Chronic leg ulcer is one of the morbidities associated with sickle cell anaemia (SCA). Chronic leg ulcer is a wound on the skin that occurs between the knee and the foot, showing no signs of healing after 3 months of proper treatment.¹ In SCA patients, the polymerisation of haemoglobin S (HbS) leads to the formation of sickled red blood cells (RBCs) which become trapped in the microcirculatory system. This leads to microvascular vaso-occlusion causing tissue ischaemia and associated pain. Occlusion of the veins in the legs leads to venous hypertension, which may cause varicose eczema, deposition of scar tissue and iron pigments in the skin, and oedema in the lower leg. This may result in the breakdown of the skin or delay healing in the case of a leg injury, leading to chronicity.² Any leg ulcer in the presence of a venous disorder is described as a venous ulcer. Other considerations for venous ulcer diagnosis are an ankle brachial pressure index greater than 0.8 with absence of features of rheumatoid vasculitis, malignancies and diabetic mellitus. The gold standard in the management of chronic venous leg ulcers is the four-layered compression therapy bandaging system.

Sickle cell associated ulcers (SCUs) can be precipitated by many factors such as trauma, infection, severe anaemia and usually occur with venous stasis disease, which requires compression therapy.² The microorganisms invading the tissues of the skin contribute to the delayed healing observed in chronic leg ulcers.³ Bacteria produce and also stimulate the production of substances (from activated neutrophils) that are detrimental to the body’s wound healing processes.^4,5 These substances include proteases such as metalloproteases, elastases and collagenases that destroy the building blocks needed for normal wound healing. In this proteolytic environment, bacteria can continue to multiply and use up local resources such as oxygen and nutrients that are also needed for the wound healing.⁴ Diabetes mellitus increases the risk for the development of infection and impaired wound healing in individuals due to a decreased cell and growth factor response.⁶ The effect of diabetes mellitus in SCUs is yet to be assessed.

Ulcer incidence in sickle cell disease (SCD) patients in the United States ranges from 2.5% to 25% and 75% in Jamaica.^7,8 In Nigeria and Ghana, it is about 10%,^9,10 and the rate of recurrence of ulcers is high (> 70%).^9,11,12 Chronic leg ulcer thus contributes to recurrent and prolonged misery in these patients. Compression therapy increases the rate of healing of SCUs and also reduces the rate of recurrence.^7,8,9 There is inadequate education on the prevention and management of leg ulcers among people living with SCD and their caregivers. The therapeutic strategy for SCUs is complex and multidisciplinary efforts to offer holistic care is poor. This study is therefore designed to address the paucity of information about the laboratory markers of SCUs among people living with SCD and also serves as a basis for health promotion interventions for the prevention of SCUs and improvement in clinical interventions in Nigeria and other African countries.

This study was carried out to evaluate the haematological parameters in patients with SCA and chronic leg ulcers, and also to assess the haematological changes during healing of these ulcers while being managed with high compression bandaging, an as yet unemployed method of chronic leg ulcer treatment in Nigeria. There were marked differences in some haematological parameters between SCA patients with and without chronic leg ulcers and haematological parameters improved with healing of the ulcers. Monitoring of haematological parameters for improvement during treatment of chronic leg ulcers and after wound closure in SCA patients will aid healing and might also reduce the rate of recurrence.

The mean HGB and HCT of the case patients (those with chronic leg ulcers) at T₀ were significantly lower than those of the control patients (those who have never had a chronic leg ulcer). A high rate of haemolysis is one of the major causes of a reduced steady state haemoglobin in sickle cell patients. Sickle cell anaemia patients with a lower steady state haemoglobin concentration are at a higher risk of developing chronic leg ulcer.^14,15 According to Ladizinski et al.,¹⁶ the inability of a wound to heal could be a result of an inadequate supply of blood or a very low haemoglobin level (< 8 g/dL). One of the causes of SCUs is lack of oxygen which may be attributable to overall anaemia and reduced oxygen-carrying capacity of sickled haemoglobin.⁸ The addition of recombinant human erythropoietin (a glycoprotein hormone that stimulates red blood cell production) subcutaneously at weekly intervals resulted in a rapid and complete healing of a chronic leg ulcer.¹⁷ Hence, treatment of chronic leg ulcers should aim at anaemia correction. However, this should be done with caution and within a threshold that will be beneficial to the patient as a much higher HCT may also lead to hyperviscosity and increase the risk of vaso-occlusion.

A wider red cell distribution width as compared to the control group, with a mean corpuscular volume within normal haematological range, in the test patients alludes to anaemia caused by bleeding from regular treatments, folate deficiency or vitamin B12 deficiency. There was a slight improvement in the HCT level from T₀ to T₂ mainly due to constant education of the patients on the need to improve the quality of their diet and better compliance with routine haematinics.

