A treatment algorithm to identify therapeutic approaches for leg ulcers in patients with sickle cell disease

Abstract

Sickle cell leg ulcers (SCLUs) are a common complication of sickle cell disease (SCD). Patients who develop ulcers appear to have a more severe haemolysis‐associated vasculopathy than individuals who do not develop them, and manifest other complications such as priapism and pulmonary hypertension. SCLUs are slow to heal and often recur, affecting both the emotional and physical well‐being of patients. Here we summarise what is known about the pathophysiology of SCLUs, describe available treatment options and propose a treatment algorithm.

Introduction

Sickle cell leg ulcers (SCLUs) are the most common cutaneous manifestation of sickle cell disease (SCD) 1 and continue to present a significant clinical challenge for this patient population. They occur at a young age, starting in the second decade of life, are accompanied by severe, unremitting chronic pain, have an indolent course and a high recurrence rate. The presence of SCLUs significantly impacts quality of life, may cause or exacerbate depression and is associated with increased health care costs.2 Their development may also suggest that these patients are afflicted with a severe SCD phenotype, characterised by haemolysis‐associated vasculopathy.3 Thus, clinicians must be vigilant in assessing for complications such as the development of priapism or pulmonary hypertension, observed in 50% and 22% of patients with existing leg ulcers, respectively 3, 4.

The prevalence of leg ulcers in patients with SCD varies greatly geographically, with frequencies as high as 75% in Jamaica and as low as 1% in Saudi Arabia 5, 6. Healing times last from months to years, and ulcers often have a characteristic healing‐relapsing course. The 2‐year recurrence rate in USA is 75·4%; however, it has been reported as high as 97% in numerous Jamaican studies 6, 7.

Unfortunately, there is no standardised protocol for treating SCLUs. A review of the literature over the last 30 years provides mostly anecdotal case reports, supplemented by a few cohort studies and randomised controlled trials (RCTs). Thus, practitioners do not have guidelines for treating these atypical ulcers.

This literature review attempts to fill these voids. We have compiled and analysed treatment approaches published since 1985. Along with the pathophysiological summary, our primary aim is to propose a treatment protocol for treating SCLUs using widely available methods.

Methods

For this review, we searched PubMed using the search terms ‘sickle cell’ and ‘ulcer’, ‘sickle cell’ and ‘wound’ and ‘sickle cell’ and ‘lesion’. Additionally, we scanned the reference lists of identified articles. Inclusion criteria included RCTs, cohort studies, case reports published since 1985 and review articles published since 1995, pertaining to leg ulcers in patients with SCD.

Pathogenesis of sickle cell leg ulcers

Development of a successful treatment approach for SCLUs requires an understanding of the pathophysiological mechanisms responsible for their development. The pathogenesis of SCLUs is multifactorial and not completely elucidated. SCD is a haemoglobinopathy characterised by chronic anaemia and haemolysis, with resultant end‐organ damage, high morbidity; and premature mortality. Because of a point mutation in the gene encoding, the β‐globin subunit of haemoglobin, the amino acid valine is substituted for glutamic acid, forming haemoglobin S (HbS). Upon deoxygenation, haemoglobin S polymerises and forms large rods that distort the membrane of the red blood cells (RBCs) and result in the classic sickle shape. Intracellular precipitation of the sickle haemoglobin results in vaso‐occlusion, endothelial dysfunction, hypercoagulable state, chronic inflammation and ischaemia reperfusion injury 1. Additionally, SCD patients have some degree of immunological and reticuloendothelial system dysfunction 2.

Mechanical obstruction of the microcirculation

Vaso‐occlusion is a hallmark of SCD. As sickle cells become entrapped in the microcirculation, they increase blood viscosity, decrease flow through the venules and capillaries and haemolyse, resulting in chronic anaemia, ischaemia‐reperfusion injury and chronic inflammation, that lead to end‐organ damage 8.

The marginal cutaneous blood supply of the malleoli exposes the vulnerability of the microcirculation to obstruction by this mechanism 9. Thus, even minor abrasions become foci of inflammation, with an ensuing cycle of ischaemia and tissue destruction. Not surprisingly, the medial and lateral malleoli are the most common sites for ulcer development 10.

