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Hemofilia A; Equipo multidisciplinar; Telefarmacia Haemophilia A; Multidisciplinary care team; Telepharmacy Hemofilia A; Equip multidisciplinar; Telefarmàcia Objetivo definir las recomendaciones consensuadas para mejorar la coordinación asistencial entre Farmacia Hospitalaria, Hematología y Enfermería, inter e intra-centros, en la atención a los pacientes con hemofilia. Método se identificaron y valoraron las recomendaciones para la mejora de la coordinación asistencial en el abordaje de los pacientes con hemofilia, por parte de un panel multidisciplinar de profesionales con experiencia en este campo (Farmacia Hospitalaria, Hematología y Enfermería) y apoyado en la evidencia científica. La valoración de las recomendaciones identificadas se realizó por metodología de consenso Rand/UCLA (Delphi-adaptado) con base en su adecuación y, posteriormente, a su necesidad. En ambos casos, se empleó la escala ordinal de Likert. Los datos se analizaron estadísticamente a través de diferentes métricas. Resultados se identificaron 53 recomendaciones para la mejora de la coordinación asistencial entre Farmacia Hospitalaria, Hematología y Enfermería en el manejo del paciente con hemofilia, agrupadas en 8 ámbitos de actuación: i) Unidades de Hemofilia, centros de referencia y abordaje multidisciplinar; ii) papel de Hematología, Farmacia Hospitalaria y Enfermería en el recorrido asistencial de los pacientes con hemofilia; iii) telefarmacia y telemedicina; iv) monitorización farmacocinética; v) transición al régimen de paciente adulto; vi) educación sanitaria al paciente; vii) cirugía, urgencias e ingreso hospitalario; y viii) evaluación de los resultados. Todas las recomendaciones fueron valoradas por el panel de expertos externos como adecuadas y necesarias. Conclusiones el recorrido asistencial del paciente con hemofilia es complejo y depende de diversas variables. Además, requiere la implicación de distintos profesionales sanitarios que deben actuar de manera coordinada e integrada en todas las etapas de la vida del paciente, de manera adaptada a sus necesidades individuales. Las recomendaciones identificadas y consensuadas pueden suponer una mejora para la continuidad y calidad asistencial, pues facilitan la integración y coordinación de los profesionales implicados en el abordaje de esta enfermedad, especialmente de Farmacia Hospitalaria, Hematología y Enfermería. Objective Define consensus recommendations to improve care coordination between Hospital Pharmacy, Haematology and Nursing, inter- and intra-center, in the care of haemophilia patients. Method Recommendations for the improvement of care coordination in the management of haemophilia patients were identified and assessed by a multidisciplinary panel of professionals with experience in this field (Hospital Pharmacy, Haematology and Nursing) and supported by scientific evidence. The identified recommendations were assessed by Rand/UCLA consensus methodology (Delphi-adapted) based on their appropriateness and, subsequently, on their necessity. In both cases, it was used ordinal Likert scale. Data were statistically analysed through different metrics. Results Fifty-three recommendations for the improvement of care coordination between Hospital Pharmacy, Haematology and Nursing in the management of haemophilia patients were identified, grouped into eight areas of action: i) Haemophilia units, reference centers and multidisciplinary care; ii) Role of Haematology, Hospital Pharmacy and Nursing in the patient journey of haemophilia patients; iii) Telepharmacy and telemedicine; iv) Pharmacokinetic monitoring; v) Transition to adult patient regimen; vi) Patient health education; vii) Surgery, emergency room and hospital admission; and viii) Outcome evaluation. All recommendations were assessed as appropriate and necessary by the external expert panel. Conclusions Haemophilia patient journey is complex and depends on different variables. It also requires the involvement of different healthcare professionals who must act in a coordinated and integrated manner at all stages of the patient's life, adapted to their individual needs. On this matter, the identified and agreed recommendations may improve continuity and quality of care, as they facilitate the integration and coordination of the professionals involved in the management of this pathology, especially Hospital Pharmacy, Haematology and Nursing. Para la realización de este trabajo se ha contado con el patrocinio de CSL-Behring.

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.

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.

Introduction: The purpose of this study is to evaluate the degree of education and empowerment of the patients of the Haemophilia Unit at 'La Paz' University Hospital (Madrid, Spain).Materials and methods: Haemophilic patients attending routine haemophilia consultations were asked to complete a questionnaire with a view to determining the patient´s perceived knowledge about the disease; their ability to make individual and group decisions; and whether the frequency of their hospital visits could be reduced.Results: Patients were shown to have ample knowledge about the disease. Knowledge had been acquired chiefly through personal experience and from the interaction with healthcare providers. Nearly 70% of patients felt capable of making decisions on matters affecting their health. Over half of the patients considered that their hospital visits could be reduced if they had more information. Patients experiencing the largest number of bleeding episodes were those showing the highest levels of empowerment. Over half the patients were satisfied with the institutional support they received.Conclusion: These patients with haemophilia are in general reasonably empowered on account of their personal experiences and their interaction with the healthcare providers. Current widespread access to information makes it easier to step up educational interventions in patients at lower haemorrhagic risk.

