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Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultrarare microvascular disease caused by the deficiency of the metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs 13). Approximately half of all cases remain undiagnosed until a triggering event in adulthood; therefore, the prevalence rates may be underestimated. The current standard of care is based on regular transfusions of fresh frozen plasma, which often lead to allergic reactions in patients. Recombinant ADAMTS13 (rADAMTS13) is a novel treatment for cTTP, which has been approved for use in the USA, Europe, and Japan., Objectives: The primary objective of this real-world data collection was to comprehensively analyze the clinical data of pediatric patients with cTTP and to provide real-world evidence of the effectiveness of rADAMTS13 treatment in the pediatric population., Methods: Nine pediatric patients with cTTP were treated with an intravenous infusion of rADAMTS13 every 2 weeks., Results: The results showed an increase in platelet count and a decrease in lactate dehydrogenase levels compared with baseline. None of the patients experienced any adverse events or complications as a result of treatment. Patients reported an improved quality of life due to fewer hospital visits and a reduced number of recurrent episodes of cTTP., Conclusion: Treatment with rADAMTS13 resulted in the normalization of laboratory parameters in all pediatric patients with cTTP., Competing Interests: Declaration of competing interests P.L. received monetary compensation for lectures given to Takeda, Roch, Novonordisk, Pfizer, Sobi, Novartis, and AstraZeneca. W.M. received monetary compensation for medical consultations with Takeda. M.W. received monetary compensation for the lectures given to Takeda. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients are not responsive to standard rituximab in approximately 10% to 15% of cases, and oral immunosuppressants showed controversial results with significant toxicity. Targeting plasma cells with bortezomib appears promising, but the available evidence is scarce and stems only from isolated reports in the precaplacizumab era., Objectives: To evaluate the safety and efficacy of bortezomib in rituximab-refractory iTTP patients., Methods: We conducted a retrospective observational multicenter study among 13 Italian iTTP treating centers, collecting data from May 2017 to May 2023 (caplacizumab was licensed in Italy in January 2020)., Results: Bortezomib was effective in 10/17 patients (59%). Eleven were treated in the acute phase (9/11 responders, 82%, allowing discontinuation of caplacizumab in 5/6 treated patients), and 7 during clinical remission (2/7 responders, 28%). Responses occurred at a median time of 30 days, but 3 patients responded after 4 months. The median duration of response was 22 months (IQR, 10-38), still ongoing in 6 patients at the time of data cutoff. Responders had fewer previous acute iTTP episodes than nonresponders (median [IQR], 1 [1,2] vs 5.5 [2-7]; P = .03). Eight subjects (47%) reported toxicities, mostly in those treated with ≥2 cycles., Conclusion: Durable responses to bortezomib were registered in about 60% of multirefractory iTTP patients with mild to moderate toxicities. The occurrence of late responses (ie, after 30 days) suggests a "watchful waiting" approach after bortezomib treatment., Competing Interests: Declaration of Competing Interests A.A., P.A., M.C., and B.F. received honoraria for participating as a speaker at educational meetings organized by Sanofi; I.M. received honoraria for participating as a speaker at educational meetings organized by Instrumentation Laboratory and Sanofi; M.B. received conference fees from Novartis, Incyte, and AbbVie; M.N. acted as a consultant for Bayer, CSL Behring, and Novo Nordisk and received speaker fees from Bayer, Takeda, Sobi, Novo Nordisk, CSL Behring, Sanofi, Amgen, Novartis, and Grifols; F.P. has received honoraria for participating as a speaker in education meetings organized by Sanofi, Spark, and Takeda and she is member of scientific advisory boards of CSL Behring, BioMarin, Roche, Sanofi, and Sobi. The other authors do not have any conflict of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal thrombotic microangiopathic disorder that can result from human immunodeficiency virus (HIV) infection. The pathogenesis involves a deficiency of the von Willebrand factor (vWF) cleaving protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs member 13) and the presence of anti-ADAMTS13 autoantibodies. However, there is insufficient information regarding the epitope specificity and reactivity of these autoantibodies. This study aimed to perform epitope-mapping analysis to provide novel insights into the specific epitopes on ADAMTS13 domains affected by autoantibodies., Materials and Methods: The study analysed 59 frozen citrate plasma samples from HIV-associated TTP patients in South Africa, measuring ADAMTS13 activity using Technozyme® ADAMTS13 activity test, total immunoglobulin (Ig) M and IgA antibodies levels using ELISA kit and purifying IgG antibodies using NAb™ Protein G spin columns. A synthetic ADAMTS13 peptide library was used for epitope mapping., Results: Overall, 90% of samples showed anti-ADAMTS13 IgG autoantibodies, with 64% of these antibodies being inhibitory, as revealed by mixing studies. Samples with ADAMTS13 antigen levels below 5% showed high anti-ADAMTS13 IgG autoantibody titres (≥50 IU/mL), whereas those with 5%-10% levels had low autoantibody titres (<50 IU/mL).The metalloprotease, cysteine-rich and spacer domains were 100% involved in binding anti-ADAMTS13 IgG antibodies, with 58% of samples containing antibodies binding to the C-terminal part of the ADAMTS13 disintegrin-like domain, indicating different pathogenic mechanisms., Conclusion: The metalloprotease, cysteine-rich and spacer domains are the primary targets for anti-ADAMTS13 IgG autoantibodies in patients with HIV-associated TTP. These findings suggest potential effects on the proteolytic activity of ADAMTS13, highlighting the complex nature of the pathogenic mechanisms involved., (© 2024 The Author(s). Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Several international registries have reported on the efficacy of caplacizumab for the treatment of immune thrombotic thrombocytopenic purpura (iTTP). Similar real-world data from the United States (US) are limited. In this single center retrospective study, we sought to describe caplacizumab prescribing patterns and review clinical outcomes for US patients with iTTP. Subjects were eligible for inclusion if they were diagnosed with acute iTTP and received care at University of Pittsburgh Medical Center-affiliated hospitals from 2012 to 2022. Subjects were divided into an historical cohort who received standard of care therapy alone, and early and late administration cohorts (EA and LA) who received caplacizumab within and greater than 72 h of admission, respectively, plus standard of care. Clinical data were collected from the electronic record. Thirty-two subjects were included: 16 historical, 12 EA, and 4 LA subjects. Refractoriness occurred more frequently in the LA and historical cohorts as compared to the EA cohort (4 (100%) vs. 6 (38%) vs. 3 (25%), p = 0.02). The LA cohort also experienced longer lengths of hospital stay, required more TPE procedures, and were exposed to the greatest amount of donor plasma (p < 0.05 for all) as compared to the other cohorts. Time to platelet count normalization was longest in the LA cohort (p = 0.013). There were no significant between-group differences in bleeding events. Because we are unable to predict which patients will develop refractoriness, we recommend frontline administration of caplacizumab to all patients with iTTP., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency. Caplacizumab, an anti-von Willebrand factor nanobody, is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet count recovery and survival. We conducted a retrospective study on 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased after the first caplacizumab dose. Baseline characteristics and patient outcomes were compared with a control group of 59 patients with iTTP receiving frontline treatment with TPE, caplacizumab, and immunosuppression. The main outcome was the time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractory iTTP, iTTP-related deaths, and the time to platelet count doubling. The median time to platelet count normalization was similar between the 2 cohorts (3 and 4 days; P = .31). There were no significant differences in clinical response, exacerbations, refractoriness, iTTP-related deaths, or time to platelet count doubling, reflecting the short-term treatment response. Four patients did not respond to the first caplacizumab dose, and TPE was subsequently initiated. Cytomegalovirus infection, HIV/hepatitis B virus coinfection, an ovarian teratoma with associated antiplatelet antibodies, and multiple platelet transfusions before the correct diagnosis may have impeded the immediate treatment response in these patients. In conclusion, caplacizumab and immunosuppression alone, without TPE, rapidly controlled thrombotic microangiopathy and achieved a sustained clinical response in iTTP. Our study provides a basis for TPE-free iTTP management in experienced centers via shared decision-making between patients and treating physicians., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Immune thrombotic thrombocytopenic purpura (i-TTP) is a life-threatening thrombotic microangiopathy linked to ADAMTS-13 deficiency. It has long been assumed that the activation of endothelial cells is the triggering factor for the thrombotic thrombocytopenic purpura crisis. Circulating endothelial cells (CECs) have been shown to be a biomarker of vascular damage and are associated with the clinical severity of i-TTP. However, the mechanisms leading to endothelial cell detachment remain unclear., Objectives: We investigated junctional destabilization the mechanisms underlying cell detachment in thrombotic thrombocytopenic purpura., Methods: We quantified CECs in i-TTP patients and investigated the effect of plasmas in vitro by measuring phosphorylation and internalization of vascular endothelial (VE)-Cadherin and in vivo in a vascular permeability model., Results: In plasma from i-TTP patients, we show that CEC count is associated with severity and correlated to intracellular calcium influx (P < .01). In vitro, serum from i-TTP patients induced stronger detachment of human umbilical vein endothelial cells than serum from control patients (P < .001). Plasma from i-TTP patients induced a higher calcium-dependent phosphorylation (P < .05) and internalization (P < .05) of VE-cadherin compared with plasma from control patients. This effect could be reproduced by immunoglobulin (Ig)G fraction isolated from patient plasma and, in particular, by the F(ab)'2 fragments of the corresponding IgG. In addition, subcutaneous injection of i-TTP plasma into mice resulted in higher vascular permeability than plasma from control patients. An inhibitor of endothelial calcium influx, ITF1697, normalized this increase in permeability., Conclusion: Our results suggest that plasma-induced endothelial activation also leads to an increase in vascular permeability. They contribute to the understanding of the mechanisms behind the presence of elevated CECs in patients' blood by linking endothelial activation to endothelial injury., Competing Interests: Declaration of competing interests P.P. is a member of the scientific advisory boards of Ablynx-Sanofi. The other authors declare no competing financial interests., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Thromboinflammation/immunothrombosis plays a role in several diseases including thrombotic thrombocytopenic purpura (TTP) and COVID-19. Unlike the extensive research that has been conducted on COVID-19 cytokine storms, the baseline and acute phase cytokine profiles of TTP are poorly characterized. Moreover, we compared the cytokine profiles of TTP and COVID-19 to identify the disease-specific/general characteristics of thromboinflammation/immunothrombosis. Plasma concentrations of 33 soluble mediators (SMs: cytokines, chemokines, soluble receptors, and growth factors) were measured by multiplex bead-based LEGENDplex™ immunoassay from 32 COVID-19 patients (32 non-vaccinated patients in three severity groups), 32 TTP patients (remission/acute phase pairs of 16 patients), and 15 control samples. Mainly, the levels of innate immunity-related SMs changed in both diseases. In TTP, ten SMs decreased in both remission and acute phases compared to the control, one decreased, and two increased only in the acute phase compared to remission, indicating mostly anti-inflammatory changes. In COVID-19, ten pro-inflammatory SMs increased, whereas one decreased with increasing severity compared to the control. In severe COVID-19, sixteen SMs exceeded acute TTP levels, with only one higher in TTP. PCA identified CXCL10, IL-1RA, and VEGF as the main discriminators among their cytokine profiles. The innate immune response is altered in both diseases. The cytokine profile of TTP suggests a distinct pathomechanism from COVID-19 and supports referring to TTP as thromboinflammatory rather than immunothrombotic, emphasizing thrombosis over inflammation as the driving force of the acute phase.

