Valerie P. Castle

Frequency and mechanism of neonatal thrombocytopenia

We performed a 1-year prospective study of 807 consecutive infants admitted to a regional neonatal intensive care unit to determine the frequency, natural history, mechanism(s), and cause of thrombocytopenia. Thrombocytopenia developed in 22% of the infants. The platelet count nadir usually occurred by day 4 and resolved by day 10. Possible mechanisms responsible for the thrombocytopenia were assessed by comparing mean platelet volume, platelet-associated IgG (PAIgG), and coagulation test results in those infants whose platelet count fell below 100 X 10(9)/L (n = 97) with values in age-, weight-, and disease-matched control infants without thrombocytopenia (n = 80). In some thrombocytopenic infants, 111In-labeled-platelet survival, an estimate of megakaryocyte number in bone marrow biopsy specimens obtained at autopsy, and response to platelet infusions were also assessed. The thrombocytopenia was caused by increased platelet destruction, as shown by short 111In-labeled-platelet survival (12 to 128 hours), a rising mean platelet volume during the first week of life, normal numbers of megakaryocytes, and a poorer than predicted response to platelet infusions. A potential cause for the thrombocytopenia could be found in the majority of infants: 52% had elevated levels of PAIgG, 21% had laboratory evidence of disseminated intravascular coagulation, and 12% had had exchange transfusions. In contrast, the control infants had normal coagulation assay results, and only 15% had elevated levels of PAIgG. Birth asphyxia was identified as an associated risk factor for thrombocytopenia. This study demonstrates that transient, destructive thrombocytopenia develops in a large proportion (22%) of infants admitted to a neonatal intensive care unit, and that birth asphyxia is an important risk factor.

Successful treatment of infantile Hemangiomas with Interferon-α-2b

PURPOSE Hemangiomas are benign tumors occurring in 10% of infants. A small percentage are complicated by blockage of vital structures, consumptive coagulopathy, or heart failure, resulting in a mortality of -20% of patients with complications. Here, we describe four infants with complicated hemangiomas responding to interferon-alpha-2b therapy. PATIENTS AND METHODS Four children with hemangiomas were treated with interferon-alpha-2b for complicating heart failure (1), visual impairment (2), or coagulopathy (1). Patients received interferon-alpha-2b alone or in conjunction with corticosteroid therapy over 2 to 9 months. Imaging studies and urinary basic fibroblast growth factor (bFGF) levels were used to monitor treatment response. RESULTS Three of four patients demonstrated involution of the hemangiomas with improvement in their coagulopathy or visual impairment. The fourth patient expired due to cardiac complications despite radiologic evidence of hemangioma involution. Side effects associated with interferon-alpha-2b treatment included elevated transaminases (2) and leukocytosis (2), which resolved upon completion of therapy. One patient developed mild gross motor delay (1), which improved after cessation of therapy. Decreased urinary bFGF levels correlated with hemangioma involution. CONCLUSION Interferon-alpha-2b therapy is an effective, well-tolerated treatment for complicated hemangiomas. Measurement of urinary bFGF levels may provide an objective method for monitoring treatment response.

Clinical impact of neonatal thrombocytopenia

In a 1-year prospective study, the outcome in infants with a platelet count less than 100 X 10(9)/L (n = 97) was compared with the outcome in an age-, weight-, and disease-matched nonthrombocytopenic control group (n = 80). The hemostatic impact of the thrombocytopenia was assessed by modified template bleeding time, hemorrhage score, and determination of the presence and extent of intraventricular hemorrhage (IVH) in thrombocytopenic infants weighing less than 1500 at birth (n = 39) compared with all nonthrombocytopenic infants less than 1500 g (n = 122) admitted during the study period. The development outcome in infants less than 1500 g was compared at 12 months after delivery. Neonatal thrombocytopenia had a major impact on hemostatic integrity: bleeding time was inversely related to platelet count (r = -0.56, P less than 0.001) and became prolonged when the platelet count fell to less than 100 X 10(9)/L. In addition, many infants (40%) had evidence of platelet dysfunction with prolonged bleeding times despite only moderately reduced platelet counts (75 to 150 X 10(9)/L). The hemorrhage score was greater in the thrombocytopenic infants compared with the sick control infants, and increased as the platelet count fell (r = -0.58, P less than 0.001). The incidence of IVH in thrombocytopenic infants less than 1500 g was 78%, compared with 48% in the nonthrombocytopenic infants (P less than 0.01). In addition, the more severe grades of IVH were more frequent in the thrombocytopenic infants. The serious neurologic morbidity for the surviving infants less than 1500 g was 41% in the thrombocytopenic infants and 7% in the nonthrombocytopenic infants. Thus, on the basis of three indices of abnormal bleeding, thrombocytopenic infants are at greater risk for bleeding than equally sick nonthrombocytopenic infants. The thrombocytopenia itself may have contributed to the high mortality and neurologic morbidity.

Reversal of protein-losing enteropathy with heparin therapy in three patients with univentricular hearts and Fontan palliation☆☆☆★★★

We studied three pediatric patients with protein-losing enteropathy in conjunction with univentricular hearts and right atrial to pulmonary artery anastomosis (Fontan operation) before and during heparin therapy. Each patient showed dramatic improvements in symptoms, marked elevations in serum albumin levels, and quantitative reversal of enteric protein loss within a few weeks of beginning therapy. These findings suggest that heparin may be an important treatment for this poorly understood condition.

Successful treatment of neonatal arterial thromboses with recombinant tissue plasminogen activator

Seven newborns were treated with recombinant tissue plasminogen activator for arterial thromboses. Complete lysis occurred in four of seven and partial in two of seven patients. Serious bleeding complications were observed in two of seven patients. This and published experience suggest that successful lysis with recombinant tissue plasminogen activator occurs in most patients and that hemorrhagic complications are unusual but are not.

