Sickle Cell Disease & Wound Care: Lower Extremity Ulcers in “Crisis”

  WATCH: Author Jayne R. Penne, PA-C discusses her article.

  Sickle cell anemia, a result of mutations in hemoglobin formation that cause red blood cells to deform and collapse, leads to significant physical pain and emotional distress among patients who spend their entire lives with the genetic disease. Known for its tendency to produce sickle-moon-shaped cells that become occluded within blood vessels with resultant surrounding tissue ischemia,¹ the condition’s ramifications have been known to include intensely painful vaso-occlusive “crises” that may require hospital admission for hydration, pain management, and (sometimes) transfusion with packed red cells.¹ Diagnosed and monitored with complete blood count and hemoglobin electrophoresis, which allows determination of genotype of sickle cell and percent of destructive hemoglobin S in the blood,¹ the disease’s only approved treatment by the US Food and Drug Administration (FDA) remains hydroxyurea, a chemotoxic agent that raises percentage of protective fetal hemoglobin.¹ Pain is often managed with extensive narcotic medication under the supervision of primary care or pain-management professionals.¹ Damage from sickle cell presents as anemia, retinopathy, nephropathy, reduced immunity, humoral and femoral avascular necrosis, priapism, pulmonary hypertension, and lower extremity ulcers. The epidemiology, evaluation, and management of lower extremity ulcers are the focus of this article.¹

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Epidemiology

  About 1-3% of the US population (approximately 100,000 people) lives with sickle cell disease (SCD). Of all SCD patients worldwide, 25-75% also experience leg ulcers. Ulcer incidence in the US ranges from 2.5-25%, whereas Jamaican studies have shown 75% incidence in that country, which may be due to differences in socioeconomic status.^2,3 Most ulcers do not occur in patients younger than 10 years and occur with increasing frequency with age. The specific cause of sickle leg ulcers is unknown, but it is presumed to be a result of microvascular blockage due to sickled cells in areas with already limited circulation.^2,4 It is not due to venous stasis, although this condition will worsen prognosis. A past study shows hydroxyurea may have contributed to ulcer formation, but it was an observation of much older patients (none of whom lived with SCD). It is not thought that hydroxyurea contributes to or worsens ulcers now.⁵

Diagnosis

  Sickle cell leg ulcers are diagnosed clinically. Most begin spontaneously or via trauma as small scabbed areas over the medial or lateral malleoli and more rarely over the anterior tibia.^3,6 Characterized by a relapsing-remitting course, these ulcers often take months to heal and recur quickly and painfully over days to weeks.³ Because they are difficult to heal, they often progress to cover large surface areas, sometimes becoming circumferential.³ They are staged similarly to decubitus ulcers with stage I involving skin redness or darkening, stage II including breakdown of the first skin layers, stage III with deterioration through the dermis, and stage IV with exposure of tendons and bones.³ The ulcers also can become superficially infected with bacteria resulting in increased redness, purulent drainage, and odor.³ If ulcers are extensive and recalcitrant to treatment, radiographs are useful for ruling out osteomyelitis. Conducting CT, MRI, and bone scans are also appropriate for determining early bone infection.³

General Treatment

  There is no treatment approved by the FDA specifically for sickle cell leg ulcers.⁷ Standard therapy includes wet-to-dry dressings, protection from trauma, loose-fitting clothing around the ankles to avoid friction, and use of pressure dressings like an Unna’s boot.^8,9 Debridement may be used but is often impossible due to intolerable levels of pain.⁸ Alternatively, biological debridement is a possibility.³ Sometimes bed rest can be useful in extremely recalcitrant cases.⁹ Research has revealed other promising approaches including oxygen, vessel and clotting-focused treatments, biofilm and inflammation reduction, matrix enhancement, and systemic options such as nitric oxide and arginine butyrate treatments.

  Damage to skin in sickle cell ulcers occurs in part due to lack of oxygen. Some of this lack is attributable to overall anemia and reduced oxygen-carrying capacity of malformed hemoglobin and some is due to the physical obstruction of vaso-occlusive crisis in an already limited supply of blood.¹⁰ Hyperbaric oxygen therapy (HBOT) seeks to force intake of more oxygen to allow a higher concentration of oxygen to reach damaged tissues in order to heal.¹¹ Dangers include temporary myopia, eardrum rupture, lung collapse due to barotrauma, seizures due to oxygen toxicity, and fire. Most evidence in favor of HBOT is anecdotal.³

