Elevated Proangiogenic Markers are Associated with Vascular Complications within Ghanaian Sickle Cell Disease Patients

Abstract

Sickle cell disease (SCD) is an inherited blood disorder that can result in vasculopathy and end organ damage. Angiogenesis has been implicated as a key contributing factor to vascular mediated tissue injury in SCD. The relative plasma levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and vascular endothelial growth factor (VEGF) greatly influence angiogenesis. Dysregulation of these growth factors, leading to a pro-angiogenic state in SCD patients, has been documented in the developed world but there is very little data in Africa. There is the need, therefore, for studies in Ghanaian SCD patients. The aim of this study was to assess plasma levels of Ang-1, Ang-2, and VEGF in homozygous (HbSS) SCD patients with or without complications and healthy controls (HbAA) in Ghana. The study was a case-control study involving 544 participants: 396 HbSS SCD patients and 148 HbAA healthy controls. The study was conducted at the Center for Clinical Genetics (Sickle Cell Clinic) and Accra Area Blood Centre for National Blood transfusion at the Korle-Bu Teaching Hospital, Accra, Ghana. The plasma levels of Ang-1, Ang-2, and VEGF of study participants were measured with a double sandwich enzyme-linked immunosorbent assay (ELISA) technique. Complete blood count (CBC) was measured with an autoanalyser. The mean plasma Ang-1, Ang-2, and VEGF were significantly higher in HbSS SCD patients with or without complications than healthy controls (p < 0.001). The Ang-2/Ang-1 ratio was significantly lower in the controls than the HbSS patients (p < 0.001). The Ang-2/Ang-1 ratio was higher in the HbSS patients with leg ulcers as compared with patients with other complications and healthy controls (p < 0.001). There were higher leucocyte counts in HbSS patients than healthy controls. Overall, there was elevated plasma levels of Ang-1, Ang-2, and VEGF in SCD patients. The higher Ang-2/Ang-1 plasma levels in patients with leg ulcers suggests a possible ongoing angiogenesis and response to inflammatory stimuli. The study provides a first report on plasma levels of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factors in homozygous sickle cell disease patients in Ghana.

Sickle Cell Anemia Patients Display an Intricate Cellular and Serum Biomarker Network Highlighted by TCD4+CD69+ Lymphocytes, IL-17/MIP-1β, IL-12/VEGF, and IL-10/IP-10 Axis

“…Angiogenesis is a highly regulated process and requires coordinated signaling events among a variety of angiogenic factors [95]. Gürkan et al [96], Solovey et al [97], and Cao et al [98] demonstrated higher levels of VEGF and FGFbasic in HbSS patients at steady state corroborating our results and even higher levels in SCA patients with painful vasoocclusive crises.…”

Oxidative Profile of Patients with Sickle Cell Disease

“…The trend in Hb, RBC, and HCT levels were expected due to the chronic haemolysis associated with SCD as well as a possible blood loss in haematuria. Our previous study reported that SCD patients with HbSS VOC have significantly lower levels of Hb and RBC counts compared to those in the steady state [42]. In this present study, we also noticed that of all the study participants, those with HbSS VOC had a significantly lower Hb level.…”

Decreased parasite burden and altered host response in children with sickle cell anemia and severe anemia with malaria

“…Children with SCA in this study also had increased Angpt-2 and a low L-arginine/ADMA ratio, which have been previously associated with disease severity and risk of complications, including mortality, in adults and children. 20,46,47,[73][74][75] In our cohort, lower levels of TNF-a were associated with increased risk of all-cause postdischarge mortality or readmission, whereas increased levels of Angpt-2 were associated with increase uncomplicated malaria incidence postdischarge. Children with SCA experienced both of these host responses during severe anemia with P falciparum parasitemia.…”

“…Specific factors associated with severe disease and mortality in severe malaria, including the proinflammatory cytokine tumor necrosis factor a (TNF-a) and components of the angiopoietin (Angpt)-Tie-2 system, are also associated with clinical severity in SCA. [17][18][19][20][21][22][23] However, there have been no studies to date comparing these and other host responses in children with HbSS vs HbAA during episodes of severe anemia with Plasmodium falciparum parasitemia, or how the host response may alter parasite sequestration and density. In the present study, we assessed differences in children with HbSS vs HbAA in parasite biomass and markers of inflammation and endothelial activation during severe anemia with P falciparum parasitemia to better determine how SCA affects the host response to P falciparum during severe malaria.…”

“…1,19,23,[29][30][31][32][33] Recent data have implicated the Angpt-Tie-2 system in the pathogenesis of SCA and severe malaria, where elevated Angpt-2 and decreased Angpt-1 correlate with disease severity. [17][18][19][20][21][22] We quantitated levels of these and other biomarkers of endothelial activation as well as angiogenic cytokines vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) in this study population (Table 2). Median Angpt-2 was threefold higher in the children with HbSS compared with HbAA (5.0 vs 1.7 ng/mL; P 5 .01; Table 2).…”