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Background: Plasma exchange (PEX) treatment for patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has risk for major complications.Study Design and Methods: Data for PEX-related complications have been prospectively collected on all patients enrolled in the Oklahoma TTP-HUS Registry, 1996 to 2011. PEX-related complications have been defined as major or minor and as central venous catheter related or plasma related.Results: During 15 years, 1996 to 2011, 72 (24%) of 302 consecutive patients had major PEX-related complications. Analysis of five consecutive 3-year cohorts demonstrated that there has been a significant trend for decreasing frequency of all PEX-related major complications (p = 0.014) and central venous catheter-related major complications (p = 0.021) but not for the less common plasma-related major complications (p = 0.380). ADAMTS13 activity was measured in 288 (95%) of the 302 patients. Analysis of the 66 patients with ADAMTS13 activity of less than 10% demonstrated a significant trend for decreasing frequency of PEX-related major complications (p = 0.036); the trend for the 222 patients with ADAMTS13 activity of at least 10% was not significant (p = 0.118). The decreased frequency of PEX-related major complications among patients with ADAMTS13 activity of less than 10% may be related to a significant trend for decreasing duration of PEX treatment (p = 0.040) and decreasing frequency of requirement for more than one central venous catheter (p = 0.044). The decreased duration of PEX treatment may be related to increased use of adjunctive treatments: corticosteroids (p < 0.001) and rituximab (p < 0.001).Conclusions: The frequency of PEX-related major complications has decreased from 1996 to 2011, possibly related to increased use of corticosteroids and rituximab and the decreased duration of PEX required to achieve remission. [ABSTRACT FROM AUTHOR]

Introduction: Previous reports and meta-analyses derived from small case series reported a mortality rate of up to 40% in patients with coronavirus disease 2019 associated cerebral venous thrombosis (COVID-CVT). We assessed the clinical characteristics and outcomes in an international cohort of patients with COVID-CVT., Patients and Methods: This was a registry study of consecutive COVID-CVT patients diagnosed between March 2020 and March 2023. Data collected by the International Cerebral Venous Thrombosis Consortium from patients with CVT diagnosed between 2017 and 2018 served as a comparison. Outcome analyses were adjusted for age and sex., Results: We included 70 patients with COVID-CVT from 23 hospitals in 15 countries and 206 controls from 14 hospitals in 13 countries. The proportion of women was smaller in the COVID-CVT group (50% vs 68%, p  < 0.01). A higher proportion of COVID-CVT patients presented with altered mental state (44% vs 25%, p  < 0.01), the median thrombus load was higher in COVID-CVT patients (3 [IQR 2-4] vs 2 [1-3], p  < 0.01) and the length of hospital stay was longer compared to controls (11 days [IQR 7-20] vs 8 [4-15], p  = 0.02). In-hospital mortality did not differ (5/67 [7%, 95% CI 3-16] vs 7/206 [3%, 2-7], aOR 2.6 [95% CI 0.7-9]), nor did the frequency of functional independence after 6 months (modified Rankin Scale 0-2; 45/58 [78%, 95% CI 65-86] vs 161/185 [87%, 81-91], aOR 0.5 [95% CI 0.2-1.02])., Conclusion: In contrast to previous studies, the in-hospital mortality rate and functional outcomes during follow-up did not differ between COVID-CVT patients and the pre-COVID-19 controls., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AS reports a grant from the Swiss Heart Foundation. MRH reports grants from SITEM Research Support Funds and Swiss National Science Foundation, Swiss Heart Foundation, not directly related to this manuscript. MA reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Covidien, Daiichi Sankyo, Medtronic, Novartis, Pfizer, and Amgen. JMC has received grants paid to his institution from Boehringer Ingelheim and Bayer, and payments paid to his institution for data safety monitoring board participation by Bayer. JMF has received personal fees from Boehringer Ingelheim, Bayer, and Daiichi Sankyo as well as grants from Bayer. DAS reports travel support from Boehringer Ingelheim, speaker fees from Bayer, and Advisory Board participation for AstraZeneca. TT has received personal fees from Argenx, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva, and Portola Pharma. NR received consultant fees from Novartis. KJ has received academic grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG 965417) for research on CVT. SP received research support from BMS/Pfizer, Boehringer-Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, Helena Laboratories and Werfen as well as speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen (all outside the submitted work). TNN reports advisory board Idorsia, Brainomix. KA reports a grant from Swiss National Science Foundation and Medtronic advisory board participation in 2022, not related to this manuscript. EL has received academic grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG 942851), Swedish Neurologic Society, Elsa and Gustav Lindh’s Foundation, Wennerströms’ Foundation, P-O Ahl’s Foundation and Rune and Ulla Amlöv’s Foundation for research on CVT. All other co-authors report no disclosures.

The cornerstone treatment for immune-mediated thrombotic thrombocytopenic purpura (iTTP) in children is a combination of therapeutic plasma exchange (TPE), corticosteroids, and rituximab. Caplacizumab is an anti-von Willebrand factor (VWF) NANOBODY molecule approved as a frontline therapy of iTTP for adults and children aged ≥12 years. Using caplacizumab in children aged <12 years remains a gray area based on recommendations but with no marketing authorization. We report the first case of a pediatric patient with iTTP successfully treated with a caplacizumab dose adjustment of 5 mg daily based on ADAMTS13 activity. We also review all published cases of iTTP in children aged <12 years treated with caplacizumab. This is a 7-year-old girl with clinical thrombotic microangiopathy, in the absence of diarrhea and kidney injury. With a French score of 2 and a PLASMIC score of 7 (high risk), the diagnosis of TTP was suspected and later confirmed by severely low ADAMTS13 activity (<5%). Immune-mediated TTP was distinguished from the congenital one due to the presence of a functional ADAMTS13 inhibitor. Daily TPE and intravenous corticosteroids were started on day 0 (D0). Rituximab was added on D4, and due to refractoriness under daily TPE, we considered off-label administration of caplacizumab from D12. A clinical answer, with a significant increase in the platelet count, was observed within 48 h. A complete ADAMTS13 recovery was reached on D62. No major adverse events were observed during the treatment. She was discharged from the hospital over 3 months ago with a platelet count still within normal ranges. In the literature, we identified a total of four case reports describing five iTTP patients aged <12 years treated with caplacizumab, with a 100% success and tolerability rate. These published data attest to the efficacy and safety of the systematic use of caplacizumab and rituximab as frontline therapy in pediatric iTTP under 12 years of age. Therefore, prospective data are needed to support commercial authorization of caplacizumab in this subpopulation. Close monitoring of ADAMTS13 activity is particularly of interest among children to limit the number of caplacizumab injections., Competing Interests: Caplacizumab treatment was financed by Sanofi. JK is a member of the advisory board of Takeda, a member of the Takeda group of companies, for the development of recombinant ADAMTS13, and of Ablynx, now part of Sanofi for the development of caplacizumab, and has received lecture fees from Takeda and Sanofi. All honoraria are paid to her employer, Insel Gruppe AG, Bern, Switzerland. PC is a member of Sanofi's advisory board and has received honoraria for participating in symposia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Chavaz, Cimasoni, Kremer Hovinga, Coppo and Ansari.)

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) may lead to microvascular thrombosis and mortality, despite patients receiving appropriate standard of care treatment (immunosuppressive therapy and therapeutic plasma exchange). Caplacizumab directly inhibits von Willebrand factor-platelet interaction and consequently prevents microthrombi formation., Objectives: This study aimed to determine the efficacy and safety of caplacizumab in diverse, clinically relevant patient subgroups., Methods: In this post hoc analysis of phase 3 HERCULES study (NCT02553317), patients were categorized by clinically relevant subgroups (prior iTTP history, iTTP severity at presentation, and initial immunosuppression regimen)., Results: In patients with previous acute iTTP episodes, less severe disease at presentation, or those who received a corticosteroid-only initial immunosuppression regimen, time to platelet count response was shorter with caplacizumab vs placebo. Across all subgroups, fewer patients experienced a composite outcome of iTTP-related death, exacerbation, or major thromboembolic event on caplacizumab vs placebo. Placebo-treated patients remained at risk of exacerbations and refractoriness on either initial immunosuppression regimen (ie, corticosteroids only or corticosteroids plus rituximab). In the corticosteroids plus rituximab group, no exacerbations were reported in caplacizumab-treated patients, but 8 of the 16 (50%) patients experienced exacerbations in the placebo group. Safety outcomes were consistent with the findings of the main HERCULES study., Conclusion: Caplacizumab treatment of acute iTTP, in combination with therapeutic plasma exchange and immunosuppression, was safe and effective regardless of prior iTTP history, severity, or initial immunosuppression regimen and improved patient outcomes across clinically diverse subgroups. These findings emphasize the need for treatments with rapid onset of action that can reduce mortality and iTTP-related complications., (© 2024 The Authors.)

