Manuela Albisetti

Impact of Thrombophilia on Risk of Arterial Ischemic Stroke or Cerebral Sinovenous Thrombosis in Neonates and Children A Systematic Review and Meta-Analysis of Observational Studies

Background— The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. Methods and Results— A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95% CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95% CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95% CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95% CI, 2.29 to 5.53); and factor II, 2.02 (95% CI, 1.02 to 3.99). Conclusions— The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigated.

Impact of Inherited Thrombophilia on Venous Thromboembolism in Children A Systematic Review and Meta-Analysis of Observational Studies

Background— The aim of the present study was to estimate the impact of inherited thrombophilia (IT) on the risk of venous thromboembolism (VTE) onset and recurrence in children by a meta-analysis of published observational studies. Methods and Results— A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2007 was conducted using key words in combination as both MeSH terms and text words. Citations were independently screened by 2 authors, and those meeting the inclusion criteria defined a priori were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, VTE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios and 95% CIs were calculated with both fixed-effects and random-effects models. Thirty-five of 50 studies met inclusion criteria. No significant heterogeneity was discerned across studies. Although >70% of patients had at least 1 clinical risk factor for VTE, a statistically significant association with VTE onset was demonstrated for each IT trait evaluated (and for combined IT traits), with summary odds ratios ranging from 2.63 (95% CI, 1.61 to 4.29) for the factor II variant to 9.44 (95% CI, 3.34 to 26.66) for antithrombin deficiency. Furthermore, a significant association with recurrent VTE was found for all IT traits except the factor V variant and elevated lipoprotein(a). Conclusions— The present meta-analysis indicates that detection of IT is clinically meaningful in children with, or at risk for, VTE and underscores the importance of pediatric thrombophilia screening programs.

Normal values for aortic diameters in children and adolescents – assessment in vivo by contrast-enhanced CMR-angiography

BackgroundContrast-enhanced CMR angiography (CE-CMRA) is being increasingly used for diagnosing aortic arch anomalies, planning interventions and follow-up assessment. We sought to establish normal values for the diameters of the thoracic aorta and reference curves related to body growth in children using CE-CMRA.ResultsCE-CMRA was performed in 53 children without cardiovascular disease. The median age was 9 years (range 2 – 20 years), weight 30 kg (range 12 – 75 kg), height 131 cm (range 81 – 184 cm), body surface area (BSA) 1.05 m2 (range 0.52–1.9 m2). Aortic diameters were measured at nine standardized sites on oblique maximum-intensity projection (MIP) images. Regression analysis of diameters in relation to BSA demonstrated linear relationship between the cross-sectional aortic diameters and the square root of BSA (BSA0.5). Normative diameters were (0.57 + 19.37*BSA0.5) mm for the aortic sinus, (-3.52 + 18.66*BSA0.5) mm for the first segment of the aortic arch, (-3.37 + 16.52*BSA0.5) mm for the isthmic region and (-1.27 + 9.89*BSA0.5) mm for the descending aorta at the level of the diaphragm. Normative curves are presented.ConclusionThis study provides normative values for aortic diameters in children measured by CE-CMRA. These data may serve for making the diagnosis of pediatric arch anomalies, assessing the need for treatment and planning interventions.

Low molecular weight heparin in children

Abstract. Low molecular weight heparins potentially have significant advantages over unfractionated heparin and oral anticoagulants for both the prevention and treatment of thromboembolic events in children. Compared to standard heparin, low molecular weight heparins have superior bioavailability, a longer half-life, and a dose-independent clearance, which results in a more predictable anticoagulant response. Low molecular weight heparins are administered subcutaneously and require minimal laboratory monitoring and dose adjustment, offering important benefits to children with poor venous access. In addition, complications including osteoporosis and heparin-induced thrombocytopenia are relatively rare with low molecular weight heparins compared to unfractionated heparin. Conclusion: based on the available data, low molecular weight heparins seem to be an efficient and safe alternative to standard anticoagulation therapy with unfractionated heparin and oral anticoagulants for both treatment and prevention of thromboembolic events in children of varying ages and underlying disorders.

