Vinod V. Balasa

Low-dose tissue plasminogen activator thrombolysis in children

Purpose To compare results of low-dose tissue plasminogen activator (TPA) in children with arterial and venous thrombi relative to standard published dosing. Methods Subjects consisted of all consecutive children with objectively confirmed thrombi for whom TPA thrombolysis was clinically ordered by the authors. Initial dosing used published standard dose (0.1–0.5 mg/kg per hour). With experience, a low-dose regimen (0.01–0.06 mg/kg per hour) was given in an attempt to derive a minimal effective dose. Results Thirty-five children were treated with TPA. Either standard or low-dose infusions of TPA resulted in complete thrombolysis of 28 of 29 (97%) acute thrombi, while all 6 chronic thrombi had a partial response. In contrast to the recommended adult-derived dosages of 0.1 to 0.5 mg/kg per hour, the authors found that initial doses of less than 0.01 mg/kg per hour were effective in 12 of 17 patients with acute thrombosis. Neonates required 0.06 mg/kg per hour. Route of administration (local or systemic) did not affect efficacy. Major bleeding occurred in only one extremely preterm infant. Minor bleeding, primarily oozing at intravenous sites, occurred in 27% of children during TPA infusions. Prophylactic unfractionated or low-molecular-weight heparin was infused concomitant with TPA in 42% of the children and did not increase the risk of bleeding. Conclusions TPA in very low doses appears to be safe and effective for thrombolysis of acute thromboses in most children, given appropriate patient selection.

Legg-Calvé-Perthes disease and thrombophilia

BACKGROUND Thrombophilia has previously been identified as a potential etiologic factor in Legg-Calve-Perthes disease. We prospectively studied the association between Legg-Calve-Perthes disease and coagulation abnormalities by comparing seventy-two children who had the disease with 197 healthy controls. METHODS A nonselected, consecutive series of seventy-two patients with Legg-Calve-Perthes disease (mean age [and standard deviation], 6.6 +/- 2.6 years) was studied in their order of referral and compared with 197 healthy controls (mean age, 7.6 +/- 5.1 years). Assays were done for factor-V Leiden, prothrombin G20210A, methylenetetrahydrofolate reductase C677T, and plasminogen activator inhibitor-1 4G/5G gene mutations. Levels of anticardiolipin antibodies immunoglobulin G and M (IgG and IgM), homocysteine, protein C, protein S, antithrombin III, and plasminogen activator inhibitor-1 were also measured. RESULTS The factor-V Leiden mutation was more common in the patients (eight of seventy-two) than in the controls (seven of 197) (chi-square = 5.7, p = 0.017). After we controlled for the false-discovery rate, the case-control difference remained significant (p = 0.017). The odds ratio for the development of Legg-Calve-Perthes disease in the presence of the factor-V Leiden mutation was 3.39 with a 95% confidence interval of 1.18 to 9.73. A high level of anticardiolipin antibodies (IgG and/or IgM) was found in nineteen of the seventy-two patients compared with twenty-two of the 197 controls (chi-square = 9.5, p = 0.002). After we controlled for the false-discovery rate, the case-control difference remained significant (p = 0.002). The odds ratio of patients with Legg-Calve-Perthes disease having one or more abnormalities in factor V, anticardiolipin antibody IgG, or anticardiolipin antibody IgM as opposed to normal values for all three variables was 3.29 (95% confidence interval, 1.73 to 6.24; p = 0.0003). CONCLUSIONS Two thrombophilic risk factors, the factor-V Leiden mutation and anticardiolipin antibodies, are associated with Legg-Calve-Perthes disease, an association that may reflect causality. LEVEL OF EVIDENCE Prognostic study, Level II-1 (retrospective study). See Instructions to Authors for a complete description of levels of evidence.

Disparity in the management of iron overload between patients with sickle cell disease and thalassemia who received transfusions.

BACKGROUND: Transfusion therapy is frequently used to prevent morbidity in sickle cell disease (SCD), and subsequent iron overload is common. The objective of this study was to evaluate the current standard of care in monitoring iron overload and related complications in patients with SCD compared to thalassemia (Thal).