Abstract: New analytical techniques can assess hundreds of proteins simultaneously with high sensitivity, facilitating the observation of their complex interplay and role in disease mechanisms. We hypothesized that proteomic profiling targeting proteins involved in thrombus formation, inflammation, and the immune response would identify potentially new biomarkers for heparin-induced thrombocytopenia (HIT). Four existing panels of the Olink proximity extension assay covering 356 proteins involved in thrombus formation, inflammation, and immune response were applied to randomly selected patients with suspected HIT (confirmed HIT, n = 32; HIT ruled out, n = 38; and positive heparin/platelet factor 4 [H/PF4] antibodies, n = 28). The relative difference in protein concentration was analyzed using a linear regression model adjusted for sex and age. To confirm the test results, soluble P-selectin was determined using enzyme-linked immunosorbent assay (ELISA) in above mentioned patients and an additional second data set (n = 49). HIT was defined as a positive heparin-induced platelet activation assay (washed platelet assay). Among 98 patients of the primary data set, the median 4Ts score was 5 in patients with HIT, 4 in patients with positive H/PF4 antibodies, and 3 in patients without HIT. The median optical density of a polyspecific H/PF4 ELISA were 3.0, 0.9, and 0.3. Soluble P-selectin remained statistically significant after multiple test adjustments. The area under the receiver operating characteristic curve was 0.81 for Olink and 0.8 for ELISA. Future studies shall assess the diagnostic and prognostic value of soluble P-selectin in the management of HIT., (© 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.)

Background: Congenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known., Methods: In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment., Results: A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy., Conclusions: During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.)., (Copyright © 2024 Massachusetts Medical Society.)

Pregnancy is a potential trigger of acute thrombotic thrombocytopenic purpura (TTP). The management of pregnancy-associated immune-mediated TTP (iTTP) can be challenging, especially when it is refractory to standard treatment. Caplacizumab, a nanobody to von Willebrand factor (VWF) blocking its A1 domain, is a valuable new therapeutic option. Its use is, however, not approved during pregnancy and breastfeeding. We describe the successful off-label administration of caplacizumab during pregnancy and delivery in a patient with refractory iTTP. The favourable outcome without significant thrombotic or haemorrhagic complications indicates that caplacizumab may be an effective and safe treatment option in refractory iTTP during pregnancy., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Importance: Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice., Objective: To evaluate the current diagnostic practice for managing the suspicion of HIT., Design, Setting, and Participants: This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT., Exposures: Suspicion of HIT., Main Outcomes and Measures: The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests., Results: Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2 × 2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively., Conclusions and Relevance: In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.

One hundred years ago, in 1924, the first description of a patient with a disease, now known as thrombotic thrombocytopenic purpura (TTP) was published by Dr. Eli Moschcowitz. In honor of this report, this article, written by distinguished specialists in TTP, reviews the increase in scientific knowledge on this disease during the last 100 years. It covers the scientific progress from plasma therapy, the first beneficial treatment for TTP, to the elucidation of the pathophysiology, the discovery of ADAMTS13, the development of assays and targeted therapies up to the modern treatment concepts, that improved the outcome of TTP from an incurable disease to a well understood and treatable disorder., Competing Interests: PK: Grants or contracts from any entity: Sanofi/Ablynx, Novo Nordisk, Takeda, Roche. Consulting fees: Sanofi/Ablynx, Novo Nordisk, Takeda, Roche. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sanofi/Ablynx, Novo Nordisk, Takeda, Roche, Technoclone. Support for attending meetings and/or travel: Sanofi/Ablynx, Novo Nordisk, Takeda, Roche. Participation on a Data Safety Monitoring Board or Advisory Board: Sanofi/Ablynx, Novo Nordisk, Takeda.BL: Consulting fees: Hämatologie Praxis Bern, Monthly consultation and case discussions. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Lecture fee, Long-term burden of TTP, Virtual meeting Takeda 18.05.2021; Lecture fee, History of ADAMTS13 and TTP, Educational meeting Alexion, Liverpool, 20.09.2023. Participation on a Data Safety Monitoring Board or Advisory Board: Chairman of DMCs for studies of recombinant ADAMTS13 in hereditary and acquired TTP, run by Takeda; Chairman of DMC of Mayari study, treatment of acquired TTP using caplacizumab and immunosuppression without plasma exchange, run by Sanofi., (Thieme. All rights reserved.)

Background  Guidelines surrounding emicizumab prophylaxis and perioperative treatment for people with hemophilia A (PwHA) with factor (F)VIII inhibitors undergoing surgeries are limited. The phase IIIb multicenter, single-arm STASEY study evaluated safety and tolerability of emicizumab prophylaxis in PwHA aged ≥12 years with FVIII inhibitors. This analysis assesses surgeries during study conduct, associated hemophilia medications, and postoperative bleeds (treated and untreated). Methods  PwHA with FVIII inhibitors received emicizumab 3.0 mg/kg/week for 4 weeks, then 1.5 mg/kg/week until 2 years. Surgeries were managed and documented by treating physicians. Bleeds and treatments were recorded by physicians and participants. Results  Forty-six participants had ≥1 on-study surgery, 37 underwent 56 minor surgeries, and 13 underwent 22 major surgeries. Four participants underwent both minor and major surgeries. Of 18 (81.8%) and 4 (18.2%) major surgeries managed with/without additional hemostatic medication, 33.3 and 25.0% were associated with a treated postoperative bleed, respectively. Of 24 (42.9%) and 32 (57.1%) minor surgeries managed with/without additional hemostatic medication, 15.6 and 25.0% were associated with a treated postoperative bleed, respectively. Recombinant activated FVII was the most common medication for prophylaxis and bleed treatment. There were no thrombotic microangiopathies (TMAs). One hypertrophic clot, considered unrelated to emicizumab, occurred following tooth extraction. Conclusion  In this challenging population with a high bleeding risk, major surgeries were performed in PwHA receiving emicizumab with/without additional hemostatic medication. Postoperative bleeds occurred following 59.1% of major surgeries; 53.8% were treated. No arterial/venous thrombotic events or TMAs occurred due to concomitant emicizumab and bypassing agents. Trial registration  This trial is registered at ClinicalTrials.gov (NCT03191799)., Competing Interests: Conflict of Interest G.C. has received consulting fees from CSL Behring and F. Hoffmann-La Roche Ltd; has received payment or honoraria for speaking at company satellite symposia/webinar from BioMarin, Grifols, LFB, Kedrion, Takeda, F. Hoffmann-La Roche Ltd, Novo Nordisk, CSL Behring, Sanofi, SOBI, and Werfen; and has participated on advisory boards for Bayer, BioMarin, CSL Behring, LFB, SOBI, Pfizer, F. Hoffmann-La Roche Ltd, and Takeda. F.P. has received speaker fees for participating in educational meetings for Grifols, F. Hoffmann-La Roche Ltd; and has participated on advisory boards for Sanofi, SOBI, Takeda, F. Hoffmann-La Roche Ltd, and BioMarin. J.A.K.H. has acted in a consultation or advisory role for Bayer, CSL Behring, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, SOBI, and Takeda; has received speakers' bureau from CSL Behring, F. Hoffmann-La Roche Ltd, Sanofi, SOBI, and Takeda; has received research funding for the Interprofessional Hemophilia Care EHCCC Inselspital from Bayer, CSL Behring, Novo Nordisk, F. Hoffmann-La Roche Ltd, and SOBI, and for the hereditary TTP registry: Baxter, now part of Takeda; has given expert testimony for Federal Office of Public Health, Switzerland, and has received fees for travel, accommodation, and expenses from Bayer and SOBI. R.E.G.S. has acted in a consultation or advisory role for Bayer and Novartis and received research funding from Bayer, CSL Behring, Hemab, Novo Nordisk, Octapharma, and SOBI. S.R. and K.M. are employees of and shareholders in F. Hoffmann-La Roche Ltd. V.J-Y. has received grants or contracts from F. Hoffmann-La Roche Ltd, Novo Nordisk, SOBI, Takeda, Grifols, Bayer, Pfizer, Octapharma, and CSL Behring, and consulting fees and payment or honoraria for lectures, presentations, speakers' bureau, manuscript writing or educational events from F. Hoffmann-La Roche Ltd, Novo Nordisk, Sanofi, SOBI, Takeda, Grifols, Bayer, Pfizer, Spark Therapeutics, BioMarin, Octapharma, and CSL Behring., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Introduction: Cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is a severe disease with high mortality. There are few data on sex differences in CVST-VITT. The aim of our study was to investigate the differences in presentation, treatment, clinical course, complications, and outcome of CVST-VITT between women and men., Patients and Methods: We used data from an ongoing international registry on CVST-VITT. VITT was diagnosed according to the Pavord criteria. We compared the characteristics of CVST-VITT in women and men., Results: Of 133 patients with possible, probable, or definite CVST-VITT, 102 (77%) were women. Women were slightly younger [median age 42 (IQR 28-54) vs 45 (28-56)], presented more often with coma (26% vs 10%) and had a lower platelet count at presentation [median (IQR) 50x10 9 /L (28-79) vs 68 (30-125)] than men. The nadir platelet count was lower in women [median (IQR) 34 (19-62) vs 53 (20-92)]. More women received endovascular treatment than men (15% vs 6%). Rates of treatment with intravenous immunoglobulins were similar (63% vs 66%), as were new venous thromboembolic events (14% vs 14%) and major bleeding complications (30% vs 20%). Rates of good functional outcome (modified Rankin Scale 0-2, 42% vs 45%) and in-hospital death (39% vs 41%) did not differ., Discussion and Conclusions: Three quarters of CVST-VITT patients in this study were women. Women were more severely affected at presentation, but clinical course and outcome did not differ between women and men. VITT-specific treatments were overall similar, but more women received endovascular treatment., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.S. has received a grant from Swiss Heart Foundation; C.C. has received speaker honoraria from Boehringer Ingelheim, personal fees for advisory board participation from AstraZeneca and Biogen, and personal fees for steering committee participation from Biogen and Bristol Myers Squibb; T.J.K. has received educational meeting cost assistance from Boehringer Ingelheim; T.S.F. receives in-kind study medication from Bayer Canada and advisory board honoraria from HLS Therapeutics; S.P. received research support from BMS/Pfizer, Boehringer-Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, Helena Laboratories and Werfen as well as speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen (all outside the submitted work); R.L. reports fees paid to his institution for consultancy by Boehringer Ingelheim, Genentech, Ischemaview, Medtronic and Medpass; E.L. has received academic grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG 942851), Swedish Neurologic Society, Elsa and Gustav Lindh’s Foundation, Wennerströms’ Foundation, P-O Ahl’s Foundation and Rune and Ulla Amlöv’s Foundation for research on CVT; A.C. received speaker grants from Alexion Pharma, Italfarmaco, and Daiichi-Sankyo; M.W. has received consulting fees from Portola/Alexion; C.J. has received speaker honoraria from Alexion, CSL Behring, TEVA and Sanofi Genzyme, personal fees for advisory board participation from Alexion, Roche, Novartis and Merck Serono; H.K. has received personal fees for consulting and data safety monitoring board activities for Octapharma, Grifols, CSL Behring, UCB, Argenx, Takaeda, Alexion and his institution has received clinical trial support from Takaeda; S.N. has received consulting fees from Brainomix and lecture fees from Boehringer Ingelheim and BMS Pfizer; T.G. has received travel grants and speaker honoraria from Boehringer Ingelheim, Bayer, Novartis, BMS / Pfizer and Alexion; A.G. has received personal fees from Bayer Vital, Bristol Myers Squibb, and Daiichi Sankyo; K.J. has received academic grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG 965417) for research on CVT; T.T. has received personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva, and Portola Pharma; D.A.S. reports travel support from Boehringer Ingelheim, speaker fees from Bayer, and Advisory Board participation for AstraZeneca; J.M.F. has received personal fees from Boehringer Ingelheim, Bayer, and Daiichi Sankyo as well as grants from Bayer; J.M.C. has received grants paid to his institution from Boehringer Ingelheim and Bayer, and payments paid to his institution for data safety monitoring board participation by Bayer; M.A. reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Covidien, Daiichi Sankyo, Medtronic, Novartis, Pfizer, and Amgen; M.R.H. reports grants from the Swiss Heart Foundation and from the Bangerter Foundation, and Advisory Board participation for Amgen. All other authors have nothing to disclose.