  Oxygen content in the blood can also be increased by increasing hemoglobin volume with blood transfusions. Patients should not be transfused to hemoglobin levels > 10, as this can lead to hypercoagulability.⁸ Red cell exchange can achieve close to 30-50% hemoglobin S, which effectively lowers the propensity to sickle.⁸ Side effects include transfusion reactions, secondary hemochromatosis, and risk of bloodborne disease transmission.⁸ There is no research supporting the use of simple or exchange transfusions, though they are commonly used to encourage healing in these ulcers and anecdotally have been described as helpful.⁸

Anticoagulation

  Sickle cell ulcers are characterized in part by an increase in clotting ability due to increased platelet count and hypercoagulability intrinsic to the disease as well as to a measured increase in clotting factors at the wound itself.^12,13 A 2014 case study shows healing of sickle ulcers in one patient after repeated application of topical heparan.¹⁴ This principle is also manipulated by administration of aspirin and heparin to the patient to ready the wound bed prior to placing skin grafts.¹⁵ Evidence is anecdotal in nature.

Biofilm & Inflammation

  Biofilm and inflammation reduction are important in sickle cell ulcer treatment to prevent prolonged infection due to carriage of bacteria such as Pseudomonas.¹⁶ Antibiotics covering atypical organisms and staphylococcus are often necessary for healing to progress.¹⁷ Ciprofloxacin provides good coverage for Pseudomonas species and doxycycline and trimethoprim-sulfamethoxazole cover well for staphylococcus species including methicillin-resistant Staphylococcus aureus.^8,18 Doxycycline may also be used to lower pro-inflammatory cytokine levels including TNF-a and matric metalloproteinases, and thereby induce healing.¹⁴ Metronidazole may also have helpful anti-inflammatory effects.⁸ Culture plus appropriate antibiotics, with inclusion of doxycycline if possible, is recommended if the patient has no allergies or intolerance to treatment.

  MEDIHONEY® (Derma Sciences, Princeton, NJ) and silver are bactericidal for many biofilm organisms. Destruction of biofilm discourages eschar and chronic wound infection, so healing is more likely. MEDIHONEY may be a useful adjunct in standard therapy and has few side effects.³ Silver resulted in faster healing in chronic venous leg ulcers.¹⁹ There is limited information on silver or honey in sickle cell ulcers, but they may be beneficial and risk is minimal. Their use is recommended if affordable.

  Zinc supplementation may also advance wound healing²⁰ and is most helpful in patients whose levels are low, which is common with sickle cell. Studies recommend checking for all dietary deficiencies and supplementing appropriately since other levels (B12, folate) are often low. Zinc’s place in therapy is in the later stages of healing since it is instrumental in formation of granulation and scar tissue. Supplements should not exceed normal amounts; sufficient levels are achieved with 220 mg taken by mouth three times daily.⁸

Matrix Enhancement

  Treatment may also be achieved by forming or enhancing the wound matrix. In the past this has been accomplished with myocutaneous flaps and muscle flaps from the latissimus dorsi and gracilis.^21,22 Now microvascular-free flaps are the preferred option for lower leg ulcers. A study that confirmed these findings used exchange transfusion to attain a hemoglobin S of < 30% and gave the patient aspirin and heparin to ready the wound for grafting. The graft itself was preserved from sickling with an aspirin, heparin, and saline solution soak.²¹ Typically, grafts require several weeks in the hospital for completion and most (75%) fail within two years.²³ It is used as a last resort if other therapies have failed.²³

  The matrix may be synthetically enhanced with application of arginylglycylaspartic (RGD) peptide matrix. In a randomized, controlled trial including 55 patients, RGD application along with standard wet-to-dry therapy showed faster healing in larger, more recalcitrant ulcers than in the control group. Major side effects were mild blistering, erythema, itching, and rash. The study proposed more frequent application may speed healing further. Recurrence rates were not noted.⁹ This study was one of the few recommended by a Cochrane review of available information.²⁴ Use of RGD matrix is recommended if tolerable and affordable.

  Healing activity in the wound itself may be increased by the use of propionyl-L-carnitine (PLC), a topical application that, along with standard twice-daily dressing changes, chemical debridement, and oral zinc, showed healing in ulcers in 79% of patients in a 15-patient pilot study. PLC enhanced healing by increasing activity of adenosine triphosphate, which allowed more energy for the skin to use in order to heal.18 As with other topical therapies, its risk is minimal. Provided it is tolerated by the patient and is affordable, PLC is an acceptable option for therapy.

