Thrombophilic risk factors are associated with thromboembolism in children but data in infants an... more Thrombophilic risk factors are associated with thromboembolism in children but data in infants and neonates are not well established. The authors report a series of 9 infants with thrombotic events and the associated genetic risk factors. The clinical and laboratory records of newborns and infants with a history of thrombotic events were summarized, while patients with underlying diseases were excluded. The frequency of the genetic mutations was compared to a control group of 80 children from the same ethnic origin. In 6 patients a cerebrovascular accident was diagnosed and in 3 newborns, CT scan could diagnose antenatal brain infarct. In another 2 patients deep-vein thrombosis associated with femoral catheterization was diagnosed. Seven infants were factor V Leiden heterozygous and another one homozygous. Methylenetetrahydrofolate reductase genotype was found in 5 infants. Five cases were found to be double heterozygous for those two mutations, and another one double heterozygous for FVL and factor II. The results of this small series of patients indicate that cerebrovascular accident is the major thrombotic event in infants and the combination of more than one prothrombotic factors may be the cause of those events. The correct management, including anticoagulant therapy, is still under discussion and waiting for larger series and long-term follow-up results until accurate recommendations can be made.
... DISEASE Ariel Koren (Kurlat), MD, and Rafael Halevi, MD 0 Pediatric Department B, Central Eme... more ... DISEASE Ariel Koren (Kurlat), MD, and Rafael Halevi, MD 0 Pediatric Department B, Central Emek Hospital, Afula 18101, Israel ... pain 2. Hebbel RP, Eaton JW, Steinberg MH, White JG: Erythrocyte/endothelial interactions in the patho-...
Legg-Calvé-Perthes disease is an idiopathic osteonecrosis or avascular necrosis of the capital fe... more Legg-Calvé-Perthes disease is an idiopathic osteonecrosis or avascular necrosis of the capital femoral epiphysis and the associated complications thereof occurring in an immature growing child. The association between osteonecrosis of the femoral head and thrombophilia was postulated by Glueck in 1994. We describe Legg-Calvé-Perthes disease associated with protein C deficiency and beta-thalassemia major in two children among a cohort of 79 beta-thalassemia patients treated in our clinic. The association of thrombophilia, aseptic necrosis of the femoral head, and beta-thalassemia has not been previously described in the literature.
Two siblings with congenital neutropenia are reported. The first patient, female, died after Pseu... more Two siblings with congenital neutropenia are reported. The first patient, female, died after Pseudomonas sepsis. The second patient male, suffered from recurrent pyogenic infections, with a more benign course. Bone Marrow (BM) and Peripheral Blood (PB) analysis in the second patient revealed a reduced number of granules and myelin bodies in the PB neutrophils, suggesting a developmental defect of primary and secondary granules. BM promyelocytes were almost normal, but the myelocytes and metamyelocytes showed defective granulogenesis. The BM in vitro granulocyte-macrophage-colony-forming cell (GM-CFC) growth and the PB white blood cells (WBC) granulocyte-macrophage-colony-stimulating factor (GM-CSF) production, which were analyzed in the second patient, showed normal numbers of GM-CFC, with differentiation mostly toward monocytes and a defect in the GM-CSF production capacity. The second patient's PB mononuclear cells or serum did not inhibit normal GM-CFC when added to control BM cells. We suggest that in this specific form of congenital neutropenia, which is probably an autosomal recessive disorder, the abnormal neutrophil granule production and the defective provision of GM-CSF by PB WBC are unique pathognomonic characteristics, possibly associated with the overt neutropenia.
Two cases of unilateral and bilateral periorbital hematomas occurred in patients with sickle cell... more Two cases of unilateral and bilateral periorbital hematomas occurred in patients with sickle cell anemia. The cause of periorbital swelling in these cases was found to be orbital and frontal bone infarctions, respectively, diagnosed by technetium Tc 99m medronate bone scintigraphy. To our knowledge, periorbital bone infarction, as a part of the differential diagnosis of periorbital hematoma and as part of the possible ocular manifestations in patients with sickle cell anemia, has not previously been described.