Background: Current ADAMTS13 activity assays are important for diagnosing thrombotic thrombocytopenic purpura (TTP) but are unreliable to assay ADAMTS13 activity in animal models. The Cattle-FRETS71 assay is capable of detecting ADAMTS13 activity in plasma from multiple animal species, making it a potentially useful reagent at all stages of clinical research. The performance of Cattle-FRETS71 in TTP diagnosis is not yet known., Objectives: We evaluated the performance of the Cattle-FRETS71 substrate against the human FRETS-rVWF71 and the FRETS-VWF73 commercial substrates in human plasma and serum samples to validate its utility in diagnosing TTP in patients., Methods: Internal validation was performed using heparinized plasma samples (n = 81). External validation was a blinded study using serum samples from the Oklahoma TTP Registry (n = 118, collected 2004-2014) that had been initially assayed by FRETS-VWF73 within 1 year of collection. Additional validation was performed with citrated plasma samples with variable ADAMTS13 activities (n = 32) that were analyzed by FRETS-VWF73., Results: There was an excellent correlation (r = 0.94) between Cattle-FRETS71 and FRETS-rVWF71 for assayed heparinized plasma samples (n = 81). Assay results between Cattle-FRETS71 and FRETS-VWF73 of Oklahoma TTP Registry serum samples (n = 118) and citrated plasma samples (n = 32) were comparably good (r = 0.81 and r = 0.85, respectively)., Conclusion: The Cattle-FRETS71 assay is comparable with other assays in quantifying ADAMTS13 activity in human plasma collected from patients with documented or suspected TTP. The versatility of Cattle-FRETS71, combined with its specificity and sensitivity, makes it a useful tool for the standardization of ADAMTS13 activity across basic and clinical research paradigms., Competing Interests: Declaration of competing interests J.M. holds the patent, “Fluorogenic substrate for ADAMTS13,” US 8663912, issued to Washington University. J.C.B., C.A., F.Z.M., R.K., J.A.K.H., D.T., S.K.V., and J.G. have no conflicts of interest., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). Remarkably, cases of cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) have rarely been reported from LMICs., Aims: We studied the frequency, manifestations, treatment, and outcomes of CVST-VITT in LMICs., Methods: We report data from an international registry on CVST after COVID-19 vaccination. VITT was classified according to the Pavord criteria. We compared CVST-VITT cases from LMICs to cases from high-income countries (HICs)., Results: Until August 2022, 228 CVST cases were reported, of which 63 were from LMICs (all middle-income countries [MICs]: Brazil, China, India, Iran, Mexico, Pakistan, Turkey). Of these 63, 32 (51%) met the VITT criteria, compared to 103 of 165 (62%) from HICs. Only 5 of the 32 (16%) CVST-VITT cases from MICs had definite VITT, mostly because anti-platelet factor 4 antibodies were often not tested. The median age was 26 (interquartile range [IQR] 20-37) versus 47 (IQR 32-58) years, and the proportion of women was 25 of 32 (78%) versus 77 of 103 (75%) in MICs versus HICs, respectively. Patients from MICs were diagnosed later than patients from HICs (1/32 [3%] vs. 65/103 [63%] diagnosed before May 2021). Clinical manifestations, including intracranial hemorrhage, were largely similar as was intravenous immunoglobulin use. In-hospital mortality was lower in MICs (7/31 [23%, 95% confidence interval (CI) 11-40]) than in HICs (44/102 [43%, 95% CI 34-53], p  = 0.039)., Conclusions: The number of CVST-VITT cases reported from LMICs was small despite the widespread use of adenoviral vaccines. Clinical manifestations and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.C. received honoraria from Boehringer-Ingelheim, AstraZeneca, Biogen, Bristol Myers Squibb; T.J.K. received cost-assistance from Boehringer-Ingelheim; T.S.F. receives study medication from Bayer Canada and honoraria from HLS Therapeutics; S.P. received support from BMS/Pfizer, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, German Federal Ministry of Education and Research, Helena Laboratories, Werfen, Alexion, AstraZeneca, Bayer, Boehringer-Ingelheim, Portola; R.L. reports fees by Boehringer-Ingelheim, Genentech, Ischemaview, Medtronic, Medpass; A.S. received grants from Swiss Heart Foundation; E.L. received grants from Swedish state, Swedish Neurologic Society, Elsa and Gustav Lindh’s Foundation, Wennerströms’ Foundation, P-O Ahl’s Foundation, Rune and Ulla Amlöv’s Foundation; A.G. received fees from Bayer Vital, Bristol Myers Squibb, Daiichi Sankyo; K.J. received grants from Swedish state; T.T. received fees from Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Inventiva, Portola Pharma; M.R.H. reports grants from Swiss Heart Foundation and Bangerter Foundation and Advisory Board participation for Amgen; M.A. reports fees from AstraZeneca, Bayer, Bristol Myers Squibb, Covidien, Daiichi Sankyo, Medtronic, Novartis, Pfizer, Amgen; D.A.S. reports travel support from Boehringer-Ingelheim, fees from Bayer, and Advisory Board participation for AstraZeneca; J.M.F. received fees from Boehringer-Ingelheim, Bayer, and Daiichi Sankyo and grants from Bayer; J.M.C. received grants from Boehringer-Ingelheim and Bayer and payments for DSMB participation by Bayer; the other authors have no disclosures.

