Publications by authors named "Victor Jiménez-Yuste"

115 Publications

Concomitant use of bypassing agents with emicizumab for people with haemophilia A and inhibitors undergoing surgery.

Haemophilia 2021 May 14. Epub 2021 May 14.

Department of Hematology, Oslo University Hospital, Oslo, Norway.

Introduction: Surgery in people with haemophilia and factor VIII inhibitors is typically managed with perioperative administration of haemostatic agents to prevent or control the occurrence of bleeding events. Practical experience of surgery in patients with inhibitors who are receiving treatment with emicizumab is growing; however, the novelty of the situation means that standardised guidelines are lacking with regard to the concomitant administration of haemostatic agents, including dose and laboratory monitoring.

Aim: To review approaches to haemostatic management during major and minor invasive procedures in patients with haemophilia A and inhibitors, and to provide recommendations for controlling bleeding events.

Methods: A search was conducted, limited to the past 4 years (January 2016-April 2020), pertaining to published evidence of surgery for patients receiving emicizumab. Publications identified from the search were manually reviewed to determine studies and case reports relevant for inclusion.

Results: Identified literature and practical experience of the authors were used to build a consensus of practical recommendations for the concomitant administration of haemostatic agents during the perioperative period for elective surgery in patients with inhibitors who are receiving emicizumab.

Conclusions: The current evidence base indicates that surgery can be successfully performed in patients with inhibitors who are receiving emicizumab and that bypassing agents can be used concomitantly. Data from prospective studies are required to further support recommendations for haemostatic management of surgery in patients receiving emicizumab.
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http://dx.doi.org/10.1111/hae.14322DOI Listing
May 2021

The Importance of Platelet Glycoside Residues in the Haemostasis of Patients with Immune Thrombocytopaenia.

J Clin Med 2021 Apr 13;10(8). Epub 2021 Apr 13.

Hematology Unit, La Paz University Hospital-IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain.

Loss of sialic acid from the carbohydrate side chains of platelet glycoproteins can affect platelet clearance, a proposed mechanism involved in the etiopathogenesis of immune thrombocytopaenia (ITP). We aimed to assess whether changes in platelet glycosylation in patients with ITP affected platelet counts, function, and apoptosis. This observational, prospective, and transversal study included 82 patients with chronic primary ITP and 115 healthy controls. We measured platelet activation markers and assayed platelet glycosylation and caspase activity, analysing samples using flow cytometry. Platelets from patients with ITP with a platelet count <30 × 10/µL presented less sialic acid. Levels of α1,6-fucose (a glycan residue that can directly regulate antibody-dependent cellular cytotoxicity) and α-mannose (which can be recognised by mannose-binding-lectin and activate the complement pathway) were increased in the platelets from these patients. Platelet surface exposure of other glycoside residues due to sialic acid loss inversely correlated with platelet count and the ability to be activated. Moreover, loss of sialic acid induced the ingestion of platelets by human hepatome HepG2 cells. Changes in glycoside composition of glycoproteins on the platelets' surface impaired their functional capacity and increased their apoptosis. These changes in platelet glycoside residues appeared to be related to ITP severity.
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http://dx.doi.org/10.3390/jcm10081661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069668PMC
April 2021

Applying World Health Organization 2020 guidelines on physical activity and sedentary behavior to people with hemophilia.

Expert Rev Hematol 2021 May 10:1-8. Epub 2021 May 10.

Department of Hematology, La Paz University Hospital, Madrid, Spain.

: The new World Health Organization (WHO) guidelines on physical activity incorporate new concepts, such as sedentary behavior, recommendations for specific age groups and for people living with chronic conditions and disability. This could be extrapolated for the first time to people with hemophilia (PWH) within the framework in which these recommendations are applicable. The benefits of physical activity for PWH include physical, psychological and social benefits.: This is a narrative review of the literature. We searched the MEDLINE and the Cochrane Library for WHO guidelines and articles related to physical activity in PWH. For all population groups, the benefits of performing exercise outweigh the possible harms. In PWH, there is a perceived increased risk of bleeding associated with physical activity. However, research suggests that this risk is associated with trauma during activity rather than intensity of physical activity, which offers the most health benefits.: Given the hematological, physical and functional conditions of PWH are highly variable, individualized counseling is needed based on age, therapeutic strategy, degree of arthropathy and level of disability. In this article, we analyze the applicability of the WHO recommendations to PWH, which is important to further promote healthy lifestyle motivation.
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http://dx.doi.org/10.1080/17474086.2021.1924054DOI Listing
May 2021

Impact of COVID-19 Pandemic on Patients with Immune Thrombocytopaenia.

Medicina (Kaunas) 2021 Mar 1;57(3). Epub 2021 Mar 1.

Hematology Unit, La Paz University Hospital-IdiPAZ, Paseo de la Castellana 261, Hospital Universitario La Paz, 28046 Madrid, Spain.