Other Options

  Nitric oxide is another systemic option that may enhance wound healing. When blood hemolyzes due to sickled cells, the hemolysis products bind and react with nitric oxide, which leads to an overall deficit of nitric oxide. This deficit causes vasoconstriction that limits wound healing. Supplementation of nitric oxide may reverse vasoconstriction, allow better blood flow, and induce healing.¹³ It is not routinely recommended for treatment, but is an interesting area for future research. Intravenous infusion of arginine butyrate also may induce healing. In a randomized, controlled trial, arginine was given at 500 mg/kg/dose given five days per week along with standard wet-to-dry dressings. Though levels of fetal hemoglobin rose, incidental healing in ulcers was observable prior to the increase. Mechanisms for both processes are unknown, but may have to do with increased nitric oxide and decreased production of inflammatory cytokines. The most common side effects were headache and nausea, which were easily controlled with acetaminophen and antiemetics. Recurrence rates were not noted. Arginine butyrate is not standard therapy.⁷

Pain Management

  Pain must be controlled when sickle cell ulcers are present.²⁵ Pain control is best achieved by one physician or office with whom the patient has signed a pain contract that regulates when and how they will receive medication.²⁵ This office is usually the primary care, hematologist, or pain-management practice.²⁵ Some patients can manage their pain with ibuprofen and lower-potency narcotics such as codeine or hydrocodone in combination with acetaminophen.²⁵ Many patients take long-acting narcotics such as sustained-release formulations of morphine or oxycodone; fentanyl, oxymorphone, or methadone with short-acting narcotics including hydrocodone-acetaminophen; oxycodone alone or in combination with acetaminophen; or hydromorphone used for breakthrough pain.²⁵ Patients should be advised not to drive or operate heavy machinery while taking narcotics.²⁵ Random drug screens are recommended to be sure patients are taking only what is prescribed.²⁵ State prescription monitoring programs as well as emergency room and hospital records should be utilized to monitor use.²⁵ Adjunct therapy may be accomplished with antidepressants (eg, duloxetine or venlafaxine), muscle relaxers (eg, cyclobenzaprine or methocarbamol), neurologics (eg, gabapentin or pregabalin), and topical pain-relief creams (eg, lidocaine gel or topical diclofenac).²⁵

Conclusion

  Sickle cell ulcers are painful, debilitating, and difficult to heal. They often recur, causing weeks or months of distress. The best treatment is prevention with appropriate protective clothing, good diet, and skin care. Once ulcers occur they should be addressed with topical wet-to-dry dressings, pressure dressings, topical therapies, antibiotics, and dietary supplementation. Transfusions and grafting are also possibilities. There is limited data on effective treatments for SCD and a definite need for further research to adequately address appropriate options for therapy.

Jayne R. Penne, Benjamin M. Goodman III, and Ian A. Chen are on staff at Eastern Virginia Medical School Internal Medicine & Sickle Cell Clinic, Norfolk, VA.

References

1. Buchanan GR, Yawn BP, Afenyi-Annan AN, Tanabe PJ, Ballas SK, Ware RE, et al. Evidence-based management of sickle cell disease: Expert panel report, 2014. National Heart, Lung and Blood Institute. Accessed online: www.nhlbi.nih.gov/health-pro/guidelines/sickle-cell-disease-guidelines.

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3. Minniti CP, Eckman J, Sebastiani P, Steinberg MH, Ballas SK. Leg ulcers in sickle cell disease. Amer J Hematol. 2010;85(10):831-3.

4. Minniti CP, Delaney KM, Gorbach AM, Xu D, Lee CC, Malik N, et al. Vasculopathy, inflammation, and blood flow in leg ulcers of patients with sickle cell anemia. Amer J Hematol. 2014;89(1):1-6.

5. Sirieix M-E, Debure C, Baudot N, Dubertret L, Roux M-E, Morel P, et al. Leg ulcers and hydroxyurea: Forty-one cases. Arch Dermatol. 1999;135(7):818-20.

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8. Ladizinski B, Bazakas A, Mistry N, Afsaneh A, Sibbald RG, Salcido R. Sickle cell disease and leg ulcers. Adv Skin Wound Care. 2012;25(9):420-8.

9. Wethers DL, Ramirez GM, Koshy M, Steinberg MH, Phillips GJ, Siegel RS, et al. Accelerated healing of chronic sickle-cell leg ulcers treated with RGD peptide matrix. RGD Study Group. Blood. 1994;84(6):1775-9.

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

21. Spence RJ. The use of a free flap in homozygous sickle cell disease. Plast Reconstr Surg. 1985;76(4):616-9.

22. Heckler FR, Dibbell DG, McCraw JB. Successful use of muscle flaps or myocutaneous flaps in patients with sickle cell disease. Plast Reconstr Surg. 1977;60(6):902-8.

23. Cackovic M, Chung C, Bolton LL, Kerstein MD. Leg ulceration in the sickle cell patient. J Am Coll Surg. 1998;187(3):307-9.

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