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Adult-onset Still's disease (AOSD) is a rare, systemic inflammatory disorder characterised by daily fever, arthritis, a salmon-pink rash and leucocytosis. Thrombotic thrombocytopenic purpura (TTP) is included in the class of thrombotic microangiopathies and manifests clinically as microangiopathic haemolytic anaemia (MAHA), thrombocytopenia and ischaemic tissue injury secondary to microthrombi. TTP is caused by either an autoimmune, congenital or idiopathic deficiency of ADAMTS13 and carries a high mortality rate. TTP can be seen in patients diagnosed with other rheumatologic conditions, with systemic lupus erythematosus being the most common, but is rarely seen in AOSD. Permanent complication rates from TTP in the setting of AOSD have been reported to be >50%. This case study aims to report one of the rare instances of TTP presenting in a patient with known AOSD to broaden the knowledge base regarding these rare coexisting pathologies., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The pathophysiology of Acute Pancreatitis (AP) may be complicated by endothelial activation. von Willebrand Factor (vWF)- ADAMTS13 axis is a marker of endothelial activation. The study aimed to investigate the axis in AP, comparing it in patients with and without persistent organ failure (OF), with and without pancreatic necrosis, and correlating it with the standard severity scores (CRP, APACHE II, BISAP, SOFA, and qSOFA) METHODS: vWF-Antigen (vWF:Ag), vWF-Collagen-Binding-Assay (vWF:CBA), and ADAMTS13 activity (ADAMTS13:act) levels were measured within 5 days of symptom onset in consecutive patients (n = 98), who were admitted with a first episode of AP (Dec 2021-May 2023)., Results: Of the 98 patients admitted with AP, 78(79.6 %) had no or transient OF; 20(20.4 %) had persistent OF. Age was comparable (43.73 ± 15.36 vs 38.65 ± 13.69) [mean ± SD](years), and males were predominant in both groups (70.5 % vs 80 %). Patientswith persistent OF had higher vWF:CBA(%)[323(279-486.5) vs 199.5(159.1-295.75)] and lower ADAMTS13:act(%)[35.4(23.8-56.85) vs 56.35(44.1-71.9)][median (25th - 75th percentile)](P = 0.001) than those with no or transient OF. Patients with pancreatic necrosis (n = 19) had lower ADAMTS13:act(%)[42.79 ± 18.69] than those without pancreatic necrosis (n = 18) [62.49 ± 22.64] (P < 0.01). ADAMTS13:act had a negative correlation(r = -0.2), whereas vWF:Ag and vWF:CBA had a positive correlation (r = 0.2) with the standard severity scores (P < 0.05). ADAMTS13:act could predict pancreatic necrosis [AUROC-0.737, P < 0.05] and persistent OF [AUROC-0.746, P < 0.001], while vWF:CBA could predict persistent OF [AUROC- 0.73, P < 0.001]., Conclusion: vWF-ADAMTS13 axis helps to predict severe disease and is associated with poor outcomes in acute pancreatitis., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

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.)

Introduction: Coronavirus disease 2019 (COVID-19) patients are predisposed to thrombotic events. COVID-19 coagulopathy can be associated with ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats 13) levels. ADAMTS-13, the cleaving protease of highly thrombogenic ultra-large von Willebrand Factor (vWF) multimers, was rarely investigated in COVID-19 patients and inconsistent results were obtained. We measured ADAMTS-13 levels of patients admitted to emergency department., Methodology: A prospective study was carried out with 180 individuals at the Emergency Department of Uşak Training and Research Hospital. The patients were divided into three groups: mild COVID-19 (group 2), severe COVID-19 with oxygen saturation below 94% (group 3), and control group (group 1). ADAMTS-13 levels were analyzed with an enzyme linked immunosorbent assay (ELISA) kit (SunRed, Shanghai, China). Demographic data, clinical findings, and routine laboratory test results (alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell, lymphocyte, platelet, C-reactive protein (CRP), lactate dehydrogenase (LDH), prothrombin time, international normalized ratio (INR), partial thromboplastin time, D-dimer, creatinine, urea) were evaluated., Results: ADAMTS-13 serum levels were slightly lower in groups 2 and 3 compared to the control group, with no significant difference between the ADAMTS-13 median values (p > 0.05). Groups 1 and 2 exhibited comparable outcomes. Group 3 demonstrated notably elevated levels of CRP, LDH, D-dimer, AST, ALT, creatinine; and decreased platelet counts and INR levels (p < 0.05)., Conclusions: COVID-19-associated coagulopathy is still unclear. Based on our data, ADAMTS-13 levels cannot be used as a biomarker to help stratify patients' risks at the time of admission., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Hüseyin H Kutlu, Arzu Sahin, Soycan Mizrak, Abdurrahman Yilmaz, Songul Doganay, Serdar Gungor, Sema Yilmaz.)

Objectives: Severe thrombotic antiphospholipid syndrome (APS) frequently affects the kidney, heart, and central nervous system. The precise frequency, clinical picture, differential diagnoses, and outcome of APS-related hematological involvement are lacking, especially in patients requiring ICU admission. This study aimed to describe the hematological manifestations associated with critically ill thrombotic APS patients and catastrophic antiphospholipid syndrome., Methods: This French, national, multicenter, retrospective study, conducted, from January 2000 to September 2018, included all APS patients admitted to 24 participating centers' ICUs with any new thrombotic manifestation. The prevalence of hematological manifestations and their associated outcomes were studied., Results: One hundred and thirty-four patients, female 72%, median [IQR] age 45 [34-56] years, with 152 episodes were included. Anemia was present in 95% of episodes and thrombocytopenia in 93%. The lowest values for hemoglobin and platelets were 7.1 [6.3-8.8] g/dL and 38 [21-60] g/L, respectively. The lowest platelet count below 20 g/L was significantly associated with a higher in-ICU mortality rate (50%, p < 0.0001). A thrombotic microangiopathy syndrome (TMA) syndrome was seen in 16 patients (12%) and was associated with higher in-hospital mortality (p = 0.05). Median ADAMTS-13 levels were 44% [27-74]. Anti-ADAMTS13 antibodies were tested in 11 patients and found negative in all. A suspicion of heparin-induced thrombocytopenia (HIT) was raised in 66 patients but only four patients were classified as definite HIT. Disseminated intravascular coagulation (DIC) was seen in 51% of patients., Conclusion: Thrombocytopenia is very frequent in severe APS patients and may be related to TMA, HIT, or DIC. Deciphering the mechanisms of thrombocytopenia is decisive in CAPS patients. Key Points • Thrombocytopenia is the hallmark laboratory finding in CAPS. • A complete thrombotic microangiopathy pattern is infrequent in CAPS patients. • Alternate diagnoses of CAPS, especially heparin-induced thrombocytopenia, need to be adequately investigated., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Common variable immunodeficiency (CVID) is a disorder characterized by hypogammaglobulinemia resulting in recurrent infections. While autoimmune disorders are common in patients with CVID, no association has been reported between CVID and immune thrombotic thrombocytopenic purpura (iTTP), a disorder most often caused by autoantibodies that compromise the activity of the enzyme ADAMTS13. Reduced ADAMTS13 activity results in the accumulation of large von Willebrand factor multimers that can consume platelets and cause microvascular thrombosis and organ injury, ultimately resulting in mortality in most cases of untreated iTTP. Here, we report a 12-year-old male with CVID who developed iTTP, underwent therapeutic plasma exchange (TPE), and subsequently recovered. We conducted a systematic review for other cases of CVID co-occurring with iTTP and present additional cases of this rare presentation. We highlight the importance of prompt recognition of iTTP in a patient with CVID and timely initiation of TPE., (© 2024 The Author(s). Journal of Clinical Apheresis published by Wiley Periodicals LLC.)