: The aim of this study was to determine the impact of the COVID-19 pandemic on the lives of patients with immune thrombocytopaenia (ITP) treated at our hospital. : The study was conducted in the Community of Madrid, which has the highest number of COVID-19 cases in Spain. We included 143 adult patients with ITP (130 with chronic ITP, 8 with persistent ITP, and 5 with newly diagnosed ITP). We conducted a telephone survey to collect the data and created a registry. : Overall, 24 patients presented symptoms suggestive of COVID-19, which was confirmed by RT-PCR in 8 cases. The cumulative incidence of confirmed SARS-CoV-2 infection was higher in the patients with ITP than in the Madrid population. There were no differences in the disease incidence or clinical course of infection in the patients treated with immunosuppressants. Almost all of the patients reported adherence to the prescribed treatment, although 49.2% of the hospital visits were either cancelled or postponed, 17.2% because of the patients' fear of coming to the centre. Nearly half of the cohort was considered vulnerable, and 17% had been granted a dependency or disability benefit. : COVID-19 had a major impact on the psychosocial, occupational, and quality of care of patients with ITP.
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http://dx.doi.org/10.3390/medicina57030219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002062PMC
March 2021

Selective T-cell depletion targeting CD45RA as a novel approach for HLA-mismatched hematopoietic stem cell transplantation in pediatric nonmalignant hematological diseases.

Int J Hematol 2021 Mar 27. Epub 2021 Mar 27.

Pediatric Onco-Hematology Department, La Paz University Hospital, Madrid, Spain.

Severe aplastic anemia and congenital amegakaryocytic thrombocytopenia are rare bone marrow failure syndromes. Treatment for aplastic anemia consists of hematopoietic stem cell transplantation (HSCT) from a matched sibling donor or immunosuppressant drugs if there is no donor available. Congenital amegakaryocytic thrombocytopenia is a rare autosomal recessive disease that causes bone marrow failure and has limited treatment options, except for transfusion support and HSCT. In the absence of a suitable matched sibling donor, matched-unrelated, haploidentical, or mismatched donors may be considered. A 2-step partial T-cell-depletion strategy can remove CD45RA+ naïve T cells responsible for graft-versus-host disease (GvHD) while preserving memory T cells. Five patients underwent transplantation using this strategy with rapid neutrophil and platelet recovery. Acute and chronic GvHD ≥ grade 2 appeared in two and one patient, respectively. No severe infections were observed before day + 100. A high (60%) incidence of transplant-associated microangiopathy was observed. Three patients (60%) remain alive, with a median follow-up of 881 (range 323-1248) days. CD45RA-depleted HSCT is a novel approach for patients lacking a suitable matched donor; however, further improvements are needed.
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http://dx.doi.org/10.1007/s12185-021-03138-2DOI Listing
March 2021

Practical considerations for nonfactor-replacement therapies in the treatment of haemophilia with inhibitors.

Haemophilia 2021 Mar 20. Epub 2021 Mar 20.

Unit for Haemostasis, Thrombosis and Benign Diseases of Haematopoietic System, Division of Haematology, Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia.

New therapeutic agents for haemophilia with inhibitors that are in development or already licensed are expected to provide transformative treatment options. Many of these new therapies are not based on simply replacing the missing factor; new strategies include bispecific antibody technology that mimics factor VIII coagulation function (emicizumab), and inhibition of anticoagulant proteins such as tissue factor pathway inhibitor (eg PF-06741086) and antithrombin (eg fitusiran). These agents are administered subcutaneously and should significantly reduce treatment burden and increase the ability to deliver prophylaxis for patients. Limited real-world data and validated practical guidance on these recently licensed/upcoming treatments resulted in the authors convening to discuss recommendations on their use. Emicizumab is currently the only licenced nonfactor therapy; thus, our recommendations focus on this product. Target candidates for emicizumab prophylaxis are difficult-to-treat patients with haemophilia A and inhibitors and/or venous access issues, frequent bleeds and target joints. In case of breakthrough bleeding while receiving emicizumab, patients still require treatment with bypassing agents; the adjunct treatment of choice is recombinant activated factor VII. This treatment is also recommended to prevent bleeds in patients with inhibitors undergoing surgery. Our recommendations on suitable laboratory assays and monitoring new products, as well as the benefit of patient-reported outcomes (such as pain and physical activity levels), are included. We also briefly discuss future treatment options for patients with haemophilia B and inhibitors. Although these nonfactor treatments offer great promise, further data and real-world evidence are needed.
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http://dx.doi.org/10.1111/hae.14167DOI Listing
March 2021

The role of early natural killer cell adoptive infusion before engraftment in protecting against human herpesvirus-6B encephalitis after naïve T-cell-depleted allogeneic stem cell transplantation.

Transfusion 2021 May 13;61(5):1505-1517. Epub 2021 Mar 13.

Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain.

Background: Naïve T-cell-depleted grafts have been employed as an ex vivo T-cell depletion (TCD) platform to prevent graft-versus-host disease (GvHD) and improve immune reconstitution by providing rapid donor memory T-cell reconstitution after allogenic hematopoietic stem cell transplantation (allo-HSCT). CD45RA memory T cells confer protection against viruses such as cytomegalovirus, Epstein-Barr virus, and adenovirus; however, reports have shown an unexpectedly high incidence of human herpesvirus (HHV)-6B encephalitis among pediatric allo-HSCT patients.

Methods: We report the first 18 consecutive allo-HSCT, 16 haplo-HSCT, and two human leukocyte antigen-matched related donors implanted with naïve TCD grafts. All donors were administered three cell products: first, a CD34 stem cell product; second, a CD45RA TCD graft, followed by an adoptive natural killer (NK) cell infusion within 10 days after HSCT. The study's primary endpoint was the incidence of HHV-6B encephalitis.