Haemolysis‐vascular dysfunction syndrome

Haemolysis is a salient feature of sickle cell anaemia. Sickling results in RBC membrane damage, cell breakdown and subsequent release of the intracellular contents 11. Ordinarily, nitric oxide (NO) present in the plasma reacts with the vascular endothelium facilitating small blood vessel vasodilation 8. However, with intravascular haemolysis, the released haemoglobin sequestrates the NO, negating its vasodilatory effects. This further promotes chronic vasoconstriction, tissue hypoxia and pain 8, 11

Venous incompetence

The role of venous blood flow in the pathogenesis of SCLUs is debated in the literature. Early studies using manometry and venography did not find evidence of venous insufficiency in SCD patients with leg ulcers. However, oedema and pain often precede ulceration in these patients. The aetiology of the oedema is poorly understood 2.

Mohan et al. noted that SCD patients experienced a decrease in ankle venous refilling times and cutaneous RBC flux recovery time, with diminished venous drainage at the ankle 12. They thus hypothesised that venous hypertension, rather than venous insufficiency, promotes ulcer development.

Studies by Clare and Cumming demonstrated that venous incompetence was more frequent in patients with SCLUs 13, 14. They suggested that dependency, turbidity, hypoxia‐induced sickling, increased white blood cell (WBC) counts, hypercoagulability and impaired linear blood flow across venous valves could all contribute to sluggish circulation 13.

Physical examination often reveals evidence of venous insufficiency. Cutaneous haemosiderosis, dermatosclerosis and the prominence of superficial veins are frequent findings among SCD patients 13, 15 Additionally, pathology reports describe fibrin thrombi and vascular occlusions, confirming the presence of venostasis in SCD patients with ulcers 10.

Finally, the tendency of these ulcers to worsen with prolonged standing and improve with bed rest and compression therapy is further evidence that venous incompetence likely plays a role in their development, persistence and recurrence 6, 13, 15.

Hypercoagulability and thrombosis

The sickling‐induced obstruction of small blood vessels and ischaemia causes injury to RBCs, which initiates the upregulation of RBC integrins. These proteins, present in the red cell membrane, promote a cascade that involves RBC adhesion to the endothelium, platelet aggregation and granulocyte recruitment with the release of pro‐inflammatory cytokines 16. This inflammatory cascade causes further vessel obstruction, exacerbating the ischaemia and necrosis and resulting in end‐organ damage.

Minniti et al. provided histopathological evidence of microthrombi and fibrinous deposition on the luminal surface of blood vessels in and around ulcers, suggesting pathological haemostasis 17. Along with a significant reduction in protein S (PS) activity (P < 0·01), levels of Factor VIII (both in steady state and during crisis) and plasminogen activator inhibitor‐1 (PAI‐1) were significantly elevated (both P < 0·0001), which is further evidence of a prothrombotic predisposition 18. Reduced levels of antithrombin III (AT) have also been identified in SCD patients 19.

In summarising the above observations, vasculopathy appears to be a major contributor to the development of SCLUs. A combination of microvascular occlusion, inflammation, thrombosis and venostasis places patients at greater risk of developing ischaemia. With subsequent tissue damage, the cycle repeats, further contributing to the damage of tissues such as venous valves, which, when damaged, exacerbate fluid retention and inflammation, fostering a pro‐ulcerative environment.

Autonomic dysfunction

In addition to increased cardiac output 6, patients with SCD also have aberrant venoarteriolar reflex responses 2. Normally, when the leg is lowered from a horizontal to a dependent position, cutaneous vasoconstriction occurs; however, SCD patients exhibit more pronounced vasoconstriction at ulcer sites when leg is lowered 6. As noted above, vasoconstriction results in the worsening of tissue ischaemia, necrosis, delayed healing and pain.

Bacterial colonization

The role of bacteria in the pathogenesis of SCLUs is unclear. Bacterial colonisation of wounds is inevitable. Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes are the most frequently cultured organisms in sickle cell ulcers 20. While bacteria likely do not play a role in initiating ulcers, colonisation can cause persistent inflammation of surrounding tissues and delay healing (e.g. secondary infection has been cited as a complication of skin grafting of ulcers in surgical patients) 9, 21.

Studies by Baum et al. suggest that the use of topical triple antibiotics improves healing 22. However, with the use of topical antibiotics comes the risk of development of contact sensitisation, bacterial resistance and difficulties with wound moisture balance 8.

Genetic factors

Studies suggest that the expression of other genes contribute to the development of SCLUs in SCD patients. For example, patients with the HLA‐B35 and CW14 alleles have a 17‐fold greater risk of developing leg ulcers 2, 10. Other studies have found associations between genes and signalling pathways that impact endothelial NO production and angiogenesis 10. Large‐scale gene expression studies of SCD patient populations are needed to provide further insights into the pathophysiology of SCLU.

