Strategies to Prevent and Manage Thrombotic Complications of Acute Lymphoblastic Leukemia in Children and Young People Vary Between Centers in the United Kingdom.

There is a lack of evidence-based guidance for the prevention and management of thrombosis in children and young people treated for acute lymphoblastic leukemia. To determine current UK practice, a survey was sent to 28 centers participating in the Medical Research Council UKALL 2011 trial. Marked variation in practice was noted. In total, 43% of centers defer central venous access device insertion until end of induction for treatment of low-risk disease. Central venous access devices are removed at the end of intensive blocks in 38% and end of treatment in 42%. Duration of anticoagulation for line-associated thrombosis is 6 weeks in 43% and 3 months in 33% and for cerebral sinovenous thrombosis is 3 months in 71% and 6 months in 24%. Platelet transfusion to maintain platelet count >50×10/L, in preference to interrupting therapeutic anticoagulation, is used by 50% for line-associated thrombosis and 73% for cerebral sinovenous thrombosis. Conformity of practice was seen in some areas. In total, 70% treat thrombosis with twice-daily low-molecular weight heparin and 86% monitor antifactor Xa activity levels. In total, 91% reexpose individuals to asparaginase following a thrombotic event. Given this variation in practice, in the absence of high-quality evidence, consensus guidelines may be helpful.

Aspects of anticoagulation in children.

The number of children receiving anticoagulation is increasing. Thromboembolic events are associated with significant risk of morbidity and mortality although the optimal management of asymptomatic events remains unclear. Specific challenges in paediatrics include the diagnosis of thrombosis, delivery and monitoring of anticoagulation in a wide range of ages from neonates through to adolescents. The development of the haemostatic system as children age results in changing pathophysiology of thrombosis and response to anticoagulation agents. Although registry and observational studies have provided vital information, specific paediatric, prospective anticoagulation studies have been few and limited in design. The result is that much of current practice is extrapolated from adult studies. Traditional anticoagulants have significant limitations. Both heparin and warfarin are in widespread use but many fundamental questions regarding dose, therapeutic range, efficacy and optimum duration have not been fully answered. Alternative agents, such as direct thrombin inhibitors and the selective anti-factor Xa inhibitor fondaparinux, may have advantages for children. Clinical trials in adults and preliminary data in children are promising but caution should be applied until specific paediatric studies have demonstrated safety and efficacy.

Thrombosis and acute lymphoblastic leukaemia.

Venous thrombosis is more frequent in patients treated for acute lymphoblastic leukaemia (ALL) than other malignancies and has distinctive causes, clinical features and remedies. The reported incidence varies from 1% to 36%, depending on the chemotherapy protocol and whether the reported cases are symptomatic or detected on screening radiography. The risk is thought to arise from increased thrombin generation at diagnosis combined with reduced thrombin inhibitory capacity due to depletion of circulating anti-thrombin (AT) by asparaginase. A number of patient and treatment variables have been reported to influence the risk of thrombosis including hereditary thrombophilia, early insertion of central venous catheters and exposure to a combination of steroids and asparaginase during induction. Erwinia asparaginase is associated with a lower risk of thrombosis compared with Escherichia coli asparaginase. The majority of symptomatic thromboses are related to central venous catheters and involve the upper venous system. Central nervous system thrombosis involving the cerebral venous sinuses is a unique feature of asparaginase-related thrombosis and is reported to occur in 1-3% of patients. Conclusive evidence to support the use of anti-coagulant treatment or AT concentrates for primary prevention is lacking, as is evidence for the efficacy of AT concentrates in the management of established thrombosis. Preventative strategies are hampered by conflicting data on factors that would enable identification of those at highest risk of thrombosis.

Fatal pulmonary hemorrhage associated with micrococcal infection in two children with acute lymphoblastic leukemia.

Pulmonary hemorrhage is a rare cause of death in patients with acute leukemia. Within a 2-month period the authors observed two fatal pediatric cases, which were associated with opportunistic organisms of the genus Micrococcus. Both patients were receiving consolidation treatment for acute lymphoblastic leukemia. The authors discuss the causes of pulmonary hemorrhage in patients with leukemia and review the relevant literature. Micrococci have previously been considered as non-pathogenic, but there is considerable evidence for morbidity and mortality occurring, particularly in immunocompromised patients. The authors propose that micrococcal infection may have been a major predisposing factor for pulmonary hemorrhage in these thrombocytopenic patients.