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 thrombocy-topaenia (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, This research was funded by FIS-Fondos FEDER PI19/00631, FIS-Fondos FEDER PI19/00772 and Platelet Disorder Support Association

Background and Objectives: 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. Materials and Methods: 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. Materials and Methods: 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. Conclusions: COVID-19 had a major impact on the psychosocial, occupational, and quality of care of patients with ITP., This study was supported by FIS-Fondos FEDER PI19/00631 and PI19/00772 and by the Platelet Disorder Support Association

We describe the case of a patient with severe hemophilia A who underwent major orthopedic surgery managed postoperatively by telemedicine (TM). The case is a splendid example of the implementation of TM and good collaboration between a Comprehensive Hemophilia Treatment Center (CHTC) and a local hospital.

In times of crisis, continuous adaptation is necessary. Communication between all members of a research team is key to adapting the development of clinical trials to the context of the epidemiological crisis of coronavirus. We are accustomed to performing day‐to‐day tasks to fulfil protocol requirements with precision. To this end, we typically have had protocol‐guided face‐to‐face visits and we have followed a detailed sequenced procedure during each visit.

Background: Primary immune thrombocytopenia (ITP) is a megakaryocytic (MK)/platelet-specific autoimmune disorder characterized by platelet count It is widely accepted the involvement of platelet autoantibodies on deterioration of platelets from patients with ITP. Moreover, an enhanced activity of neuraminidase may also reduce sialic acid from glycoside residues on platelet surface, especially from the highly glycosylated von Willebrand factor (vWF) receptor. Because controversial results regarding the functionality of platelets from ITP patients can be found in literature, we aimed to determine platelet ability to be stimulated by agonists. Moreover, we aimed to determine the way anti-platelet auto- antibodies (abs) and neuraminidase activity may affect the function of platelets derived from MKs of healthy controls. Methods: This observational, prospective and transversal study included 42 patients with chronic primary ITP and 55 healthy controls. Platelet fibrinogen and vWF receptors and activation markers (PAC1 binding to activated fibrinogen receptor and exposure of P-selectin after agonists treatment), were evaluated by flow cytometry. Presence of Antibodies (abs) against platelet's glycoproteins in ITP serum was analysed with a Luminex based assay (LifecodesPak Lx). Neuraminidase (NEU) activity in serum was determined with the substrate 20-(4-methylumbelliferyl)-a-D-N-(MUNANA). Human CD34 + cell-enriched population was obtained with CliniMACS (MiltenyiBiotec) from G-CSF mobilized peripheral blood of a healthy donor. For MK differentiation, CD34 + cells were cultured 12 days in StemSpan™ Serum-Free Expansion Medium II (SFEM II) with 50ng/ml of recombinant human thrompoietin. Then, 10% of serum from healthy controls (4) or ITP patients (4) were added to the culture of mature MKs and incubated for 3 days. Phenotypic analysis of MKs and culture derived-platelets was carried out using abs against CD34, CD41, CD42a and CD42b.Platelet-like particles were considered as CD41-positive events with a size (FSC) and granularity (SSC) scatter properties similar to blood platelets. Culture-derived platelets were stimulated with 100 µM TRAP and 10 µM ADP and activation markers were analyzed by flow cytometry. Results: Expression of fibrinogen receptor on platelets from ITP patients were similar to those from healthy controls but showed a reduced capacity to be activated. Impairment in platelet degranulation measured as exposition of P-selectin after agonist's stimulation was also observed in platelets from these patients (Figure 1). Of note, surface content of CD42b subunit of vWF receptor was reduced (Figure 1). To determine whether diminished platelet function might be due to a plasma component, we induced platelet production from MK of healthy controls as referred in Methods. Abs against platelets and neuraminidase activity were determined in serum samples. Serum from 4 healthy controls or from 4 ITP patients (1 with anti-CD42b, 1 with anti-GPIa-IIa and 2 with undetectable abs) were added to MKs culture. No differences existed in MK differentiation and platelet production between MKs incubated with serum from healthy controls or from ITP patients, but similarly as observed in platelets from ITP patients, MK-derived platelets had an impaired ability to be activated (Table 1). Platelets derived from MKs incubated with ITP serum with anti-platelet abs had also a diminished exposure of CD42b (73±8% of controls). Moreover, neuraminidase content of these samples was slightly higher than that from ITP samples without abs (130 vs 100 % of controls). Conclusion: Platelets from ITP patients had a diminished ability to be stimulated. In vitro study showed that megakaryopoiesis was normal in presence of ITP serum, but released platelets had a lower ability to be activated. Involvement of abs in this effect cannot be ruled out despite we detected abs only in 2 of the tested sera because efficiency of method to detect these abs is ~ 50%. On the other hand, reduced levels of CD42b might be due to the increased activity of neuraminidase. Reduction of sialic acid from CD42b might initiate its metalloproteinase-mediated cleavage or change affinity of the ab used for its detection. Research funded by ISCIII-Fondos FEDER PI19/00772 and Platelet Disorder Support Association Figure 1 Figure 1. Disclosures Alvarez Román: Pfizer: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; CSL-Behring: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novo-Nordisk: Consultancy, Honoraria, Research Funding. García Barcenilla: Roche: Speakers Bureau; Takeda: Speakers Bureau; Bayer: Speakers Bureau; SOBI: Speakers Bureau. Canales: Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Eusa Pharma: Consultancy, Honoraria; Incyte: Consultancy; Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; iQone: Honoraria; Sandoz: Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Jiménez-Yuste: Grifols: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; Sobi: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding. Butta: Novo-Nordisk: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Roche: Speakers Bureau; CSL-Behring: Research Funding.

