Acute Thrombotic Thrombocytopenic Purpura Research Articles

Practical Considerations for the Use of the Rapid AcuStar® ADAMTS13 Activity Assay in the Diagnosis of Acute Thrombotic Thrombocytopenic Purpura (TTP)

Introduction: Conventional practice in the management of acute TTP entails empirical treatment of suspected cases whilst awaiting confirmatory ADAMTS13 deficiency testing. Rapid ADAMTS13 assays offer increased accessibility and rapid diagnostics. The new automated HemosIL AcuStar® ADAMTS13 assay has seen increasing use among UK TTP Specialist Centres alongside the traditional ELISA method to confirm severe ADAMTS13 deficiency. Methods: A multi-centre retrospective case-control study was performed to review patients demonstrating discrepant ADAMTS13 activity results measured using rapid (AcuStar®) and ELISA assays in parallel from September 2019 to December 2021. Cases were compared with a cohort of suspected TTP patients exhibiting no difference in assay results and in relation to their presenting characteristics and pre-test probability of a diagnosis of TTP. Results: Where the clinical index of suspicion for TTP was high at presentation, acute TTP was confirmed using the AcuStar® assay < 0.2 IU/dL and subsequently < 10 IU/dL by ELISA with zero incidence of discrepancy. For patients with low clinical suspicion of acute TTP, a discrepancy between the AcuStar® and ELISA assay results was observed in 2% of cases; 5–10 IU/dL in AcuStar®, confirmed as >20 IU/dL by ELISA. A concurrent cancer diagnosis or sepsis was observed in 40% of discrepant cases. Conclusions: Where acute TTP is strongly suspected, there is a good correlation between the rapid AcuStar® ADAMTS13 assay and the conventional ELISA assay. Where the clinical suspicion of acute TTP is low, caution should be exercised in the interpretation of the ADAMTS13 activity using the AcuStar® assay. Accurate interpretation requires robust ADAMTS13 testing algorithms to be incorporated into diagnostic pathways.

Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura

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

Mechanism underlying severe deficiency of plasma ADAMTS-13 activity in immune thrombotic thrombocytopenic purpura

BackgroundImmune-mediated thrombotic thrombocytopenic purpura is caused by autoantibodies against ADAMTS-13, a plasma enzyme that cleaves von Willebrand factor. However, the mechanism resulting in severe deficiency of plasma ADAMTS-13 activity remains controversial. ObjectivesTo determine the mechanism of autoantibody-mediated severe deficiency of plasma ADAMTS13 activity in immune-mediated thrombotic thrombocytopenic purpura. MethodsFluorescence resonance energy transfer-VWF73 was used to determine plasma ADAMTS-13 activity. Enzyme-linked immunosorbent assay (ELISA) was used to determine anti–ADAMTS-13 immunoglobulin G. ELISA and capillary electrophoresis–based Western blotting were employed to assess plasma ADAMTS-13 antigen. ResultsWe showed that plasma ADAMTS-13 antigen levels varied substantially in the samples collected on admission despite all showing plasma ADAMTS-13 activity of <10 IU/dL (or <10% of normal level) using either ELISA or Western blotting. More severe deficiency of plasma ADAMTS-13 antigen (<10%) was detected in admission samples by ELISA than by capillary Western blotting. There was a significant but moderate correlation between plasma ADAMTS-13 activity and ADAMTS-13 antigen by either assay method, suggesting that severe deficiency of plasma ADAMTS-13 activity is not entirely associated with low levels of ADAMTS-13 antigen. ConclusionWe conclude that severe deficiency of plasma ADAMTS-13 activity primarily resulted from antibody-mediated inhibition, but the accelerated clearance of plasma ADAMTS-13 antigen via immune complexes may also contribute significantly to severe deficiency of plasma ADAMTS-13 activity in a subset of patients with acute immune-mediated thrombotic thrombocytopenic purpura.

ADAMTS13 recovery in acute thrombotic thrombocytopenic purpura after caplacizumab therapy

AbstractCaplacizumab prevents the interaction between von Willebrand factor and platelets and is used to treat immune thrombotic thrombocytopenic purpura (iTTP). Its administration has been associated with a delay in ADAMTS13 activity restoration after plasma exchange (PEX) suspension. We analyzed the outcomes of 113 iTTP episodes, 75 of which were treated with caplacizumab, in 108 patients from the Spanish Registry of Thrombotic Thrombocytopenic Purpura. Caplacizumab shortened the time to platelet count normalization and reduced PEX requirement, exacerbations, and relapses. There was no difference in the time to achieve ADAMTS13 activity ≥20% after PEX end between caplacizumab-treated and nontreated episodes (median [interquartile range], 14.5 [7.7-27.2] vs 13.0 [8.0-29.0] days, P = .653). However, considering the 36 episodes in which caplacizumab was started ≤3 days after iTTP diagnosis, the time for ADAMTS13 restoration from PEX end was higher than in those episodes in which caplacizumab was started >3 days after iTTP diagnosis (20.0 [12.0-43.0] vs 11.0 [3.5-20.0] days, P = .003) or than in non-caplacizumab-treated episodes (P = .033). This finding could be related to a significantly shorter duration of PEX in early caplacizumab-treated episodes than in late caplacizumab-treated episodes (5.5 [4.0-9.0] vs 15.0 [11.0-21.5] days, P < .001) or non-caplacizumab-treated episodes (11.0 [6.0-26.0] days, P < .001). There were no differences in time to ADAMTS-13 restoration from PEX start (28.0 [17.2-47.5], 27.0 [19.0-37.5] and 29.5 [15.2-45.0] days in early caplacizumab-treated, late caplacizumab-treated and non-caplacizumab-treated episodes). Early administered caplacizumab does not prevent the requirement for immunosuppression but has beneficial effects by shortening PEX requirement without major safety concerns.