Serum immunoglobulin concentrations (IgG, IgA, and IgM) were measured in 34 children before and a... more Serum immunoglobulin concentrations (IgG, IgA, and IgM) were measured in 34 children before and after splenectomy. Splenectomy was performed either after trauma or for an underlying hematologic disorder. In the patients with a hematologic disorder, we found a significant decrease in the IgM level after splenectomy. The IgM concentration remained low for a two-year period. Those patients who were "afebrile" during the study period had the lowest IgM levels. No significant changes were observed in the IgM levels in the group that underwent a splenectomy because of trauma. No significant changes were found in IgG or IgA levels in either group. A low IgM level in patients with hematologic disorders may have contributed to a defect in opsonization and to a high incidence of overwhelming infection soon after splenectomy in this group. In the group that underwent a splenectomy because of trauma, the normal IgM level may have protected them and contributed to the lower incidence of infection in this group.
SummaryThe etiology and pathophysiology of cerebral sinus venous thrombosis (CSVT) in the paediat... more SummaryThe etiology and pathophysiology of cerebral sinus venous thrombosis (CSVT) in the paediatric population is still poorly understood, and the role of thrombophilic risk factors remains to be elucidated. In our multi-center case-controlled study we studied 46 patients with CSVT diagnosed from April 1996 to December 2003, consecutively referred for thrombophilia work-up. The results of thrombophilia screen were compared to 112 healthy paediatric controls. Anticoagulant therapy was applied according to treating physicians’ decisions, and all cases were prospectively followed for a median of 4.1 years. Of 46 children, 8 had CSVT diagnosed in the neonatal period and therefore were analyzed separately. The prevalence of single thrombophilia markers and combinations of thrombophilic risk factors were similar among cases and controls. Among children with CSVT co-morbid systemic illness was present in most patients at diagnosis. Seven out of 8 children with idiopathic CSVT had thrombophilic risk factors as compared to 31/38 patients with co-morbid conditions. Anticoagulation was initiated in most patients, 11/46 patients continued therapy for a total of one year or more post event. Neither clinical presentation nor initial treatment decisions were affected by presence of thrombophilic risk factors in our study group. Thrombophilia prevalence was not increased in children with CSVT as compared to controls, however thrombophilia was more frequent among children with idiopathic CSVT. Thus, those selected patients would benefit most from thrombophilia work-up, required for long-term therapy considerations.
Severe protein C deficiency due to biallelic PROC mutations is an extremely rare thrombophilia, m... more Severe protein C deficiency due to biallelic PROC mutations is an extremely rare thrombophilia, most commonly presenting during the neonatal period as purpura fulminans. Despite treatment, severe morbidity and mortality are frequent. The current study reports 3 unrelated patients harboring novel homozygous PROC mutations and their clinical phenotypes. We discuss how the cytoprotective activity of protein C and its role in the stabilization of endothelial barriers may account for the unique symptoms of this thrombophilia.
