Sickle cell anemia (SCA) is a genetic disease with autosomal recessive inheritance in which the gene encoding the human [beta]-globin subunit contains a DNA substitution at the 17th nucleotide of adenine for thymine.1 This point mutation results in a subsequent translated protein having valine substituted for glutamic acid at the sixth amino acid in the [beta]-globin chain.2 This resultant protein is known as HbS.

Sickle cell disease is a broad term that refers to all of the different genotypes that lead to the standard clinical syndrome; SCA (homozygous form) accounts for 70% of all symptomatic cases.1 Sickle cell disease is characterized by hemoglobin polymerization when the substituted protein undergoes hydrophobic interaction with another hemoglobin molecule in the RBCs, resulting in a distortion of the cell's shape and causing erythrocyte rigidity.2 Disease severity is primarily determined by the rate and extent of polymerization of HbS. The presence of HbF in the erythrocyte can effectively reduce this harmful polymerization.1

Management options for SCUs include systemic therapies, surgical debridement, and topical treatments, including dressings.3 The wound bed preparation paradigm as a framework4 for the assessment, diagnosis, and treatment of patients with SCUs will be used in this article.

ETIOLOGY OF A LEG UCLER IN SCD

A careful and systematic evaluation of the patient with a leg ulcer is important for the establishment of the correct diagnosis. Accurate wound diagnosis with proper management plans is best approached through a holistic interprofessional effort because of the nature of these complex wounds. The detailed history should include: duration of the ulcer, signs and symptoms of infection, including occasional osteomyelitis, and systemic symptoms, related to SCD. The documentation of systemic manifestations, such as increasing pain and intermittent fever, is also an important part of the assessment that may be linked to infection. Specific laboratory assessment depends on the findings of the clinical evaluation. If the patient does not have a diagnosis of SCD, but there is a high index of suspicion or indicators of SCD during the differential diagnosis, laboratory testing should include a sickle cell "prep" and hemoglobin electrophoresis. Other clinical testing should include ankle brachial pressure index (ABPI) testing as a screening measure. The presence or absence of the pulses should be recorded, or if the pulse is weak or absent, an ABPI index (0.5 mm Hg) or toe pressure (>55 mm Hg) should be recorded, to determine if the blood supply is adequate for wound healing in these patients. The assessment of the wound "healability" helps clinicians to set realistic goals of treatment.4

COMPRESSION THERAPY

When SCUs occur in the setting of concurrent venous disease, compression bandaging is an important part of the treatment. Lifestyle and occupation are the 2 important factors in choosing a type of compression.5 The Cochrane review of venous ulcers and compression therapy randomized controlled trials demonstrated that compression therapy is the cornerstone of venous ulcer treatment. In addition to improving the healing rate of ulcers, compression therapy reduces edema, improves venous reflux, and reduces pain.6 Compression bandages are classified into 2 major classes: elastic bandages and support (nonelastic) bandages. The elastic system provides compression at rest and with lower compression associated with muscle contraction, but the support system has low pressure at rest, with most of the compression with muscle contraction from activities such as walking. This pressure results from the calf muscle contraction against a rigid bandage. Compression bandages are used for the treatment of existing ulcers, and the compression garments (stockings) are for prevention. Compression bandages may consist of a single component (1 bandage layer) or a system of multiple components (several different bandages used together).7 They may be further classified into low, medium, high, and extra high compression bandages reflecting the compressive force exerted by each subclass.

A review of the literature for randomized controlled trials comparing single-component compression with multicomponent systems demonstrated statistically greater healing outcomes utilizing the higher sub-bandage pressure from multicomponent compression systems.7 Commonly used multicomponent systems include short stretch/inelastic, inelastic paste system (Unna boot), and 3- or 4-layer elastic and inelastic systems.7

It has been suggested that the efficacy of any compression treatment modality may be dependent on the skills and knowledge of the person applying the bandage,8 and where application competency is a question, the use of compression hosiery may be indicated.7 If the ABPI is 0.8 or greater, a high compression system should be utilized; a modified lower compression system for ABPIs between 0.65 and 0.8; and very low compression used with expert guidance and caution with ABPIs between 0.5 and 0.65.

