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.

Clinical efficacy in bleeding and surgery in von Willebrand patients treated with Fanhdi a highly purified, doubly inactivated FVIII/VWF concentrate.

Therapy with factor VIII/von Willebrand factor (FVIII/VWF) concentrate is the mainstay therapy in patients with von Willebrand disease (VWD) unresponsive to desmopressin. There are several commercially available FVIII/VWF concentrates that have been tested in VWD patients. We retrospectively analized the clinical efficacy in bleeding episodes and surgery of a highly purified FVIII/VWF complex with two inactivation steps (Fanhdi) in VWD patients. Sixty patients were included in the study. Treatment schedule consisted of one or more doses (standard dose 40 IU/kg body weight of FVIII) of Fanhdi. One hundred and fifty bleeding episodes were treated. These were: 28 serious bleedings; 92 moderate and 30 mild. An excellent clinical efficacy in almost 95% of cases was observed. Fanhdi was administered during 66 surgical procedures (38 major and 28 minor) with an overall efficacy of 98%. Fanhdi a highly purified, doubly virus-inactivated FVIII/VWF concentrate, with a high content of active VWF and an excellent record of clinical safety, is a valid choice in treating VWD.

Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients.

BACKGROUND: The pharmacokinetics of factor VIII replacement therapy in preschool previously treated patients (PTPs) with hemophilia A have not been well characterized. OBJECTIVES: To assess the pharmacokinetics, efficacy and safety of a plasma-free recombinant FVIII concentrate, ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method, rAHF-PFM], in children < 6 years of age with severe hemophilia. PATIENTS/METHODS: Fifty-two boys, one girl, mean (+/- SD) age 3.1 +/- 1.5 years and >or= 50 days of prior FVIII exposure, were enrolled in a prospective study of ADVATE rAHF-PFM at 23 centers. RESULTS: The mean terminal phase half-life (t(1/2)) was 9.88 +/- 1.89 h, and the mean adjusted in vivo recovery (IVR) was 1.90 +/- 0.43 IU dL(-1) (IU kg(-1))(-1). Over the 1-6-year age range, t(1/2) of rAHF-PFM increased by 0.40 h year(-1). IVR increased by 0.095IU dL(-1)(IU kg(-1))(-1) (kg m(-2))(-1) in relation to body mass index (BMI). Patients primarily received prophylaxis. Median (range) annual joint bleeds were 0.0 (0.0-5.8), 0.0 (0.0-6.1) and 14.2 (0.0-34.5) for standard prophylaxis, modified prophylaxis and on-demand treatment, respectively. Bleeds were managed in 90% (319/354) of episodes with one or two rAHF-PFM infusions; response was rated excellent/good in 93.8% of episodes. Over a median 156 exposure days, no FVIII inhibitors were detected and no related severe adverse events or unusual non-serious adverse events were seen. CONCLUSIONS: Children < 6 years of age appear to have shorter FVIII t(1/2) and lower IVR values than older subjects. However, these parameters increased with age (t(1/2)) and BMI (adjusted IVR), respectively. rAHF-PFM was clinically effective and well tolerated, with no signs of increased immunogenicity in previously treated young children with hemophilia A.

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.

The occurrence of adverse events during the infusion of autologous peripheral blood stem cells is related to the number of granulocytes in the leukapheresis product.

Toxicity related to autologous PBSC infusion is well known and traditionally attributed to the presence of DMSO as cryoprotectant. But despite DMSO depletion, adverse events continue appearing. We have conducted a retrospective study to determine the incidence of adverse events related to the PBSC infusion in a large series of 144 patients. Adverse effects were observed in 67.36% of patients, although most of them were of grade 1 or 2. The adverse events most frequently reported were allergic reactions, followed by general, gastrointestinal and respiratory symptoms. In the univariate analysis, age (P=0.01), the volume infused (P=0.005), the amount of DMSO (P=0.008), the total nucleated cells (P=0.002), the total number of granulocytes (P=0.000001) and clumping (P=0.000001) were associated with the occurrence of adverse events. In the multivariate analysis, two protective factors, age (P=0.05) and sex (P=0.004), and two risk factors, the number of granulocytes, with a relative risk of 1.18 (95% confidence interval, 1.06-1.31) (P=0.002), and clumping, with an relative risk of 1.94 (95% confidence interval, 1.15-3.29) (P=0.013), were identified. The best cutoff point for the prediction of the occurrence of adverse events, with a sensitivity of 47% and specificity of 89%, was 6.065 x 10(9) granulocytes.