Introduction: The management of Factor (F) VII deficiency is complex due to the lack of a clear correlation between FVII levels and the bleeding manifestations of the patients, with a variety of responses to the treatments. Additionally,the presence of FVII inhibitors may also occur. Thus, it is essential to be able to monitoring the hemostatic profile and the effect of the different therapies in each patient individually. Our aim was to perform a personalized analysis of the coagulation status of patients with FVII deficiency and to evaluate their response to new potential therapies using five different coagulation tests. Methods: Six patients were included (clinical data in Table-1):4 with bleeding symptoms on prophylaxis with recombinant activated FVII (rFVIIa), one of them with FVII inhibitors; and 2 untreated patients without bleeding episodes. Blood samples obtained from patients on prophylaxis were collected predose. Prothrombine time (PT) and activated partial thromboplastin time (aPTT)were tested using HemosIL ® RecombiPlasTin 2G, and SynthASil respectively. Rotational Thromboelastometry (ROTEM ®) was performed for monitoring the clot formation using blood with corn trypsin inhibitor (CTI) to inhibit contact activation and a low amount of Tissue Factor (TF) as trigger (dilution 1:50,000 of EXTEM reagent). The thrombin generation (TG) was tested with the Calibrated Automated Thrombogram (CAT) system using platelet poor plasma (PPP) obtained from blood with CTI and activated with only 1 pM TF plus phospholipids (PPP-Low ®, Stago). The plasmin generation (PG) was measured in citrated PPP using a comercial kit (Synapse). The total thrombus-formation analysis system (T-TAS ®, Zacros) was conducted by loading CTI blood samples in AR-chips coated with collagen and thromboplastin for assessing thrombus formation mediated by the activation of the coagulation under flow conditions (High shear). The Area under the flow pressure curve (AUC) was calculated over 30 min after starting. Effects of ex vivo spiking doses of factor replacement (rFVIIa) or non-factor replacement treatments (anti-TFPI, clone mAb2021, Creative Biolabs) were tested. Results: aPTT values remained normal in all patients. FVII deficiency significantly affected PT and patients with more severe bleeding phenotype (patient #1, 2, 3, and 4) showed much longer PT values. Similarly, ROTEM and T-TAS assays showed that FVII deficiency only caused an important delayed clotting time (CT) and very anomalous thrombus formation (AUC) in patients with severe bleeding symptoms.More prolonged lag time (LT) and an important decrease in the peak of thrombin and plasmin generation was also observed in the same patients (#1, 2, 3, and 4). Patient #1 with FVII inhibitors presented a more affected hemostatic profile according to all the coagulation parameters obtained with the five different assays. In contrast, the patients #4 and #5 with absence of bleeding complications showed most of these values within the normal reference range obtained from healthy controls. Concentrations of 1µg/ml (equivalent to 90 μg/kg) of the factor-replacement treatment rFVIIa, showed the normalization of the PT, the clotting time (CT), and the restoration of the thrombin and plasmin generation, and the regularization of the coagulation-dependent thrombus formation in all the patients. In vitro spiking with anti-TFPI (400-800 ng/ml), an alternative non-factor replacement treatment,corrected the thrombus formation (AUC) defects under high shear flow observed in the patients, and produced a significant reduction of CT and LT, and increments of thrombin generation although less effectively than the factor replacement therapy. Conclusions: All the global tests, performed with the described conditions in this study, were sensitive enough to show an abnormal hemostatic profile in the FVII-deficient patients with worst clinical symptoms, validating their use to monitor the risk of bleeding events and the responses to different treatments in this deficiency. These assays may allow to monitoring more personalized treatments to these patients. The results also pointed to the possibility that inhibition of TFPI might be useful for treatment of patients with FVII deficiency, opening the idea of its usage especially as an alternative therapy for patients with inhibitors. Research funded by ISCIII-Fondos FEDER PI19/00772 and PI19/00631 Figure 1 Figure 1. Disclosures Alvarez Román: Pfizer: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Novo-Nordisk: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; CSL-Behring: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. García Barcenilla: Roche: Speakers Bureau; Takeda: Speakers Bureau; SOBI: Speakers Bureau; Bayer: Speakers Bureau. Canales: Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Incyte: Consultancy; Sanofi: Consultancy; Novartis: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; iQone: Honoraria; Sandoz: Honoraria, Speakers Bureau; Eusa Pharma: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria. Butta: CSL-Behring: Research Funding; Roche: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Novo-Nordisk: Speakers Bureau. Jiménez-Yuste: Octapharma: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