Treatment of sickle cell leg ulcers

Practitioners utilise a wide variety of treatments for SCLUs primarily because there is no standard protocol of care. Moreover, there is a paucity of RCTs in the literature, with most treatment suggestions based on anecdotal case reports. Management options range from topical medication and dressings to systemic therapy and surgical methods. We will review cited treatment options before outlining our protocol.

Topical treatment

Baum et al. published one of the few RCTs on the topical treatment of SCLUs. They hypothesised that S. aureus, P. aeruginosa and S. pyogenes produce cytotoxic exotoxins that prevent ulcer healing 22. They used topical triple antibiotics therapy in 15 patients and compared the change in ulcer size to a control group. By the end of the 8‐week trial, treated ulcers were 66% of the original size, a statistically significant reduction compared with the control group. However, a 2014 Cochrane Review suggests that this trial had a high risk of bias and emphasised the need for confirmatory studies 23. Much of the literature since 1987 questions the role of bacterial infections in wound pathogenesis.

A triple‐armed RCT compared the use of DuoDerm (ConvaTec, Greensboro, NC) hydrocolloid dressing with twice‐daily applications of Solcoseryl cream, a de‐proteinised extract from calf's blood that is meant to improve the tissue utilisation of oxygen. Both therapies were compared to a control treatment, where wounds were cleansed with a mild antiseptic agent, Eusol, and then covered with a wet dressing. Neither of these interventions significantly reduced ulcer size when compared with the control treatment 24.

The 2014 Cochrane Review found that only the 1994 trial that used an arginine‐glycine‐aspartic acid matrix (RGD peptide matrix) achieved noticeable benefit in the treatment of SCLUs 23, 25. The RGD peptide matrix is believed to act as a synthetic extracellular matrix to promote cell migration, keratinocyte layer formation and wound strengthening. Chronic ulcers treated with RGD peptide matrix had a statistically significant decrease in surface area (54·4% compared with 19% in controls, P = 0·0085) 25. However, the Cochrane Review assesses this single trial as having a high risk of bias and recommends further studies 23.

A retrospective cohort study (n = 18) emphasised the importance of a moist wound‐healing approach. Ten of the patients in the study had previous surgical treatment, such as debridement, split‐thickness skin grafts and muscle flaps. Additional previous treatments included wet‐to‐dry dressings, Unna boots, hydroxyurea, recombinant human erythropoietin and arginine butyrate. However, all wounds either failed to heal or recurred with the cessation of treatment. Ultimately, all patients were treated with topical hydrocolloid dressing (DuoDerm CGF by ConvaTec). The eight patients who had not received surgical treatment healed completely within 2–16 months, with only one recurrence at 4 months. Of the ten patients who had previous surgical treatment, six healed without recurrence at 30 months, two experienced recurrence with resolution upon the reapplication of DuoDerm and two did not heal but did not experience worsening of their ulcers. While the study was limited by numerous confounding factors and a small sample size, it did succeed in its goal of demonstrating the efficacy of a simple moist wound‐healing approach for SCLUs, especially when compared with the large health care costs associated with advanced medical and surgical treatments 7.

A recent phase 1 trial of escalating doses of topical sodium nitrite demonstrated a dose‐dependent effect on promoting ulcer healing and, most interestingly, decreasing pain at the ulcer site 17. Although this was a toxicity and tolerability study, the delivery of NO to the wound bed resulted in promoting healing, reduction of bacterial colonisation and platelet aggregation and vasodilation. All these known effects of NO are beneficial in wound healing.

Apart from the six RCT studies reported in the Cochrane review 23, treatment approaches to SLCUs are limited to case reports. Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) has been employed topically and via intracutaneous injection 26, 27. The cytokine activates macrophages and induces the proliferation of keratinocytes and differentiation of myofibroblasts. While it was shown to be beneficial in wound healing 26, 27, 28, cost and severe vaso‐occlusive and even fatal events were a major limiting factor discouraging its use 29.

