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The skin often provides initial clues of hypercoagulability with features such as livedo reticularis, livedo racemosa, retiform purpura, necrosis, and ulcerations. Because these cutaneous manifestations are nonspecific, laboratory testing is often needed to evaluate for underlying causes of hypercoagulability. Importantly, these disorders are reported to be the most common mimicker, resulting in an erroneous diagnosis of pyoderma gangrenosum. Understanding inherent properties of, and indications for, available tests is necessary for appropriate ordering and interpretation of results. Additionally, ordering of these tests in an indiscriminate manner may lead to inaccurate results, complicating the interpretation and approach to management. This second article in this continuing medical education series summarizes information on methodology, test characteristics, and limitations of several in vitro laboratory tests used for the work up of hypercoagulability and vasculopathic disease as it pertains to dermatologic disease.

The efficacy and safety of caplacizumab in individuals with acquired thrombotic thrombocytopenic purpura (aTTP) have been established in the phase 2 TITAN and phase 3 HERCULES trials. Integrated analysis of data from both trials was conducted to increase statistical power for assessing treatment differences in efficacy and safety outcomes. Caplacizumab was associated with a significant reduction in the number of deaths (0 vs 4; P < .05) and a significantly lower incidence of refractory TTP (0 vs 8; P < .05) vs placebo during the treatment period. Consistent with the individual trials, treatment with caplacizumab resulted in a faster time to platelet count response (hazard ratio, 1.65; P < .001), a 72.6% reduction in the proportion of patients with the composite end point of TTP-related death, TTP exacerbation, or occurrence of at least 1 treatment-emergent major thromboembolic event during the treatment period (13.0% vs 47.3%; P < .001), and a 33.3% reduction in the median number of therapeutic plasma exchange days (5.0 vs 7.5 days) vs placebo. No new safety signals were identified; mild mucocutaneous bleeding was the main safety finding. This integrated analysis provided new evidence that caplacizumab prevents mortality and refractory disease in acquired TTP and strengthened individual trial findings, with a confirmed favorable safety and tolerability profile. These trials were registered at www.clinicaltrials.gov as #NCT01151423 and #NCT02553317.

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.

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.

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.

Introduction Atypical hemolytic uremic syndrome (aHUS) is a progressive and potentially life-threatening disease characterized by complement-mediated thrombotic microangiopathy. Patients with aHUS may experience fatigue, which can negatively impact their lives, but there is a knowledge gap regarding disease burden in these patients. Methods In this longitudinal study, patients with aHUS from the Global aHUS Registry who completed patient-reported outcome assessments (Functional Assessment of Chronic Illness Therapy-Fatigue scale [FACIT-Fatigue], general health status, and work status) at ≥2 time points were assessed relative to treatment status: (i) never treated with eculizumab; (ii) on eculizumab at registry enrollment and continued therapy; and (iii) started eculizumab after registry enrollment. Results Patients who started eculizumab after the baseline visit (n = 23) exhibited improvements in fatigue (nearly 75% achieved clinically meaningful improvement), improved general health status (55%), and 25% to 30% rate reduction in symptoms of fatigue, weakness, irritability, nausea/vomiting, and swelling at last follow-up. Among patients already on eculizumab at registry enrollment (n = 295) and those never treated (n = 233), these parameters changed minimally relative to the baseline. Emergency room visits and hospital admissions were similar between groups. The number of health care provider visits and work days missed were higher in patients who started eculizumab after registry enrollment. Conclusion These real-world findings confirm the detrimental effects of aHUS on patients’ daily lives, including high levels of fatigue and impairments in general health status. The results suggest clinically meaningful improvement in fatigue, other patient-reported outcomes, and symptoms with eculizumab initiation after enrollment into the aHUS registry.

Thrombotic thrombocytopenic purpura (TTP) is fatal in 90% of patients if left untreated and must be diagnosed early to optimize patient outcomes. However, the very low incidence of TTP is an obstacle to the development of evidence-based clinical practice recommendations, and the very wide variability in survival rates across centers may be partly ascribable to differences in management strategies due to insufficient guidance. We therefore developed an expert statement to provide trustworthy guidance about the management of critically ill patients with TTP. As strong evidence was difficult to find in the literature, consensus building among experts could not be reported for most of the items. This expert statement is timely given the recent advances in the treatment of TTP, such as the use of rituximab and of the recently licensed drug caplacizumab, whose benefits will be maximized if the other components of the management strategy follow a standardized pattern. Finally, unanswered questions are identified as topics of future research on TTP.

Terminal complement inhibition therapy with eculizumab (a humanized monoclonal antibody to C5) has revolutionized the treatment of patients with thrombotic microangiopathy (TMA). Successful responders are often placed on long-standing therapy to prevent disease recurrence in the native kidney or allograft. The tissue deposition of eculizumab in patients with C3 glomerulopathy has been described but no studies have yet investigated tissue deposition of eculizumab in cases where it was indicated for thrombotic microangiopathy which, unlike C3 glomerulopathy, does not usually show immune-type electron dense deposits. To evaluate this, we reviewed biopsies from 13 patients who received eculizumab for TMA treatment or prevention of recurrence. We found IgG2, IgG4, and kappa positivity within arterioles corresponding to eculizumab deposits, with similar distribution to C5b-9, in all but one patient. In that patient eculizumab therapy had been discontinued 24 months prior to biopsy. Deposits in arterioles could be seen as early as one day after infusion and after a single dose of eculizumab, and were detected up to 162 days after therapy discontinuation. This may play a role in controlling local complement activation-associated vascular changes in these patients. Thus, IgG subclass staining by immunofluorescence is important to avoid misdiagnoses of immune-complex or monoclonal immunoglobulin deposition disease in patients with TMA who received eculizumab.

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 versus 68.6 years, P=0.031), females (49.7 years versus 72.9 years, P

iTTP survivors experience high rates of adverse health sequelae and increased mortality over long-term follow up. We conducted this multi-center 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 [HR 3.74 (95% CI 1.65-8.48, P=0.002), increasing age [HR 1.04 (95% CI 1.01-1.07), P=0.011] and number of iTTP episodes [HR 1.10 (95% CI 1.01-1.20), P=0.022] were associated with mortality in a model adjusted for African American race [HR 0.70 (95% CI 0.30-1.65), P=0.702], hypertension [HR 0.47 (95% CI 0.20-1.08), P=0.076], CKD [HR 1.46 (95% CI 0.65-3.30, P=0.358] and site [HR 1.46 (95% CI 0.64-3.30), P=0.358]. There was a trend towards shorter survival in patients with lower ADAMTS13 activity during remission (P=0.078). In conclusion, iTTP survivors are at higher risk of death compared with a reference population and cardiovascular disease is a leading cause of death. Our study highlights the need for survivorship care, and investigation focused on cardiovascular disease and early mortality in TTP survivors.

