Sickle cell disease: Clinical presentation and management of a global health challenge.

Sickle cell disease is an autosomal recessive, multisystem disorder, characterised by chronic haemolytic anaemia, painful episodes of vaso-occlusion, progressive organ failure and a reduced life expectancy. Sickle cell disease is the most common monogenetic disease, with millions affected worldwide. In well-resourced countries, comprehensive care programs have increased life expectancy of sickle cell disease patients, with almost all infants surviving into adulthood. Therapeutic options for sickle cell disease patients are however, still scarce. Predictors of sickle cell disease severity and a better understanding of pathophysiology and (epi)genetic modifiers are warranted and could lead to more precise management and treatment. This review provides an extensive summary of the pathophysiology and management of sickle cell disease and encompasses the characteristics, complications and current and future treatment options of the disease.

The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study.

Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. SUMMARY: Background The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.

Characteristics and quality of oral anticoagulation treatment in pediatric patients in the Netherlands based on the CAPS cohort.

Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients. SUMMARY: Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of ≤ 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year.

A long-term follow-up study of subtotal splenectomy in children with hereditary spherocytosis.

BACKGROUND: Hereditary spherocytosis (HS) is a heterogeneous hemolytic anemia treated with splenectomy in patients suffering from severe or moderate disease. Total splenectomy, however, renders patients vulnerable to overwhelming postsplenectomy infection despite preventive measures. Although subtotal splenectomy has been advocated as an alternative to total splenectomy, long-term follow-up data are scarce. We investigated how often hematologic recurrences requiring secondary total splenectomy occurred. PROCEDURE: With a follow-up of at least 5 years, we analyzed the data of 12 patients, aged 11 years maximum (median 6.5 years), who had undergone intended subtotal splenectomy, and 9 patients (median age 11.9 years), who had undergone total splenectomy. We compared their hematologic results and searched for factors associated with secondary spleen surgery. RESULTS: Hemolysis was reduced after subtotal splenectomy and absent after total splenectomy. Subtotal splenectomy was not successful in three children because no functional splenic remnant remained after 6 months (one conversion at surgery; one necrosis of splenic remnant; one early secondary splenectomy). Four children required secondary splenectomy after a median of 5 years for hematologic recurrence. In the remaining five patients, a functional splenic remnant was present for at least 5.5 years. The median time to secondary total splenectomy after intended subtotal splenectomy was 5.2 years. In all patients requiring secondary total splenectomy, increased reticulocyte levels within 2 years indicated hematologic recurrence. CONCLUSIONS: Subtotal splenectomy can be an alternative for total splenectomy in young patients with HS. It allows for hematologic improvement and may preserve splenic immune function for as many as 5 years.

Adherence to treatment in a Western European paediatric population with haemophilia: reliability and validity of the VERITAS-Pro scale.

Treatment adherence in haemophilia is strongly associated with quality of life and the cost-benefit of treatment. Therefore, it is important to quantify and monitor it. This study aimed to validate a translation of the VERITAS-Pro cross-culturally and analyse treatment adherence in a Dutch population of paediatric haemophilia patients. Children aged 1-18 years with haemophilia were included from three Haemophilia Treatment Centres, on prophylactic clotting factor replacement therapy for more than 1 year. Parents and adolescents were analysed separately. The adherence scale for prophylactic therapy (VERITAS-Pro) was translated according to international guidelines. This instrument contains a total of six subscales ('Time', 'Dose', 'Plan', 'Remember', 'Skip' and 'Communicate') each with four items. Lower scores reflect higher adherence. Overall response rate was 85%, leading to a study population of 60 children. Mean age was 10 years (SD 4.1). Internal consistency reliability: Mean Cronbach's alphas were adequate (>0.70) for total score and the subscales 'Skip' and 'Communicate'. Item-own subscale correlations were stronger than most item-other subscale correlations. Convergent validity: Total scores were higher for non-adherent participants compared with adherent participants according to patient infusion logs (n = 48; P < 0.05). Test-retest correlations: Significant for all scales except 'Dose' (n = 58; P < 0.01). This study demonstrates applicability of VERITAS-Pro outside the United States, as total score and most subscales effectively quantified treatment adherence in a Dutch paediatric population on prophylactic therapy. Non-adherent respondents' total scores were significantly higher, demonstrating the ability of VERITAS-Pro to identify non-adherent individuals.

Reliability and validity of a novel haemophilia-specific self-efficacy scale.