Data are limited on the impact of commencing antiplatelet therapy on von Willebrand Factor Antigen (VWF:Ag) or von Willebrand Factor propeptide (VWFpp) levels and ADAMTS13 activity, and their relationship with platelet reactivity following TIA/ischaemic stroke. In this pilot, observational study, VWF:Ag and VWFpp levels and ADAMTS13 activity were quantified in 48 patients ≤4 weeks of TIA/ischaemic stroke (baseline), and 14 days (14d) and 90 days (90d) after commencing aspirin, clopidogrel or aspirin+dipyridamole. Platelet reactivity was assessed at moderately-high shear stress (PFA-100® Collagen-Epinephrine / Collagen-ADP / INNOVANCE PFA P2Y assays), and low shear stress (VerifyNow® Aspirin / P2Y12, and Multiplate® Aspirin / ADP assays). VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d in the overall population (P ≤ 0.03). In the clopidogrel subgroup, VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d (P ≤ 0.01), with an increase in ADAMTS13 activity between baseline vs. 90d (P ≤ 0.03). In the aspirin+dipyridamole subgroup, there was an inverse relationship between VWF:Ag and VWFpp levels with both PFA-100 C-ADP and INNOVANCE PFA P2Y closure times (CTs) at baseline (P ≤ 0.02), with PFA-100 C-ADP, INNOVANCE PFA P2Y and C-EPI CTs at 14d (P ≤ 0.05), and between VWF:Ag levels and PFA-100 INNOVANCE PFA P2Y CTs at 90d (P = 0.03). There was a positive relationship between ADAMTS13 activity and PFA-100 C-ADP CTs at baseline (R 2  = 0.254; P = 0.04). Commencing/altering antiplatelet therapy, mainly attributed to commencing clopidogrel in this study, was associated with decreasing endothelial activation following TIA/ischaemic stroke. These data enhance our understanding of the impact of VWF:Ag and VWFpp especially on ex-vivo platelet reactivity status at high shear stress after TIA/ischaemic stroke., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background:  Neutrophil NETosis and neutrophil extracellular traps (NETs) play a critical role in pathogenesis of coronavirus disease 2019 (COVID-19)-associated thrombosis. However, the extents and reserve of NETosis, and potential of thrombus formation under shear in whole blood of patients with COVID-19 are not fully elucidated. Neither has the role of recombinant ADAMTS13 or caplacizumab on the accumulation of NETs and thrombus in COVID-19 patients' whole blood under shear been investigated., Methods:  Flow cytometry and microfluidic assay, as well as immunoassays, were employed for the study., Results:  We demonstrated that the percentage of H3Cit + MPO+ neutrophils, indicative of NETosis, was dramatically increased in patients with severe but not critical COVID-19 compared with that in asymptomatic or mild disease controls. Upon stimulation with poly [I:C], a double strain DNA mimicking viral infection, or bacterial shigatoxin-2, the percentage of H3Cit + MPO+ neutrophils was not significantly increased in the whole blood of severe and critical COVID-19 patients compared with that of asymptomatic controls, suggesting the reduction in NETosis reserve in these patients. Microfluidic assay demonstrated that the accumulation of NETs and thrombus was significantly enhanced in the whole blood of severe/critical COVID-19 patients compared with that of asymptomatic controls. Like DNase I, recombinant ADAMTS13 or caplacizumab dramatically reduced the NETs accumulation and thrombus formation under arterial shear., Conclusion:  Significantly increased neutrophil NETosis, reduced NETosis reserve, and enhanced thrombus formation under arterial shear may play a crucial role in the pathogenesis of COVID-19-associated coagulopathy. Recombinant ADAMTS13 or caplacizumab may be explored for the treatment of COVID-19-associated thrombosis., Competing Interests: X.L.Z. is a consultant for Alexion, Sanofi, Takeda, Apollo, GC Biopharma, and Stago. X.L.Z. is also the co-founder of Clotsolution. All other authors have declared no relevant conflict., (Thieme. All rights reserved.)

Background: Immune thrombotic thrombocytopenic purpura (iTTP) in children is a rare, severe thrombotic microangiopathy. This condition is characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia due to reduced activity of the von Willebrand factor-cleaving protease ADAMTS13., Methods: A retrospective case series evaluating data collected from the medical files of 4 children diagnosed with iTTP., Results: The presented case series depicts a variety of iTTP presentations: 1 case of primary iTTP, 1 case induced by Shiga toxin, 1 associated with RAS-associated autoimmune leukoproliferative disease (RALD), and 1 initial manifestation of systemic lupus erythematosus (SLE). Notably, 2 patients recovered without undergoing plasma exchange., Conclusion: Early ADAMTS13 testing in children with unexplained hemolysis or thrombocytopenia is crucial. The diverse underlying causes, including infections and autoimmune disorders, underscore the complexity of iTTP in the pediatric population. These cases highlight the necessity for personalized treatment approaches that consider each patient's unique clinical situation and potential alternatives or modifications to conventional therapeutic regimens., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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: 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.)