Thrombotic microangiopathy (TMA) encompasses a range of disorders characterized by blood clotting in small blood vessels, leading to organ damage. It can manifest as various syndromes, including thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and others, each with distinct causes and pathophysiology. Thrombo-inflammation plays a significant role in TMA pathogenesis: inflammatory mediators induce endothelial injury and activation of platelet and coagulation cascade, contributing to microvascular thrombosis. Primary TMA, such as TTP, is primarily caused by deficient ADAMTS13 metalloproteinase activity, either due to antibody-mediated inhibition or intrinsic enzyme synthesis defects. In cancer patients, a significant reduction in ADAMTS13 levels and a corresponding increase in VWF levels is observed. Chemotherapy further decreased ADAMTS13 levels and increased VWF levels, leading to an elevated VWF/ADAMTS13 ratio and increased thrombotic risk. Drug-induced TMA (DITMA) can result from immune-mediated or non-immune-mediated mechanisms. Severe cases of COVID-19 may lead to a convergence of syndromes, including disseminated intravascular coagulation (DIC), systemic inflammatory response syndrome (SIRS), and TMA. Treatment of TMA involves identifying the underlying cause, implementing therapies to inhibit complement activation, and providing supportive care to manage complications. Plasmapheresis may be beneficial in conditions like TTP. Prompt diagnosis and treatment are crucial to prevent serious complications and improve outcomes.

Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a complication of adenoviral-based vaccine against SARS-CoV-2 due to prothrombotic immunoglobulin (Ig) G antibodies to platelet factor 4 (PF4) and may be difficult to distinguish from heparin-induced thrombocytopenia (HIT) in patients treated with heparin., Objectives: We assessed the usefulness of competitive anti-PF4 enzyme immunoassays (EIAs) in this context., Methods: The ability of F(ab')2 fragments of 1E12, 1C12, and 2E1, 3 monoclonal anti-PF4 antibodies, to inhibit the binding of human VITT or HIT antibodies to PF4 was evaluated using EIAs. Alanine-scanning mutagenesis was performed to define the amino acids involved in the interactions between the monoclonal antibodies and PF4., Results: A strong inhibition of VITT IgG binding to PF4 was measured with 1E12 (median inhibition, 93%; n = 8), whereas it had no effect on the binding of HIT antibodies (median, 6%; n = 8). In contrast, 1C12 and 2E1 inhibited VITT (median, 74% and 76%, respectively) and HIT antibodies (median, 68% and 53%, respectively) binding to PF4. When a competitive anti-PF4 EIA was performed with 1E12 for 19 additional VITT samples, it strongly inhibited IgG binding to PF4, except for 1 patient, who had actually developed HIT according to the clinical history. Epitope mapping showed that 1E12 interacts with 5 key amino acids on PF4, of which 4 are also required for the binding of human VITT antibodies, thus explaining the competitive inhibition., Conclusion: A simple competitive anti-PF4 EIA with 1E12 could help confirm VITT diagnosis and distinguish it from HIT in patients when both diagnoses are possible., Competing Interests: Declaration of competing interests C.V. reports honorarium from Viatris. J.R. reports research grant from Stago. H.G. reports transport fees from Stago. F.M. reports speaker fees from Fresenius, Technoclone, and Werfen, all outside the submitted work. Y.G. reports research grant and symposium fees from Stago. C.P. reports research grant from Stago. All other authors of this paper have no conflicts of interest., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening, often immune-mediated disease that affects 2-13 persons per million per year. Hemolytic anemia, thrombocytopenia, and end-organ damage due to the formation of microthrombi are characteristic of TTP. ADAMTS13 is a disintegrin, metalloproteinase, cleaving protein of von Willebrand factor (VWF) that processes the VWF multimers to prevent them from interacting with platelets and, in turn, to microvascular thrombosis. Prompt diagnosis of TTP is critical yet challenging. Thrombotic microangiopathies have similar clinical presentation. Measurement of ADAMTS13 activity helps in the differential diagnosis. Less than 10% ADAMTS13 activity is indicative of TTP. Laboratory ADAMTS13 activity assays include incubating the test plasma with the substrate (full-length VWM multimers) and detection with direct or indirect measurement of the cleavage product. The purpose of this study is to examine the diagnostic potential, advantages, and weaknesses of the ADAMTS13 potency in TTP.

Background: Laboratory diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains challenging when ADAMTS-13 activity ranges between 10% and 20%. To prevent misdiagnosis, open ADAMTS-13 conformation gained clinical attention as a novel biomarker, especially to diagnose acute iTTP in patients with diagnostic undecisive ADAMTS-13 activity. Plasma ADAMTS-13 conformation analysis corrects for ADAMTS-13 antigen, with both parameters being characterized in enzyme-linked immunosorbent assay (ELISA)-based reference assays requiring expert technicians., Objectives: To design ADAMTS-13 antigen and conformation assays on automated, easy-to-use fiber optic surface plasmon resonance (FO-SPR) technology to promote assay accessibility and diagnose challenging iTTP patients., Methods: ADAMTS-13 antigen and conformation assays were designed on FO-SPR technology. Plasma of 20 healthy donors and 20 acute iTTP patients were quantified, and data from FO-SPR and ELISA reference assays were compared., Results: Following assay design, both antigen and conformation FO-SPR assays were optimized and characterized, presenting strong analytical sensitivity (detection limit of 0.001 μg/mL) and repeatability (interassay variation of 14.4%). Comparative analysis suggested positive correlation (Spearman r of 0.92) and good agreement between FO-SPR and ELISA assays. As expected, FO-SPR assays showed a closed or open ADAMTS-13 conformation in healthy donors and acute iTTP patients, respectively., Conclusion: Both ADAMTS-13 antigen and conformation assays were transferred onto automated, easy-to-use FO-SPR technology, displaying potent analytical sensitivity and reproducibility. ADAMTS-13 antigen and conformation were determined for healthy donors and acute iTTP patients showing strong correlation with ELISA reference. Introducing FO-SPR technology in clinical context could support routine diagnosis of acute iTTP patients, notably when ADAMTS-13 activity fluctuates between 10% and 20%., Competing Interests: Declaration of competing interests J.L. is a member of the Board of Directors of FOx Biosystems. Q.B., C.D., T.B., E.T., G.K., B.S.J., A.V., P.C., C.T., S.F.D.M., and K.V. have no conflicts of interest to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Abstract: Previous studies have demonstrated that >38% of patients with immune-mediated thrombotic thrombocytopenic purpura in remission with activity >50% had an open ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) conformation. We assessed ADAMTS13 conformation in remission (ADAMTS13 activity >60%), focusing on peak ADAMTS13 activity levels and longitudinal assessment in 420 samples across 157 patients. Fewer cases had an open conformation at peak ADAMTS13 activity than unselected remission samples with ADAMTS13 activity >60% (23% vs 43%). Patients with a closed ADAMTS13 conformation at peak ADAMTS13 activity had an eightfold lower relapse rate in the subsequent year (9% vs 46%) and a fivefold lower relapse rate within 2 years (23% vs 62%) compared with cases with an open conformation. Patients with an open conformation at peak ADAMTS13 activity required preemptive anti-CD20 treatment earlier than those with a closed conformation (median, 10 vs 25 months). Longitudinally, an open conformation was evident at, and often preceded relapse. When the conformation was already open before relapse, an increase in the conformation index at relapse was seen despite the undetectable anti-ADAMTS13 immunoglobulin G (IgG) antibody. In cases with detectable anti-ADAMTS13 IgG antibody, these became undetectable before achieving a closed conformation, highlighting the relapse risk even with undetectable anti-ADAMTS13 IgG antibody and the clinical utility of open/closed during monitoring. To our knowledge, this is the first study to show an association between relapse risk and ADAMTS13 conformation when activity levels are at a peak. The open conformation identifies antibody-mediated subclinical disease that is not detectable by the current ADAMTS13 testing., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: von Willebrand factor (VWF) is an essential contributor to microvascular thrombosis. Physiological cleavage by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) limits its prothrombotic properties, explaining why ADAMTS13 deficiency leads to attacks of microthrombosis in patients with thrombotic thrombocytopenic purpura (TTP). We previously reported that plasminogen activation takes place during TTP attacks in these patients. Furthermore, stimulation of plasminogen activation attenuates pathogenesis in preclinical TTP models in vivo. This suggests that plasmin is an endogenous regulator of VWF thrombogenicity, in particular when ADAMTS13 falls short to prevent microvascular occlusions. VWF cleavage by plasmin is biochemically distinct from cleavage by ADAMTS13. We hypothesized that plasmin-cleaved VWF (cVWF) holds value as a biomarker of microvascular thrombosis. Here, we describe the development of a variable domain of heavy-chain-only antibody (VHH)-based bioassay that can distinguish cVWF from intact and ADAMTS13-cleaved VWF in plasma. We validate this assay by tracking cVWF release during degradation of microthombi in vitro. We demonstrate that endogenous cVWF formation takes place in patients with TTP during acute attacks of thrombotic microangiopathy but not in those in remission. Finally, we show that therapeutic plasminogen activation in a mouse model of TTP amplifies cVWF formation, which is accompanied by VWF clearance. Our combined findings indicate that cVWF is released from microthrombi in the context of microvascular occlusion., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Immune-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., Objectives: To determine the mechanism of autoantibody-mediated severe deficiency of plasma ADAMTS13 activity in immune-mediated thrombotic thrombocytopenic purpura., Methods: Fluorescence 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., Results: We 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., Conclusion: We 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., Competing Interests: Declaration of competing interest X.L.Z. is a consultant for Alexion, Apollo, Sanofi, Takeda, Apollo, GC Biopharma, and Stago and a cofounder of Clotsolution., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

