Effect of

Treatment of Lower Limb Ulcers in Patients with Thalassemia Major

Pentoxifylline

N. S.

on

Angelides, M.D., Ph.D., F.A.C.A., Ch. Angastiniotis, M.D.

F.I.C.A.

and N. Pavlides, M.D.

NICOSIA, CYPRUS

Abstract The possible healing effect of deferoxamine and pentoxifylline on persisting lower limb ulcers was studied in 51 patients with thalassemia major. The results indicated that the regular use of deferoxamine at an intravenous dose of 20 mg/kg did not affect the healing progress and the recurrence rate of these ulcers significantly. On the contrary, the oral administration of pentoxifylline at a dose of 1,200 mg daily during the ulcer’s healing time and at a low longterm maintenance dose of 400 mg daily during the ulcer-free intervals improved their healing ability impressively and diminished their recurrence rate signifi-

cantly. Introduction Recurrent ulcers of the malleoli and of the lower calf may occur in some patients with thalassemia major, creating serious problems and considerable discomfort to the sufferers.’-3 Tissue hypoxia plays a major role in the development and duration of these ulcers. A considerable reduction in the hemoglobin level, abnormal rheologic behavior of the diseased erythrocytes characterized by increased rigidity of their cellular membrane, and the incapability of oxygen tissue diffusion as a result of chronic local edema and fibrosis are factors that may contribute to tissue hypoxia. The treatment of choice should, therefore, be aimed mainly at the correction of tissue hypoxia by improving or eliminating all the factors that contribute to its formation. One promising approach, in addition to other treatments, appears to be the oral administration of pentoxifylline, because of its multifunctional hemorheologic properties.4-9’’3 From the

Department of Cardiovascular Surgery, Nicosia General Hospital, Cyprus

549

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550 Clinical Data

TABLE I of Two Patient

Groups

The aim of this study was to determine whether oral long-term administration of pentoxifylline has a significant therapeutic effect on lower limb ulcers of patients with thalassemia major and offers significant prevention of their recurrence. Another aim of this study was to determine whether iron chelation treatment with deferoxamine affects considerably the incidence of lower limb ulcers and their recurrence rate. ’

Materials and Methods

Fifty-one patients suffering from thalassemia major and recurrent lower limb ulcers were included in this study. They were graded into two groups (Table 1). Group 1 included 18 patients (10 men, 8 women) with a mean age of 28.4 years; 72 % of the patients had had a splenectomy. Their hemoglobin level was greater than 8 g/ 100 mL and they needed occasional blood transfusions. Patients of group 1 were not receiving iron chelation treatment with deferoxamine. Group 2 included 23 patients (13 females, 10 males) with a mean age of 19.6 years; 68 % of the patients had had a splenectomy. They all had a low hemoglobin level that was kept above 8 g/100 mL with regular blood transfusions. They also had iron chelation therapy with regular use of deferoxamine (20 mg/kg). Patients in both groups were followed up over a period of six years (1983-89) for their lower limb ulcers on an outpatient and sporadically on an inpatient basis. Noninvasive assessment of their arterial and venous flow was carried out regularly at sixmonth intervals by means of Doppler ultrasound and spectrum analysis. Segmental pressures and pressure indices at rest and after one minute exercise on the treadmill at 4.5 km/hr were the parameters used for the arterial assessment, whereas the presence of superficial and deep refluxes was carefully assessed. All patients had normal arteries and veins to their lower extremities. The size of the ulcerated area, its microbial flora, and the healing time in days were carefully recorded. Also, the incidence of recurrent ulcers, their healing time, and the incidence of blood transfusions per year were carefully recorded in each group of patients studied. Patients in group 2, apart from deferoxamine treatment, which was carried out at regular intervals throughout the six-year follow-up period, were also treated with oral pentoxifylline during the last three years of the study (1986-89), in order to evaluate its possible beneficial effect on healing of ulcers. Pentoxifylline was administered at a dose of 1,200 mg daily (400

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551 mg three times a day) when an ulcer or a recurrent ulcer was present and at a maintenance low dose of 400 mg daily during the ulcer-free intervals. A polyurethane foam sponge and an elastic bandage were applied to the lesion and the lower limb was supported by a below-knee elastic stocking, to control the local edema successfully. The microbial flora of the ulcerated area was regularly monitored and treated accordingly. Finally, blood transfusion with a high hemoglobin content was regularly given to the patients so that the hemoglobin level was always maintained above 8 g/100 mL.