Background:Joint damage is the most frequent and most debilitating comorbidity of haemophilia and can be prevented by adequate prophylactic treatment. Nevertheless, many causes and not only plasma levels of the factor affect joint damage in severe haemophilia (SH) patients. One to be considered is variability on fibrin polymerization capacity since it might influence the bleeding tendency and, consequently, would affect the joint condition in SH patients. To our knowledge, there are not enough studies about that. Aim:This work aimed to evaluate if there exists a relationship between fibrin capacity of polymerization and joint condition in SH patients. Methods:This is a prospective and transversal study that was approved by Ethics Committee from Hospital Universitario La Paz. Twenty eight SH patients (25 with SHA, 5 of them with inhibitors; 3 with SHB, 2 of them with inhibitor), median age [p25-p75]=41 [29.8-51.3] years old) were recruited. Joint condition was evaluated using the HEAD-US score. Plasma level of fibrinogen (Fib) was determined by Clauss method. Rotational thromboelastometry (ROTEM) was performed with fibTEM, an extrinsically activated test with tissue factor and the platelet inhibitor cytochalasin D. fibTEM results correlate well in many cases with the Clauss Fib assay, but is additionally influenced by fibrin polymerization ability which cannot reliably be detected with clotting tests. Fibrinogen capacity to increase the clot strength was evaluated by the ratio R= Fib/fibTEM maximum clot firmness (MCFfibTEM) which means the plasma concentration of Fib needed to increase maximum clot firmness in 1 mm. Data were analysed with GraphPrism Pad 6.0. Results:Median value of Fib was 306 [263-341] mg/dl, MCFfibTEM = 12 [10-15] mm and R= 25.0 [20.5-29.5] mg/dl/mm. Patients were classified taking into account the value of the 25th percentile of each variable (Fib, MCFfibTEM and R). Subjects with Fib ≤ 263 mg/dl were considered patients with low fibrinogen level, those with MCFfibTEM ≤ 10 mm were considered patients with low platelet independent maximum clot strength and subjects with a R < 20.5 mg/dl/mm were considered good responders to fibrinogen. Based on this analysis, neither Fib nor MCFfibTEM influenced the joint condition. However, patients with poor response to fibrinogen (R ≥ 20.6 mg/dl/mm) had a significantly greater joint damage than the good responders to fibrinogen (R < 20.6 mg/dl/mm) (Table 1). Poor responders to fibrinogen had frequently joint damage in ankles followed by elbows and knees being cartilage the most commonly affected joint compartment. Good responders to fibrinogen only presented milder joint alterations in elbows and ankles. Conclusions: Our results suggested that polymerization capacity of fibrin may be variable between patients with SH and might influence joint condition. More patients need to be recruited to confirm this finding. This work was supported by grants from FIS-FONDOS FEDER (PI19/00631 and PI19/00772). EMM holds a predoctoral fellowship from Fundación Española de Trombosis y Hemostasia (FETH-SETH). Disclosures Fernandez-Bello: Pfizer:Speakers Bureau;Novartis:Speakers Bureau;Stago:Speakers Bureau;Roche:Speakers Bureau;NovoNordisk:Current Employment, Research Funding, Speakers Bureau;Takeda:Research Funding, Speakers Bureau;SOBI,:Research Funding.de la Corte:Pfizer:Research Funding, Speakers Bureau;NovoNordisk:Research Funding, Speakers Bureau;Takeda:Speakers Bureau;Roche:Research Funding, Speakers Bureau;Sobi:Research Funding, Speakers Bureau;Bayer:Speakers Bureau.Alvarez Román:Novartis:Speakers Bureau;Bayer:Consultancy;Grifols:Research Funding;Pfizer,:Research Funding, Speakers Bureau;Roche:Speakers Bureau;NovoNordisk,:Research Funding, Speakers Bureau;Takeda:Research Funding, Speakers Bureau;SOBI,:Consultancy, Research Funding, Speakers Bureau.Martín:SOBI:Research Funding;NovoNordisk:Speakers Bureau;Novartis:Speakers Bureau;Roche:Speakers Bureau;Pfizer:Research Funding, Speakers Bureau.Rivas Pollmar:Pfizer:Speakers Bureau;Roche:Speakers Bureau;Novartis:Speakers Bureau.García Barcenilla:Novartis:Speakers Bureau;Bayer:Speakers Bureau;Roche:Speakers Bureau;Pfizer,:Speakers Bureau;Takeda:Research Funding, Speakers Bureau;NovoNordisk:Research Funding, Speakers Bureau.Canales:Janssen:Honoraria;Sandoz:Speakers Bureau;Takeda:Speakers Bureau;Karyopharm:Honoraria;Novartis:Honoraria;Celgene:Honoraria;Roche:Honoraria;Gilead:Honoraria;Sandoz:Honoraria;iQone:Honoraria;Janssen:Speakers Bureau;Janssen:Honoraria;Roche:Speakers Bureau;Karyopharm:Honoraria;Sandoz:Speakers Bureau;Novartis:Honoraria;Takeda:Speakers Bureau;Roche:Honoraria;Sandoz:Honoraria;Janssen:Speakers Bureau;Roche:Speakers Bureau.Butta:Takeda:Research Funding, Speakers Bureau;SOBI:Speakers Bureau;Pfizer:Speakers Bureau;ROCHE:Research Funding, Speakers Bureau;Novartis:Speakers Bureau;Grifols:Research Funding;NovoNordisk:Speakers Bureau.Jimenez-Yuste:F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer:Consultancy;Grifols, Novo Nordisk, Takeda, Sobi, Pfizer:Research Funding;F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer, Grifols, Octapharma, CSL Behring, Bayer:Honoraria.