Apligraf – a bi‐layered epidermis/dermis construct origin – has been approved by Food and Drug Administration (FDA) since 2000 for the treatment of diabetic foot ulcers and venous leg ulcers (VLUs) that have not responded within 4 weeks to standard of care (SOC) therapy. The improved efficacy of SOC plus Apligraf over SOC therapy alone for recalcitrant VLUs has been demonstrated in multiple RCTs 28, 30, 31, and recent guidelines from the Society of Vascular Surgery approves the use of Apligraf for the treatment of VLUs [‘Level A’ evidence (Grade 2)] 32. The optimal frequency of use of Apligraf, however, remains controversial. Current clinical practice is for 1–3 weeks of observation after an initial application to determine its effectiveness before reapplication is considered. Although allogenic skin replacements have not gained FDA approval for the treatment of SCLUs, use of Apligraf may be justified if concomitant venous insufficiency is present.

Gordon and Bui examined the utility of direct application of keratinocytes and fibroblasts to an SCLU using Apligraf, the bi‐layered skin equivalent. Prior to application, researchers used a 4‐week regimen of hydrogel, followed by 1 week of wet‐to‐dry dressings and 1 week of wet‐to‐dry dressings plus application of papain‐urea debriding ointment (Accuzyme). After 6 weeks, the ulcer was sufficiently optimized for closure. The use of Apligraf resulted in complete healing, and the ulcer remained healed at the last follow‐up (33 months) 33.

Amini‐Adle et al. used sheets of allogenic keratinocytes to promote the migration of autologous keratinocytes from the peripheral wound bed. They applied sheets of cells twice per month, successfully healing a chronic ulcer within 3 months, without recurrence at follow‐up at 8 months 34. Collagen matrix (Collistat) has also been shown to be efficacious. Two patients with chronic ulcers were treated with Collistat every 4 weeks and experienced complete healing by 10 and 12 weeks. One of the patient's ulcers recurred within 3 months 35.

Gilli et al. described the use of an autologous platelet gel to treat SCLUs in five patients. Autologous platelet‐enriched plasma was applied to the wound margins, and fibrin matrix clot to the wound bed, before covering with moist saline gauze. Researchers noted significant local release of platelet‐derived growth factors (PDGF, P < 0·001), transforming growth factor‐β (TGF‐β, P = 0·015) and vascular endothelial growth factor (VEGF, P = 0·03). Three of the patients showed a reduction of the SCLU area by 85·7–100% within 6–10 weeks. Two other patients with ulcers 3–10‐fold larger experienced 20·5% and 35·2% decreases in the ulcer area within the same time frame. The authors concluded that the use of autologous platelet gel offers a promising and cost‐effective adjuvant treatment for SCLUs 36.

Recently, Hayek et al. studied the use of Cacipliq20, a synthetic, bioengineered heparan sulfate solution, in SCLU treatment. The solution is designed to function as a glycosaminoglycan mimetic, potentially restoring the extracellular matrix scaffold and enhancing growth factor recruitment to aid in collagen production and angiogenesis, and to restore tissue homeostasis and protect the wound from further damage. The patient in this case report had failed to respond to numerous treatments, including moist wound therapy, grafting and energy‐based modalities. The patient experienced complete healing after 8 weeks of twice‐weekly applications.37.

There are also a few reports of energy‐based modalities in the literature. Low‐frequency non‐contact ultrasound has been utilised to accelerate healing in a wide variety of acute and chronic wounds, including sickle cell ulcers. Its mechanism of action is attributed to the effective removal of bacteria and biofilm and the reduction of chronic inflammation. At the cellular level, it appears to promote the release of NO and growth factors, thereby stimulating vasodilation, angiogenesis and collagen deposition. While complete closure without the need for surgical intervention is always a primary objective, this modality can also be used to optimally prepare the wound for grafting 38.

More recently, low‐level laser therapy was reported to result in an 80% reduction in the area of an SCLU after just five 10–15 minute sessions, leading to a marked improvement in the patient's quality of life. The patient had been struggling with recurrent painful, infected ulcers for more than 20 years 39. Low‐level laser therapy has previously been reported to modulate wound healing by increasing mitotic activity, fibroblast production, collagen synthesis and angiogenesis and may have a role in the apoptotic processes of wound healing 40.

Negative pressure wound therapy (NPWT) is a widely used wound care technique, though only a single report describes its use for treating SCLUs. Paggiaro et al. examined the use of different wound care methods to optimally prepare sickle cell ulcer beds. Following surgical debridement and before grafting, three wounds were treated by three different methods: a rayon and normal saline solution dressing, calcium alginate and gauze and negative pressure therapy. Researchers found that the NPWT‐treated wounds had a more homogenous surface with better vascularisation in comparison with those treated with calcium alginate or rayon dressing with normal saline. All three wounds received a split‐thickness skin graft. While the other wounds experienced subsequent graft failure, the NPWT‐treated wound did not, and the ulcers had not recurred by the time of follow‐up (11 months) 41. However, the painful nature of SCLUs may be a limiting factor in the use of NPWT.

