SLR - August 2014 - Rahul Bhatt

Vasculopathy, Inflammation, and Blood Blow in Leg Ulcers of Patients with Sickle Cell Anemia

Reference: Minniti CP, Delaney KH, Gorbach AM, Xu D, Lee CR,  Malik N, Koroulakis A, Antalek M, Maivelett J, Peters-Lawrence M, Novelli EM, Lanzkron SM, Axelrod KC, Kato GJ. American Journal of Hematology, Vol. 89, No. 1, January 2014.

Scientific Literature Review

Reviewed By: Rahul Bhatt, DPM
Residency Program: Forest Hills Hospital, Forest Hills, NY

Podiatric Relevance: Patients with Sickle Cell Disease (SCD) are known to have a myriad of end organ complications as a result of vascular dysfunction. Chronic leg ulcers are one such complication faced by foot and ankle physicians. Little is known, however, about the microcirculatory and histopathological changes that occur with these wounds. This study utilizes new, noninvasive techniques such as Laser speckle contrast imaging (LSCI) and infrared (IR) thermography to examine the regional blood flow of ulcer beds, and the immediate surrounding tissues compared to unaffected skin area in patients with SCD and chronic leg ulcers, in order to understand its role in ulcer pathogenesis and perpetuation.

Methods: Eighteen subjects with sickle cell anemia (homozygous SS), eight men and 10 women, ages 20–59, with active chronic leg ulcers were enrolled in this study. Inclusion criteria required a subject to be at least 18 years old, have sickle cell disease, and have a leg ulcer of at least four weeks duration, between 2.5 and 100 cm2 in size and not acutely infected. Subjects underwent thorough medical screening. Laboratory evaluations were performed in the Clinical Center Department of Laboratory Medicine at the National Institutes of Health by standard clinical laboratory assays. One ulcer per patient was examined using either LSCI or IR. Both modalities measured tissue regions at and in the vicinity of the ulcer site. LSCI blood flow measurements are reported in arbitrary units (AU) and represent the number of red cells detected in the image area per measured unit of time. IR temperature recordings were in degrees Celsius and have a sensitivity of 0.015?C. Additionally, Punch biopsies, 2–4 mm in diameter, of the skin were obtained from the edge of leg ulcers or symptomatic lesions in three patients

Results: The ulcers had been present for a median of 10 months (range 2–300 months) and treated with approximately eight therapies per patient. Half of the patients had one ulcer and half had more than one, up to 10 in one subject. Blood flow was greatest in the wound and periwound area compared to distant skin, as measured by LSCI red blood cell flux. The highest blood flow was measured in the ulcer center with progressively lower flow measurements moving away from the ulcer. LSCI was lower in the periwound and in a distant area. These differences were statistically significant (overall P<0.01). Further supporting the LCSI evidence of increased regional blood flow around the ulcer, periwound temperature was elevated compared to other regions, as measured by IR thermography. Periwound temperature was inversely correlated to ulcer size (Pearson correlation r=-0.51, P<0.03). No correlation was found between periwound IR temperature and hemoglobin, patient’s age, use of hydroxyurea, or blood transfusions. Skin biopsies were obtained in four subjects who consented to the procedure, three from the ulcer edge, and one from an area in the same extremity, but away from the actual ulceration. Histopathology showed a sharply demarcated ulcer edge (Fig. 2A). The base of ulcer was composed of granulation tissue with chronic inflammatory infiltrate and early scar formation. The epidermal changes adjacent to the ulcer were characterized by acanthosis, hyperkeratosis, and attenuated rete ridges. There were vasculopathic changes involving some of the small blood vessels subjacent to the base of ulcer, characterized by mural fibrin thrombi causing luminal narrowing and progressive vascular occlusion.

Conclusions: The study shows that in sickle cell patients, chronic leg ulcer beds and their immediate surroundings have high blood flow, underlying vasculopathy, venostasis, and thrombosis. The majority of the treatment modalities available today require more investigation such as prospective randomized trials and anecdotal evidence for their benefit. Laser speckle contrast imaging (LSCI) and infrared (IR) thermography are new, noninvasive techniques useful in the in vivo study of skin and wound perfusion in animal models and humans. The high resolution of LSCI offers an advantage over traditional laser Doppler imaging techniques and can image the entire physiologic range of blood flow velocities within a small diameter vasculature to a depth of approximately 300 mm. IR measures tissue temperature up to 1 cm from the surface of the skin and its measurements correlate to forearm blood flow in patients with sickle cell disease. The findings support involvement of vasculopathy in leg ulceration in SCD and may stimulate new conceptual models and investigation of therapeutic options.

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