Background: Anecdotal reports suggest that the correlation between heparin/platelet factor 4 (PF4) antibody assays for the diagnosis of heparin-induced thrombocytopenia (HIT) is limited., Objectives: To investigate the correlation between widely used assays and examine possible factors contributing to variability., Methods: This is a large, prospective cohort study with 10 participating tertiary care hospitals including 1393 patients with suspected HIT in clinical practice. HIT was defined by a positive heparin-induced platelet activation (HIPA) assay (washed platelet reference standard test). Three different immunoassays were used to measure heparin/PF4 antibodies: chemiluminescent immunoassay, enzyme-linked immunosorbent assay, and particle gel immunoassay. Various factors that could influence the assays were examined: sex (male or female), age (<65 years or ≥65 years), unfractionated heparin exposure, presence of thrombosis, cardiovascular surgery, and intensive care unit. Spearman's correlation coefficients were calculated. Z-scores and diagnostic odds ratios were determined in the aforementioned subgroups of patients., Results: Among 1393 patients, 119 were classified as HIT-positive (prevalence, 8.5%). The median 4Ts score was 5 (IQR, 4-6) in patients with HIT compared with 3 (IQR, 2-4) in patients without HIT. Correlations (r s ) between immunoassays were weak (0.53-0.65). Inconsistencies between immunoassays could not be explained by further analyses of z-scored test results and diagnostic odds ratios in subgroups of patients., Conclusion: The correlation between widely used heparin/PF4 antibody assays was weak, and key factors could not explain this variability. Standardization of immunoassays is requested to improve comparability., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Aims of the Study: Acquired haemophilia A is a rare disease with an annual incidence of 1.48 per million. Based on clinical observations, we suspect a higher incidence in southern Switzerland, and aimed at providing local epidemiological data, and clinical information regarding diagnosis, treatment and outcome in our region., Methods: All adult patients with acquired haemophilia A treated between 2013 and 2019 in our facility were included in the present retrospective analysis., Results: We treated 11 patients with acquired haemophilia A between 2013 and 2019, resulting in an annual incidence of 4.5 per million (95% confidence interval [CI] 0-9.0). Median delay from first symptoms to diagnosis was 4.5 days, and the median age at diagnosis was 79 years (range 23-87). Possible causative conditions were: pregnancy (n = 1), polyarteritis nodosa (n = 1), myelodysplastic syndrome (n = 1), chronic human immunodeficiency virus (HIV) (n = 1), and HIV postexposure prophylaxis (n = 1). In five patients no underlying or associated condition was identified. Median activated partial thromboplastin time (aPTT)) at baseline was 79 seconds (65-117; ref. value <38 sec), and FVIII:C 2.15% (<1-3.75%). A FVIII:C <1% was present in 4/10 patients. Median FVIII-inhibitor titre was 10.3 BU/ml (2.4-75.0 BU/ml). All patients had bleeding symptoms, 5/10 patients had major bleedings, and 7/10 patients were treated with bypassing agents. All patients received corticosteroids; 7/10 patients received immunosuppressive combination therapy. FVIII levels of ≥50% were achieved after a median of 40 days (8-62). One patient had a severe immunosuppressive therapy-related infection. An 87-years-old woman died for reasons not related to acquired haemophilia A or immunosuppressive therapy., Conclusions: Acquired haemophilia A is a rare disease, but manageable despite the advanced patient age and comorbidities. Its incidence in Southern Switzerland is higher than previously suspected.

A 27-year-old patient with a history of severe obstetrical complications and arterial thrombosis received a diagnosis of hereditary thrombotic thrombocytopenic purpura (TTP) due to severe ADAMTS13 deficiency when she presented with an acute episode in the 30th week of her second pregnancy. When the acute episode of hereditary TTP became plasma-refractory and fetal death was imminent, weekly injections of recombinant ADAMTS13 at a dose of 40 U per kilogram of body weight were initiated. The patient's platelet count normalized, and the growth of the fetus stabilized. At 37 weeks 1 day of gestation, a small-for-gestational-age boy was delivered by cesarean section. At the time of this report, the patient and her son were well, and she continued to receive injections of recombinant ADAMTS13 every 2 weeks. (Funded by the Swiss National Science Foundation.)., (Copyright © 2022 Massachusetts Medical Society.)

Introduction: Caplacizumab demonstrated efficacy and safety in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in the phase 3 HERCULES trial. However, data on long-term outcomes following caplacizumab treatment are limited., Objectives: The post-HERCULES trial (NCT02878603) evaluated long-term outcomes of patients with iTTP treated with caplacizumab in HERCULES and safety and efficacy of repeated caplacizumab use., Patients/methods: Over 3 years of follow-up, patients could receive open-label caplacizumab with therapeutic plasma exchange (TPE) and immunosuppressive therapy (IST) in case of recurrence. Adverse events (AEs) were assessed during the overall study period (intention-to-observe [ITO] population) and during recurrences (recurrence population). TTP-related events (TTP-related death, recurrence, major thromboembolic events) were assessed in the efficacy ITO population (patients without recurrence during HERCULES or before post-HERCULES)., Results: Among 104 enrolled patients, incidences of AEs and serious AEs were similar between patients who had received caplacizumab + TPE + IST during HERCULES (n = 75) and those treated with placebo + TPE + IST (placebo; n = 29). TTP-related events occurred in 8% of patients (4/49) randomized to caplacizumab during HERCULES versus 38% (11/29) randomized to placebo. Nineteen patients had ≥1 recurrence; 13 of these were treated with caplacizumab. The first recurrence episode was resolved or resolving for all patients treated with caplacizumab, including nine patients with repeat caplacizumab use. All second recurrences (6/6) were resolved. Safety profile of caplacizumab for treatment of recurrence was consistent with HERCULES; most bleeding events were nonserious. No major cases of organ dysfunction were observed., Conclusions: Long-term follow-up supports the safety and efficacy of caplacizumab for iTTP and its repeated use for recurrences., (© 2022 Sanofi and The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: Diagnosing heparin-induced thrombocytopenia (HIT) at the bedside remains challenging, exposing a significant number of patients at risk of delayed diagnosis or overtreatment. We hypothesized that machine-learning algorithms could be utilized to develop a more accurate and user-friendly diagnostic tool that integrates diverse clinical and laboratory information and accounts for complex interactions., Methods: We conducted a prospective cohort study including 1393 patients with suspected HIT between 2018 and 2021 from 10 study centers. Detailed clinical information and laboratory data were collected, and various immunoassays were conducted. The washed platelet heparin-induced platelet activation assay (HIPA) served as the reference standard., Findings: HIPA diagnosed HIT in 119 patients (prevalence 8.5%). The feature selection process in the training dataset (75% of patients) yielded the following predictor variables: (1) immunoassay test result, (2) platelet nadir, (3) unfractionated heparin use, (4) CRP, (5) timing of thrombocytopenia, and (6) other causes of thrombocytopenia. The best performing models were a support vector machine in case of the chemiluminescent immunoassay (CLIA) and the ELISA, as well as a gradient boosting machine in particle-gel immunoassay (PaGIA). In the validation dataset (25% of patients), the AUROC of all models was 0.99 (95% CI: 0.97, 1.00). Compared to the currently recommended diagnostic algorithm (4Ts score, immunoassay), the numbers of false-negative patients were reduced from 12 to 6 (-50.0%; ELISA), 9 to 3 (-66.7%, PaGIA) and 14 to 5 (-64.3%; CLIA). The numbers of false-positive individuals were reduced from 87 to 61 (-29.8%; ELISA), 200 to 63 (-68.5%; PaGIA) and increased from 50 to 63 (+29.0%) for the CLIA., Interpretation: Our user-friendly machine-learning algorithm for the diagnosis of HIT (https://toradi-hit.org) was substantially more accurate than the currently recommended diagnostic algorithm. It has the potential to reduce delayed diagnosis and overtreatment in clinical practice. Future studies shall validate this model in wider settings., Funding: Swiss National Science Foundation (SNSF), and International Society on Thrombosis and Haemostasis (ISTH)., Competing Interests: AC has served as a consultant for Synergy; has received authorship royalties for UpToDate; and his institution has received research support on his behalf from Alexion, Bayer, Novartis, Novo Nordisk, Pfizer, Sanofi, Spark, and Takeda. The institution of BG received grant support and CME support from Pfizer, Thermo Fisher Scientific, Axonlab, Sanofi, Alnylam, Bayer, BMS, Daiichi-Sankyo, Octapharma, Takeda, SOBI, Janssen, Novo Nordisk, Mitsubishi Taneba, outside of the current work. The institution of JKH received grant support, consultancy fees, or honoraria from SNSF, Baxter/Takeda, Bayer, CSL-Behring, NovoNordisk, Octapharma, Roche, SOBI, Roche, Sanofi, FOPH, and Swiss Hemophilia Society, outside of the current work. MN received research grants from Bayer Healthcare, Roche diagnostics, Siemens healthineers, Pentapharm, and Bühlmann laboratories, outside of the current work. Dr. Greinacher reports personal fees from Aspen, grants from Ergomed, grants from Boehringer Ingelheim, personal fees from Bayer Vital, grants from Rovi, grants from Sagent, personal fees from Chromatec, personal fees from Instrumentation Laboratory, grants and personal fees from Macopharma, grants from Portola, grants from Biokit, personal fees from Sanofi-Aventis, grants from Fa. Blau Farmaceutics, grants from Prosensa/Biomarin, grants and other from DRK-BSD NSTOB, grants from DRK-BSD Baden-Würtemberg/Hessen, personal fees from Roche, personal fees from GTH e.V., grants from Deutsche Forschungsgemeinschaft, grants from Deutsche Forschungsgemeinschaft, grants from Deutsche Forschungsgemeinschaft, grants from Robert-Koch-Institut, non-financial support from Veralox, grants from Dilaflor, non-financial support from Vakzine Projekt Management GmbH, grants from GIZ Else-Körner-Stiftung, grants from GIZ Else-Körner-Stiftung, non-financial support from AstraZeneca, non-financial support from Janssen Vaccines & Prevention B.V., personal fees from Takeda Pharma, personal fees from Falk Foundation e.V., grants from European Medicines Agency, outside the submitted work; In addition, AG has a patent Screening Methods for transfusion related acute lung injury (TRALI) with royalties paid to EP2321644, 18.05.2011. TM reports grant support, consultancy fees, honoraria, or support for attending meetings from DFG, Stiftung Transfusionsmedizin und Immunhämatologie e.V, DRK Blutspendedienst, Deutsche Herzstiftung, Ministerium für Wissenschaft, Forschung und Kunst Baden Würtemberg, Gesellschaft für Thrombose-und Hämostaseforschung, Berufsverband Deutscher Internisten, CoaChrom Diagnostica GmbH, Robert Bosch GmbH, Ergomed, Bayer, Bristol-Myers Squibb, Doctrina Med AG, Leo Pharma GmbH, Schöchl medical education GmbH, Mitsubishi Tanabe GmbH, Novo Nordisk GmbH, Swedish Orphan Biovitrium GmbH. All other authors declare that no conflict of interest exists., (© 2022 The Author(s).)