The Bioluminescent Modified Ham Test Identifies the Classical Pathway As the Major Driver of Complement Activation in Atypical Hemolytic Uremic Syndrome and Primary Antiphospholipid Syndrome

Introduction: The role of complement is increasingly recognized in disease pathogenesis, however diagnostic assays are limited by low predictive value, technical requirements, and inability to assess relative contributions of each pathway of complement (classical, alternative, or lectin). The traditional mHam was developed as a functional assay of complement-mediated eukaryotic cell death in atypical hemolytic uremic syndrome (aHUS). However, broader use of the assay has been limited by inter-operator dependence and technical requirements. We have developed a bioluminescent mHam that is robust and easily performed (no cell washes or exogenous reagent addition) and utilizes an autonomously bioluminescent HEK293 cell line to allow for real-time assessment of changes in metabolic health due to complement activation. Given both HEK293 and endothelial cells lack complement receptor 1 (CR1), a crucial regulator of the classical pathway (CP), this assay measures complement activity of greater relevance to disease pathogenesis. Methods: The bioluminescent mHam uses LiveLight (LL) HEK293 cells (490 BioTech) engineered to stably express the bacterial luciferase ( lux) and flavin reductase genes ( luxF) to create autonomous bioluminescence. A PIGA null clone (LL PIGA- HEK293) was created through proaerolysin selection (removing GPI-anchored complement regulators CD55 and CD59). To perform the assay, 40,000 cells were harvested with trypsin/EDTA and plated as triplicates in gelatin veronal buffer (GVB ++,80 µL). Serum (20 µL) was added after specified treatments (heat inactivation or inhibitor addition). Activity was monitored by serial luminescence measurements every 5 min at 37 °C. A relative luminescence of &amp;lt;25% at one hour is designated as positive based upon lowest replicate of any healthy control. Results: The bioluminescent mHam, unlike the original mHam, provides continuous measurement of complement activity (example tracing Figure 1). The complement specificity of the luminescent changes were demonstrated with heat inactivation, terminal complement blockade with eculizumab, and calcium/magnesium dependence. The relative contribution of CP to changes in luminescence was confirmed with the specific CP inhibitor sutimlimab as well as use of pathway specific buffers. Healthy control (HC) samples show a relative luminescence of 53.7% (95%CI 44.0-63.4) with no difference observed in acute thrombotic thrombocytopenic purpura (TTP) (mean 56.2%, 95%CI 41.2-71.2, p=&amp;gt;0.9999). We next utilized samples of aHUS patients known to be in remission, off complement inhibitor therapy. A large proportion of these patients have ongoing assay positivity even in the traditional mHam (9 of 13 in one unpublished cohort). The bioluminescent mHam shows that 5 of 6 aHUS patients in remission have ongoing positivity (mean 17.56%, 95%CI -10.5-45.6, p=0.0131). An acute aHUS sample showed similar results (17.8% after plasmapheresis). Unexpectedly, the relative luminescence is rescued by addition of either C1s or C5 inhibitors, but use of alternative pathway (AP) inhibitors has no significant rescuing effect ( Figure 1-2). Of aHUS patients tested while on complement inhibition, 91% (10/11) show greater than 88% blockade ( Figure 2 aHUS on therapy) . Finally, in one cohort, the traditional mHam was positive in 52% (14/27) of primary antiphospholipid syndrome (PAPS) cases and 15% (10/66) of secondary APS (SAPS) (unpublished data). Thus far, the bioluminescent mHam shows abnormal complement activity in 92% (12/13) of PAPS and 17% (2/12) of patients in SAPS ( Figure 2). Again, complement inhibition with C1s or C5 inhibitors abrogated the effect in a dose dependent manner. Conclusions: The bioluminescent mHam test is an exquisitely sensitive real-time measure of abnormal complement activity. It is easy to perform, more closely approximates the complement regulators on renal endothelium, can be utilized for therapeutic monitoring, and has already offered novel disease insights through the use of specific pathway inhibitors. Although aHUS is traditionally categorized as a disorder of the AP, these results suggest the “trigger” mediating disease pathology is the classical pathway. Also, we show that a large proportion of primary APS patients have abnormal CP activation responsive to C1s and C5 inhibition, suggesting the disease may be responsive to complement-based therapeutics.