Introduction: Emicizumab is a humanized, monoclonal, bispecific antibody that binds factor (F) FX and FIXa allowing thrombin generation in the absence of FVIII, which is used for routine treatment of patients with Hemophilia A (HA) with and without inhibitors. Plasma level of FIX will be an important limiting factor for the formation of the FX-FIXa-emicizumab ternary complex in the absence of FVIII, suggesting the potential use of FIX concentrates to regulate the procoagulant function of emicizumab and therefore, to use it as an alternative treatment in certain circumstances to stop or prevent bleedings in patients on prophylaxis with emicizumab. At the present time there are several recombinant FIX concentrates with differences in their content of activated FIX (FIXa) and in their half-life (standard or extended) that may differ in their procoagulant effects when combined with emicizumab. Aim: The aim of this study was to evaluate if there were differences in thein vitroprocoagulant effects of two recombinant FIX concentrates, one with standard half-life (rFIX Nonacog Alfa, BeneFIX®, Pfizer) and the other with extended half-life (rFIX fused to rAlbumin, Albutrepenonacog Alfa, Idelvion®, CLS Behring) in samples from patients on prophylaxis with Emicizumab. Methods: This is a prospective and transversal pilot study that was approved by the Ethics Committee from La Paz University Hospital. Two patients with haemophilia A (HA) with inhibitors in prophylaxis with emicizumab were recruited and one haemophilia B (HB) patient was included as a control for the effects of FIX. Blood samples were collected in tubes with corn trypsin inhibitor (CTI, Haematologic Technologies, USA), to block thecontact phase and to only evaluate coagulation mediated by the extrinsic pathway. Levels of FIXa in concentrates of FIX were quantified using the Spectrozyme® FIXa chromogenic substrate (LOXO) and measuring the increase in OD at 405 nm. Rotational thromboelastometry (ROTEM) was performed using whole blood activated by a low concentration of tissue factor solution (final dilution 1:50,000 of EXTEM reagent) plus recalcification. Parameters evaluated in ROTEM were CT (cloting time), defined as time until detection of a clot firmness of 2 mm; and CFT (clot formation time), defined as time between detection of a clot firmness from 2 to 20 mm. Calibrated automated thrombogram (CAT)was performed using platelet free plasma (PFP) activated by low concentration of tissue factor plus phospholipids (PPP-Reagent LOW®, Stago). Parameters evaluated in CAT were: Peak, defined as maximum thrombin concentration reached, in nM; and ETP, defined as the total amount of thrombin generated over time, in nMxmin. Results: The presence of FIXa activity assayed by a chromogenic substrate was not detectable with 20 IU of Idelvion while BeneFIX® showed a specific concentration-dependent FIX activity that was blocked with the serine protease inhibitor EGR-chloromethylketone (Figure 1). ROTEM (Figure 2) and CAT (Figure 3) results showed that the addition of increased concentrations of both concentrates of rFIX produces an enhanced procoagulant effect of Emicizumab similar to the effect produced by the addition of the bypassing agent rFVIIa (NovoSeven®, NovoNordisk). These results also showed that it is necessary three-four times higher concentration (U/dl) of Idelvion® to get similar procoagulant effects that those obtained with BeneFIX®. The higher procoagulant effects of BeneFIX® were also observed in samples of a patient with severe HB. Conclusion: Global coagulation assays suggest that increasing endogenous FIX levels with two rFIX concentrates that have different FIXa content and half-life, produce an enhanced procoagulant effect of Emicizumab opening the idea of the use of these concentrates as an alternative treatment for bleedings in patients with inhibitors on prophylaxis with Emicizumab. Further studies need to be performed to evaluate the procoagulant activity of the concomitant use of different rFIX concentrates and Emicizumab, and to assess security of this therapeutic approach. This work was supported by grants from FIS-FONDOS FEDER (PI19/00631 and P19/00772). EMM holds a predoctoral fellowship from Fundación Española de Trombosis y Hemostasia (FETH-SETH). Disclosures Fernandez-Bello: Novartis:Speakers Bureau;Stago:Speakers Bureau;Takeda:Research Funding, Speakers Bureau;NovoNordisk:Current Employment, Research Funding, Speakers Bureau;Roche:Speakers Bureau;SOBI,:Research Funding;Pfizer:Speakers Bureau.García Barcenilla:Pfizer,:Speakers Bureau;Takeda:Research Funding, Speakers Bureau;Roche:Speakers Bureau;Bayer:Speakers Bureau;Novartis:Speakers Bureau;NovoNordisk:Research Funding, Speakers Bureau.Alvarez Román:Roche:Speakers Bureau;Novartis:Speakers Bureau;Takeda:Research Funding, Speakers Bureau;Pfizer,:Research Funding, Speakers Bureau;Bayer:Consultancy;SOBI,:Consultancy, Research Funding, Speakers Bureau;Grifols:Research Funding;NovoNordisk,:Research Funding, Speakers Bureau.Martín:NovoNordisk:Speakers Bureau;SOBI:Research Funding;Pfizer:Research Funding, Speakers Bureau;Roche:Speakers Bureau;Novartis:Speakers Bureau.Rivas Pollmar:Novartis:Speakers Bureau;Roche:Speakers