Arterial Leg Ulcerations Associated With Beta-Thalassemia

Possible Treatment Modalities and Recent Follow-Up Prognosis

A 65-year-old female patient with past medical history of b-thalassemia presented with chronic, painful bilateral arterial leg ulcerations, located at the left lateral leg and right medial ankle (Figure 1 and Figure 2). The left lateral leg arterial ulcer was the more recent ulcer, with initial presentation around one year prior. This wound measured 9.0 cm (L) x 8.0 cm (W) x 0.1 cm (D). The right medial ankle wound measured 5.2 cm x 5.2 cm x 0.1 cm.
 
Both wounds presented with a granular base extending peripherally and encompassing 80–90% of the wound, with fibrous base circumferentially encompassing the remaining 10–20% of the wound.^1,2 Erythema with friable and thin tissue was noted at the immediate periwound region. Signs of acute infection were not noted.
 
The patient was unable to tolerate debridement, and described her pain level as a 5 out of a total score of 10 on a visual analog scale. She stated that her pain waxes and wanes throughout the day, with increased severity in the evenings. This also posed a challenge to proper wound culture. Despite the wound history of greater than 6 months, biopsy was not indicated, given the patient’s history of b-thalassemia, risk of bleeding, and risk of worsening the wound.³ The patient conducted her own dressing changes 2–3 times daily, utilizing her own wound care supplies after cleansing the wounds with saline and water.
 
Significant past medical history includes b-thalassemia intermedia, osteonecrosis of the mandible (possibly associated with b-thalassemia), squamous cell carcinoma (SCC), gout, hepatitis, and arthritis. Her past surgical history includes mandibular reconstruction secondary to osteonecrosis with fibular graft. Associated relevant podiatric medications include topical Xenaderm (90U-87mg-788mg/gram, apply 1g topically twice a day) and topical SANTYL (Smith and Nephew) (250U/gram, apply 1g topically twice a day). Allergies include sulfa antibiotics.

What the Exam Revealed

On physical examination, the patient’s vascular status was concerning with nonpalpable bilateral dorsalis pedis (DP) and posterior tibial (PT) pulses. These findings were also accompanied by absent bilateral digital hair growth and shiny skin. Doppler ultrasound examination indicated biphasic signals from the right DP artery. In addition, monophasic or pathologic signals were appreciated from the right PT artery and left DP and PT arteries. In addition to the previous dermatologic findings, a hyperkeratotic lesion was noted at the lateral fifth digit at the dorsolateral proximal interphalangeal joint (PIPJ). A prominent medial eminence was noted at bilateral first metatarsal heads, with reduced dorsiflexory and plantarflexory range of motion at the first MTPJs. These findings were consistent with mild hallux abductovalgus deformities bilaterally. On musculoskeletal examination, 4/5 strength was noted with expected significant reduction in eversion strength on the right. Neurological status was largely intact.
 
Results from radiographs (Figure 3) indicated skeletally mature bilateral ankles. The proximal and mid-shaft areas of the fibula were absent on the right secondary to mandibular bone reconstruction using a fibular graft. There were no signs of soft tissue infection radiographically. Significant frontal plane deformity at the ankle was noted with a valgus position of the talus in the ankle mortise bilaterally. On the lateral view, osseous degeneration was noted at the tarsal and hindfoot joints associated with hindfoot collapse, consistent with severe pes planovalgus foot type. No other findings were noted.

Initial Treatment

On the initial visit (05/26/22), we recommended the patient seek additional clarification on an updated regimen for blood transfusions to manage delayed healing of ulcerations secondary to b-thalassemia. She indicated that her Hb levels were 6.0g/dL (Normal: 12.0–16.0g/dL).⁴ She was consulting a hematologist to manage these transfusions.
 
However, the patient was amenable to determining if additional transfusions or increased frequency of transfusion were required. Currently, this regimen is a transfusion every 3 weeks, although staff were trying to push it for every 4weeks. We also advised application of collagenase SANTYL and mupirocin wound cleanser with daily dressing changes.
 
On a subsequent visit on 06/28/22, patient reported a burning sensation from the collagenase SANTYL cream and verbally expressed discontent. We advised continued use especially in light of intolerance of manual debridement methods as she has full sensation. We additionally began and advised application of a xeroform petrolatum dressing prior to placement of the tube end of transdermal continuous oxygen therapy device. Superficial application of Tegaderm (3M) (or equivalent) was advised in order to ensure a vacuum seal of the device and improve the delivery of a hyperoxic environment.
 