Abstract: While awaiting confirmatory results, empiric therapy for patients suspected to have immune thrombotic thrombocytopenic purpura (iTTP) provides benefits and also accrues risks and costs. Rapid assays for ADAMTS13 may be able to avoid the cost and risk exposure associated with empiric treatment. We conducted, to our knowledge, the first cost-effectiveness evaluation of testing strategies with rapid vs traditional ADAMTS13 assays in patients with intermediate- to high-risk PLASMIC scores, with and without caplacizumab use. We built a Markov cohort simulation with 4 clinical base-case analyses: (1) intermediate-risk PLASMIC score with caplacizumab; (2) intermediate-risk PLASMIC score without caplacizumab; (3) high-risk PLASMIC score with caplacizumab; and (4) high-risk PLASMIC score without caplacizumab. Each of these evaluated 3 testing strategies: (1) rapid assay (<1-hour turnaround); (2) in-house fluorescence resonance energy transfer (FRET)-based assay (24-hour turnaround); and (3) send-out FRET-based assay (72-hour turnaround). The primary outcome was the incremental net monetary benefit reported over a 3-day time horizon and across accepted willingness-to-pay thresholds in US dollars per quality-adjusted life-year (QALY). While accruing the same amount of QALYs, the rapid assay strategy saved up to $46 820 (95% CI, $41 961-$52 486) per patient tested. No parameter variation changed the outcome. In probabilistic sensitivity analyses, the rapid assay strategy was favored in 100% (3 base cases and scenario analyses) and 99% (1 base-case and scenario analysis) across 100 000 Monte Carlo iterations within each. Rapid ADAMTS13 testing for patients with intermediate- or high-risk PLASMIC scores yields significant per patient cost savings, achieved by reducing the costs associated with unnecessary therapeutic plasma exchange and caplacizumab therapy in patients without iTTP., (© 2024 by The American Society of Hematology. 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.)

Abstract: Caplacizumab 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., (© 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-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.)

Background: von Willebrand factor (VWF) and its cleaving protease, ADAMTS-13, form a pivotal axis that regulates hemostasis. However, the role of the VWF-ADAMTS-13 axis in the risk of future venous thromboembolism (VTE) is unknown., Objectives: To investigate whether plasma ADAMTS-13 levels and an imbalance with VWF levels, assessed as the VWF/ADAMTS-13 ratio, are associated with the risk of future VTE., Patients/methods: A population-based nested case-control study, comprising 383 incident VTE cases and 780 age- and sex-matched controls, was derived from the Tromsø study cohort (1994-2007). Antigen levels of ADAMTS-13 and VWF were measured in plasma samples obtained at cohort baseline. Odds ratios (ORs) with 95% CIs were estimated according to quartile cutoffs of ADAMTS-13 and VWF/ADAMTS-13 ratio determined in controls., Results: In age- and sex-adjusted analysis, ADAMTS-13 levels were inversely associated with the VTE risk, with an OR of 1.40 (95% CI, 0.99-1.99) for the lowest vs highest quartiles. The VWF/ADAMTS-13 ratio was linearly associated with the VTE risk (P for trend = .001), with an OR of 1.70 (95% CI, 1.19-2.43) for the highest vs lowest quartiles, and the association was particularly pronounced for unprovoked VTE (OR, 2.81; 95% CI, 1.65-4.81). The ORs were only slightly attenuated after additional adjustments for body mass index and C-reactive protein., Conclusions: Lowered ADAMTS-13 levels and an imbalance between ADAMTS-13 and VWF levels, reflected by an increased VWF/ADAMTS-13 ratio, were associated with an increased risk of future VTE. Our findings suggest that the VWF-ADAMTS-13 axis is involved in the pathogenesis of VTE., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Obstructive sleep apnea (OSA) is strongly associated with obesity, metabolic diseases, coronary artery disease (CAD), stroke, hypertension, and other disorders. This study assessed the relationship between circulating a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13) levels and the presence of OSA., Materials and Methods: This cross-sectional study included a total of 223 patients. We used a powerful high-throughput multiplexed immunobead-based assay to detect circulating levels of ADAMTS13. The associations between circulating ADAMTS13 levels and OSA were evaluated by multivariate logistic regression analysis., Results: Circulating ADAMTS13 levels were significantly elevated in patients with OSA compared with controls (0.8 vs. 2.7  μ g/mL, respectively, P < 0.001). After adjusting for confounding factors, circulating ADAMTS13 levels were significantly independently associated with the presence of OSA (odds ratio = 9.96, 95% confidence interval (CI) =4.11-24.13, P < 0.001). Furthermore, circulating ADAMTS13 levels showed discriminatory accuracy in assessing the presence of OSA (area under the curve: 0.87, 95% CI 0.81-0.93, P < 0.001)., Conclusion: Circulating ADAMTS13 levels were significantly correlated with the presence of OSA. ADAMTS13 may therefore function as a novel biomarker for monitoring the development and progression of OSA., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2022 Mengling Huang et al.)

Background: Thrombotic microangiopathy has been invoked as one of the most important mechanisms of damage in COVID-19 patients. Protease ADAMTS13 is a marker of microangiopathy responsible for controlling von Willebrand multimers size. Von Willebrand factor/ADAMTS13 ratio has been found impaired in COVID-19 patients outside pregnancy., Methods: We prospectively investigated 90 pregnant women admitted to two tertiary academic hospitals in Italy with a laboratory-confirmed diagnosis of SARS-CoV-2 infection. Demographic, clinical information and routine laboratory data were collected at the hospital admission and until discharge. We investigated whether vonWillebrand /ADAMTS13 axis imbalance is a predictor of adverse outcomes. Logistic regression analysis, which controlled for potential confounders, was performed to evaluate the association between laboratory parameters and clinical outcomes., Results: Most women (55.6%) were parae, with median gestational age at admission of 39 weeks. At hospital admission, 63.3% were asymptomatic for COVID-19 and 24.4% showed more than one sign or symptom of infection. Nulliparae with group O showed Willebrand / ADA MTS-13 ratios significantly lower than non-O, whereas in multiparae this difference was not observed. Logistic regression showed that ratio von Willebrand to ADAMTS13 was significantly and independently associated with preterm delivery (OR 1.9, 95%CI 1.1-3.5)., Conclusion: This study shows an imbalance of vonWillebrand /ADAMTS13 axis in pregnant women with COVID-19, leading to a significantly higher and independent risk of preterm delivery. Monitoring these biomarkers might support decision making process to manage and follow-up pregnancies in this setting., (© 2022. The Author(s).)

