Endothelium-dependent and endothelium-independent vasodilatation of the cutaneous circulation in sickle cell disease.

BACKGROUND: Whilst there is evidence of endothelial dysfunction in sickle cell disease (SCD), whether this affects regulation in the microcirculation is not known. METHODS: We studied 19 patients with SCD, eight with sickle cell-haemoglobin C (HbSC), 11 with homozygous sickle cell (HbSS) disease and 11 matched control subjects with normal haemoglobin genotype (HbAA). Vasodilator responses were evoked by iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) in finger and forearm, cutaneous red cell flux (RCF) being measured by laser Doppler fluximetry. RESULTS: Increases in RCF evoked in the finger by ACh were not different between SCD and HbAA subjects (P = 0·789), but were smaller in patients with HbSS than HbSC (P < 0·05). By contrast, increases in RCF evoked in forearm by ACh were greater in SCD than HbAA subjects (P < 0·05) and similar in patients with HbSC and HbSS. Increases in RCF evoked by SNP did not differ between patients with SCD and HbAA subjects in finger or forearm. CONCLUSIONS: Our results indicate that endothelium-dependent cutaneous vasodilatation is augmented in forearm of patients with SCD relative to HbAA subjects, but impaired in the finger of SCD patients with the more severe HbSS genotype. Thus, endothelial dysfunction associated with SCD is not accompanied by generalised impairment in endothelium-dependent dilatation, but with more localised impairment that includes the fingers of patients with HbSS.

Leg ulceration in sickle cell disease: medieval medicine in a modern world.

Leg ulceration is now recognized as an important complication of sickle cell disease, especially of the SS genotype. Since there is no convincing evidence of delayed healing of operation scars or of wounds elsewhere in the body, it must be concluded that factors specific to the lower leg render patients prone to delayed healing at this site. Many lesions are traumatic in origin and since there is considerable variation in healing rates among the normal population, it is useful to define chronic leg ulceration on the basis of a minimal duration, which in Jamaican studies has required at least 3 months and sometimes 6 months before healing. This minimal duration avoids the difficulties of interpreting the significance of briefer lesions since the moment of final healing may be poorly defined (patients may conclude that a scab represents healing whereas small lesions persist beneath) and often goes undocumented as patients may not report and medical attendants may not enquire, the date of final healing.

Plasma levels of tissue factor and soluble E-selectin in sickle cell disease: relationship to genotype and to inflammation.

BACKGROUND: Microvascular occlusion, the pathophysiological hallmark of sickle cell disease (SCD), is a complex multifactorial process with alterations in coagulation, endothelial function and inflammation. However, relationships between these process in the two most common genotypes, HbSS and HbSC, are unknown. We hypothesized differences in the hypercoagulable state [as assessed by tissue factor (TF), fibrinogen and D-dimer], endothelial function [markers soluble E-selectin (sE-sel) and von Willebrand factor (vWf)], and inflammation [markers interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP)] in these two SCD genotypes. Citrated plasma TF, sE-sel, vWf, fibrinogen and fibrin D-dimer, and serum IL-6 and hsCRP (enzyme-linked immunosorbent assay/Clauss) were measured in 64 patients with SCD (27 with HbSS disease) and 42 AA subjects matched for age and ethnic origin. TF (P = 0.0014), sE-sel (P = 0.001) and, as expected, vWf, D-dimer, and hsCRP (all P < or = 0.01), but not fibrinogen or IL-6, were raised in the SCD patients compared with the AA subjects. However, only vWf and, as expected, D-dimer (all P < or = 0.01) were higher in HbSS disease than in HbSC disease. Raised plasma TF and sE-sel in SCD compared with HbAA subjects may contribute to the increased risk of thrombotic disease in this group. Raised vWf in HbSS compared with HbSC may be important in determining pathophysiology in these two genotypes. Positive correlations between IL-6 and TF in both HbSC and HbSS disease leads us to speculate that inflammation may be important in coagulation activation in these patients, or vice versa. However, lack of correlation of sE-sel with inflammatory markers implies that other mechanisms are responsible for increased levels of this marker of endothelial activation.