We report on a 12-year-old boy with congenital thrombotic thrombocytopenic purpura, on who had an erroneous diagnosis as chronic immune thrombocytopenia. The patient presented with complaints of jaundice and skin rash. Laboratory analysis showed nonimmune hemolytic anemia and severe thrombocytopenia. Peripheral blood smear showed 8% schistocytes, polychromasia, and anisocytosis. The ADAMTS13 antigen and activity were suspected to be lower than 5% with any antibodies against the enzyme. The DNA sequence analyses resulted in compound heterozygosity consisting of c.291&#95;391del in exon 3 and c.4143dupA in exon 29. Schistocyte (fragmented erythrocytes) on the peripheral blood smear is a light that illuminates the diagnosis. Early recognition of the disease can prevent inappropriate treatments and morbidities due to organ damage., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Acquired thrombocytopenic thrombotic purpura (aTTP) is an autoantibody-mediated disease against the enzyme A Disintegrin and Metalloprotease domain with ThromboSpondin-1 type motif 13, which until now has been treated with plasma exchange (PEX) and corticosteroids. A 29-year-old female patient, who presented with aTTP in the context of pregnancy, has developed multiple relapses after treatment with PEX, corticosteroids, and rituximab. Recently, caplacizumab, a nanobody against von Willebrand factor, has been approved for the treatment of aTTP. In our patient, caplacizumab achieved better disease control, with a lower platelet count restoration time, days of PEX and hospitalization duration, as compared to standard therapy, reproducing the results of clinical trials. Caplacizumab represents a significant advance in the treatment of aTTP, especially in cases of recurrent relapses., (© 2021 S. Karger AG, Basel.)

Objective: As COVID-19 is a new emerging disease, the hematological/immunological changes that develop in the infected patients remain unknown. This study aims to systematically review the hematologic autoimmune complications in these patients., Method: Data from three online databases including Medline (via PubMed), Scopus and Web of Science were searched on 19 December 2020, and after excluding duplicate, irrelevant and inappropriate records, eligible documents were identified. Afterwards, information such as patients' history, presentations, paraclinical data, treatment course and outcome were extracted from the records., Results: A total of 58 documents were considered to be eligible for data extraction which described 94 patients with COVID-19 who developed hematologic autoimmune disorder in their course of infection. Of these patients with COVID-19, the most common hematologic autoimmune disorder was immune thrombocytopenic purpura (55 cases) followed by autoimmune hemolytic anemia (22 cases). Other hematologic autoimmune disorders include antiphospholipid syndrome, thrombotic thrombocytopenic purpura, Evans syndrome and autoimmune neutropenia., Conclusion: The current study would help us to always consider an autoimmune etiology for cases with abnormal hematologic finding which further lead to an appropriate treatment of the patients, especially when the symptoms present in about 1-2 weeks after the first manifestation of the infection symptoms. Maybe, at least in this pandemic, it should be recommended to evaluate patients with unexpected and unexplained decrease in their hemoglobulin or platelet count for COVID-19. Another challenging issue is the treatment options. Given the multiorgan involvement and multifaceted nature of the infection, an individualized approach should be taken for each patient.

