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In clinical medicine, shared decision making (SDM) is a well-recognized strategy to enhance engagement of both patients and clinicians in medical decisions. The success of liver-directed gene therapy (GT) to transform severe congenital haemophilia A (HA) from an incurable to a curable disease has launched a shift beyond current standards of treatment. However, GT acceptance remains low in the community of HA persons. We argue for both persons with haemophilia (PWH) and specialists in HA care including clinicians, as needing SDM-oriented educational programs devoted to GT. Here, we provide an ad hoc outline to implement education to SDM and tailor clinician information on GT to individual PWHs. Based on routine key components of SDM: patient priorities; recommendations based on individual risk reduction; adverse effects; drug-drug interactions; alternatives to GT; and ongoing re-assessment of the objectives as risk factors (and individual priorities) change, this approach is finalized to exploit efficacious communication., Competing Interests: Declaration of Competing Interest GDM: speaker or a member of a speaker bureau for: BioMarin, Bayer, CSL Behring, Roche, Takeda, Viatris Pharmaceuticals; consultant or ad-hoc speaker/consultant for: BioMarin, Bayer, Pfizer, Takeda, Viatris Pharmaceuticals. G.C.: Grant/Research support from: CSL Behring, Pfizer, Sobi, Consultant for: blynx, Alexion, Bayer, Takeda, CSL Behring, Novo Nordisk, Pfizer, Roche, Sanofi, SOBI, uniQure (Membership on an entity's Board of Directors or advisory committees), Speaker Bureau of: Bayer, Roche, Sobi, Grifols, Novo Nordick, Werfen, Kedrion. CS: speaker or a member of a speaker bureau for: Bayer, CSL Behring, Novo Nordisk, Takeda; consultant for: Bayer, Novo Nordisk, CSL Behring, Sobi, Roche, Biomarin, Takeda, Kedrion; RDC: Speaker Bureau of Bayer, Sobi, CSL Behring, and Takeda, FP: speaker or a member of a speaker bureau for Grifols and Roche, on advisory boards for Sanofi, SOBI, Takeda, Roche, and BioMarin, MDM: grants and honoraria from Sobi, Pfizer, Bayer, Novo-Nordisk, Takeda, Roche, and Daiichi Sankyo, FM: speaker or a member of a speaker bureau for: Gilead Sciences, Giuliani SPA, Advance Pharma, Albireo Pharma, Mirum, Nutrilinea SRL, BioMarine, AL: Speaker bureau for BioMarin, and CSL Behring, MF: Speaker bureau for BioMarin, and CSL Behring. GS, GG, NMM, and NDL declare no interests which might be perceived as posing a conflict or bias., (Copyright © 2023. Published by Elsevier Ltd.)

In persons with congenital severe hemophilia A (HA) living in high-income countries, twice weekly intravenous infusions of extended half-life (EHL) factor VIII (FVIII) products, or weekly/biweekly/monthly subcutaneous injections of emicizumab are the gold standard home treatments to grant days without hurdles and limitations. Once weekly/twice monthly infusions of EHL Factor IX (FIX) products achieve the same target in severe hemophilia B (HB). Gene therapy, which is likely to be licensed for clinical use within 1-2 years, embodies a shift beyond these standards. At an individual patient level, a single functional gene transfer leads to a > 10-yr almost full correction of the hemostatic defect in HB and to a sustained (3-6-yrs) expression of FVIII sufficient to discontinue exogenous clotting factor administrations. At the doses employed, the limited liver toxicity of systemically infused recombinant adeno-associated virus (rAAV) vectors is documented by long-term (12-15 yrs) follow-ups, and pre-existing high-titer neutralizing antibodies to the AAV5 vector are no longer an exclusion criterion for effective transgene expression with this vector. A safe durable treatment that converts a challenging illness to a phenotypically curable disease, allows persons to feel virtually free from the fears and the obligations of hemophilia for years/decades. Along with patient organizations and health care professionals, communicating to government authorities and reimbursement agencies the liberating potential of this substantial innovation, and disseminating across the Centers updated information on benefits and risks of this strategy, will align expectations of different stakeholders and establish the notion of a potentially lifelong cure of hemophilia., (Copyright © 2022. Published by Elsevier Ltd.)

