies (PBT) in patients with cTTP, to identify sources of variability, and to evaluate the relationship between ADAMTS13 activity and the probability of isolated TTP manifestations. Methods:The PopPK analysis included data from phase 1 (NCT02216084), pivotal phase 3 (NCT03393975), and phase 3b continuation (NCT04683003) studies of rADAMTS13. Exposure-response analyses included data from NCT03393975 where patients received rADAMTS13 or PBT in prophylaxis treatment period 1 and crossed over to the opposite treatment in period 2. PBT consisted of fresh frozen plasma, solvent/detergent-treated plasma or factor VIII/von Willebrand factor concentrates. A covariate analysis was conducted to identify sources and assess the significance of variability on the PK of ADAMTS13 activity. Exposure-response models were developed to assess the relationship between the average ADAMTS13 plasma activity for a given dosing interval (C ave) and the count of isolated TTP manifestations: thrombocytopenia (platelet count decreased ≥25% of baseline or a platelet count <150,000/µL) or MAHA (increased lactate dehydrogenase >1.5 × of baseline or >1.5 × upper limit of normal). Cox proportional hazard modeling using recurring events was performed to demonstrate the treatment effect of rADAMTS13 over PBT, and explain carry-over prophylactic effects. Repeated time to event was performed using longitudinal data from all periods to demonstrate ADAMTS13-dependent reduction in the hazard of thrombocytopenia. Results: A 2-compartment PK model with linear elimination adequately characterized the time profiles of ADAMTS13 activity following body-weight-based IV administration of rADAMTS13 or PBT (N=65 patients). Following body-weight-based dosing, dosing interval (once per week [Q1W] vs every 2 weeks [Q2W]) and treatment type (rADAMTS13 vs PBT) were the only significant extrinsic factors found with an impact on ADAMTS13 PK. ADAMTS13 C ave was associated with a significant reduction of the thrombocytopenia hazard in an activity-dependent manner (Figure). Exposure-response model simulations suggested that >95% of patients treated with rADAMTS13 are predicted to have plasma C ave ADAMTS13 >0.13 IU/mL (equivalent to 13% activity), with high (>70%) protection against thrombocytopenia regardless of dosing intervals (Q2W or Q1W) and age. In contrast, a similar level of protection against thrombocytopenia is expected in only ~10% of patients treated with PBT (Table). Similarly, a significant exposure-response relationship was identified between ADAMTS13 C ave and MAHA.In treatment period 1, rADAMTS13 was associated with a higher probability of zero counts of thrombocytopenia versus PBT from week 2 onwards. Patients switching from rADAMTS13 to PBT in period 2 initially had a slightly higher probability of having zero counts of thrombocytopenia than patients switching from PBT to rADAMTS13, suggesting that treatment with rADAMTS13 led to a carry-over prophylactic effect maintained for some time after treatment cessation. Conclusions: Besides body-weight-based dosing, no additional dose adjustments of rADAMTS13 are needed in the cTTP patient population. A consistent and significant ADAMTS13 activity-response relationship was identified in which rADAMTS13 reduced the hazard of objective laboratory based TTP manifestations (thrombocytopenia and MAHA) in an activity-dependent manner. Overall, these findings suggest that rADAMTS13 at 40 IU/kg Q2W or Q1W offers a favorable prophylactic treatment effect over PBT that is attributable to higher ADAMTS13 activity.

Caplacizumab Frontline Added to Therapeutic Plasma Exchange and Immunosuppression Prevents Unfavorable Outcomes in Immune-Mediated TTP: An International Real-World Study of the TTP-IWG (The Capla 500 Project)