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.

Background and Aims Ravulizumab is a long-acting C5 inhibitor, derived from eculizumab, that is dosed every 8 weeks. Ravulizumab was approved in the United States for patients with atypical haemolytic uraemic syndrome (aHUS) and it is currently under evaluation in the EU based on the phase 3 trial (NCT02949128) efficacy and safety results at 26 weeks in patients with aHUS. Here, we report longer term efficacy and safety of ravulizumab obtained from the trial during the ongoing extension period. Method This phase 3 trial was a single arm, global, open label study in adults (≥18 years of age) with aHUS naïve to complement-inhibitor therapy. Ravulizumab was administered by intravenous infusion (IV) every 8 weeks during the maintenance phase. Patients fulfilling laboratory criteria for active TMA, ADAMTS13>5%, and negative STEC-HUS testing were eligible. Patients that completed the 26-week initial evaluation period could enter the extension period. The primary endpoint was complete TMA response (normalisation of platelet count and lactate dehydrogenase [LDH], and ≥ 25% improvement in serum creatinine from baseline, measured at 2 separate assessments obtained at least 28 days apart). Secondary endpoints included changes from baseline in haematological parameters, kidney function, and FACIT-fatigue scores. Treatment emergent adverse events were also evaluated. Here, interim cumulative data on primary and secondary endpoints through at least 52 weeks are reported. Results Forty-seven of 56 enrolled patients completed the initial evaluation period and received at least one dose of ravulizumab in the extension period. All patients achieved complete inhibition of terminal complement as demonstrated by sustained suppression of free-C5 ( Although three new SAEs were reported during the extension period, there were no further fatal adverse events. As in the primary analysis period, no meningococcal infections occurred through the last patient follow-up. Conclusion In the extension period of the phase 3 trial, ravulizumab continued to have a good benefit: risk profile. At last follow-up, the cumulative efficacy of ravulizumab to treat complement mediated TMA in patients with aHUS improved to 61% from 54% in the initial evaluation period. Most AEs occurred in the first 26 weeks, and there were no meningococcal infections identified in the study. These results suggest that with ravulizumab further improvement in efficacy is possible with longer treatment with no compromise in safety and improved convenience of 8-week dosing intervals.

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.

Transplant-associated thrombotic microangiopathy (TA-TMA), a complication of hematopoietic cell transplant (HCT), is associated with significant morbidity and mortality. The pathophysiology and overlap of TA-TMA with other posttransplant complications such as graft-versus-host disease (GVHD) is poorly understood. We retrospectively identified cases of TA-TMA among patients with grade 3/4 gastrointestinal (GI) GVHD, reviewed intestinal biopsy specimens, and performed correlative testing of biomarkers associated with TA-TMA. TA-TMA was more common in patients with steroid-refractory GVHD compared with steroid-responsive GVHD (79.3% vs 42.1%; P = .001). Among patients surviving 100 days post-HCT, 1-year survival from day 100 was significantly better for patients who had not developed TA-TMA in the first 100 days (69.5% vs 36.7%; P < .001). Only 1 of 7 proposed TA-TMA histology criteria (mucosal hemorrhage) differed significantly based on GVHD steroid response. In multivariable modeling, steroid-refractory GVHD was a risk factor for development of TA-TMA (hazard ratio, 3.09; 95% confidence interval, 1.68-5.67; P < .001). There were no differences in complement activation at GVHD onset; however, 2 to 6 weeks later, patients with TA-TMA had higher levels of BBPlus and C5b-9, markers of alternative and terminal pathway activation (BBPlus: median, 600 vs 209.3 ng/mL; P = .0045) (C5b-9: median, 425.9 vs 258.4 ng/mL; P = .029). TA-TMA is associated with poor overall survival (OS) following HCT and may be detected early by histologic findings and may be differentiated from GVHD by measurement of alternative and terminal complement pathway activation. It is unknown whether treatment of TA-TMA will improve survival in steroid-refractory GVHD.

ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) is a metalloprotease responsible for cleavage of ultra-large von Willebrand factor (VWF) multimers. Severely deficient activity of the protease can trigger an acute episode of thrombotic thrombocytopenic purpura (TTP). Our understanding of the pathophysiology of TTP has allowed us to grasp the important role of ADAMTS13 in other thrombotic microangiopathies (TMAs) and thrombotic disorders, such as ischemic stroke and coronary artery disease. Through its action on VWF, ADAMTS13 can have prothrombotic and proinflammatory properties, not only when its activity is severely deficient, but also when it is only moderately low. Here, we will discuss the biology of ADAMTS13 and the different assays developed to evaluate its function in the context of TTP, in the acute setting and during follow-up. We will also discuss the latest evidence regarding the role of ADAMTS13 in other TMAs, stroke, and cardiovascular disease. This information will be useful for clinicians not only when evaluating patients who present with microangiopathic hemolytic anemia and thrombocytopenia, but also when making clinical decisions regarding the follow-up of patients with TTP.

Managing Acquired TTP without Plasma Exchange A case of acquired thrombotic thrombocytopenic purpura is reported in a Jehovah’s Witness who had neurologic manifestations but would not accept plasma...

Background/rationale Romiplostim is a thrombopoietin receptor agonist recommended as a second-line therapy for immune thrombocytopenia. An initial dose of 1 mcg/kg/week subcutaneously with weekly 1 mcg/kg dose escalation is recommended per package labeling. Optimizing romiplostim dosing for hospitalized, corticosteroid- and intravenous immunoglobulin-refractory patients with severe thrombocytopenia secondary to immune thrombocytopenia may be critical for improving platelet responses, reducing the risk of bleeding, and decreasing hospital length of stay. Limited data are available evaluating the efficacy and safety of higher initial doses. Objective The primary objective of this study was to compare the time to platelet ≥ 10 × 109/L between patients who received an initial romiplostim dose of ≥2 mcg/kg/week compared to the standard initial dose of 1 mcg/kg/week. Secondary objectives included time to platelet response ≥ 30 × 109/L and ≥50 × 109/L, percentage of patients achieving platelet responses, hospital length of stay, and incidence of adverse events and bleeding complications. Methods This was a retrospective, single-center, cohort study including hospitalized adults with corticosteroid- and intravenous immunoglobulin-refractory immune thrombocytopenia. A baseline platelet 9/L was required. Patients were stratified by their initial romiplostim dose into Cohort 1 (1 mcg/kg/week) and Cohort 2 (≥2 mcg/kg/week). A review of electronic medical records and descriptive statistics generated findings. Results A total of 18 patients were included, 4 in Cohort 1 and 14 in Cohort 2. Patients in Cohort 2 had a median initial dose of 4.5 mcg/kg/week. Patients in Cohort 2 achieved a platelet ≥ 10 × 109/L in a median of 2 days versus 4.5 days for Cohort 1. More patients in Cohort 2 achieved a platelet ≥ 30 × 109/L (42.9% vs. 25%) and platelet ≥ 50 × 109/L (28.6% vs. 25%). The median hospital length of stay was shorter in Cohort 2 (13.5 vs. 20 days). Clinically relevant nonmajor bleeding was noted less frequently in Cohort 2 (28.6% vs. 75%), while major bleeding was more frequent in Cohort 2 (14.3% vs. 0%). No thrombotic events occurred. Conclusion Our study suggests that higher initial romiplostim doses may be safe for hospitalized patients with treatment-refractory immune thrombocytopenia. Compared to Food and Drug Administration-approved dosing, higher initial doses may shorten time to platelet responses and hospital length of stay. Further large-scale studies are needed to confirm these findings.

