•Upfront triple combined immunosuppressive regimen (CyDRi) produces very high remission rates and survival in elderly AHA patients.•High efficacy of CyDRi is combined with low toxicity and good ...tolerability.
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Acquired hemophilia A (AHA) is a rare severe autoimmune bleeding disorder with significant morbidity and mortality. Although critical for disease control, there is no consensus for the best immunosuppressive regimen. Most authors use steroids first line, followed by other agents for steroid failures. Upfront combined regimens offer the advantage of reduced steroid exposure and toxicity as well as increased efficacy. We retrospectively analyzed data from 32 patients with AHA treated on an identical such institutional protocol: cyclophosphamide 1000 mg on days 1 and 22, dexamethasone 40 mg on days 1, 8, 15, and 22, and rituximab 100 mg on days 1, 8, 15, and 22 (the regimen was termed CyDRi). All patients received at least 1 cycle of CyDRi. If necessary, CyDRi was repeated until remission, no sooner than day 43 of the previous cycle. Bleeding control was rapidly achieved. The median time for bleeding control was 15.5 days (range, 0-429 days; interquartile range, 2.5-29.5 days). Thirty-one (96.8%) of 32 patients achieved durable complete remission (CR); 29 (90.6%) of 32 patients were alive at last follow-up, all of them in CR. The median time to reach first CR was 77 days (range, 19-939 days; interquartile range, 31-115 days). Toxicity and side effects were acceptable and milder than those of commonly used, prolonged steroid therapies. In conclusion, the CyDRi regimen produced markedly higher CR rates and overall survival than currently used sequential regimens. Taken together, CyDRi proved to be an attractive option for the immunosuppression of elderly patients with AHA.
In acquired hemophilia A, autoantibodies block factor VIII leading to severe bleeding requiring expensive hemostatic therapy. Immunosuppression is needed. However, this regimen can be slow to resolve the problem, and it is associated with substantial toxicity. Simon et al describe a novel regimen comprising of standard immunosuppressive drugs that yields excellent results (97% complete response rate), including control of bleeding within a median of 16 days and with acceptable toxicity.
There are currently three thrombopoietin receptor agonists (TPO-RAs) approved in Europe for treating patients with immune thrombocytopenia (ITP): romiplostim (Nplate®), eltrombopag (Revolade®), and ...avatrombopag (Doptelet®). However, comparative clinical data between these TPO-RAs are limited. Therefore, the purpose of this study was to perform a literature review and seek expert opinion on the relevance and strength of the evidence concerning the use of TPO-RAs in adults with ITP. A systematic search was conducted in PubMed and Embase within the last 10 years and until June 20, 2022. A total of 478 unique articles were retrieved and reviewed for relevance. The expert consensus panel comprised ITP senior hematologists from eight countries across Central Europe. The modified Delphi method, consisting of two survey rounds, a teleconference and email correspondence, was used to reach consensus. Forty articles met the relevancy criteria and are included as supporting evidence, including five meta-analyses analyzing all three European-licensed TPO-RAs and comprising a total of 31 unique randomized controlled trials (RCTs). Consensus was reached on seven statements for the second-line use of TPO-RAs in the management of adult ITP patients. In addition, the expert panel discussed TPO-RA treatment in chronic ITP patients with mild/moderate COVID-19 and ITP patients in the first-line setting but failed to reach consensus. This work will facilitate informed decision-making for healthcare providers treating adult ITP patients with TPO-RAs. However, further studies are needed on the use of TPO-RAs in the first-line setting and specific patient populations.
Introduction Acquired Hemophilia A (AHA) is a rare autoimmune disorder characterized by the emergence of inhibitors that specifically target coagulation Factor VIII, frequently resulting in severe ...bleeding episodes. Methods We conducted a retrospective analysis of the medical records of a 68-year-old male patient who presented with adalimumab-induced AHA. Results The patient received adalimumab, a tumor necrosis factor inhibitor antibody, as part of his treatment for rheumatoid arthritis. The patient’s clinical journey, characterized by intense bleeding and coagulopathy, was effectively managed with the application of recombinant Factor VIIa (rFVIIa) and the CyDRi protocol. Discussion The case emphasizes the importance of prompt coagulation assessment in patients with bleeding symptoms receiving disease-modifying therapy for rheumatoid arthritis that includes adalimumab therapy, considering the rare yet life-threatening nature of AHA. Additionally, this report provides an extensive review of the existing literature on drug-induced AHA, with a special emphasis on cases linked to immunomodulatory medications. Through this two-pronged approach, our report aims to enhance understanding and awareness of this severe complication among healthcare providers, promoting timely diagnosis and intervention.