Higher self-efficacy in chronic disease patients is associated with higher development of self-management skills and increased quality-of-life. Quantification and monitoring of self-efficacy is therefore of importance. Self-efficacy in haemophilia patients has received little attention due to lack of standardized scales. To validate the novel Haemophilia-specific Self-Efficacy Scale (HSES) in haemophilia patients on prophylactic home treatment, haemophilia patients aged 1-18 years on prophylactic treatment ≥1 year were included from three Dutch Haemophilia Treatment Centres. The HSES consists of 12 items, relating to perceptions of the ability to function on a day-to-day basis with regard to patient's disease. Retest was performed in a subsample. Validity was proven by the General Self-Efficacy Scale and by the health-related quality-of-life assessment tool Haemo-QoL. Data were analysed from 53 children (response 75%), with a mean age of 9.8 years (SD 4.0). Mean total scale score of HSES was 55.5 (SD 4.7; range 38-60), with a ceiling effect of 17%. The HSES showed adequate internal consistency (Cronbach's alpha 0.72) and good test-retest reliability (Intra-Class-Correlation coefficient 0.75; P < 0.01; n = 37). The convergent validity was adequate as haemophilia-specific self-efficacy correlated significantly with general self-efficacy (r = 0.38; P < 0.01). High HSES scores correlated significantly with quality-of-life as measured by the Haemo-QoL (r = -0.42; P ≤ 0.01). The novel HSES is a reliable and valid tool to assess self-efficacy in paediatric haemophilia patients on prophylactic home treatment. High self-efficacy correlated with higher quality-of-life, further underlining the importance to standardly assess, monitor and improve self-efficacy.

Perceived competence in children and adolescents with haemophilia: an explorative study.

With the introduction of prophylaxis, restricting children with haemophilia to participate in physical activities was no longer necessary. Subsequently, many studies report on improved physical functioning in children and adolescents with haemophilia. However, little is known about psychological aspects such as perceived competence and impact of disease. Therefore, the aims of this study were to explore: (i) perceived competence, (ii) perceived impact of illness, and (iii) analyse associations between perceived competence and demographic factors, disease-related factors and joint status in young haemophiliacs in the Netherlands. Fifty-four children (age 8-12 years) and 72 adolescents (12-18 years) with haemophilia participated in this cross-sectional, multi-centre, explorative study. Measurements included perceived competence (Self Perception Profile for Children/Adolescents; range 6-24/5-20), impact of disease (Revised Perception Illness Experience; range 1-5), demographic factors, disease-related factors, joint status and functional status. Mean (SD) scores for perceived competence in the children ranged from 17.3 (±4.0) to 19.6 (±4.0), and for adolescents from 13.3 (±2.4) to 15.7 (±2.8) points. In general, scores were comparable with those of healthy peers, but children with haemophilia had a lower global self-worth score and competence in close friendship was lower for adolescents when compared with those of healthy peers. Mean (SD) scores for impact of disease ranged from 1.2 (±0.4) to 2.3 (±0.8) in children and from 1.3 (±0.4) to 2.0 (±0.8) in adolescents. Severe haemophilia, prophylactic medication, high impact of disease and a shorter walking distance showed a weak to moderate association with perceived competence. Children and adolescents with haemophilia in general have a perceived competence that is nearly comparable with that of healthy peers, with the exception of a lower global self-worth in children and a lower competence for close friendship in adolescents. Haemophiliacs seem to perceive their disease as having relatively low impact on their life. Severe disease, prophylactic treatment and low functional status seemed to be associated with lower perceived competence.

Recurrent thrombo-embolism in a child with a congenital disorder of glycosylation (CDG) type Ib and treatment with mannose.

Thrombosis is a multifactorial disorder. Congenital disorders of glycosylation (CDG) are one of the known risk factors for its occurrence. These disorders result in glycosylation defects of glycoproteins, including those of the (anti-)coagulation system. CDG-Ib can specifically be treated with mannose, as illustrated by the case of a 4-year-old girl in whom deep venous thrombosis was the presenting symptom after a common viral infection. The diagnosis was made after recurrent episodes of thrombo-embolism and consumptive coagulopathy. After treatment with mannose no such episodes recurred. The pathophysiology of CDG as a risk factor for thrombotic disease is discussed.

[Management of pregnancy and childbirth in carriers of haemophilia]. / Begeleiding van de zwangerschap en de partus bij draagsters van hemofilie.

3 pregnant women, aged 27, 33 and 31 years respectively, were carriers of haemophilia A. The first patient had a caesarean section without prior measurement or substitution of factor VIII. She gave birth to a healthy boy, but developed severe diffuse abdominal bleeding after a few hours. The second patient had a normal level of factor VIII, and lived 100 km away from the nearest haemophilia treatment centre. Ultrasound investigation revealed a female foetus. She gave birth in the local hospital. The third patient was pregnant with a male foetus, but refused further prenatal investigation. Contrary to medical advice she gave birth at home. For carriers of haemophilia, there are several options for prenatal diagnosis and managing labour and delivery. Early referral is advised and the need for adequate counselling is explained. It is important to have an experienced haemophilia treatment centre nearby, where haematologists, gynaecologists, geneticists and paediatricians cooperate in caring for pregnant carriers of haemophilia.