Results into two different sections. The first section deals with the incidence of recurrent lower limb ulcers and their healing rate in patients with thalassemia major who were not in need of deferoxamine treatment (group 1) and in patients with thalassemia major who were receiving deferoxamine treatment regularly (group 2). Table I summarizes the mean values and standard deviation of the two groups. These groups, although not absolutely identical, were comparable and did not show any significant difference in the incidence of recurrent lower limb ulcers and their healing period. Table II analyzes the per patient values, which are further demonstrated in the form of a bivariate analysis in Figure 1. These results suggested that iron chelation treatment with deferoxamine The results

can

be

separated

TABLE II Results Without and With Use

of Deferoxamine

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552

FIG. 1. Number of recurrent lower limb ulcers per year. Group 1: patients with thalassemia, no use of deferoxamine, Group 2: patients with thalassemia, regular use of deferoxamine.

Ftc. 2. Number of recurrent lower limb ulcers without and with use of pentoxifylline.

does not seem to affect significantly the incidence of recurrent ulcers and their healing in thalassemia major. The second section of results deals with the incidence of recurrent lower limb ulcers and their healing rate in thalassemia patients who were treated regularly for a three-year period with deferoxamine only and then with a combination of deferoxamine and pentoxifylline for an ,

equal three-year period. Table III analyzes the per patient values with and without pentoxifylline treatment, which are further demonstrated in Figure 2 in the form of a bivariate analysis. Table III and Figure 2 clearly showed that pentoxifylline treatment decreased both the incidence of lower limb ulcers and their healing time in thalassemia major patients. Discussion

Nowadays, there is a sharp reduction of the incidence of thalassemia major as a result of the antenatal thalassemia program. We still deal, however, with a number of thalassemia patients who suffer from recurrent lower limb ulcers that are not responding favorably to any kind of treatment. These patients are mainly victims of microcirculatory disturbances characterized by a reduced oxygen supply to the affected areas and by impaired removal of metabolic waste products.9.11 In these patients, even tiny injuries to the skin at the malleoli area can give rise to a lesion that has no tendency to heal and increases progressively. Whether the deposition of iron to the skin and the superficial tissues of these patients is also a significant factor in the formation of lower limb ulcers is questionable.’-’ Our results demonstrated that there is no significant difference in the incidence of lower limb ulcers and their recurrence rate in two comparable groups of patients with thalassemia major, of which only one group was treated with deferoxamine regularly. On the basis of these results, we have focused our therapeutic interest on the correct local

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553 TABLE ill Results Without and With

Pentoxifylline

treatment of the malleolar ulcers in

transfusion, and

on

thalassemia patients, on the correction of anemia by blood the oral administration of pentoxifylline at a therapeutic dose (1,200 mg

daily) during the healing period

and at maintenance dose (400 mg

daily)

when the ulcer has

healed. Local treatment included the regular application of a polyurethane sponge on the malleolar ulcer and of a firm below-knee elastic support to the lower limb to minimize the local edema of the affected areas. This enabled a normal way of life to be continued without the need for prolonged bed rest by improving the venous and the lymphatic drainage and by minimizing the incidences of local infection and of minor local injuries. Blood transfusions were necessary to increase the oxygen transportation capacity of the blood and to normalize the impaired blood rheology, whereas iron chelation therapy helped to decrease iron deposition to the tissues and to increase tissue vitality. Our results indicated that the inclusion of pentoxifylline in the treatment regimen of patients with thalassemia ulcers improved their healing ability impressively and diminished their recurrence rate significantly. This may be the result of the multifunctional hemorheologic properties of pentoxifylline that improve the arterial inflow and relieve the venous and lymphatic outflow. The decreased flexibility and deformability of the erythrocytes lead to their adhesion, to capillary microthrombosis, and to microischemia, especially at the malleolar areas of these