Pregnancy is a high-risk time for the development of different kinds of thrombotic microangiopathy (TMA). Three major syndromes including TTP (thrombotic thrombocytopenic purpura), PE/HELLP (preeclampsia/hemolysis, elevated liver function tests, low platelets), and aHUS (atypical hemolytic- uremic syndrome) should be sought in pregnancy-TMA. These severe disorders share multiple clinical features and overlaps and even the coexistence of more than one pathologic mechanism. Each of these disorders finally ends in endothelial damage and fibrin thrombi formation within the microcirculation that fragments RBCs (schystocytes), aggregates platelets, and creates ischemic injury in the targeted organs i.e.; kidney and brain. Although the mechanisms of these severe disorders have been revealed, pregnancy-related TMA still interfaces with diagnostic and therapeutic challenges. Here, we highlight the current knowledge of diagnosis and management of these complications during pregnancy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Thrombotic thrombocytopenic purpura (TTP) is a known menace in hematology and is quite rare in practice with known triggers. Lately, in the COVID-19 pandemic, hematology has seen a new pathology amongst which TTP associated with COVID-19 messenger RNA (mRNA) vaccine is unique. We report a case of a 69-year-old male with multiple comorbidities who presented to the hospital with severe fatigue and shortness of breath. Labs were significant for thrombocytopenia, anemia, and hemolysis with schistocytes consistent with TTP with a second dose of BNT162b2 mRNA vaccine as a likely culprit been documented., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Extremely rare reactions characterized by thrombosis and thrombocytopenia have been described in subjects that received ChAdOx1 nCoV-19 vaccination 5-16 days earlier. Although patients with vaccine-induced thrombotic thrombocytopenia (VITT) have high levels of antibodies to platelet factor 4 (PF4)-polyanion complexes, the exact mechanism of the development of thrombosis is still unknown. Here we reported serum studies as well as proteomics and genomics analyses demonstrating a massive complement activation potentially linked to the presence of anti-PF4 antibodies in a patient with severe VITT. At admission, complement activity of the classical and lectin pathways were absent (0% for both) with normal levels of the alternative pathway (73%) in association with elevated levels of the complement activation marker sC5b-9 (630 ng/mL [n.v. 139-462 ng/mL]) and anti-PF4 IgG (1.918 OD [n.v. 0.136-0.300 OD]). The immunoblotting analysis of C2 showed the complete disappearance of its normal band at 110 kDa. Intravenous immunoglobulin treatment allowed to recover complement activity of the classical pathway (91%) and lectin pathway (115%), to reduce levels of sC5b-9 (135 ng/mL) and anti-PF4 IgG (0.681 OD) and to normalize the C2 pattern at immunoblotting. Proteomics and genomics analyses in addition to serum studies showed that the absence of complement activity during VITT was not linked to alterations of the C2 gene but rather to a strong complement activation leading to C2 consumption. Our data in a single patient suggest monitoring complement parameters in other VITT patients considering also the possibility to target complement activation with specific drugs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Vaccine-induced immune thrombotic thrombocytopenia is a rare syndrome following the ChAdOx1 nCov-19 or Ad26.COV2.S vaccine. Reported patients developed mainly venous thrombosis. We describe a case of a young healthy women suffering from acute ischemic stroke due to large vessel occlusion without cerebral venous thrombosis 8 days after vaccination and its consequences on recanalization strategy. Considering the thrombocytopenia, intravenous thrombolysis was contraindicated. She underwent mechanical thrombectomy with complete recanalization and dramatically improved clinically. Positive detection of anti-PF4-heparin-antibodies confirmed vaccine-induced immune thrombotic thrombocytopenia diagnosis. In case of acute ischemic stroke after recent ChAdOx1 nCov-19 or Ad26.COV2.S vaccine, platelet count should be systematically checked before giving thrombolysis, and direct mechanical thrombectomy should be proposed in patients with large vessel occlusion., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Coronavirus is a novel human pathogen causing fulminant respiratory syndrome (COVID-19). Although COVID-19 is primarily a disease of the lungs with florid respiratory manifestations, there are increasing reports of cardiovascular, musculoskeletal, gastrointestinal, and thromboembolic complications. Developing an effective and reliable vaccine was emergently pursued to control the catastrophic spread of the global pandemic. We report a fatal case of vaccine-induced immune thrombotic thrombocytopenia (VITT) after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. We attribute this fatal thrombotic condition to the vaccine due to the remarkable temporal relationship. The proposed mechanism of VITT is production of rogue antibodies against platelet factor-4 resulting in massive platelet aggregation. Healthcare providers should be aware of the possibility of such fatal complication, and the vaccine recipients should be warned about the symptoms of VITT., Competing Interests: Conflict of Interest The authors declare that they have no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening and easily misdiagnosed thrombotic microangiopathy disease. Few studies have reported the use of therapeutic plasma exchange (TPE) for TTP in emergency departments in China. The present study was a retrospective analysis of patients with TTP who were treated with TPE in our emergency intensive care unit (EICU)., Methods: This study retrospectively analyzed patients with TTP who received TPE management from July 1, 2014 to February 1, 2020. The following clinical data of these patients were collected: laboratory results, first symptoms, ADAMTS13 levels, glucocorticoid levels, TPE times and outcomes., Results: The study included 19 patients (9 male and 10 female) with 20 clinical episodes, and 1 female patient had two episodes. TPE was used in 17 patients, and TPE was performed once every 2-3 days in patients. The volume for each TPE treatment was 2000 ml. In total, 4 male patients died, and 15 patients survived. One female experienced a relapse. No significant differences in age, RBC, HGB, PLT, ALT, AST, BUN, Cr, LDH, or bilirubin were noted between the survival and death groups. The mortality rate of male patients was significantly higher than that of female patients(p = 0.0325, p < 0.05), and the mean age of deceased patients was 64.25 ± 4.78 years, which was older than the mean age of survivors (47.38 ± 4.30). However, no significant difference was noted (p = 0.0787)., Conclusion: TPE had satisfactory results for TTP patients although it was not performed every day. Older male TTP patients exhibited a relatively increased risk of death., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020. Published by Elsevier Inc.)

The metalloproteinase ADAMTS13 (a disintegrin with a thrombospondin type 1 motif, member 13), also known as VWF (von Willebrand factor) protease, may be assessed in a vast array of clinical conditions. Notably, a severe deficiency of ADAMTS13 characterizes TTP (thrombotic thrombocytopenic purpura), a rare but potentially fatal disorder associated with thrombosis due to accumulation of prothrombotic ultra-large VWF multimers. Although prompt identification/exclusion of TTP can be facilitated by rapid ADAMTS13 testing, the most commonly utilized assays are based on ELISA (enzyme linked immunosorbent assay) and require long turnaround time and have relatively limited throughput. Nevertheless, several rapid ADAMTS13 assays are now available, at least in select geographies. The current mini-review discusses these issues, as well as the potential utility of ADAMTS13 testing in a range of other conditions, including coronavirus disease 2019 (COVID-19)., (© 2021 Wiley Periodicals LLC.)