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) results from autoantibody-mediated severe deficiency of ADAMTS13, the Von Willebrand factor (VWF)-cleaving protease. In this context, ultra-large VWF multimers accumulate in the circulation, leading to increased platelet clumping, with subsequent severe thrombocytopenia, microangiopathic hemolytic anemia and multiorgan failure. The anti-VWF nanobody caplacizumab is licensed for adults with iTTP. Prospective controlled trials and national real-world studies have provided evidence that caplacizumab improved outcome of the acute phase of the disease. However, whether caplacizumab decreases mortality, and the optimal timing of caplacizumab initiation, remain to be determined. To address these questions, an international survey, the Capla 500+ project, has been conducted. An academic call for observations involving experienced teams from 10 worldwide countries recruited 942 adult patients treated with a regimen of daily therapeutic plasma exchange (TPE), caplacizumab and immunosuppression with corticosteroids ± rituximab (caplacizumab group). Cases were compared to historic controls (control group) randomly selected from 2015 to 2018 by 4 teams in a 2:1 ratio (N=495), treated with TPE and immunosuppression. Primary outcome was 3-month survival post-first TPE. Key secondary outcomes were refractoriness and exacerbations, time to clinical response, number of TPE to achieve clinical response, time to ADAMTS13 activity recovery ≥20%, and caplacizumab-related adverse events. Clinical presentation and severity were comparable between groups ( Table). All patients received TPE in both caplacizumab and control groups, in association with corticosteroids (99% and 93%, respectively), and rituximab (92% and 71%, respectively) frontline or as salvage therapy. Caplacizumab was started within 3 days (715 patients), or delayed by≥4 days from first TPE (218 patients); for those with delayed initiation, caplacizumab was added for management of exacerbation or refractoriness (63 cases) or a slow improvement to TPE/immunosuppression (155 cases). The 3-month survival post-first TPE in the caplacizumab group was 98.6% vs 93.3% in the control group (p<0.0001). Failure to achieve clinical response was 5-times less likely in the caplacizumab group as compared to the control group (95% confidence interval, 0.1-0.37, p<0.0001). Deaths in the caplacizumab group occurred after a median of 4.5 days (interquartile range [IQR], 3-5), mostly due to uncontrolled iTTP. Patients receiving caplacizumab experienced less refractoriness and exacerbations, and required less TPE to achieve clinical remission than controls (p<0.0001 for all), regardless of the use of rituximab. Forty-six patients experienced an exacerbation following caplacizumab interruption while ADAMTS13 activity was still undetectable. Time to ADAMTS13 activity ≥20% was shorter in the caplacizumab group (p=0.01) ( Table), where rituximab was more systematically used. In patients with delayed caplacizumab initiation, clinical response was obtained after a median of 4 days (IQR, 2-8) following caplacizumab introduction. This result was comparable to the time to clinical response obtained in patients who initiated caplacizumab within 3 days of the first TPE (median, 4 days [IQR, 3-6], p=0.8). In patients with early caplacizumab initiation, unfavorable outcomes were particularly infrequent (death, 1%; refractoriness, 1.1%; exacerbations, 5.3%),andtime to clinical response in survivors was half the time compared to control group survivors (p<0.0001) ( Figure). Caplacizumab-related adverse events occurred in 220 patients (23%). They consisted of major bleeding (N=19, 2.2%), including: digestive tract bleeding (N=8), intracranial hemorrhage, severe central venous catheter insertion bleeding, metrorrhagia (N=2 cases each). Clinically relevant non-major bleeding (N=34, 3.7%), non-clinically relevant non-major bleeding (N=114, 14%), and inflammatory reaction at the injection site (N=35, 4.5%) were also reported. This unprecedented, international academic effort on such a rare disease provides convincing evidence that caplacizumab added to TPE and immunosuppression prevents unfavorable outcomes during the acute phase of iTTP, including mortality, and alleviates the burden of care at the potential expense of rare, major bleeding events.