Orthopaedic surgery for inhibitor patients: a series of 27 procedures (25 patients).

We report on a series of 27 orthopaedic surgical procedures. It includes 20 radiosynoviortheses and seven major orthopaedic procedures, performed on 26 patients. The average age of patients was 36 years (range: 8-53) and the average follow-up time was 2.5 years (range:1-5). There were 23 good results and four fair. In the synoviorthesis group (20 patients, 20 synoviortheses) the average age was 13.5 years (range: 9-26) and the average follow-up was 4.5 years (range: 1-7). There were 19 good results and one fair. All synoviortheses were done with activated prothrombin complex concentrates (FEIBA), all the responses being good except in one case (which had the final fair result). The total dose of FEIBA used was 600 IU kg(-1,) except in a patient that had a haemorrhagic complication. In fact, he required a prolongation of treatment up to a total dose of 2000 IU kg(-1). In the group of major orthopaedic procedures, the average age of the six patients was 30.5 years (range: 11-53) and the average follow-up was 2.5 years (range: 1-5). There were six good results and one fair. Postoperative bleeding complications occurred in one of the seven major orthopaedic procedures performed (arterial pseudoaneurym after a total knee arthroplasty). Despite such complication, which had the final fair result, our study has shown that haemophilic patients with high inhibitor titres requiring orthopaedic surgery can undergo such procedures with a high expectation of success. In other words, orthopaedic surgery is now possible in haemophilia patients with high-titre inhibitors, leading to an improved quality of life for these patients.

[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)

[Management, prevention and control of megaloblastic anemia, secondary to folic acid deficiency]. / Manejo, prevención y control de la anemia megaloblástica secundaria a déficit de ácido fólico.

Folic acid deficiency is the second most common cause of anemia in our environment, after anemia secondary to iron deficiency. Folates are essential components of human and animal diet. Folic acid is mainly in poliglutamate form, and it is hydrolyzed in the proximal jejunum. It is important to identify adequately the exact vitamin deficiency that causes megaloblastic anemia, because vitamin B12 administration in folate deficiency may correct partially megaloblastic alterations, but administration of folic acid in cobalamin deficient patients improves haematological parameters but deteriorates the neurological syndrome. Main causes of anemia secondary to folate deficiency are inadequate dietetic administration, increased requirements, impaired absorption and pharmacologic interactions. Folates are altered by light, high temperature and by water affinity, which facilitates its elimination by washing or cooking.

Manejo, prevención y control de la anemia megaloblástica secundaria a déficit de ácido fólico / Management, prevention and control of megaloblastic anemia, secondary to folic acid deficiency

La deficiencia de ácido fólico es la causa más frecuente de anemia en nuestro medio, después del síndrome anémico de origen ferropénico. Los folatos son componentes esenciales de la dieta humana y animal. En los alimentos el ácido fólico se encuentran principalmente en forma de poliglutamatos, formas que luego son hidrolizadas en el intestino delgado a nivel de yeyuno proximal. Es importante definir con exactitud el defecto vitamínico causante de la anemia megaloblástica, puesto que, la administración de vitamina B12 a pacientes con deficiencia de folatos puede corregir parcialmente las alteraciones megaloblásticas, sin embargo, la administración de ácido fólico a pacientes con deficiencia de cobalamina induce mejoría hematológica, pero empeora el cuadro neurológico. Las principales causas de anemia por deficiencia de folatos son un aporte dietético insuficiente, un aumento de los requerimientos, defectos de su absorción o interacción con fármacos. Los folatos, pueden verse perjudicados por la sensibilidad a la luz y a las altas temperaturas así como por su alta afinidad por el agua, lo que facilita su eliminación por lavado o cocción (AU)

Folic acid deficiency is the second most common cause of anemia in our environment, after anemia secondary to iron deficiency. Folates are essential components of human and animal diet. Folic acid is mainly in poliglutamate form, and it is hydrolyzed in the proximal jejunum. It is important to identify adequately the exact vitamin deficiency that causes megaloblastic anemia, because vitamin B12 administration in folate deficiency may correct partially megaloblasticalterations, but administration of folic acid in cobalamin deficient patients improves haematological parameters but deteriorates the neurological syndrome. Main causes of anemia secondary to folate deficiency are inadequate dietetic administration, increased requirements, impaired absorption and pharmacologic interactions. Folates are altered by light, high temperature and by water affinity, which facilitates its elimination by washing or cooking (AU)

[Management, prevention and control of pernicious anemia]. / Manejo, prevención y control de la anemia perniciosa.

