Haemophilia: Current Treatment and Clinical Outcomes, Challenges and Opportunities

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 10981

Special Issue Editor


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Guest Editor
Haemophilia Centre, Department of Medicine, University of Padua Medical School, 35128 Padova, Italy
Interests: hemophilia A and B; Von Willebrand disease; rare coagulation disorders; antipholipid antibodies (lupus anticoagulant, anticardiolipin antibodies); deep vein thrombosis and pulmonary embolism; venous thromboembolism; arterial thrombosis
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Special Issue Information

Dear Colleagues,

In recent years, several new drug treatments have been developed for treating haemophilia patients. Recombinant clotting factor concentrates FVIII/FIX extended half-life, and new haemostasis agents administered subcutaneously (weekly to monthly) are available. These innovative approaches have the potential to enhance the standard of care by decreasing infusion frequency in order to increase compliance, promote prophylaxis, offer alternatives to inhibitor patients, and ease the administration route.

Prophylaxis is the gold-standard treatment in haemophilia to prevent bleeding and recurrent hemarthrosis, which progresses towards an inevitable haemophilic arthropathy, yet numerous unanswered issues remain that concern new drugs. Although EHL products are promising, the optimal strategy for the treatment of bleeds between prophylactic doses and dosing regimens will likely have to be individualized according to patient pharmacokinetics, accounting for age and physical activity. Emicizumab appears to be able to improve haemostasis in haemophilia patients, probably including those with inhibitors; however, they do not currently appear to be able to prevent all bleeding. What is the best treatment to reduce the risk of severe bleeding for newborns, such as intracranial haemorrhage? Could emicizumab and EHL equally protect joints from developing haemophilic arthropathy? What is the best product for active patients? There is much more to cover. This Special Issue, “Haemophilia: Current Treatment and Challenges”, aims to provide an overview of current and developing drugs for haemophilia treatments, endeavouring to give some answers to the many questions and concerns that exist.

Prof. Dr. Ezio Zanon
Guest Editor

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Keywords

  • haemophilia A and B
  • FVIII EHL, FIX EHL
  • prophylaxis
  • emicizumab
  • health-related quality of life
  • population pharmacokinetics

Published Papers (9 papers)