neurological recovery in both cases. This approach allowed definitive neuraxis radiation therapy ... more neurological recovery in both cases. This approach allowed definitive neuraxis radiation therapy to be deferred until transplant conditioning for Case 1, and this was the planned therapy for Case 2. The role of haematopoietic stem cell transplantation in the management of Ph+ ALL is likely to evolve, but patients with unfavourable features, such as the cases presented, are likely to benefit from allogeneic transplantation following intensive induction therapy combined with a tyrosine kinase inhibitor. An excellent response measured by MRD detection may identify a subgroup with a good survival following transplantation (Cazzaniga et al, 2002; Lee et al, 2009). Additional post-transplant tyrosine kinase inhibitor therapy is well tolerated and may be an important factor in maintaining remission (Carpenter et al, 2007). In summary, we conclude that dasatinib and multi-agent chemotherapy are effective in controlling multiple childhood intracranial Ph+ ALL tumours and can be used as an alternative to emergent cranial radiation therapy. We suggest that this approach strikes a balance between maintaining the chance of cure whilst at the same time minimizing the potential for neurocognitive late effects. Acknowledgements
Thrombophilic risk factors are associated with thromboembolism in children but data in infants an... more Thrombophilic risk factors are associated with thromboembolism in children but data in infants and neonates are not well established. The authors report a series of 9 infants with thrombotic events and the associated genetic risk factors. The clinical and laboratory records of newborns and infants with a history of thrombotic events were summarized, while patients with underlying diseases were excluded. The frequency of the genetic mutations was compared to a control group of 80 children from the same ethnic origin. In 6 patients a cerebrovascular accident was diagnosed and in 3 newborns, CT scan could diagnose antenatal brain infarct. In another 2 patients deep-vein thrombosis associated with femoral catheterization was diagnosed. Seven infants were factor V Leiden heterozygous and another one homozygous. Methylenetetrahydrofolate reductase genotype was found in 5 infants. Five cases were found to be double heterozygous for those two mutations, and another one double heterozygous for FVL and factor II. The results of this small series of patients indicate that cerebrovascular accident is the major thrombotic event in infants and the combination of more than one prothrombotic factors may be the cause of those events. The correct management, including anticoagulant therapy, is still under discussion and waiting for larger series and long-term follow-up results until accurate recommendations can be made.
... DISEASE Ariel Koren (Kurlat), MD, and Rafael Halevi, MD 0 Pediatric Department B, Central Eme... more ... DISEASE Ariel Koren (Kurlat), MD, and Rafael Halevi, MD 0 Pediatric Department B, Central Emek Hospital, Afula 18101, Israel ... pain 2. Hebbel RP, Eaton JW, Steinberg MH, White JG: Erythrocyte/endothelial interactions in the patho-...
Legg-Calvé-Perthes disease is an idiopathic osteonecrosis or avascular necrosis of the capital fe... more Legg-Calvé-Perthes disease is an idiopathic osteonecrosis or avascular necrosis of the capital femoral epiphysis and the associated complications thereof occurring in an immature growing child. The association between osteonecrosis of the femoral head and thrombophilia was postulated by Glueck in 1994. We describe Legg-Calvé-Perthes disease associated with protein C deficiency and beta-thalassemia major in two children among a cohort of 79 beta-thalassemia patients treated in our clinic. The association of thrombophilia, aseptic necrosis of the femoral head, and beta-thalassemia has not been previously described in the literature.
Two siblings with congenital neutropenia are reported. The first patient, female, died after Pseu... more Two siblings with congenital neutropenia are reported. The first patient, female, died after Pseudomonas sepsis. The second patient male, suffered from recurrent pyogenic infections, with a more benign course. Bone Marrow (BM) and Peripheral Blood (PB) analysis in the second patient revealed a reduced number of granules and myelin bodies in the PB neutrophils, suggesting a developmental defect of primary and secondary granules. BM promyelocytes were almost normal, but the myelocytes and metamyelocytes showed defective granulogenesis. The BM in vitro granulocyte-macrophage-colony-forming cell (GM-CFC) growth and the PB white blood cells (WBC) granulocyte-macrophage-colony-stimulating factor (GM-CSF) production, which were analyzed in the second patient, showed normal numbers of GM-CFC, with differentiation mostly toward monocytes and a defect in the GM-CSF production capacity. The second patient's PB mononuclear cells or serum did not inhibit normal GM-CFC when added to control BM cells. We suggest that in this specific form of congenital neutropenia, which is probably an autosomal recessive disorder, the abnormal neutrophil granule production and the defective provision of GM-CSF by PB WBC are unique pathognomonic characteristics, possibly associated with the overt neutropenia.
Two cases of unilateral and bilateral periorbital hematomas occurred in patients with sickle cell... more Two cases of unilateral and bilateral periorbital hematomas occurred in patients with sickle cell anemia. The cause of periorbital swelling in these cases was found to be orbital and frontal bone infarctions, respectively, diagnosed by technetium Tc 99m medronate bone scintigraphy. To our knowledge, periorbital bone infarction, as a part of the differential diagnosis of periorbital hematoma and as part of the possible ocular manifestations in patients with sickle cell anemia, has not previously been described.
