Evaluation of EC50 of factor VIII as predictor of prophylaxis efficacy in patients with severe haemophilia A.

Trough factor (F) VIII level is a not reliable bleeding risk indicator to predict prophylaxis efficacy in severe haemophilia A (SHA), therefore, accurate biomarkers are much needed. Thrombelastography (TEG) monitors both thrombin and clot formation addressing the global haemostatic status but its usefulness to tailor prophylaxis in haemophilia has been poorly evaluated. In this study, correspondence between individual pharmacodynamic/pharmacokinetic profile of FVIII and joint condition, physical activity and bleeding phenotype of SHA patients under prophylactic treatment was assessed. Nineteen SHA patients < 18 years old on long-term prophylaxis treatment with FVIII were studied in an observational cross-sectional study. Whole blood was withdrawn before FVIII administration and at five time-points after infusion for a TEG-based pharmacodynamic- and pharmacokinetic-study. Type of prophylaxis and joint condition at inclusion and physical activity as well as onset of treated spontaneous bleeding events in the previous two years were retrospectively assessed. Six patients had suffered at least one treated spontaneous bleeding event and were named as "bleeders". The rest were named as "non-bleeders". Only the half maximal effective concentration of FVIII (FVIII-EC50) for TEG parameters R-time, K-time and α-angle correlated with the bleeding phenotype being significantly higher in bleeders suggestive of a poorer response to FVIII. Poorer joint condition, trough FVIII levels or type of prophylaxis were not definitive predicting variables of bleeding phenotype. In conclusion, this study reveals FVIII-EC50 for the first time as a valuable biomarker to anticipate individual efficacy of prophylaxis in SHA.

Head trauma in the haemophilic child and management in a paediatric emergency department: Descriptive study.

INTRODUCTION: Haemophilia is one of the most common inherited bleeding disorders in the Emergency Department (ED). The most dangerous site of bleeding is the central nervous system. AIMS: To describe the characteristics of haemophiliacs arrived to our ED following a head trauma and to analyse the incidence of intracranial haemorrhage (ICH). MATERIALS AND METHODS: Retrospective, analytical, observational study, conducted in a Paediatric ED. We included haemophilic patients aged from birth to 16 years who consulted after a head trauma over a 6-year period. Data collected included age, type of haemophilia and head trauma, symptoms, prophylaxis status, CT imaging, treatment and number of visits to the ED. RESULTS: About 46 males and 85 episodes were analysed. The median age was 2.38 years. Severe haemophilia A was the most frequent type of disease (50%). All head injuries were mild, and the most frequent mechanism was a collision with an object (38.8%). In 62 episodes (72.9%) the patients were asymptomatic. The rest 23 events had symptomatology, being the most common headache (26%), emesis (21.7%) and drowsiness (17.4%). Head CT was obtained in 31 episodes, founding altered results in 10 (6 of them corresponding to ICH). All the patients with ICH had symptomatology. About 37 episodes required admission. CONCLUSION: Intracranial haemorrhage is one of the most dangerous events in haemophiliacs and it may occur after a head trauma. Our study suggests that, in case of head trauma, CT must be obtained in symptomatic patients and in those with additional risk factors. Asymptomatic patients must have prolonged observation.

Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial.

BACKGROUND: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia. OBJECTIVES: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B. METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 µg kg(-1) ) or s.c. (50-3000 µg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24). RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h µg mL(-1) and a maximum mean concentration of 247 µg mL(-1) was measured at the highest dose. CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.

Effects of thrombopoietin receptor agonists on procoagulant state in patients with immune thrombocytopenia.