Systemic treatment

The use of systemic therapy in SCLU has not been rigorously studied. Zinc replacement has long been advocated for patients with chronic wounds accompanied by serum zinc deficiency 2. Serjeant et al. reported that 220 mg of zinc sulfate administered orally three times a day significantly improved the healing of SCLUs 42. Thirteen of the 15 patients taking zinc versus eight of the 14 taking placebos experienced greater healing (8·1 mm²/day versus 2·8 mm²/day, respectively) 42. Unfortunately, this is the only study that investigated the effects of zinc supplementation on the healing rate of SCLUs. Moreover, the results are hard to interpret as neither the length of supplementation with oral zinc or statistical analysis was provided.

Pentoxifylline was originally marketed for patients with peripheral vascular disease to improve claudication. Pentoxifylline improves RBC and leukocyte deformability, thus potentially decreasing blood viscosity; the drug also inhibits platelet aggregation and thrombus formation and decreases plasma fibrinogen levels 43. These multiple effects ultimately increase microcirculatory flow and tissue oxygen levels, making it ideal for SCLU treatment. Although no large‐scale trials were ever conducted, one case report reported that 400 mg of oral pentoxifylline three times a day (TID) helped completely heal an SCLU within 3 months 44. It has also been used off‐label for the treatment of VLUs. In nine RCTs (eight of which were against placebo treatments) involving 572 patients, pentoxifylline combined with compression bandages improved ulcer healing with a relative risk ratio of 1·4 [95% confidence interval (CI), 1·19–1·66] 32, 45. The 2014 clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum recommends the use of pentoxifylline for treatment of long‐standing or large VLUs (Grade‐1; Level of Evidence‐B) 32. As venous insufficiency is often present in SCD patients, pentoxifylline may be a good adjunct treatment option in the management of SCLUs.

Systemic therapy of SCLUs with l‐carnitine has been reported in only one RCT and a case study. The drug potentially improves tissue hypoxia by allowing more efficient oxidative metabolism. The studies involved patients on concomitant transfusion therapy, making it difficult to isolate the role of l‐carnitine 46, 47.

More recently, McMahon et al. published results from a phase II clinical trial on the use of arginine butyrate 48. Theoretically, arginine stimulates collagen production, improves immune function and prevents vascular re‐stenosis. Butyrate can stimulate PDGF production and also downregulate TGF‐β, tumour necrosis factor alpha (TNF‐α) and matrix metalloproteinases (inflammatory cytokines and enzymes that slow wound healing). The results are promising with a significant increase in the ulcers healed in the treatment arm after 3 months (78% versus 24% in controls, P < 0·001) 48. However, the requirement for an intravenous catheter limits the potential of this therapy.

Bosentan is an endothelin receptor blocker used to treat pulmonary hypertension in a sickle cell patient. Incidentally, the patient experienced complete healing, without recurrence, of lower extremity ulcers. Researchers attributed the healing to the blockade of the endothelin receptor, permitting vasodilation in a patient likely suffering from low NO bioavailability. Unfortunately, the patient also received transfusions during this period, possibly confounding the results 49.

The role of hydroxyurea (HU) in the development or in the treatment of SCLUs is not defined. HU increases foetal haemoglobin levels, decreasing the intracellular polymerisation of HbS, the incidence of painful crises and the need for transfusions in SCD patients 50. Moreover, HU is a known NO donor and decreases WBC counts 51. Theoretically, these effects should decrease the incidence of leg ulcers. However, leg ulcers have been observed in patients with chronic myeloproliferative disorders who use HU, which often resolved several months after the discontinuation of this medication 52. Vélez et al. described similar findings in a two‐patient case report, suggesting that HU causes an acquired blood dyscrasia that puts patients at risk of ulcerations 53. Other multicentre studies have seen no evidence of an association between hydroxyurea and leg ulceration 1. Thus, at present, it is difficult to conclude if hydroxyurea causes or exacerbates SCLUs.