Serum immunoglobulin concentrations (IgG, IgA, and IgM) were measured in 34 children before and a... more Serum immunoglobulin concentrations (IgG, IgA, and IgM) were measured in 34 children before and after splenectomy. Splenectomy was performed either after trauma or for an underlying hematologic disorder. In the patients with a hematologic disorder, we found a significant decrease in the IgM level after splenectomy. The IgM concentration remained low for a two-year period. Those patients who were "afebrile" during the study period had the lowest IgM levels. No significant changes were observed in the IgM levels in the group that underwent a splenectomy because of trauma. No significant changes were found in IgG or IgA levels in either group. A low IgM level in patients with hematologic disorders may have contributed to a defect in opsonization and to a high incidence of overwhelming infection soon after splenectomy in this group. In the group that underwent a splenectomy because of trauma, the normal IgM level may have protected them and contributed to the lower incidence of infection in this group.
SummaryThe etiology and pathophysiology of cerebral sinus venous thrombosis (CSVT) in the paediat... more SummaryThe etiology and pathophysiology of cerebral sinus venous thrombosis (CSVT) in the paediatric population is still poorly understood, and the role of thrombophilic risk factors remains to be elucidated. In our multi-center case-controlled study we studied 46 patients with CSVT diagnosed from April 1996 to December 2003, consecutively referred for thrombophilia work-up. The results of thrombophilia screen were compared to 112 healthy paediatric controls. Anticoagulant therapy was applied according to treating physicians’ decisions, and all cases were prospectively followed for a median of 4.1 years. Of 46 children, 8 had CSVT diagnosed in the neonatal period and therefore were analyzed separately. The prevalence of single thrombophilia markers and combinations of thrombophilic risk factors were similar among cases and controls. Among children with CSVT co-morbid systemic illness was present in most patients at diagnosis. Seven out of 8 children with idiopathic CSVT had thrombophilic risk factors as compared to 31/38 patients with co-morbid conditions. Anticoagulation was initiated in most patients, 11/46 patients continued therapy for a total of one year or more post event. Neither clinical presentation nor initial treatment decisions were affected by presence of thrombophilic risk factors in our study group. Thrombophilia prevalence was not increased in children with CSVT as compared to controls, however thrombophilia was more frequent among children with idiopathic CSVT. Thus, those selected patients would benefit most from thrombophilia work-up, required for long-term therapy considerations.
Severe protein C deficiency due to biallelic PROC mutations is an extremely rare thrombophilia, m... more Severe protein C deficiency due to biallelic PROC mutations is an extremely rare thrombophilia, most commonly presenting during the neonatal period as purpura fulminans. Despite treatment, severe morbidity and mortality are frequent. The current study reports 3 unrelated patients harboring novel homozygous PROC mutations and their clinical phenotypes. We discuss how the cytoprotective activity of protein C and its role in the stabilization of endothelial barriers may account for the unique symptoms of this thrombophilia.
neurological recovery in both cases. This approach allowed definitive neuraxis radiation therapy ... more neurological recovery in both cases. This approach allowed definitive neuraxis radiation therapy to be deferred until transplant conditioning for Case 1, and this was the planned therapy for Case 2. The role of haematopoietic stem cell transplantation in the management of Ph+ ALL is likely to evolve, but patients with unfavourable features, such as the cases presented, are likely to benefit from allogeneic transplantation following intensive induction therapy combined with a tyrosine kinase inhibitor. An excellent response measured by MRD detection may identify a subgroup with a good survival following transplantation (Cazzaniga et al, 2002; Lee et al, 2009). Additional post-transplant tyrosine kinase inhibitor therapy is well tolerated and may be an important factor in maintaining remission (Carpenter et al, 2007). In summary, we conclude that dasatinib and multi-agent chemotherapy are effective in controlling multiple childhood intracranial Ph+ ALL tumours and can be used as an alternative to emergent cranial radiation therapy. We suggest that this approach strikes a balance between maintaining the chance of cure whilst at the same time minimizing the potential for neurocognitive late effects. Acknowledgements
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