Diagnostic value of cerebrospinal fluid examination in children with peripheral facial palsy and suspected Lyme borreliosis.

Our objective was to determine the diagnostic value of CSF examinations in the diagnosis of neuroborreliosis in children with peripheral facial palsy(PFP). Paired serum and CSF samples from 21 children with PFP were investigated for antibody responses to Borrelia burgdorferi antigens using three different ELISA systems and one Western blot assay. Twenty of the children (95%) had detectable immunoglobin (Ig) M or IgG in the acute-phase serum, but discrepancies between serologic assays were noted in 33% for IgM and 22 to 50% for IgG. Intrathecal specific-antibody production was detected in five of the 20 seropositive children (25%). These five patients showed seroconversion in convalescent sera in at least one assay. Similar seroconversion suggesting recent infection with B. burgdorferi was observed in eight of the 10 children (80%) without intrathecal specific-antibody production, from whom convalescent serum samples could be obtained. All patients with intrathecal antibodies or seroconversion had shown lymphocytic pleocytosis in the acute phase of PFP. In the acute phase of PFP the detection of intrathecal production of antibodies to B. burgdorferi allows prompt diagnosis of neuroborreliosis. For patients with lymphocytic pleocytosis but no detectable intrathecal antibodies, analysis of convalescent serum may help to establish this diagnosis.

Port-A-Cath–Related Thrombosis and Postthrombotic Syndrome in Pediatric Oncology Patients

OBJECTIVE To investigate Port-A-Cath (PAC)-related thrombosis and postthrombotic syndrome (PTS) in children with cancer. STUDY DESIGN The study population was a consecutive cohort of children diagnosed with cancer and a PAC implanted at diagnosis. Children were evaluated for the presence of PAC-related thrombosis by magnetic resonance venography and the presence of congenital prothrombotic risk factors and PTS. RESULTS A total of 114 children (median age, 6.04 years) were included. Of these children, 48 (42%) were treated for solid tumors and 66 (58%) were treated for hematopoietic tumors, including 38 for acute lymphoblastic leukemia. At the time of magnetic resonance venography, 42 children (37%) had the PAC still in place, and 72 (63%) had the PAC removed. Overall, PACs were in place for a total of 324.92 PAC-years. PAC-related thrombosis was detected in 45 children (39.5%) with a current or previous PAC. Of these, 21 (47%) had a solid tumor, 14 (31%) had acute lymphoblastic leukemia, and 10 (22%) had another hematopoietic tumor. Younger age at diagnosis, female sex, duration of PAC use, and left-side PAC placement were independently associated with an increased risk of thrombosis, whereas asparaginase therapy and the presence of inherited prothrombotic risk factors were not. Mild PTS (ie, presence of prominent collateral vessels in the skin) was present in 5.6% of the children. CONCLUSION PAC-related thrombosis is common in pediatric oncology patients. In some children, thrombotic complications can lead to the development of PTS.

Congenital Prothrombotic Disorders in Children with Peripheral Venous and Arterial Thromboses

Aims: To evaluate the prevalence of congenital prothrombotic disorders in children with peripheral venous and arterial thromboses. Methods: Deficiencies in antithrombin (AT), proteins C (PC) and S (PS), and increased lipoprotein (a), and the presence of factor V (FV) G1691A, prothrombin G20210A and methylenetetrahydrofolate reductase (MTHFR) mutations were investigated. Results: Forty-eight patients (mean age, 3.4 years) were investigated. Of these patients, 23 had venous thrombosis, 22 had arterial thrombosis, and 3 had both. No patients had AT, PC or PS deficiency. FV G1691A mutation was present in 2 (7.6%) and 3 (12%) patients with venous and arterial thromboses, respectively. The prothrombin G20210A mutation was present in 1 (4%) patient with arterial thrombosis. Homozygous MTHFR C677T mutation was detected in 4 (18%) and 2 (9%) patients with venous and arterial thromboses, respectively. Increased lipoprotein (a) was present in 2 (10%) and 1 (4.5%) patients with venous and arterial thromboses, respectively. Regarding acquired risk factors, 79% of all thrombotic events were related to catheter usage. An underlying disease was present in 96% of the patients. Conclusions: Compared to acquired risk factors, congenital prothrombotic disorders are rarely present in children with peripheral venous and arterial thromboses. These results do not support general screening of children with venous and arterial thromboses for congenital prothrombotic disorders.