Introduction: Our previous qualitative studies of immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors revealed that patients did not communicate to their hematologists about residual cognitive and fatigue issues. A way to overcome this communication barrier is implementation of patient-reported outcomes (PROs) in routine care. Integration of PROs into the clinical care of other diseases has resulted in improved patient-provider communication, symptom management, quality of life and overall patient satisfaction. However, decisions about the mode of administration are challenging. Although 92% of the United States population has access to the internet, studies have shown minorities prefer alternative modes of administration. Given that iTTP disproportionately affects Black women, understanding patient preference is critical for integrating PRO instruments into routine care. The primary study goal was to determine the preferred mode of administration of PRO instruments in iTTP. Furthermore, many individuals use the internet as a source of medical information/advice. A study of iTTP literacy reported that only 34% of survivors correctly identified disease relapse risk factors suggesting a critical knowledge gap. A secondary goal was to describe iTTP survivors' behaviors regarding using the internet for medical information or support. Methods: We utilized a cross-sectional study design. iTTP survivors were recruited from August 2019 until present. Eligibility included: 1) age >18 years, 2) documented ADAMTS13 deficiency (< 10% activity) at diagnosis or during a relapse and 3) > 1-year clinical remission. Multi-center recruitment of survivors included: Oklahoma University, Ohio State University, University of Minnesota, Johns Hopkins University, University of Rochester, University of Pennsylvania, University of Alabama at Birmingham, University of Utah and the University of Vermont. Following informed consent, survivors were administered the PROMIS ® cognitive function ability, anxiety and fatigue instruments via their preferred mode (online, telephone, or self-administered). Typical internet usage, behaviors regarding searching for health information online and demographics were also obtained. Results: To date, 94 survivors have completed the study (83% female; 54% White; 34% Black; median age 49 years [range 26-85 years]). A majority (54%) preferred completing PROMIS ® surveys online vs. self-administered or telephone administered. However, among Black survivors, only 38% preferred online administration and among survivors aged ≥65 years only 22% preferred online administration. Interestingly, there was an overall shift in a preference toward online administration following the onset of the COVID-19 pandemic (45% (21/47) preferred online pre vs 66% (31/47) preferred online post). Ninety-one percent (86/94) of survivors reported at least occasional internet use vs 8 (9%) reported none. Similarly, 82% (70/85) had searched the internet for health/medical information for themselves in the past year. Also 62% (53/86) of the survivors selected 'strongly agree' or 'agree' to the statement that the internet helps them determine if symptoms are important enough to see a doctor. Likewise, 62% used the internet to interpret doctor's recommendations. Additionally, 47% (40/86) 'strongly agree/agree' the internet helped determine if they would take a medication/seek alternative treatment. Moreover, 64% (55/86) agreed the internet was a good way to find others experiencing similar health problems. However, when asked about behaviors over the past year, only 42% (36/85) used online social networking sites like Facebook to look for health information or find others with iTTP and only 36% (31/85) had actually participated in online iTTP support groups. Conclusions: Overall iTTP survivors preferred online PRO administration; however, Black and older survivors preferred other methods. Recognizing these preferences is a vital step toward integrating PROs into routine care. Furthermore, iTTP survivors are using the internet as a source of medical support and information. Therefore, it is critical to not only educate iTTP survivors about credible online resources but also to create additional content. Also, future studies are needed to further explore the impact of the COVID-19 pandemic on online health behaviors. Disclosures Terrell: Sanofi: Consultancy; Takeda: Consultancy. Journeycake: HEMA Biologics: Honoraria; LFB: Honoraria. Mazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. Cuker: Spark Therapeutics: Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Bayer: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Synergy: Consultancy. Chaturvedi: Dova: Other: Advisory board member; UCB: Other: Advisory board participation; Argenx: Other: Advisory board member; Alexion: Other: Advisory board member; Sanofi Genzyme: Other: Advisory board member. Lim: Hema Biologics: Honoraria; Sanofi Genzyme: Honoraria; Dova Pharmaceuticals: Honoraria. Gangaraju: Alexion: Consultancy; Sanofi Genzyme: Consultancy. Cataland: Alexion: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Ablynx/Sanofi: Consultancy, Research Funding; Takeda: Consultancy.

