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

Deadline for manuscript submissions: closed (15 April 2022) | Viewed by 35610

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Prof. Dr. Ezio Zanon

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Haemophilia Centre, General Medicine, Padua University Hospital, 35128 Padua, Italy
Interests: haemophilia A and B; von willebrand disease; rare coagulation disorders; acquired haemophilia; luus anticoagulant and antiphospholipid antibodies

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, promoting prophylaxis, offering alternatives to inhibitor patients, and easing the administration route.

Prophylaxis is the gold standard treatment in haemophilia to prevent bleeding and recurrent haemarthrosis which progresses towards an inevitable haemophilic arthropathy. Yet, numerous unanswered issues remain also concerning new the drugs.Although EHL products are promising, the optimal strategy for 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 hemostasis in hemophilia patients, probably including those with inhibitors; however, they do not currently appear to be able to prevent all bleeding. What is the best treatment for newborns to reduce the risk of severe bleeding, such as intracranial hemorrhage? Could emicizumab and the EHL equally protect the joints from developing haemophilic arthropathy? What is the best product for active patients? And much more. This special issue “Haemophilia: Current Treatment and Challenges” aims to provide an overview of current and developing drugs for haemophilia treatment, endeavouring to give some answers to the many questions and concerns.

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

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14 pages, 867 KiB

Open AccessArticle

Six-Year, Real-World Use of Prophylaxis with Recombinant Factor IX–Albumin Fusion Protein (rIX-FP) in Persons with Hemophilia B: A Single-Center Retrospective–Prospective Study

by Antonio Coppola, Gianna Franca Rivolta, Gabriele Quintavalle, Annalisa Matichecchia, Federica Riccardi, Rossana Rossi, Anna Benegiamo, Paola Ranalli, Valeria Coluccio and Annarita Tagliaferri

J. Clin. Med. 2024, 13(5), 1518; https://doi.org/10.3390/jcm13051518 - 6 Mar 2024

Cited by 1 | Viewed by 1390

Abstract

Background: Extended half-life (EHL) factor IX (FIX) concentrates allow for prophylaxis with prolonged dosing intervals and high bleeding protection in persons with hemophilia B. Long-term real-world studies are lacking. Methods: In a retrospective–prospective study, the six-year use of prophylaxis with the EHL recombinant FIX–albumin fusion protein (rIX-FP) was analyzed, comparing outcomes with previous standard half-life (SHL) FIX in patients already on prophylaxis. Results: Prophylaxis with rIX-FP was prescribed in 15 patients (10 severe, 5 moderate; follow-up: 57 ± 17 months). Based on a pharmacokinetic assessment and clinical needs, the first regimen was 47 ± 7 IU/Kg every 9 ± 2 days. All but one patient remained on rIX-FP prophylaxis, adjusting infusion frequency and/or dose; the last prescribed frequency was ≥10 days in 10/13 patients, being reduced in seven and increased in four vs. the first regimen. The weekly FIX dose was unchanged; FIX trough levels were >5% in all patients. The annual infusion number and FIX IU/Kg significantly decreased (~60%) in eight patients previously on SHL FIX prophylaxis, with similar concentrate costs. Very low bleeding rates (most traumatic bleeds and the last quartile of the infusion interval), improved orthopedic and pain scores, unchanged HEAD-US scores and problem joints, and high treatment adherence (>90%) and satisfaction were registered. Conclusions: Personalized, carefully adjusted rIX-FP regimens contribute to the diffusion and optimization of prophylaxis in persons with severe and moderate hemophilia B, with long-term favorable bleeding, joint, and patient-reported outcomes. Full article

(This article belongs to the Special Issue Haemophilia: Current Treatment and Challenges)

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10 pages, 544 KiB

Open AccessArticle

Real-World Clinical Outcomes and Replacement Factor VIII Consumption in Patients with Haemophilia A in Italy: A Comparison between Prophylaxis Pre and Post Octocog Alfa (BAY 81-8973)

by Paolo Angelo Cortesi, Giovanni Di Minno, Ezio Zanon, Gaetano Giuffrida, Rita Carlotta Santoro, Renato Marino, Lucia Sara D’Angiolella, Ippazio Cosimo Antonazzo, Ginevra Squassabia, Francesco Clemente, Danilo Di Laura, Ernesto Cimino, Samantha Pasca, Daniela Nicolosi and Lorenzo Giovanni Mantovani