Thrombotic Thrombocytopenic Purpura (TTP) Survivors Exhibit Impaired Stress Perfusion on Cardiac MRI

Introduction: Thrombotic thrombocytopenic purpura (TTP) survivors have increased rates of cardiovascular morbidity and mortality when compared with the general population. In this prospective pilot study, we sought to further characterize the long-term cardiovascular sequelae of TTP survivors through pharmacologic stress cardiac magnetic resonance imaging (CMR). Stress CMR has been increasingly utilized to detect clinical and subclinical structural and functional changes. A CMR biomarker of myocardial remodeling is extracellular volume (ECV); an increase in ECV may indicate the development of interstitial myocardial fibrosis. ECV was chosen for structural assessment as it has been implicated with diastolic dysfunction and other cardiac issues in other hematologic diseases, like sickle cell anemia. Methods: Adult patients (age ≥18 years of age) with TTP (immune-mediated or congenital) in the Ohio State University (OSU) TTP registry were prospectively consented and enrolled from March 2023 through July 2023 to undergo adenosine stress CMR at standard clinical dosing. All patients in the TTP cohort had confirmed diagnosis based on ADAMTS13 activity &amp;lt;15% during an acute episode and were in clinical remission at the time of CMR testing. Standard baseline and stress CMR parameters were obtained and compared with an age and sex matched control population, selected from patients without TTP who underwent identical stress CMR protocol for other indications and demonstrated normal stress perfusion. Patients in the control cohort predominantly had diagnoses of arrhythmia, stable angina, or heart failure. We collected data on patient demographics, details of TTP history, and underlying comorbidities. On CMR standard structural measurements were evaluated, and ECV was calculated (normal range 25.3 ± 3.5%). Perfusion was measured per standard protocols via global myocardial blood flow (MBF) as ml/min/g. Differences between the TTP and control populations were tested using the Fischer's exact test for categorical variables and Mann-Whitney U test for continuous variables. Results: A total of 10 TTP patients (9 immune-mediated, 1 congenital) were enrolled between March and July 2023. Median age at enrollment was 44.5 years (IQR 40.8-49.5) and 80% (8/10) were female. Patients were in documented clinical and ADAMTS13 activity remission with median ADAMTS13 activity of 68% (64.0-84.5), excluding the activity level of the congenital patient. Median time from initial diagnosis was 15 years (range 0.5 - 41 years) and median number of acute TTP episodes was 2 (IQR 1.0-4.5). Characteristics of the study (n= 10) and control cohort (n = 13) are summarized in Table 1. There were no significant differences in the TTP and control cohorts with respect to age, sex, race, and presence of hypertension or diabetes. Patients in the TTP cohort had significantly higher BMI (median 34.5 mg/m 2 vs 26.5 mg/m 2, p = .012), diastolic blood pressure (94 mmHg vs 82 mmHg, p = .003), and a lower rate of known cardiac disease (10% vs 85%, p&amp;lt;.001). Stress CMR showed reduced myocardial perfusion in TTP survivors: Nine out of 10 (90%) TTP survivors had evidence of structural or perfusion deficits on CMR. The median ECV in the TTP cohort (28.5%, 24.8 - 31.5) was increased compared with controls (26%, 23.5 - 27.5) though it did not reach significance (p = .08). There were no significant differences in median global MBF at rest in the TTP group (1.30, 1.16 - 1.37) compared with controls (1.18, 1.07 - 1.31, p = .210). However, TTP survivors had significantly reduced stress MBF (3.28, 2.21 - 3.53) vs controls (4.1, 3.88 - 4.22, p &amp;lt;.001) with adenosine. Reductions in quantitative stress perfusion in the TTP cohort was primarily noted in the subendocardium as shown in Figure 2. Conclusion: Asymptomatic structural changes and reduction in quantitative perfusion are common in TTP survivors. The study is ongoing to recruit more patients to ensure clinical significance and generalizability of these preliminary findings. Stress CMR may detect subclinical myocardial damage in TTP survivors who otherwise do not exhibit overt cardiovascular symptoms until a later time and may provide the basis to understand increased cardiovascular morbidity and mortality in this population.

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 &amp;gt;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.

OC 26.3 Main Features of Ischemic Stroke in Patients with Acute Immune-Mediated Thrombotic Thrombocytopenic Purpura

OC 26.3 Main Features of Ischemic Stroke in Patients with Acute Immune-Mediated Thrombotic Thrombocytopenic Purpura

Immune thrombotic thrombocytopenic purpura: Spotlight on long-term outcomes and survivorship.

Advances in diagnosis and treatment have dramatically improved survival of acute immune thrombotic thrombocytopenic purpura (iTTP) and iTTP has evolved from an acute fatal condition to a chronic relapsing disorder. In addition to the risk of iTTP relapse, iTTP survivors are at risk of multiple adverse health outcomes including higher than expected rates of all-cause mortality, increased rates of stroke and other cardiovascular disease, and higher rates of morbidities such as obesity, hypertension, and autoimmune disorders. iTTP survivors also report neurocognitive impairment, depression, and reduced quality of life. Women with iTTP are at risk for recurrent iTTP, preeclampsia, and other maternal and fetal complications in subsequent pregnancies. ADAMTS13 activity during clinical remission has emerged as an important targetable risk factor for iTTP relapse and other outcomes including stroke and all-cause mortality. This review summarizes current literature regarding the epidemiology and potential mechanisms for adverse long-term sequelae of iTTP, outlines current best practices in iTTP survivorship care, and highlights a research agenda to improve long-term iTTP outcomes.

