Dermatology Online Journal

An unusual adverse effect of nadroparin injections: Calcinosis cutis
Almudena Nuno-Gonzalez¹, Leticia Calzado-Villarreal¹, Marta Gutierrez-Pascual¹, Reyes Gamo-Villegas¹, Henar Sanz-Robles¹, Araceli Sanchez-Gilo¹, Fernando Pinedo-Moraleda², Jose Luis Lopez-Estebaranz¹
Dermatology Online Journal 17 (11): 4

1. Unit of Dermatology
2. Unit of Pathology
Hospital Universitario Fundacion Alcorcon, Madrid, Spain

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Abstract

In 1988, Tumiati et al described the first case of calcinosis cutis related to a calcium-containing heparin. Since then, only 18 cases have been reported in the literature; they usually have an altered calcium-phosphate product, an elevated parathyroid hormone (PTH), or both. We report a 33-year-old patient who developed calcinosis cutis at sites of nadroparin injections without any disturbance of calcium-phosphate product, PTH, or vitamin D. The pathogenesis of calcinosis cutis secondary to nadroparin injections remains controversial; Proposed causes included metastatic, dystrophic, iatrogenic, or multifactorial etiologies. This is the first case of multiple nodules of calcinosis cutis without alterations of calcium-phosphate product, PTH, or vitamin D, which supports an iatrogenic mechanism. We also suggest that calcinosis cutis could be more frequent than we thought and is probably an underdiagnosed entity.

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Introduction

Calcinosis cutis is the term employed to define a group of disorders characterized by an abnormal deposit of calcium and phosphate salts in the skin. Iatrogenic calcinosis has been described in patients undergoing electromyography, electroencephalography, or auditory evoked potential testing secondary to the application of an electrode paste containing calcium chloride [1]. Also iatrogenic calcinosis cutis can be produced by extravasation of intravenous calcium gluconate, calcium chloride, or solutions containing phosphate or calcium alginate dressings [2]. Exceptionally, subcutaneous injection by calcium heparin with and without chronic renal failure has been associated [1, 3, 4-12].

Local side effects at the injection site of low molecular weight heparins (LMWH) can have an immunologic or a non-immunologic origin. Hematoma, which is the most frequent adverse effect, heparin necrosis, heparin-induced thrombocytopenia with thrombosis syndrome, delayed allergic skin reaction, urticarial reaction, and induration have all been described [3].

In 1988, Tumiati et al described a rare side effect of calcium-containing subcutaneous heparins [5]. Injection site nodules showed histologic features of calcinosis cutis, calcium deposits along collagen fibers. Since then, only 18 similar cases have been described in the literature; all of them except one exhibited an altered calcium-phosphate product, elevated parathyroid hormone (PTH), or both [1, 3-12].

We report a 33-year-old man who developed multiple nodules of calcinosis cutis at sites of nadroparin injections without alteration of calcium-phosphate product, which, to our knowledge, is the first case described in the literature.

Case report

Figure 1	Figure 2
Figure 1. Subcutaneous nodules located in the abdomen at sites of nadroparin injections Figure 2. Basophilic deposits of calcium salts throughout the dermis and subcutis (H&E, x40)

A 33-year-old otherwise healthy man presented with an episode of atrial fibrillation (AF) detected during a routine medical check. He started treatment with enoxaparin. Three weeks later, AF persisted and amiodarone was added to treatment. After a month of treatment, AF had resolved and both drugs were discontinued by his cardiologists. A week later he was admitted to the hospital because of a new episode of AF and then treatment with a calcium-containing heparin, nadroparin, and amiodarone was started. Eight days later the patient became aware of several firm, erythematous, well demarcated, slightly painful, subcutaneous nodules on the abdomen, located at sites of nadroparin injections (Figure 1). The patient thought that the nodules were secondary to using incorrect technique when he injected nadroparine, because he did it tangentially. Because an adverse effect related to nadroparin treatment was suspected, it was discontinued and replaced by enoxaparin; since then, no new lesions have appeared.

Figure 3
Figure 3. Calcium deposits along collagen fibers (H&E, x100)

A biopsy of one of the nodules was done. It showed calcium deposits scattered throughout the dermis along collagen fibers. There was a palisading inflammatory reaction around the calcium and collagen fibers. These calcium deposits extended into the subcutis along the fibrous septa and between adipocytes. Vessels were spared. The epidermis was unremarkable (Figures 2 and 3). The biopsy was not decalcified because we did not know previously it contained calcium deposits.