Introduction: Severe COVID-19 is associated with an important increase of von Willebrand factor and mild lowering of ADAMTS13 activity that may, in the presence of a strong inflammatory reaction, increase the risk of acute thrombotic thrombocytopenic purpura (TTP). Although acute episodes of immune-mediated TTP associated with COVID-19 or SARS-CoV-2 vaccination have been reported, data about clinical evolution of hereditary TTP (hTTP) during the pandemic are scarce., Method: We conducted a survey among adult patients of the International Hereditary TTP Registry about SARS-CoV-2 vaccination, COVID-19, and occurrence of acute hTTP episodes., Results: Of 122 adult hTTP patients invited to participate, 86 (70.5%) responded. Sixty-five had been vaccinated (75.6%), of which 14 had received in addition a booster, resulting in 139 individual vaccine shots. Although vaccinations in patients on plasma prophylaxis were done within 1 week of the last plasma infusion, all 23 patients treated with plasma on demand were vaccinated without prior plasma infusions. One patient on uninterrupted weekly plasma infusions presented within 3 days from his second vaccination with neurological symptoms and computed tomography scan 9 days later showed subacute ischemic/hemorrhagic frontal lobe infarction. A second male patient developed acute myocarditis after his second dose of mRNA-1273 vaccine. Twelve (14%) patients had COVID-19, associated with an acute hTTP episode in three of them: one patient had a transient ischemic attack, one a stroke, and a pregnant woman was hospitalized to intensify plasma treatment., Discussion: The risk of an acute episode triggered by COVID-19 seems higher than following vaccination in hTTP patients, who can be safely vaccinated against SARS-CoV-2., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Cerebral venous thrombosis (CVT) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe condition, with high in-hospital mortality rates. Here, we report clinical outcomes of patients with CVT-VITT after SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccination who survived initial hospitalization., Methods: We used data from an international registry of patients who developed CVT within 28 days of SARS-CoV-2 vaccination, collected until February 10, 2022. VITT diagnosis was classified based on the Pavord criteria. Outcomes were mortality, functional independence (modified Rankin Scale score 0-2), VITT relapse, new thrombosis, and bleeding events (all after discharge from initial hospitalization)., Results: Of 107 CVT-VITT cases, 43 (40%) died during initial hospitalization. Of the remaining 64 patients, follow-up data were available for 60 (94%) patients (37 definite VITT, 9 probable VITT, and 14 possible VITT). Median age was 40 years and 45/60 (75%) patients were women. Median follow-up time was 150 days (interquartile range, 94-194). Two patients died during follow-up (3% [95% CI, 1%-11%). Functional independence was achieved by 53/60 (88% [95% CI, 78%-94%]) patients. No new venous or arterial thrombotic events were reported. One patient developed a major bleeding during follow-up (fatal intracerebral bleed)., Conclusions: In contrast to the high mortality of CVT-VITT in the acute phase, mortality among patients who survived the initial hospitalization was low, new thrombotic events did not occur, and bleeding events were rare. Approximately 9 out of 10 CVT-VITT patients who survived the acute phase were functionally independent at follow-up.

Objective: Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality., Methods: We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis., Results: Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54)., Conclusions: In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

In Covid-19, anticoagulation with heparin is often administered to prevent or treat thromboembolic events. Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin treatment, caused by heparin-dependent, platelet activating anti-platelet factor 4 (PF4)/heparin antibodies. Diagnosis of HIT is based on the combination of clinical parameters, allowing to determine the pretest probability, and laboratory testing for anti-PF4/heparin antibodies and confirmatory functional assays, such as the heparin-induced platelet activation (HIPA) test.We report the case of a patient with severe Covid-19 pneumonia requiring ECMO treatment, who developed recurrent clotting of the ECMO filter and a drop in platelet count under heparin treatment. He was therefore suspected to have HIT and the anticoagulation was switched to argatroban. Despite high clinical probability and high titres of anti-PF4/heparin antibodies, the functional HIPA test was negative. Nevertheless, argatroban was continued rather than to reinstate anticoagulation with heparin. Reevaluation 7 days later then demonstrated a strongly positive functional HIPA test and confirmed the diagnosis of HIT. Under anticoagulation with argatroban the patient gradually improved and was finally weaned off the ECMO.In conclusion, this case highlights the critical importance of clinical judgement, exploiting the 4 T score, given that Covid-19 patients may present a different pattern of routine laboratory test results in HIT diagnostics. The possibility of a false negative HIPA test has to be considered, particularly in early phases of presentation. In cases of a discrepancy with high clinical probability of HIT and/or high titre anti-PF4/heparin antibodies despite a negative HIPA test, a reevaluation within 3 to 5 days after the initial test should be considered in order to avoid precipitant reestablishment of unfractionated heparin, with potentially fatal consequences., (© 2022. The Author(s).)

Background: Prevention of recurrent venous thromboembolism (VTE) is considered a main goal of VTE management. However, the extent to which physicians adhere to the recommendations from evidence-based guidelines is unknown., Aim: From a large, prospective clinical cohort, we aimed to (1) quantify the adherence of treatment recommendations to evidence-based guidelines and establish its predictors, and (2) estimate its impact on clinical outcomes and costs in patients with VTE., Methods: We included 6'243 consecutive patients with VTE treated at the university outpatient unit. Detailed clinical characteristics and treatment recommendations were recorded. Adherence of treatment recommendations to evidence-based guidelines at risk assessment was assessed in terms of duration of anticoagulant treatment. Data on death were obtained from the Swiss Central Compensation Office. Health care claims data recorded between 2014 and 2019 were retrieved from Helsana, one of the largest Swiss health insurance companies., Results: The adherence to evidence-based guidelines was 36.1%. Among patients with non-adherence, overtreatment was present in 70.1%. Significant patient-related predictors of guideline adherence were (a) age above 50 years, (b) male sex, (c) pulmonary embolism, (d) unprovoked VTE, (e) multiple VTE, (f) laboratory tests not ordered, and (g) various cardiovascular comorbidities. Non-adherence was not significantly associated with mortality, hospitalization, admission to nursing home, and costs., Conclusions: The adherence to evidence-based guidelines was low, and several unrelated predictors appeared. Although these results need to be confirmed in other settings, they highlight the need for implementation of evidence-based guidelines in clinical practice., Competing Interests: This study received funding from an unrestricted research grant of Bayer Healthcare. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. EB reports grants from Novartis, grants from MSD, grants from Vifor, grants from Bayer, grants from Swiss Cancer Research Foundation, outside the submitted work. JK reports grants from Baxalta US Inc., member of the Takeda group of companies, personal fees from Shire, member of the Takeda group of companies, personal fees from Ablynx, now part of Sanofi, personal fees from Roche, from SOBI, from Federal Office of Public Health, Switzerland, outside the submitted work; and The Hemophilia Comprehensive Care Center (HCCC) is part of the Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, which receives third party funds for the project “Interprofessional Hemophilia Care” by Bayer, CSL-Behring, Octapharma, Novo Nordisk, Roche, and Sobi. All fees or honoraria go to JK's institution Insel Gruppe AG, Inselspital, Bern University Hospital. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mertins, Nilius, Boss, Knuchel, Signorell, Huber, Blozik, Kremer Hovinga, Bachmann and Nagler.)