Background: Thrombotic thrombocytopenic purpura (TTP), a rare, potentially life-threatening thrombotic microangiopathy, manifests either as congenital TTP or acquired forms. It is caused by the absence or severe depletion of a disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) protease, leading to the accumulation of ultra large von Willebrand factor multimers as well as extensive platelet adhesion and clumping, which can ultimately cause severe secondary end-organ damage. Pregnancy can provoke or exacerbate TTP, leading to maternal and fetal complications., Objective: In this report, we focused on pregnancy outcomes in a recently recognized cohort of congenital TTP patients of Bedouin Arab descent in southern Israel who were all homozygous for a novel c.3772delA variant of the ADAMTS13 gene, leading to the clinical manifestations of TTP largely during pregnancy., Study Design: All patients presented in this study belong to 2 closely related families of Arab Bedouin descent and were found to be homozygous for a novel ADAMTS13-c.3772delA variant. The cohort consisted of 19 females; 16 of them had congenital TTP and had been pregnant and were thus included. Patient data were collected from electronic medical records., Results: Of note, 13 women from our cohort, who delivered 14 fetuses (owing to 1 twin pregnancy), were diagnosed with congenital TTP following complicated pregnancies, which included recurrent pregnancy loss, stillbirth, early onset preeclampsia (both mild and severe), hemolysis, elevated liver enzymes and low platelet count syndrome, intrauterine growth restriction with abnormal Doppler flow, preterm premature rupture of membranes, and a total perinatal mortality rate of 30.7% (4/13). An additional 3 women, who were diagnosed owing to complications outside of pregnancy and at older ages, experienced TTP during their pregnancies, which occurred before diagnosis. Subsequent pregnancies were treated with fresh frozen plasma leading to a 100% fetal survival rate in the pregnancies that reached fetal viability. All placentas had lesions consistent with maternal vascular underperfusion. However, the severity and frequency of these lesions were lower in the 8 placentas from pregnancies treated with fresh frozen plasma., Conclusion: This case series details a distinctive cohort of congenital TTP patients, all homozygous for the same, novel ADAMTS13 variant, who presented with clinical complications during pregnancy and maternal vascular lesions of underperfusion in the placenta. Our findings imply that the variant identified in the ADAMTS13 gene in our cohort may have a specific functional impact on the placenta, and that treatment with fresh frozen plasma during pregnancy ameliorates the course of the disease, leading to a milder phenotype or a normal pregnancy in the majority of cases., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Thrombotic thrombocytopenic purpura (TTP) which can cause significant mortality is a thrombotic microangiopathy due to deficiency of VWF cleaving protease ADAMTS13 and as per medical literature there are examples that TTP can be caused by COVID 19 infection. A 35 years old female after admission with right sided weakness and slurring of speech was found to be COVID positive and diagnosed as a case of TTP. Patient had absent ADAMTS13 level on day 1. Treatment was started with therapeutic plasma exchange (TPE) later injection Vincristine and Rituximab was given after 4th TPE as it was suspected as refractory case. Finally patient received 16 TPE procedures with cryo poor plasma as exchange fluid and gradually her platelet count started to maintain normal and she was discharged. Specific management and such association of this type of cases need to be studied more judiciously., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

TTP is a life-threatening disorder diagnosed using a combination of clinical information and laboratory results. ADAMTS13 activity and antibody testing represent a major advance in the field, but results can sometimes be difficult to interpret due to technical aspects of the tests and characteristics of the causative antibodies in acquired TTP. Genetic testing for ADAMTS13 mutations is also now available to assist with the diagnosis of inherited TTP. This review will focus on ADAMTS13 testing and will highlight patient and laboratory aspects that can lead to diagnostic difficulty. The effects of TTP therapies on test results will also be discussed., (© 2021 John Wiley & Sons Ltd.)

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening thrombotic microangiopathy (TMA) characterized by the severe deficiency of ADAMTS13 activity (<10%). Rapid ADAMTS13 testing is crucial for early diagnosis and optimal management of TTP patients and other TMAs. The objective of this study was to retrospectively evaluate the performance of the recently commercialized HemosIL Acustar ® ADAMTS13 activity chemiluminescent immunoassay (Instrumentation Laboratory, Bedford, Massachusetts, United States) in a multicentric study between Spain and Portugal., Methods: A comparison method was performed to compare HemosIL Acustar ® with an in-house FRETS-VWF73 assay and two commercial ELISA assays: the TECHNOZYM ® ADAMTS13 Activity (Technoclone GmbH, Vienna, Austria) and the DG-EIA ADAMTS-13 Activity (Diagnostic Grifols, SA, Barcelona, Spain). A set of 241 frozen plasma samples with known ADAMST13 levels was used. Agreement between methods was assessed with focus on two cut-off ADAMTS13 activity values: <10% (the clinical accepted cut-off value to confirm TTP diagnosis) and <5%., Results: HemosIL AcuStar ® showed high agreement with the other methods in correctly classify patients with ADAMTS13 values below 10% (Kappa = 0.89) and even below 5% (Kappa = 0.94) with no false negatives and few false positives (5.40%; 95% CI: 2.20 to 8.60%). However, it also tended to underestimate ADAMTS13 levels, especially for the high assay range values (>40%) (absolute mean bias of 8.40% (95% CI: 6.53 to 10.42%)) when compared to other assays., Conclusions: HemosIL AcuStar ® is highly sensitive to detect ADAMTS13 values below 10% and 5%. A large prospective validation study is needed to corroborate its utility in clinical practice., (© 2020 John Wiley & Sons Ltd.)

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., (© 2021 by The American Society of Hematology.)

Thrombotic thrombocytopenic purpura is a rare but life threatening medical condition. Early recognition and treatment of thrombotic thrombocytopenic purpura is important especially in patients who do not present with the classic pentad to reduce the high mortality. Herein, we describe a case of a patient who does not fulfil the classic pentad features thrombotic thrombocytopenic purpura that was induced by dengue fever. The patients' initial full blood picture did not have all the typical features of microangiopathic haemolytic anaemia but there were fragmented red blood cells. However, even a small number of fragmented red blood cells in the peripheral blood should alert physicians of the possible diagnosis of thrombotic thrombocytopenic purpura together with other symptoms. Furthermore, signs and symptoms of thrombotic thrombocytopenic purpura and dengue fever can overlap such as fever, thrombocytopenia, neurological deficit mimicking dengue encephalopathy and dengue induced acute kidney injury.