Comprehensive evidence-based guidelines and well-validated assessment scales for pain in people with hemophilia (PwH) are needed. Here, we report 28 statements covering five topics on pain assessment and management in pediatric and adult PwH that were developed by 60 Italian hemophilia specialists during a Delphi consensus process. Overall, a clear consensus was achieved for 19 of the 28 statements. Consensus was reached on all statements on the topic of pain assessment and quality of life (QoL), including the need for regular pain assessment on a quantitative scale, the importance of distinguishing between different pain types, and the need to evaluate the impact of pain on patient QoL. The other four topics concerned acute and chronic pain management in adults and in children. Consensus was reached on statements regarding non-pharmacologic treatment and the use of first-line paracetamol (acetaminophen). There was a lack of consensus regarding the use of non-steroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, or opioids., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Not all patients with severe hemophilia A (HA) respond optimally to a given dose of a given product. Within-individual variance in cross-over studies makes each patient unique in the response to each standard half-life (SHL) factor VIII (FVIII) product in pharmacokinetic (PK) terms. This hampers the prediction of efficacy when a SHL FVIII product is employed. PK data showing that half-lives of SHL rFVIII are unsatisfactory to achieve zero bleeding in individual HA patients provide the rationale for switching from SHL to extended half-life (EHL) products. However, not all subjects receiving prophylaxis with EHL products achieve zero bleeding, the most cogent objective of personalized prophylaxis. Known determinants of FVIII half-life (age, von Willebrand factor [VWF] levels, blood group) cumulatively account for one third of the total inter-individual variation in FVIII clearance in subjects with severe HA. Investigations into precision, and accuracy of laboratory measurement to be employed; newer pathways for the clearance of both free-FVIII and VWF-bound FVIII, and adequately powered studies on omics and phenotypic heterogeneity, are likely to provide additional information on the remaining two thirds of inter-individual variation in FVIII clearance in HA. Variability in the clinical response has also been documented in patients when FVIII activity is mimicked by fixed subcutaneous doses of the bispecific antibody emicizumab. National registries that collect PK data of available FVIII products and ad hoc information on the individual response to emicizumab should be encouraged, to establish newer standards of care and ease personalized clinical decisions to achieve zero bleeding., (Copyright © 2021. Published by Elsevier Ltd.)

With liver-directed gene therapy, congenital haemophilia has the potential to progress from an incurable to a phenotypically curable condition. However, the proportion of haemophilia population likely to benefit from gene therapy remains to be established. Achieving a phenotypic curative goal is presently hampered by: 1) availability of effective treatments (e.g. extended half-life products, non-factor therapies) that address major unmet needs in haemophilia; 2) key differences between hope and reality that patients undergoing gene therapy face (e.g. unknown risks and long-term follow-up, durability of the therapeutic effect, possibility of re-administering the vector), 3) lack of expertise of health care professionals (HCP) in managing/monitoring unexpected side effects in patients, and 4) lack of expertise of HCP in advising payers on key issues for cost-effectiveness analyses of gene therapy (e.g., eligibility criteria, predictability of response, unknown risks, long-term complications). There is also uncertainty about the possibility to absorb the cost of the "one-time, one-dose cure" by payers that are used to different payment models. An active partnership between regulators, payers, patients and health care professionals is key to identify patient sub-populations that might benefit the most from gene therapy, and to align the interests of patients (needing effective disease correction and improved quality of life) and pharma companies (reluctant to lose the profitability of lifelong repeated treatments). Educational programs will provide the healthcare chain with information on the strategy that is expected to transform morbidity and mortality patterns and how it should be regarded as part of the future therapeutic options in haemophilia., (Copyright © 2020. Published by Elsevier Ltd.)

