Leg ulcerations are a serious and debilitating complication of sickle cell disease (SCD) and other hemolytic anemias, whose etiology is not completely understood. Wound healing involves an ordered progression of vasoconstriction (hemostatic phase), followed by vasodilatation (inflammatory and proliferative phase) and epithelialization. Little is known about the changes in the microcirculation of chronic wounds in patients with sickle cell disease. Endothelial function affects microcirculation and regulates blood flow. Endothelial dysfunction is a recognized pathway to end organ dysfunction in SCD. Laser speckle contrast imaging (LSCI) and Infrared Thermography (IR) are non-invasive technique used to assess dynamic changes in blood flow in response to vaso-reactive and other insults in both health and disease, while peripheral arterial tonometry is utilized for early detection of cardiovascular disease. The aim of this study was to evaluate skin's microvasculature response and endothelial function in adults with HbSS and chronic leg ulceration.
Twelve adults with HbSS and chronic leg ulcers (> 1 month duration) were evaluated at steady state with a detailed medical and ulcer history, physical examination, and clinical labs. Clinical and laboratory data were compared to 269 adults with Hb SS, without active leg ulcers, enrolled in a Pulmonary Hypertension screening protocol (Clin trial no. NCT00011648). Blood flow (LCSI) and IR measurements of the ulcer bed, the peri-ulcer area and of a distant, unaffected area (baseline) were obtained and compared. Peripheral arterial tonometry (PAT) was obtained to calculate the ratio of post-occlusion dilatation to baseline reactive hyperemia index: RHI. An RHI>1.67 is indication of normal endothelial function.
Mean age for the 12 subjects with chronic active leg ulcer: 31 years ± 11yrs, 5 male, 5 had a history of trauma. When compared to SS patients without active leg ulcers: mean MAP 82 vs 103 mmHg (p <0.0001), Hb 7.6 vs 9.0 g/dL (p=0.001), and LDH 533 vs. 375 (p=0.023). CRP was higher, 9.4 vs 0.81(p<0.0001), Arginine/ornithine ratio was lower (0.66 vs. 1.06) in patients with active leg ulcers (p=0.005). Thrombophila w/u was negative in 11, but half of patients were on anticoagulation for previous PE/DVT's. A third of the patients had been admitted for VOC in the previous 12 months and 11/12 were taking daily opioids. Blood flow was highest in the ulcer center: 731+421, with progressively lesser flow measurements in the periwound: 370+157 and in the distal region(or baseline) 165+89. Temperature, as measured by IR, was higher (34.9 C°) in the periwound area than in the distant, or baseline area (34.5 C°) (p <0.03). Blunted RHI on PAT was seen in 5/12 subjects, with values <1.67.
With this study we confirm that patients with HbSS and leg ulcers represent a subgroup with severe disease, as demonstrated by the high use of HU and/or transfusion, and number of complications at a relatively young age. We report high blood flow in the ulcer bed and immediate surrounding regions, compared to unaffected areas, never prior demonstrated. It is probable that the increase in blood flow observed in the wound and peri-wound regions reflect s a high vasodilated state, resulting from severe anemia, relative hypotension, and chronic inflammation. Laboratory and clinical data supports the presence of a persistent inflammatory and hemolytic state, as well as low arginine bioavailabitlity. Laser Speckle Contrast Imaging, Infrared Thermography and Peripheral Arterial Tonometry are effective, non invasive novel techniques useful for studying microvascular and endothelial function in patients with SCD and leg ulcers.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.