New Developments in Diagnosis and Management of Acquired Hemophilia and Acquired von Willebrand Syndrome

Acquired hemophilia A and acquired von Willebrand syndrome are rare, but life-threatening bleeding disorders that require prompt diagnosis and treatment by hematologists. Acquired hemophilia A is defined as an acquired severe bleeding tendency caused by autoantibody formation against coagulation factor VIII. Acquired von Willebrand syndrome is characterized by a new onset bleeding tendency caused by a reduced concentration and/or function of von Willebrand factor. These disorders are associated with a variety of underlying disorders, including various hematological malignancies, for example, plasma cell disorders, lymphoproliferative disorders, monoclonal gammopathy of undetermined significance, and myeloproliferative neoplasms. It is of utmost important to recognize these acquired bleeding disorders in these patients who are at risk for severe bleeding, and to perform additional diagnostic hemostasis laboratory evaluation. This will enable immediate diagnosis of the acquired bleeding disorder and management of both the bleeding episodes and the causative underlying disorder. In recent years, several new etiological factors for acquired hemophilia A, such as treatment with immune checkpoint inhibitors or DPP-4 inhibitors and SARS-CoV2 infection, and for acquired von Willebrand syndrome, for example, left ventricular assist devices, have been identified and also new treatment options have become available. In this concise review, the most recent data on etiology, diagnosis, and treatment of acquired bleeding disorders are presented and discussed

Construction and functional analysis of hybrid interleukin-6 variants Characterization of the role of the C-terminus for species specificity

AbstractWe have constructed several hybrid human interleukin-6 (IL-6) variants in which the carboxyl-terminus, which includes a receptor binding site of IL-6 has been replaced with the C-terminus of various proteins homologous to human IL-6, IL-6 hybrids with the C-terminus of human growth hormone and human granulocyte-colony stimulating factor maintain part of the biological activity of human IL-6. Replacing the C-terminus of human IL-6 with the C-terminus of mouse and rat IL-6 resulted in a normal or increased activity on a mouse cell line; however, this gave a low (to 200-fold less) activity on a human cell line compared to wild-type human IL-6. We therefore conclude that the C-terminus of IL-6 plays in important role in the species specificity of IL-6

Prognostic markers in young patients with premature coronary heart disease

AbstractObjectivesTo evaluate the survival and prognostic implications of cardiovascular, inflammatory and prothrombotic risk factors in young patients with premature coronary heart disease (CHD).MethodsFollow-up data were obtained from 353 young patients with a first cardiac event (men ≤45 years and women ≤55 years). Baseline characteristics on traditional risk factors were collected at the time of the first event, and plasma levels of C-reactive protein (CRP), von Willebrand Factor (VWF), and fibrinogen were measured one to three months after the first event to exclude an acute phase response. We performed age and sex adjusted Cox regression analyses to assess the relationship between these factors and recurrent events with three different endpoints: all cause mortality, recurrent cardiac event (myocardial infarction or revascularisation procedure), and any recurrent event (cardiac event, cerebrovascular event or all cause mortality).ResultsDuring a total follow-up time of 1483 person years (mean 4.2 years), 11 patients died (3%), 42 patients had a recurrent cardiac event (12%), and 53 patients had any recurrent event (15%). CRP was associated with an increased risk of any recurrent event (HR 1.28[95% CI = 1.02–1.59] per unit increase in lnCRP). Also, both CRP (5.00[1.04–24.04]) and fibrinogen (5.04[1.05–24.23]) were associated with all cause mortality when levels were above the 50th percentile.ConclusionsFifteen percent of young patients with a first cardiac event have a recurrent event or die within a median follow-up of 4.2 years. In these young patients we have shown that, independently of cardiovascular risk factors, high CRP levels contribute to the risk of recurrent events, including all cause mortality, and high fibrinogen levels are associated with all cause mortality

Desmopressin to prevent and treat bleeding in pregnant women with an inherited bleeding disorder:a systematic literature review