J. Clin. Med. 2022, 11(12), 3434; https://doi.org/10.3390/jcm11123434 - 15 Jun 2022

Cited by 2 | Viewed by 2688

Abstract

(1) Background: new generations of rFVIII products offered the possibility to improve personalized therapeutic approaches, reducing the number of infusions or increasing the protection against bleeding risk. The aim of this study was to assess the effectiveness of prophylaxis with BAY 81-8973 (octocog alfa, Kovaltry^®, Bayer Pharma AG) in the real-world setting and its impact on FVIII consumption compared to previous standard half-life treatments. (2) Methods: a retrospective observational study was conducted in five Italian Haemophilia Centers. Patients with haemophilia A under prophylactic treatment with BAY 81-8973 for at least one year, and previously on prophylaxis with a different product were included in the study. Annual bleeding rate (ABR) and annual FVIII consumption were compared. (3) Results: forty-four patients were included in the study. After switching to BAY 81-8973, ABR was significantly reduced (1.76 vs. 0.23; p = 0.015), the percentage of patients with zero bleeds increased from 54.6% to 84.1% (p = 0.003), and the overall FVIII consumption decreased by 25,542 (−7.2%, p = 0.046) IU per patient-year. Patients treated every 3 days or 2 times per week increased from 0% to 27.3%. (4) Conclusion: our results suggest that prophylaxis with BAY 81-8973 can improve clinical outcomes and reduce FVIII consumption, in the real-world practice, compared with the previous prophylaxis regimen with standard half-life products. Full article

(This article belongs to the Special Issue Haemophilia: Current Treatment and Challenges)

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8 pages, 1565 KiB

Open AccessArticle

Challenges in the Diagnosis and Management of Non-Severe Hemophilia

by Estera Boeriu, Teodora Smaranda Arghirescu, Margit Serban, Jenel Marian Patrascu, Eugen Boia, Cristian Jinca, Wolfgang Schramm, Adina Traila and Cristina Emilia Ursu

J. Clin. Med. 2022, 11(12), 3322; https://doi.org/10.3390/jcm11123322 - 9 Jun 2022

Cited by 4 | Viewed by 2740

Abstract

(1) Background: Mild and moderate hemophilia, synonymous with non-severe hemophilia (NSH), are of constant interest for the clinicians. Bleeding occurs usually after trauma, injury, surgery, or inhibitor development, sometimes leading to a shift of the clinical phenotype from mild to severe, even with life-threatening and unexpected outcomes. (2) Methods: We performed a retrospective observational study conducted on 112 persons with congenital coagulopathies, 26 of them with NSH, admitted to our clinic in the period 2000 to 2022. For the diagnosis, we used laboratory studies (complete blood cell count, coagulation assays, biochemistry, thromboelastography, genetic tests) and imaging investigations (X-ray, ultrasound, CT, MRI). We selected four cases confronted with pitfalls of diagnosis and evolution in order to illustrate the sometimes provocative field of NSH. (3) Results: Confronted with challenging cases with under-, missed or delayed diagnosis and severe consequences, we aimed at presenting four such selected cases with mild or moderate hemophilia, real pitfalls in our clinical activity. (4) Conclusions: In the field of NSH, if not timely recognized, tending sometimes to remain ignored by caregivers and patients themselves, we can be confronted with challenging diagnostic situations and life-threatening bleeds. Full article

(This article belongs to the Special Issue Haemophilia: Current Treatment and Challenges)

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10 pages, 626 KiB

Open AccessArticle

Intracranial Haemorrhage in Haemophilia Patients Is Still an Open Issue: The Final Results of the Italian EMO.REC Registry

by Ezio Zanon, Samantha Pasca, Francesco Demartis, Annarita Tagliaferri, Cristina Santoro, Isabella Cantori, Angelo Claudio Molinari, Chiara Biasoli, Antonio Coppola, Matteo Luciani, Gianluca Sottilotta, Irene Ricca, Berardino Pollio, Alessandra Borchiellini, Alberto Tosetto, Flora Peyvandi, Anna Chiara Frigo and Paolo Simioni