Bureau;Pfizer:Speakers Bureau.Canales:Roche:Honoraria;Celgene:Honoraria;Roche:Honoraria;Janssen:Honoraria;Novartis:Honoraria;Sandoz:Speakers Bureau;Sandoz:Honoraria;Janssen:Speakers Bureau;iQone:Honoraria;Sandoz:Honoraria;Gilead:Honoraria;Takeda:Speakers Bureau;Novartis:Honoraria;Karyopharm:Honoraria;Janssen:Honoraria;Takeda:Speakers Bureau;Janssen:Speakers Bureau;Roche:Speakers Bureau;Sandoz:Speakers Bureau;Roche:Speakers Bureau;Karyopharm:Honoraria.Butta:Grifols:Research Funding;Novartis:Speakers Bureau;ROCHE:Research Funding, Speakers Bureau;Pfizer:Speakers Bureau;SOBI:Speakers Bureau;Takeda:Research Funding, Speakers Bureau;NovoNordisk:Speakers Bureau.Jimenez-Yuste:F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer, Grifols, Octapharma, CSL Behring, Bayer:Honoraria;F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer:Consultancy;Grifols, Novo Nordisk, Takeda, Sobi, Pfizer:Research Funding.

Introduction: Platelet surface glycoproteins (GPs) are highly glycosylated and are key elements for platelet function since most of them constitute receptors for adhesion ligands. However, exact role of their glycan composition is not clear. Under normal conditions, platelets contain sialic acid in the carbohydrate side chains of their GPs, and it has been described that alterations in the degree of their sialinization can affect the clearance of platelets. This mechanism has been proposed as involved in etiopathogenesis of immune thrombocytopaenia (ITP), mainly in those patients who do not respond to treatments. Thus, after the loss of sialic acid, there would be a greater exposure of galactose and of N-acetyl-glucosamine residues on the surface of circulating platelets to hepatic Ashwell-Morell receptors, which could induce their phagocytosis and platelet clearance. On the other hand, procoagulant platelets, defined as the platelet subpopulation that binds functional prothrombinase, exposed on their surface increased levels of P-selectin and GPIb, two glycan rich GPs. So, it is tempting to speculate that changes in glycan residues on platelet surface may induce changes in their function. Aim: We aimed to assess in ITP patients whether changes in platelet glycosylation, mainly the loss of sialic acid, may condition platelet function, apoptosis and binding of prothrombinase complex. Methods: This is an observational, prospective and transversal study approved by Ethics Committee from La Paz University Hospital. One hundred and eight patients with chronic primary ITP (68 with a platelet count ≥30x103 platelets/µL and 40 with a platelet count Platelet activation markers were determined in platelet rich plasma; whereas platelet glycosylation, binding of prothrombinase, annexin V and caspase's activities were assayed in washed platelets. Samples were analyzed by flow cytometry. Table 1 shows lectins tested and their sugar-binding specificity. Data were analyzed with GraphPad Prism 6.0 software. Results: Platelets from ITP patients with a platelet count These differences in glycosylation observed in ITP patients with a platelet count Conclusion: Changes in glycoside composition of GPs on platelet's surface impaired their functional capacity, increases their apoptosis and modifies conditions for the binding of coagulation proteins. These modifications in platelet's glycoside residues seem to be related to severity of ITP. This work was supported by grants from FIS-FONDOS FEDER (PI19/00772) and and Platelet Disorder Support Association. EMM holds a predoctoral fellowship from Fundación Española de Trombosis y Hemostasia (FETH-SETH). Disclosures Butta: Grifols: Research Funding; Novartis: Speakers Bureau; ROCHE: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; SOBI: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; NovoNordisk: Speakers Bureau. Alvarez Román:Grifols: Research Funding; Bayer: Consultancy; Novartis: Speakers Bureau; Roche: Speakers Bureau; Pfizer,: Research Funding, Speakers Bureau; SOBI,: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; NovoNordisk,: Research Funding, Speakers Bureau. Martín:SOBI: Research Funding; Pfizer: Research Funding, Speakers Bureau; Roche: Speakers Bureau; Novartis: Speakers Bureau; NovoNordisk: Speakers Bureau. Rivas Pollmar:Novartis: Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau. Justo Sanz:Takeda: Current Employment. García Barcenilla:NovoNordisk: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Pfizer,: Speakers Bureau; Roche: Speakers Bureau; Bayer: Speakers Bureau; Novartis: Speakers Bureau. Canales:Celgene: Honoraria; Janssen: Speakers Bureau; Novartis: Honoraria; Roche: Honoraria; Gilead: Honoraria; Sandoz: Honoraria; iQone: Honoraria; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Sandoz: Honoraria; Roche: Honoraria; Takeda: Speakers Bureau; Novartis: Honoraria; Sandoz: Speakers Bureau; Karyopharm: Honoraria; Roche: Speakers Bureau; Janssen: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria. Jimenez-Yuste:F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer, Grifols, Octapharma, CSL Behring, Bayer: Honoraria; F. Hoffman-La Roche Ltd, Novo Nordisk, Takeda, Sobi, Pfizer: Consultancy; Grifols, Novo Nordisk, Takeda, Sobi, Pfizer: Research Funding.