Autoantibodies enhance ADAMTS-13 clearance in patients with immune thrombotic thrombocytopenic purpura

BackgroundSevere deficiency in ADAMTS-13 (<10%) and the loss of von Willebrand factor–cleaving function can precipitate microvascular thrombosis associated with thrombotic thrombocytopenic purpura (TTP). Patients with immune-mediated TTP (iTTP) have anti-ADAMTS-13 immunoglobulin G antibodies that inhibit ADAMTS-13 function and/or increase ADAMTS-13 clearance. Patients with iTTP are treated primarily by plasma exchange (PEX), often in combination with adjunct therapies that target either the von Willebrand factor-dependent microvascular thrombotic processes (caplacizumab) or the autoimmune components (steroids or rituximab) of the disease. ObjectivesTo investigate the contributions of autoantibody-mediated ADAMTS-13 clearance and inhibition in patients with iTTP at presentation and through the course of the PEX therapy. Patients/MethodsAnti-ADAMTS-13 immunoglobulin G antibodies, ADAMTS-13 antigen, and activity were measured before and after each PEX in 17 patients with iTTP and 20 acute TTP episodes. ResultsAt presentation, 14 out of 15 patients with iTTP had ADAMTS-13 antigen levels of <10%, suggesting a major contribution of ADAMTS-13 clearance to the deficiency state. After the first PEX, both ADAMTS-13 antigen and activity levels increased similarly, and the anti-ADAMTS-13 autoantibody titer decreased in all patients, revealing ADAMTS-13 inhibition to be a modest modifier of the ADAMTS-13 function in iTTP. Analysis of ADAMTS-13 antigen levels between consecutive PEX treatments revealed that the rate of ADAMTS-13 clearance in 9 out of 14 patients analyzed was 4- to 10-fold faster than the estimated normal rate of clearance. ConclusionThese data reveal, both at presentation and during PEX treatment, that antibody-mediated clearance of ADAMTS-13 is the major pathogenic mechanism that causes ADAMTS-13 deficiency in iTTP. Understanding the kinetics of ADAMTS-13 clearance in iTTP may now enable further optimization of treatment of patients with iTTP.

Delayed normalization of ADAMTS13 activity in acute thrombotic thrombocytopenic purpura in the caplacizumab era

AbstractThe benefits of caplacizumab in acute immune-mediated thrombotic thrombocytopenic purpura (iTTP) are well established. We identified a delayed normalization of a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13 (ADAMTS13) activity (>30%) in a subgroup treated with caplacizumab, not evident in the precaplacizumab era. Patients treated with caplacizumab (n = 64) achieved ADAMTS13 activity >30% at median 31 days after plasma exchange (PEX), compared with 11.5 days in the noncaplacizumab group (n = 50, P = .0004). Eighteen of 64 (28%) patients treated with caplacizumab had ADAMTS13 activity <10% at stopping caplacizumab with a longer time to ADAMTS13 activity >30% (median, 139 days after completing PEX). Eighteen of 64 (28%) patients receiving extended caplacizumab (31-58 days) failed to achieve ADAMTS13 activity >30% at the time of caplacizumab cessation, compared with 4 of 47 (8.5%) historical controls at a similar timepoint (30 + 28 days, P < .0001). Failure to achieve ADAMTS13 activity >30% within 30 + 28 days was 6 times more likely with caplacizumab (odds ratio, 6.3; P = .0006). ADAMTS13 antigen <30% at caplacizumab cessation was associated with increased iTTP recurrence (4/10 vs 0/9 in patients with ADAMTS13 antigen ≥30%). Admission anti-ADAMTS13 immunoglobulin G (IgG) antibody level did not predict recurrence. Anti-ADAMTS13 IgG antibody levels, immunosuppression, and ethnicity did not account for differences in ADAMTS13 activity response. ADAMTS13 antigen levels ≥30% may be useful to guide stopping caplacizumab therapy after extended use with ADAMTS13 activity <10%. The reason for delayed ADAMTS13 normalization is unclear and requires further investigation.

Combination regimens containing daratumumab for initial diagnosed acquired thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia associated with disseminated microvascular platelet-rich thrombus. Before the introduction of plasma therapy, acute TTP was almost universally fatal, which improved survival from < 10 to 80-90%. However, patients who survived an acute attack were at high risk for recurrence and long-term morbidity. It was reported that daratumumab can eradicate persistent ADAMTS13-inhibiting autoantibodies and restore ADAMTS13 activity in two patients with relapsed immune-mediated TTP without associated adverse drug reactions. Here we report a case series of patients with initial diagnosed acquired TTP treated with combination regimens containing daratumumab. All the patients achieved clinical response after the initial treatment. Three patients achieved clinical remission, one patient relapsed and one patient suffered an exacerbation during follow-up. The two patients were retreated with glucocorticoids, plasma exchange combined with daratumumab, and clinical remission was achieved again. Combination of daratumumab in the treatment of initial diagnosed acquired thrombotic thrombocytopenic purpura can rapidly restore ADAMST13 activity and turn negative for ADAMST13 inhibitors, resulting in long-term remission in patients.