Background Ravulizumab, a humanized anti-complement C5 monoclonal antibody designed by targeted modification of eculizumab to achieve an extended half-life, is approved to treat aHUS in the USA (2019), EU and Japan (2020). Data at 26 weeks (wk) and 1 year (yr) from the phase 3 studies of ravulizumab in adults and children with aHUS have been published. Here we report 2-yr data from these trials. Methods Efficacy and safety data from ravulizumab clinical trials in adults naïve to complement inhibitor treatment (NCT02949128), and in children either naïve to (naïve) or switched from (switch) eculizumab (NCT03131219), were assessed at 2 yr and presented alongside data from the initial 26-wk evaluation periods; patients were dosed every 8 wk (adult), or every 4 or 8 wk (children), according to body weight. Descriptive statistical analyses were conducted on these data. No statistical comparisons between data at 26 wk and 2 yr, or between trials, were conducted. Results Efficacy data in adults and treatment-naïve children are presented in the Table. Complete thrombotic microangiopathy (TMA) response (platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine from baseline, met concurrently at 2 separate assessments, at least 4 wk apart) was achieved in more patients at 2 yr vs 26 wk in both studies (adult: 34 [61%) vs 30 [54%]; naïve: 18 [90%] vs 15 [75%]). All complete TMA response components were either numerically improved or maintained at 2 yr vs 26 wk. Kidney function continued to improve, with the median change in estimated glomerular filtration rate from baseline numerically increasing at 2 yr vs 26 wk in both adults (35 vs 29 mL/min/1.73m 2) and naïve children (82.5 vs 80 mL/min/1.73m 2). Most patients receiving dialysis at baseline were able to discontinue dialysis at 26 wk; this was sustained in adults (67% vs 67%) while all naïve children receiving dialysis at baseline had discontinued by 2 yr (83% vs 100%). No patients who discontinued dialysis by 26 wk subsequently restarted. Chronic kidney disease (CKD) stage improved in most patients through 26 wk in both studies (adult, 68%; naïve, 88%); improvements were sustained at 2 yr (adult, 71%; naïve, 94%). No naïve children experienced a worsening of CKD stage at 2 yr. Improvements from baseline in quality of life were seen at both 26 wk and 2 yr, as measured by Functional Assessment of Chronic Illness Therapy-Fatigue (adults: 20 vs 12; naïve: 10 vs 8), EQ-5D-3L visual analog scale (adults: 32 vs 33) and EQ-5D-3L time trade-off (adults: 0.32 vs 0.31). Most adverse events (AEs) and serious AEs (SAEs) occurring in these studies were reported during the initial 26-wk evaluation period, with a general reduction in the number of patients with any new S/AE events being reported at 2 yr. The most common AEs reported through 2 yr, which had not met the 15% reporting threshold through 26 wk, were (n, %): adults - constipation (9, 16%), fatigue (9, 16%) and nasopharyngitis (9, 16%); naïve children - abdominal pain (6, 25%), contusion (5, 21%), cough (5, 21%), nausea (4, 17%), myalgia (4, 17%), rash (4, 17%) and rhinorrhea (4, 17%); switch children - upper respiratory tract infections (URTI; 4, 40%), oropharyngeal pain (3, 30%), pharyngitis (3, 30%), cough (2, 20%), gastroenteritis (2, 20%), nasopharyngitis (2, 20%), otitis media (2, 20%), viral URTI (2, 20%) and dehydration (2, 20%). No patients discontinued either study due to treatment-emergent AEs after 26 wk. No meningococcal infections were recorded in either study at any timepoints. One adult patient, who had previously met complete TMA response criteria while receiving therapy, discontinued treatment by choice and subsequently experienced recurrent disease, as evidenced by an increase in serum creatinine (SCr). This patient then restarted therapy, leading to improvements in SCr levels. Conclusions In both treatment-naïve adults and children, ravulizumab was associated with numerically sustained or increased improvements in hematologic outcomes and kidney function at 2 yr vs 26 wk. Fewer S/AEs were reported during the extension period of these studies vs the initial 26-wk evaluation periods. Importantly, no meningococcal infections were reported in either study at any timepoint. The data suggest that long-term treatment with ravulizumab is well tolerated and may be associated with continuing improvements in TMA parameters and renal function in adults and children with aHUS. Figure 1 Figure 1. Disclosures Dixon: Apellis Pharmaceuticals: Consultancy; Horizon Pharmaceuticals: Consultancy; Alexion Pharmaceuticals: Consultancy. Kavanagh: Gyroscope Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Apellis: Honoraria, Speakers Bureau; Idorsia: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Alexion Pharmaceuticals: Honoraria, Speakers Bureau. Kang: Alexion Pharmaceuticals: Honoraria, Research Funding; Handok: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Amgen: Research Funding; Bayer: Research Funding. Wang: Alexion, AstraZeneca Rare Disease Inc.: Current Employment. Garlo: Alexion: Current Employment; AstraZeneca: Current Employment. Greenbaum: Alexion Pharmaceuticals: Honoraria, Research Funding. Ogawa: Alexion Pharmaceuticals: Current Employment. Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Alexion: Consultancy, Research Funding; Takeda: Consultancy. Miyakawa: Sanofi: Consultancy; Zenyaku Kogyo: Consultancy; Sanofi: Research Funding; argenx: Consultancy, Research Funding.