Blood transfusions are often used in the care of SCD patients. They have also been advocated as a treatment modality for patients with SCLUs. Transfusions increase the oxygen delivery to tissues by increasing total haemoglobin and decreasing the HbS concentration 1. A variety of transfusion recommendations have been proposed to prevent the recurrence of or to treat existing ulcers 2. Some authors suggest achieving a haemoglobin of 10 g/dl for successful surgical treatment, although a level between 8–9 g/dl may be more realistic and adequate for wound healing 8. Interestingly, data supporting any true benefit is largely lacking, and there have been no prospective randomised controlled trials. While the use of transfusion could be beneficial, it does not come without risks 6. Continued transfusions lead to iron overload and deposition in organs such as the heart and liver, requiring use of iron‐chelating agents and/or phlebotomy. Additionally, alloimmunisation occurs at high rates in patients with SCD, and there is a small risk of contracting an infectious disease 8.

Patients with SCD have impaired immunity. Dysfunction of the reticulo‐endothelial system and functional asplenia make them prone to systemic infection with encapsulated organisms. As discussed above, numerous reports document bacterial colonisation of SCLUs, but there is still no consensus on the utility of topical antibiotics. However, colonisation may lead to infection or perhaps a state of chronic inflammation. The use of systemic antimicrobials with anti‐inflammatory properties, along with adequate debridement of the ulcer, can aid in fostering a healing wound bed. Systemic antibiotics with anti‐inflammatory properties include doxycycline, clindamycin and metronidazole. These agents may facilitate healing if deep and/or surrounding tissues are persistently inflamed because of bacterial infection 8.

Surgical treatment

Surgical modalities are cited throughout the literature for the treatment of SCLUs. However, surgical treatments are often accompanied by high rates of failure and recurrence 9. Additionally, with each subsequent graft and recurrence, the scar tissue becomes denser and less vascular, progressively shortening the ulcer‐free interval 54.

Given the paucity of blood supply in the most affected regions, microsurgical free flap transfers are a popular modality as they include their own blood supply 9. However, they require a period of obligate ischaemia during the procedure, and numerous case reports published in the 1990s were complicated by thrombi, microemboli and infection – many required debridement and split‐thickness skin grafts 9, 21, 54, 55. Even when grafts take successfully, recurrence rates remain high. A skin graft does not alter the pathophysiology of RBC sickling nor does it induce angiogenesis in regions with a marginal blood supply 6.

Owing to the high rates of failure, numerous recommendations have been made to decrease the incidence of graft failure. Perioperative transfusion to decrease HbS levels to less than 30% is recommended, with transfusions beginning 1–2 weeks prior to surgery and continuing for 6 months post‐operatively 2, 9. Some have even suggested that lifelong transfusions are required 55. Additionally, some surgeons advocate the use of anticoagulation with heparin and/or aspirin, antibiotics and the rinsing of flaps with warm, heparinised solution prior to attachment 9.

Surgical success rates remain poor. RCTs and longer periods of follow‐up are required to assess the true value of surgery in the treatment of SCLUs.

Other modalities

Beyond medications and surgery, bed rest has long been a recommended (albeit impractical) treatment modality. Patients who underwent 2–3 weeks of strict bed rest experienced complete closure of their wounds within 2–3 months. In addition to reducing venous backpressure and oedema around the ankle, patients developed improvements in RBC deformability, possibly secondary to decreased plasma volume, which also aided healing 56.

Compression garments for oedema control were universally recommended in a recent survey of care providers treating SCLUs 1. The use of Unna boots is also highly recommended by practitioners as the zinc oxide‐impregnated boots are useful in treating lower extremity lesions exacerbated by venous insufficiency. Multi‐component compression systems have been shown to be the most effective in reducing oedemas and improving venous reflux 8.

As venous insufficiency is often found in SCD patients, the clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum are also applicable for treatment of SCLUs if venous disease is present. The guidelines recommend compression therapy over no compression therapy to increase VLU healing (Grade‐1; Level of Evidence‐A) and to decrease the risk of ulcer recurrence (Grade‐2; Level of Evidence‐B) and the use of multi‐component compression bandages over single‐component bandages (Grade‐2; Level of Evidence‐B) 32.

Pain should not be underestimated in patients with SCLUs. Many experience pain that requires chronic opioid use. In attempts to reduce this reliance, Ballas et al. dissolved oxycodone and meperidine tablets in water and applied it locally to provide topical analgesia. Total pain relief was reported, likely because of modification of peripheral opioid receptors 57. While this treatment is not commercially available, these findings suggest that further research is warranted.