Background: Endotheliopathy is a key element in COVID-19 pathophysiology, contributing to both morbidity and mortality. Biomarkers distinguishing different COVID-19 phenotypes from sepsis syndrome remain poorly understood., Objective: To characterize circulating biomarkers of endothelial damage in different COVID-19 clinical disease stages compared with sepsis syndrome and normal volunteers., Methods: Patients with COVID-19 pneumonia (n = 49) were classified into moderate, severe, or critical (life-threatening) disease. Plasma samples were collected within 48 to 72 h of hospitalization to analyze endothelial activation markers, including soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), von Willebrand Factor (VWF), A disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13 (ADAMTS-13) activity, thrombomodulin (TM), and soluble TNF receptor I (sTNFRI); heparan sulfate (HS) for endothelial glycocalyx degradation; C5b9 deposits on endothelial cells in culture and soluble C5b9 for complement activation; circulating dsDNA for neutrophil extracellular traps (NETs) presence, and α2-antiplasmin and PAI-1 as parameters of fibrinolysis. We compared the level of each biomarker in all three COVID-19 groups and healthy donors as controls (n = 45). Results in critically ill COVID-19 patients were compared with other intensive care unit (ICU) patients with septic shock (SS, n = 14), sepsis (S, n = 7), and noninfectious systemic inflammatory response syndrome (NI-SIRS, n = 7)., Results: All analyzed biomarkers were increased in COVID-19 patients versus controls (P < 0.001), except for ADAMTS-13 activity that was normal in both groups. The increased expression of sVCAM-1, VWF, sTNFRI, and HS was related to COVID-19 disease severity (P < 0.05). Several differences in these parameters were found between ICU groups: SS patients showed significantly higher levels of VWF, TM, sTNFRI, and NETS compared with critical COVID-19 patients and ADAMTS-13 activity was significantly lover in SS, S, and NI-SIRS versus critical COVID-19 (P < 0.001). Furthermore, α2-antiplasmin activity was higher in critical COVID-19 versus NI-SIRS (P < 0.01) and SS (P < 0.001), whereas PAI-1 levels were significantly lower in COVID-19 patients compared with NI-SIRS, S, and SS patients (P < 0.01)., Conclusions: COVID-19 patients present with increased circulating endothelial stress products, complement activation, and fibrinolytic dysregulation, associated with disease severity. COVID-19 endotheliopathy differs from SS, in which endothelial damage is also a critical feature of pathobiology. These biomarkers could help to stratify the severity of COVID-19 disease and may also provide information to guide specific therapeutic strategies to mitigate endotheliopathy progression., Competing Interests: ABM-C is an advisory board member for Siemens, outside of the submitted work. MDR and EC have been granted by and received honoraria from Jazz Pharmaceuticals. PC and SF have collaborated with Jansen, Gilead, Kite, MSD, Alexion, and Pfizer, outside of the submitted work. MP received speaker's fee from Jazz Pharmaceuticals. CCC has received research support from ADC Therapeutics and Rhizen Pharmaceuticals; has served as consultant or advisor for Servier, Novartis, Genenta Science srl, ADC Therapeutics, Roche, Sanofi, Karyopharm, and Jazz Pharmaceuticals; and has received honoraria for speaker engagements from Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, Astra-Zeneca. JMM reports grants and consulting honoraria from Jazz Pharmaceuticals, during the conduct of the study; consulting honoraria and travel expenses from Gilead, consulting honoraria from Novartis, Sandoz, and Takeda, outside the submitted work. PGR reports a consulting or advisory role for Karyopharm, Oncopeptides, Celgene, Janssen, Takeda, and Sanofi; and research funding from Oncopeptides, Celgene, Takeda, and Bristol-Myers Squibb . The rest of authors have no actual or potential conflict of interest to declare., (Copyright © 2021 by the Shock Society.)

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.)

A mild decrease of ADAMTS13 (a disintegrin and metalloprotease with thrombospodin type 1 motif 13) could attribute to stroke and coronary heart disease in general population. However, the role of ADAMTS13 in hemodialysis (HD) patients remains to be explored. This cross-sectional and observational cohort study enrolled 98 chronic HD patients and 100 normal subjects with the aims to compare the ADAMTS13 activity between chronic HD patients and normal subjects, and to discover the role of ADAMTS13 on the newly developed cardiovascular events for HD patients in a 2-year follow-up. Our HD patients had a significantly lower ADAMTS13 activity than normal subjects, 41.0 ± 22.8% versus 102.3 ± 17.7%, p < 0.001. ADAMTS13 activity was positively correlated with diabetes, triglyceride and hemoglobin A1c, and negatively with high-density lipoprotein cholesterol levels in HD patients. With a follow-up of 20.3 ± 7.3 months, the Cox proportional hazards model revealed that low ADAMTS13, comorbid diabetes, and coronary heart diseases have independent correlations with the development of cardiovascular events. Our study demonstrated that chronic HD patients have a markedly decreased ADAMTS13 activity than normal subjects. Although ADAMTS13 seems to correlate well with diabetes, high triglyceride and low high-density lipoprotein cholesterol levels, ADAMTS13 deficiency still carries an independent risk for cardiovascular events in chronic HD patients., (© 2021. The Author(s).)