Although demonstrated to be an effective aid in the healing of venous ulcers, there are some risks associated with compression therapy, including pressure damage from reduced blood supply to the skin and impaired arterial blood supply. Uncompensated heart failure and clinically significant arterial disease have been described as contraindications for compression therapy in the treatment of venous leg ulcers.6

PATIENT-CENTERED CONCERNS

Sickle cell-associated leg ulcers are extremely painful. Uncontrolled pain can be devastating and stressful and affect activities of daily living. Patients with SCD may experience recurrent sickle cell painful crises. It is recommended that the World Health Organization pain assessment and treatment ladder be utilized as a guide for treatment. A visual analog assessment tool for consistent pain evaluation and the response to the treatment is necessary (eg, 0- to 10-point numerical verbal rating scale). Topically applied and locally injected anesthetics, including a dressing containing slow-release pain analgesics, have been successfully utilized. Systemic medications including nonnarcotic agents (such as nonsteroidal anti-inflammatory agents) for moderate pain and weak to stronger narcotics are indicated for moderate to severe pain, respectively. Short-acting agents are used to determine the dose of long-acting agents (equal analgesic effects) and also for breakthrough pain. The neuropathic component of leg ulcer-associated pain may respond to selective serotonin reuptake inhibitors, tricyclic agents, gabapentin, pregablin, or other pain-reducing agents. Proper pain control increases the patient adherence and optimizes patient-centered care. On the numerical rating scale (0-10), most patients are comfortable with a reported pain level of 3 to 4; higher levels of pain have been found to interfere with the activities of daily living.9,10

LOCAL WOUND CARE

Sibbald et al4 proposed that the wound bed is optimally prepared via debridement of any eschar or slough. Debridement of the devitalized tissue is required after the assessment of the wound's healability. Sharp debridement may promote wound healing by removing senescent cells and bacterial biofilms; however, it is associated with risks of pain and bleeding and may not be feasible in painful SCUs.4 If a wound does not have the ability to heal, aggressive debridement is contraindicated, and only nonviable slough should be removed from the surface. Appropriate dressings for healable wounds may provide autolytic debridement (calcium alginates, hydrogels, and hydrocolloids).

Sharp debridement is the most selective method but may be challenging in patients with SCD because of severe pain. The debridement of ulcers in these patients needs local anesthesia to control the pain. Pain management as noted earlier is mandatory during debridement.3

Moisture Balance

Healable wounds treated with moist wound healing are less painful and heal faster. There are numerous wound dressings available on the market. In conjunction with other therapies, the proper wound dressing can have a direct effect on healing rates. Dressings should be selected with several factors in mind, such as debridement, control of critical colonization, inflammation, and moisture balance.4

The selection of an appropriate dressing is also imperative for the maintenance of moisture balance in SCUs. Excess fluid may cause damage to the surrounding skin, whereas inadequate moisture can promote eschar formation, which impedes wound healing.4 Use of occlusive, semiocclusive, absorptive, or hydrating dressings, including foams (higher levels of exudate, fluid exchange), hydrofibers (fluid lock), calcium alginates (bioresorbing converting to a sodium alginate hydrogel and promoting homeostasis), hydrocolloids (some absorption but also hydrophobic components), hydrogels (70%-90% water for hydration of wounds), and films (protection and handle minimal fluid), can all improve healing rates of chronic ulcers by controlling moisture balance.4

Infection and Inflammation

Patients with SCD are prone to recurrent infection and deep infections including osteomyelitis. If patients have coexisting hepatitis C virus, the risk of infections was high at 13.9% in a series of patients reported by Neto et al.11 This series of 1415 patients also found a higher level of infection in SCD patients with adult T-cell lymphoma virus type 1 (4.7%), hepatitis B (3.1%), Chagas disease (2.8%), HIV (0.8%), and syphilis (0.4%). Radiographic assessments are indicated to rule out osteomyelitis. It is important to consider the combined radiographic test sensitivity and specificity. For example, computed tomography is more sensitive than magnetic resonance imaging, and plain radiographs are very specific but not sensitive. Therefore, by the time the osteolytic lesions appear on the X-ray, there is a lost opportunity for the early diagnosis of osteomyelitis. A bone biopsy for histology and bacterial culture gives a high degree of both sensitivity and specificity and enhances the combined sensitivity and specificity of the diagnostic tools. In the presence of fever or an increased white blood cell count (leukocytosis), rubor, color, and dolor (redness, fever, and pain), clinicians should have a high index of suspicion for local and systemic infection. Sickle cell disease patients are prone to develop infections, and these infections can include less common organisms, such as Salmonella.