J. Clin. Med. 2022, 11(7), 1969; https://doi.org/10.3390/jcm11071969 - 1 Apr 2022

Cited by 9 | Viewed by 3182

Abstract

Background: Intracranial hemorrhage (ICH) is a highly serious event in patients with haemophilia (PWH) which leads to disability and in some cases to death. ICH occurs among all ages but is particularly frequent in newborns. Aim: The primary aim was to assess the incidence and mortality due to ICH in an Italian population of PWH. Secondary aims were to evaluate the risk factors for ICH, the role of prophylaxis, and the clinical management of patients presenting ICH. Methods: A retrospective-prospective registry was established in the network of the Italian Association of Haemophilia Centers to collect all ICHs in PWH from 2009 to 2019 reporting clinical features, treatments, and outcomes. Results: Forty-six ICHs were collected from 13 Centers. The ICHs occurred in 15 children (10 < 2 years), and in 31 adults, 45.2% of them with mild hemophilia. Overall, 60.9% patients had severe haemophilia (15/15 children). Overall ICH incidence (×1000 person/year) was 0.360 (0.270–0.480 95% CI), higher in children <2 years, 1.995 (1.110–3.442 95% CI). Only 7/46 patients, all with severe haemophilia, had received a prophylactic regimen before the ICH, none with mild. Inhibitors were present in 10.9% of patients. In adult PWHs 17/31 suffered from hypertension; 85.7% of the mild subjects and 29.4% of the moderate/severe ones (p < 0.05). ICH was spontaneous in the 69.6% with lower rate in children (46.7%). Surgery was required in 21/46 patients for cerebral hematoma evacuation. Treatment with coagulation factor concentrates for at least three weeks was needed in 76.7% of cases. ICH was fatal in 30.4% of the cases. Of the survivors, 50.0% became permanently disabled. Only one-third of adult patients received long term prophylaxis after the acute treatment. Conclusion: The results from our Registry confirm the still high incidence of ICH in infants <2 years and in adults, particularly in mild PWHs presenting hypertension and its unfavorable outcomes. The majority of PWHs were treated on-demand before ICH occurred, suggesting the important role of prophylaxis in preventing such life-threatening bleeding. Full article

(This article belongs to the Special Issue Haemophilia: Current Treatment and Challenges)

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10 pages, 366 KiB

Open AccessArticle

Current Choices and Management of Treatment in Persons with Severe Hemophilia A without Inhibitors: A Mini-Delphi Consensus

by Antonio Coppola, Massimo Franchini, Giovanni Pappagallo, Alessandra Borchiellini, Raimondo De Cristofaro, Angelo Claudio Molinari, Rita Carlotta Santoro, Cristina Santoro and Annarita Tagliaferri

J. Clin. Med. 2022, 11(3), 801; https://doi.org/10.3390/jcm11030801 - 2 Feb 2022

Cited by 5 | Viewed by 3244

Abstract

Background. Regular treatment to prevent bleeding and consequent joint deterioration (prophylaxis) is the standard of care for persons with severe hemophilia A, traditionally based on intravenous infusions of the deficient clotting FVIII concentrates (CFCs). In recent years, extended half-life (EHL) CFCs and the non-replacement agent emicizumab, subcutaneously administered, have reduced the treatment burden. Methods. To compare and integrate the opinions on the different therapies available, eight hemophilia specialists were involved in drafting items of interest and relative statements through the Estimate-Talk-Estimate (ETE) method (“mini-Delphi”), in this way reaching consensus. Results. Eighteen items were identified, then harmonized to 10, and a statement was generated for each. These statements highlight the importance of personalized prophylaxis regimens. CFCs, particularly EHL products, seem more suitable for this, despite the challenging intravenous (i.v.) administration. Limited real-world experience, particularly in some clinical settings, and the lack of evidence on long-term safety and efficacy of non-replacement agents, require careful individual risk/benefit assessment and multidisciplinary data collection. Conclusions. The increased treatment options extend the opportunities of personalized prophylaxis, the mainstay of modern management of hemophilia. Close, long-term clinical and laboratory follow-up of patients using newer therapeutic approaches by specialized hemophilia treatment centers is needed. Full article

(This article belongs to the Special Issue Haemophilia: Current Treatment and Challenges)

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13 pages, 1058 KiB

Open AccessArticle

Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study

by Gili Kenet, Yeu-Chin Chen, Gillian Lowe, Charles Percy, Huyen Tran, Annette von Drygalski, Marc Trossaërt, Mark Reding, Johannes Oldenburg, Maria Eva Mingot-Castellano, Young-Shil Park, Flora Peyvandi, Margareth C. Ozelo, Johnny Mahlangu, Jennifer Quinn, Mei Huang, Divya B. Reddy and Benjamin Kim