Rapid Diagnosis of Acute Thrombotic Thrombocytopenic Purpura (TTP) Using a New Fully Automated Chemiluminescent Assay for Adamts-13 Activity. Clinical Performance and Cost-Effectiveness Analysis

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy (TMA) that can be caused by congenital or acquired severe deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), an enzyme that cleaves von Willebrand factor (VWF). ADAMTS-13 deficiency leads to the accumulation of ultra-large VWF multimers, leading to platelet aggregation and microthrombi formation. Aside clinical symptoms, the diagnosis of TTP is based on laboratory parameters such as thrombocytopenia, hemolytic anemia with the presence of schistocytes, and severely reduced activity of ADAMTS-13 (<10%). As TTP is a life-threatening condition characterized by microvascular thrombosis, it is of great importance to shorten the time to the treatment, and according to the French recommendations, patients with suspected TTP must be treated with the triplet therapy including plasma exchange (PEX), rituximab, and caplacizumab, plus corticosteroids until the results of ADAMTS-13 was obtained. As this therapy must be pursued only in the case of deficiency, a rapid ADAMTS-13 testing is critical for early diagnosis and optimal management of acute TTP. Design and aims of the study: We first retrospectively compared the performance of a rapid fully automated chemiluminescent assay (HemosIL AcuStar ADAMTS-13) to those of the FRETS-VWF73 assay in the diagnosis of TTP. Then, we compared the cost-effectiveness of a strategy based on the on-site measurement of ADAMTS-13 activity using the AcuStar assay vs. its centralized measurement in a reference laboratory, as it is currently the case at our institution. For that purpose, we created two scenarios based on either the local measurement of ADAMTS-13 activity with a maximum time-to-result of 16 hours (assay performed during daytime, 7/7) or its centralized measurement with a median time-to-result of 4 days (range: 2-8), as demonstrated from the 2018-2021 estimates. The triplet therapy was hypothesized to be started on admission and stopped if ADAMTS-13 activity was >10%. In case of ADAMTS-13 activity <10%, an inhibitor screening would be performed at the reference laboratory, as this assay was not expected to be locally implemented. For the calculation, we considered the costs of reagent, shipping/handling of the samples to the reference laboratory, laboratory staff workload, reimbursement rates, and treatments administered in patients with suspected TTP until availability of the ADAMTS-13 result. Results: In the plasma from 56 patients with acute TMA, ADAMTS-13 activity was not significantly different when evaluated using the HemosIL AcuStar ADAMTS-13 and the FRETS-VWF73 assays [median=72.6% (range: 0.2-126) vs. 79% (range: 5-150); p=0.08]. The concordance of test results as whether ADAMTS-13 activity was below (n=5) or above the threshold of 10% using the 2 assays was excellent (kappa=1.00), allowing an accurate diagnosis of the 5 patients with confirmed TTP. Based on the local activity between 2018 and 2021, there was a mean of 60 prescriptions of ADAMTS-13 activity per year. Most were for the follow-up of TTP patients and for patients with non-TTP TMA, whereas 7 were for the diagnosis of acute TTP, as suggested by the French score, which was confirmed in 4 cases (mean values). As shown in the Table, the local measurement of ADAMTS-13 activity was found to be cost-effective with a 16%-reduction of the costs compared to its centralized measurement in the 7 patients with suspected TTP during the first 4 days. This equates to 4,508 € saved per patient with suspected acute TTP. Conclusions: Together with its short turnaround time (33 min) and its full automation, our results suggest that the HemosIL AcuStar ADAMTS-13 activity assay could be an assay of choice to rapidly measure ADAMTS-13 activity in the plasma and thus to establish the diagnosis of acute TTP in emergency settings. Considering the local costs, using the strategy based on the local evaluation of ADAMTS-13 activity led to a 16%-reduction of the overall costs during the first 4 days after admission of the 7 patients with suspected acute TTP. Moreover, by dramatically decreasing the time-to-result (<1 day vs. 4 days), unnecessary potentially harmful and expensive treatments could be withheld earlier in patients in whom the diagnosis of TTP was ruled out based on an ADAMTS-13 activity >10%. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hereditary thrombotic thrombocytopenic purpura and COVID‐19: Impacts of vaccination and infection inrare disease

1 IntroductionSevere COVID‐19 is associated with an important increase of von Willebrand factor and mild lowering of ADAMTS13 activity that may, in the presence of a strong inflammatory reaction, increase the risk of acute thrombotic thrombocytopenic purpura (TTP). Although acute episodes of immune‐mediated TTP associated with COVID‐19 or SARS‐CoV‐2 vaccination have been reported, data about clinical evolution of hereditary TTP (hTTP) during the pandemic are scarce. 2 MethodWe conducted a survey among adult patients of the International Hereditary TTP Registry about SARS‐CoV‐2 vaccination, COVID‐19, and occurrence of acute hTTP episodes. 3 ResultsOf 122 adult hTTP patients invited to participate, 86 (70.5%) responded. Sixty‐five had been vaccinated (75.6%), of which 14 had received in addition a booster, resulting in 139 individual vaccine shots. Although vaccinations in patients on plasma prophylaxis were done within 1 week of the last plasma infusion, all 23 patients treated with plasma on demand were vaccinated without prior plasma infusions. One patient on uninterrupted weekly plasma infusions presented within 3 days from his second vaccination with neurological symptoms and computed tomography scan 9 days later showed subacute ischemic/hemorrhagic frontal lobe infarction. A second male patient developed acute myocarditis after his second dose of mRNA‐1273 vaccine. Twelve (14%) patients had COVID‐19, associated with an acute hTTP episode in three of them: one patient had a transient ischemic attack, one a stroke, and a pregnant woman was hospitalized to intensify plasma treatment. 4 DiscussionThe risk of an acute episode triggered by COVID‐19 seems higher than following vaccination in hTTP patients, who can be safely vaccinated against SARS‐CoV‐2.