The Use of a Large Electronic Health Records System to Define and Characterize a Thrombotic Thrombocytopenic Purpura Population

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening microangiopathy due to a deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13. Microangiopathic hemolytic anemia, severe thrombocytopenia and ischemic end organ injury due to microvascular thrombi are the defining features of TTP. TTP can be caused by auto-antibodies against ADAMTS13 enzyme (immune TTP [ITTP]) or by inherited mutations of the ADAMTS13 gene (congenital TTP [CTTP]). Therapeutic plasma exchange (TPE) to replenish ADAMTS13, with or without steroids, has been the mainstay of treatment. Due to the auto-immune nature of ITTP the International Society on Thrombosis and Hemostasis (ISTH) made a strong recommendation in 2020 to add corticosteroids to TPE for ITTP and a conditional recommendation to add the CD20 inhibitor rituximab as well the VWF monoclonal antibody caplacizumab. Objective: To define and characterize TTP in a living population from a large electronic health record (EHR) database in terms of disease prevalence, demographic characteristics and therapeutic interventions and procedures in light of recent ISTH guidelines. Methods: We conducted a study of data from TriNetX Analytics Network, which contains EHRs from >140 million individuals from 79 Health Care Organizations in the US. We used ICD-10-CM diagnosis codes, ATC and CPT codes applied in the last 10 years to evaluate TTP disease prevalence, therapeutic interventions and procedural interventions respectively. Eligibility criteria applied to define the TTP cohort were as follows: Inclusion criteria: ICD-10 M31.1 diagnosis of thrombotic microangiopathy (TMA)History of thrombocytopenia (platelet volume ≤150,000 per microliter)ICD-10-PCS code for pheresis of plasma or a CPT code for therapeutic apheresis, for plasma pheresis Exclusion criteria: ICD-10-CM codes linked to etiologies of TMA other than TTP (hemopoietic stem cell-associated TMA [M31.11], hemolytic uremic syndrome [D59.3], disseminated intravascular coagulation [D65], antiphospholipid syndrome [D68.61], malignant hypertension [I10, I15])Deceased Results: As of July 31, 2023, there were a total of 142,046,930 living individuals registered in the database in the last 10 years. Of these, 560 individuals met eligibility criteria to define the TTP population (prevalence 0.0004% or 4 cases per million). Demographic characteristics included mean age at diagnosis (39.3 years [SD=14.3]), gender (73% female, 27% male), race (White = 44%, Black or African American = 33%, Asian = 3%, Other or unknown = 20%) and ethnicity (Not Hispanic or Latino = 73%, Unknown = 16%, Hispanic or Latino = 12%). Therapeutic interventions included systemic glucocorticoids (93% [prednisone 84%, methylprednisolone 68%, hydrocortisone 46%, dexamethasone 38%, triamcinolone 14%, betamethasone 9%, prednisolone 5%]), antithrombotics (86% [heparin group 79%, platelet aggregation inhibitors {excluding heparin} 29%, enzymes 27%, other antithrombotic agents {including caplacizumab} 18%, vitamin K antagonists 7%, direct factor Xa inhibitors 7%, direct thrombin inhibitors 2%]) and CD20 inhibitors (including rituximab) (40%). Conclusion: This this is the first report to define and characterize a TTP population from a large US EHR database using a combination administrative codes and laboratory data. The study found a very low prevalence rate; that closely aligns with previously published estimates from registries of 4-5 cases per million for ITTP and 1-2 cases per million for CTTP. It was not possible to differentiate between CTTP and ITTP cases in this study due to a lack of ADAMTS13 genomic data. Demographic findings were consistent with previous registry data (median age of acute TTP presentation in the third to fourth decade of life, typically affecting females more than males). We found a high level of systemic glucocorticoid use as expected, but also high percentage of patients treated with rituximab in line with recent ISTH guidance. The authors are aware of other potential treatments in early development including gene therapy candidates for CTTP and cell therapy candidates for ITTP. This represents a tantalizing prospect for this population; however, to demonstrate efficacy and safety, these new therapies will require scientifically rigorous and well planned clinical studies including robust long-term follow-up.

Recent Advances in the Management of Microangiopathic Hemolytic Anemias (MAHA): A Narrative Review.

