Extensive Coagulation Profile in Children with Sickle Cell Disease and Its Role in Cerebral Micro-Vasculopathy

Abstract 3247

Activation of the coagulation system is present in adults with Sickle Cell Disease (SCD) who display higher levels of thrombin-antithrombin complex (TAT), prothrombin fragment F1+2, D-dimer, tissue factor and platelet activity. Whether the activation of the coagulation system is a bystander phenomenon or a main determinant of clinical complications is under investigation. Although thrombotic complications in SCD arise since infancy, the coagulation system in children has been poorly explored. We performed a comprehensive and systematic evaluation of the coagulation system in children with SCD and investigated its possible role in the development of the main clinical manifestations of SCD in childhood.

The following markers of hemostatic and endothelial function were evaluated during steady state: factor VIII activity (FVIII), von Willebrand factor antigen (vWF:Ag) and collagen binding activity (vWF:CBA), PAI-1 antigen (PAI-1:Ag), t-PA antigen (t-PA:Ag), D-dimer, P-selectin, Nitric Oxide (NO), F1+2, TAT, ADAMTS-13 antigen (ADAMTS-13:Ag) and activity (ADAMTS-13:act). Markers of hemolysis (hemoglobin, reticulocytes, aptoglobin, bilirubin, LDH), inflammation (white blood cells, neutrophils, C reactive protein) were measured. Children were not in chronic transfusion.

Magnetic Resonance (MRI), Angio Magnetic Resonance (MRA), Transcranial Doppler (TCD), Tricuspid Regurgitant Velocity (TRV) data and frequency of clinical complications were correlated with coagulation parameters. Continuous variables were compared using two-sided Student's t-test and Mann-Whitney non-parametric test, categorical variables using Chi-square and Fisher's exact test. Correlations between variables were evaluated by the Pearson or Spearman coefficient.

Thirty-five HbS/HbS- 3 HbS/betathalassemia° (20 M and 18 F, mean age 6.49 years), and 6 HbS/HbC patients (3 M and 3 F, mean age 11.2 years) were evaluated. 60% of HbS/HbS and HbS/betathalassemia° children presented higher level of FVIII, D-dimer, F1+2 and lower level of NO, revealing coagulation activation since early age in HbS/HbS and HbS/betathalassemia° but not in HbS/HbC (Table 1). Coagulation variables correlated positively with markers of inflammation, hemolysis, endothelial activation demonstrating a broad involvement of the coagulation system in these processes, while correlated negatively with HbF (Table 2). No correlation was seen between coagulation variables and cerebral large vessel vasculopathy investigated by TCD and MRA nor TRV (p >0.05). Patients with Silent Infarcts on MRI (n.9) showed significant decrease in t-PA (4.53 vs 7.67, p 0.03) and ADAMTS-13 Ag (1.15 vs 1.50, p 0.05) -suggesting the presence of endothelial dysfunction- and a tendency toward higher D-dimer (2879.01 vs 1569.51), F1+2 (319 vs 231), TAT (17.17 vs 10.46) -suggesting a trend towards enhanced clotting activation compared to patients without Silent infarcts (n.21). Increase in D-dimer was associated with a Relative risk of 6 (p <0.05) to develop Silent Infarcts. No correlation was found between coagulation activation and Acute Chest Syndrome or Vaso-occlusive crisis.