Thrombopoietin receptor agonists (TPO-RA) have recently been introduced for the treatment of immune thrombocytopenia (ITP), an anti-platelet-antibodies autoimmune disease. The observation of a low frequency of bleeding episodes despite their thrombocytopenia suggests the existence of a compensatory mechanism. This study aimed to evaluate the effect of TPO-RA treatment on platelet function and on the procoagulant state in ITP patients before (ITP-bR) and after responding (ITP-aR) to treatment. Plasma- and microparticle (MP)-associated procoagulant capacity from ITP patients was similar before and after responding to the TPO-RA regimen but higher than the healthy control values. High MP-associated procoagulant activity did not seem to be due to increased platelet activation, since platelet stimulation by agonists was reduced in ITP-bR and ITP-aR patients. It could be related to increased platelet apoptosis, evaluated in terms of surface phosphatidylserine (PS), observed in both ITP groups. In summary, TPO-RA treatment increased platelet count but did not ameliorate their function and did not change plasma- and MP-associated procoagulant state of ITP patient responders to this therapy.

Surgery in haemophilia patients with inhibitors, with special emphasis on orthopaedics: Madrid experience.

We report on a series of 92 surgical procedures (90 patients). It includes 35 orthopaedic procedures (33 patients) and 57 non-orthopaedic procedures (57 patients). The orthopaedic procedures include 27 radiosynovectomies (minor surgery) and eight major orthopaedic procedures. The non-orthopaedic procedures include 52 minor interventions and five major procedures. The average age of patients was 34 years (range: 8-56), and the average follow-up time was 3 years (range: 1-6). Of the 92 surgical procedures, 42 were performed with activated prothrombin complex concentrates [factor eight inhibitor bypassing agent (FEIBA)] and 47 with recombinant-activated factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). Regarding FEIBA treatment in minor surgery, the initial dose was 100 IU kg(-1). After 6 h, we continued with 50 IU kg(-1) every 12 h for at least 4 days (radiosynovectomies). In minor non-orthopaedic procedures, the dose was continued until day 14. In patients who underwent surgery with the haemostatic control achieved by means of rFVIIa, the initial dose of rFVIIa in minor procedures (both orthopaedic and non-orthopaedic) was 90-120 microg kg(-1). In postoperative days 1-5, the dose was 2-4 x 90-120 microg kg(-1) q3-6 h for 24 h. In major procedures (both orthopaedic and non-orthopaedic), the dose was 120 microg kg(-1) pre-operatively, 120 microg kg(-1) q 3 h day 2/day 3-5, and then 90-120 microg kg(-1) q 6 h until day 14. There were 87 good results, four fair results and one poor result. Our study has shown that haemophilic patients with inhibitors requiring surgery can undergo orthopaedic and non-orthopaedic procedures with a high expectation of success. In other words, surgery (orthopaedic and non-orthopaedic) is now possible in haemophilia patients with inhibitors, leading to an improved quality of life for these patients.

Prophylaxis in 10 patients with severe haemophilia A and inhibitor: different approaches for different clinical situations.

The effect of bypassing agents is not as predictable as replacement therapy with the deficient factor in inhibitor patients. Consequently, these patients have more levels of arthropathy than patients without inhibitors. Prophylaxis for inhibitor patients has gained attention over the last decade and some papers have reported that bypassing agents could work in the prevention of arthropathy. However, there is a lack data to support any specific agent or regimen or even to recommend their use in different clinical conditions. We report ten patients with haemophilia A and inhibitors treated prophylacticaly with bypassing agents (5 with FEIBA and 5 with NovoSeven). The variable conditioning the choice of one agent or the other was the intention to initiate of immune tolerance induction therapy (ITI) in the future. In 8/10 patients (4 in FEIBA group and 4 in rFVIIa group) there was a decrease of bleeding episodes while 9/10 maintained or increased their joint range of motion (ROM). In the rFVIIa prophylaxis group, prophylaxis can be considered primary since all of them had had less than one joint bleed before prophylaxis. Economic analysis showed that prophylaxis is an expensive treatment. In our experience both agents seem to be safe and effective in reducing the number of bleeds in patients with inhibitors. The anamnestic response provoked by FEIBA could be an issue while awaiting a decline in titres before ITI can be initiated and so rFVIIa may be the best option for prophylaxis in patients with inhibitors who have not yet begun ITI.

Experiences in the prevention of arthropathy in haemophila patients with inhibitors.