Patients with haemophilia A (HA) or B (HB) experience spontaneous limb- or life-threatening bleedings which are prevented by regular prophylactic intravenous infusions of the deficient coagulation factor (FVIII or FIX). Prophylaxis with subcutaneous long-acting non-factor products that improve in vivo thrombin generation is now under intensive investigation (concizumab, fitusiran) or successfully employed (emicizumab) in haemophilia patients. Both haemophilia patients with/without inhibitors take advantage of non-factor products employed alone. In those who also need bypassing agents (or FVIII concentrates) for breakthrough bleeds, thromboembolic events and/or thrombotic microangiopathy may occur. By enhancing thrombin generation, prothrombotic mutations co-segregating with FVIII/FIX gene mutations may trigger thrombotic episodes in HA patients carrying acquired thrombogenic factors (e.g. venous catheters). A thorough knowledge of individual needs increasingly contributed to improve comprehensive care and personalize treatments in haemophilia. Integrating genomics, lifestyle and environmental data is expected to be key to: 1) identify which haemophilia patients are less likely to benefit from a given intervention; 2) define optimal dosing and scheduling of bypassing agents (or FVIII) to employ in combination with non-factor products; 3) establish tests to monitor in vivo thrombin generation; 4) improve communication and deliver results to individuals. As individual outcomes will be improved and the risk of adverse events minimized, non-factor products will come into wider use within the haemophilia community, and patients will hopefully have no more risks of breakthrough bleeds. The risks of a normal life for a "former haemophilia patient" is likely to change the treatment landscape and the structure of haemophilia Centers., Competing Interests: Declaration of competing interest All the Authors assisted with the writing of this manuscript. None of the Authors received remuneration for preparation of this manuscript and no sponsors were involved with writing of the manuscript. The views expressed in the manuscript are those of the authors alone. The authors stated that they had no interests which might be perceived as posing a conflict or bias. PC, protein C; APC, activated protein C; AT, antithrombin; TF, tissue factor; TFPI, tissue factor pathway inhibitor; EPCR, endothelial protein C receptor; PAR1, protease activated receptor 1. Abbreviations: APC = activated protein C; TFPI = tissue factor pathway inhibitor; TF = tissue factor; EPCR = Endothelial protein C receptor (key for active transport and storage of FVIIa in extravascular tissue and for PAR1 activity [barrier protection]). See text for details. Natural anticoagulant mechanisms are indicated (red lines) and points of interventions of current non-factor products are reported (purple boxes). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.), (Copyright © 2019. Published by Elsevier Ltd.)

Following a chance discovery made by a medical student who was searching for a clot-promoting activity in tissue extracts, it took 15-20 years to attain the therapeutic use of standard unfractionated heparin (UFH), due to problems with the purification and extraction of the active material. Soon it was found that: 1) thrombin inactivation by UFH was associated with the formation of molecular complexes between antithrombin and the activated forms of factor X (FXa) and thrombin, 2) low-molecular-weight fractions of UFH lose their antithrombin activity while still interacting with FXa, 3) a pentasaccharide sequence of UHF increases FXa (but not thrombin) inactivation by antithrombin. Low-molecular-weight heparins (LMWHs) with little effect on thrombin and strongly active versus FXa were then developed. In patients, LMWHs (and the pentasaccharide sequence) came up as a useful class of drugs to prevent and treat thrombosis, their greatest advantage over UFH being the convenience of the once/twice daily subcutaneous injections at a fixed dose without any laboratory monitoring. In addition to providing major information on in vivo modulation of thrombin generation, the heparin saga served as a paradigm to support an alternative coagulation scheme that includes platelets and tissue factor as integral parts of the model. Forthcoming work with this scheme - also supported by studies in hemophilia and rare bleeding disorders - is expected to provide major hints for understanding why some patients benefit more than others from the small amount of thrombin they form and directions to tailor prevention and treatment of thromboembolic disorders., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Haemophilia is marked by joint bleeding (haemarthrosis) leading to cartilage damage (arthropathy). Lifelong prophylaxis-initiated after the first bleeding episode-leads to a dramatic decrease in arthropathy in haemophilia patients. However, adherence to continuous intravenous administrations of factor VIII (FVIII) or FIX products is challenging, and patients potentially suffer from breakthrough bleedings while on prophylaxis. Newer FVIII/FIX products with enhanced convenience attributes and/or easier infusion procedures are intended to improve adherence. However, pharmacokinetic data should be harmonised with information from individual attitudes and treatment needs, to tailor intravenous dosing and scheduling in patients who receive extended half-life products. Nor is there sound evidence as to how subcutaneous non-FVIII/FIX replacement approaches (concizumab; emicizumab; fitusiran) or single intravenous injections of adeno-associated viral vectors (when employing gene therapy) will revolutionize adherence in haemophilia. In rheumatoid arthritis, repeated ultrasound examination of a patient's major joints is a valuable tool to educate patients and parents to understand the disease and provide an objective framework for clinicians to acknowledge patient's adherence. Joint ultrasound examination in haemophilia significantly correlates with cartilage damage, effusion, and synovial hypertrophy evaluated by magnetic resonance imaging. Furthermore, in patients with haemophilia undergoing prophylaxis with an extended half-life product for a ≈ 2.8 year period, a significant continued improvement in joint health is detected at the physical examination. This provides the rationale for studies on repeated ultrasound examinations of joint status to attempt to remedy sub-optimal medication adherence and help identify which approach is most suited on which occasion and for which patient., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The pathogen safety of blood/plasma-derived products has historically been a subject of significant concern to the medical community. Measures such as donor selection and blood screening have contributed to increase the safety of these products, but pathogen transmission does still occur. Reasons for this include lack of sensitivity/specificity of current screening methods, lack of reliable screening tests for some pathogens (e.g. prions) and the fact that many potentially harmful infectious agents are not routinely screened for. Methods for the purification/inactivation of blood/plasma-derived products have been developed in order to further reduce the residual risk, but low concentrations of pathogens do not necessarily imply a low level of risk for the patient and so the overall challenge of minimising risk remains. This review aims to discuss the variable level of pathogenic risk and describes the current screening methods used to prevent/detect the presence of pathogens in blood/plasma-derived products., (Copyright © 2015. Published by Elsevier Ltd.)