Background: Although desmopressin (DDAVP) is an accessible and inexpensive hemostatic drug, its use in pregnancy is still debated due to safety uncertainties. Objectives: We aimed to review the safety and effectiveness of DDAVP in women with an inherited bleeding disorder during pregnancy and delivery. Methods: Databases were searched for articles up to July 25, 2022, reporting maternal and/or neonatal outcomes. PRISMA methodology for systematic reviews and meta-analyses was followed (PROSPERO CRD42022316490). Results: Fifty-three studies were included, comprising 273 pregnancies. Regarding maternal outcomes, DDAVP was administered in 73 women during pregnancy and in 232 during delivery. Safety outcome was reported in 245 pregnancies, with severe adverse events reported in 2 (1%, hyponatremia with neurologic symptoms). Overall, DDAVP was used as monotherapy in 234 pregnancies, with effectiveness reported in 153 pregnancies (82% effective; 18% ineffective). Regarding neonatal outcomes, out of 60 pregnancies with reported neonatal outcomes after DDAVP use during pregnancy, 2 children (3%) had a severe adverse event (preterm delivery n = 1; fetal growth restriction n = 1). Of the 232 deliveries, 169 neonates were exposed to DDAVP during delivery, and in 114 neonates, safety outcome was reported. Two children (2%) experienced a moderate adverse event (low Apgar score n = 1; transient hyperbilirubinemia not associated with DDAVP n = 1). Conclusion: DDAVP use during pregnancy and delivery seems safe for the mother, with special attention to the occurrence of hyponatremia and for the child, especially during delivery. However, due to poor study designs and limited documentation of outcomes, a well-designed prospective study is warranted.</p

Modelling benefits, costs and affordability of a novel gene therapy in hemophilia A

Abstract The objective was to assess undertake an early cost-effectiveness assessment of valoctocogene roxaparvovec (valrox;Roctavian®) compared to factor (F)VIII prophylaxis or emicizumab (Hemlibra®) in patients with severe Hemophilia A (HA) without FVIII-antibodies. Secondary, weWe also aimed to incorporate and quantify novel measures of value such as treatment durability, maximum value-based price (MVBP) and break-even time (i.e., time until benefits begin to offset upfront payment). We constructed a A Markov-model was constructed to model bleeds over time which were linked to costs and quality-of-life decrements. In the valrox arm, FVIII% over time were first estimated combining initial effect and treatment waning and then linked to bleeds. In FVIII- and emicizumab-arms, bleeds were based on trial evidence. Evidence and assumptions were validated using via expert elicitation. Model robustness was tested via sensitivity analyses. A Dutch societal perspective was applied with a 10-year time-horizon. Valrox in comparison to FVIII, and emicizumab showed small increases in quality-adjusted life years atand lower costs, and was therefore dominant. Valrox’ base case MVBP was estimated at €2.65 million/treatment compared to FVIII and €3.5 million/treatment versus to emicizumab. Mean break-even time was 8.03 years compared to FVIII and 5.68 years to emicizumab. Early modelling cost-effectiveness analysis Treatment of patients with HA in the Netherlands treated with valrox was estimated to resultresulted in estimated improved health and lower cost compared to prophylactic FVIII and emicizumab. We also demonstrated feasibility to of incorporation ofmodelincorporate treatment durability was demonstrated and , as well as quantification of novel outcomes such as value-based pricing scenarios and break-even ti¬me. However, more work is needed to beter characterize uncertainties, define affordability and increase informativeness for decision making. Future work should aim to better characterize uncertainties and increase translation of early economic evaluationsmodelling to direct research efforts

Desmopressin for bleeding in non-severe hemophilia A:Suboptimal use in a real-world setting

Background Desmopressin is an important treatment option in nonsevere hemophilia A because it has several benefits compared with factor (F) concentrates, including no inhibitor risk and much lower costs. Despite these advantages, data are limited on the real-world use of desmopressin in the treatment of bleeds. Objective To describe the clinical use of desmopressin in relation to other therapeutic modalities in the treatment of bleeding episodes in patients with nonsevere hemophilia A. Methods Patients with nonsevere hemophilia A aged 12-55 years were included from the DYNAMO cohort study. Data on the desmopressin test response and treated bleeding events in the period January 2009 to July 2020 were retrospectively collected from medical files. An adequate desmopressin test response was defined based on a peak FVIII level of >= 30 IU/dl. Results A total of 248 patients with a median age of 38 years (interquartile range 25-49) were included. An adequate desmopressin test response was documented in 25% and 73% of patients with moderate and mild hemophilia, respectively. In adequate responders, 51% of bleeds were exclusively treated with FVIII concentrates, 24% exclusively with desmopressin, 21% with a combination of both and 4% with other treatments. In 54% of bleeds treated with a single dose of factor concentrates, the expected FVIII level after desmopressin exceeded the level targeted. Conclusion Most bleeds in patients with an adequate response to desmopressin are treated with factor concentrates. These findings may indicate a suboptimal use of desmopressin and that barriers to the use of desmopressin should be explored.Thrombosis and Hemostasi