Anticoagulation therapy in children.

Thromboembolic disease (TED) is increasingly recognized as a major cause of morbidity and mortality in tertiary pediatrics. Children younger than 1 year of age and teenage girls are at greatest risk of thromboembolism. Although anticoagulation therapy is the treatment of choice for TED, the treatment strategy is often difficult, especially in children. Treatment relies largely on anticoagulation with heparin and warfarin. Recommendations for antithrombotic therapy in children have been loosely extrapolated from recommendations for adults; however, it is likely that optimal treatment of children with TED differs from adults because of important ontogenic features of hemostasis that affect both the pathophysiology of the thrombotic processes and the response to antithrombotic agents. Until recently, the primary treatment for TED has been unfractionated heparin (UFH) in conjunction with warfarin. Warfarin, the most commonly used oral anticoagulant, acts through inhibition of the vitamin K-dependent transcarboxylation reactions that convert precursors of clotting factors into their active form. Appropriate use of UFH and warfarin requires close patient monitoring and dosage adjustments to ensure tolerability and efficacy. In recent years, low molecular weight heparins (LMWH) have become available as alternatives to UFH and warfarin, for both the prevention and treatment of TED. Potentially, LMWH have significant advantages. They have superior pharmacokinetics, which results in minimal laboratory monitoring, offering important benefits to children with poor venous access. Based on available data, LMWHs are at least as effective and well tolerated as UFH, and are more convenient. Although LMWHs are more expensive than UFH, the expense is likely to be offset by savings from a reduced hospital stay.

Stratification of Wilms tumor by genetic and epigenetic analysis.

Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicated in Wilms tumor, the commonest childhood kidney cancer. In this study we analysed all five loci in 120 Wilms tumors. We identified epigenetic 11p15 abnormalities in 69% of tumors, 37% were H19 epimutations and 32% were paternal uniparental disomy (pUPD). We identified mutations of WTX in 32%, CTNNB1 in 15%, WT1 in 12% and TP53 in 5% of tumors. We identified several significant associations: between 11p15 and WTX (P=0.007), between WT1 and CTNNB1 (P less than 0.001), between WT1 and pUPD 11p15 (P=0.01), and a strong negative association between WT1 and H19 epimutation (P less than 0.001). We next used these data to stratify Wilms tumor into three molecular Groups, based on the status at 11p15 and WT1. Group 1 tumors (63%) were defined as 11p15-mutant and WT1-normal; a third also had WTX mutations. Group 2 tumors (13%) were WT1-mutant. They either had 11p15 pUPD or were 11p15-normal. Almost all had CTNNB1 mutations but none had H19 epimutation. Group 3 tumors (25%) were defined as 11p15-normal and WT1-normal and were typically normal at all five loci (P less than 0.001). We also identified a novel clinical association between H19 epimutation and bilateral disease (P less than 0.001). These data provide new insights into the pattern, order, interactions and clinical associations of molecular events in Wilms tumor.

Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor.

Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor. We explored their possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.

The impact of transfusion of leucodepleted platelet concentrates on cytomegalovirus disease after allogeneic stem cell transplantation.

The impact of transfusion of leucodepleted platelet concentrates (PCs) on cytomegalovirus (CMV) disease was assessed in 215 allogeneic (145 unrelated and 70 related donor) transplants over 3 years. In 43%, both donor and patient were CMV seronegative (CMV-/-). All received CMV-seronegative red cells and random leucodepleted PCs. No CMV disease occurred in any CMV-/- (low risk) transplant. CMV infection occurred in 31 seropositive patients (26%); 13 died and five deaths were attributable to CMV disease. When compared with historical controls, who received CMV-seronegative PCs, we found no difference in transfusion-acquired CMV in the current cohort.