BackgroundThrombotic complications in Sickle Cell Disease (SCD) arise since infancy, but the role of the coagulation system in children has been poorly explored. To determine its role in the development of clinical complications in childhood we measured coagulation and endothelial parameters in children with SCD at steady state.MethodsMarkers of thrombin generation, fibrin dissolution and endothelial activation were evaluated in 38 children with SS-Sβ°, 6 with SC disease and 50 age and blood group matched controls. Coagulation variables were correlated with markers of hemolysis and inflammation, with the presence of cerebral and lung vasculopathy and with the frequency of clinical complications.ResultsSS-Sβ° patients presented higher levels of factor VIII, von Willebrand factor antigen (VWF:Ag) and collagen binding activity, tissue plasminogen activator antigen (t-PA:Ag), D-dimer, p-selectin, prothrombin fragment1+2 (F1+2) and lower ADAMTS-13:activity/VWF:Ag (p<0.05) compared to controls and SC patients. In SS-Sβ° patients coagulation variables correlated positively with markers of inflammation, hemolysis, and negatively with HbF (p<0.05). Patients with cerebral silent infarcts showed significant decrease in t-PA:Ag and ADAMTS-13 Antigen and a tendency toward higher D-dimer, F1+2, TAT compared to patients without them. D-dimer was associated with a six fold increased risk of cerebral silent infarcts. No correlation was found between coagulation activation and large vessel vasculopathy or other clinical events except for decreased t-PA:Ag in patients with tricuspid Rigurgitant Velocity >2.5m/sec.ConclusionsSS-Sβ° disease is associated with extensive activation of the coagulation system at steady state since young age. ADAMTS-13 and t-PA:Ag are involved in the development of cerebral silent infarcts.

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Cerebrovascular complications are frequent events in children with sickle cell disease, yet routinely used techniques such as Transcranial Doppler (TCD), Magnetic Resonance (MRI) and Angiography (MRA), insufficiently explain the cause of poor cognitive performances. Forty children with SS-Sβ° (mean age 8 years) underwent neurocognitive evaluation and comprehensive brain imaging assessment with TCD, MRI, MRA, Resting State (RS) Functional MRI with evaluation of the Default Mode Network (DMN). Sixteen healthy age-matched controls underwent MRI, MRA and RS functional MRI.Children with SCD display increased brain connectivity in the DMN even in the absence of alterations in standard imaging techniques. Patients with low neurocognitive scores presented higher brain connectivity compared to children without cognitive impairment or controls, suggesting an initial compensatory mechanism to maintain performances. In our cohort steady state haemoglobin level was not related to increased brain connectivity, but SatO2<97% was. Our findings provide novel evidence that SCD is characterized by a selective disruption of connectivity among relevant regions of the brain, potentially leading to reduced cognition and altered functional brain dynamics. RS functional MRI could be used as a useful tool to evaluate cognition and cerebral damage in SCD in longitudinal trials.

INTRODUCTIONSickle Cell Disease (SCD) is the most common genetic disease worldwide. In the past decades advances in basic research and clinical investigations have produced a marked decrease in morbidity and mortality during early childhood. Newborn screening, prophylactic penicillin, effective vaccinations, and stroke prevention have largely contributed to these results [1][2]. Even though comprehensive medical care has been shown to decrease health care resource utilization and to improve quality of life [3] for patients with SCD, in the United States only 36% of children with SCD perform at least one hematology visit per year for comprehensive care [4] and the rate of missed appointments is around 45% [5]. Moreover, although medical advances have resulted in availability of improved treatments for children with SCD, less than 50% are enrolled in Transcranial Doppler (TCD) screening programs for stroke prevention both in Europe [6][7] and the United States [8][9].In many countries SCD affects people belonging to minority communities, such as African Americans in the United States or African immigrants in Europe [10]. Immigrants present cultural, social, and financial barriers in accessing the health system and these factors have an effect on the management of chronic illnesses [11][12][13].New models of comprehensive care need to be developed in order to ensure that all patients with SCD receive high quality care and benefit from the advances in clinical research, overcoming patient-related and health system-related barriers to specialized health care [14].Italy does not have a hemoglobinopathy newborn screening program and for many years pediatric hematology services have focused primarily on thalassemia. SCD has emerged as an important health condition in the last decade due to immigration, mainly from Africa and Albania, and the number of affected children is steadily increasing [15]. The majority of patients are diagnosed with SCD in the Emergency Room during acute events or because referred to a specialized center by the pediatric general practitioner, by friends or relatives. SCD is considered a rare disease and, according to the legislation of European countries, if a patient is registered as having a rare disease by a specialized reference center, patients and families can apply for disability benefits, care is free, and drugs are provided almost for free, with only a minimum contribution (prescription token). Children usually refer to their pediatric general practitioner for routine primary care, to local hospitals for emergencies and to tertiary care reference centers for specialized care.The Clinic of Pediatric Hematology-Oncology of the Azienda Ospedaliera-Università di Padova began assisting patients with SCD in 2003.From 2003 to 2005, several patient-related and health-operator related barriers to care had been noted. Patient-related barriers in seeking and accepting care regarded mainly language difficulties, socioeconomic factors (no permit of stay, precarious living conditions, low income, dif...