Intravascular hemolysis (IH) contributes to the development of endothelial dysfunction (ED) in sickle cell anemia (SCA), and the effects of hydroxyurea (HU, the only approved drug that decreases the frequency and severity of vaso-oclussive crises) on IH and ED in SCA remain unclear. We evaluated and compared the markers of IH among steady-state adult Brazilians with SCA and HbAA individuals. Overall, this cross-sectional study enrolled 30 SCA patients not receiving HU therapy (HbSS), 25 SCA patients receiving HU therapy (HbSS&#95;HU), and 32 HbAA volunteers (HbAA). The IH markers evaluated were serum Lactate Dehydrogenase (LDH), total heme, plasma hemoglobin (pHb), and soluble CD163 (sCD163). The ED markers analyzed were plasma von Willebrand factor (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo) levels, antigen of VWF-cleaving protease (ADAMTS13:Ag), thrombospondin-1, endothelin-1 levels, and ADAMTS13 Activity (ADAMTS13:Act). The levels of VWF:Ag, VWF:RCo, total heme, thrombospondin-1, and endothelin-1 were significantly higher in SCA patients (HbSS and HbSS&#95;HU) compared to HbAA individuals. Also, pHb, LDH, and thrombospondin-1 levels were significantly higher in the HbSS group than in the HbSS&#95;HU group. Contrarily, the levels of sCD163, ADAMTS13:Ag, and ADAMTS13:Act were significantly lower in both groups of SCA patients than HbAA controls, and ADAMTS13:Act levels were significantly lower in HbSS compared to HbSS&#95;HU patients. The higher ADAMTS13 activity levels in those on HU therapy may be attributed to lower pHb and thrombospondin-1 levels as previously shown by in vitro studies that thrombospondin-1 and pHb are bound to VWF. Thus, VWF is restrained from ADAMTS13 activity and cleavage., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) is a multidomain metalloprotease for which until now only a single substrate has been identified. ADAMTS13 cleaves the polymeric force-sensor von Willebrand factor (VWF) that unfolds under shear stress and recruits platelets to sites of vascular injury. Shear force-dependent cleavage at a single Tyr-Met peptide bond in the unfolded VWF A2 domain serves to reduce the size of VWF polymers in circulation. In patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP), a rare life-threatening disease, ADAMTS13 is targeted by autoantibodies that inhibit its activity or promote its clearance. In the absence of ADAMTS13, VWF polymers are not adequately processed, resulting in spontaneous adhesion of blood platelets, which presents as severe, life-threatening microvascular thrombosis. In healthy individuals, ADAMTS13-VWF interactions are guided by controlled conversion of ADAMTS13 from a closed, inactive to an open, active conformation through a series of interdomain contacts that are now beginning to be defined. Recently, it has been shown that ADAMTS13 adopts an open conformation in the acute phase and during subclinical disease in iTTP patients, making open ADAMTS13 a novel biomarker for iTTP. In this review, we summarize our current knowledge on ADAMTS13 conformation and speculate on potential triggers inducing conformational changes of ADAMTS13 and how these relate to the pathogenesis of iTTP., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Early descriptions of COVID-19 associated coagulopathy identified it as a disseminated intravascular coagulation (DIC). However, recent studies have highlighted the potential role of endothelial cell injury in its pathogenesis, and other possible underlying mechanisms are being explored. This study aimed to analyse the coagulation parameters of critically and noncritically ill patients with COVID-19 bilateral pneumonia, determine if coagulation factors consumption occurs and explore other potential mechanisms of COVID-19 coagulopathy. Critically and noncritically ill patients with a diagnosis of COVID-19 bilateral pneumonia were recruited. For each patient, we performed basic coagulation tests, quantification of coagulation factors and physiological inhibitor proteins, an evaluation of the fibrinolytic system and determination of von Willebrand Factor (vWF) and ADAMTS13. Laboratory data were compared with clinical data and outcomes. The study involved 62 patients (31 ICU, 31 non-ICU). The coagulation parameters assessment demonstrated normal median prothrombin time (PT), international normalized ratio (INR) and activated partial thromboplastin time (APTT) in our cohort and all coagulation factors were within normal range. PAI-1 median levels were elevated (median 52.6 ng/ml; IQR 37.2-85.7), as well as vWF activity (median 216%; IQR 196-439) and antigen (median 174%; IQR 153.5-174.1). A mild reduction of ADAMTS13 was observed in critically ill patients and nonsurvivors. We demonstrated an inverse correlation between ADAMTS13 levels and inflammatory markers, D-dimer and SOFA score in our cohort. Elevated vWF and PAI-1 levels, and a mild reduction of ADAMTS13 in the most severe patients, suggest that COVID-19 coagulopathy is an endotheliopathy that has shared features with thrombotic microangiopathy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Complement system hyperactivation has been proposed as a potential driver of adverse outcomes in severe acute respiratory syndrome coronavirus 2 infected patients, given prior research of complement deposits found in tissue and blood samples, as well as evidence of clinical improvement with anticomplement therapy. Its role in augmenting thrombotic microangiopathy mediated organ damage has also been implicated in coronavirus disease 2019 (COVID-19). This study aimed to examine associations between complement parameters and progression to severe COVID-19 illness, as well as correlations with other systems. Blood samples of COVID-19 patients presenting to the emergency department (ED) were analyzed for a wide panel of complement and inflammatory biomarkers. The primary outcome was COVID-19 severity at index ED visit, while the secondary outcome was peak disease severity over the course of illness. Fifty-two COVID-19 patients were enrolled. C3a (p = 0.018), C3a/C3 ratio (p = 0.002), and sC5b-9/C3 ratio (p = 0.021) were significantly elevated in with severe disease at ED presentation. Over the course of illness, C3a (p = 0.028) and C3a/C3 ratio (p = 0.003) were highest in the moderate severity group. In multivariate regression controlled for confounders, complement hyperactivation failed to predict progression to severe disease. C3a, C3a/C3 ratio, and sC5b-9/C3 ratio were correlated positively with numerous inflammatory biomarkers, fibrinogen, and VWF:Ag, and negatively with plasminogen and ADAMTS13 activity. We found evidence of complement hyperactivation in COVID-19, associated with hyperinflammation and thrombotic microangiopathy. Complement inhibition should be further investigated for potential benefit in patients displaying a hyperinflammatory and microangiopathic phenotype., (© 2021 Wiley Periodicals LLC.)