On follow-up on 08/09/22, the patient reported improvements in her pain profile. Wound measurements were markedly improved, with left lateral leg wound: 9.2cm x 6.5cm x 0.1cm and right medial ankle leg wound: 5.0cm x 4.7cm x 0.1cm (Figure 4 and Figure 5). Reduced hyperfusion and reduced erythema were noted at the ulceration at the right medial ankle, with approximate coloration comparable to periwound skin. Peripheral epithelialization was noted at the anterolateral and posterolateral margins of the left lateral leg wound. The patient was advised to continue applying the collagenase cream twice daily and to utilize the tube end of the transdermal continuous oxygen therapy device. She wrapped her wounds with Island Dressing (McKesson) and paper tape as requested (Figure 6 and Figure 7). A follow-up did not take place due to the patient’s schedule conflict.
 
Her last visit on 12/1/22 showed that the right leg was 100% resolved. The ulcer on the left leg was measured 9.8cm x 6.2cm x 0.2cm, which was less deep as compared to the ulcer on her initial visit. We will continue with the current therapy including increasing transfusions and the transdermal oxygen therapy.

A Closer Look at the Pathophysiology of Thalassemia

Thalassemia is a sub-group of hemoglobin synthesis disorders that are central to the generation of red blood cells in bone marrow. Beta-thalassemia is a heterogenous mutation that impacts the b-globulin locus, thereby resulting in a quantitative reduction in b-globins.⁵ The intermedia subtype of b-thalassemia has been reported to have increased incidence of gall stone and leg ulcers, possible pathologies related to thrombosis (deep vein thrombosis, portal vein thrombosis, stroke and pulmonary embolism).^6–8
 
Osteoporosis is a significant clinical manifestation in b-thalassemia intermedia. This is most evident in our patient’s initial radiographs. Other manifestations include cortical thinning and subclinical fractures.^9,10 Nutritional deficits inherent to b-thalassemia may explain the pathologies of osteoporosis.¹¹ Shi and colleagues noted an incidence of spontaneous osteonecrosis of the jaw (left maxillary alveolus).¹² They suggest that hyperplasia of the intermedullary canal with subsequent expansion of cancellous bone may have precipitated occlusion of secondary vessels, directly leading to observed necroses. This suggested pathophysiology seems likely in the setting of her past medical and surgical histories, although this is a mere association rather than a direct correlation.
 
Biomechanically, in this case, we believe that an argument can be made that compensatory mechanisms following ankle instability with the implementation of the proximal fibula and fibular shaft grafts initiated valgus deformities that increased medial pressures on the right, thereby precipitating the superficial ulceration. This line of thinking, however, fails to explain the lateral malleolar ulceration at the left ankle. Irrespectively, the relative lack of innate Hb production in b-thalassemia intermedia may have a direct causal relationship with eventual development of superficial ankle ulcerations.

Treating Leg Ulcerations Secondary to b-Thalassemia

The dearth of research describing pathophysiology and treatment modalities for leg ulcers secondary to b-thalassemia is the first hurdle to effective management.¹³ In all inherited hemoglobinopathies, one of the primary risk factors influencing ulcer development is likely severe untreated, or undertreated, chronic anemia.
 
Compared to those patients receiving regular transfusions, those who were not on a regular regimen for transfusions has a 27% increased incidence for developing leg ulcerations (13% vs 40%, respectively).¹³ Ironically, increasing transfusion frequency without appropriate assessment of risks can precipitate iron overload. The rationale is that iron overload can contribute to the development of ulcers due to increased oxidative damage and perpetuation of the chronicity of the ulcer. In fact, authors have also identified increased serum ferritin concentrations in the setting of chronic leg ulcerations that nearly mirror serum ferritin concentrations in the most severe iteration of b-thalassemia major (1,108 ± 207 µg/L vs 1,045 ± 86 ng/mL, respectively).^13,14

Pearls for Treatment

The role of fetal hemoglobin (HbF) in b-thalassemia is intimately linked to morbidity. Many treatment modalities used in b-thalassemia stem from a related inherited heoglobinopathy, sickle cell disease. However, careful assessment of risks and benefits of this modality need to be determined. Regardless, hydroxyurea (HU) appears to be a good option to remedy the effects of iron overload due to reduced volume of blood transfused and frequency of transfusions.^15–18
 
Two additional transfusion adjuncts were mentioned in the same manner—5-azacytidine and short chain fatty acids (FAs), with remarkable results reported with the use of the former. Methylation of the promoter region of the 5-azacytidine inhibitor will upregulate g-globin production, and thereby increase production of HbF.¹⁹ Though favorable results were achieved with short chain Fas with similar elevations in g-globins (2- to 6-fold increase)20, it was later discovered that these agents also have antiproliferative effects on bone marrow.²¹
 
The efficacy of collagenase-based topical agents on ulcers with pressure, burn, or venous pathologies have long been purported in literature.²² Collagenase is a selective enzymatic debriding agent that is derived from the C histolyticum bacterium. These have been demonstrated to be most effective in wounds with high bacterial load but within the realm of a normal, physiologic pH.²³ The only FDA approved cream that exists remains SANTYL, and its safety and efficacy has been demonstrated in numerous studies.²⁴ Oxygen therapies such as hyperbaric oxygen therapy (HBOT) and transdermal continuous oxygen therapy have been reported to show short-term and long-term improvements in wound health. However, healthcare providers and patients often run into problems with insurance approval for HBOT.
 