Calcinosis cutis secondary to nadroparin injections was diagnosed. Laboratory data revealed normal values in the hemogram, serum creatinine, calcium, phosphorus, PTH, and vitamin D. Skin lesions solved spontaneously after six months.

Discussion

Adverse skin reactions to LMWH are rare, even though their true incidence is probably underestimated because of under-reporting. The most frequent adverse effect is hematoma at the injection site. Other reactions can be classified into three categories: 1) An urticarial-like eruption, presumably related to local histamine release (a type I immediate hypersensitivity reaction); 2) Skin necrosis, often due to vasculitis (Type III Arthus reaction) or heparin-induced trombocytopenia and thombosis syndrome (microvascular occlusion syndrome); 3) Erythematous, well-circumscribed lesions without necrosis, usually secondary to a delayed type IV hypersensitivity reaction. Although most LMWH-induced skin lesions are benign, treatment should be discontinued [3, 13].

A very rare side effect of calcium-containing heparins is calcinosis cutis. This phenomenon, secondary to nadroparin injections, has almost invariably been described in association with an underlying disease, usually a disturbed calcium-phosphate balance, typically seen in renal failure, secondary hyperparathyroidism, or osteomalacia [3]. Patients with renal failure can have other forms of calcinosis cutis, usually of metastatic ethiology, like benign nodular calcification or calciphylaxis.

The histopathological findings of calcinosis cutis consist of calcium deposits disposed predominantly along collagenous and elastic fibers in the dermis and hypodermis [3, 4]. This deposit of calcium causes skin inflammation; this process can produce reabsorption of calcium salts or transepidermal elimination (and secondary ulceration) in weeks or months. This picture must be differentiated from vascular calcification or calciphylaxis, a fatal disease that rarely affects this group of patients with end-stage chronic renal failure [14].

Since Tumiati described the first case in 1988 [5], only eighteen cases of calcinosis cutis as injection site reactions have been reported [1, 3-12]. These cases are summarized in Table 1. The largest series of cases was reported by Eich et al [5] and it includes five cases. Most of the calcinosis cutis lesions secondary to nadroparin disappeared after discontinuation of the drug, as in our patient, although one case required surgery to remove the nodules [7]. We only have found a single case reported with normal calcium, phosphate, PTH, or vitamin D values, as our patient had, but this patient had a single calcified nodule [11].

Classically, four types of cutaneous calcification are described: metastatic, dystrophic, iatrogenic, and idiopathic calcinosis [3, 4]. The pathogenesis of calcinosis cutis secondary to nadroparin injections has been widely discussed. Some authors propose a metastatic mechanism because of the abnormal calcium-phosphate metabolism seen in the vast majority of these patients. However, others support a dystrophic theory, that tissue is damaged because of the injection and significant amount of calcium containing-heparin is introduced [5]. Finally, a third group of authors propose an iatrogenic mechanism related to tissue precipitation of the calcium contained in the nadroparin preparation [3]. The exact mechanisms of calcinosis cutis related to heparins are not yet well understood. It has been proposed that injections of calcium-containing heparins in the presence of hyperphosphatemia can increase the calcium and phosphate solubility product locally and lead calcium to precipitate [1, 3]. Although calcinosis cutis related to nadroparin, in patients with renal disease, can be explained by a metastasic calcification mechanism, in our case, we have dismissed the possibility of metastatic calcinosis cutis because our patient had normal levels of calcium, phosphate, PTH, and vitamin D. Our patient’s calcinosis cutis could be related to a combination of dystrophic calcinosis secondary to incorrect injection technique, as our patient suggested, in addition to an iatrogenic calcification because of the calcium contained in the drug. We believe this entity is more frequent than we thought and that it is probably under-diagnosed or under-reported.

In conclusion, calcinosis cutis secondary to nadroparin is an unusual side-effect of an extensively used drug. We describe the first patient with normal calcium, phosphate, PTH, and vitamin D levels that presented with multiple nodules of calcinosis cutis after nadroparin injections. We must be aware of this adverse side effect, which may be under-diagnosed, and avoid this calcium containing heparin in patients with abnormal calcium-phosphate product or PTH, but recognize that it can also occur when these values are normal.

References

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