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Research

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9 pages, 225 KiB  
Article
Major Orthopaedic Surgery in Persons with Haemophilia A with and without Inhibitors Treated by Emicizumab: A Mid-Term, Large, and Successful Series at a Single Center
by Christian Carulli, Giovanna Daniele, Silvia Linari, Lisa Pieri, Mariastefania Littera, Matteo Mazzetti, Carlo Tamburini, Domenico Prisco and Giancarlo Castaman
J. Clin. Med. 2024, 13(9), 2646; https://doi.org/10.3390/jcm13092646 - 30 Apr 2024
Viewed by 817
Abstract
Introduction: Patients with Haemophilia (PWH) need orthopaedic treatments and often they undergo surgery. Classically, PWH with inhibitors have to face such procedures earlier than other patients. Major orthopaedic surgery is not easy and complications are frequent. Emicizumab is the first monoclonal antibody introduced [...] Read more.
Introduction: Patients with Haemophilia (PWH) need orthopaedic treatments and often they undergo surgery. Classically, PWH with inhibitors have to face such procedures earlier than other patients. Major orthopaedic surgery is not easy and complications are frequent. Emicizumab is the first monoclonal antibody introduced for haematological prophylaxis for PWH with inhibitors, achieving an efficacious haemostasis also in patients with severe haemophilia A with inhibitors, later demonstrated for PWH without inhibitors. A few years ago, emicizumab was also proposed for PWH undergoing surgery, as it supports excellent bleeding control. The literature on orthopaedic surgery using an emicizumab protocol is scarce: only isolated case reports with short-term follow-ups are available. Aim: The purpose of this study is the assessment of the mid-term outcomes of major orthopaedic surgery performed in a population of patients with and without inhibitors and an emicizumab regimen. Methods: We reviewed the records of 13 PWH (eight with high-titre inhibitors, five without) with a mean age of 54.6 years, undergoing 15 orthopaedic surgical procedures between 2017 and 2022: primary knee and hip arthroplasty, revision, pseudotumor excision, or amputation. Their prophylaxis consisted of the combination of emicizumab and boluses of rFVIIa (PWH with inhibitors) or rFVIII (PWH without inhibitors). The clinical parameters of evaluation were: VAS, Haemophilic Joint Health Score (HJHS), and standard radiologic studies. Follow-up was conducted at 1, 3, 6 months, and then yearly. The survival rate of all implants was also assessed. Results: The mean follow-up was 38.8 months (range: 12–65). All patients were successfully treated without complications during surgery. During the postoperative period, a patient affected by a septic complication two months after his pseudotumor excision underwent an above-the-knee amputation. All patients were regularly discharged to the rehabilitative ward, reporting satisfaction for pain reduction and improved joint and global function at the VAS and HJHS scores. No revisions or implant failures were recorded. Conclusions: A prophylaxis regimen with emicizumab and factor replacement in PWH with or without inhibitors undergoing major orthopaedic surgery ensures effective bleeding control and good postoperative clinical outcomes at mid-term follow-up, and may be routinely adopted in dedicated high-volume hospitals. This series is the most consistent to date reported at a single Haemophilia centre. Full article
17 pages, 11305 KiB  
Article
Cartilage Destruction by Hemophilic Arthropathy Can Be Prevented by Inhibition of the Ferroptosis Pathway in Human Chondrocytes