Diagnostic uncertainty presented barriers to the timely management of acute thrombotic thrombocytopenic purpura in the United Kingdom between 2014 and 2019

BackgroundAcute thrombotic thrombocytopenic purpura (TTP) is a life‐threatening emergency and plasma exchange (PEX) is the initial treatment shown to reduce acute mortality. ObjectivesTo compare current practice in the United Kingdom (UK) against the standards set out in the 2012 British Society of Haematology guideline, and to better understand the issues affecting prompt initiation of PEX. Patients/MethodsThe trainee research network HaemSTAR conducted a retrospective nationwide review of adults presenting to UK hospitals with a first episode of acute TTP. ResultsData on 148 patients treated at 80 UK hospitals between 2014 and 2019 demonstrated that 64.8% of patients received PEX within 24 h. Diagnostic uncertainty was the most commonly cited reason for delayed treatment. Conversely, a shorter time to PEX occurred in patients who had red cell fragments or severe thrombocytopenia identified on their first complete blood count. Availability of on‐site PEX was associated with a greater proportion of patients receiving PEX within 8 h compared to patients transferred, but by 24 h there was no difference between the two groups and two‐thirds of all patients had received their first PEX. The mortality rate for patients that received PEX was 9.2%, with 27.8% of deaths linked to delayed treatment initiation. ConclusionsThis is the first multi‐center evaluation of treatment delays in acute TTP and it will inform targeted pathways to improve prompt access to life‐saving intervention.

Mortality in Acute Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP) Is Unpredictable: Poor Statistical Performance of Mortality Prediction Models

Background:Mortality due to acute immune thrombotic thrombocytopenic purpura (iTTP) is estimated at 10% with current standard treatment with plasma exchange (PLEX) and corticosteroids. Caplacizumab was recently shown to reduce mortality in acute iTTP, but may not be cost-effective in treating all patients. Predicting the risk of iTTP-related mortality has been of interest as it may help individualize treatment by considering more intensive treatment approaches that could further reduce mortality, as well as improving cost-effectiveness by restricting caplacizumab use to high-risk patients. The French Thrombotic Microangiopathy (TMA) Reference Score was developed as predictive model for acute iTTP mortality and was validated in the French TMA registry. External validation of the score on a large United States population has not been performed. The USTMA iTTP registry contains outcome data on 771 patients diagnosed with iTTP from 15 high-volume TTP referral centers. The aim of this study was to validate or improve upon the French TMA Reference Score using the USTMA iTTP registry.Methods:We included participants with initial presenting iTTP episode (n=419) from the USTMA iTTP registry (n=771) between 1985 and 2019. We analyzed thirty different baseline patient demographics, laboratory findings and treatment variables at time of initial presentation. We excluded ADAMTS13 inhibitor/antibody levels due to inconsistency in reporting of assays. We defined acute iTTP mortality as death within 30 days of last PLEX.Validation of French score:Risk scores of 0 - 4 were assigned according to the French TMA Reference score based on age, lactate dehydrogenase (LDH) level, and presence of neurologic symptoms. After the analysis demonstrated low area under the receiver operating characteristic curve (AUC) in our population, we then utilized our registry to develop a novel mortality prediction model.Development of the USTMA TTP Mortality Index:Patient characteristics at presentation were compared between first episode survivors vs. non-survivors, and those with p values < 0.1 were entered as candidate predictors to develop a logistic regression model. Missing values were imputed using multiple imputation using chained equations (MICE), and 15 augmented datasets were generated. For each of the imputed datasets a model was selected using the Lasso method, and then the coefficients from the 15 models were averaged to form a final prediction model. Odds ratios (ORs), 95% confidence intervals (CIs) and p-values were reported from the final model. AUC was evaluated on the pre-imputed data (n=348), as well as using 5 fold cross validation on the imputed data sets.Results:Validation of the French TMA Reference Score:We found that the French TMA Reference Score performed poorly to predict death from acute iTTP in our cohort: AUC 0.63 (95% CI: 0.50-0.77) (Figure 1a), compared to the AUC of 0.77 reported in the French population. Using a cut-off of ≥ 3, the sensitivity was 0.35, specificity was 0.84, and positive predictive value was 0.1.Development of the USTMA TTP Mortality Index:There were 24 deaths (5.7%) in our cohort. We identified six variables to be included in the predictive model below. A nomogram for the model was developed and is depicted in Figure 2. •Age: OR = 1.12 (0.99,1.58)•Male sex: OR = 1.16 (0.93,3.04)•Stupor or coma on presentation: OR: 2.08 (0.90,8.87)•Hemoglobin level (g/dL): OR = 1.23 (1.00,1.43)•LDH level (U/L): OR = 1.08 (0.91,1.32)•Creatinine level mg/dL: OR = 1.10 (1.00,1.81)Performance of the USTMA TTP Mortality Index model:The model has an AUC of 0.78 (95% CI 0.67-0.90) on the pre-imputation cohort of 348 patients who had complete data on the model variables (Figure 1b), and a 5 fold cross-validated AUC of 0.69 (95% CI: 0.58 ~ 0.78) (Figure 1c).Conclusion:Both the French TMA Reference score and the USTMA TTP Mortality Index demonstrated poor performance in predicting iTTP mortality in our study. The low mortality rate observed in this database is consistent with recent randomized trials, but is lower than historically reported, and may contribute to poor accuracy of prediction models. We therefore conclude that mortality due to acute iTTP may be unpredictable with available models. Attempts to tailor caplacizumab specifically to patients with higher risk for acute iTTP-related death, based on available models, may not succeed in reducing mortality or improving cost-effectiveness. [Display omitted] DisclosuresMazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. Lim: Dova Pharmaceuticals: Honoraria; Hema Biologics: Honoraria; Sanofi Genzyme: Honoraria.