Introduction: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially lethal thrombotic microangiopathy; however, prompt therapy with plasma exchange and immunosuppression leads to survival in over 90% of patients. Though TTP survivors were previously thought to return to baseline levels of health, recent reports suggest that TTP survivors have high rates of adverse health sequelae including hypertension, stroke, cognitive impairment, and poor quality of life as well as higher mortality rates compared with an age, race, and sex matched controls population. We conducted this multi-center cohort study to evaluate long term mortality and causes of death in patients that survived their first TTP episode. Methods: All available patients in The Ohio State University and Johns Hopkins Hospital Thrombotic Microangiopathy (TMA) registries were reviewed. Patients with confirmed iTTP based on ADAMTS13 activity Results: A total of 222 patients were enrolled in the Ohio State University and Johns Hopkins TTP registries between 2003 and 2020, of which 70.3% were female, and median age at enrollment was 42 (IQR [interquartile range] 29, 55) years. There were 38 deaths over a median follow up of 4 (IQR 0, 11) years (and a total of 1318 patient years of follow up). Characteristics of the study cohort are summarized in Table 1. Of the 38 patients that died, 9 died during their first episode of TTP and 29 died after surviving the first TTP episode. Median age at death among those that survived the first TTP episode was 49 (IQR 39, 65) years. Among survivors of acute TTP, cardiovascular disease was the leading primary cause of death (27.6%) followed by relapsed TTP (27.6%), malignancy (20.7%), infection (13.8%), and other/unknown causes (10.3%) (Table 2). Cardiovascular disease was the primary or secondary cause of death in 31% (9 of 29) patients. Cardiovascular causes of death included myocardial infarction, arrhythmia, decompensated heart failure, stroke, and hypertensive emergency. The median age of death from any cardiovascular cause (primary or secondary) was 49 years. Among TTP survivors, male sex [HR 4.39 (95% CI 1.83-10.52, P=0.001), age [HR 1.03 (95% CI 1.01-1.06), P=0.039] and number of TTP episodes [HR 1.12 (96% CI 1.05-1.21), P=0.001] were risk factors for mortality in a Cox regression model also adjusted for hypertension [HR 0.60 (95% CI 0.26-1.37), P=0.228], CKD [HR 1.38 (95% CI 0.61-3.13, P=0.436] and SLE [HR 1.26 (95% CI 1.04-1.21), P=0.771]. The mortality rate in TTP survivors was significantly higher than the expected mortality rate from an age and sex standardized reference US population (2228.3 per 100,000 person years versus 1273.8 per 100,000 person years, P = 0.007) (Figure 1). The median age at death was also lower in TTP survivors compared with the general population (49 versus 78.7 years). Conclusions: TTP survivors have two-fold higher mortality rate than expected rates from a reference US population, adjusted for age, sex and race. Cardiovascular disease is a leading cause of death in patients that survive their first episode of TTP. This may be due to higher rates of cardiovascular risk factors such as hypertension in TTP survivors. Reduced ADAMTS13 activity is a risk factor for all cause and cardiovascular death in the general population (Sonneveld et al.Arterioscler Thromb Vasc Biol. 2016) and may contribute to cardiovascular death in TTP survivors. Our results highlight the need to screen and aggressively manage cardiovascular risk factors in TTP survivors, and for prospective studies examining the vascular sequelae of TTP. Disclosures Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Chaturvedi:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Immune mediated thrombotic thrombocytopenic purpura (iTTP) is defined by thrombocytopenia and microangiopathic hemolytic anemia caused by severely deficient ADAMTS13 activity ( Patients/Methods: This analysis utilized samples from patients enrolled in the Ohio State University TMA registry beginning in 2003 until 2014. Patients were followed every 3 months to monitor for relapse and for the development of long-term complications. Clinical data (CBC, chemistry, LDH, ADAMTS13 biomarkers) were obtained on each visit to confirm remission in addition to research samples. Clinical and demographic data in addition to biomarkers of complement activation that were performed on banked samples were used to develop a model to quantify the risk for relapse in the following 3 months. A Lasso logistic regression model (Tibshirani et al 1996) with relapse in the following 3 months as the response variable using the R package glmnet (https://cran.r-project.org/web/packages/glmnet/index.html) was used to identify those variables most predictive of relapse from the 17 studied (Table 1). The data from all subjects were split into training data (75%) and testing data (25%) to develop and subsequently test the performance of the model. The final predictors were then standardized to develop the final model and the program to predict the risk of relapse (%) in the following 3 months. Results: Data from a total of 131 patient encounters from 42 patients in a clinical remission were included in the study to develop the statistical model (Table 2). 31(75.6%) were White and 10 (24.4%) were African American. The average age was 42 (18-69), and 31 (75.6%) were women. The median number of encounters from each patient was 2 (range, 1 to 10). From these 131 encounters, 39 relapses occurred in 20 patients over the next 3 months following their clinic visit. The 39 relapse encounters were compared to the 92 encounters where no relapse occurred to develop the model. The performance of both the 11-factor and 6-factor models are shown in Table 3. Given the comparable data in terms of the AUC, sensitivity and specificity to the 11-factor model to predict relapse, the 6-factor model was judged to be more practical given the fewer number of variables. Both the 11-factor and 6-factor models performed better than the ADAMTS13 activity alone. In this model, the presence of ULVWF multimers, increased levels of LDH, complement activation as measured by C3a (log transformed), a lower ADAMTS13 activity (log transformed), ADAMTS13 antigen (log transformed), and younger age increased the risk for relapse. These variables would be entered into the model with the result being read out as a percent risk for relapse in the following 3 months as described in the hypothetical examples in Table 4. Conclusion: Utilizing a model that includes a combination of biomarkers in asymptomatic patients in remission from iTTP provides more accurate identification of patients at increased risk of relapse in the next 3 months, when compared to using the ADAMTS13 activity alone. This model would allow physicians to initiate preemptive therapy with rituximab to patients at the greatest risk for relapse, and potentially avoiding therapy in patients whose risk may be lower than what would be predicted by the ADAMTS13 activity alone. Disclosures Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding.

Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill defined. This report, by an international multidisciplinary working group of obstetricians, nephrologists, hematologists, intensivists, neonatologists, and complement biologists, summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, coexisting symptoms, first-line laboratory workup, and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are: to rule thrombotic thrombocytopenic purpura (TTP) in or out, with urgency, using ADAMTS13 activity testing; to consider alternative disorders with features of TMA (preeclampsia/eclampsia; hemolysis elevated liver enzymes low platelets syndrome; antiphospholipid syndrome); or, ultimately, to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion). Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is paramount as both require urgent specific treatment.

Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. In this global, phase 3, single arm study in complement inhibitor-naive adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. The primary endpoint was complete thrombotic microangiopathy response defined as normalization of platelet count and lactate dehydrogenase and 25% or more improvement in serum creatinine. Secondary endpoints included changes in hematologic variables and renal function. Safety was also evaluated. Ravulizumab treatment resulted in an immediate, complete, and sustained C5 inhibition in all patients. Complete thrombotic microangiopathy response was achieved in 53.6% of patients. Normalization of platelet count, lactate dehydrogenase and 25% or more improvement in serum creatinine was achieved in 83.9%, 76.8% and 58.9% of patients, respectively. Improvement in estimated glomerular filtration rate by one or more stage was achieved in 68.1% of patients by day 183. No unexpected adverse events were reported across a safety analysis set of 58 patients. Four deaths occurred (three within one month of study initiation, including one in a patient excluded based on eligibility criteria after the first dose) with none considered treatment-related by the study investigator. Thus, treatment with ravulizumab once every eight weeks resulted in rapidly improved hematologic and renal endpoints with no unexpected adverse events in adults with atypical hemolytic uremic syndrome.

BACKGROUND Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune thrombotic microangiopathy. Caplacizumab, an anti-von Willebrand Factor Nanobody® , is effective for treating aTTP episodes and is well tolerated. OBJECTIVES AND METHODS In the phase 3 HERCULES trial (NCT02553317), patients with aTTP received double-blind caplacizumab or placebo during daily therapeutic plasma exchange (TPE) and for ≥30 days thereafter. Patients who experienced an exacerbation while on blinded study drug treatment switched to receive open-label caplacizumab plus re-initiation of daily TPE. Exacerbations were defined as recurrence of disease occurring within 30 days after cessation of daily TPE. RESULTS Thirty-one patients (placebo, n = 28; caplacizumab, n = 3) had an exacerbation during double-blind treatment. Twenty-eight patients switched to open-label caplacizumab (placebo, n = 26; caplacizumab, n = 2); the three others discontinued upon exacerbation. Median time to platelet count response (≥150 x 109 /L) was 3.49 days upon receiving caplacizumab. There were no deaths. During open-label treatment, further exacerbation or a major thromboembolic event (vena cava thrombosis) was experienced by one patient (3.6%) each. Consistent with the double-blind phase, the most frequent treatment-emergent adverse events were catheter site hemorrhage (28.6%), headache (21.4%), and epistaxis (17.9%). CONCLUSIONS These results suggest that caplacizumab was efficacious and well tolerated in patients with aTTP who experienced a disease exacerbation during double-blind treatment in HERCULES.

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.