[Clinical reasoning and decision-making in practice. A young boy with fever, pancytopenia and an enlarged spleen]. / Klinisch denken en beslissen in de praktijk. Een jongetje met koorts, pancytopenie en een grote milt.

A 5-year-old boy presented with fever and fatigue after a holiday in northern Italy. On physical examination a marked splenomegaly was found. Laboratory investigations showed a pancytopenia as well as several markers suggesting an autoimmune disease. The splenomegaly and pancytopenia continued to progress despite treatment with prednisolone and intravenous immunoglobulins. One and a half years after presentation, the spleen had grown to such an extent that it was causing mechanical problems. Splenectomy was performed for diagnostic and therapeutic purposes. Histological investigation of the spleen showed amastigotes of Leishmania. PCR confirmed the diagnosis visceral leishmaniasis. Leishmaniasis is too often considered to be a tropical disease only. In recent years it has frequently been seen in southern European countries around the Mediterranean Sea.

[Anaemia in adopted children, not always iron deficiency]. / Anemie bij adoptiekinderen, niet altijd ijzergebrek.

Anaemia was diagnosed in four adopted children during a standard screening examination 1-4 weeks after arrival. Further investigation revealed a number of causes which could then be specifically treated. The children were a girl aged 14 months from China with iron-deficiency anaemia, a boy aged 16 months from Nigeria with sickle cell anaemia, a girl aged 5 from Haiti who had alpha-thalassaemia, and a boy aged 7 from Brazil with spherocytosis. Iron deficiency is the most common cause of anaemia in childhood. However, in adopted children from sub-tropical areas other causes of anaemia like haemoglobinopathies or erythrocyte membrane defects should be borne in mind, particularly as a history of disease and family history are often lacking. Additional investigations may be necessary. An incorrect diagnosis of iron deficiency may result in ongoing and unjustified iron supplementation leading to harmful iron accumulation in thalassaemia and a delay in the correct treatment in sickle cell anemia or spherocytosis which could carry considerable risk.

[Rituximab instead of splenectomy in 4 children with chronic or refractory autoimmune haemolytic anaemia]. / Rituximab in plaats van splenectomie bij 4 kinderen met chronische of refractaire auto-immune hemolytische anemie.

4 children, a boy aged 10 years and 3 girls aged 3, 3, and 16 years, suffering from chronic or refractory autoimmune haemolytic anaemia (AIHA), who were dependent on high doses of steroids and were refractory to immunosuppressants, were treated with rituximab at a dose of 375 mg/m2 once a week for 3 or 4 weeks as an alternative to splenectomy. Rituximab is a monoclonal anti-CD20 antibody that prevents the production ofautoantibodies by selective destruction of B-lymphocytes. Haemoglobin levels increased and the parameters of chronic haemolysis (reticulocyte count, lactate dehydrogenase activity, bilirubin concentration) decreased to normal values. 3 patients were taken off corticosteroids completely; 1 of these was also no longer dependent on blood transfusions. Circulating B-lymphocytes were absent for 6 to 15 months after the treatment and the rituximab was well-tolerated. During the treatment, immunoglobulins were substituted and infectious complications were not seen. Rituximab was valuable in the treatment of chronic or refractory AIHA and eliminated the need for splenectomy. 1 patient did not respond to rituximab.

Chemo- and radiosensitivity testing in a patient with ataxia telangiectasia and Hodgkin disease.

Treatment of Hodgkin disease (HD) in ataxia telangiectasia (AT) patients is hampered by hypersensitivity to radiation and chemotherapy. Most patients die, due to toxicity or, rarely, to progressive disease. The authors report on a 9-year-old girl with stage IIA HD and AT She was treated with a tailored combined modality approach. No unacceptable toxicity was found, but the girl died of a relapse outside the irradiation field. In comparison with fibroblasts of non-AT patients, the fibroblasts of the patient were 3 times as sensitive for radiotherapy but just 1.2 times as sensitive for doxorubicin. A good correlation was shown between in vitro radio- and chemosensitivity testing and the observed clinical toxicity. The authors suggest, therefore, treating AT patients as much as possible according to standard protocols by adjusting the radiotherapy delivery and the chemotherapy regimen to individual doses derived from in vitro radio- and chemosensitivity testing.