Susanna Ranta

Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia - a multicentre study from the Nordic Society of Paediatric Haematology and Oncology.

We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 2008 protocol. The cumulative incidence of CSVT was 2%. Sixteen of the thromboses were related to asparaginase and 16 to steroids. Most CSVTs occurred in the consolidation phase. Nearly all were treated with low molecular weight heparin without bleeding complications. Mortality related to CSVT directly or indirectly was 10%, emphasizing the importance of this complication.

Hypercalciuria in children with haemophilia suggests primary skeletal pathology

Several factors can compromise optimal bone mass accrual during childhood and predispose to osteoporosis later in life. Patients with haemophilia are already at risk of low bone mass during childhood, partly due to reduced physical activity related to joint bleeds and haemarthrosis. The introduction of primary prophylaxis with regular infusions of the deficient coagulation factor has enabled reduction or prevention of haemophilic arthropathy. Finnish children with severe haemophilia start prophylaxis early and are encouraged to participate in physical activities. We hypothesized that prophylactic therapy would ensure normal childhood bone mass development and carried out a case–control study in 29 children with haemophilia (2 mild, 6 moderate, 21 severe) and 58 age‐matched controls. Their bone health was determined by fracture history, blood and urine biochemistry, bone densitometry and spinal imaging. Bone mineral density was lower in children with haemophilia but there was no evidence for significantly increased fracture rate. The patients had significantly higher urinary calcium excretion and higher serum calcium concentration, and reduced bone resorption as compared with the controls. Our findings suggest primary skeletal pathology, resulting in increased urinary calcium loss and altered bone metabolism, which may over time contribute to the development of osteoporosis in patients with haemophilia.

Detection of central nervous system involvement in childhood acute lymphoblastic leukemia by cytomorphology and flow cytometry of the cerebrospinal fluid

Therapy directed at the central nervous system (CNS) is an essential part of the treatment for childhood acute lymphoblastic leukemia (ALL). The current evaluation of CNS involvement based on cytomorphological examination of the cerebrospinal fluid (CSF) alone is not as sensitive with low cell counts as flow cytometric immunophenotyping (FCI) of the CSF. However, the importance of low CSF blasts counts at diagnosis is uncertain. We sought to determine the significance of FCI in relation to conventional morphological examination.

Antithrombin deficiency after prolonged asparaginase treatment in children with acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) have several risk factors for deep venous thromboses (DVTs) such as central venous catheters and asparaginase (ASP), related antithrombin (AT) deficiency. After introduction of a new standard and intermediate-risk ALL treatment protocol with prolonged continuous ASP treatment, two symptomatic DVTs in 10 patients were observed at the Childrens Hospital, Helsinki, Finland. To prevent further thrombotic complications yet ensuring continuous exposure to ASP, an AT substitution strategy was adopted in Helsinki. The same ALL treatment protocol is used without AT substitution in the other Nordic countries. In this retrospective study, we describe the effect of prolonged ASP treatment on AT and fibrinogen levels in children without AT substitution in Stockholm, Sweden (n = 39) and the AT substitution in children with AT activity below 0.55 kIU/l in Helsinki (n = 36, intervention group). The intervention group is compared with children treated similarly earlier in Helsinki without AT substitution (n = 10). The median lowest AT activity during the ASP treatment without AT substitution was 0.55 kIU/l. Fibrinogen level of 1.0 g/l or less was found in 14% of all routine samples during the ASP treatment. In the intervention group, 23 (64%) received AT concentrate. Two (20%) children had symptomatic DVT before initiation of the AT substitution and two (6%) thereafter. We conclude that most children are exposed to low AT activity during ASP treatment predisposing to thrombosis. The effect of prophylactic AT substitution remains unclear.

Peripheral quantitative computed tomography (pQCT) reveals alterations in the three-dimensional bone structure in children with haemophilia

Children with haemophilia are at risk of suboptimal bone mass accrual and low bone mineral density (BMD). We recently demonstrated that although BMD in Finnish children with haemophilia was within the normal range, their whole body BMD was significantly lower and hypercalciuria more prevalent than in controls. This study sought to determine the bone structure and strength in physically active children with haemophilia. To investigate the underlying mechanisms in this group, we conducted a case–control study to assess bone structure and strength by peripheral quantitative computed tomography (pQCT) at the radius. The study group comprised 29 patients (mean age 12.2 years) and 46 age‐matched controls. Children with haemophilia had decreased total BMD Z‐score at the distal radius (P ≤ 0.001), but increased cortical bone density at the proximal radius (P ≤ 0.001). Total bone area at the proximal radius was significantly lower in children with haemophilia (P = 0.002), whereas there were no differences in cortical bone area or in polar Strength‐Strain Index, a parameter of bone strength, between the patients and controls. Patients with mild to moderate haemophilia and on‐demand treatment had inferior bone strength compared to those with moderate to severe haemophilia and prophylaxis. Our findings suggest altered skeletal development in patients with haemophilia in the radius, resulting in smaller bone size and higher cortical bone density. Importantly, bone strength at the radius appears equal to healthy children. Prophylactic treatment seems to have a beneficial effect on bone health.