Results: Engraftment was achieved in 94.5% of cases; 2-year overall survival, event-free survival, and GvHD/relapse-free survival were 87.2% (95% CI 78.6-95.8), 67.3% (95% CI 53.1-81.5), and 64% (95% CI 50.5-78.1), respectively. HHV-6B reactivation occurred in 7 of the haplo-HSCT patients, six of who received a cell infusion with an NK/CD4 ratio <2. None of the patients developed encephalitis.

Conclusions: In this clinical study, we show that early adoptive NK cell infusion after a 45RA TCD allo-HSCT graft is safe and can prevent HHV-6B encephalitis. We recommend infusing adoptive NK cells after allo-HSCT using CD45RA TCD grafts.
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http://dx.doi.org/10.1111/trf.16354DOI Listing
May 2021

Ultrasound evaluation of joint damage and disease activity in adult patients with severe haemophilia A using the HEAD-US system.

Haemophilia 2021 Feb 23. Epub 2021 Feb 23.

Medical Affairs, Pfizer SLU, Madrid, Spain.

Introduction: The Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) system and scoring scale has proven to be an accurate and time-efficient imaging method for identifying joint damage in patients with haemophilia.

Aim: Observational, multicentre, cross-sectional study conducted in 8 centres in Spain that assessed the joint status of adult patients with severe haemophilia A (SHA) using HEAD-US.

Methods: Joint status of the elbow, knee and ankle was evaluated in adults with SHA receiving on-demand (OD) treatment, or primary (PP), secondary (SP), tertiary (TP) or intermittent (IP) prophylaxis.

Results: Of the 95 patients enrolled, 87 received prophylaxis (6.3% PP, 38.9% SP, 43.2% TP and 3.2% IP). Mean age was 35.2 years, and 59% of patients had not undergone image testing in the last year. The HEAD-US score was 0 in all joints in 6.3% of patients. The ankle was the most affected joint, regardless of treatment regimen. Patients receiving OD treatment, TP or IP had the overall worst scores, mainly in the ankles and elbows; a similar but milder profile was observed in patients on SP; and patients on PP had the best score in all joints.

Conclusion: Joint function may be effectively preserved in patients with SHA on PP, but OD treatment or later initiation of prophylaxis does not seem to prevent progression of arthropathy. Disease worsening was observed in patients OD, TP or IP, most often affecting ankles and elbows. Closer ultrasound imaging monitoring may improve management of these patients.
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http://dx.doi.org/10.1111/hae.14280DOI Listing
February 2021

Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study.

Thromb Haemost 2021 Feb 13. Epub 2021 Feb 13.

Octapharma AG, Lachen, Switzerland.

Introduction:  FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line.

Methods:  The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL (≥0.6 to <5 low-titre, ≥5 high titre).

Results:  A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa. mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null mutations developed inhibitors.

Conclusion:  In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null mutations.
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http://dx.doi.org/10.1055/s-0040-1722623DOI Listing
February 2021

Health-related quality of life and health status in adolescent and adult people with haemophilia A without factor VIII inhibitors-A non-interventional study.

Haemophilia 2021 Feb 12. Epub 2021 Feb 12.

Department of Medical Psychology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

Introduction: Real-world data on health-related outcomes in persons with haemophilia A (PwHA) can provide useful information for improving patient care. The global, non-interventional study (NIS; NCT02476942) prospectively collected high-quality data in PwHA, including those without factor VIII (FVIII) inhibitors treated according to local routine clinical practice.

Aim: To report health-related quality of life (HRQoL) and health status of adult/adolescent PwHA without FVIII inhibitors.

Methods: Participants were PwHA without FVIII inhibitors age ≥12 years; they remained on existing episodic treatment or prophylaxis. HRQoL was assessed by Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) or Haemophilia-Specific Quality of Life Assessment for Children and Adolescents Short Form (Haemo-QoL-SF II). Health status was assessed through EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score and visual analogue scale (EQ-VAS).

Results: Ninety-four participants enrolled; median age was 34.0 years (range 12-76). Forty-five received episodic treatment and 49 received prophylaxis for a median time of 27.7 weeks and 30.4 weeks, respectively. Mean (standard deviation) baseline Haem-A-QoL total scores were 40.1 (17.0) for the episodic group and 26.6 (14.6) for the prophylaxis group, indicating impairments in HRQoL, which remained consistent over time. Mean EQ-5D-5L IUS scores were similar between treatment regimens (0.8 episodic; 0.9 prophylaxis) and consistent over time. The mean EQ-VAS scores were similar between treatment regimens, and lower on days when bleeding occurred (79.0 vs 85.0 for episodic treatment; 77.0 vs 82.0 for prophylaxis, respectively).

Conclusions: Adult and adolescent PwHA without FVIII inhibitors had HRQoL impairments regardless of whether they were treated with episodic or prophylactic standard care with FVIII.
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http://dx.doi.org/10.1111/hae.14270DOI Listing
February 2021

Principles of care for acquired hemophilia.

Eur J Haematol 2021 Jun 18;106(6):762-773. Epub 2021 Mar 18.

University Hospital Centre Zagreb, School of Medicine, University of Osijek and Medical School University of Zagreb, Croatia.

Objective: To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management.

Method: These principles were developed by the Zürich Haemophilia Forum, an expert panel of European hemophilia specialists comprising physicians and nursing and laboratory specialists.