by Nele Wagener, Sebastian Hardt, Matthias Pumberger and Friederike Schömig
J. Clin. Med. 2024, 13(2), 559; https://doi.org/10.3390/jcm13020559 - 18 Jan 2024
Viewed by 989
Abstract
(1) Background: Around 50% of hemophilia patients develop severe arthropathy, with even subclinical hemorrhage in childhood potentially leading to intra-articular iron deposition, synovia proliferation, neoangiogenesis, and eventual damage to articular cartilage and subchondral bone. Treatments typically include coagulation factor substitution, radiosynoviorthesis, and joint [...] Read more.
(1) Background: Around 50% of hemophilia patients develop severe arthropathy, with even subclinical hemorrhage in childhood potentially leading to intra-articular iron deposition, synovia proliferation, neoangiogenesis, and eventual damage to articular cartilage and subchondral bone. Treatments typically include coagulation factor substitution, radiosynoviorthesis, and joint replacement for advanced cases. This study aims to elucidate programmed cell death mechanisms in hemophilic arthropathy (HA) to identify novel treatments. (2) Methods: Human chondrocytes were exposed to lysed/non-lysed erythrocytes, ferroptosis inducer ML-162, cytokines (IL-1ß, TNFα), and ferric citrate, then assessed for metabolic activity, DNA content, and cell death using Alamar Blue, cyQUANT, and Sytox assays. Three-dimensional spheroids served as a cartilage model to study the effects of erythrocytes and ML-162. (3) Results: Erythrocytes caused significant cell death in 2D cultures (p < 0.001) and damaged 3D chondrocyte spheroids. Iron citrate and erythrocytes reduced chondrocyte DNA content (p < 0.001). The ferroptosis pathway was implicated in cell death, with no effects from apoptosis and necroptosis inhibitors. (4) Conclusions: This study offers insights into HA’s cell death pathway, suggesting ferroptosis inhibitors as potential therapies. Further studies are needed to evaluate their efficacy against the chronic effects of HA. Full article
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9 pages, 738 KiB  
Communication
Rare within Rare: A Girl with Severe Haemophilia A and Turner Syndrome
by Cristina Blag, Margit Serban, Cristina Emilia Ursu, Cristina Popa, Adina Traila, Cristian Jinca, Ciprian Tomuleasa, Madalina Bota, Ioana Ionita and Teodora Smaranda Arghirescu
J. Clin. Med. 2023, 12(23), 7437; https://doi.org/10.3390/jcm12237437 - 30 Nov 2023
Viewed by 841
Abstract
A coincidental occurrence of severe haemophilia A and Turner syndrome in a female person is extremely rare (less than 10 cases published). In such challenging cases, a multidisciplinary approach based on medicine of precision with full access to genetic and bio-molecular exploration is [...] Read more.
A coincidental occurrence of severe haemophilia A and Turner syndrome in a female person is extremely rare (less than 10 cases published). In such challenging cases, a multidisciplinary approach based on medicine of precision with full access to genetic and bio-molecular exploration is indispensable. The article presents an eight-year-old girl, with a family history of haemophilia, without significant disease signs (only post-dental extraction bleeding and a shorter stature). Discordantly, however, the investigations revealed a challenging condition: a genotype of 46,X,i(Xq), with an Isochromosome Xq responsible for the Turner syndrome and simultaneously, for the detrimental transformation, interfering with X chromosome inactivation, of an obligate hemophilia carrier into a severe hemophilia case—two distinct and provocative diseases. Full article
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Review