Gastrointestinal bleeding (GIB) is a potentially fatal and avoidable medical condition that poses a burden on global health care costs. Current understanding of the roles of platelet activation and thrombin generation/activity in vascular medicine has led to the development of effective antithrombotic treatments. However, in parallel with a sustained coronary and cerebral flow patency, the increasingly intensive treatment with warfarin; direct oral anticoagulant drugs [DOACs], and/or with aspirin ± clopidogrel (or ± prasugrel or ± ticagrelor), has increased the burden of GIBs related to the use of antithrombotic agents. Compelling evidence concerning this issue is accumulating to indicate that: 1) the risk of GIB related to the use of antithrombotic drugs dramatically differs in different clinical settings; and 2) the characteristics of patients (e.g., severity of illness, comorbidities) in whom it is used exert a greater impact on the risk of GIB than the type of antithrombotic agent employed. The latter concept argues for the occurrence of GIB as reflecting the presence of patients at the highest risk for adverse outcomes. The HAS-BLED score identifies subjects at risk of bleeding among those untreated and those treated with warfarin, DOACs and/or low-dose aspirin. Its use within the frame of a severity score (e.g., the CHA2DS2-VASc score in patients with atrial fibrillation) helps balance the benefits and the risks of an antithrombotic treatment and identify those patients in whom the absolute gain (vascular events prevented) outweighs the risk of GIB. Potential implications of the latter information in settings other than atrial fibrillation is thoroughly discussed., (Copyright © 2015. Published by Elsevier Ltd.)

Glanzmann's thrombasthenia (GT) and congenital factor VII deficiency (FVII CD) are rare autosomal recessive bleeding disorders: GT is the most frequent congenital platelet function disorder, and FVII CD is the most common factor-deficiency disease after haemophilia. The frequency of these disorders in the general population ranges from 1:500,000 to 1:2,000,000. Because GT and FVII CD are both rare, registries are the only approach possible to allow the collection and analysis of sufficient observational data. Recombinant activated factor VII (rFVIIa, eptacog alfa activated) is indicated for the treatment of acute bleeding episodes and for surgery coverage in patients with GT who are refractory to platelets and have antiplatelet or anti-human leukocyte antigen (HLA) antibodies, and for the prevention and treatment of bleeding in patients with FVII CD. This article summarises published data on the mechanism of action and use of rFVIIa in these disorders from two international, prospective, observational registries: the Glanzmann's Thrombasthenia Registry (GTR) for GT; and the Seven Treatment Evaluation Registry (STER) for FVII CD. Haemostatic effectiveness rates with rFVIIa were high across all patients with GT and those with FVII CD, and treatment with rFVIIa in the GTR and STER registries was well tolerated. The GTR and the STER are the largest collections of data in GT and FVII CD, respectively, and have expanded our knowledge of the management of these two rare bleeding disorders., (Copyright © 2015 Elsevier Ltd. All rights reserved.)