Acquired factor V inhibitor (AFVI) is a rare autoimmune bleeding disorder. The treatment of AFVI is challenging, and patients often require both bleeding control and inhibitor eradication.
We ...conducted a retrospective analysis of the medical records of a 35-year-old Caucasian woman who presented with severe AFVI-induced bleeding and subsequent immunosuppressive therapy.
To provide haemostasis, rFVIIa was given with good efficacy. The patient was treated with various combinations of immunosuppressive regimens over the course of 2.5 years, including plasmapheresis plus immunoglobulins, dexamethasone + rituximab, cyclophosphamide + dexamethasone + rituximab + cyclosporine, cyclosporin + sirolimus + cyclophosphamide + dexamethasone, bortezomib + sirolimus + methylprednisolone, and sirolimus + mycophenolate mofetil. Although these treatment modalities resulted in intermittent partial reversals of AFVI over 2.5 years, eventually the inhibitor became therapy-resistant. However, following the discontinuation of all immunosuppressive therapy, the patient experienced a partial spontaneous remission, which was followed by a pregnancy. During the pregnancy, the FV activity increased to 54% and the coagulation parameters returned to normal levels. The patient underwent Caesarean section without any bleeding complications and delivered a healthy child.
The use of an activated bypassing agent for bleeding control is effective in patients with severe AFVI. The presented case is unique because the treatment regimens included multiple combinations of immunosuppressive agents. This demonstrates that AFVI patients may undergo spontaneous remission even after multiple courses of ineffective immunosuppressive protocols. Additionally, pregnancy-associated improvement of AFVI is an important finding that warrants further investigation.
Healthy subjects frequently report minor bleedings that are frequently ‘background noise’ of normality rather than a true disorder. Nevertheless, unexpected or unusual bleeding may be alarming. Thus, ...the distinction between normal and pathologic bleeding is critical. Understanding the underlying pathologic mechanism in patients with an excessive bleeding is essential for their counseling and treatment. Most of these patients with significant bleeding will result affected by non‐severe inherited bleeding disorders (BD), collectively denominated mild or moderate BD for their relatively benign course. Unfortunately, practical recommendations for the management of these disorders are still lacking due to the current state of fragmented knowledge of pathophysiology and lack of a systematic diagnostic approach. To address this gap, an International Working Group (IWG) was established by the European Hematology Association (EHA) to develop consensus‐based guidelines on these disorders. The IWG agreed that grouping these disorders by their clinical phenotype under the single category of mild‐to‐moderate bleeding disorders (MBD) reflects current clinical practice and will facilitate a systematic diagnostic approach. Based on standardized and harmonized definitions a conceptual unified framework is proposed to distinguish normal subjects from affected patients. The IWG proposes a provisional comprehensive patient‐centered initial diagnostic approach that will result in classification of MBD into distinct clinical‐pathological entities under the overarching principle of clinical utility for the individual patient. While we will present here a general overview of the global management of patients with MBD, this conceptual framework will be adopted and validated in the evidence‐based, disease‐specific guidelines under development by the IWG.
Introduction
Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is complement-mediated due to the lack of complement inhibitors in the hemopoietic cell membranes, making complement inhibition the ...best approach to manage PNH. Three complement inhibitors are approved by the European Medicines Agency as targeted therapy for PNH: eculizumab and ravulizumab, two humanized monoclonal antibodies targeting the same complement 5 (C5) epitope, approved in 2007 and 2019, respectively, and the more recently approved cyclic peptide, the complement 3 (C3) inhibitor pegcetacoplan. Although national and international PNH treatment guidelines exist, they do not take into consideration the latest clinical trial evidence. Given the lack of evidence-based data for some clinical situations encountered in real life, we identified specific populations of patients who may benefit from switching to proximal C3 from terminal C5 inhibition.
Methods
The expert recommendations presented here were created using a Delphi-like process by a group of expert PNH specialists across Central Europe. Based on an initial advisory board meeting discussion, recommendations were prepared and reviewed as part of a Delphi survey to test agreement.
Results
Using a systematic approach, literature databases were searched for relevant studies, and 50 articles were reviewed by the experts and included as supporting evidence.
Conclusion
Implementation of these recommendations uniformly across healthcare institutions will promote the best use of complement inhibition in managing PNH, and has the potential to positively impact patient outcomes in Central Europe and worldwide.