(1) Background: Thrombophilia testing utility has remained controversial since its clinical introduction, because data on its influence on treatment decisions are limited. (2) Methods: We conducted a single-center retrospective cohort study of 3550 unselected patients referred for thrombophilia consultation at the Bern University Hospital in Switzerland from January 2010 to October 2020. We studied the influence of thrombophilia testing results on treatment decisions and evaluated the association between thrombophilia and thromboembolic and pregnancy-related morbidity events after testing up to 03/2021. (3) Results: In 1192/3550 patients (34%), at least one case of thrombophilia was found and 366 (10%) had high-risk thrombophilia. A total of 211/3550 (6%) work-ups (111/826 (13%) with low-risk thrombophilia and 100/366 (27%) with high-risk thrombophilia) led to an appropriate decision to extend or initiate anticoagulation, and 189 (5%) negative results led to the withholding of anticoagulation therapy inappropriately. A total of 2492 patients (69%) were followed up for >30 days, with a median follow-up of 49 months (range, 1−183 months). Patients with high-risk thrombophilia had a higher risk of subsequent venous thromboembolic events and pregnancy-related morbidity compared to those without thrombophilia. (4) Conclusions: Our study demonstrated the limited usefulness of thrombophilia work-up in clinical decision-making. High-risk thrombophilia was associated with subsequent venous thromboembolism and pregnancy-related morbidity.

Rare immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening disease resulting from a severe autoantibody-mediated ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13) deficiency. Acute iTTP episodes are medical emergencies, but when treated appropriately &gt;95% of patients survive. However, at least half of survivors will eventually experience a relapse. How remission of an initial episode is achieved and factors contributing to reemergence of anti-ADAMTS13 Abs and a relapsing course are poorly understood. In acquired hemophilia and systemic lupus erythematosus, anti-idiotypic Abs counteracting and neutralizing pathogenic autoantibodies contribute to remission. We selected and amplified the splenic anti-idiotypic IgG&lt;sub&gt;1&lt;/sub&gt; Fab κ/λ repertoire of two relapsing iTTP patients on previously generated monoclonal inhibitory anti-ADAMTS13 Fabs by phage display to explore whether anti-idiotypic Abs have a role in iTTP. We obtained 27 single anti-idiotypic Fab clones, half of which had unique sequences, although both patients shared four H chain V region genes (V&lt;sub&gt;H&lt;/sub&gt;1-69*01, V&lt;sub&gt;H&lt;/sub&gt;3-15*01, V&lt;sub&gt;H&lt;/sub&gt;3-23*01, and V&lt;sub&gt;H&lt;/sub&gt;3-49*03). Anti-idiotypic Fab pools of both patients fully neutralized the inhibitor capacity of the monoclonal anti-ADAMTS13 Abs used for their selection. Preincubation of plasma samples of 22 unrelated iTTP patients stratified according to functional ADAMTS13 inhibitor titers (&gt;2 Bethesda units/ml, or 1-2 Bethesda units/ml), with anti-idiotypic Fab pools neutralized functional ADAMTS13 inhibitors and restored ADAMTS13 activity in 18-45% of those cases. Taken together, we present evidence for the presence of an anti-idiotypic immune response in iTTP patients. The interindividual generalizability of this response is limited despite relatively uniform pathogenic anti-ADAMTS13 Abs recognizing a dominant epitope in the ADAMTS13 spacer domain., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Competing Interests: Competing interests: None declared.

Background and Objectives: Cerebral venous sinus thrombosis (CVST) as a part of the thrombosis and thrombocytopenia syndrome is a rare adverse drug reaction of severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) vaccination. Estimated background rate of CVST with thrombocytopenia is 0.1 per million per month. We assessed the age-stratified risk of CVST with and without thrombocytopenia after SARS-CoV-2 vaccination., Methods: We estimated the absolute risk of CVST with and without thrombocytopenia within 28 days of a first dose of 4 SARS-CoV-2 vaccinations using data from the European Medicines Agency's EudraVigilance database (until June 13, 2021). As a denominator, we used data on vaccine delivery from 31 European countries. For 22.8 million adults from 25 countries, we estimated the absolute risk of CVST after the first dose of ChAdOx1 nCov-19 per age category., Results: The absolute risk of CVST within 28 days of first-dose vaccination was 7.5 (95% confidence interval [CI] 6.9-8.3), 0.7 (95% CI 0.2-2.4), 0.6 (95% CI 0.5-0.7), and 0.6 (95% CI 0.3-1.1) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2, and mRNA-1273, respectively. The absolute risk of CVST with thrombocytopenia within 28 days of first dose vaccination was 4.4 (95% CI 3.9-4.9), 0.7 (95% CI 0.2-2.4), 0.0 (95% CI 0.0-0.1), and 0.0 (95% CI 0.0-0.2) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2, and mRNA-1273, respectively. In recipients of ChAdOx1 nCov-19, the absolute risk of CVST, both with and without thrombocytopenia, was the highest in the 18- to 24-year-old group (7.3 per million, 95% CI 2.8-18.8 and 3.7 per million, 95% CI 1.0-13.3, respectively). The risk of CVST with thrombocytopenia in ChAdOx1 nCov-19 recipients was the lowest in the age group ≥70 years (0.2, 95% CI 0.0-1.3). Age <60 years compared to ≥60 years was a predictor for CVST with thrombocytopenia (incidence rate ratio 5.79, 95% CI 2.98-11.24, p < 0.001)., Discussion: The risk of CVST with thrombocytopenia within 28 days of first-dose vaccination with ChAdOx1 nCov-19 was higher in younger age groups. The risk of CVST with thrombocytopenia was slightly increased in patients receiving Ad26.COV2.S compared with the estimated background risk. The risk of CVST with thrombocytopenia was not increased in recipients of SARS-CoV-2 mRNA vaccines., (© 2021 American Academy of Neurology.)

Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy. It is caused by a severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, 13) deficiency due to circulating autoantibodies, and is associated with significant morbidity and mortality. Current treatment options include plasma exchange, immunosuppression, and caplacizumab. When remission is achieved, the risk of relapse is high, especially in patients with persistent ADAMTS13 deficiency. We report the eradication of persistent ADAMTS13 inhibitory autoantibodies and restoration of normal ADAMTS13 activity using the anti-CD38 antibody daratumumab in two patients with iTTP. One patient had a frequently relapsing course, and the other a treatment-refractory first episode. There were no relevant adverse drug reactions., (© 2022 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.)

Background and Purpose: High mortality rates have been reported in patients with cerebral venous sinus thrombosis (CVST) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) after vaccination with adenoviral vector SARS-CoV-2 vaccines. The aim of this study was to evaluate whether the mortality of patients with CVST-VITT has decreased over time., Methods: The EudraVigilance database of the European Medicines Agency was used to identify cases of CVST with concomitant thrombocytopenia occurring within 28 days of SARS-CoV-2 vaccination. Vaccines were grouped based on vaccine type (adenoviral or mRNA). Cases with CVST onset until 28 March were compared to cases after 28 March 2021, which was the day when the first scientific paper on VITT was published., Results: In total, 270 cases of CVST with thrombocytopenia were identified, of which 266 (99%) occurred after adenoviral vector SARS-CoV-2 vaccination (ChAdOx1 nCoV-19, n = 243; Ad26.COV2.S, n = 23). The reported mortality amongst adenoviral cases with onset up to 28 March 2021 was 47/99 (47%, 95% confidence interval 37%-58%) compared to 36/167 (22%, 95% confidence interval 16%-29%) in cases with onset after 28 March (p < 0.001). None of the four cases of CVST with thrombocytopenia occurring after mRNA vaccination died., Conclusion: The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector-based SARS-CoV-2 vaccines has significantly decreased over time, which may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after VITT., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Cerebral venous sinus thrombosis (CVST) has been described after vaccination against SARS-CoV-2. The clinical characteristics of 213 post-vaccination CVST cases notified to the European Medicines Agency are reported., Methods: Data on adverse drug reactions after SARS-CoV-2 vaccination notified until 8 April 2021 under the Medical Dictionary for Regulatory Activities Term 'Central nervous system vascular disorders' were obtained from the EudraVigilance database. Post-vaccination CVST was compared with 100 European patients with CVST from before the COVID-19 pandemic derived from the International CVST Consortium., Results: In all, 213 CVST cases were identified: 187 after AstraZeneca/Oxford (ChAdOx1 nCov-19) vaccination and 26 after a messenger RNA (mRNA) vaccination (25 with Pfizer/BioNTech, BNT162b2, and one with Moderna, mRNA-1273). Thrombocytopenia was reported in 107/187 CVST cases (57%, 95% confidence interval [CI] 50%-64%) in the ChAdOx1 nCov-19 group, in none in the mRNA vaccine group (0%, 95% CI 0%-13%) and in 7/100 (7%, 95% CI 3%-14%) in the pre-COVID-19 group. In the ChAdOx1 nCov-19 group, 39 (21%) reported COVID-19 polymerase chain reaction tests were performed within 30 days of CVST symptom onset, and all were negative. Of the 117 patients with a reported outcome in the ChAdOx1 nCov-19 group, 44 (38%, 95% CI 29%-47%) had died, compared to 2/10 (20%, 95% CI 6%-51%) in the mRNA vaccine group and 3/100 (3%, 95% CI 1%-8%) in the pre-COVID-19 group. Mortality amongst patients with thrombocytopenia in the ChAdOx1 nCov-19 group was 49% (95% CI 39%-60%)., Conclusions: Cerebral venous sinus thrombosis occurring after ChAdOx1 nCov-19 vaccination has a clinical profile distinct from CVST unrelated to vaccination. Only CVST after ChAdOx1 nCov-19 vaccination was associated with thrombocytopenia., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson)., Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS., Design, Setting, and Participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination., Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria., Main Outcomes and Measures: Clinical characteristics and mortality rate., Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later., Conclusions and Relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.