Hyperbaric oxygen therapy for treatment of vaso‐occlusive crises and SCLUs intuitively appears to be a sound treatment option. There are a number of case reports describing its potential benefit 1, 58, 59. However, paucity of research, potential adverse side effects, lack of treatment protocols, limited availability and economic factors restrict its use.

Discussion

While SCLUs are not a life‐threatening complication, they are severely debilitating. Unfortunately, there is a dearth of quality evidence on the optimal wound care recommendations that will maximise healing and quality of life. As described in this review, dozens of topical, systemic and surgical modalities have been used to treat these chronic, recurrent ulcers. However, large controlled trials have not been carried out to confirm the benefits of these therapies. Synthesising the available information allows us to propose a guideline for practitioners to use in treating patients with sickle cell ulcers. However, we strongly encourage further rigorous evaluations of treatment modalities in order to develop more evidence‐based recommendations.

Prevention

Prevention of leg ulcers is paramount in SCD patients. A previous history of SCLUs is the greatest predictor of developing another leg ulcer, increasing the risk 23‐fold 2. While spontaneous ulcers are unpredictable, traumatic ulcers can be prevented. Encouraging patients to regularly check their skin for signs of early ulcers allows early and aggressive treatment, while preventing local trauma by wearing properly fitting shoes, using bug spray to prevent bites and refusing blood draws and intravenous lines in the lower extremities may also decrease the risk of developing SCLUs. Wearing appropriately sized above‐the‐knee compression stockings can reduce oedema and prevent new and recurrent ulcers 2, 16.

Treatment of systemic factors

Once SCLUs develop, compliance becomes the most important determinant of successful wound healing. Patients must be properly educated on the severity of their condition, treatment options and proper ulcer management. A multidisciplinary approach to the care of these patients is essential. This frequently includes consultations with the haematologist, dietician, and wound care and infectious disease specialists to investigate the use of systemic therapies aimed at ameliorating the underlying disease.

Nutrition

Nutrition is known to be important in the management of ulcers, and patients should be checked for nutritional deficiencies and treated appropriately. Zinc deficiency has been shown to be prevalent in SCD patients. While it remains an adjunct treatment, diagnosing and correcting zinc deficiency can help foster a healing systemic environment. The current recommendation is 220 mg of zinc sulfate thrice a day. Serum zinc levels should be re‐measured 2 and 4 weeks after initiation of supplementation and therapy discontinued if levels normalise.

Thrombosis

Assessment and treatment of occult deep venous thrombosis is essential. Anticoagulation therapy may be necessary to treat proven innate hypercoagulability and a higher propensity for microcirculatory thrombosis.

Pain

Non‐steroidal anti‐inflammatory agents are often inadequate therapy for the severe, unremitting, sharp pain of SCLUs, while the side effect profile of chronic opioids makes their use undesirable. While topical analgesia is an interesting area for future study, there are currently no standard recommendations for its use. Regional nerve blocks provide an excellent alternative to systemic opioids (I.A. Altman and W.J. Ennis, personal observation). Not only do patients achieve good pain control, but secondary vasodilation occurs through reduction of stress‐related catecholamine release. Some patients may be opposed to this invasive procedure because of the presence of an indwelling pain catheter, the increased risk of local soft tissue infection and the need for frequent clinic visits for pain‐pump refills.

Wound care

SCLUs are notoriously resistant to treatment and tend to recur. Wound bed optimisation and adjunct care modalities are essential for the successful management of SCLUs. First, the ulcer must be converted into a healable wound and kept free of infection. Debridement of the biofilm and necrotic, non‐viable tissue from the base and the edge of the wound is essential to begin the healing process 38, 60. Traditionally, several types of wound debridement techniques have been used in clinical practice such as autolytic, enzymatic, biological, mechanical and sharp. Various factors determine the choice of debridement method: suitability to the patient, the type of wound, its anatomical location and the extent of debridement required 61. Guidelines for frequency of sharp debridement of SCLUs have not been established; however, regular weekly debridements of most chronic wounds, as part of a multifaceted treatment strategy, resulted in improved healing 62. Sharp debridement can be an incredibly difficult and painful experience for SCD patients. It may only be possible with adequate analgesia, either topical, injectable or in the operating room under general anaesthesia. Frequently, a combination of all of these methods is necessary 2.