Results: The 10 proposed principles for AHA care are as follows: (a) Improving initial diagnosis of AHA; (b) Differential diagnosis of AHA: laboratory assessment of patients with unusual bleeding; (c) Effective communication between laboratories, physicians, and specialists; (d) Improving clinical care: networking between healthcare professionals in the treating hospital and specialist hemophilia centers; (e) Comprehensive assessment of bleeding; (f) Appropriate use of bypassing agents; (g) Long-term follow-up and monitoring for efficacy and safety of immunosuppressive treatment; (h) Inpatient/outpatient settings; (i) Access to innovative and disruptive treatments; (j) Promotion of international collaborative research.

Conclusion: The proposed principles for holistic AHA care aim to ensure swift diagnosis and optimal patient management. Key to achieving this goal is training for healthcare personnel in non-specialist hospitals and collaboration between different specialists. We hope these principles will increase awareness of AHA in the wider medical community and catalyze efforts toward improving its practical, multidisciplinary management.
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http://dx.doi.org/10.1111/ejh.13592DOI Listing
June 2021

Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies.

Blood 2021 Apr;137(16):2231-2242

Department of Immunohaematology and.

Prophylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.
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http://dx.doi.org/10.1182/blood.2020009217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065240PMC
April 2021

Key questions in the new hemophilia era: update on concomitant use of FVIII and emicizumab in hemophilia A patients with inhibitors.

Expert Rev Hematol 2021 Feb 27;14(2):143-148. Epub 2021 Jan 27.

Haematology Department, Hospital Universitario La Paz, Autónoma University, Madrid, Spain.

: Immune tolerance induction (ITI) is the primary therapeutic strategy and only proven method to eradicate inhibitors to coagulation factor VIII (FVIII) in hemophilia A. Emicizumab, a humanized bispecific monoclonal antibody that mimics the function of activated FVIII, has expanded options to treat hemophilia A. The availability of emicizumab necessitates a revisit of recommendations for managing patients with inhibitors.: Current evidence is reviewed about the concomitant use of emicizumab and FVIII concentrates during and after ITI. Areas where data are lacking are highlighted and ongoing studies designed to address these issues are described.: Inhibitor eradication remains a desirable goal. All patients with inhibitors should be offered at least one attempt at ITI. Emicizumab monotherapy is an option for inhibitor patients who are not candidates for ITI. Evidence is emerging about the use of emicizumab during ITI to prevent bleeds. Studies are currently addressing the safety, efficacy, and feasibility of concomitant emicizumab and FVIII in ITI. As evidence regarding the risk of inhibitor recurrence and need for continued FVIII to maintain immune tolerance post-ITI is limited, the role of emicizumab alone or in combination with FVIII after ITI is the subject of an upcoming study.
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http://dx.doi.org/10.1080/17474086.2021.1875817DOI Listing
February 2021

Procoagulant State of Sleep Apnea Depends on Systemic Inflammation and Endothelial Damage.

Arch Bronconeumol 2020 Dec 24. Epub 2020 Dec 24.

Hematology Unit, Hospital Universitario La Paz-IdiPAZ, Paseo de la Castellana 261, Madrid 28046, Spain. Electronic address:

Introduction: Growing evidence shows a hypercoagulable state in obstructive sleep apnea (OSA) that could be a risk factor for thromboembolic disease.

Objectives: We aimed to elucidate mechanisms involved in the procoagulant profile observed in patients with OSA and to investigate the potential utility of global tests in its characterization.

Methods: Thirty-eight patients with severe OSA without previous history of thrombosis and nineteen healthy age- and sex-matched controls were included. Kinetic of clot formation was determined using rotational thromboelastometry. Haemostatic capacity of plasma and microparticles was determined by Calibrated Automated Thrombinography. Platelet surface receptors, activation markers and formation of platelet/leukocytes aggregates were analyzed by flow cytometry.

Results: Thromboelastometry showed a procoagulant state in patients with OSA that did not seem to be related to a basal activation of platelets but by the increased existence of platelet/leukocyte aggregates. Patients with OSA presented many signs of endothelial damage such as increased plasma levels of E-selectin and cfDNA and enhanced thrombin generation due to the presence of microparticles rich in tissue-factor, which is related to OSA severity.

Conclusions: OSA induces an enhancement in the dynamics of clot formation which appears to be caused by at least two pathological mechanisms. First, a greater formation of platelet-leukocyte aggregates; secondly, endothelial damage which provokes a greater procoagulant potential due to the increase in tissue factor-rich microparticles. Moreover, this study has identified thromboelastometry and thrombin generation assay as useful tools to evaluate the prothrombotic state in these patients.
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http://dx.doi.org/10.1016/j.arbres.2020.11.017DOI Listing
December 2020

Beneficial Effect of Systemic Allogeneic Adipose Derived Mesenchymal Cells on the Clinical, Inflammatory and Immunologic Status of a Patient With Recessive Dystrophic Epidermolysis Bullosa: A Case Report.

Front Med (Lausanne) 2020 26;7:576558. Epub 2020 Nov 26.

Department of Bioengineering, Carlos III University (UC3M), Madrid, Spain.