BACKGROUND In acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor-cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia. Caplacizumab, an anti-von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets. METHODS In this double-blind, controlled trial, we randomly assigned 145 patients with TTP to receive caplacizumab (10-mg intravenous loading bolus, followed by 10 mg daily subcutaneously) or placebo during plasma exchange and for 30 days thereafter. The primary outcome was the time to normalization of the platelet count, with discontinuation of daily plasma exchange within 5 days thereafter. Key secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period; recurrence of TTP at any time during the trial; refractory TTP; and normalization of organ-damage markers. RESULTS The median time to normalization of the platelet count was shorter with caplacizumab than with placebo (2.69 days [95% confidence interval {CI}, 1.89 to 2.83] vs. 2.88 days [95% CI, 2.68 to 3.56], P=0.01), and patients who received caplacizumab were 1.55 times as likely to have a normalization of the platelet count as those who received placebo. The percentage of patients with a composite outcome event was 74% lower with caplacizumab than with placebo (12% vs. 49%, P

The original version of this article unfortunately contained a mistake. The penultimate row of Table 4 shows INR > 1.5 which is incorrect. The correct figure is INR

Thrombotic thrombocytopenia purpura (TTP) and atypical hemolytic uremic syndromes (aHUS) are distinct clinical disorders characterized by hemolytic anemia, thrombocytopenia, microthrombi, and end organ damage. TTP is characterized by a low ADAMTS13 activity level at diagnosis of10 % ADAMTS13 activity, while aHUS is characterized as having10 % ADAMTS13 activity. Despite clinical remission, survivors of thrombotic microangiopathy suffer significant comorbidity and decreased quality of life (QOL) than their healthy counterparts. The reason for this is unclear. Is it a lingering effect from their initial acute episode or ongoing subclinical injury/inflammation despite clinical remission? Common clinical complaints validated in practice include increased depression, deficits in memory, concentration, mood, and mental endurance. We suspect headaches may be an important clinical tool toward understanding patient morbidity and decreased QOL. To date, no studies report headache frequency or severity in this population. To answer this question, adult patients3 months since their last acute episode of TTP or aHUS were approached to take a Headache Impact Test (HIT-6) survey. Between June 1, 2013 and May 30, 2014, 31 patients in remission (21 patients with prior TTP and 10 patients with prior aHUS) completed the HIT-6 survey. The survey scores were then compared to the HIT-6 normative population data established by Qualitymetric incorporated. Overall, TTP patients had a significantly higher average HIT-6 score of 59.9 compared to an average HIT-6 score of 51 seen in sex-matched controls (SD 9.6, p value 0.002). No significant difference was seen in the HIT-6 scores of aHUS patients. Of TTP patients studied, approximately 57 % (12/21) had three or more episodes and were24 months since the last episode. The average time since last acute episode in TTP patients was 37.5 months. There was no significant correlation between TTP survivor HIT-6 scores and the number of prior episodes (1, 2, or3) or timing from the last episode (3-6, 7-12, 13-24, or24 months). About 19/21 (90 %) patients, who are TTP survivors, also had a normal ADAMTS13 activity level (10 %) on the day of the survey. Our study suggests that headaches have significant impact on TTP survivors and should be followed in the clinical setting to prevent undue patient morbidity. Larger studies are needed to understand how headaches impact long-term survival and risk of relapse.

Answering TTP was established to engage the thrombotic thrombocytopenic purpura (TTP) community to further the common goals of patient support, education of patients and medical professionals, and the funding of research to improve the treatment and care of TTP patients. Answering TTP convened a dinner symposium on 23 June 2015 in Toronto, Canada during the International Society of Thrombosis and Haemostasis (ISTH) Congress to bring TTP clinicians and research together to highlight the key clinical and research questions in the field. These questions are increasingly important given the recent advances and novel therapies that have or will soon enter clinical study for patients with TTP.

Although steroids are routinely used as an adjunct to plasma exchange (PEX) therapy in the treatment of immune-mediated thrombotic thrombocytopenic purpura (iTTP), limited data regarding their efficacy or effect on ADAMTS13 biomarkers are available. We report the results of a prospective, randomized study that compared the effectiveness of prednisone or cyclosporine (CSA) as adjuncts to PEX in the treatment of iTTP. A total of 26 of the planned 72 subjects were enrolled and treated from November 2007 until February 2014 before the study was halted after a planned interim analysis. Fourteen patients were randomly assigned to the prednisone arm, and 12 to the CSA arm of the study. One patient died in each arm of the study, and 2 patients in the prednisone arm of the study failed to achieve a response and crossed over to the CSA arm, leaving 11 patients in each arm of the study evaluable for the primary end point of exacerbation. One of the 11 prednisone-treated subjects (9%) suffered an exacerbation, whereas 3 of the 11 (27%) patients in the CSA arm suffered an exacerbation. Although there was no significant difference in the exacerbation rate, suppression of the anti-ADAMTS13 antibodies and improvement in ADAMTS13 activity in the first month after stopping PEX were significantly better in the prednisone-treated subjects. Side effects were manageable and comparable in both arms of the study. These data demonstrate the superiority of prednisone over CSA as an adjunct to PEX in the suppression of the anti-ADAMTS13 antibodies and improvement in ADAMTS13 activity. This trial was registered at www.clinicaltrials.gov as #NCT00713193.

Essentials The standard of care for patients with TTP remains daily plasma exchange in addition to immune suppressive therapy.Despite the improved treatment options for TTP, the acute mortality of TTP remains between 15‐20%.Caplacizumab reduces the time to platelet recovery and the exacerbation rate in acute TTP.A better understanding of the cause and treatments of long‐term complications of TTP are needed. Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and a consumptive thrombocytopenia, as a result of severe deficiency of ADAMTS13. The standard of care of the acute episode is treatment with plasma exchange and immunosuppression. After the acute episode is resolved, patients face a significant risk of relapse and long‐term complications associated with significant morbidity and even mortality. Novel treatments have been under development and will be discussed in this review. Caplacizumab, a nanobody that blocks the interaction between VWF and platelets, has shown promising results in decreasing the time to recover from the acute events that will hopefully translate into long‐term clinical benefit for patients. In addition, identifying biomarkers to allow us to better predict the risk for relapse and the development of these long‐term complications in patients with TTP are a few of the challenges that require our attention moving forward.