EPIFLO Transdermal Cutaneous Oxygen Therapy (Ogenix) has been purported as an effective treatment in recent years by various studies, albeit limited in scope and study type.^25–28 Observations from previous studies appear to support the hypothesis that this treatment effectively contrast inflammation and promotes wound healing.²⁷ Though a definitive conclusion cannot be made at the current juncture to consider EPIFLO as an effective alternative to HBOT, significant improvements are positive indicators for more widespread adoption of this treatment modality

Further Insights on Treatment

Given the etiology of b-thalassemia, first line of treatment should depend first on appropriate blood transfusion regimen. Our case study focused on the b-thalassemia intermedia, which remains distinct in its clinical presentation for several reasons. It has a variable transfusion requirement. Clinical manifestations include pseudoxantoma elasticum, DVT/PE, gall stones, leg ulcerations, and osteoporosis with associated osteonecrosis from cancellous bone hyperplasia.
 
Leg ulcers are the most common clinical manifestation of b-thalassemia intermedia (8% incidence) in the lower extremity.¹⁴ It is important to understand the need for moderation in transfusion volume and frequency. Inappropriate transfusions can precipitate oxidative damage and perpetuate the chronicity of ulcerations. Treatment modalities vary, but generally adjunct therapies to induce production of g-globins have been suggested to mediate increased HbF in the setting of b-thalassemia. HbF resolves this issue by completely replacing the g-globin with the g-globin. In addition, these Hbs have a reported right shift on the dissociation curve, which means they have a higher rate of dissociation and are better able to oxygenate tissues. These modalities have varying success rates; however, it can be said from various literature that the HU adjunct appears to the most safe and provides the most moderate inductive properties on HbF production.
 
Collagenase SANTYL and mupirocin topical cleanser are yet another modality. The safety and efficacy of either agent has been well supported in literature, with mupirocin the accepted topical agent for superficial methicillin-resistant Staphylococcus aureus (MRSA) infections. Despite newer and more potent agents that have appeared on the market, mupirocin remains the most effective and safest. Both SANTYL and mupriocin are in accordance with the TIME guidelines for wound preparation to improve rates of healing. Therefore, both should be used as an adjunct with either of the two following therapies.

In Conclusion

Despite the wealth of knowledge on the pathophysiology of b-thalassemias, the development of the most common clinical manifestation in the lower extremity, leg ulcerations, still remains unclear. Additionally, there remains a plethora of suggested adjunctive treatments. However, there is a blatant lack of conclusive data that compared these combinations or simply a comparison of these modalities against the other. This leaves too much freedom for practitioners to pick and choose treatment modalities. Inherently, this freedom also unnecessarily complicates managing b-thalassemia intermedia patients with leg ulcerations, thereby negatively affecting outcomes.
 
Future research should target an understanding of the etiology of leg ulcerations in the setting of b-thalassemia, with a goal in the direct underlying causes of leg ulcerations and how these can be targeted. If the primary avenue for treatment—blood transfusions—appears to precipitate ulcerations from iron overload, then perhaps other avenues should be explored. A definitive assessment of treatment modalities, perhaps first by focusing on comparing the two hyperoxic therapies (HBOT, EPIFLO) should be conducted first before addressing other treatment modalities. Given the low incidence of b-thalassemia (1/1,000,000) and incidence of leg ulcerations with the thalassemia (8%), conducting these studies on human subjects would prove to be difficult. Therefore, guidelines may be better elucidated from animal models. However, it is also important to expand our horizons and first determine the better therapy among all leg ulcerations.
 
Our case study demonstrates only one unique instance where EPIFLO could be applied, with moderate improvements noted. It needs to be said that much more research needs to be conducted before EPIFLO can be declared superior to HBOT. As of yet, our patient appears to be lost to follow-up, and has not returned to clinic. Although short-term prognosis demonstrated notable improvements, these determinations need to be withheld until long-term prognoses can be determined. We recognize that this remains one of the main limitations of this case study. We are confident that should more research arise in our field relating to this treatment modality, either in the setting of b-thalassmia, or with broader applications in wound care, EPIFLO may be the recommended treatment both from a prognostic and cost-effective standpoint.
 
Zhisheng Chasen Shao, BA, is a fourth-year/ student at the Temple University School of Podiatric Medicine in Philadelphia.
 
Khurram Khan, DPM, is a Clinical Associate Professor and Chairman in the Department of Podiatric Medicine at the Temple University School of Podiatric Medicine in Philadelphia.

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