Chronic ulcers should be evaluated for possible bacterial damage that may also contribute to wound deterioration or delayed or stalled healing. Although deep and surrounding tissue infection may require the use of systemic therapy, superficial critical colonization may be treatable with one of several antimicrobial wound dressings.4 Silver, iodine, honey, and polyhexamethylene biguanide dressings have antibacterial properties, and their use in chronic ulcers has been documented to aid healing by reducing critical colonization.4 The effect on ulcer healing rates of these dressings has yet to be evaluated specifically in the SCD population. The majority of reports on the effectiveness of topical treatments have been anecdotal in nature.12 Minniti et al13 conducted a randomized controlled trial of a topical, triple antibiotic preparation consisting of neomycin, bacitracin, and polymyxin B, demonstrating a significantly greater reduction in ulcer size and associated pain versus control over an 8-week period. Although the mechanism of healing is unclear, the antibiotic preparation may act on organisms such as Staphylococcus aureus and Pseudomonas aeruginosa that commonly occur in SCUs, and these organisms may impair wound healing.14 Despite the evidence that this study demonstrated some degree of healing, the use of topical antibiotics is not recommended because of risk of contact sensitization, bacterial resistance, and the lack of moisture balance/autolytic debridement.

The control of abnormal prolonged inflammation is also an important factor. There is a role for the use of anti-inflammatory agents with protease-modulating effect, such as dressings with topical collagen, oxidized reduced cellulose, and silver. Systemic anti-inflammatory antibiotics include doxycycline, cotrimoxazole, clindamycin, and metronidazole, which can all facilitate healing if the deep and surrounding component of the wound has persistent inflammation associated with bacterial damage.15,16

Advanced Treatments

When wound bed preparation of a healable wound has been optimized, and the wound healing is stalled, advanced treatment modalities may be considered. Surgical interventions include sharp debridement and the use of split-thickness skin grafts and myocutaneous flaps, or alternative treatment in the treatment of some SCD leg ulcers.3

Recalcitrant ulcers that have failed to epithelialize may benefit from the introduction of an autologous skin graft,3,17,18 which can provide continuous coverage, pain relief, and rapid healing of chronic ulcers.19 Vascular insufficiency and circulatory difficulties in the sickle cell patient, however, may lead to high rates of skin graft failure.3,17

Microsurgical free flaps may be more effective for the treatment of refractory ulcers as they contain their own vasculature and blood supply.3 Literature reports of successful SCD ulcers with free tissue transfers have included axial,20 gracilis,21 latissimus dorsi muscles,22,23 temporoparietal fascia,23 and split omentum24 free flaps. Myocutaneous free flaps, however, still carry a risk of flap necrosis and failure. Some reports have suggested the use of prophylactic anticoagulation to prevent postoperative thrombosis and facilitate flap survival.18,25

SYSTEMIC THERAPY

Blood Transfusion

Transfusion of packed RBCs is a commonly utilized therapy for the prevention and regulation of many clinical manifestations of SCD, including anemia, acute chest syndrome, and pulmonary hypertension.26 The aim of transfusion therapy is to increase the oxygen-carrying capacity of the blood by reducing HbS concentration and increasing normal hemoglobin concentration.3 Transfusion is also commonly used to aid in the treatment of recalcitrant SCUs, despite a lack of organized clinical trials on this subject.17 Potential complications, including iron overload and alloimmunization, must be monitored in patients treated with repetitive transfusions. Iron overload occurs when abnormal levels of iron accumulate in the body; the areas most commonly affected include the heart, liver, and endocrine glands. A patient with iron overload may require repetitive phlebotomies or treatment with an iron-chelating agent.27 This problem may be minimized with the use of exchange transfusions where sickle cell-containing blood is removed and replaced with normal and ABO matching donors. Excess iron can cause severe organ damage that is generally irreversible.

Alloimmunization occurs when the transfusion recipient has an immune response to the donor blood antigens. The antigens most commonly involved include human leukocyte antigens, granulocyte-specific antigens, platelet-specific antigens, and RBC-specific antigens.28

What is a Realistic Hemoglobin Level?