BACKGROUND Platelets (PLTs) have been associated with the highest rate of transfusion-associated adverse events (AEs) among all blood products. Most of PLT-associated AEs are considered to have an inflammatory mechanism. However, it is still unclear whether prolonged storage of platelets is associated with an increased rate of transfusion-related AEs, especially in the era of universal prestorage leucoreduction. METHODS/MATERIALS In this retrospective study, 52 649 PLT products consisting of about 80% apheresis PLTs and 20% whole blood-derived (WBD) PLTs were transfused to 9415 patients from July 2011 to March 2017. All the PLTs were leucoreduced prior to storage. All but 69 units of the apheresis PLTs were irradiated and none of WBD PLTs were irradiated. During this period, a total of 284 AEs that were reported to the transfusion service were analysed. RESULTS Univariate and multivariate logistic analyses showed that apheresis/irradiated PLTs and PLT age were associated with a significantly increased frequency of inflammation type AEs (OR (95% CI): 2·24 (1·32, 4·15) and 1·30 (1·12, 1·52), respectively). There was a significant increase in the frequency of inflammation AEs associated with prolonged storage of apheresis/irradiated PLTs [OR (95% CI): 1·26 (1·03, 1·53)]. In contrast, there was no association between allergic symptoms and PLT age. Moreover, the frequency of transfusion AEs associated with apheresis/irradiated PLTs (57·2/10 000) was significantly higher than that of WBD/nonirradiated PLTs (26·0/10 000) (P

Background Thrombotic thrombocytopenic purpura (TTP) requires immediate treatment with plasma exchange (PE) to prevent disease mortality and/or morbidity. Frequently, PE is initiated before blood sample is collected to confirm ADAMTS13 deficiency. However, the effect of PE treatments on the evaluation of ADAMTS13 is uncertain. Moreover, the pertinence of ADAMTS13 activity during PE therapy to prediction of treatment outcomes is unclear. Thus, clarification of the diagnostic and prognostic values of ADAMTS13 activity obtained during PE treatment is an unmet clinical need. Study Design and Methods A total of 212 sequential samples were obtained during the course of daily PE treatment from 19 patients with acquired TTP. ADAMTS13 activity levels were determined in these longitudinal samples for analysis. Results After the initial three daily PE procedures, the sensitivities of ADAMTS13 activity in diagnosis of TTP (

Historically, attempts were made to differentiate acquired thrombotic thrombocytopenic purpura (TTP) from atypical hemolytic uremic syndrome (aHUS) based upon the age at presentation and the presence of neurologic or renal injury. Although these means of differentiating acquired TTP from aHUS have now been demonstrated to be inaccurate, there were no clinical consequences as the treatment for both disorders remained plasma exchange therapy (PEX). With the regulatory approval and remarkable efficacy of eculizumab (Soliris) for the treatment of aHUS, the accurate and timely differentiation of acquired TTP from aHUS now has real clinical consequences. In the following review we will address the emerging methods of clinically differentiating acquired TTP from aHUS using collectively their clinical presentation, laboratory data, and initial response to PEX therapy to differentiate patients more consistent with a diagnosis of aHUS, and therefore more likely to benefit from complement inhibition therapy.

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening thrombotic microangiopathy, with an untreated mortality rate of >90%. Prompt treatment with therapeutic plasma exchange (TPE) and immunosuppression improves outcomes in patients with aTTP, but 10-20% of patients still die acutely from this disease. The aim of this analysis was to describe in more detail the characteristics and disease courses of the patients who died during the caplacizumab clinical development program. Methods: Patient narratives on all deaths occurring during the phase 2 TITAN and phase 3 HERCULES studies were extracted. Results: In the overall study periods, a total of 6 patients died, 2 patients enrolled in TITAN (Patients 1 and 2) and 4 patients enrolled in HERCULES (Patients 3-6). Five patients received placebo, while 1 (Patient 6) received caplacizumab. Demographics and baseline disease characteristics are summarized in Table 1. The patient narratives are provided below. Patient 1 (placebo) was a 57-year-old male, with a recurrent episode of aTTP. Baseline platelet count was 25 x109/L and ADAMTS13 activity Patient 2 (placebo) was a 49-year-old female, with an initial presumed aTTP episode. Baseline platelet count was 7 x109/L and baseline ADAMTS13 activity was 75%. The patient did not respond to therapy (TPE and corticosteroids), with platelet counts remaining below 35 x109/L over the whole period. On Day 10 of the study, the patient experienced a cerebral hemorrhage, for which study drug treatment was permanently discontinued. The patient was intubated and died the next day of cerebral hemorrhage. Patient 3 (placebo) was a 62-year-old female with an initial aTTP episode. Baseline platelet count was 18 x109/L and ADAMTS13 activity Patient 4 (placebo) was a 72-year-old female with an initial aTTP episode. Baseline platelet count was 21 x109/L and baseline ADAMTS13 activity was Patient 5 (placebo) was a 30-year-old female enrolled with her third aTTP episode. Baseline platelet count was 21 x109/L and ADAMTS13 activity Patient 6 (caplacizumab) was a 77-year-old female with her initial aTTP episode. Baseline platelet count was 38 x109/L and ADAMTS13 activity Conclusion: Although the use of TPE and immunosuppression reduces mortality in patients with aTTP, the disease is still associated with a substantial risk of mortality. The fact that all 5 immediate deaths occurred in the placebo arm suggests that the use of caplacizumab has the potential to reduce acute mortality in patients with aTTP. Table 1. Baseline demographics and disease characteristics. Table 1 Disclosures Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Scully:Alexion: Consultancy; Ablynx/Sanofi: Consultancy; Novartis: Consultancy; Shire/Takeda: Consultancy; Shire: Research Funding. Peyvandi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria; Kedrion: Honoraria; Alnylam: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Knoebl:Roche: Consultancy; Shire/Takeda: Consultancy; Novo-Nordisk: Consultancy, Research Funding; CSL-Behring: Consultancy; Ablynx/Sanofi: Consultancy. Kremer Hovinga:Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Coppo:Ablynx/Sanofi: Consultancy; Alexion: Consultancy; Shire: Consultancy. Metjian:Genentech: Consultancy, Research Funding; AblynxNV/Sanofi: Consultancy, Research Funding. De La Rubia:Takeda: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy. Pavenski:Ablynx: Honoraria, Research Funding; Bioverativ: Research Funding; Shire: Honoraria; Octapharma: Research Funding; Alexion: Honoraria, Research Funding. De Winter:Ablynx, a Sanofi company: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.