Haemophilia patients with inhibitor have a higher level of arthropathy and more severe joint morbidity than patients without inhibitors. In recent years, interest has grown in the possibility that bypassing agent regimens could prevent bleeding and, consequently, arthropathy in inhibitor patients. Nevertheless, doubts about efficacy, complications and cost exist, questioning the justification of an uncertain prophylaxis in patients with inhibitors. Activated prothrombin complex concentrate (aPCC) has been used in more than 70 haemophilia patients with inhibitors in different clinical situations. aPCC prophylaxis seems to be safe and effective for the reduction of bleeding episodes in some patients. Recombinant activated factor VII (rFVIIa) has been employed prophylactically in over 44 haemophilia patients with inhibitors; 22 patients were included in the only randomized, prospective clinical trial of bypassing agents in prophylaxis. Bleeding frequency was reduced and this reduction was maintained during the postprophylaxis period. No thromboembolic events were reported during prophylaxis with rFVIIa. Although the effect of aPCC can last longer than that of rFVIIa, their efficacy rates are similar, suggesting that the biological effect of rFVIIa is actually much longer than indicated by its short plasma half-life. aPCC contains residual factor VIII antigen and may cause an anamnestic response in the inhibitor titre. This is crucial when immune tolerance induction is postponed to allow the inhibitor titre to decline to <10 Bethesda Units. In this setting, aPCC is not recommended as a first-line prophylaxis because of its potential to protract anamnesis, and rFVIIa is the preferred agent.

[Therapeutic recommendations in the oncohematological patient]. / Recomendaciones nutricionales en el paciente oncohematológico.

More than 10 million new cancer cases are detected each year worldwide, 95% of which are caused by predisposing factors, and of those, more than one third are linked to dietary factors as the main cause. The ability of maintaining an adequate nutritional status in oncohematologic patients is a common problem since the disease itself and the therapy may lead to a protein-caloric hyponutrition state that influence their quality of life and survival. For that reason, in this section we will focus on the prevalence and etiology of hyponutrition in oncologic patients, assessing the possible causes related with the tumor itself, with the patient and with administered therapies. We will also discuss performing a correct nutritional assessment in this type of patients and thus determining the main effects derived from hyponutrition status; finally, we will discuss the objectives of nutritional support and the best nutritional plan that will have to be adjusted to each patient.

Recomendaciones nutricionales en el paciente oncohematológico / Therapeutic recommendations in the oncohematological patient

Globalmente, en el mundo, se producen cada año más de 10 millones de casos nuevos de cáncer, el 95% de los cuales están causados por factores ambientales y, de ellos, más de la tercera parte están ligados a factores dietéticos como causa principal. La capacidad para mantener un estado nutricional adecuado en el paciente oncohematológico es un problema común; ya que tanto el desarrollo de la propia enfermedad como su tratamiento, pueden dar lugar a un estado de desnutrición calórico proteico, que afecta a su calidad de vida y su supervivencia. Por ello en este apartado, abordaremos la prevalencia y la etiología de la desnutrición en el paciente oncológico, valorando las posibles causas relacionadas con el propio tumor, con el paciente o con los tratamientos administrados. Pero también se mencionarán las pautas para realizar una correcta evaluación nutricional en este tipo de pacientes y determinar así los principales efectos derivados del estado de desnutrición, y por último se abordarán los objetivos del soporte nutricional así como un plan nutricional óptimo que deberá ser ajustado a cada paciente (AU)

More than 10 million new cancer cases are detected each year worldwide, 95% of which are caused by predisposing factors, and of those, more than one third are linked to dietary factors as the main cause. The ability of maintaining an adequate nutritional status in oncohematologic patients is a common problem since the disease itself and the therapy may lead to a protein-caloric hyponutrition state that influence their quality of life and survival.For that reason, in this section we will focus on the prevalence and etiology of hyponutrition in oncologic patients, assessing the possible causes related with the tumor itself, with the patient and with administered therapies.We will also discuss performing a correct nutritional assessment in this type of patients and thus determining the main effects derived from hyponutrition status; finally, we will discuss the objectives of nutritional support and the best nutritional plan that will have to be adjusted to each patient (AU)