Nolan et al.¹⁴ and Hassan et al.¹⁸ found that patients with leg ulcers had higher WBCs as is the case in this study. The majority of the patients with leg ulcers had elevated WBC counts at the beginning of the study. Elevated WBC, which is due to recurrent inflammation and vasculopathy, is one of the hallmarks of disease severity.^19,20,21 Patients with elevated WBC may be more susceptible to developing chronic leg ulcer because leukocytes stick to other blood cells and the endothelium due to an upregulation of adhesion molecules, thereby promoting vaso-occlusion.²² Vaso-occlusion of the veins in the leg may cause tissue ischaemia with a resultant breakdown of the skin or delayed healing of wounds, leading to chronicity.² Higher WBC may also be due to microbial colonisation or infection of the ulcers. A lower WBC count was observed at T₂ and this may be due in part to the use of antibiotics prescribed (based on the result of an antibiotic sensitivity test) a week before T₁ sampling. Infections that are not resolved may lead to the non-healing of wounds.¹⁶ There is a the need to control infections to promote wound closure and healing. In this study, wound size was positively correlated with WBC. Therefore, efforts to reduce elevated WBC in leg ulcer treatment may aid wound closure.

There was a significantly higher number of platelets in the leg ulcer patients than in the control group of this study. In Jamaica, Cumming et al.²³ found that leg ulceration was associated with higher PLT. Hypercoagulability can trigger leg ulcer formation as it may cause ischaemia to the skin, resulting in friability and ulceration.²⁴ SCUs are characterised partly by an increase in clotting ability as a result of increased PLT, hypercoagulability and a measured increase in clotting factors at the wound itself.⁷ In this study, PLT was also positively correlated with wound size. Wirth et al.²⁵ asserted that an efficient decrease in PLT may lead to healing of skin ulcers.

There was a negative correlation between HGB and WBC as well as between HGB and PLT. This means a higher rate of haemolysis may result in elevated WBC and PLT counts. The observation that these three parameters were not significantly correlated in patients without chronic leg ulcers lends credence to the notion that lower steady state HGB and elevated WBC and PLT counts may predispose sickle cell patients to chronic leg ulcers.

Koshy et al.¹⁵ noted that there was a lower incidence of leg ulcers in SCD patients with a HbF concentration higher than 10%. In Jamaica, Cumming et al.²³ also found that ulceration was negatively associated with foetal haemoglobin levels. In this study however, the difference in HbF levels between the two study groups was not statistically significant, probably due to the small sample size. The presence of HbF may help to reduce the rate of haemolysis by reducing sickling potential. Having HbF within the cell reduces its ability to polymerise due to the formation, in HbS and HbF mixtures, of asymmetrical hybrid tetramers of the type α₂β^Sγ. The contact sites of Hb β^S for polymerisation is abolished, and hence prevents sickling²⁶ and this may also reduce subsequent inflammatory reactions. However, elevated HbF levels may not always be protective as the pancellular distribution, rather than the concentration of HbF in the haemolysate is more effective in inhibiting polymerisation.²⁷

The level of HbS was lower in the control patients. A lower HbS level is usually due to higher HbF levels or the presence of alpha or beta thalassemia which was not assayed in this study. Reduced HbS concentration leads to a lower rate of sickling and, consequently, a reduced rate of haemolysis. Haemolysis of sickled RBCs leads to the release of activated molecules (plasma haemoglobin) which react with nitric oxide to form inert nitrate. Nitric oxide maintains vascular function and normal blood flow^28,29 and has also been shown to be vital to cutaneous wound healing.^30,31 Nitric oxide suppresses aggregation of platelets, secretion of procoagulant proteins and the expression of cell adhesion molecules on endothelial cells, thereby promoting blood flow.²⁸ Hence, improvement in leg ulcer management may be achieved by the introduction of agents that have the capacity to reduce sickle erythrocyte density as well as those that can make nitric oxide more available in tissues.

None of the chronic leg ulcer patients in this study was diabetic. Diabetes is quite rare in sickle cell patients^6,32,33 and does not have anything to do with the non-healing ulcers of patients in this study. Venous incompetence leads to reduced blood flow, and may cause increased blood vessel permeability with the attendant leaking of fluid and proteins into tissue spaces, a condition known as oedema.³⁴ Localised oedema traps leukocytes in the tissues, and oxygen-free radicals and harmful substances released by the leukocytes are capable of causing tissue damage, which may eventually lead to the development of ulceration. Blood clotting factors are also triggered in reduced blood flow.^35,36 According to Clare et al.,³⁷ ‘hypoxia-induced sickling, the rheological effects of white cell counts, and activation of components of the coagulation system may all contribute’ to venous incompetence. This explains why reduced HCT, elevated PLT and WBC may increase the risk of leg ulceration in individuals with SCD.

Compression therapy aids healing of leg ulcers by increasing venous blood flow,³⁸ thereby making more readily available the supply of adequate nutrients and other factors necessary for wound healing. On the other hand, the risk of blood clot formation and oedema is reduced, thereby promoting healing. However, there may be a recurrence of ulcers if haematological conditions are not monitored and addressed. This was the case for 3 of the previously healed participants in this study. Management and prevention of chronic leg ulcer in SCD patients should address underlying haematological indices as no one method of dressing may totally prevent recurrence.^39,40 The wearing of compression stockings after wound healing may help to maintain normal venous pressure and prevent recurrence due to skin tissue breakdown.^41,42