Simple blood transfusions may be utilized to reach a normal hemoglobin concentration of 8 to 9 g/dL.1 The optimal concentration may vary in response to SCD crises, such as cerebrovascular accident, multiorgan failure, or acute neurological deficit, following which a hemoglobin concentration of 10 g/dL should be sought. Preoperative exchange transfusions may be necessary to reduce HbS concentration to less than 30% for major surgical procedures and increase hemoglobin to 10 g/dL for moderate or low-risk procedures.1

Hydroxyurea

Hydroxyurea (hydroxycarbamide) is a chemotherapeutic agent and the only Food and Drug Administration (FDA)-approved drug therapy for SCD. One mechanism of action is thought to be based on its reduction of deoxyribonucleotide production via inhibition of the enzyme ribonucleotide reductase. In the treatment of SCD, hydroxyurea acts to reduce disease severity by inhibiting polymerization of HbS via increased production of HbF, the precise mechanism of which is unknown.2,29 Other therapeutic benefits include a decrease in leukocyte and erythrocyte adhesion to the vascular endothelium.30,31

The role of hydroxyurea in SCUs is unclear as conflicting results have been reported. Some authors have demonstrated that hydroxyurea may aid in the treatment of refractory leg ulcers in SCD patients,17 whereas others suggest it has no influence on the development of leg ulcers.9,32,33 Several reports have also indicated that hydroxyurea may augment the development of leg ulcers.31,34 Sirieix et al34 reported the results of a multicenter retrospective study of 41 patients who developed leg ulceration while undergoing hydroxyurea treatment. Of these patients, 70% had no prior history of leg ulceration. Complete resolution of the ulcers was noted in 80% of patients following discontinuation of hydroxyurea therapy for an average of 3 months. Definitive, randomized controlled studies are needed to further elucidate the relationship between hydroxyurea therapy and SCUs.

Arginine Butyrate (not FDA approved for SCUs)

Arginine butyrate, the butyric acid salt of the amino acid arginine, has been shown to increase production of HbF with a resultant reduction in clinical manifestations in patients with SCD.2 The relationship between arginine butyrate therapy and SCUs was first reported by Perrine et al35 in 1993 following phase I/II dosing trials with an incidental observation of complete recalcitrant leg ulcer resolutions. Weinberg et al36 proposed a mechanism of action by which arginine butyrate improves the efficiency of translation of hemoglobin mRNA, leading to increased production of HbF.36

In 2010, 23 patients with refractory SCUs of at least 6 months' duration were included in a randomized phase II trial of arginine butyrate versus standard therapy consisting of twice-daily wound cleaning, wet-to-dry dressing changes, and surgical debridement as indicated.37 After 3 months of therapy, subjects on the treatment arm exhibited healing in 78% of ulcers as compared with 24% in the control population (P < .001). In addition, complete resolution was observed in 30% of ulcers treated with arginine butyrate versus 8% treated with standard therapy alone.37

Although increased levels of HbF have been shown to reduce SCD-associated morbidities, the wound-healing activity of arginine butyrate is thought to occur via a separate, unknown mechanism.37 This study demonstrated the commencement of wound healing within 3 weeks of initiation of therapy, although HbF levels did not significantly increase until 6 to 8 weeks after introduction of arginine butyrate. Further studies encompassing larger patient populations are indicated.

Nitric Oxide

Nitric oxide (NO), also known as nitrogen monoxide, is a naturally occurring free radical that serves as a cellular signaling molecule. Nitric oxide has been demonstrated to act by a number of mechanisms, including oxidation of iron-containing proteins, activation of guanylate cyclase, and activation of iron regulatory factors. Nitric oxide has receptors in the endothelium of blood vessels, which initiate relaxation of the surrounding smooth muscle, resulting in vasodilatation and increased blood flow, and also serves to reduce neutrophil adhesion.1,38 Reduced bioavailability of NO in patients with SCD has been linked to a hemolytic-vascular dysfunction syndrome, the characteristics of the syndrome include priapism, pulmonary hypertension, and cutaneous leg ulcers.39 Hemolysis of sickled RBCs in patients with SCD leads to extrusion of cell contents into the plasma, causing a disturbance in the diffusion barrier of plasma hemoglobin.39 These activated molecules react with NO to form inert nitrate, which is bioinactive. The ensuing NO deficit results in vasoconstriction, contributing to clinical morbidities associated with SCD outlined previously.