Background: Coagulation disorders are common in patients with hemophagocytic lymphohistiocytosis (HLH), associated with an increased risk of bleeding and death. We aim to investigate coagulation disorders and their outcome implications in critically ill patients with HLH., Methods: We prospectively evaluated 47 critically ill patients with HLH (median age of 54 years [42-67]) between April 2015 and December 2018. Coagulation assessments were performed at day 1. Abnormal standard coagulation was defined as prothrombin time (PT) <50% and/or fibrinogen <2g/L. HLH aetiology was mostly ascribed to haematological malignancies (74% of patients)., Results: Coagulation disorders and severe bleeding events were frequent, occurring in 30 (64%) and 11 (23%) patients respectively. At day 1, median fibrinogen level was 2∙65g/L [1.61-5.66]. Fibrinolytic activity was high as suggested by increased median levels of D-dimers, fibrin monomers, PAI-1 (plasminogen activator inhibitor) and tPA (tissue plasminogen activator). Forty-one (91%) patients had a decreased ADAMTS13 activity (A Disintegrin-like And Metalloproteinase with ThromboSpondin type 1 repeats, member 13). By multivariable analysis, the occurrence of a severe bleeding (OR 3.215 [1.194-8.653], p = 0∙021) and SOFA score (Sepsis-Related Organ Failure Assessment) at day 1 (OR 1.305 per point [1.146-1.485], p<0∙001) were independently associated with hospital mortality. No early biological marker was associated with severe bleeding., Conclusions: Hyperfibrinolysis may be the primary mechanism responsible for hypofibrinogenemia and may also participate in ADAMTS13 degradation. Targeting the plasmin system appears as a promising approach in severe HLH-related coagulation disorders., Competing Interests: The authors have declared that no competing interests exist.

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.)

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.)

The coronavirus disease 2019 (COVID-19) increases thrombotic risk. The mechanisms that lead to this prothrombotic state are not well established. The main aim was to evaluate the von Willebrand factor (VWF) antigen and plasma ADAMTS13 activity as endothelial injury markers in COVID-19. We present a prospective study in COVID-19 patients recruited in our institution. VWF antigen, ADAMTS13 activity, D-dimer, and fibrinogen were measured during the first week once COVID-19 was diagnosed. Fifty COVID-19 inpatients [44% in the intensive care unit (ICU)] and 102 COVID-19 outpatients were enrolled. Thirty age and gender matched non-COVID-19 ward inpatients and 30 non-COVID-19 healthy individuals were recruited. The COVID-19 inpatients had higher D-dimer, fibrinogen, and VWF antigen levels and a lower ADAMTS13 activity compared with the COVID-19 outpatients (p < 0.05). ICU patients had higher D-dimer and VWF antigen levels compared with the ward patients and the lowest ADAMTS13 activity (p < 0.05). An imbalance in VWF antigen/ADAMTS13 ratio was observed in COVID-19, reaching the highest in ICU patients. In contrast to other ward non-COVID-19 inpatients, a significative reduction in ADAMTS13 activity was observed in all COVID-19 patients. There is an increase in VWF antigen and an ADAMTS13 activity reduction in COVID-19 related to disease severity and could predict poor clinical outcomes. The ADAMTS13 activity reduction could be a marker associated with COVID-19 compared to other non-critical medical conditions., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.)

Introduction: Severe COVID-19 is often compounded by a prothrombotic state that is associated with poor outcomes. In this investigation, we aimed to evaluate ADAMTS13 activity, von Willebrand factor level (VWF:Ag), and the corresponding ADAMTS13 activity/VWF:Ag ratio, in patients with COVID-19 and for associations with disease progression and acute kidney injury (AKI)., Methods: Patients presenting to the emergency department (ED) with COVID-19 were enrolled in this prospective, observational study. ADAMTS13 activity and VWF:Ag were measured at index ED visit. The primary endpoint was severe AKI defined by KDIGO stage 2 + 3 criteria, while the secondary endpoint was peak 30-day COVID-19 severity., Results: A total of 52 adult COVID-19 patients were enrolled. Overall, we observed that 23.1% of the cohort had a relative deficiency in ADAMTS13 activity, while 80.8% had elevated VWF:Ag. The ADAMTS13 activity/VWF:Ag ratio was significantly lower in patients with severe AKI (P = .002) and those who developed the severe form of COVID-19 (P = .020). The ADAMTS13 activity/VWF:Ag ratio was negatively correlated with age (P < .001) and LDH (P < .001), while positively correlated with hemoglobin (P = .041). After controlling for confounders, a one-unit increase in ADAMTS13/VWF:Ag ratio was associated with 20% decreased odds of severe AKI., Conclusion: A low ADAMTS13 activity:VWF:Ag ratio at ED presentation is associated with progression to severe COVID-19 disease and severe AKI, with a pattern suggestive of a secondary microangiopathy. Further interventional studies should be conducted to assess the restoration of ADAMTS13:VWF:Ag ratio in hospitalized patients with COVID-19., (© 2020 John Wiley & Sons Ltd.)

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.)

Background: Von Willebrand Factor (VWF) multimers are cleaved into smaller and less coagulant forms by the metalloprotease ADAMTS13. The aim of this study was to investigate the association between VWF and ADAMTS13 and mortality in dialysis patients., Methods: We prospectively followed 956 dialysis patients. VWF levels and ADAMTS13 activity were measured. Cox proportional hazard analyses were used to calculate hazard ratios (HRs) with 95 % confidence intervals (CIs) to investigate the association between quartiles of VWF levels and ADAMTS13 activity and all-cause mortality. HRs were adjusted for age, sex, body mass index, cardiovascular disease, dialysis modality, primary kidney disease, use of antithrombotic medication, systolic blood pressure, albumin, C-reactive protein and residual GFR., Results: Of the 956 dialysis patients, 288 dialysis patients died within three years (mortality rate 151 per 1000 person-years). The highest quartile of VWF as compared with lower levels of VWF was associated with a 1.4-fold (95 %CI 1.1-1.8) increased mortality risk after adjustment. The lowest quartile of ADAMTS13 activity as compared with other quartiles was associated with a 1.3-fold (95 %CI 1.0-1.7) increased mortality risk after adjustment. The combination of the highest VWF quartile and lowest ADAMTS13 quartile was associated with a 2.0-fold (95 %CI 1.3-3.0) increased mortality risk as compared with the combination of the lowest VWF quartile and highest ADAMTS13 quartile., Conclusions: High VWF levels and low ADAMTS13 activity were associated with increased mortality risks in dialysis patients.