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by severe ADAMTS13 deficiency. The acquired form is associated with autoantibodies directed against ADAMTS13. Both noninhibitory and inhibitory autoantibodies can be detected by ELISA assay, while only inhibitory autoantibodies are detected by Bethesda assay. Due to its short TAT and good performance, chemiluminescence (CliA) ADAMTS13 activity (HemosIL Acustar) has proven to be a good choice in the diagnosis of TTP in emergency settings. Aim of this study was to analyse the performance of the CliA ADAMTS13 activity assay in detecting inhibitory ADAMTS13 antibodies using the Bethesda assay., Methods: A method comparison study was performed on 69 stored samples: 11 acute TTPs, 38 TTP follow-ups, 5 TTP relapses, 1 congenital TTP, 10 HUS, 4 suspected TTPs. We retrieved the results of tests previously run in ELISA for both activity and autoantibodies. At the same time, we reran new tests including ELISA and CliA activity, ELISA autoantibodies, and ELISA and CliA Bethesda assays on thawed frozen samples., Results: Very good correlation was observed between ELISA and CliA activity assay results (r = 0.96) and between archived ELISA and CliA activity results (r = 0.93). Agreement between the anti-ADAMTS13 assays ranged from good (k = 0.63) to very good (k = 0.92)., Conclusions: CliA and ELISA Bethesda assays showed very good agreement with samples run at the same time using ELISA ADAMTS13-autoantibody assay. Albeit more expensive, the CliA Bethesda assay identified inhibitory anti-ADAMTS13 within almost the same TAT as ELISA, but with better automation and limited operator involvement., (© 2020 John Wiley & Sons Ltd.)

Introduction: Thrombotic microangiopathies are a group of disorders that are mainly related to endothelial dysfunction. This category of endothelial dysfunction results of several imbalances between platelets, endothelium and immune system, also cytokine production., Aim of This Study: To report cases with thrombotic thrombocytopenic purpura (TTP) and COVID-19 and review COVID-19 endothelial dysfunction literature., Methods: Primary laboratory data, peripheral blood smear, ADAMTS13 antigen activity level, and antibody ordered for each of these four patients. Treatments for COVID-19 administered for all patients. Traditional treatments for TTP also were administered., Results: There were numerous schistocytes (more than 5%) in peripheral blood smears for each patient. ADAMTS13 antigen activity level was below 10%, and ADAMTS13 antibody was elevated for each patient. COVID-19 PCR was positive for all patients, and CT-Scans were indicative of the involvement of COVID-19., Conclusion: In this case series, we reported four COVID-19 patients who presented with signs and symptoms of anemia and thrombocytopenia, resulting in thrombotic thrombocytopenic purpura., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introductions: Patients with acquired thrombotic thrombocytopenic purpura (TTP) show no severe abnormalities in coagulation or fibrinolysis. However, the exact extent of the abnormalities is unclear., Materials and Methods: This study analyzed 138 patients with acquired TTP and 46 patients with septic disseminated intravascular coagulation (DIC) who were included in a Japanese registry. Complete blood cell counts and 8 coagulation or fibrinolysis parameters were compared between the 2 groups., Results: Platelet counts in the acquired TTP group were significantly lower than those in the septic DIC group (P < .001). The international normalized ratio of prothrombin time and the activated partial thromboplastin time in the septic DIC group were significantly higher and longer, respectively, than those in the acquired TTP group (P < .01). The antithrombin (AT) values were significantly lower in the septic DIC group than in the acquired TTP group (P < .001), the latter of which were almost normal. Although both groups revealed elevations of fibrinogen degradation product (FDP) and D-dimer, these levels were significantly higher in the septic DIC group than in the acquired TTP group (P < .001). Of 138 patients with acquired TTP, 25 (18.1%) were diagnosed with septic DIC by the diagnostic criteria of the Japanese Ministry Health, Labour and Welfare, and 78 (56.5%) by those of the Japanese Association of Acute Medicine. Receiver operating characteristic curve analysis showed that acquired TTP could be diagnosed based on severe thrombocytopenia (<20 × 10 9 /L), normal AT level (>87%), and mildly elevated FDP (<23 µg/mL)., Conclusions: Our results indicate that 3 routine laboratory tests could differentiate between acquired TTP and septic DIC.

Acquired Immune thrombotic thrombocytopenic purpura (iTTP) is considered among clinical situations that needs not only urgent treatment in acute setting but also long term management to prevent relapses. Important progresses have been made in management of these patients that are definitely associated with reduced mortality and relapse rate. However, there are still noticeable percentage of patients that may relapse despite application of modern treatment strategies including preemptive rituximab infusions. Hereby, we share our experience concerning a frequently relapsing iTTP due to development of anti-rituximab antibody. In our case administration of obinutuzumab, a humanized type II anti CD-20 antibody was associated with complete peripheral blood B cell depletion and increasing plasma ADAMTS-13 activity.

The anti-von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care., (© 2021 by The American Society of Hematology.)