Pernicious anemia is the most frequent cause of megaloblastic anemia in our area, and it is the result of a vitamin B12 deficiency due, itself, to the decrease or absence of intrinsic factor (IF) because of gastric mucosa atrophy or autoimmune destruction of IF-producing parietal cells. With the existence of a severe gastric atrophy, there is a decrease in acid and IF production and a further change in vitamin B12 absorption. Fifty percent of the cases are associated to anti-IF antibodies, which presence in other autoimmune diseases is exceptional. In patients with pernicious anemia, measurement of anti-IF antibodies has high specificity (95%); however, measurement of anti-parietal cells antibodies has low specificity. The first-choice treatment is administration of vitamin B12 intramuscularly. The regimen is the administration of 1 mg of vitamin B12 daily for one week, weekly thereafter for one month and, then, every 2-3 months for life.

Manejo, prevención y control de la anemia perniciosa / Management, prevention and control of pernicious anemia

La anemia perniciosa es la causa más frecuente de anemia megaloblástica en nuestro medio y es consecuencia de una deficiencia de vitamina B12 debido a su vez a la disminución o ausencia de factor intrínseco (FI) por atrofia de la mucosa gástrica o por destrucción autoinmune de las células parietales productoras de éste. Ante la existencia de una atrofia gástrica intensa, se origina un descenso en la producción de ácido y FI y una posterior alteración en la absorción de vitamina B12. En un 50% de los casos se asocia a anticuerpos anti FI, cuya presencia en otras enfermedades auto-inmunes es excepcional. En pacientes con anemia perniciosa la determinación de anticuerpos anti FI tiene una alta especificidad (95%), sin embargo, la determinación de anticuerpos anticélulas parietales cuentan con una especificidad baja. El tratamiento de elección es la administración de B12 intramuscularmente. La pauta consiste en administrar 1 mg. de Vitamina B12 diariamente durante una semana, posteriormente semanal durante un mes y después cada 2-3 meses de por vida (AU)

Pernicious anemia is the most frequent cause of megaloblastic anemia in our area, and it is the result of a vitamin B12 deficiency due, itself, to the de-crease or absence of intrinsic factor (IF) because of gastric mucosa atrophy or autoimmune destruction of IF-producing parietal cells. With the existence of a severe gastric atrophy, there is a decrease in acid and IF production and a further change in vitamin B12 absorption. Fifty percent of the cases are associated to anti-IF antibodies, which presence in other autoimmune diseases is exceptional. In patients with pernicious anemia, measurement of anti-IF antibodies has high specificity (95%); however, measurement of anti-parietal cells antibodies has low specificity. The first-choice treatment is adminis-tration of vitamin B12 intramuscularly. The regimen is the administration of 1 mg of vitamin B12 daily for one week, weekly thereafter for one month and, then, every 2-3 months for life (AU)

Psychometric field study of the new haemophilia quality of life questionnaire for adults: the 'Hemofilia-QoL'.

Although there is a worldwide interest in the assessment of health-related quality-of-life (HRQoL) in haemophilia patients, no non-disease specific instruments (for adults) are readily available. In this paper, a haemophilia-specific quality-of-life assessment measure for adults (the Hemofilia-QoL questionnaire) has been developed and tested for psychometric properties in 121 adults with haemophilia living in Spain. The Hemofilia-QoL questionnaire is a self-report modular instrument that assesses nine relevant HRQoL domains for patients with haemophilia (e.g. physical health, daily activities, joint damage, pain, treatment satisfaction, treatment difficulties, emotional functioning, mental health, relationships and social activity). Psychometric examination involved the assessment of data quality, scaling assumptions, reliability (internal consistency and test-retest) and validity (concurrent; external clinical criterion and sensitivity). The Hemofilia-QoL 36-item version questionnaire had acceptable internal consistency and retest reliability values. The questionnaire shows excellent concurrent validity (with the SF-36 Health Survey) and external clinical criterion validity (haemophilia clinical status) and sensitivity (health status changes) as well. The Hemofilia-QoL is now available for adult assessment and is ready for use in clinical research in Spain.