Respiratory failure in coronavirus disease 2019 (COVID-19) patients is one of the most frequent causes for referral to the ICU. A significant percentage of these patients does not survive the infection due to thromboembolic complications. Furthermore, the vascular system seems also to be involved in the pathogenesis. To investigate the role of hemostasis and endothelium on the outcome of COVID-19 patients admitted to the ICU. Blood was drawn from 16 ICU COVID-19 patients for hemostatic analysis. Patients were followed-up till discharge (n = 11) or death (n = 5). Parameters related to both coagulation and fibrinolysis, though disturbed, were not associated with mortality. Contrarily, activated Von Willebrand factor was increased and ADAMTS13 levels were decreased by two-fold in nonsurvivors compared with survivors. Our data established the involvement of the Von Willebrand factor-ADAMTS13 axis in the COVID-19 pathogenesis, thereby demonstrating that these plasma proteins seem to be strong predictors for ICU mortality., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

von Willebrand factor (VWF) is a large adhesive multimeric protein involved in hemostasis. The larger the size (or number of VWF multimers), the greater the functionality of the protein. A deficiency or defect of VWF can lead to von Willebrand disease (VWD) and cause bleeding. Conversely, an increase in VWF may create an environment that promotes thrombosis. ADAMS-13 ( a d isintegrin a nd m etalloproteinase with a t hrombo s pondin type 1 motif, member 13 ), sometimes called VWF-cleaving protease, is primarily responsible for controlling the size of VWF. The most severe deficiency (<10% of normal levels) of ADAMTS-13 arises in thrombotic thrombocytopenic purpura, a condition characterized by the presence of ultralarge VWF and clinically resulting in enhanced risk of thrombosis. However, ADAMTS-13 deficiency may result from other pathological processes. Of relevance is the recent finding that COVID-19 (coronavirus disease 2019) is associated with both increased levels and activity of VWF as well as generally decreased (or occasionally normal) activity levels of ADAMTS-13. Thus, in COVID-19 there is an alteration in the VWF/ADAMTS-13 axis, most often described by increased VWF/ADAMTS-13 ratio (or reduced ADAMTS-13/VWF ratio). COVID-19 is also associated with high prothrombotic risk. Thus, the imbalance of VWF and ADAMTS-13 in COVID-19 may be providing a milieu that promotes (micro)thrombosis, in a clinical picture resembling a secondary thrombotic microangiopathy in some patients. This review therefore assesses the literature on VWF, ADAMTS-13, and COVID-19. Whenever reported in COVID-19, VWF has always been identified as raised (compared with normal reference ranges or control populations). Reports have included VWF level (i.e., VWF antigen) and in some cases one or more VWF "activity" (e.g., collagen binding; platelet glycoprotein Ib [GPIb] binding, using ristocetin cofactor or more modern versions including VWF:GPIbR [recombinant] and VWF:GPIbM [mutant]). Whenever reported, ADAMTS-13 has been reported as "normal" or reduced; however, it should be recognized that "normal" levels may still identify a relative reduction in individual cases. Some reports also discuss the raised VWF/ADAMTS-13 (or reduced ADAMTS-13/VWF) ratio, but very few provide actual numerical data., Competing Interests: None declared., (Thieme. All rights reserved.)

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.)

Patients with novel coronavirus pneumonia show increased thrombotic risk. Although hemostatic alterations have been described in novel coronavirus pneumonia patients, case-control studies of von Willebrand factor (VWF), factor VIII (FVIII), and a disintegrin-like and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) are lacking. VWF, ADAMTS13, FVIII, d-dimer, C-reactive protein, and routine blood cells and chemistry were measured in 10 novel coronavirus pneumonia patients and 10 non-novel coronavirus pneumonia controls. Hemostatic factors were measured less than 48 h of hospital admission in patients without invasive ventilation. d-Dimer, C-reactive protein, and fibrinogen concentrations, high in both groups, did not differ significantly in novel coronavirus pneumonia vs. non-novel coronavirus pneumonia patients. Median VWF-antigen (324 vs. 153 IU/dl, P < 0.0001), VWF-Rco (342 vs. 133 IU/dl, P < 0.001), and FVIII-activity levels (203 vs. 123 IU/dl, P < 0.0001) were significantly higher in novel coronavirus pneumonia cases vs. controls ADAMTS13-activity was normal in both groups. Coronavirus pneumonia cases vs. non-novel coronavirus pneumonia controls showed marked VWF/FVIII elevation, suggesting specific virus-induced endothelial activation causing VWF/FVIII hypersecretion, which may represent a therapeutic target in novel coronavirus pneumonia., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Differentiating preeclampsia with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome from thrombotic thrombocytopenic purpura (TTP) can present a diagnostic dilemma., Case: We report the case of a 34-year-old woman, G1P0, with monochorionic diamniotic twins who presented with new-onset blurry vision, hypertension, and a platelet count of 4×109/L. After a multidisciplinary discussion, a diagnosis of atypical HELLP syndrome was made, despite overlapping features concerning for TTP. Her platelet count and ADAMTS13 activity testing showed appropriate recovery after delivery, without plasma exchange therapy, supporting the diagnosis of HELLP syndrome., Conclusion: Hemolysis, elevated liver enzymes, and low platelet count syndrome may present with severe thrombocytopenia and severe ADAMTS13 activity deficiency in ranges otherwise known to be more common with TTP., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Recent studies of acute liver failure (ALF) in man and animals have suggested that rebalanced hemostasis occurs, with distinct hypercoagulable features clinically evidenced by a low risk of bleeding. Rodent models have shown a link between intrahepatic microthrombus formation and progression of ALF. We sought to confirm these earlier findings in a large series of patients with well-characterized ALF from the Acute Liver Failure Study Group., Approach and Results: Citrated plasma samples taken on admission from 676 patients with ALF or acute liver injury (international normalized ratio ≥2.0 without hepatic encephalopathy) were used to determine levels of von Willebrand factor (VWF), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity, thrombomodulin-modified thrombin generation, and clot lysis time (CLT) and compared with the levels in 40 healthy controls. Patients had 3-fold increased VWF levels, 4-fold decreased ADAMTS13 activity, similar thrombin generating capacity, and 2.4-fold increased CLT, compared with controls. Increasing disease severity was associated with progressively more elevated VWF levels as well as hypofibrinolysis. Patients who died or underwent liver transplantation within 21 days of admission had higher VWF levels, lower ADAMTS13 activity, but similar thrombin generation and a similar proportion of patients with severe hypofibrinolysis, when compared with transplant-free survivors. Likewise, patients with bleeding complications had higher VWF levels and lower ADAMTS13 activity compared to those without bleeding. Thrombin generation and CLT did not differ significantly between bleeding and nonbleeding patients., Conclusions: Rebalanced hemostatic status was confirmed in a large cohort of patients with acute liver injury/ALF, demonstrating that VWF/ADAMTS13 imbalance is associated with poor outcome and bleeding. The association between VWF/ADAMTS13 imbalance and bleeding suggests that bleeding in ALF relates more to systemic inflammation than a primary coagulopathy., (© 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

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.)

