Page 62 - Haematologica July

S. Tewari et al.
expressed with respect to SCI status, either with or with- out controlling for HU status.
Discussion
Our study found that the presence of SCI in SCA is associated with higher systolic blood pressures, an associ- ation that was also found in the SIT trial.8 Blood pressure is relatively low in SCA,23 possibly related to chronic ane- mia and subsequent vasodilatation, and the levels found in our study, with a mean of 115mmHg in the SCI group, would not be considered hypertensive. The exact way in which relative systolic hypertension is associated with SCI in children with SCA is unknown, although systolic hypertension is linked with other vascular complications in SCA (overt stroke,23 renal insufficiency,24 and high tri- cuspid jet velocity24). Systolic hypertension is also a risk factor for SCI in the non-sickle population.25 The associa- tion between relative systolic hypertension and SCI in SCA seems robust, and is biologically plausible, although there is currently no evidence on whether it is beneficial to lower blood pressure in children with SCA, and at what level such treatment should be considered.
We also found that higher HbF levels were protective against SCI. Increased HbF levels lessen the severity of SCA, with a clear association with decreased pain and longer life expectancy,2 but a more complex association with cerebrovascular complications. In the SIT Trial, HbF was not associated with SCI in a logistic regression model8 and analysis of data from the Cooperative Study of Sickle Cell Disease also showed no protective effect of higher HbF levels.26 Other studies have suggested that there may be neurological benefit to having higher HbF levels. In France, HbF levels were higher in children without SCIs compared to those with (16.5% vs. 13.1%, P=0.02);27 a Dutch study found that although HbF did not protect against the occurrence of SCIs, higher levels were associ- ated with a smaller volume of white matter hyperintensi- ties;28 a study on Brazilian patients showed protection against stroke was associated with genetic determinants of high HbF levels, particularly BCL11A alleles.29 It seems likely that the inherited ability to make more HbF offers some protection against neurological injury in SCA, although this may not always be reflected in the measured HbF percentage, particularly in small studies.
The unbiased proteomic discovery part of this study identified 44 peptides from 17 different proteins which were significantly up- or down-regulated compared to lev- els in the control population, without correction for mul- tiplicity (Tables 2 and 3). Many of these proteins can be plausibly implicated in pathogenesis of SCI and fall in to three broad groups.
Prothrombotic proteins
Four proteins which were found at higher levels in the SCI patients are known to be prothrombotic. α2-antiplas- min is a serine protease inhibitor which inactivates plas- min and decreases the rate of fibrinolysis; high levels are associated with increased ischemic stroke in the non-sick- le population.30 Similarly, α2-macroglobulin has prothrom- botic properties via the inactivation of plasmin, and ele- vated levels have been linked to stroke and white matter lesions in non-sickle patients.31 The fibrinogen g chain was increased 1.33 fold in the SCI population, and is at the cen-
Table 5. Known biomarkers of neurological disease showing significant differ- ences between SCI and control populations, although none of these maintain significance when correcting for multiple tests.
Von Willebrand factor C domain 2 containing Protein
Unadjusted P value 0.03
Corrected P value 0.62
0.62 0.62 0.62 0.62 0.62 0.62
Smooth muscle-associated protein 2 ADAM metalloproteinase domain 22 ADAM metalloproteinase domain 23 Scavenger receptor class A member 5 TNF receptor superfamily member 12A Bone morphogenetic protein 4
0.02 0.04 0.04 0.03 0.02 0.03
1140
ter of fibrin polymerization, interaction with platelets and regulation of factor XIII activity.32 Increased levels have been associated with vasculopathy, higher levels being increased in inflammation and also possibly inherited.33 Fourthly, thrombospondin-4 was increased 1.32 fold with SCI. Thrombospondins mediate cellular adhesion to other cells and matrix, and are implicated in many thrombotic and vasculopathic processes. Thrombospondin-1 levels have been found to be increased in children with SCA in association with both SCI34 and overt stroke,35 although thrombospondin-4 has not previously been studied in this context. These findings support the potential use of anti- coagulant and antiplatelet agents to prevent and treat SCI in SCA.
Pro-inflammatory proteins
Elevated levels of α2-macroglobulin, complement C1s and complement C3 in the SCI patients suggest that there is increased inflammation, which is known to predispose towards vasculopathy and stroke. As mentioned previous- ly, α2-macroglobulin is a prothrombotic protease inhibitor, but is also involved in inflammatory states, as a carrier for interleukin-6.31 Both complements C1s and C3 are elevat- ed in inflammation, and high levels of C3 are a known risk factor for atherosclerosis and stroke in the general popula- tion.36 Inflammation is known to be an important compo- nent of pathophysiology in SCA, and the role of anti- inflammatory agents in preventing SCIs should be explored further.
Lipoproteins
Apolipoprotein B-100 is the main component of low density lipoprotein cholesterol (LDL-C) and high levels are a well-established risk factor for atherosclerosis. Various studies have shown that drugs which reduce LDL-C also reduce the rate of cardiovascular events, including ischemic stroke,37 suggesting a possible thera- peutic option for children with SCA and ischemic stroke for drugs such as statins. We also found that apolipopro- tein A-IV levels were higher in the SCI population, which is perhaps paradoxical in that it is thought to be protective against coronary syndromes,38 although it has not been directly implicated in cerebrovascular disease or studied in children. A recent study suggested that higher levels were associated with reduced glomerular filtration rates,39 and this could be one explanation for the differ- ences in our study.
haematologica | 2018; 103(7)