Introduction: The incidence of bleeding in patients with severe (S) haemophilia A (HA) on prophylaxis with emicizumab is similar to that seen in patients with moderate-mild HA, therefore these patients will require administration of factor (F) VIII concentrates (patients without inhibitors) or bypassing agents (patients with inhibitors) in case of acute bleeding or surgery. In the absence of FVIII, thrombin generation is guided by the FIX plasma levels that becomes the limiting factor for the formation of the FX-FIXa-emicizumab ternary complex. We hypothesize that the increment of level of FIX in patients on prophylaxis with emicizumab would increase their procoagulant function. Objectives: To measure the in vitro procoagulant effect of increasing factor IX activity in patients on prophylaxis with emicizumab. Material and Methods: We performed a study in 6 patients on prophylaxis with emicizumab (2 patients with inhibitors) and 20 healthy controls. We evaluated the in vitro procoagulant effect of therapeutic concentrations of recombinant activated FVII (rFVIIa), activated prothrombin complex concentrate (aPCC) and several concentrations of FIX using global assays as thrombin generation test (CAT) and thromboelastometry (ROTEM). Results: In correspondence with our hypothesis, our ROTEM results indicated that increasing concentration of FIX up to 110% was able to normalize the procoagulant capacity of all patients. Further increment of in vitro FIX concentrations up to 125% had a procoagulant effect similar to what would be obtained after one standard dose of 90 mcg/kg rFVIIa. In regard to aPCC, we needed to increase FIX levels up to 200 IU/dl to achieve a procoagulant effect similar to what would be obtained with a dose of 2.5 IU/kg of aPCC. CAT showed total normalization of thrombin generation in all patients with levels of 125 IU/dl of FIX which support the idea of normalization of procoagulant function of patients on prophylaxis with emicizumab in response to low increments of FIX. Moreover, similar to ROTEM, 200 IU/dl of FIX had comparable procoagulant effect to concentrations of aPCC that would be obtained after one dose of 2.5 IU/kg aPCC. With these results we might speculate on a possible good safety profile of this high level of FIX in patients on prophylaxis with emicizumab if we take into account that 2.5 IU/kg aPCC is 20 times lower than aPCC dose [50 IU/kg] used in HAVEN-1 with no associated incidence of thrombotic events, however, more studies are needed to explore this hypothesis. Conclusions: In vitro increment of FIX plasma levels enhances in vitro procoagulant function of patients on prophylaxis with emicizumab opening the idea of an alternative hemostatic treatment in this type of patient. The use of FIX concentrates with much longer half-life compared to FVIII concentrates or bypassing agents in patient on prophylaxis with emicizumab might produce longer period of time with a normalized haemostatic function which might speed up the recovery, might reduce the incidence of bleeding complication and would require much less number of administrations, this later of paramount importance in patients with limited venous access. However, more studies should be addressed to confirm these results. Moreover, and even more important, prothrombotic risk of combinatory therapy with FIX and emicizumab should be carefully studied in pre-clinical studies. NB holds a tenure track grant from FIS-FONDOS FEDER (CP14/00024). Disclosures Fernandez-Bello: Novartis, Pfizer, ROCHE, Stago: Speakers Bureau. Alvarez Román:Novartis: Speakers Bureau; Novo Nordisk: Speakers Bureau; Bayer: Speakers Bureau; CSL Behring: Speakers Bureau; Roche: Speakers Bureau; Sobi: Speakers Bureau; Amgen: Speakers Bureau; Shire (Takeda): Research Funding, Speakers Bureau. Martín:Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau; SOBI: Research Funding. Rivas Pollmar:Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau; SOBI: Research Funding. García Barcenilla:SOBI: Research Funding; Bayer, Pfizer, Takeda, Novartis: Speakers Bureau. Canales:Sandoz: Honoraria; Gilead: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria, Speakers Bureau; Takeda: Speakers Bureau; SOBI: Research Funding; Celgene: Honoraria; iQone: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Novartis: Honoraria. Butta:Novartis: Consultancy; Roche, Pfizer: Speakers Bureau. Jimenez-Yuste:Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Shire: Consultancy, Honoraria, Other: reimbursement for attending symposia/congresses , Research Funding, Speakers Bureau.