Background: Little is known about long-term survival after the initial treatment of venous thromboembolism (VTE). In a prospective cohort study, we aimed to assess the long-term mortality and key predictor variables relating to disease severity, treatment intensity, and comorbidities. Materials and Methods: Between 1988 and 2018, 6,243 consecutive patients with VTE from a University outpatient unit were prospectively included and followed until December 2019; clinical characteristics, measures of disease severity, and treatment details were recorded. Dates of death were retrieved from the Swiss Central Compensation Office. Results: Overall, 254 deaths occurred over an observation period of 57,212 patient-years. Compared to the Swiss population, the standardized mortality ratio was 1.30 (95% CI: 1.14, 1.47; overall mortality rate: 4.44 per 1,000 patient-years). The following predictors were associated with increased mortality: Unprovoked VTE (hazard ratio [HR]: 5.06; 95% CI: 3.29, 7.77), transient triggering risk factors (HR: 3.46; 95% CI: 2.18, 5.48), previous VTE (HR: 2.05; 95% CI: 1.60, 2.62), pulmonary embolism (HR: 1.45, 95% CI: 1.10, 1.89), permanent anticoagulant treatment (HR: 3.14; 95% CI: 2.40, 4.12), prolonged anticoagulant treatment (7-24 months; HR: 1.70; 95% CI: 1.16, 2.48), and cardiovascular comorbidities. Unprovoked VTE, previous VTE, permanent and prolonged anticoagulation remain independent risk factors after adjustment for age, sex, and comorbidities. Conclusion: Survival after VTE was significantly reduced compared to the Swiss general population, especially in patients with more severe disease, cardiovascular comorbidities, and longer anticoagulant treatment., Competing Interests: This study received funding from an unrestricted research grant of Bayer Healthcare. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. EB reports grants from Novartis, grants from MSD, grants from Vifor, grants from Bayer, grants from Swiss Cancer Research Foundation, outside the submitted work. JK reports grants from Baxalta US Inc., member of the Takeda group of companies, personal fees from Shire, member of the Takeda group of companies, personal fees from Ablynx, now part of Sanofi, personal fees from Roche, from SOBI, from Federal Office of Public Health, Switzerland, outside the submitted work; and The Hemophilia Comprehensive Care Center (HCCC) is part of the Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, which receives third party funds for the project “Interprofessional Hemophilia Care” by Bayer, CSL-Behring, Octapharma, Novo Nordisk, Roche, and Sobi. All fees or honoraria go to JK's institution (Insel Gruppe AG, Inselspital, Bern University Hospital). SE reports personal fees from Bayer, personal fees from Pfizer, personal fees from Daiichi-Sankyo, personal fees from Boehringer-Ingelheim, personal fees from BMS, personal fees from CSL-Behring, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nilius, Mertins, Boss, Knuchel, Blozik, Kremer Hovinga, Eichinger and Nagler.)

Importance: Cases of cerebral venous sinus thrombosis in combination with thrombocytopenia have recently been reported within 4 to 28 days of vaccination with the ChAdOx1 nCov-19 (AstraZeneca/Oxford) and Ad.26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccines. An immune-mediated response associated with platelet factor 4/heparin antibodies has been proposed as the underlying pathomechanism., Objective: To determine the frequencies of admission thrombocytopenia, heparin-induced thrombocytopenia, and presence of platelet factor 4/heparin antibodies in patients diagnosed with cerebral venous sinus thrombosis prior to the COVID-19 pandemic., Design, Setting, and Participants: This was a descriptive analysis of a retrospective sample of consecutive patients diagnosed with cerebral venous sinus thrombosis between January 1987 and March 2018 from 7 hospitals participating in the International Cerebral Venous Sinus Thrombosis Consortium from Finland, the Netherlands, Switzerland, Sweden, Mexico, Iran, and Costa Rica. Of 952 patients, 865 with available baseline platelet count were included. In a subset of 93 patients, frozen plasma samples collected during a previous study between September 2009 and February 2016 were analyzed for the presence of platelet factor 4/heparin antibodies., Exposures: Diagnosis of cerebral venous sinus thrombosis., Main Outcomes and Measures: Frequencies of admission thrombocytopenia (platelet count <150 ×103/μL), heparin-induced thrombocytopenia (as diagnosed by the treating physician), and platelet factor 4/heparin IgG antibodies (optical density >0.4, in a subset of patients with previously collected plasma samples)., Results: Of 865 patients (median age, 40 years [interquartile range, 29-53 years], 70% women), 73 (8.4%; 95% CI, 6.8%-10.5%) had thrombocytopenia, which was mild (100-149 ×103/μL) in 52 (6.0%), moderate (50-99 ×103/μL) in 17 (2.0%), and severe (<50 ×103/μL) in 4 (0.5%). Heparin-induced thrombocytopenia with platelet factor 4/heparin antibodies was diagnosed in a single patient (0.1%; 95% CI, <0.1%-0.7%). Of the convenience sample of 93 patients with cerebral venous sinus thrombosis included in the laboratory analysis, 8 (9%) had thrombocytopenia, and none (95% CI, 0%-4%) had platelet factor 4/heparin antibodies., Conclusions and Relevance: In patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, and heparin-induced thrombocytopenia and platelet factor 4/heparin antibodies were rare. These findings may inform investigations of the possible association between the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines and cerebral venous sinus thrombosis with thrombocytopenia.

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in patients with hTTP is largely lacking. This study reports prospective data on 87 patients from the Hereditary TTP Registry (clinicaltrials.gov #NCT01257269) for survival, frequency, and severity of acute episodes from enrollment until December 2019. The 87 patients, followed up for a median of 4.2 years (range, 0.01-15 years), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and 18 years (range, 0.0-70 years for both), respectively. Forty-three patients received regular plasma prophylaxis, whereas 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes, of which 91 (69%) occurred in patients receiving regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95% confidence interval [CI], 0.29-0.44) with regular plasma treatment and of 0.41 (95% CI, 0.30-0.56) without regular plasma treatment. More than one-third of acute episodes (n = 51) were documented in children <10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients aged >40 years (1.18 [95% CI, 0.88-1.55] vs 0.14 [95% CI, 0.08-0.23]). The prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, and caregivers, patients, and their guardians are reluctant to start regular plasma infusions, from which children particularly would benefit., (© 2021 by The American Society of Hematology.)

Background: Heparin-induced thrombocytopenia (HIT) is a severe adverse reaction to heparin caused by heparin-dependent, platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Heparin is a cornerstone of treatment in critically ill COVID-19 patients. HIT antibodies can be detected by antigen tests and functional tests. Often strong reactivity in the antigen test is used as a surrogate marker for the presence of clinically relevant, platelet-activating antibodies. We observed an unexpectedly high percentage of COVID-19 patients, clinically suspected to have HIT, with high titer anti-PF4/heparin antibodies, but a negative functional test., Objective: We investigated whether in COVID-19 patients a serum-derived factor inhibits the heparin-induced platelet activation test (HIPA)., Methods and Results: Twelve COVID-19 patients with suspected HIT were tested. Three samples tested negative in all assays; nine samples tested positive by antigen tests, among which only three tested also positive by HIPA. When we spiked COVID-19 serum or control serum with the human HIT antibody like monoclonal antibody 5B9, reactivity of 5B9 remained the same. Also, the purified IgG fractions of COVID-19 sera testing strongly positive in the PF4/heparin antigen test but negative in the functional test did not show increased reactivity in the functional test in comparison to the original serum. Both results make a functionally inhibitory factor in the serum/plasma of COVID-19 patients highly unlikely., Conclusion: COVID-19 patients often present with strong reactivity in PF4/heparin antigen tests without the presence of platelet-activating antibodies. Diagnosis of HIT requires confirmation of heparin-dependent, platelets activating antibodies to avoid overdiagnosis and overtreatment with non-heparin anticoagulants., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

The efficacy and safety of caplacizumab in individuals with acquired thrombotic thrombocytopenic purpura (aTTP) have been established in the phase 2 TITAN and phase 3 HERCULES trials. Integrated analysis of data from both trials was conducted to increase statistical power for assessing treatment differences in efficacy and safety outcomes. Caplacizumab was associated with a significant reduction in the number of deaths (0 vs 4; P < .05) and a significantly lower incidence of refractory TTP (0 vs 8; P < .05) vs placebo during the treatment period. Consistent with the individual trials, treatment with caplacizumab resulted in a faster time to platelet count response (hazard ratio, 1.65; P < .001), a 72.6% reduction in the proportion of patients with the composite end point of TTP-related death, TTP exacerbation, or occurrence of at least 1 treatment-emergent major thromboembolic event during the treatment period (13.0% vs 47.3%; P < .001), and a 33.3% reduction in the median number of therapeutic plasma exchange days (5.0 vs 7.5 days) vs placebo. No new safety signals were identified; mild mucocutaneous bleeding was the main safety finding. This integrated analysis provided new evidence that caplacizumab prevents mortality and refractory disease in acquired TTP and strengthened individual trial findings, with a confirmed favorable safety and tolerability profile. These trials were registered at www.clinicaltrials.gov as #NCT01151423 and #NCT02553317., (© 2021 by The American Society of Hematology.)