Background: The 50% hemolytic complement (CH50) assay is a non-specific qualitative assay of complement function. CH50 is sometimes used in patients with complement-mediated thrombotic microangiopathy such as atypical hemolytic uremic syndrome (aHUS) to monitor response to complement inhibition. There are multiple commercial assays as well as research-based CH50 assays that are not directly comparable in outcomes or methods. Ravulizumab is a long-acting anti-C5 monoclonal antibody engineered from eculizumab, currently being investigated for the treatment of aHUS. A fully validated free C5 assay, supporting the primary pharmacodynamic endpoint, was utilized in clinical trials of ravulizumab. We have compared local CH50 results from participating sites with the free C5 assay, performed centrally, in patients with aHUS participating in the clinical trial. Methods: Adults and children with aHUS enrolled in phase 3 trials of ravulizumab (NCT02949128 and NCT03131219) were included in this analysis. A validated Gyros-based immunoassay with a fluorescence readout was used to quantify free C5 during the trial. The regulatory-accepted threshold for complete terminal complement inhibition is a free C5 value Results: CH50 data from 10 patients with aHUS (5 adults and 5 children) from four countries (US, Spain, France and UK) were available. A scatter plot of serum CH50 and free C5 versus time is shown in the figure. Complete terminal complement inhibition throughout the evaluation period was demonstrated by the free C5 assay. Results of CH50 did not consistently confirm full complement inhibition, demonstrating discordance with the free C5 assay. Relative to the adults, there was qualitatively more variability in the CH50 results in the pediatric patients. Conclusions: Results from the CH50 assays inconsistently demonstrated full complement inhibition, with discordance with free C5 levels. This discordance requires further investigation. In clinical practice, this has potential to cause different interpretations of complement blockade and highlights the important limitations of CH50 as a technique for assessing complete terminal complement blockade in patients receiving ravulizumab. This study also underscores the need for a commercially available validated measure for determining complement inhibition. Disclosures Cataland: Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. Ariceta:Alexion: Consultancy, Honoraria. Chen:Alexion: Employment. Dixon:Alexion: Consultancy; Apellis Pharmaceuticals: Consultancy; Horizon Pharmaceuticals: Consultancy. Garlo:Alexion: Employment. Greenbaum:Alexion: Consultancy, Honoraria, Research Funding. Rondeau:Alexion: Consultancy, Honoraria. Scully:Novartis: Consultancy; Shire: Research Funding; Shire/Takeda: Consultancy; Alexion: Consultancy; Ablynx/Sanofi: Consultancy. Ortiz:Alexion: Employment.

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is an acute, life-threatening thrombotic microangiopathy that requires urgent and specialized treatment. Prior to the introduction of caplacizumab, the treatment for aTTP was based on daily therapeutic plasma exchange (TPE; to replenish functional ADAMTS13 enzyme) plus immunosuppression (mainly corticosteroids and rituximab; to suppress anti-ADAMTS13 autoantibody production). TPE combined with immunosuppressive therapy improved outcomes in patients; however, episodes of aTTP are still associated with an acute mortality of up to 20% as these therapies do not have an immediate effect on the pathologic microvascular thrombosis. The primary results of the randomized, double-blind, placebo-controlled phase 3 HERCULES study showed that, in combination with TPE and corticosteroids, caplacizumab shortened the time to platelet count response and reduced the incidence of a composite outcome of TTP-related death, exacerbation, or major thromboembolic events, by inhibiting vWF-platelet interaction and, thereby, stopping the formation of microthrombi. As additional immunosuppression per local practice was permitted in HERCULES, the present analysis aimed to determine whether there was any difference in the efficacy of caplacizumab according to the initial immunosuppression regimen. Methods: Data of patients participating in HERCULES were stratified based on the type of first-line immunosuppression regimen (i.e. therapy started up to Day 3 of the treatment period) and analyzed descriptively. The main 2 groups analyzed were those receiving corticosteroids only and those receiving a combined regimen of corticosteroids and rituximab. Differences in dose or dosing frequency were not taken into consideration in this descriptive analysis. Results: Of the 145 randomized patients in the HERCULES study, 112 (77.2%) patients received only corticosteroids as first-line immunosuppressive therapy, while 24 (16.6%) patients received corticosteroids and rituximab (initiated within the first 3 days of the study). Three patients (2.1%) received another type of initial immunosuppression (cyclophosphamide + corticosteroids [n=1], hydroxychloroquine [n=1], and mycophenolate mofetil + corticosteroids [n=1]), 1 patient (0.7%) started immunosuppression later in the study (cyclophosphamide + corticosteroids), while 5 patients (3.4%) did not receive any immunosuppressive treatment during the study. Baseline characteristics between the main 2 subgroups were well balanced (Table 1). Immunosuppressive therapy intensification occurred in 38 patients (33.9%) initiated on corticosteroids alone (most often addition of rituximab [n=37], others included splenectomy [n=2], bortezomib [n=1], mycophenolate mofetil [n=1]), and in 3 patients (12.5%) initiated on corticosteroids with rituximab (bortezomib [n=1] and mycophenolate mofetil [n=3]). Caplacizumab treatment improved outcomes in patients with aTTP irrespective of the type of initial immunosuppression. Data on time to platelet count response and clinical outcomes are summarized in Table 2. Caplacizumab reduced the rate of the composite endpoint of TTP-related death, exacerbation, and major thromboembolic events during the double-blind treatment period irrespective of baseline immunosuppression regimen. Notably, in the placebo arm, exacerbations occurred in both subgroups to a similar extent, indicating that corticosteroids, with or without rituximab, are not immediately effective. Overall, recurrences (exacerbations or relapses) during the study were also reduced by caplacizumab in both subgroups (Table 2). Two placebo patients died during the treatment period in the corticosteroid only subgroup versus none in the corticosteroid plus rituximab subgroup (one other placebo patient died during the study drug treatment period while receiving another type of immunosuppression). Conclusion: Immunosuppressive therapy in aTTP aims to control the underlying autoimmune disease, but requires time to take effect; this exposes patients to thrombotic complications and death. Caplacizumab treatment prevents disease exacerbations and death, irrespective of the type of initial immunosuppression used, allowing time for immunosuppressive therapy to take effect. Disclosures Pavenski: Ablynx: Honoraria, Research Funding; Shire: Honoraria; Alexion: Honoraria, Research Funding; Octapharma: Research Funding; Bioverativ: Research Funding. Knoebl:Novo-Nordisk: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy; CSL-Behring: Consultancy; Shire/Takeda: Consultancy; Roche: Consultancy. Scully:Shire: Research Funding; Alexion: Consultancy; Ablynx/Sanofi: Consultancy; Shire/Takeda: Consultancy; Novartis: Consultancy. Kremer Hovinga:Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology). Coppo:Shire: Consultancy; Ablynx/Sanofi: Consultancy; Alexion: Consultancy. Peyvandi:Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria; Kedrion: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Metjian:Genentech: Consultancy, Research Funding; AblynxNV/Sanofi: Consultancy, Research Funding. De La Rubia:Celgene Corporation: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; AMGEN: Consultancy; Janssen: Consultancy. De Winter:Ablynx, a Sanofi company: Employment. de Passos Sousa:Sanofi: Employment. Callewaert:Sanofi (formerly employed by Ablynx, a Sanofi company): Employment.