Real-World Variability in ADAMTS13 Assay Methods May Impact upon Follow up for Patients with Thrombotic Thrombocytopenic Purpura (TTP)

IntroductionADAMTS13 activity (ADAMTS13:Ac) measurement is an important diagnostic marker in acute TTP (defined as a level of <10%). Increasing numbers of commercial assays have been developed (ELISA, FRET and chemiluminesence) for diagnostic purposes. The International Council for Standardization in Haematology have not made specific recommendations on ADAMTS13 assay selection in a recent publication in 2020.ADAMTS13:Ac has traditionally been used for diagnostic purposes but can also be useful for monitoring disease status and relapse risk. Patients between levels of 10-50% may require increased monitoring and subsequently treatment to avoid frank relapse, with an inverse relationship between ADAMTS13:Ac levels and intensity of clinical monitoring.We seek to compare the differences between different commercial assays available to measure the ADAMTS13:Ac in patients who have a history of TTP and whether this influences clinical practice.MethodsPatients with an acute diagnosis of TTP as an inpatient or outpatient surveillance with past history of TTP were reviewed at Guy's and St Thomas' Hospital, London, UK, and samples were taken to measure ADAMTS13:Ac as part of disease monitoring between February and July 2021. A comparison was performed between an ELISA (Technozym ADAMTS13 activity, Technoclone) and FRET (Technofluor, Technoclone), with all samples processed in parallel. With no international consensus, broadly, levels of <10% were defined as either active TTP or relapse; patients with 10-30% required more intensive outpatient monitoring to detect for relapse and >50% was defined as within the normal range.Results47 samples from 31 known or newly diagnosed TTP patients were processed over a six month period. Intra- and inter-assay CV for both ELISA and FRET on laboratory testing was as expected from manufacturers guidelines.Figure 1 plots the ADAMTS13:Ac ELISA vs FRET, with a Pearson correlation of p=0.949 across all samples. Ranges were for ELISA (0 - 109.3) and FRET (1.6 - 130.3). Mean ADAMTS13:Ac difference was 16±13.5%, with consistent positive bias in favour of the FRET assay. Higher levels demonstrated greater variability as demonstrated in Table 1, with the mean difference between ELISA and FRET increasing with increasing levels.Based on the above definitions as in the methods, there were 14/47 (29%) samples which had discordant results between the ELISA and FRET methods: 3 discordant samples on diagnosis of relapse, 8 discordant for where the ELISA detected levels <30% and FRET >30%; and 2 discordant for where ELISA <50% and FRET >50%.ConclusionReal-world clinical testing demonstrates substantial variability within a single manufacturer between two separate methods and demonstrates an impact on patient follow up and implications in decisions on follow-up intervals and treatment. There was a consistent positive bias in ADAMTS13:Ac by FRET measurement as compared with the ELISA. Greater consistency was demonstrated at the lower end of testing, where there was good concordance at levels of <10%, confirming that both assays were effective at determining a diagnosis or relapse of TTP. Further interrogation of other commercial platforms is warranted to establish the variability of results to inform on clinical practice in the monitoring of patients with TTP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Single-Center Experience of the Utility of a Rapid ADAMTS13 Assay