Snakeborne Armillifer pentastomiasis is an emerging human parasitic infection in rural tropical areas where snake meat is eaten. After a series of severe ocular A. grandis larval infections and ...anecdotal abdominal infection in Sankuru District, Democratic Republic of the Congo, during 2014-2015, we systematically investigated possible pentastomid etiology in patients who underwent surgery in the region. Histologic and molecular analyses by established pentastomid 18S rDNA- and newly developed Armillifer-specific cytochrome oxidase PCRs revealed larval pentastomid lesions in 3.7% of patients. Some persons had A. armillatus and A. grandis co-infections. Another pentastomid larva, Raillietiella sp., was molecularly detected in 1 patient who had concomitant A. grandis and A. armillatus infection. The PCRs used were suitable for detecting pentastomid species even in highly necrotic tissues. Phylogenetic analyses of Armillifer cytochrome oxidase genes detected multiple local strains.
The Szekler horse was a small-sized mountain horse of the Carpathian Mountains whose official stud book ceased to exist after WWII. Despite that, individual horses preserving all the characteristics ...of the Szekler horse remained scattered in remote areas. This study aims to evaluate the mitochondrial D-loop sequence (608 bp) of the founder population (n = 59) in 2021 of a breed reconstruction project started in 2012. D-loop showed 68 polymorphic sites. The number of haplotypes was 34, with haplotype diversity (Hd) 0.966 and nucleotide diversity (π) 0.02232. The value of Fu’s Fs statistic (−6.566) was significant (p < 0.001), which rejects a stable population status. Thirteen haplogroups (HG) were found with a nearly equal number of representatives (HG(n)—A (5), D (1), E (2), G (4), I (4), J–K (1), M (4), N (2), O’P (4), and R (1)). In contrast, the Q, L, and B HGs occurred in more horses (15, 9, and 7, respectively). Based on a large number of polymorphic sites and haplotypes, the founder stock is considered diverse. Since the HG Q is characteristic of Asian horses, the examined stock haplotype distribution reflects the eastern origin of the Hungarian horses brought from the East in 896 AD. It is complemented by the gene pool of horses from Europe (e.g., L) and the Middle East (e.g., B).
Ocular pentastomiasis is a rare infection caused by the larval stage of pentastomids, an unusual group of crustacean-related parasites. Zoonotic pentastomids have a distinct geographical distribution ...and utilize reptiles or canids as final hosts. Recently, an increasing number of human abdominal infections have been reported in Africa, where pentastomiasis is an emerging, though severely neglected, tropical disease. Here we describe four ocular infections caused by pentastomids from the Democratic Republic of the Congo. Two cases underwent surgery and an Armillifer grandis infection was detected by morphological and molecular approaches. Thus far, 15 other cases of ocular pentastomiasis have been reported worldwide. Twelve cases were caused by Armillifer sp., recorded almost exclusively in Africa, where such infections occur as a consequence of hunting and consuming snakes, their final hosts. Seven further cases were caused by Linguatula serrata, a cosmopolitan pentastomid whose final hosts are usually canids. Intraocular infections caused permanent visual damage in 69% and a total loss of vision in 31% of reported cases. In contrast, ocular adnexal cases had a benign clinical course. Further research is required to estimate the burden, therapeutic options and pathogenesis of this neglected disease.
Background
A number of new assays with different measuring principles are available to measure von Willebrand factor (VWF) glycoprotein Ib (GPIb)‐binding activity, but little is known about how these ...assays might behave differently for subtypes of von Willebrand disease (VWD).
Objectives
The Comparison of Assays to Measure VWF Activity (COMPASS‐VWF) study was designed to compare all available VWF GPIb‐binding activity assays for VWF. We specifically searched for particular assay behavior differences.
Patients/Methods
To sort out random differences from systematic assay behavior deviations, all assays were performed in different laboratories on the same samples in a blinded fashion. Samples from 53 normal controls and 42 well‐characterized VWD patients were reanalyzed in this study to dissect assay‐specific discrepancies.
Results
No assay behavior differences were found for 53 normal controls. For VWD patients, we found the following systematic assay behavior patterns: (a) All ELISA assays for VWF:GPIbR as well as VWF:GPIbM are insensitive to detect the low VWF activity of VWD type 2B patients with loss of high molecular weight multimers; (b) VWF:Ab assay reports higher activity for the p.V1665E mutation than all other assays; and (c) all ristocetin‐based assays (including VWF:RCo using fixed platelets) but the AcuStar assay report discrepantly low VWF activity for the p.P1467S polymorphism. No systematic assay‐specific difference was observed for either the particle agglutination VWF:GPIbM assay or the AcuStar assay using magnetic beads.
Conclusions
Different assay principles may lead to discrepant results for certain VWD types or mutations. Therefore, a more extensive study for a large number of patients is needed to better characterize the incidence and relevance of such assay‐specific differences.
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