J. Clin. Med. 2021, 10(24), 5959; https://doi.org/10.3390/jcm10245959 - 18 Dec 2021

Cited by 14 | Viewed by 5432

Abstract

Regular prophylaxis with exogenous factor VIII (FVIII) is recommended for individuals with severe haemophilia A (HA), but standardised data are scarce. Here, we report real-world data from a global cohort. Participants were men ≥18 years old with severe HA (FVIII ≤ 1 IU/dL) receiving regular prophylaxis with FVIII. Participants provided 6 months of retrospective data and were prospectively followed for up to 12 months. Annualised bleeding rate (ABR) and FVIII utilisation and infusion rates were calculated. Differences between geographic regions were explored. Of 294 enrolled participants, 225 (76.5%) completed ≥6 months of prospective follow-up. Pre-baseline and on-study, the median (range) ABR values for treated bleeds were 2.00 (0–86.0) and 1.85 (0–37.8), respectively; the median (range) annualised FVIII utilisation rates were 3629.0 (1008.5–13541.7) and 3708.0 (1311.0–14633.4) IU/kg/year, respectively; and the median (range) annualised FVIII infusion rates were 120.0 (52.0–364.0) and 122.4 (38.0–363.8) infusions/year, respectively. The median (range) Haemo-QoL-A Total Score was 76.3 (9.4–100.0) (n = 289), ranging from 85.1 in Australia to 67.7 in South America. Physical Functioning was the most impacted Haemo-QoL-A domain in 4/6 geographic regions. Despite differences among sites, participants reported bleeding requiring treatment and impaired physical functioning. These real-world data illustrate shortcomings associated with FVIII prophylaxis for this global cohort of individuals with severe HA. Full article

(This article belongs to the Special Issue Haemophilia: Current Treatment and Challenges)

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10 pages, 541 KiB

Open AccessArticle

One Session Effects of Knee Motion Visualization Using Immersive Virtual Reality in Patients with Hemophilic Arthropathy

by Roberto Ucero-Lozano, Raúl Pérez-Llanes, José Antonio López-Pina and Rubén Cuesta-Barriuso

J. Clin. Med. 2021, 10(20), 4725; https://doi.org/10.3390/jcm10204725 - 14 Oct 2021

Cited by 3 | Viewed by 1620

Abstract

(1) Background: Hemophilic knee arthropathy is characterized by a loss of muscle mass and decreased strength of the quadriceps muscle. The visualization of movement aims to favor the recruitment of the motor system in the same premotor and parietal areas, as would happen with the active execution of the observed action. The aim was to evaluate changes in quadriceps activation in patients with hemophilic knee arthropathy following immersive VR visualization of knee extension movements. (2) Methods: We recruited 13 patients with severe hemophilia A and knee arthropathy. Patients underwent a 15 min session of immersive VR visualization of knee extension movements. The quadriceps muscle activation was evaluated by surface electromyography. (3) Results: After the intervention, there were no changes in the muscle activation of vastus medialis, vastus lateralis, or rectus femoris muscles. There was a large effect size of changes in rectus femoris muscle activation. Age and knee joint damage did not correlate with changes in quadriceps activation. Dominance, inhibitor development, and type of treatment were not related with post-intervention muscle activation. (4) Conclusions: A session of immersive VR visualization of knee extension movement does not modify quadriceps muscle activation. A specific protocol for patients with hemophilic knee arthropathy may be effective in improving the activation of the rectus femoris muscle. Full article

(This article belongs to the Special Issue Haemophilia: Current Treatment and Challenges)

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9 pages, 1877 KiB

Open AccessFeature PaperArticle

Real-World Data on Bleeding Patterns of Hemophilia A Patients Treated with Emicizumab

by Sarina Levy-Mendelovich, Tami Brutman-Barazani, Ivan Budnik, Einat Avishai, Assaf A. Barg, Tamara Levy, Mudi Misgav, Tami Livnat and Gili Kenet

