Coagulation Activation in Children with Sickle Cell Disease Is Associated with Cerebral Small Vessel Vasculopathy

Abstract

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.

Safety Evaluation of a Standardized &lt;i&gt;Macleaya cordata&lt;/i&gt; Extract in a Ninety Day Feeding Study in Weaned Piglets

“…A decrease in haptoglobin level was often linked to hemolytic anemia, while an increase in haptoglobin level can be attributed to inflammatory diseases or physiological changes such as acute stress [22] [23]. In this study, the increase in haptoglobin level in the treatment group did not correlate with alterations in inflammatory markers (e.g., white blood cell counts did not increase) [24] and no signs of inflammatory responses or tissue damage were observed in the animals; therefore, the variation in haptoglobin measurements is not toxicologically relevant. The total serum protein levels for castrated male piglets in the T3 and T4 group were found to be significantly lower than those in the T1 group; for female piglets, total protein level was increased in T2 group but decreased in T3 group.…”

Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies

“…In addition, plasma D-dimer level was inversely correlated with the time to the next pain episode (22). However, no associations were found between both plasma TAT and D-dimer levels obtained at steady state and the frequency of acute pain crises in other studies of adults and children with SCD (23,24). The reason for these conflicting data is uncertain, but may be related to the difficulty in accurately defining the steady state in patients with SCD.…”

“…The plasma level of coagulation factor VIII (FVIII) is elevated in patients with SCD at “steady state” and during acute pain episodes compared with non-SCD controls (14,23,93–96). In one report, FVIII activity correlated with plasma levels of D-dimer, suggesting a contribution of elevated FVIII activity to coagulation activation in SCD (94).…”

“…However, the presence of thrombosis in the large and small cerebral arteries commonly described at autopsy of SCD patients with ischemic stroke suggests the participation of coagulation abnormalities to the pathogenesis of this devastating complication (111,112). Multiple studies have evaluated the association of various parameters of coagulation and cerebrovascular disease in SCD patients (21,23,24,30,143–146) (Table 2). All of these studies had cross-sectional designs and included only small numbers of patients with cerebrovascular disease.…”

What's new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura

“…Moderately decreased AD-AMTS13 activity has been reported in some patients with malaria 29,30 and sickle cell disease, 31 but ADAMTS13 <10% does not seem to occur. Plasma hemoglobin rarely exceeds 1 mg/mL in these conditions, which appears insufficient to inhibit ADAMTS13.…”