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable inherited mucocutaneous fragility disorder characterized by recurrent blisters, erosions, and wounds. Continuous blistering triggers overlapping cycles of never-ending healing and scarring commonly evolving to chronic systemic inflammation and fibrosis. The systemic treatment with allogeneic mesenchymal cells (MSC) from bone marrow has previously shown benefits in RDEB. MSC from adipose tissue (ADMSC) are easier to isolate. This is the first report on the use of systemic allogeneic ADMSC, correlating the clinical, inflammatory, and immunologic outcomes in RDEB indicating long-lasting benefits. We present the case of an RDEB patient harboring heterozygous biallelic gene mutations and with a diminished expression of C7. The patient presented with long-lasting refractory and painful oral ulcers distressing her quality of life. Histamine receptor antagonists, opioid analgesics, proton-pump inhibitors, and low-dose tricyclic antidepressants barely improved gastric symptoms, pain, and pruritus. Concomitantly, allogeneic ADMSC were provided as three separate intravenous injections of 10 cells/kg every 21 days. ADMSC treatment was well-tolerated. Improvements in wound healing, itch, pain and quality of life were observed, maximally at 6-9 months post-treatment, with the relief of symptoms still noticeable for up to 2 years. Remarkably, significant modifications in PBL participating in both the innate and adaptive responses, alongside regulation of levels of profibrotic factors, MCP-1/CCL2 and TGF-β, correlated with the health improvement. This treatment might represent an alternative for non-responding patients to conventional management. It seems critical to elucidate the paracrine modulation of the immune system by MSC for their rational use in regenerative/immunoregulatory therapies.
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http://dx.doi.org/10.3389/fmed.2020.576558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726418PMC
November 2020

Paradoxical effect of SARS-CoV-2 infection in patients with immune thrombocytopenia.

Br J Haematol 2021 03 10;192(6):973-977. Epub 2020 Sep 10.

Unit of Thrombosis and Hemostasis, Hematology Department, La Paz University Hospital - IdiPAZ, Madrid, Spain.

Thrombocytopenia has been identified as a common complication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the general population. In an attempt to determine the impact of coronavirus disease 2019 (COVID-19) in patients with immune thrombocytopenia (ITP), a retrospective single-centre study was performed. Thrombocytosis was observed in patients with chronic ITP after SARS-CoV-2 infection, frequently needing treatment adjustment or even discontinuation of therapy. Relapses and newly diagnosed cases showed a fast response after initial treatment compared to ITP. Reduced immune activity due to lymphopenia during COVID-19 could explain this paradoxical effect, although further studies are needed.
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http://dx.doi.org/10.1111/bjh.17077DOI Listing
March 2021

Challenges and key lessons from the design and implementation of an international haemophilia registry supported by a pharmaceutical company.

Haemophilia 2020 Nov 23;26(6):966-974. Epub 2020 Oct 23.

Georgetown University Medical Center, Washington, DC, USA.

Introduction: Real-world data are lacking regarding the relationship between prospectively collected patient-reported outcomes (PROs), clinical outcomes and treatment in people with haemophilia (PWH). The Expanding Communications on Hemophilia A Outcomes (ECHO) registry was designed to address this data gap, but a range of difficulties led to early study closure.

Aim: To describe the challenges faced and lessons learned from implementing a multinational haemophilia registry.

Methods: The Expanding Communications on Hemophilia A Outcomes was planned as a five-year observational cohort study to collect data from 2000 patients in nine countries. Based on direct observations, feedback from patients enrolled in ECHO, challenges of the study design and input from study-sponsor representatives, the ECHO Steering Committee systematically identified the challenges faced and developed recommendations for overcoming or avoiding them in future studies.

Results: The study closed after two years because few countries were activated and patient recruitment was low. This was related to multiple challenges including delayed implementation, stringent pharmacovigilance requirements, objections of investigators and patients to the burden of multiple PROs, data collection issues, lack of resources at study sites, little engagement of patients and competing clinical trials, which further limited recruitment. At study closure, 269 patients had been enrolled in four of nine participating countries.

Conclusions: Researchers planning studies similar to ECHO may want to consider the barriers identified in this global registry of PWH and suggestions to mitigate these limitations, such as greater patient involvement in design and analysis, clearer assessment and understanding of local infrastructure and potential changes to the administration of the study.
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http://dx.doi.org/10.1111/hae.14144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894355PMC
November 2020

Quality of electronic treatment records and adherence to prophylaxis in haemophilia and von Willebrand disease: Systematic assessments from an electronic diary.

Haemophilia 2020 Nov 21;26(6):999-1008. Epub 2020 Oct 21.

Bonn University, Bonn, Germany.

Introduction: Haemoassist 2 is an electronic system designed for people with bleeding disorders and their physicians to record prophylactic infusions and treatment of bleeds. It aims to improve adherence by permitting reminders and accuracy of documentation by facilitating real-time reporting.

Aim: To assess documentation quality and adherence to prophylactic regimens in patients with haemophilia A, haemophilia B or von Willebrand disease who are using Haemoassist 2.

Methods: Ten centres enrolled consecutive patients, who had been using Haemoassist 2 for ≥ 3 months (Cohort 1, 'quality of documentation'). Of these, patients who had a specified prophylactic regimen in Haemoassist 2 for ≥ 3 months were eligible for inclusion in Cohort 2 ('adherence to prophylaxis').