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.)

Sickle cell disease (SCD) comprises a group of genetic disorders characterized by the presence of the hemoglobin (Hb) S in homozygosis or in heterozygosis with some other Hb variant or in interaction with thalassemia. SCD is characterized by a very complex pathophysiology, which determines a wide variability of clinical manifestations, including a chronic state of hypercoagulability responsible for the increased risk of thromboembolic events. ADAMTS13 and von Willebrand factor (VWF) play an important role in arterial and venous thrombosis. Thus, the aim of this study was to understand how the ADAMTS13-VWF axis behaves in sickle cell disease, as well as whether there is an association of these markers with the use of hydroxyurea (HU). This is a cross-sectional study conducted with 40 patients diagnosed with SCD and 40 healthy individuals. The analysis of the ADAMTS13-VWF axis was comparatively performed between groups of patients and controls and, afterwards, between patients with SCD who were users and non-users of HU. ADAMTS13 activity, ADAMTS13 activity/VWF:Ag, and ADAMTS13:Ag/VWF:Ag ratios were significantly lower and VWF:Ag levels significantly higher in SCD patients when compared to the controls. There was no statistically significant difference in ADAMTS13:Ag and VWF collagen binding (VWF:CB) levels between the groups evaluated. Among the categories of HU use, there was no statistically significant difference in any of the evaluated markers. As a conclusion, we could observe that the ADAMTS13-VWF axis is altered in SCD when compared to healthy individuals and that there is no association between these markers and the use of HU.

Background: Severe coronavirus disease 2019 (COVID-19) is characterized by an increased risk of thromboembolic events, with evidence of microthrombosis in the lungs of deceased patients., Objectives: To investigate the mechanism of microthrombosis in COVID-19 progression., Patients/methods: We assessed von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin-cofactor (VWF:RCo), VWF multimers, VWF propeptide (VWFpp), and ADAMTS13 activity in a cross-sectional study of 50 patients stratified according to their admission to three different intensity of care units: low (requiring high-flow nasal cannula oxygenation, n = 14), intermediate (requiring continuous positive airway pressure devices, n = 17), and high (requiring mechanical ventilation, n = 19)., Results: Median VWF:Ag, VWF:RCo, and VWFpp levels were markedly elevated in COVID-19 patients and increased with intensity of care, with VWF:Ag being 268, 386, and 476 IU/dL; VWF:RCo 216, 334, and 388 IU/dL; and VWFpp 156, 172, and 192 IU/dL in patients at low, intermediate, and high intensity of care, respectively. Conversely, the high-to-low molecular-weight VWF multimers ratios progressively decreased with increasing intensity of care, as well as median ADAMTS13 activity levels, which ranged from 82 IU/dL for patients at low intensity of care to 62 and 55 IU/dL for those at intermediate and high intensity of care., Conclusions: We found a significant alteration of the VWF-ADAMTS13 axis in COVID-19 patients, with an elevated VWF:Ag to ADAMTS13 activity ratio that was strongly associated with disease severity. Such an imbalance enhances the hypercoagulable state of COVID-19 patients and their risk of microthrombosis., (© 2020 International Society on Thrombosis and Haemostasis.)

Background:  The relationship between von Willebrand factor antigen (VWF:Ag), VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio, ADAMTS13 activity, and microembolic signal (MES) status in carotid stenosis is unknown., Methods:  This prospective, multicenter study simultaneously assessed plasma VWF:Ag levels, VWFpp levels and ADAMTS13 activity, and their relationship with MES in asymptomatic versus symptomatic moderate-to-severe (≥50-99%) carotid stenosis patients. One-hour transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES+ve or MES-ve., Results:  Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the "early phase" (≤4 weeks) and 37 patients in the "late phase" (≥3 months) after transient ischemic attack (TIA)/ischemic stroke. VWF:Ag levels were higher ( p  = 0.049) and VWFpp/VWF:Ag ratios lower ( p  = 0.006) in early symptomatic than in asymptomatic patients overall, and in early symptomatic versus asymptomatic MES-ve subgroups ( p ≤0.02). There were no intergroup differences in VWFpp expression or ADAMTS13 activity ( p ≥0.05). VWF:Ag levels and ADAMTS13 activity decreased ( p ≤ 0.048) and VWFpp/VWF:Ag ratios increased ( p  = 0.03) in symptomatic patients followed up from the early to late phases after TIA/stroke. Although there were no differences in the proportions of symptomatic and asymptomatic patients with blood group O, a combined analysis of early symptomatic and asymptomatic patients revealed lower median VWF:Ag levels in patients with blood group O versus those without blood group O (9.59 vs. 12.32 µg/mL, p  = 0.035)., Discussion:  VWF:Ag expression, a marker of endothelial ± platelet activation, is enhanced in recently symptomatic versus asymptomatic carotid stenosis patients, including in MES-ve patients, and decreases with ADAMTS13 activity over time following atherosclerotic TIA/ischemic stroke., Competing Interests: S.J.X.M. reports grants from Trinity College Dublin Innovation Bursary, Meath Foundation, Joint IICN/Merck Serono Fellowship in Neuroscience, The Vascular Neurology Research Foundation, unrestricted educational grant from Bayer HealthCare Ireland, and unrestricted educational grant from Verum Diagnostica, GmbH, outside the submitted work.S.T.L. reports grants from Meath Foundation, the Irish Institute of Clinical Neuroscience (IICN)/Novartis Ireland Fellowship Grant, the Irish Heart Foundation Stroke Prevention Bursary, the Vascular Neurology Research Foundation, Ireland, and unrestricted educational grant funding from Biogen Idec Ireland, outside the submitted work.D.J.H.M. reports grants from the Trinity College Dublin Innovation Bursary, Trinity College Dublin, Ireland, the Meath Foundation, Ireland, Joint IICN/Merck Serono Fellowship in Neuroscience, the Vascular Neurology Research Foundation, Bayer HealthCare Ireland, Verum Diagnostica, GmbH, the Irish Institute of Clinical Neuroscience (IICN)/Novartis Ireland Fellowship Grant, the Irish Heart Foundation Stroke Prevention Bursary, and Biogen Idec Ireland, during the conduct of the study., (Thieme. All rights reserved.)