(Stroke. 1997;28:2421-2424.)
© 1997 American Heart Association, Inc.
Articles |
Pseudoxanthoma Elasticum Lesions and Cardiac Complications as Contributing Factors for Strokes in ß-Thalassemia Patients
From the First Department of Internal Medicine, University of Athens, School of Medicine, Laiko General Hospital (A.A., D.F., I.R., D.L.), and the Thalassemia Unit, The Aghia Sophia Children's Hospital (M.K.), Athens, Greece.
Correspondence to A. Aessopos, MD, First Department of Internal Medicine, University of Athens, School of Medicine, Laiko General Hospital, 17 Aghiou Thoma St, Athens 115 27, Greece. E-mail aaisopos{at}atlas.uoa.gr
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Abstract |
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Background and Purpose Pseudoxanthoma elasticum (PXE) lesions, which lead to intracranial hemorrhages and cardiac complications, predisposing to thrombotic strokes, are frequent findings in ß-thalassemia. Nevertheless, the association of these lesions with strokes in thalassemic patients has not been previously discussed.
Methods Ten ß-thalassemic patients who developed an intracranial hemorrhage or a thrombotic stroke were reviewed.
Results In the group of the four patients presenting with hemorrhage, one had PXE lesions, one had cardiac abnormalities, and one both PXE and cardiac disorders. In the group presenting with thrombotic stroke, all six patients had cardiac abnormalities and platelet count elevation due to splenectomy. Three also had PXE findings. No other predisposing factor for stroke was present.
Conclusions Cardiac complications and PXE may be risk factors for strokes in ß-thalassemia. Their frequent coexistence leads to a therapeutic dilemma in patients requiring antithrombotic therapy.
Key Words: antithrombotic therapy • heart disease • risk factors • stroke • thalassemia
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Pseudoxanthoma elasticum and cardiac abnormalities are not rare findings in ß-thalassemia, particularly in older patients.1 2 PXE is known to lead to hemorrhagic cerebrovascular disorders,3 while cardiac abnormalities such as atrial fibrillation and impaired left ventricular contractility may lead to thrombus formation and thrombotic stroke. A few cases of strokes in ß-thalassemia have been reported in the recent literature.4 5 6 This is a study of 10 novel cases of TS and ICH that sheds more light on the possible pathogenetic mechanisms.
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Subjects and Methods |
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During the period 1992 to 1997, among the approximately 600 ß-thalassemic patients followed in our two units, 10 ß-thalassemic patients (3 males and 7 females) presented with a stroke, thrombotic or hemorrhagic, unrelated to transfusion. The diagnosis was confirmed by brain CT scan. All the patients were normotensive, all but one were nonsmokers, and none of the female patients were on oral contraceptives. Most of the patients had already been investigated for PXE manifestations, ie, the typical skin lesions and the ocular findings known as angioid streaks, in the course of previous studies.1 PXE skin lesions consist of small yellowish papules or larger coalescent plaques with an appearance similar to plucked chicken skin, which mainly develop at flexular areas, such as the neck, axillae, or antecubital fossae. Angioid streaks, on the other hand, are funduscopic findings, consisting of single or multiple, asymmetrical, bilateral, dark-red, brown, or gray bands radiating from the optic disk.
All patients were reexamined during the stroke episode. Cardiac
investigation, performed routinely on an annual basis as well as during
the stroke episode, consisted of clinical examination,
electrocardiogram, chest x-ray, and full
echocardiographic study. The clinical and laboratory
data of the patients are shown in the
Table
. Five patients had TM and 5 had TI.
The mean age at stroke was 23 years for the TM cases, 43.4 years for
the TI cases, and 33.4 years in total (range, 15 to 62 years). The mean
number of blood units transfused up until the stroke was 267.4 (range,
40 to 501). The mean hemoglobin and serum ferritin levels over the
preceding 5 years was 9.1 g/dL (range, 7.8 to 9.9 g/dL)
and 3942.2 µg/L (range, 400 to 7000 µg/L),
respectively. All but one patient were splenectomized, and the mean
platelet count was 487.7x109/L (range, 250 to
730x109/L). All patients had a normal lipidemic profile,
and the serum cholesterol level was below 5.46
mmol/L (210 mg/dL). Three patients had diabetes mellitus
treated by oral antidiabetic agents. In all patients with TS, color
Doppler angiography of the carotid arteries and measurements of
proteins C and S, antithrombin III, anticardiolipin antibody, and
lupus anticoagulant were performed.
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Results |
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Four patients presented with an ICH: 2 (patients 1 and 4) with intracerebral and 2 (patients 2 and 3) with subarachnoid hemorrhage. Six patients (patients 5 through 10) had a TS. PXE manifestations (skin and/or ocular lesions) and cardiac abnormalities (atrial fibrillation, decreased fractional shortening, and clinical manifestations of congestive heart failure) were found in both ICH and TS patients.
Among the patients presenting with an ICH, 2 (patients 3 and 4) had
PXE ocular findings (Fig 1), and 2
(patients 2 and 3) had cardiac abnormalities. One had both PXE findings
and heart impairment. No significant PT prolongation was observed (PT
14 s). Three of the 4 were splenectomized and had elevated
platelet counts.