Results: Cohort 1 comprised 796 patients (71% with severe haemophilia A; median 20.5 months of Haemoassist 2 use). The most common method of documentation for patients was using the mobile app; the median time between infusion and documentation was 4 hours using the app, compared with 85 hours using a web portal on a stationery device. The median total annualised number of infusions was consistent in the first and last 3 months of documentation (128; IQR: 70-184 and 120; IQR 64-176, respectively). Cohort 2 comprised 202 patients (79% severe haemophilia A; median of 13 months on prophylactic regimen in Haemoassist 2). The rate of adherence to prophylaxis was 83%; median deviation between planned and actual infusion time was ± 2 hours.

Conclusion: Haemoassist 2 was used consistently over prolonged periods of time and allowed for precise analysis of adherence to prophylaxis.
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http://dx.doi.org/10.1111/hae.14178DOI Listing
November 2020

Insights into the Procoagulant Profile of Patients with Systemic Lupus Erythematosus without Antiphospholipid Antibodies.

J Clin Med 2020 Oct 14;9(10). Epub 2020 Oct 14.

Hematology Unit, University Hospital La Paz-Idipaz, Paseo de la Castellana 231, 28046 Madrid, Spain.

We aimed to identify the key players in the prothrombotic profile of patients with systemic lupus erythematosus (SLE) not mediated by antiphospholipid antibodies, as well as the potential utility of global coagulation tests to characterize hemostasis in these patients. Patients with SLE without antiphospholipid antibodies and without signs of thrombosis were included. The kinetics of clot formation were determined by ROTEM. Platelet activation markers were determined by flow cytometry. Thrombin generation associated with Neutrophil Extracellular Traps (NETs) and microparticles (MPs) was measured by calibrated automated thrombogram (CAT). The plasma levels of PAI-1 were also determined. ROTEM showed a procoagulant profile in SLE patients. SLE patients had activated platelets and more leukocyte/platelet aggregates at basal conditions. The plasma PAI-1 and platelet aggregates correlated with several ROTEM parameters. The thrombin generation associated withthe tissue factor (TF) content of MPs and with NETs was increased. Our results suggest the utility of global tests for studying hemostasis in SLE patients because they detect their procoagulant profile, despite having had neither antiphospholipid antibodies nor any previous thrombotic event. A global appraisal of hemostasis should, if possible, be incorporated into clinical practice to detect the risk of a thrombotic event in patients with SLE and to consequently act to prevent its occurrence.
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http://dx.doi.org/10.3390/jcm9103297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602183PMC
October 2020

Impact of hematologic malignancy and type of cancer therapy on COVID-19 severity and mortality: lessons from a large population-based registry study.

J Hematol Oncol 2020 10 8;13(1):133. Epub 2020 Oct 8.

Hematology Department, University Hospital Fundación Jiménez Díaz, Madrid, Spain.

Background: Patients with cancer have been shown to have a higher risk of clinical severity and mortality compared to non-cancer patients with COVID-19. Patients with hematologic malignancies typically are known to have higher levels of immunosuppression and may develop more severe respiratory viral infections than patients with solid tumors. Data on COVID-19 in patients with hematologic malignancies are limited. Here we characterize disease severity and mortality and evaluate potential prognostic factors for mortality.

Methods: In this population-based registry study, we collected de-identified data on clinical characteristics, treatment and outcomes in adult patients with hematologic malignancies and confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection within the Madrid region of Spain. Our case series included all patients admitted to 22 regional health service hospitals and 5 private healthcare centers between February 28 and May 25, 2020. The primary study outcome was all-cause mortality. We assessed the association between mortality and potential prognostic factors using Cox regression analyses adjusted for age, sex, comorbidities, hematologic malignancy and recent active cancer therapy.

Results: Of 833 patients reported, 697 were included in the analyses. Median age was 72 years (IQR 60-79), 413 (60%) patients were male and 479 (69%) and 218 (31%) had lymphoid and myeloid malignancies, respectively. Clinical severity of COVID-19 was severe/critical in 429 (62%) patients. At data cutoff, 230 (33%) patients had died. Age ≥ 60 years (hazard ratios 3.17-10.1 vs < 50 years), > 2 comorbidities (1.41 vs ≤ 2), acute myeloid leukemia (2.22 vs non-Hodgkin lymphoma) and active antineoplastic treatment with monoclonal antibodies (2·02) were associated with increased mortality; conventional chemotherapy showed borderline significance (1.50 vs no active therapy). Conversely, Ph-negative myeloproliferative neoplasms (0.33) and active treatment with hypomethylating agents (0.47) were associated with lower mortality. Overall, 574 (82%) patients received antiviral therapy. Mortality with severe/critical COVID-19 was higher with no therapy vs any antiviral combination therapy (2.20).

Conclusions: In this series of patients with hematologic malignancies and COVID-19, mortality was associated with higher age, more comorbidities, type of hematological malignancy and type of antineoplastic therapy. Further studies and long-term follow-up are required to validate these criteria for risk stratification.
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http://dx.doi.org/10.1186/s13045-020-00970-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542567PMC
October 2020

What COVID-19 can mean for people with hemophilia beyond the infection risk.

Expert Rev Hematol 2020 10 17;13(10):1073-1079. Epub 2020 Sep 17.

Department of Hematology, La Paz University Hospital-IdiPaz , Madrid, Spain.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic represents an unprecedented global health crisis. To combat its effects, many governments have opted for strategies of social isolation that involve a radical change in people's behavior.