Red blood cells (RBCs) start to break down early in hemolytic anemia, which can be chronic or life-threatening. It should be considered while determining if normocytic or macrocytic anemia is present. Hemolysis in the reticuloendothelial system may happen intravascularly, extravascularly, or both. It accounts for a broad spectrum of laboratory and clinical situations, both physiological and pathological. Whenever the frequency of RBCbreakdown is rapid enough to lower hemoglobin levels below the normal range, hemolytic anemia occurs. Microangiopathic hemolytic anemia (MAHA) is a term used to describe non-immune hemolysis induced by intravascular RBC fragmentation caused by substances in the tiny blood arteries that generate schistocytes in the peripheral circulation. Microvasculature abnormalities, such as small arterioles and capillaries, are usually involved. Furthermore, MAHA can also be brought on by intravascular devices like a prosthetic heart valve or assistive technologies. Poor deformity results in entrapment, phagocytosis, antibody-mediated elimination through phagocytosis or direct complement activation, fragmentation brought about by microthrombi or acute mechanical stress, oxidation, or spontaneous cellular death. Hemolysis may cause acute anemia, jaundice, hematuria, dyspnea, tiredness, tachycardia, and possibly hypotension. This article aimsto synthesize existing research, identify therapeutic strategies, and provide insights into current and emerging approaches for managing this complex hematological disorder.

Viral interactions with host factors (TIM-1, TAM -receptors, Glut-1) are related to the disruption of glucose and ascorbate transport and homeostasis, causing the haemorrhagic manifestations of viral haemorrhagic fevers.

The haemorrhagic features of viral haemorrhagic fevers may be caused by common patterns of metabolic disturbances of the glucose and ascorbate homeostasis. Haemorrhages and vasculature disfunctions are a clinical feature not only of viral haemorrhagic fevers, but also in scurvy, diabetes and thrombotic microangiopathic haemolytic anaemia. Interestingly, the expression of glucose and ascorbate transporter Glut-1 on the erythrocyte membrane is associated with the inability to synthesize ascorbate and is restricted to that very species that are susceptible to Filoviruses (primates, humans and fruit bats). Glut-1 may play a pivotal role in haemorrhagic fever pathogenesis. TIM-1 and TAM receptors have been recognized to enhance entry of Ebola, Lassa and Dengue viruses and viral interferences with TIM-1 could disturb its function, disturbing the expression of Glut-1.

Acute myocardial infarction in a patient with thrombotic thrombocytopenic purpura: a case report and literature review

Acute myocardial infarction (AMI) induced by thrombotic thrombocytopenic purpura (TTP) has been previously reported, but comorbidity with autoimmune hemolytic anemia is rare. The index patient, a 55-year-old woman, presented with acute ST-elevation myocardial infarction (STEMI). A diagnosis of TTP was established on the presence of thrombocytopenia, microangiopathic hemolytic anemia, acute kidney injury, fever, and neurologic symptoms (ischemic stroke); autoimmune hemolytic anemia was established based on Comboost test. Percutaneous coronary intervention and dual antiplatelet therapy were not initiated due to elevated risk of bleeding. Instead, the patient was treated with glucocorticosteroid and plasmapheresis. Despite the treatment, the patient suffered a watershed acute cerebral infarction, and finally died of gastrointestinal bleeding. This case highlights the challenges in managing STEMI in TTP patients.

Viral interactions with host factors (TIM-1, TAM -receptors, Glut-1) are related to the disruption of glucose and ascorbate transport and homeostasis, causing the haemorrhagic manifestations of viral haemorrhagic fevers.

The haemorrhagic features of viral haemorrhagic fevers may be caused by common patterns of metabolic disturbances of the glucose and ascorbate homeostasis. Haemorrhages and vasculature disfunctions are a clinical feature not only of viral haemorrhagic fevers, but also in scurvy, diabetes and thrombotic microangiopathic haemolytic anaemia. Interestingly, the expression of glucose and ascorbate transporter Glut-1 on the erythrocyte membrane is associated with the inability to synthesize ascorbate and is restricted to that very species that are susceptible to Filoviruses (primates, humans and fruit bats). Glut-1 may play a pivotal role in haemorrhagic fever pathogenesis. TIM-1 and TAM receptors have been recognized to enhance entry of Ebola, Lassa and Dengue viruses and viral interferences with TIM-1 could disturb its function, disturbing the expression of Glut-1.