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12 pages, 635 KiB  
Review
Haemophilia and Cancer: A Literature Review
by Ezio Zanon, Annamaria Porreca and Paolo Simioni
J. Clin. Med. 2024, 13(6), 1770; https://doi.org/10.3390/jcm13061770 - 19 Mar 2024
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Abstract
Background: Opinions in the literature on the impact of cancer on patients with haemophilia are contradictory. There is a lack of data on the clinical presentation and management of cancer in patients with haemophilia (PWH). Methods: Papers were found following a comprehensive search [...] Read more.
Background: Opinions in the literature on the impact of cancer on patients with haemophilia are contradictory. There is a lack of data on the clinical presentation and management of cancer in patients with haemophilia (PWH). Methods: Papers were found following a comprehensive search in PubMed, Google Scholar, and Scopus using the terms “cancer” and “haemophilia” without time limits and using the English language as a filter. The references from all the retrieved original articles and reviews were assessed for additional relevant articles. Results: The emergence of malignancies is one of the important causes of morbidity and mortality in PWH. In the past decade, the literature mainly focused on the epidemiology and outcome of blood-borne cancers in the haemophilia patient group, as the incidence of hepatitis B virus (HBV), hepatitis C (HCV), and HIV infection were high among them. However, with the introduction of recombinant clotting factor concentrates (CFCs), physicians now pay attention to non-virus-related malignancies. Bleeding and thrombotic complications are important causes of morbidity and mortality in critically ill patients with cancer; replacement therapy with factor VIII or IX or others should be maintained during antitumour treatment. Conclusion: Overall, managing cancer in patients with haemophilia requires careful evaluation and individualised planning involving a multidisciplinary team of physicians experienced in haematology, oncology, and surgery. Full article
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13 pages, 1774 KiB  
Review
Blood-Induced Arthropathy: A Major Disabling Complication of Haemophilia
by Alexandre Leuci and Yesim Dargaud
J. Clin. Med. 2024, 13(1), 225; https://doi.org/10.3390/jcm13010225 - 30 Dec 2023
Cited by 1 | Viewed by 984
Abstract
Haemophilic arthropathy (HA) is one of the most serious complications of haemophilia. It starts with joint bleeding, leading to synovitis which, in turn, can cause damage to the cartilage and subchondral bone, eventually inducing degenerative joint disease. Despite significant improvements in haemophilia treatment [...] Read more.
Haemophilic arthropathy (HA) is one of the most serious complications of haemophilia. It starts with joint bleeding, leading to synovitis which, in turn, can cause damage to the cartilage and subchondral bone, eventually inducing degenerative joint disease. Despite significant improvements in haemophilia treatment over the past two decades and recent guidelines from ISTH and WFH recommending FVIII trough levels of at least 3 IU/dL during prophylaxis, patients with haemophilia still develop joint disease. The pathophysiology of HA is complex, involving both inflammatory and degenerative components. Early diagnosis is key for proper management. Imaging can detect joint subclinical changes and influence prophylaxis. Magnetic resonance imagining (MRI) and ultrasound are the most frequently used methods in comprehensive haemophilia care centres. Biomarkers of joint health have been proposed to determine osteochondral joint deterioration, but none of these biomarkers has been validated or used in clinical practice. Early prophylaxis is key in all severe haemophilia patients to prevent arthropathy. Treatment is essentially based on prophylaxis intensification and chronic joint pain management. However, there remain significant gaps in the knowledge of the mechanisms responsible for HA and prognosis-influencing factors. Better understanding in this area could produce more effective interventions likely to ultimately prevent or attenuate the development of HA. Full article
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11 pages, 243 KiB  
Review
Pharmacological Thromboprophylaxis in People with Hemophilia Experiencing Orthopedic Surgery: What Does the Literature Say in 2023?
by Emerito Carlos Rodriguez-Merchan
J. Clin. Med. 2023, 12(17), 5574; https://doi.org/10.3390/jcm12175574 - 26 Aug 2023
Viewed by 1821
Abstract
This narrative review of the literature, consisting of papers found in PubMed and The Cochrane Library published up to 31 July 2023, analyzed those that were deemed to be closely related to the title of this paper. It was encountered that the peril [...] Read more.
This narrative review of the literature, consisting of papers found in PubMed and The Cochrane Library published up to 31 July 2023, analyzed those that were deemed to be closely related to the title of this paper. It was encountered that the peril of deep vein thrombosis (DVT) in people with hemophilia (PWH) after orthopedic surgery is very small, such that pharmacological thromboprophylaxis is not necessary in most cases. The hemophilia literature states that the use of pharmacological thromboprophylaxis should only be performed in PWH undergoing major orthopedic surgery (total-knee arthroplasty, total-hip arthroplasty, ankle arthrodesis) who have additional venous thromboembolism (VTE) risk factors, such as old age, prior VTE, varicose veins, general anesthesia, cancer, factor V (Leiden) mutation, overweight, and treatment with the oral contraceptive pill (in females with von Willebrand’s illness). If we notice various risk factors for VTE in PWH who experience orthopedic surgery, theoretically, we should perform the identical type of pharmacological thromboprophylaxis advised for non-hemophilia patients: low-molecular weight heparins (LMWHs), such as enoxaparin (40 mg subcutaneous/24 h); or direct oral anticoagulants (DOACs), either thrombin inhibitors (dabigatran, 150 mg oral/12 h) or activated factor X (FXa) inhibitors (rivaroxaban, 20 mg oral/24 h; apixaban, 5 mg oral/24 h), or subcutaneous fondaparinux (2.5 mg/24 h subcutaneously). However, the review of the literature on hemophiliac patients has shown that only a few authors have used pharmacological prophylaxis with LMWH (subcutaneous enoxaparin) for a short period of time (10–14 days) in some patients who had risk factors for VTE. Only one group of authors used a low dose of DOAC in the dusk after the surgical procedure and the next day, specifically in individuals at elevated risk of VTE and elevated risk of bleeding after the surgical procedure. Full article