A 42-year-old woman with a history of acute myeloid leukaemia status postallogeneic stem cell transplant presented with fevers, altered mental status, pulmonary infiltrates and septic shock that further progressed to thrombocytopenia and purpura fulminans. Laboratory studies were consistent with a diagnosis of thrombotic thrombocytopenic purpura (TTP). Blood cultures grew Streptococcus pneumoniae On chart review, our patient had a history of low immunoglobulin levels following stem cell transplant, which may have predisposed her to pneumococcal infection. The patient responded to therapy with ceftriaxone, plasma exchange, rituximab and caplacizumab. This is the fourth-documented case of pneumococcal induced TTP and, to the best of our knowledge, the first-describing pneumococcal induced TTP with purpura fulminans. We conclude that patients with TTP should be evaluated for infectious aetiologies and empiric antibiotics should be considered. Clinicians should be aware of the possibility for TTP to lead to purpura fulminans., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder resulting in organ damage including ischemic strokes. We sought to characterize the neuroimaging patterns of stroke in a large cohort of patients with immune-mediated TTP (iTTP) and determined their associations with clinical and laboratory parameters and outcomes., Methods: We analyzed the Alabama TTP Registry who had laboratory confirmation of acute iTTP. We reviewed the neuroimaging patterns of those with ischemic stroke on MRI, clinical information, and laboratory results. Small ischemic strokes were ≤20 mm in their maximum diameter in the axial plane. Large ischemic strokes were >20 mm. Student t test, Mann-Whitney U test, and χ2 test were all used for data analysis., Results: Of 108 iTTP patients, 21 had ischemic stroke on neuroimaging. The median platelet count in these patients was 12 × 109/L (interquartile range, IQR, 8.8-21 × 109/L), plasma ADAMTS13 activity 1.8 U/dL (IQR 0-4.5 U/dL), and the mean plasma level of anti-ADAMTS13 IgG was 6,595.8 U/mL (SD 3,448.9 U/mL). Comparison between patients with large ischemic strokes (n = 10) and small ischemic strokes (n = 11) revealed that patients with small stroke were older (p = 0.043) and had higher plasma levels of citrullinated histone 3 (p = 0.006) and histone/DNA complex (p = 0.014) than those with large strokes. There were no significant differences between 2 stroke groups in mortality or exacerbation., Conclusions: iTTP patients can present with large ischemic strokes and are usually younger. Further research should be performed in assessing different etiologies of iTTP-associated stroke based on neutrophil extracellular trap formation biomarkers (e.g., histone markers) seen in small ischemic stroke., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Pregnancy is a precipitating factor for immune thrombotic thrombocytopenic purpura (iTTP). We compared the clinical course and outcomes of iTTP in women of reproductive age, between those with pregnancy- and non-pregnancy-related iTTP. A review of all reproductive-aged women diagnosed with iTTP during 2010-2019 in seven university hospitals in Israel. Of 42 cases of iTTP, 12 (28.6%) were pregnancy-related. At presentation, the laboratory profiles did not differ significantly between those with pregnancy- and non-pregnancy-related iTTP, including hemoglobin (median 8.4 vs 8.0 g/dL), platelet count (12.5 vs. 11.5 X 10 9 /L); and levels of bilirubin (1.23 vs. 1.82 mg/dL), lactate dehydrogenase (1615 vs. 1701 U/L), creatinine (0.61 vs. 0.79 mg/dL) and anti-ADAMTS13 antibodies titer (75 vs. 82 U/mL). The proportions of women with renal, neurologic, or hepatic involvement were similar between the groups. Cardiac involvement was more common among those with pregnancy-related disease (25.0% vs. 3.3%, P = 0.06). The median number of courses of plasma-exchange therapy was 11 for both groups. All the women were treated with parenteral corticosteroids and the rate of adjunctive treatments did not differ between the groups (P = 0.30). Four women (one-third) with pregnancy-related disease had preeclampsia. Two women (16.7%) with pregnancy-related iTTP died during the acute episode (P = 0.07); no deaths were observed in the non-pregnancy-related group. Among reproductive-aged women with iTTP, most clinical and laboratory profiles were similar between those with pregnancy- and non-pregnancy-related disease. However, the higher rates of cardiac involvement and mortality among women with pregnancy-related iTTP highlight its challenging management.

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolysis, and ischemic organ failure. The PLASMIC and French TTP scores can help guide clinical decisions when ADAMTS13 testing is not immediately available. Older individuals often present atypically, but the impact of age on these tools is not known., Study Design and Methods: We calculated the sensitivity and specificity of the PLASMIC and French TTP scores in patients enrolled in the Johns Hopkins thrombotic microangiopathy (TMA) registry., Results: Of 257 patients with TMA enrolled in the registry, we excluded patients less than 18 years of age (n = 19), with prior TMA (n = 81) or who initially presented at another hospital (n = 25). The remaining 132 patients (75 with TTP and 57 with other TMA) were analyzed. Sensitivity of a French score of 2 decreased with age and was 72.2%, 61.5%, and 46.2% for ages 18 to 39, 40 to 59, and ≥ 60 years old, respectively. A PLASMIC score ≥ 5 had higher sensitivity than the French score but this also decreased with age; sensitivity was 91.4% (95% confidence interval [CI], 76.9-98.2), 78.3% (95% CI, 56.3-92.5), and 76.9% (95% CI, 46.2-95.0) for patients 18 to 39, 40 to 59, and ≥ 60 years old, respectively. Older patients had higher platelet counts and serum creatinine than the youngest group, contributing to the loss in sensitivity., Conclusion: The PLASMIC and French TTP scores have reduced sensitivity at age ≥ 60 years and are less reliable in identifying TTP in older patients. A high index of suspicion and availability of rapid ADAMTS13 assays is required to correctly diagnose all patients with TTP., (© 2020 AABB.)

Competing Interests: Conflict-of-interest disclosure: J.A.K.H. has received research funding from Baxalta US Inc. (now part of Takeda) and is a member of advisory boards for Shire (now part of Takeda) and Ablynx (now part of Sanofi). A.L. has received research funding support from the Cancer Prevention and Research Institute of Texas (RR190104), the Hemostasis and Thrombosis Research Society (Mentored Research Award) supported by an independent medical educational grant from Shire, and National Hemophilia Foundation Shire Clinical Fellowship Award.

Double filtration plasmapheresis (DFPP) could be an alternative method to simple plasma exchange plasmapheresis in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP). In a retrospective single center case series, we studied clinical presentation, management care, and prognosis of aTTP patients from our academic center treated with DFPP and IV infusion of fresh frozen plasma (FFP) between 2009 and 2018. Nine patients were included for 11 episodes. Median age was 38 years old (IQR 26-53) with 78% women. Six episodes (55%) required admission to the ICU, four of which required mechanical ventilation. Median FFP volume transfused was 35.2 mL/kg/d of session. Response was complete for nine episodes (82%). Four patients presented an early relapse, two a late relapse. Four patients died: one had an active untreated HCV infection, and two were over 80-year-old polymorbid patients. DFPP seems to be an efficient method of therapeutic plasmapheresis in TTP when combined with FFP transfusion and immunosuppressive treatments., (© 2020 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

This guidance document was prepared on behalf of the International Council for Standardization in Haematology (ICSH), by the ADAMTS13 Assay Working Group, which comprises an international group of both clinical and laboratory experts. The document provides recommendations on best practice for the performance of ADAMTS13 assays in clinical laboratories. ADAMTS13 assays support the differential diagnosis of thrombotic microangiopathies and have utility in the management of thrombotic thrombocytopenic purpura (TTP). There are three types of assay: activity, antigen and autoantibody/inhibitor assays. Methods for activity assays differ in terms of sensitivity, specificity, precision and turnaround time. The most widely used assays involve VWF peptide substrates and either chromogenic ELISA or FRET techniques, although chemiluminescence assays and rapid screening tests have recently become available. Tests for autoantibodies and inhibitors allow confirmation of acquired, immune-mediated TTP, while antigen assays may be useful in congenital TTP and as prognostic markers. In this document, we have attempted to describe ADAMTS13 assays and the conditions that affect them, as well as: blood collection, sample processing, quality control, standardization and clinical utility; recognizing that laboratories in different parts of the world have varying levels of sophistication. The recommendations are based on expert opinion, published literature and good clinical laboratory practice., (© 2020 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)