Correlation of the C677T MTHFR genotype with homocysteine levels in children with sickle cell disease

Recently, a mild to moderate elevation in the plasma homocysteine (Hcy) level has been found to be an important risk factor for stroke. Homozygosity for a common mutation (C677T) in the gene encoding for the enzyme methylenetetrahydrofolate reductase (MTHFR) involved in Hcy metabolism has been associated with increased levels of Hcy. To determine the role of hyperhomocysteinemia in the pathogenesis of stroke in children with sickle cell disease (SCD), Hcy levels and C677T MTHFR genotype were determined in 40 patients homozygous for hemoglobin SS and compared with 197 healthy children. Eleven of 40 patients with SCD had a history of stroke. The prevalence of homozygosity for the C677T MTHFR variant was 5% in the patients with SCD. The median Hcy level was 5.8 micromol/L in the patients versus 5.4 micromol/L in the controls (Fishers, P > 0.05). There was no correlation of Hcy levels with the MTHFR genotype in patients with SCD. In patients with SCD and stroke, the median Hcy level was 4.8 micromol/L versus 6.0 micromol/L in those without stroke (P = 0.44, Mann-Whitney rank sum test). There was no difference in the proportion of patients with SCD with or without stroke who were homozygous for the C677T MTHFR mutation (0/11 versus 2/29; Fishers, P = 1.000). In conclusion, this study failed to demonstrate an elevation in plasma Hcy levels in children with SCD compared with normal controls. Furthermore, hyperhomocysteinemia did not seem to be a significant factor in the pathogenesis of stroke in children with SCD.

Hyperhomocysteinemia is associated with low plasma pyridoxine levels in children with sickle cell disease

Elevated plasma homocysteine levels have been shown to be a risk factor for endothelial cell damage and thrombosis, which are implicated in sickle cell disease (SCD)-related vaso-occlusion. The aim of this study was to determine the prevalence of hyperhomocysteinemia in SCD. Fasting and postmethionine load (PML) homocysteine, red cell folate, and the MTHFR C677T mutation were determined in 77 patients with SCD and 110 African-American controls. Plasma methylmalonic acid and pyridoxine levels were determined in 54 patients and all controls. For analysis, the subjects were divided into two age groups (2–10 years and 10.1–21 years). In both age groups, median PML homocysteine levels were significantly elevated in patients with SCD compared with controls. Fasting homocysteine levels were elevated in patients with SCD versus controls only in those older than 10 years. Hyperhomocysteinemia was noted in 38% of patients versus 7% in controls. Folate levels were higher among patients than controls and showed a significant negative correlation with PML homocysteine levels in patients with SCD. Pyridoxine levels in patients with SCD were significantly lower than in controls and showed a negative correlation with PML homocysteine levels. Among patients with SCD, pyridoxine deficiency was more common (62%) among those with hyperhomocysteinemia compared with those with normal homocysteine levels (30%). Homozygosity for the MTHFR C677T mutation was rare. These data suggest that children with SCD have significant hyperhomocysteinemia, associated with pyridoxine and relative folate deficiencies.

New anticoagulants : A pediatric perspective

Unfractionated heparin and vitamin K antagonists such as warfarin have been used as the anticoagulants of choice for over five decades. Subsequently, low molecular weight heparins (LMWHs) became widely available and have provided several advantages, especially in infants and children. The field of anticoagulation, however, has undergone a major revolution with better understanding of the structure of coagulation proteins and the development of a host of new drugs with highly specific actions. Many of these drugs have undergone extensive clinical testing in adults and have been approved for specific indications in adults. Unfortunately, clinical data and the reported use of these drugs in children are extremely limited. A lack of familiarity with the actions and pharmacokinetic properties of these drugs could be a major contributing factor. This review focuses on several of the new anticoagulants, with a special emphasis on those that could be potentially beneficial in pediatric patients with thromboembolic disorders. The need for well‐designed trials with large‐scale participation by pediatric hematologists in order to improve the antithrombotic care of young infants and children is also emphasized.