Other

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7 pages, 573 KiB  
Opinion
Joint Dysfunction as a Cause of Spontaneous Subclinical Bleeding in Infants with Hemophilia
by Elena Anna Boccalandro, Samantha Pasca, Valentina Begnozzi, Roberta Gualtierotti and Pier Mannuccio Mannucci
J. Clin. Med. 2023, 12(20), 6672; https://doi.org/10.3390/jcm12206672 - 22 Oct 2023
Viewed by 1109
Abstract
Hemophilia is an inherited hemorrhagic disorder; its main clinical manifestations being bleeding in muscles and joints. Ankles, knees, and elbows are the most frequently affected joints, followed by shoulders and hips. The clinical signs of joint involvement are reduced mobility, swelling and walking [...] Read more.
Hemophilia is an inherited hemorrhagic disorder; its main clinical manifestations being bleeding in muscles and joints. Ankles, knees, and elbows are the most frequently affected joints, followed by shoulders and hips. The clinical signs of joint involvement are reduced mobility, swelling and walking difficulties. Bleeding episodes in patients with hemophilia are usually divided into traumatic and spontaneous, but we believe that the latter are not truly spontaneous but rather the result of joint stresses owing to motion actions that create dysfunctions starting from infancy. Pharmacological prophylaxis with factor replacement therapies or non-replacement drugs markedly reduces musculoskeletal hemorrhages. However, the onset of subclinical joint stress can be reduced only by associating this therapeutic approach with the accurate observation of the child motion patterns and restoring them if dysfunctional, thereby primarily preventing subclinical bleeding and ultimately the onset or progression of hemophilic arthropathy. Full article
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9 pages, 1398 KiB  
Case Report
Surgery and Prophylaxis with Susoctocog-Alfa in Acquired Hemophilia: Case Series and Literature Review
by Carola Sella, Marco Bardetta, Federica Valeri, Cristina Dainese, Alessandra Valpreda, Massimo Massaia, Daniele Grimaldi, Annamaria Porreca, Benedetto Bruno and Alessandra Borchiellini
J. Clin. Med. 2023, 12(14), 4590; https://doi.org/10.3390/jcm12144590 - 10 Jul 2023
Viewed by 943
Abstract
Background: Acquired hemophilia A (AHA) is a rare bleeding disease due to autoantibodies directed against clotting factor VIII (FVIII). Treatment of AHA consists of inhibitor eradication with immunosuppressive therapy (IST) and prompt control of bleeding obtained with bypassing agents or recombinant porcine FVIII [...] Read more.
Background: Acquired hemophilia A (AHA) is a rare bleeding disease due to autoantibodies directed against clotting factor VIII (FVIII). Treatment of AHA consists of inhibitor eradication with immunosuppressive therapy (IST) and prompt control of bleeding obtained with bypassing agents or recombinant porcine FVIII (rpFVIII). The latter has recently been licensed for management of acute bleeding in AHA. Unlike treatment with bypassing agents, rpFVIII can be monitored to provide a successful hemostatic effect and avoid overtreatment. Correlation between rpFVIII inhibitor titers and efficacy of rpFVIII treatment remains a matter of debate. Methods: We report three cases of AHA in which rpFVIII was successfully used with an unconventional schedule despite the presence of medium–high titers of the rpFVIII. The modified Nijmegen–Bethesda inhibitor assay (NBA) was used to dose porcine FVIII inhibitors. Result: The presence of rpFVIII inhibitors prior to the exposition to susoctocog-alfa, that may suggest a cross-reactivity with human FVIII inhibitors, did not affect hemostasis. Conclusion: In our experience, rpFVIII demonstrates safety and efficacy in the presence of rpFVIII inhibitors and using an unconventional schedule in both the perioperative and outpatient settings. Laboratory measurement of inhibitors against rpFVIII during treatment is described for the first time. Full article
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12 pages, 3619 KiB  
Systematic Review
Eltrombopag for Adults and Children with Immune-Refractory Thrombocytopenic Purpura: A Systematic Review
by Danielle Francisco Honorato de Barros Torelli, Crystian Bitencourt Soares Oliveira, Gisele Alborghetti Nai, Evelinda Marramon Trindade and Luiz Euribel Prestes-Carneiro
J. Clin. Med. 2023, 12(12), 3872; https://doi.org/10.3390/jcm12123872 - 6 Jun 2023
Viewed by 1327
Abstract
Eltrombopag is an agonist that binds to the membrane-bound domain of the thrombopoietin receptor used in immune thrombocytopenic purpura (ITP). We conducted a meta-analysis of randomized controlled trials to assess the efficacy and safety of eltrombopag in adults and children with refractory ITP. [...] Read more.
Eltrombopag is an agonist that binds to the membrane-bound domain of the thrombopoietin receptor used in immune thrombocytopenic purpura (ITP). We conducted a meta-analysis of randomized controlled trials to assess the efficacy and safety of eltrombopag in adults and children with refractory ITP. Adults who received eltrombopag had a significantly better platelet response (relative risk [RR], 3.65; 95% confidence interval [CI], 2.39–5.55), but there were no differences in the incidence of bleeding (RR, 0.8; 95% CI, 0.52–1.22) and adverse effects (RR, 0.99; 95% CI, 0.55–1.78) compared with the placebo. In children, there was no difference between eltrombopag and placebo for a platelet response >50,000/mm3 (RR, 3.93; 95% CI, 0.56–27.79) and the number of adverse events (RR, 0.99; 95% CI, 0.25–1.49); however, a lower incidence of bleeding was observed (RR, 0.47; 95% CI, 0.27–0.83). Treatment with eltrombopag protected adults and children from severe disease and death. Full article
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