Prospective study of thromboembolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of Pediatric Hematology and Oncology (NOPHO) study

Essentials Children with acute lymphoblastic leukemia (ALL) are at risk of thromboembolism (TE). This is a prospective evaluation of the incidence, risk factors and outcomes of TE in 1038 children with ALL. TE occurred in 6.1% of children, with the highest incidence (20.5%) among those aged 15–17 years. A TE‐associated case fatality of 6.4% indicates that TE is a severe complication of ALL treatment.

MRI after removal of central venous access device reveals a high number of asymptomatic thromboses in children with haemophilia

Summary.  Central venous access devices (CVADs) are often required in children with haemophilia to secure venous access for prophylactic treatment or immune tolerance therapy. Complications of CVADs include infections, thrombosis and mechanical problems. This study sought to determine the outcome of the vessels by magnetic resonance imaging (MRI) in children with haemophilia and to assess risk factors for development of catheter‐related deep venous thrombosis (DVT). After the removal of CVAD an MRI of the chest and neck was performed to 20 boys with haemophilia who each had 1–3 (total number 27) CVADs placed. MRI revealed DVT in five children (25%). As their CVADs were functional at the time of the removal, the DVTs were clinically silent. However, there had been suspicion of DVT leading to replacement of the CVAD in one case. All the children with DVT had their CVADs inserted initially below the age of 1 year. The clinical signs of mild post‐thrombotic syndrome (PTS) were common: dilated chest wall veins were observed in 11 (55%) children and were associated with DVT in three cases. Arm circumference discrepancy was observed in one child with DVT. No correlation between the duration or number of CVADs and DVT was detected. None of the patients had subjective symptoms of PTS. Silent DVT is a common complication of CVAD. Catheter insertion at a young age seems to predispose to thrombosis. The long‐term consequences of the DVTs remain unknown.

Role of neuroimaging in children with acute lymphoblastic leukemia and central nervous system involvement at diagnosis.

Each year approximately 200 children and adolescents are diagnosed with acute lymphoblastic leukemia (ALL) in the five Nordic countries, and 3% of these have central nervous system (CNS) involvement confirmed by leukemic cells in the cerebrospinal fluid (CSF) or neurological symptoms. We sought to determine the significance of neuraxis imaging in such patients.

The impact of clinical practice on the outcome of central venous access devices in children with haemophilia

Central venous access devices facilitate home treatment in boys with haemophilia. These are usually fully implanted lines, referred to as ports. Caregivers are taught to manage the port using sterile techniques and maintaining patency by flushing with saline or heparin solution. National and international guidelines for the home care of ports are lacking.

Hypercalciuria and kidney function in children with haemophilia

Adults with haemophilia have a higher incidence of chronic kidney disease than general male population. We recently showed that children with haemophilia have higher urinary calcium excretion and lower whole body bone mineral density than controls in spite of prophylaxis with the deficient coagulation factor concentrate, serum vitamin D concentrations comparable to those of healthy children and physically active lifestyle. Persistent hypercalciuria may result in nephrocalcinosis and impact renal function. This study sought to assess persistence of urinary calcium excretion and kidney function in children with haemophilia. We investigated retrospectively urinary calcium excretion in 30 children with haemophilia (mean age 12.5 years) from consecutive urine samples over a 2‐year period. Renal evaluation included blood and urine specimen, blood pressure, and renal ultrasound. High number of children with haemophilia had intermittent hypercalciuria. Hypercalciuria was not associated with age, severity of haemophilia or previous hypercalciuria. Kidney function and renal ultrasound were normal with the exception of suspected kidney stone in one patient with haemophilia and transient hypercalciuria. Vitamin D concentrations improved after the families had received information and recommendations concerning vitamin D substitution. Our findings indicate that haemophilia per se predisposes to hypercalciuria which may in turn affect bone mineral content and kidney function. Whether childhood‐onset intermittent hypercalciuria contributes to hypertension and renal complications in adulthood remains to be elucidated in future studies.