Introduction: Antibody-mediated thrombotic thrombocytopenic purpura (TTP) is a rare disease with significant morbidity and mortality, requiring prompt diagnosis and intervention. The advent of rituximab use (off-label) for TTP in 2002 not only established a novel therapy for refractory disease, but also raised the possibility of prophylactic therapy. Prophylactic rituximab was found by Westwood et al. to be effective in normalizing ADAMTS13 when activity dropped ≤15% in a retrospective cohort study (Blood Advances, 2017). Treatment paradigms in TTP are changing as evidence builds for prophylactic therapy, but we remain without large, randomized data to guide who would benefit most from prophylactic rituximab.The use of a rapid assay for a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) has been shown to significantly reduce therapeutic plasma exchange (TPE) by ruling-in or -out suspected cases of TTP (Connell et al., Transfusion 2016). The role of rapid ADAMTS13 testing in assessment of response to TPE in acute TTP as well as surveillance of TTP patients in remission continues to be explored. We describe the utilization of a rapid ADAMTS13 assay and its role in the decision to use early or prophylactic rituximab in patients with TTP at the largest referral center for TTP in Rhode Island.Methods: Following IRB approval, demographic data for patients who underwent rapid ADAMTS13 testing from 1/1/13-2/28/17 at Rhode Island Hospital (Providence, RI) was obtained. Patients were deemed to have TTP if they had thrombocytopenia with microangiopathic hemolytic anemia (MAHA) and ADAMTS13 ≤ 10%, or thrombocytopenia with MAHA and a history of TTP. Each patient admission for TTP was recorded as a separate event. Data analysis was performed using Wilcoxon rank sum and Fisher's exact tests.Results: Ninety patients had ADAMTS13 testing from 1/1/13 to 2/28/17. Seven patients were excluded due to age less than 18 years. The remaining 83 patient charts were reviewed. Sixteen events of acquired TTP were diagnosed in 11 patients. Pregnancy-associated TTP did not occur, although 1 relapse of TTP had a history of post-partum TTP. Of the remaining patients, 5 had a history of TTP and underwent surveillance testing of ADAMTS13. One patient had congenital TTP. Diagnoses other than TTP were characterized in 66 patients (Figure 1). The most common other diagnosis found in patients who underwent ADAMTS13 testing was sepsis (n=12).When comparing patients who received rituximab during acute event (n=9) to those that did not (n=7) in 16 TTP events, we observed no statistically significant correlation between rituximab use and age, sex, presenting platelet count, presenting ADAMTS13 activity, presenting ADAMTS13 inhibitor value, days to platelet count normalization, or days of TPE (Table 1). We also observed no significant difference in days of TPE or days to platelet count normalization when comparing patients who received rituximab ≤ 5 days of diagnosis (n=5) versus those who received rituximab > 5 days from diagnosis but during the event (n=4). There was no significant change in rapid ADAMTS13 activity assay use, TPE use or rituximab use by year, from 2013-2016.In three patients with a history of acquired TTP, routine follow-up ADAMTS13 activity assay revealed decreased activity prior to the development of thrombocytopenia. These patients had an ADAMTS13 activity of 1%, 22%, 57% with platelet counts of 166k, 334k, 224k respectively. These patients had a history of 4, 7 and 8 prior events of TTP, respectively. Following the administration of 4 doses of weekly rituximab 375mg/m2, all had improvement in ADAMTS13 activity to >95%, none requiring TPE. These patients are recurrence-free after 7 months, 19 months, and 3 months of follow-up.Conclusions: In our single center retrospective study, early use of rituximab does not appear to confer immediate benefit through reduction of TPE or days to platelet normalization. Routine monitoring of ADAMTS13 activity by rapid assay, in conjunction with rituximab therapy as needed, has been shown to effectively normalize ADAMTS13 activity and possibly prevent relapse in three patients with history of relapsed TTP. Our experience provides evidence against the inpatient use of rituximab in relapsed TTP, and provides justification for the development of a protocol for the routine follow-up of TTP patients with implementation of prophylactic rituximab. [Display omitted] DisclosuresReagan:Teva Pharmaceutical Industries: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Speakers Bureau.

Lysine-Histone Triggers Thrombotic Thrombocytopenic Purpura in Zebrafish and Mice

Background: Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal syndrome, primarily resulting from a severe deficiency of plasma ADAMTS13 activity due to mutations in ADAMTS13 gene or autoantibodies against ADAMTS13. However, severe deficiency of plasma ADAMTS13 activity alone is often not sufficient to cause an acute episode; additional environmental and/or genetic factors may be required to trigger acute TTP.Objectives: To address the potential triggers and identify novel therapeutic targets for TTP, we established and characterized a novel Adamts13-/- zebrafish line and determined the pathogenic role of lysine-histone in triggering TTP in both zebrafish and mice.Methods and Results:CRISPR/Cas9 was employed to create an 8-nt deletion mutation in the signal peptide region of zebrafish Adamts13, resulting in complete deficiency of Adamts13 protein. Adamts13-/- zebrafish on the double transgenic (fli1-eGFP/gata1-dsRed) background showed normal size, morphology, and fertility except for the consistent appearance of a branching interseptal vessel. Adamts13-/- zebrafish larvae exhibited a significantly increased response to oxidative stress with an increased mortality rate and an accelerated rate of thrombus formation in microvasculature and caudal vessels after oxidative injury. Additionally, Adamts13-/- zebrafish demonstrated a significantly reduced number of circulating mature thrombocytes (thrombocytopenia) and an increased number of fragmented red blood cells (schistocytosis), consistent with the clinical phenotype of a spontaneous TTP. Moreover, plasma levels of histone/DNA complexes were found to be highly elevated in patients with acute TTP, but their pathogenic role is not known. Wild-Type and Adamts13-/- zebrafish and mice were challenged with a lysine rich-histone (H5505) intraperitoneally (200 μg/g body weight) and intravenously (20, 60, and 120 μg/g body weight), respectively. Complete blood counts were determined over a period of 14 and 3 days, respectively. We showed a more severe and persistent thrombocytopenia, increased fragmentation of red blood cells, as well as increased mortality rate in Adamts13-/- compared to Wild-Type zebrafish (Figure). Similar dose-dependent and profound thrombocytopenia was observed in Adamts13-/- but not in Wild-Type mice. Histological analysis of the organ tissues from Adamts13-/- zebrafish that died after histone challenge revealed the presence of microvascular thrombosis, supporting the diagnosis of TTP in these zebrafish.Conclusions: These results demonstrate for the first time the success in establishing a zebrafish model of Adamts13-/- and TTP. Such a novel animal model enables us to rapidly evaluate the role of lysine-histone and many other potential environmental or genetic factors in the onset, progression, and outcome of TTP. This model may also help to identify novel therapeutic targets for both hereditary and acquired TTP in at an unprecedented pace. [Display omitted] DisclosuresZheng:Alexion: Speakers Bureau; Ablynx: Consultancy.

Real-world experience with caplacizumab in the management of acute TTP

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti–von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.