Small studies concerning inhaled NO gas in patients with SCD suggest that the inhaled molecules bind preferentially with plasma hemoglobin, preventing these molecules from scavenging NO and limiting the vasoconstriction process.39 Similar results have been demonstrated utilizing intravenously administered nitrite (NO₂)40 and dietary supplementation of L-arginine.39

Nitric oxide has also been noted to play a role in the healing process of burns and other cutaneous wounds.41-43 The increase in NO levels in SCD patients may thus have implications in the treatment of persistent leg ulcers, in addition to reducing morbidities associated with hemolysis-vascular dysfunction syndrome. Similar to other potential therapeutic intrinsic or extrinsic substances, overproduction in the case of NO may cause untoward consequences. "Nitric oxide-releasing compounds" may be used off-label for the treatment of SCD, including Viagra for pulmonary hypertension and SCD.44,45

Hypomethylating Agents and Other Systemic Treatments of SCD (not FDA approved)

DNA hypomethylating agents such as 5-azacytidine and decitabine have been reported in small groups of patients to markedly increase HbF, resulting in a reduction of pathogenic mechanisms in patients with SCD.29 There is, however, a paucity of long-term data on patients treated with such therapies, and the relationship with SCUs is unknown.

The effects on wound healing of other systemic SCD treatments such as hematopoietic cell transplantation and gene therapy are unknown. The relatively small population of patients who have undergone such therapies does not provide sufficient clinical data from which to draw such conclusions, and further study is necessary.1

In addition to arginine butyrate, periodic transfusions, and hydroxyurea, other systemic medications and preparations, such as zinc sulfate, bosentan, and pentoxifylline, have been shown anecdotally to positively affect ulcer healing rates.3,46 Zinc deficiency has been described in patients with SCD,17 and the addition of oral zinc sulfate 220 mg three times a day to other SCD treatment modalities has been shown to significantly heal or improve the SCUs (21/29 in the active group and 11/29 of the placebo pill-treated population).47

Bosentan is a dual endothelin receptor antagonist used for the treatment of hypertension and well accepted as an important treatment for pulmonary hypertension. A study done by Serarslan et al48 on 88 patients with SCD demonstrated a high incidence of pulmonary hypertension, 31.6% of 76 patients without leg ulcers, but this percentage increased to 91.6% of the 12 patients with leg ulcers. Patients with SCD and leg ulcers should be screened for pulmonary hypertension. The use of bosentan to treat pulmonary hypertension in a patient with SCD was reported with the unintended adverse effect of complete resolution of the patient's chronic lower-leg ulcers of 18 years' duration.46 Although the mechanism of action is unknown, the facilitation of healing is thought to be due to the endothelial receptor blocker characteristics of bosentan and its effects on the high levels of endothelin 1, which may be found in patients with SCD.49

Wound healing in vascular leg ulcers has been reported with propionyl-l-carnitine; however, a randomized, double-blind, placebo-controlled pilot study showed no significant improvement in ulcer healing rates of SCD patients treated with propionyl-l-carnitine, versus placebo.50 Pentoxifylline has also demonstrated efficacy in vascular leg ulcers, but there is a paucity of data regarding its efficacy in SCUs. Frost and Treadwell51 reported the successful treatment of a sickle cell patient with pentoxifylline, which is thought to act by reducing the RBC sickling, decreasing erythrocyte deformability, and increasing leukocyte flexibility. It may also inhibit platelet aggregation, reduce blood viscosity, and decrease plasma fibrinogen levels,3,17,51 although clinical data to support these mechanism have yet to be found. Randomized controlled trials are needed to evaluate the efficacy of this and many of the other therapies for SCUs.

Conclusion

1. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010; 376 (9757): 2018-31. [Context Link]

2. Bunn HF. Pathogenesis and treatment of sickle cell disease. New Engl J Med 1997; 337: 762-9. [Context Link]

3. Trent JT, Kirsner RS. Leg ulcers in sickle cell disease. Adv Skin Wound Care 2004; 17: 410-6. [Context Link]

4. Sibbald RG, Goodman L, Woo KY, et al.. Special considerations in wound bed preparation 2011: an update. Adv Skin Wound Care 2011; 24: 415-36. [Context Link]

5. Taradaj J, Franek A, Cierpka L, et al.. Early and long-term results of physical methods in the treatment of venous leg ulcers: randomized controlled trial. Phlebology 2011; 26: 237-45. [Context Link]

6. Collins L, Seraj S. Diagnosis and treatment of venous ulcers. Am Fam Physician 2010; 81: 989-96. [Context Link]

7. O'Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database Syst Rev 2009; (1): CD000265. [Context Link]

8. Feben K. How effective is training in compression bandaging techniques? Br J Community Nurs 2003; 8 (2): 80-4. [Context Link]