Neonatal purpura fulminans in association with factor V R506Q mutation

We report a case of neonatal purpura fulminans associated with activated protein C resistance. Analysis of DNA demonstrated heterozygosity for the factor V R506Q mutation. The neonate, at 8 hours of age, had progressive purpuric skin lesions and later had evidence of microvascular, hemorrhagic thrombosis in the brain. The baby was treated with fresh frozen plasma infusions and had complete resolution of the skin lesions and no apparent long-term complications. We suggest that activated protein C resistance testing be included in the initial evaluation of neonatal purpura fulminans.

Parotid carcinoma as a second malignancy after treatment of childhood acute lymphoblastic leukemia.

The occurrence of second malignant neoplasms (SMN) in children who survive their primary malignancy is a major cause for concern. Two children with diagnoses of intermediate-risk acute lymphoblastic leukemia (ALL) at 22 months and 2 years of age were treated with multiagent chemotherapy and prophylactic cranial irradiation. They experienced painless parotid swelling 6 and 7 years after successful treatment of the ALL. The patients underwent total parotidectomy, and a diagnosis of mucoepidermoid carcinoma was made. Both patients experienced transient facial nerve paresis. The incidence of SMN in children successfully treated for primary malignancies is 3% to 12%. Salivary gland tumors are being increasingly described in this setting. Long-term follow-up for survivors of childhood ALL is recommended with prompt assessment and resection of parotid swellings, particularly in children who have received cranial irradiation.

Kasabach-Merritt syndrome: Treatment with epsilon-aminocaproic acid and assessment by indium 111 platelet scintigraphy

The association of a coagulopathy with hemangiomas is uncommon, occurring in less than 1 in 300 hemangiomas.l, 2 The coagulopathy may consist of isolated thrombocytopenia or may be accompanied by disseminated intravascular coagulation, an association originally described in 1940 by Kasabach and Merritt. 3 The morbidity and mortality rates corresponding to this syndrome are high. 4 Attempts at therapy have included corticosteroids, radiation, surgery, embolization, and anticoagulation, all with limited success.Z,5-9 Until recently, evaluation of therapeutic effects has been hindered by the lack of a noninvasive method to assess the degree of platelet entrapment within the h emangioma.10, 11 Therapeutic intervention and assessment of efficacy are further compromised in patients with multiple sites of hemangiomatous involvement or large sites with multiple vascular supplies. We describe a patient whose clinical course was complicated by major life-threatening hemorrhagic events, whose coagulopathy responded to an approach involving antifibrinolytic therapy, and whose course was followed by a new imaging technique that displays labeled platelet uptake within the tumor. CASE REPORT A large, cavernous hemangioma involving the left thigh and buttock, and extending across the midline to the right side of the perineum, developed in the patient in her first month of life. In the first 3 months of life she was treated with elastic bandage wrapping in an attempt to diminish the proliferation rate of the hemangioSupported by the Nuclear Medicine Research Fund of the Univer

Fatal lymphoproliferative disease as a complication of evans syndrome

A 9-month-old boy had bruising and petechiae. Investigation revealed a Coombs-positive hemolytic anemia and immune-mediated thrombocytopenia. The infant was treated with intravenous immunoglobulin and steroids. The infant eventually had recurrent fevers, hepatosplenomegaly, pulmonary nodules, and parenchymal central nervous system (CNS) lesions develop. Results of a lung biopsy revealed a polyclonal lymphoproliferative disease. Polymerase chain reaction analysis showed the presence of the Epstein-Barr (EB) viral genome in the lung nodules. The infant died from progressive lung disease 6 months after the initial symptoms of Evans syndrome. Lymphoproliferative disease is known to occur in a variety of settings after immunosuppression, especially in solid organ transplant recipients. We report a case of polyclonal lymphocyte proliferation in a patient with Evans syndrome.

RADIATION INDUCED APOPTOSIS IN NEUROBLASTOMA DOES NOT DEPEND ON INDUCTION OF BAX. • 925

Wild type p53 is a transcriptional activator which plays a crucial role in the control of radiation induced apoptosis. Recent evidence suggests that p53 modulates apoptosis by upregulating the expression of Bax, a bcl-2 gene family member which functions to facilitate cell death. Importantly, Bax was only induced following radiation in cells which express wt p53. In the pediatric malignancy neuroblastoma (NB) p53 mutations are rare and most NB cell lines express wt p53. In previous studies we have determined that some NB cell lines fail to upregulate p53 following gamma radiation and are resistant to radiation induced apoptosis. Single gene transfection studies have demonstrated that induction of p53 beyond threshold levels following radiation can initiate apoptosis in NB cells. The aim of the present study was to study the kinetics of Bax induction following radiation in parental and p53 transfected NB cell lines. Western blot analysis of parental Shep-1 cells radiated at 25 Gy revealed Bax was induced and maximally expressed at 24 hours. This increase in Bax expression was seen in the absence of p53 induction. These same experiments were conducted in cell lines transfected with a temperature sensitive p53 expression construct. For these experiments cells were radiated at 25 Gy and p53 was pulse induced by placing cells at the permissive temperature(32.5°C). High level p53 expression was confirmed by quantitative immunoprecipitation. In contrast to parental cells, Shep-1 cells transfected with the temperature sensitive p53 expression construct failed to demonstrate any p53 dependent increase in Bax levels following radiation and high level p53 expression. These results suggest induction of Bax is not critical for radiation induced apoptosis in NB and that the pathway of p53-mediated apoptosis does not require Bax expression in this system.