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.)

The treatment of patients with acquired hemophilia is challenging due to life-threatening hemorrhages, delayed response, and adverse effects to immunosuppressive agents. Even though immunoadsorption (IA) rapidly removes autoantibodies against factor VIII, this intervention's effectiveness is still a matter of debate. We aimed to study important outcomes of IA as adjunctive treatment in patients with acquired hemophilia. We performed comprehensive literature searches in MEDLINE and EMBASE databases. Clinical and laboratory data of all patients treated in our institution were additionally included. Literature searching yielded 498 records, of which 10 studies describing 106 patients were finally included. The number of patients varied from 1 to 65, and patients' ages ranged between 14 and 89. Treatment criteria in most patients were (1) failed response to immunosuppressive treatment alone, and/or (2) uncontrollable bleeding episodes, and/or (3) high inhibitor titer. Methodological quality was moderate. The number of IA sessions varied from 1 to 24. Within our institution, 12 patients have been treated since 2002; median age was 76 years (range 34-86); median titer of factor VIII inhibitor was 20 Bethesda units (range 3-214). Pooled estimates, modeling a random-effect binominal distribution incorporating the Freeman-Tukey double arcsine transformation, were 86% in case of factor VIII recovery (95% confidence interval 76%-94%), 95% for reduction of factor VIII inhibitor (83%, 100%), and 7% in case of death (0%, 18%). Our data suggest that IA might be a beneficial adjunctive treatment in patients with high-risk acquired hemophilia, but future studies shall confirm this observation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Emicizumab (Hemlibra&reg;, Hoffmann-La Roche, Switzerland) is now available for haemophilia A patients with or without factor VIII inhibitors. Management of bleeding events and replacement therapy for invasive procedures have to be adapted., Objective: To provide a practical guidance for the management of breakthrough bleeding events and elective or urgent surgery in adult and paediatric patients with haemophilia A without inhibitors treated with emicizumab., Methods: Based on the available literature and the experiences collected from adult and paediatric patients treated in Switzerland, the Working Party on Haemostasis of the Swiss Society of Haematology and the Swiss Haemophilia Network worked together to reach a consensus on the management of bleeding events and invasive procedures., Results and Conclusion: Minor bleeding events and invasive procedures associated with low bleeding risk can be treated without factor replacement therapy in most cases, whereas major bleeding events and high-risk surgery require additional factor VIII replacement at usual doses, at least for the first days. Emicizumab treatment should be continued throughout the procedure and during the postoperative period. Elective major surgery should be planned according to emicizumab dosing for patients with a once-a-month posology. Of note, so far only few data are available on the management of major bleeds and surgery in patients with haemophilia A treated with emicizumab and this practical guidance will have to be regularly updated with growing experience. &nbsp.

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.

The Hereditary TTP Registry is an international cohort study for patients with a confirmed or suspected diagnosis of hereditary thrombotic thrombocytopenic purpura (hTTP) and their family members. Hereditary TTP is an ultra-rare blood disorder (prevalence of ∼1-2 cases per million), the result of autosomal-recessively inherited congenital ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency (ADAMTS13 activity <10% of the normal), and associated with yet many unanswered questions. Until December 2017, the Hereditary TTP Registry had enrolled 123 confirmed hTTP patients. Their median age at disease onset was 4.5 years (range: 0-70) and at clinical diagnosis 16.7 years (range: 0-69), a difference that highlights the existing awareness gap in recognizing hTTP. The systematic collection of clinical data of individual patients revealed their substantial baseline comorbidities, as a consequence of recurring TTP episodes in the past. Most notable was the high proportion of patients having suffered from premature arterial thrombotic events, mainly transient ischemic attacks, ischemic strokes, and to a lesser extent myocardial infarctions. At 40 to 50 years of age and above, more than 50% of patients had suffered from at least one such event, and many had experienced arterial thrombotic events despite regular plasma infusions every 2 to 3 weeks that supplements the missing plasma ADAMTS13. The article by van Dorland et al. (Haematologica 2019;104(10):2107-2115) and the ongoing Hereditary TTP Registry cohort study were recognized with the Günter Landbeck Excellence Award at the 50th Hemophilia Symposium in Hamburg in November 2019, the reason to present the Hereditary TTP Registry in more detail here., Competing Interests: J.A.K.H. is a member of advisory board of Shire, member of the Takeda group of companies and of Ablynx, now part of Sanofi. All honoraria are paid to her employer, Insel Gruppe AG, Bern, Switzerland. The other authors have nothing to declare., (Thieme. All rights reserved.)

Background: Acquired hemophilia A is a rare autoimmune disease with clinically often significant bleeding diathesis resulting from circulating autoantibodies inhibiting coagulation factor VIII. Half of acquired hemophilia A cases are associated with an underlying disorder, such as autoimmune diseases, cancer, or use of certain drugs, or occur during pregnancy and in the postpartum period. In the other half, no underlying cause is identified. An association of acquired hemophilia A with plasma cell neoplasm seems to be extremely rare., Case Presentation: We describe a case of a 77-year-old Swiss Caucasian man who was diagnosed with acquired hemophilia A and smoldering multiple myeloma as an underlying cause. Acquired hemophilia A was treated with prednisolone, cyclophosphamide, and immunoadsorption. Extensive workup revealed a plasma cell neoplasm as the only disorder associated with or underlying the acquired hemophilia A. For long-term control of acquired hemophilia A, we considered treatment of the plasma cell neoplasm necessary, and a VRD (bortezomib, lenalidomide, and dexamethasone) regimen was initiated. Due to multiple complications, VRD was reduced to VRD-lite after two cycles. After nine cycles of induction therapy and five cycles of consolidation therapy, the patient is in complete remission of his acquired hemophilia A and very good partial remission of the plasma cell neoplasm. We conducted a literature review to identify additional cases of this rare association and identified 15 other cases. Case descriptions, including the sequence of occurrence of acquired hemophilia A and plasma cell neoplasm , treatment, evolution, and outcome are presented., Discussion and Conclusions: Our case, together with 15 other cases described in the literature, underscore the possibility of plasma cell neoplasm as an underlying cause of acquired hemophilia A. Physicians should consider including protein electrophoresis, immunofixation, and analysis of free light chains in laboratory diagnostics when treating a patient with acquired hemophilia A. The occurrence of excessive and unexplained bleeding in patients diagnosed with plasma cell neoplasm should raise suspicion of secondary acquired hemophilia A and trigger the request for coagulation tests, particularly in patients treated with immunomodulatory drugs such as thalidomide or lenalidomide. Additionally, early intervention with immunoadsorption can be lifesaving in cases with high-titer factor VIII inhibitors, especially when surgical interventions are necessary.

Background: Severe plasma prekallikrein (PK) deficiency is an autosomal-recessive defect characterized by isolated activated partial thromboplastin time prolongation. To date, no comprehensive methodologically firm analysis has investigated the diagnostic, clinical, and genetic characteristics of PK deficiency, and its prevalence remains unknown., Patients/methods: We described new families with PK deficiency, retrieved clinical and laboratory information of cases systematically searched in the (gray) literature, and collected blood of these cases for complementary analyses. The Genome Aggregation Database (gnomAD) and the population-based Gutenberg Health Study served to study the prevalence of mutations and relevant genetic variants., Results: We assembled a cohort of 111 cases from 89 families and performed new genetic analyses in eight families (three unpublished). We identified new KLKB1 mutations, excluded the pathogenicity of some of the previously described ones, and estimated a prevalence of severe PK deficiency of 1/155 668 overall and 1/4725 among Africans. One individual reported with PK deficiency had, in fact, congenital kininogen deficiency associated with decreased PK activity. One quarter of individuals had factor XII clotting activity below the reference range. Four major bleeding events were described in 96 individuals, of which 3 were provoked, for a prevalence of 4% and an annualized rate of 0.1%. The prevalence of cardiovascular events was 15% (6% <40 years; 21% 40-65 years; 33% >65 years) for an annualized rate of 0.4%., Conclusions: We characterized the genetic background of severe PK deficiency, critically appraised mutations, and provided prevalence estimates. Our data on laboratory characteristics and clinical course of severe PK deficiency may have clinical implications., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug effect that occurs in 0.1&ndash;5% of heparin treated patients. Management of acute HIT currently involves (1) cessation of heparin exposure, and (2) inhibition of coagulation with an anticoagulant other than heparin. Several anticoagulants can be considered for the treatment of HIT. Anticoagulant monitoring, management of drug-induced adverse events including bleeding, and therapeutic dosing schedules in selected clinical settings represent challenges to the clinician treating HIT patients. Moreover, the fact that not all registered anticoagulants are approved for HIT in Switzerland further complicates the management of HIT. The present recommendations on the anticoagulant treatment of HIT in Switzerland have been elaborated by a panel of Swiss experts belonging to the Working Party Hemostasis (WPH) of the Swiss Society of Hematology (SGH-SSH). They are intended to support clinicians in their decision making when treating HIT patients.