9. Johnson NA. Concern about use of narcotics for pain in sickle cell anemia. Am Fam Physician 1995; 51: 47-8. [Context Link]

10. Woo KY, Sibbald RG. The improvement of wound-associated pain and healing trajectory with a comprehensive foot and leg ulcer care model. J Wound Ostomy Continence Nurs 2009; 36: 184-91. [Context Link]

11. Neto JP, Lyra IM, Reis MG, Goncalves MS. The association of infection and clinical severity in sickle cell anaemia patients. Trans R Soc Trop Med Hyg 2011; 105: 121-6. [Context Link]

12. Baum KF, MacFarlane DE, Maude GH, Serjeant GR. Topical antibiotics in chronic sickle cell leg ulcers. Trans R Soc Trop Med Hyg 1987; 81: 847-9. [Context Link]

13. Minniti CP, Eckman J, Sebastiani P, Steinberg MH, Ballas SK. Leg ulcers in sickle cell disease. Am J Hematol 2010; 85: 831-3. [Context Link]

14. MacFarlane DE, Baum KF, Serjeant GR. Bacteriology of sickle cell leg ulcers. Trans R Soc Trop Med Hyg 1986; 80: 553-6. [Context Link]

15. Kanada KN, Nakatsuji T, Gallo RL. Doxycycline indirectly inhibits proteolytic activation of tryptic kallikrein-related peptidases and activation of cathelicidin. J Investigative Dermatol 2012; 132: 1435-42. [Context Link]

16. Sadler GM, Wallace HJ, Stacey MC. Oral doxycycline for the treatment of chronic leg ulceration. Arch Dermatol Res 2011. [Context Link]

17. Eckman JR. Leg ulcers in sickle cell disease. Hematol Oncol Clin North Am 1996; 10: 1333-44. [Context Link]

18. Koshy M, Entsuah R, Koranda A, et al.. Leg ulcers in patients with sickle cell disease. Blood. 1989; 74: 1403-8. [Context Link]

19. Hefton JM, Caldwell D, Biozes DG, Balin AK, Carter DM. Grafting of skin ulcers with cultured autologous epidermal cells. J Am Acad Dermatol 1986; 14: 399-405. [Context Link]

20. Heckler FR, Dibbell DG, McCraw JB. Successful use of muscle flaps or myocutaneous flaps in patients with sickle cell disease. Plast Reconstruct Surg 1977; 60: 902-8. [Context Link]

21. Spence RJ. The use of a free flap in homozygous sickle cell disease. Plast Reconstruct Surg 1985; 76: 616-9. [Context Link]

22. Khouri RK, Upton J. Bilateral lower limb salvage with free flaps in a patient with sickle cell ulcers. Ann Plast Surg 1991; 27: 574-6. [Context Link]

23. Weinzweig N, Schuler J, Marschall M, Koshy M. Lower limb salvage by microvascular free-tissue transfer in patients with homozygous sickle cell disease. Plast Reconstruct Surg 1995; 96 (5): 1154-61. [Context Link]

24. Weinzweig N, Schuler J, Vitello J. Simultaneous reconstruction of extensive soft-tissue defects of both lower limbs with free hemiflaps harvested from the omentum. Plast Reconstruct Surg 1997; 99: 757-62. [Context Link]

25. Richards RS, Bowen CV, Glynn MF. Microsurgical free flap transfer in sickle cell disease. Ann Plast Surg 1992; 29: 278-81. [Context Link]

26. Cho G, Hambleton IR. Regular long-term red blood cell transfusions for managing chronic chest complications in sickle cell disease. Cochrane Database Syst Rev 2011; (9): CD008360. [Context Link]

27. Kwiatkowski JL, Cohen AR, Garro J, et al.. Transfusional iron overload in children with sickle cell anemia on chronic transfusion therapy for secondary stroke prevention [published online ahead of print October 20, 2011]. Am J Hematol 2011. [Context Link]

28. Friedman DF, Lukas MB, Jawad A, Larson PJ, Ohene-Frempong K, Manno CS. Alloimmunization to platelets in heavily transfused patients with sickle cell disease. Blood 1996; 88: 3216-22. [Context Link]

29. Raghupathy R, Billett HH. Promising therapies in sickle cell disease. Cardiovasc Hematol Disord Drug Targets 2009; 9 (1): 1-8. [Context Link]

