Impaired microvascular function in patients with sickle cell anemia and leg ulcers improved with healing

Abstract

Leg Ulcer (LU) pathophysiology is still not well understood in sickle cell anaemia (SCA). We hypothesised that SCA patients with LU would be characterised by lower microvascular reactivity. The aim of the present study was to compare the microcirculatory function (transcutaneous oxygen pressure (TcPO₂) on the foot and laser Doppler flowmetry on the arm) and several blood biological parameters between nine SCA patients with active LU (LU+) and 56 SCA patients with no positive history of LU (LU-). We also tested the effects of plasma from LU+ and LU- patients on endothelial cell activation. We observed a reduction of the TcPO₂ in LU+ compared to LU- patients. In addition, LU+ patients exhibited lower cutaneous microvascular vasodilatory capacity in response to acetylcholine, current and local heating compared to LU- patients. Inflammation and endothelial cell activation in response to plasma did not differ between the two groups. Among the nine patients from the LU+ group, eight were followed and six achieved healing in 4.4 ± 2.5 months. Among thus achieving healing, microvascular vasodilatory capacity in response to acetylcholine, current and local heating and TcPO₂ improved after healing. In conclusion, microcirculatory function is impaired in patients with LU, and improves with healing.

Keywords: endothelial cell; leg ulcers; microcirculation; sickle cell disease; transcutaneous oxygen pressure.

FIGURE 1

Flow chart.

FIGURE 2

Skin blood flow in SCA patients in responses to various stimuli. (A) Patients with leg ulcer (LU+, grey) or without leg ulcer (LU−, black) in response to acetylcholine (n = 9 LU+ and 56 LU−), current (n = 9 LU+ and 56 LU−) and local heating (42°C) (n = 9 LU+ and 53 LU−). All responses were significantly different between LU+ and LU− (Mann–Whitney U‐test). (B) Six patients with active LU at initial visit (black, n = 6) and after healing (blue, n = 6) in response to acetylcholine, current and local heating. All responses were significantly different after healing (Wilcoxon matched pairs test).

FIGURE 3

(A) mRNA expression on endothelial cells (HDMEC) incubated with plasma of 10 patients without leg ulcer (LU−) and eight patients with leg ulcer (LU+) determined by quantitative PCR. Expression is reported to TATA‐box binding protein. Significant difference: *p < 0.05; NS: No significant difference. (B) Phosphorylated NOS/eNOS ratio and phosphorylated ERK/ERK ratio determined on endothelial cells (HDMEC) incubated with the plasma of 11 patients without leg ulcer (LU−) and eight patients with leg ulcer (LU+) by western blot. Significant difference: *p < 0.05; NS: No significant difference.