Manejo, prevención y control del síndrome anémico secundario a deficiencia férrica / Management, prevention and control of anaemia secondary to iron deficiency

La anemia ferropénica representa la anemia carencial más frecuente en nuestro medio, la primera causa de consulta hematológica y el tipo de alteración nutricional más común. Se caracteriza por la disminución o ausencia de los depósitos de hierro. La prueba deficiencia que confirma la existencia de anemia por déficit de hierro (AF) son unos niveles séricos bajos de ferritina, indicativos de una situación de depleción de hierro. Otros parámetros no permiten diferenciar la AF de la anemia trastornos crónicos. La dieta es de gran importancia en la anemia, sin embargo, ningún alimento contiene concentraciones suficientes de hierro para poder constituir un remedio práctico en los estados de carencia del mismo, por lo que el tratamiento debe realizarse por vía oral con preparados a poder ser a base de sulfato ferroso para asegurar una mejor absorción. Se recomienda una dosis inicial de 150-200 mg. de hierro elemental al día, repartido en tres tomas (3-5 mg/kg/día en niños) (AU)

Anemia secondary to iron deficiency is the most frequent anaemia in our environment, the first cause of consultation in Haematology and the most common nutritional problem. It is characterized by a diminution or absence of iron deposits. The ultimate test that confirms the diagnosis of anaemia secondary to iron deficiency is a low serum level of ferritin, which indicates iron depletion. Other parameters do not allow to distinguish iron deficiency anaemia from other chronic derangements. Diet is of utmost importance in anaemia. There is not a single food product with sufficient concentration of iron capable of restoring iron deficiency situations. Therefore, treatment of iron deficiency must be made orally with iron preparates, mainly in the form of iron sulphate in order to guarantee a better absorption. The initial recommended doses are 150-200 mg of elemental iron per day split in three ingestions (in children 3-5 mg/Kg/day) (AU)

Prophylactic treatment effects on inhibitor risk: experience in one centre.

Nowadays, the elective treatment for children with haemophilia is prophylaxis. There is a common consensus that this modality of therapeutic approach is not associated with a higher risk of inhibitor development. We analysed the inhibitor incidence in 50 haemophiliac children and its relationship with mutations, type of clotting factor used and treatment modality. There was a significant correlation between receiving on-demand treatment and an increased incidence of inhibitors, independently of mutations or factor used. We advise putting haemophiliac children under prophylactic treatment as soon as possible, especially if they have mutations associated with high risk of inhibitor development, as prophylaxis is negatively associated with the development of inhibitors.

Surgery in haemophilic patients with inhibitor: 20 years of experience.

Surgery in haemophilic patients with inhibitor against factor (F)VIII or FIX is high risk. Surgery may be performed with the administration of sufficiently high dose of FVIII in patients with low-response inhibitor or who, despite having a high response, present a low inhibitor titre at the time of surgery. The use of high doses of FX is more complicated in patients with a low-titre FIX inhibitor, as there is a high risk of anaphylactic reactions. In the case of patients with high-titre inhibitors, several treatments have been proposed, such as porcine FVIII, recombinant FVIIa (rFVIIa), and activated prothrombin complex concentrate (APCC). We present our 20 years' experience in the treatment and subsequent management of haemophilic patients with inhibitor in surgery and evaluate the results obtained with the products available for haemostatic control in 64 surgical procedures. The efficacy we obtained with FVIII is good in 100% of the cases described; we had no haemorrhagic complication (HC) in the 18 procedures in which it was used (three major and 15 minor surgery). With APCC we obtained excellent results with only one HC in a synoviorthesis in the form of bleeding and haematomas out of 32 procedures. Good results were obtained with rFVIIa with few haemorrhagic episodes. Thus, in major surgery there was one HC out of three cases. In minor surgery, greater efficacy was observed using extremely large doses of rFVIIa (> or =120 mg kg(-1) 2 h(-1)) because of the shorter half-life of this factor in this type of patients.