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554

patients. This may further lead to inflammation, which activates, attracts, and accumulates leukocytes and other plasma cells into the capillaries and the increased interstitial fluid. These cells are highly resistant to deformation, and as they pass via the narrow vessels of the microcirculation may be trapped and further occlude the small vessels. The favorable effect of pentoxifylline on red cell and white cell flexibility and deformability can exert an appreciable influence on tissue perfusion as a result of an increased blood flow and oxygen transportation in the microcirculation. 9-14 Conclusions In our series, pentoxifylline has been used at a therapeutic dose of 1,200 mg daily during the ulcer’s healing period and at a low long-term maintenance dose of 400 mg daily during the ulcer-free intervals. The therapeutic and maintenance administration of pentoxifylline is, in our view, essential for the easy healing and the prevention of a recurrence of an ulcer. In thalassemia patients, we consider early healing without recurrence of the utmost importance to avoid a vicious circle: the longer the duration of the ulcer and the greater the recurrence rate, the lesser the vitality of the malleolar area and the lesser the likelihood of its changes to heal.

Nicos

Angelides, M. D. , Ph. D. , Evangelistrias 6

F.A. C. A. , F.I. C.A.

Universal Garden, Strovolos

Nicosia, Cyprus

References 1. Pascher F, Keen R: Ulcer of the legs in Cooley’s anemia. N Engl J Med 256:1220-1222, 1957. 2. Samitz MH, Waldorf DS, Shrager J: Leg ulcers in Mediterranean anemia. Arch Dermatol 90:567-571, 1964. 3. Stevens RM, Shupak JL, Javid J, et al: Ulcers of the leg in thalassemia. Arch Dermatol 113:1558-1560, 1977. 4. Angelkort B, Maurin N, Boateng K: Influence of pentoxifylline on erythrocyte deformability in peripheral occlusive arterial disease. Curr Med Res Opin 6 :255258, 1979. 5. Buchanan N, Moodley GP: The effect of pentoxifylline on human erythrocyte adenosine triphosphate. IRCS Med Sci 5:43, 1977. 6. Ehrly AM: The effect of pentoxifylline on the deformability of erythrocytes and on the muscular oxygen pressure in patients with chronic arterial disease. J Med 10:331-338, 1979. 7. Smud R, Sermukslis B, Kartin O: Changes in blood viscosity induced by pentoxifylline. Pharmatherapeutica 1:229-233, 1976. 8. Weithermann KU: The influence of pentoxifylline on

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interactions between blood vessel wall and platelets. IRCS Med Sci 8:293-294, 1980. Angelides NS: Continuous infusion treatment with pentoxifylline in patients with severe peripheral vascular occlusive disease. Angiology 8:555-564, 1986. Seiffge D, Berthold R, Berthold F: Effect of pentoxifylline on sickle cell thalassaemia: Haemorheological and clinical results. Klin Wochenschr 61:1159-1160, 1983. Angelides NS, Weil von der Ahe CA: Effect of oral pentoxifylline therapy on venous lower extremity ulcers due to deep venous incompetence. Angiology 40:752-763, 1989. Müller R: On therapy of disturbances of blood fluidity. Angiology 36:226-234, 1985. Schröer R: Antithrombotic potential of pentoxifylline—a haemorheologically active drug. Angiology 36:387-398, 1985. Angelides NS, Weil von der Ahe CA, Themistocleus P: Comparison of skin and muscle biopsies before and after pentoxifylline treatment in patients with leg ulcers due to deep venous incompetence. Int Angiology 10:72-76, 1991.

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Effect of pentoxifylline on treatment of lower limb ulcers in patients with thalassemia major.

The possible healing effect of deferoxamine and pentoxifylline on persisting lower limb ulcers was studied in 51 patients with thalassemia major. The ...
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