Areas Covered: For patients with hemophilia, the negative consequences of these measures can be greater, given they modify aspects of health care and lifestyles needed to counteract the adverse effects of hemophilia. The long-term consequences of the pandemic on patients with hemophilia are not well known. The aim of this special report is to show what COVID-19 could mean for this population, beyond the risk of infection.

Expert Opinion: Considerations of the clinical, care, therapeutic, physical, nutritional, mental health, pain, and disability aspects that might be affected are included. Strategies are also suggested to minimize the effects that these issues can have on patients' lives. Patients, health professionals, and society as a whole must work together to mitigate the effects of the pandemic on people with hemophilia.
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http://dx.doi.org/10.1080/17474086.2020.1818066DOI Listing
October 2020

HJHS 2.1 and HEAD-US assessment in the hemophilic joints: How do their findings compare?

Blood Coagul Fibrinolysis 2020 Sep;31(6):387-392

Department of Hematology, La Paz University Hospital-IdiPaz, Madrid, Spain.

: In hemophilic patients methods are needed to better diagnose joint damage early, so that treatments can be adjusted to slow the progression of hemophilic arthropathy. The aim of this study is to investigate the relationship between the Hemophilia Joint Health Score version 2.1 (HJHS 2.1) and hemophilia early arthropathy detection with ultrasound (HEAD-US) scales, as well as each of their individual items, to better understand the value each provides on the joint condition of patients with hemophilia. The study included data from patients with hemophilia older than 16 years of age, who attended a routine check-up. HJHS 2.1 and HEAD-US assessments were performed on the elbows, knees and ankles. We studied the correlations and agreements between the two scales and analyzed the relationship between the various items of the HJHS 2.1 (inflammation, duration, atrophy, crepitation, flexion deficit, extension deficit, pain, strength, gait) and HEAD-US (synovitis, cartilage and bone). The study included 203 joints from 66 patients with hemophilia (mean age, 34 years). We found a good correlation between the two scales (r = 0.717). However, HJHS 2.1 revealed only 54% of the cases with synovitis and 75% of the cases with osteochondral damage. HEAD-US detected several relevant physical and functional aspects in less than 53% of the cases. HJHS 2.1 and HEAD-US provide complementary data on joint disease in adults with hemophilia; both assessments should therefore, be made available. HEAD-US presented the added value of detecting early joint changes (synovitis and osteochondral damage), while HJHS 2.1 showed the added value of detecting relevant physical and functional changes.
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http://dx.doi.org/10.1097/MBC.0000000000000934DOI Listing
September 2020

Transfusion medicine during COVID-19 outbreak in the hotspot of Spain.

Transfusion 2020 11 28;60(11):2762-2764. Epub 2020 Sep 28.

Hematology Service, La Paz University Hospital-IdiPAZ, Autonomous University, Madrid, Spain.

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http://dx.doi.org/10.1111/trf.16038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461430PMC
November 2020

Outcomes in children with hemophilia A with inhibitors: Results from a noninterventional study.

Pediatr Blood Cancer 2020 10 9;67(10):e28474. Epub 2020 Aug 9.

Genentech, Inc., South San Francisco, California.

Background: Data regarding management of pediatric persons with hemophilia A (PwHA) with factor VIII (FVIII) inhibitors are limited. This prospective noninterventional study (NCT02476942) evaluated annualized bleeding rates (ABRs), safety, and health-related quality of life (HRQoL) in pediatric PwHA with FVIII inhibitors.

Procedure: PwHA aged <12 years with current FVIII inhibitors and high-titer inhibitor history were enrolled. Participants remained on usual treatment; no interventions were applied. Outcomes included ABR, safety, and HRQoL.

Results: Twenty-four PwHA aged 2-11 years (median 7.5) were enrolled and monitored for 8.7-44.1 weeks (median 23.4). In the episodic (n = 10) and prophylactic (n = 14) groups, respectively, 121 of 185 (65.4%) and 101 of 186 (54.3%) bleeds were treated using activated prothrombin complex concentrate (aPCC) and/or recombinant activated FVII (rFVIIa). ABRs (95% confidence interval) were 19.4 (13.2-28.4) and 18.5 (14.2-24.0) for treated bleeds, and 32.7 (20.5-52.2) and 33.1 (22.4-48.9) for all bleeds, respectively. Most prophylactic group participants (92.9%) were prescribed aPCC; 50% adhered to their prescribed treatment regimen. Adherence to prophylactic rFVIIa was not assessed. Serious adverse events included hemarthrosis (12.5%) and mouth hemorrhage (12.5%); the most common nonserious adverse event was viral upper respiratory tract infection (12.5%). HRQoL showed functional impairment at baseline; scores remained stable throughout, with little intergroup variation.

Conclusions: ABRs remained high in pediatric PwHA with inhibitors receiving standard treatment. This study demonstrates the need for more effective treatments, with reduced treatment burden, to prevent bleeds, increase prophylaxis adherence, and improve patient outcomes.
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http://dx.doi.org/10.1002/pbc.28474DOI Listing
October 2020

Managing the front-line treatment for diffuse large B cell lymphoma and high-grade B cell lymphoma during the COVID-19 outbreak.

Br J Haematol 2020 11 10;191(3):386-389. Epub 2020 Sep 10.

Haematology Department, La Paz University Hospital, Madrid, Spain.