Introduction: Efmoroctocog alfa (Elocta®) is a recombinant coagulation FVIII-Fc (rFVIIIFc), a fully recombinant fusion protein produced in human embryonic kidney cells, with an extended half-life used for the treatment and prevention of bleeding in patients with severe hemophilia A. Using rFVIIIFc for the treatment of severe hemophilia A patients received the approval of reimbursement in Spain at the end of 2016. Therefore, there are no many comparative data published about real life use of rFVIIIFc. Objective: This work aims to describe characteristics of the treatment of severe hemophilia A patients with rFVIIIFc and to compare its results with those previously obtained employing other FVIII products. Methods: This was an open-label non-interventional retrospective study reviewing patient characteristics and treatment outcomes before and after the use of rFVIIIFc. The La Paz University Hospital Ethics Committee approved the experimental protocol. Patients with severe hemophilia A without inhibitors being treated with rFVIIIFc since at least six months before study approval by Ethics Committee were included. The following data were collected for patients included in the study: dose (IU/kg) and prophylaxis treatment regimen, number of spontaneous and traumatic bleedings, annual bleeding rate (ABR) and FVIII trough level. The statistical analysis on the variables listed above comparing before and after rFVIIIFc usage was performed by the Biostatistics Unit of La Paz University Hospital with the statistical package SPSS v.18.0 (SPSS Inc., Chicago, IL, USA). Results: Twenty two severe hemophilia A patients (median age: 20 years old, ranging from 6 to 63 years) on prophylaxis with rFVIIIFc were considered to be included in this study, but two were excluded due to lack of data. Median follow-up period was 14 months (ranging from 6 to 28 months). Nineteen severe hemophilia A patients have been previously treated with rFVIII (two of them with other extended half-life product) and one with plasma-derived FVIII. Eight of the ten severe hemophilia A patients who presented an ABR greater than 0 with previous treatments reduced their ABR when treated with rFVIIIFc (Table 1). Among those patients with an ABR=0 with previously used FVIII products, only one increased to an ABR=1 when treated with Elocta® due to a traumatic bleeding. Table 1 shows ABR across all patients before and after rFVIIIFc. There was no difference in dose per injection between other FVIII products and rFVIIIFc (median dose for patients treated with other FVIII products: 46.0 IU/kg, ranging from 26 to 65 IU/kg; median dose for patients treated with rFVIIIFc: 46.5 IU/kg, ranging from 26 to 65 IU/kg). Nevertheless, a reduction was observed in administration frequency. Among the twelve patients who received treatment with other FVIII products every 48 hours, eleven came to receive rFVIIIFc 3 times a week and the one previously receiving a plasma-derived FVIII, to twice a week. Five of the patients receiving treatment 3 times a week reduced its frequency to twice per week. Three patients maintained the same schedule of administration. To note, one of the two patients receiving another prolonged half-life product maintained the schedule of treatment and the other reduced its frequency from every 48 hours to 3 times a week. FVIII trough level in plasma (% of FVIII), expressed as median (25th-75th percentile), was 1.1 (0.1-4.0) for rFVIIIFc treatment and 0.2 (0.0-1.9) for other FVIII products (p=0.06). Conclusions: 85% of the severe hemophilia A patients from our cohort reduced the weekly dose administration after beginning treatment with rFVIIIFc. Most of the patients increased plasma trough level of FVIII with rFVIIIFc. 45% of patients reduced and 40% kept their ABR=0 when they changed rFVIIIFc. These data suggest that treatment with rFVIIIFc gives a higher protection to severe hemophilia A patients. However, further research with larger sample size is required to investigate this. This work was supported by SOBI. NB holds a tenure track grant from FIS-FONDOS FEDER (CP14/00024). Disclosures Álvarez Roman: Takeda: Research Funding; Amgen: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau. Fernandez-Bello:Novartis, Pfizer, ROCHE, Stago: Speakers Bureau. Martín:SOBI: Research Funding; Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau. Rivas Pollmar:Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau; SOBI: Research Funding. García Barcenilla:Bayer, Pfizer, Takeda, Novartis: Speakers Bureau; SOBI: Research Funding. Canales:SOBI: Research Funding; iQone: Honoraria; Karyopharm: Honoraria; Novartis: Honoraria; Takeda: Speakers Bureau; Gilead: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Sandoz: Honoraria. Butta:Roche, Pfizer: Speakers Bureau; Novartis: Consultancy. Jimenez-Yuste:Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Shire: Consultancy, Honoraria, Other: reimbursement for attending symposia/congresses , Research Funding, Speakers Bureau.