J. Clin. Med. 2021, 10(19), 4303; https://doi.org/10.3390/jcm10194303 - 22 Sep 2021

Cited by 21 | Viewed by 5045

Abstract

Emicizumab (Hemlibra™) is approved for prophylaxis of hemophilia A (HA) patients. The HAVEN studies addressed bleeding reduction in emicizumab-treated patients, but real-world data on bleeding patterns during emicizumab therapy are lacking. We aimed to compare the occurrence of breakthrough bleeding at different time points, starting from emicizumab initiation. This longitudinal prospective observational cohort study included HA patients (n = 70, aged 1 month to 74.9 years) that completed at least 18 months of follow-up in our center. We analyzed the number of spontaneous and traumatic bleeds during selected time points of the study (“bleeding periods”). The percentage of traumatic and spontaneous bleeding episodes was not significantly different among “bleeding periods” (P = 0.053 and P = 0.092, respectively). Most trauma-related treated bleeds resulted from either hemarthrosis (53%) or head trauma (33%). Spontaneous bleeding episodes were mostly hemarthroses (80%). Potential associations of the patients’ age, annualized bleeding rate before emicizumab treatment, and the presence of inhibitors with spontaneous bleed occurrence were analyzed with binomial logistic regression. The odds of bleeding while on emicizumab increased by a factor of 1.029 (P = 0.034) for every one year of age. Conclusions: Our real-world data revealed that the risk of bleeding persists, especially in older patients, despite therapy with emicizumab. These data may help clinicians in counselling their patients and in planning their management. Full article

(This article belongs to the Special Issue Haemophilia: Current Treatment and Challenges)

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15 pages, 1265 KiB

Open AccessArticle

Safety, Fear and Neuromuscular Responses after a Resisted Knee Extension Performed to Failure in Patients with Severe Haemophilia

by Joaquín Calatayud, Jonathan Martín-Cuesta, Juan J. Carrasco, Sofía Pérez-Alenda, Carlos Cruz-Montecinos, Lars L. Andersen, Felipe Querol-Giner and José Casaña

J. Clin. Med. 2021, 10(12), 2587; https://doi.org/10.3390/jcm10122587 - 11 Jun 2021

Cited by 5 | Viewed by 2463

Abstract

Background: low–moderate intensity strength training to failure increases strength and muscle hypertrophy in healthy people. However, no study assessed the safety and neuromuscular response of training to failure in people with severe haemophilia (PWH). The purpose of the study was to analyse neuromuscular responses, fear of movement, and possible adverse effects in PWH, after knee extensions to failure. Methods: twelve severe PWH in prophylactic treatment performed knee extensions until failure at an intensity of five on the Borg CR10 scale. Normalised values of amplitude (nRMS) and neuromuscular fatigue were determined using surface electromyography for the rectus femoris, vastus medialis, and vastus lateralis. After the exercise, participants were asked about their perceived change in fear of movement, and to report any possible adverse effects. Results: Patients reported no adverse effects or increased fear. The nRMS was maximal for all the muscles before failure, the median frequency decreased, and wavelet index increased during the repetitions. The vastus lateralis demonstrated a higher maximum nRMS threshold and earlier fatigue, albeit with a lower and more progressive overall fatigue. Conclusions: severe PWH with adequate prophylactic treatment can perform knee extensions to task failure using a moderate intensity, without increasing fear of movement, or adverse effects. Full article

(This article belongs to the Special Issue Haemophilia: Current Treatment and Challenges)

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Review

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11 pages, 586 KiB

Open AccessReview

The Role of Physiotherapy in the New Treatment Landscape for Haemophilia

by Sébastien Lobet, Merel Timmer, Christoph Königs, David Stephensen, Paul McLaughlin, Gaetan Duport, Cédric Hermans and Maria Elisa Mancuso

J. Clin. Med. 2021, 10(13), 2822; https://doi.org/10.3390/jcm10132822 - 26 Jun 2021

Cited by 14 | Viewed by 5620

Abstract

The physiotherapist plays an essential role for people with haemophilia, an inherited bleeding disease responsible for musculoskeletal complications. Yet, with the advent of new and advanced therapies, the medical landscape is changing, and physiotherapy must adapt alongside. This paper considers whether there will still be a need for physiotherapy in the era of advanced therapies, and discusses ways in which services should evolve to complement emerging treatment paradigms for haemostasis in people with haemophilia. Ultimately, physiotherapy will remain an important element of care, even for people with little joint damage and low risks in the era of the new mild phenotype. However, competencies will need to evolve, and physiotherapists in both primary care and specialist treatment centres should work with haematology colleagues to develop more sensitive tools for detecting early joint changes. Physiotherapists will also play a crucial role in counselling and physically coaching, monitoring the musculoskeletal status of people with haemophilia who have transitioned to new treatments. Full article

(This article belongs to the Special Issue Haemophilia: Current Treatment and Challenges)

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