Postural vasoconstriction and leg ulceration in homozygous sickle cell disease

Chronic leg ulceration is a major cause of morbidity in patients with homozygous sickle cell disease; the ulcers commonly resolve on bed rest. We have therefore compared the cutaneous vascular response to dependency in three groups of eight patients with sickle cell disease (those with an active ulcer, with an ulcer scar and with no history of ulceration) and in eight subjects with normal haemoglobin and no history of leg ulceration. We monitored with a laser Doppler flowmeter, the change in red cell (erythocyte) flux induced in the skin of the leg, at two sites proximal to the malleoli, with the leg horizontal and 5 and 10 min after moving the leg to the dependent position. With the leg horizontal, mean cutaneous red cell flux was was substantially higher in normal cells of patients with sickle cell disease than in normal subjects and was higher still at the site of the ulcer scar. On dependency, red cell flux fell not only in normal subjects but also in the patients with the sickle cell disease. The fall in red cell flux in normal skin of patients with sickle cell disease was smaller than in normal subjects when considered as a percentage of the control values, but in absolute terms the falls in red cell were similar in sickle cell patients normal subjects. By contrast, the fall in red cell flux at the ulcer/scar site was greater than in normal skin from sickle cell patients. We propose that high resting perfusion is important in patients with sickle cell disease to maintain normal integrity of cutaneous tissue and that pronounced vasoconstriction on dependency hinders the healing and encourages recurrence of the leg ulcers (AU)

Effect of thermal stimuli on peripheral blood flow in homozygous sickle cell disease: a preliminary study

Forearm blood flow (FBF) was measured in 23 patients with homozygous sickle cell (SS) disease and 20 controls with normal hemoglobin genotype (AA) using venous occlusion air plethysmography to examine the pattern of peripheral blood flow in both groups at rest, and in response to thermal stimuli. The mean resting in FBF in SSS patients was more than twice that in AA controls (P < 0.05) in FBF in the opposite arm in both SS patients and AA controls, with the response being greater in the controls. Indirect heating for 2 mimutes evoked a similar decrease in FBF of a similar magnitude in both groups. The increased FBF in response to cooling in SSS patients may be a part of an important reflex mechanism which would support the concept of the 'steal' syndrome, as recently postulated, as a possible explanation of the cold-related initiation of the painful crisis of SS disease.(AU)

Microcirculation in the legs and the effects of postural change in homozygous sickle cell (SS) disease - abstract

Chronic leg ulceration is a considerable cause of morbidity in homozygous sickle-cell disease. The role of cutaneous blood flow in the pathogenesis of the ulcers is unknown. Compromised perfusion is assumed but there is no direct evidence to support this. We evaluated the response of cutaneous red cell flux (RCF), an index of cutaneous blood flow, to postural change in patients with SS disease, with and without a history of ulcers and in AA controls. Using laser Doppler flowmetry, measurements were made at two sites in the leg in the following groups:-SS patients with a history of ulceration (Group A = ulcers, Group B = scars); without a history of ulceration (Group C) and AA controls (Group D). In Groups A & B, the sites were the ulcer/scar site and a normal site; in Group C & D, medial and lateral sites above the malleoli. A triad of measurements was performed: - the leg horizontal, lowered, then returned to the horizontal. Regardless of history of ulceration, SS patients showed a smaller fall in flow on dependency (p < 0.001), indicating failure of normal postural vasoconstriction. In Groups A & B, the greater fall in flow observed at the ulcer/scar site compared with the normal site may be significant in the development/recurrence of ulcers at these sites. Clarification of the underlying mechanisms of these observations through further study may be important for improving skin nutritive perfusion (AU)

Daily variability in resting levels of cardiovascular variable in normal subjects and those with homozygous sickle cell disease

Measurements were made of cardiovascular variables and oral temperature in 16 male subjects with homozygous sickle cell disease (SS) and in 17 matched controls (AA) at 10.00 a.m, 1.00 p.m and 4.00 p.m. All subjects were in a rested state throughout. At 10.00 a.m. mean arterial pressure was lower, while heart rate, total forearm blood flow and cutaneous red cell flux in the forearm were higher in SS than AA. Vascular resistance in total forearm and forearm skin, calculated by dividing arterial pressure by blood flow or red cell flux, were lower in SS but hand cutaneous red cell flux and vascular resistance were not significantly different in SS and AA. In both SS and AA, there were parallel increase over the three sessions, in mean arterial pressure (by approximately 12 and 10 percent respectively) forearm vascular resistance (by approximately 17 and 27 percent) and hand cutaneous vascular resistance and hand cutaneous resistance (by approximately 2240 and 350 percent) whereas forearm blood flow and hand cutaneous red cell flux fell. By contrast, forearm cutaneous resistance showed no change during the day in SS, but increased progressively in AA (by approximately 75 percent). These results indicate that, during the day, there is progressive vasconstriction in forearm muscle and hand skin in SS and AA and also in forearm skin of AA that contributes to a progressive rise in the resting level of mean arterial pressure. We suggest this daily variability should be considered in studies of cardiovascular function: within a given study they should be performed at the same time of day.(AU)