Incidence and predictors of indwelling arterial catheter-related thrombosis in children

Summary.  Background: Indwelling arterial catheters (IACs) are used for monitoring and blood sampling purposes in intensive care units. Very limited information is available on the incidence and risk factors of IAC‐related thrombosis in children. Objective: To investigate the incidence and predictors of IAC‐related thrombosis in a tertiary care pediatric hospital. Methods:  For a period of 12 months, detailed information was prospectively recorded for all consecutive children requiring IACs. Results: Six hundred and fifteen IACs were placed in a total of 473 children at a median age of 0.56 years for a total of 47 440.84 catheter hours. Of the 615 IACs, 418 (68%) were placed in the radial artery, 137 (22%) in the femoral artery, 26 (4%) in the umbilical artery, 11 (2%) in the brachial artery, and 23 (3.7%) in another artery. Thrombosis occurred in 20 cases, reflecting an overall incidence of 3.25%. Eighteen of the 20 IAC‐related thrombi were located in the femoral arteries, reflecting a relative incidence of 13% (18/137). Newborn age, lower body weight, low cardiac output and increased hematocrit were significantly related with an increased risk of femoral artery thrombosis. In logistic regression analysis, younger age (P < 0.001, odds ratio 6.51) was independently associated with an increased thrombotic risk. Conclusions: This study demonstrates that arterial thrombosis occurs with an increased incidence in children requiring IACs in the femoral location. Younger age is independently associated with an increased risk of thrombosis. The radial location is safe, and should be preferred to the femoral location.

Fibrinolytic system in adolescents: response to venous occlusion stress tests.

Recent studies indicate that the incidence of thromboembolic events is increasing as a secondary complication in children with serious underlying diseases. The mechanism to eliminate these thrombi via the thrombolytic system in children is unknown. The baseline fibrinolytic system is age dependent, with significant variation between children and adults. Adult studies would suggest that the fibrinolytic response to venous occlusion has more clinical relevance than the baseline fibrinolytic system. The aim of this study was to determine whether the fibrinolytic response to venous occlusion stress testing in healthy adolescents differs from the response in healthy adults. Healthy adolescents (13-18 y) from a school population and normal adults were recruited. Pre-and postvenous occlusion blood samples were collected using standard techniques. Plasma tissue plasminogen activator, plasminogen activator inhibitor-1, plasminogen, α2-antiplasmin, α2-macroglubulin, D-dimers, euglobulin lysis time, and fibrinogen were measured on each sample. Adolescents had significantly decreased tissue plasminogen activator antigen levels and increased plasminogen activator inhibitor-1 activity levels after venous occlusion, resulting in significantly prolonged euglobulin lysis times. The results of our study confirm developmental differences in the fibrinolytic response to venous occlusion stress testing. The age-related differences in fibrinolytic response to venous occlusion of younger children and the significance of these differences on the pathophysiology of thromboembolic events in children require further studies.

Hepatic steatosis : A frequent non-specific finding in HIV-infected children

Abstract Thirty HIV-infected children were cross-sectionally examined for morphologic hepatic abnormalities, using ultrasonography or histology. Abdominal ultrasonography was performed in 27 children. The liver structure was normal in four patients, one of whom had moderate symptoms of the HIV infection and three of them severe symptoms. Abnormal liver structure, compatible with hepatic steatosis, was found in 23 (85%) patients. Five of them were in an early stage of the HIV infection (category N or A), three patients were ranked in category B and 15 patients in category C. Histological examination of the liver was performed in 11 children and steatosis was documented in ten (91%). In seven (70%) of these ten children steatosis had been suspected by ultrasonography. In conclusion, steatosis is common in HIV-infected children. It is non-specific and has no impact on disease, diagnostic evaluation or management. Conclusion Ultrasonography is a sensitive, accurate, non-invasive screening tool. It is more reliable than liver function tests.