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In the group presenting with a TS, PXE manifestations were detected
in 3 (patients 8, 9, and 10), while cardiac abnormalities were
present in all (Fig 2). PT was not
significantly prolonged (PT 15 s). All 6 were splenectomized and had
elevated platelet counts. Color Doppler angiography of the
carotid arteries as well as proteins C and S, antithrombin III,
anticardiolipin antibody, and lupus anticoagulant were within
normal limits.
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Two of the 4 patients with an ICH died during the attack (patients 3 and 4). One of the survivors (case 1) had an intracranial vascular malformation detected by cerebral angiography and was treated by arterial embolization. The other (patient 2) died 3 years later of heart failure. All the patients with a TS survived the attack with various degrees of residual neurological deficit. Four (patients 6, 7, 8, and 9) died of heart failure over the next 3 years. It is noteworthy that patient 9 had a significant decrease in visual acuity 5 years before the stroke due to subretinal hemorrhage and macular changes, both associated with angioid streaks. The other 2 patients are still alive and undergoing regular follow-up examination in our units.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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ß-Thalassemia is a genetically inherited hemoglobin disorder caused by impaired synthesis of the ß-globin chain, which results in chronic hemolytic anemia.7 Without appropriate therapy the disorder is rapidly fatal. Currently, intensive blood transfusions and iron chelation therapy have improved the life expectancy considerably. In this context, a wide spectrum of clinical manifestations has been identified, which are due not only to the hemoglobin disorder but also to complications of treatment.8
One particular complication is PXE, the high prevalence of which among ß-thalassemia patients, particularly older ones, was recently reported elsewhere.1 9 Although the precise pathophysiology was unclear, the spectrum of clinical manifestations in thalassemia appeared similar to those in hereditary PXE. The latter is a rare (1:70 000 to 160 000) connective tissue disorder, characterized by generalized degeneration of the elastic fibers, with skin, ocular, and vascular manifestations.10 11 The same typical skin lesions were found in 16% of ß-thalassemia patients, ocular manifestations (angioid streaks) in 20%, and both skin and ocular findings in 10%.1 9
Another complication in ß-thalassemia patients is stroke, although despite the presence of some obvious predisposing factors, only a few cases have been reported. These include two cases of ICH4 and three cases of cerebral thrombosis, one in a patient with ß-TM5 and two in patients with ß-thalassemia/hemoglobin E disease.6 The 10 novel cases in the present study shed some new light on the possible pathogenetic mechanisms and raise, as we will discuss below, a therapeutic dilemma.
In the previously reported cases of ICH,4 liver dysfunction with PT prolongation was considered the main predisposing factor. This dysfunction may be the result of transfusion-induced iron overload and viral infections. In our study no significant PT prolongation was observed. Two of the four patients with ICH (patients 2 and 3), on the other hand, had PXE manifestations, and PXE-related vascular lesions are a well-known cause of both gastrointestinal and cerebral hemorrhages.3 12 In regard to TS, there seem to be several possible predisposing factors. One of these is due to splenectomy, which is performed in a large percentage (between 67% and 82%) of the patients, as reported by previous studies.13 14 Splenectomy causes platelet count elevation, which has a positive correlation with thrombosis, although not as strong as that between low platelet count and hemorrhage.15 Cardiac abnormalities (found in all TS cases), such as atrial fibrillation and impaired left ventricular contractility, also increase substantially the risk of thromboembolic stroke.15 Such abnormalities are frequent in ß-thalassemia patients, mainly because of iron overload, although chronic anemia and PXE-related lesions may also favor their appearance.2 14 16 More precisely, before the introduction of iron chelation therapy, 63% of patients of a mean age of 16 years presented cardiac failure, and more than half of them died of it within 1 year from its onset.17 This percentage was reduced by iron chelation therapy to 37% of patients with a mean age of 23 years, among whom the rate of mortality nevertheless remains high.18 Finally, deficiency of proteins C and S, another possible predisposing factor for thrombosis, has also been reported in ß-thalassemia.19
A noteworthy feature in this study is the coexistence of factors predisposing to TS with PXE lesions, which are often a cause of bleeding. This coexistence raises an obvious dilemma concerning the administration of anticoagulation or antiplatelet treatment. Antiplatelet treatment has been proposed for the prevention of pulmonary thromboembolism in splenectomized ß-thalassemic patients.20 Anticoagulants are often prescribed to patients with the aforementioned cardiac problems.15 However, in the presence of factors predisposing to bleeding, such treatment substantially increases the already present risk of ICH.21 In view of these results, we think it is essential that, in addition to the standard tests for bleeding tendency, ß-thalassemia patients be examined carefully for PXE manifestations before a decision is made regarding anticoagulation or antiplatelet treatment.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors wish to express their appreciation to Sheina Nakou, MD, for her valuable help regarding manu-script preparation.
Received June 12, 1997; revision received August 25, 1997; accepted August 27, 1997.
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References |
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