The COVID-19 pandemic has dramatically challenged care for cancer patients, especially those with active treatment who represent a vulnerable population for SARS-CoV-2 infection. Aggressive lymphoid neoplasms, such as diffuse large B cell lymphoma and high-grade B cell lymphoma, need to be treated without delay in order to get the best disease outcome. Because of that, our clinical practice was changed to minimise the risk of SARS-CoV-2 infection while continuing haematological treatment. In this report, we analyse the management of front-line therapy in 18 patients during the COVID-19 outbreak, as well as the results of the implemented measures in their outcome.
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http://dx.doi.org/10.1111/bjh.17066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436686PMC
November 2020

Adherence to prophylaxis in adult patients with severe haemophilia A.

Haemophilia 2020 Sep 22;26(5):800-808. Epub 2020 Jul 22.

Medical Department Hematology, Bayer Hispania S.L., Barcelona, Spain.

Introduction: Adherence is a cornerstone of factor VIII prophylactic treatment. Information regarding the factors with potential influence on adherence is limited, particularly in adult patients.

Aim: To assess adherence in adult patients with severe haemophilia A receiving prophylactic treatment in a real-life setting, and investigate the factors influencing adherence.

Methods: Observational, prospective study including adult patients receiving factor VIII therapy in 15 Spanish centres. Patients recorded infusion doses on a logbook and answered various questionnaires to assess their health beliefs. Adherence rate was the percentage of infused doses over the prescribed ones. Self-perceived adherence was assessed using the VERITAS-Pro questionnaire, the psychometric properties of which were validated in the Spanish population. The relationship between adherence rate and treatment, clinical and demographic characteristics, health beliefs and perceived self-efficacy was investigated.

Results: A total of 66 patients were followed up for 12 months. Mean adherence rate at the end of follow-up was 82.5%. Most of the study patients (n = 53, 80.3%) showed a moderate-to-high adherence rate (>70%). The VERITAS-Pro revealed a high perception of adherence. Multivariate analyses to predict treatment adherence identified the knee as a target joint and longer treatment duration as variables with significant (negative) influence on adherence. Adherence rate was not influenced by the patient's health beliefs or perceived self-efficacy.

Conclusion: Most adult patients receiving factor VIII prophylactic treatment in Spain have moderate-to-high treatment adherence. Treatment duration and the knee as a target joint are factors with a moderate negative influence on treatment adherence.
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http://dx.doi.org/10.1111/hae.14039DOI Listing
September 2020

Thromboprophylaxis in a patient with COVID-19 and severe hemophilia A on emicizumab prophylaxis.

J Thromb Haemost 2020 09 6;18(9):2202-2204. Epub 2020 Jul 6.

Hematology Department, Hospital Universitario La Paz, Madrid, Spain.

COVID-19 can be associated with coagulopathy (CAC, COVID-19-associated coagulopathy) with a high prothrombotic risk based on an intense inflammatory response to viral infection leading to immunothrombosis through different procoagulant pathways. Emerging evidence suggests that the use of heparin in these patients could be associated with lower mortality. Emicizumab is a bispecific humanized monoclonal antibody that bridges activated factor IX and factor X, thereby restoring the function of missing factor VIIIa in hemophilia A. The use of emicizumab has been associated with thrombotic events in patients who also received high cumulative amounts of activated prothrombin complex concentrates. Although this risk is extremely low, there is a lack of evidence on whether CAC increases the thrombotic risk in patients on emicizumab prophylaxis. We present the case of a patient with severe hemophilia A in prophylaxis treatment with emicizumab; due to the potential thrombotic risk we decided to administer low molecular weight heparin as prophylaxis treatment without any thrombotic or bleeding complications.
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http://dx.doi.org/10.1111/jth.14954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307111PMC
September 2020

Registry of patients with congenital bleeding disorders and COVID-19 in Madrid.

Haemophilia 2020 Sep 3;26(5):773-778. Epub 2020 Aug 3.

Department of Hematology, La Paz University Hospital-IdiPaz, Madrid, Spain.

Introduction: We present the first registry of patients with congenital bleeding disorders and COVID-19. The study has been carried out in the Community of Madrid, which has the highest number of cases in Spain. The objective is to understand the incidence of COVID-19, the course of the disease if it occurs and the psychosocial and occupational impact on this population.

Methods: We included 345 patients (246 of haemophilia, 69 of von Willebrand Disease, two rare bleeding disorders and 28 carriers of haemophilia). A telephone survey was used to collect the data.

Results: Forty-two patients presented symptoms suggestive of infection by COVID-19, and in six cases, the disease was confirmed by RT-PCR. The cumulative incidence of our series was 1.73%. It is worth noting the complexity of the management of COVID-19 in two patients on prophylaxis with non-factor replacement therapy. Adherence to the prescribed treatment was maintained by 95.5% of patients. Although 94% were independent for daily living activities, 42.4% had a recognized disability and 58% required assistance, provided by the Madrid Haemophilia Association (Ashemadrid) in 75% of cases. Only 4.4% of consultations were held in person.

Conclusions: Patients with congenital bleeding disorders infected with SARS-CoV-2 presented a mild course of the disease that did not require admission. Their identification and treatment by a specialist team from a Haemophilia Treatment Center are essential to make a correct assessment of the risk of haemorrhage/thrombosis. COVID-19 had a major impact on the psychosocial aspects of these patients which must be remedied with recovery plans.
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http://dx.doi.org/10.1111/hae.14089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307027PMC
September 2020