A multitude of dressings exist, from hydrocolloids, hydrogels, alginates and collagen to cell‐based biological topical therapies. Many of these dressings provide additional anti‐inflammatory and autolytic debridement properties. However, the basics of effective wound care remain the same – maintenance of a moist healing environment.

Energy‐based modalities can be helpful for their pain‐reducing and antibacterial capabilities. Low‐frequency, non‐contact ultrasound 63, electrical stimulation 64 and ultraviolet C light 65 offer a less traumatic method of facilitation of wound healing and reduction of the bacterial burden. They present an excellent adjuvant treatment option for wounds that fail to respond positively to SOC methods (I.A. Altman and W.J. Ennis, personal observation).

The use of RGD peptide matrix has shown promise as a topical treatment, although it is expensive and is not widely available. The use of allogeneic keratinocytes and autologous platelet gel offer excellent topical methods of increasing growth factors locally and are promising treatments for resistant ulcers.

Addressing venous insufficiency

Compression therapy is encouraged for the management and prevention of oedema, especially if venous insufficiency is present. Compression stockings are useful for prevention, while multi‐layer compression bandaging is recommended for treatment. Self‐applicable and adjustable short‐stretch Velcro band devices may serve as an alternative 32.

Recent clinical practice guidelines from the Society for Vascular Surgery and the American Venous Forum (2014) strongly supported the use of pentoxifylline for treatment of long‐standing or large VLUs (Grade‐1; Level of Evidence‐B) 32. As venous insufficiency is frequently found in patients with SCLUs, we advocate the use of this medication for microcirculatory support. For SCLUs with proven venous insufficiency and a poor healing trajectory – without a positive response to SOC therapies within 4–6 weeks – we suggest considering the use of Apligraf.

Minimally invasive ablation of superficial axial and perforator vein reflux in patients with active venous insufficiency and patent deep venous system is a relatively safe procedure and leads to faster healing and decreased ulcer recurrence when combined with compression therapy 66. Therefore, thorough evaluation of the venous system and a prompt referral to a vascular specialist is another critical component in the successful treatment of SCLUs.

Antibiotic therapy

Based on the Diabetic Foot Ulcers literature, there is no evidence that treating a clinically uninfected wound with antimicrobials prevents infection or improves ulcer healing 67. When there are clinical signs of infection, post‐debridement deep soft tissue or bone sample should be aseptically obtained for cultures and sensitivity. Superficial cultures obtained with cotton swabs are more easily collected but are less reliable than tissue biopsies and should be avoided 68.

Patients who are hospitalised with more severe infections and signs of cellulitis and/or sepsis typically receive intravenous (IV) antibiotic therapy initially and are then switched to oral agents once they have demonstrated clinical response and culture results are available. However, based on antimicrobial data, severity of infection and other modifying factors, a subpopulation of patients will need to complete their therapeutic course with IV antibiotics.

Finally, topical antibiotics may reduce soft tissue inflammation but do not significantly affect SCLU healing. Pharmacological treatments with tetracyclines could improve extracellular matrix functioning and represent a possible solution to support wound healing. Their immunomodulatory and anti‐inflammatory actions are beginning to be understood 69, but more studies are needed to further investigate their potential benefits.

Conclusion

After an analysis of studies of SCLU pathogenesis and the large number of treatment approaches described in the literature, we propose a step‐wise approach for clinicians managing SCLUs (Figure 1). We must emphasise, however, the need for further evaluation of the majority of these treatment modalities to allow for more rigorous evidence‐based recommendations.

Figure 1.

(1) ^†Consult with haematologist and primary care physician. (2) Consider ordering an magnetic resonance imaging (MRI) if X‐Ray is negative, the inflammatory markers are elevated and clinical suspicion is high. (3) Order bilateral lower extremity venous duplex to evaluate for reflux. *Apply three or four‐layer compression wrap only if pulses are palpable/Doppler‐able. (4) Pain clinic referral (if available) is essential. (5) Energy‐based wound therapies (if available) are usually done by physical therapy.

Many avenues for future investigations exist. We suggest further research comparing the effects of the diverse dressings available for SCLU treatment and of different NO‐based therapies. The utility of growth factors, platelet concentrates/gels and energy‐based modalities in these types of wounds needs deeper understanding.

Regarding systemic therapies, there is a need for a RCT analysing the benefit of transfusion therapy and HU in patients with SCLUs. Both treatments present potential risks to patients. Lastly, we encourage researchers to explore novel treatment options for SCLUs, a disease that greatly impacts the quality of life of many patients.