30. Hillery CA, Du MC, Wang WC, Scott JP. Hydroxyurea therapy decreases the in vitro adhesion of sickle erythrocytes to thrombospondin and laminin. Br J Haematol 2000; 109: 322-7. [Context Link]

31. Nzouakou R, Bachir D, Lavaud A, et al.. Clinical follow-up of hydroxyurea-treated adults with sickle cell disease. Acta haematol 2011; 125: 145-52. [Context Link]

32. Brawley OW, Cornelius LJ, Edwards LR, et al.. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med 2008; 148: 932-8. [Context Link]

33. Cackovic M, Chung C, Bolton LL, Kerstein MD. Leg ulceration in the sickle cell patient. J Am Coll Surg 1998; 187: 307-9. [Context Link]

34. Sirieix ME, Debure C, Baudot N, et al.. Leg ulcers and hydroxyurea: forty-one cases. Arch Dermatol 1999; 135: 818-20. [Context Link]

35. Perrine SP, Ginder GD, Faller DV, et al.. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med 1993; 328: 81-6. [Context Link]

36. Weinberg RS, Ji X, Sutton M, et al.. Butyrate increases the efficiency of translation of gamma-globin mRNA. Blood 2005; 105: 1807-9. [Context Link]

37. McMahon L, Tamary H, Askin M, et al.. A randomized phase II trial of arginine butyrate with standard local therapy in refractory sickle cell leg ulcers. Br J Haematol 2010; 151: 516-24. [Context Link]

38. Ignarro LJ, Kadowitz PJ. The pharmacological and physiological role of cyclic GMP in vascular smooth muscle relaxation. Ann Rev Pharmacol Toxicol 1985; 25: 171-91. [Context Link]

39. Kato GJ, Gladwin MT. Evolution of novel small-molecule therapeutics targeting sickle cell vasculopathy. JAMA 2008; 300: 2638-46. [Context Link]

40. Cosby K, Partovi KS, Crawford JH, et al.. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003; 9: 1498-505. [Context Link]

41. Lakshmi RT, Priyanka T, Meenakshi J, Mathangi KR, Jeyaraman V, Babu M. Low molecular weight heparin mediated regulation of nitric oxide synthase during burn wound healing. Ann Burns Fire Disasters 2011; 24 (1): 24-9. [Context Link]

42. Chin LC, Kumar P, Palmer JA, et al.. The influence of nitric oxide synthase 2 on cutaneous wound angiogenesis. Br J Dermatol 2011; 165: 1223-35. [Context Link]

43. Luo JD, Hu TP, Wang L, Chen MS, Liu SM, Chen AF. Sonic hedgehog improves delayed wound healing via enhancing cutaneous nitric oxide function in diabetes. Am J Physiol Endocrinol Metab 2009; 297: E525-31. [Context Link]

44. Salcido RS. Viagra and wound healing: the NO connection. Adv Skin Wound Care 2008; 21:106, 108-9. [Context Link]

45. Machado RF, Martyr S, Kato GJ, et al.. Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. Br J Haematol 2005; 130: 445-53. [Context Link]

46. Lionnet F, Bachmeyer C, Stankovic K, Tharaux PL, Girot R, Aractingi S. Efficacy of the endothelin receptor blocker bosentan for refractory sickle cell leg ulcers. Br J Haematol 2008; 142: 991-2. [Context Link]

47. Serjeant GR, Galloway RE, Gueri MC. Oral zinc sulphate in sickle-cell ulcers. Lancet. 1970; 2 (7679): 891-2. [Context Link]

48. Serarslan G, Akgul F, Babayigit C. High prevalence of pulmonary hypertension in homozygous sickle cell patient with leg ulceration. Clin Exp Hypertens 2009; 31: 44-8. [Context Link]

49. Hebbel RP, Vercellotti GM. The endothelial biology of sickle cell disease. J Lab Clin Med 1997; 129: 288-93. [Context Link]

50. Serjeant BE, Harris J, Thomas P, Serjeant GR. Propionyl-l-carnitine in chronic leg ulcers of homozygous sickle cell disease: a pilot study. J Am Acad Dermatol. 1997; 37 (3 Pt 1): 491-3. [Context Link]

51. Frost ML, Treadwell P. Treatment of sickle cell leg ulcers with pentoxifylline. Int J Dermatol 1990; 29: 375-6. [Context Link]