Dermatology Online Journal

Cutaneous thrombosis related to paroxysmal nocturnal hemoglobinuria: Clinical report
João Alves, Hugo Barreiros, Diogo Matos, Ricardo Coelho
Dermatology Online Journal 18 (11): 13

Hospital Garcia de Orta, Almada, Portugal

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Abstract

Paroxysmal nocturnal hemoglobinuria is a clonal stem cell disorder typically characterized by hemolysis, bone marrow failure, and venous thrombosis. The latter can affect up to 40 percent of patients and is a significant cause of mortality. Despite being recognized as a possible complication, cutaneous thrombosis is quite uncommon and a variety of findings have been reported. Owing to the rarity of this complication and the importance of its correct and timely diagnosis, we report the case of a 64-year-old man with paroxysmal nocturnal hemoglobinuria who presented with isolated and well-demarcated erythematous-violaceous plaques, mainly located on the neck and trunk. Given the history and the histological features, the diagnosis of cutaneous thrombosis related to paroxysmal nocturnal hemoglobinuria was assumed and the patient was successfully treated with therapeutic anticoagulation. The early identification of these patients is essential for necessary surveillance because they could carry a higher probability of recurrence compared with those with no prior complications.

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Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal stem cell disorder resulting from a mutation in the PIG-A (phosphatidylinositol glycan class A) gene that blocks glycosylphosphatidylinositol (GPI) anchor biosynthesis. This leads to partial or complete absence of certain GPI-linked proteins, particularly CD59 and CD55. The effect of their absence on PNH red cells is responsible for the complement-mediated intravascular hemolysis [1, 2]. It is typically characterized by hemolysis, bone marrow failure, and venous thrombosis [2].

The venous thrombosis in PNH can affect up to 40 percent of patients and is a significant cause of mortality. This event occurs primarily in the intra-abdominal, cerebral, and cutaneous veins [3]. This propensity to thrombosis is not fully understood, but has been postulated to result from the activation of complement on the platelet surface, which stimulates removal of complement complexes. The resulting microparticles are rich in phosphatidylserine and are highly thrombogenic, leading to the formation of platelet plugs [4]. The risk of thrombosis appears to be significantly related to the size of the abnormal PNH clone [2, 3]. Once thrombosis has occurred in an organ, it usually tends to recur in the same site [5]. Despite being recognized as a complication, cutaneous thrombosis is uncommon and a variety of findings have been reported, including bullae, petechiae, leg ulcers, and purpura [6, 7, 8].

Case report

Figure 1	Figure 2
Figures 1 and 2. Erythematous-violaceous plaques with a necrotic center and an erythematous halo, mostly located on the neck and trunk.

We report the case of a 64-year-old man with paroxysmal nocturnal hemoglobinuria who was referred to our dermatology department because of a 3-day history of an asymptomatic cutaneous eruption mainly located on the neck and trunk. The skin examination showed isolated, rounded, well demarcated, erythematous-violaceous nodules and plaques of varying sizes, with a necrotic center and an erythematous halo. The plaques were mostly located on the neck and trunk but also on the arms, abdomen, and thighs (Figures 1 and 2). Laboratory analysis revealed pancytopenia (hemoglobin 7.4 g/dL; leukocytes 3.7 x 10⁹/L; platelet count 82 g/L) with no other hematological, biochemical, serologic, immunologic, or coagulation alteration. Skin biopsy was performed and revealed thrombosis of the superficial and deep dermal vessels with foci of necrosis of the overlying epithelium.

Figure 3	Figure 4
Figures 3 and 4. Thrombosis of the superficial and deep dermal vessels. (H&E: Figure 3 x100; Figure 4 x400)

Figure 5
Figure 5. Residual hyperpigmented macules on the trunk after treatment.

Given the history, the clinical examination and the histological features the diagnosis of cutaneous thrombosis related to PNH was assumed. Anticoagulation therapy was started with enoxaparin 1 mg/kg twice a day. An excellent clinical response was observed. After 2 weeks of treatment there were only residual hyperpigmented macules and a few crusts in the previous necrotic areas (Figure 5).

Discussion

In patients without prior history of PNH, the differential diagnosis of cutaneous manifestations can be challenging. However, the presence of microvascular occlusion secondary to platelet plugs in cutaneous histology, associated with the presence of hemolytic anemia, often with pancytopenia, should suggest the diagnosis.

Acute thrombosis in PNH is treated similarly to venous thrombosis occurring in other settings. However, prednisone is also used because the complement activation probably initiates thrombosis in patients with PNH. Thus, both corticosteroid therapy and anticoagulants may be useful in the treatment of thrombotic episodes. Anticoagulation for an acute episode of thrombosis should be instituted with heparin given in full therapeutic doses [2, 9]. The role of eculizumab in the treatment of acute thrombosis is under consideration. This monoclonal antibody inhibits the terminal stage of the complement cascade and has been approved for the treatment of transfusion-dependent PNH [10]. Prophylactic anticoagulation with warfarin should be offered to patients with large PNH clones (PNH granulocytes >50 percent of the total) and no contraindication to anticoagulation [2].

Conclusion

This case is reported because of the rarity of this complication and the importance of its correct and timely diagnosis, avoiding unnecessary tests or therapeutic measures. Moreover, the early identification of these patients is essential for necessary surveillance because they carry a higher probability of recurrence compared with those with no prior complications.

References

1. Nishimura J, Murakami Y, Kinoshita T. Paroxysmal nocturnal hemoglobinuria: An acquired genetic disease. Am J Hematol 1999; 62(3): 175-82. [PubMed]

2. Parker C, Omine M, Richards S et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005; 106(12): 3699-709. [PubMed]

3. Brodsky RA. Advances in the diagnosis and therapy of paroxysmal nocturnal hemoglobinuria. Blood Rev 2008; 22(2):65-74. [PubMed]

4. Van Bijnen ST, Van Heerde WL, Muus P. Mechanisms and clinical implications of thrombosis in paroxysmal nocturnal hemoglobinuria. J Thromb Haemost 2012; 10(1):1-10. [PubMed]

5. Taylor SR, Hashida Y, Jaffe R. Venous thrombosis and endothelial proliferation in paroxysmal nocturnal hemoglobinuria. Pediatr Pathol 1989; 9(6):757-64. [PubMed]

6. Rietschel RL, Lewis CW, Simmons RA, et al. Skin lesions in paroxysmal nocturnal hemoglobinuria. Arch Dermatol 1978; 114:560-563.

7. Cholez C, Schmutz JL, Hulin C et al. Cutaneous necrosis during paroxysmal nocturnal haemoglobinuria: role of parvovirus B19? J Eur Acad Dermatol Venereol 2005; 19(3):381-2. [PubMed]

8. White JM, Watson K, Arya R et al. Haemorrhagic bullae in a case of paroxysmal nocturnal haemoglobinuria. Clin Exp Dermatol 2003; 28(5):504-5. [PubMed]

9. Rosse WF. Treatment of paroxysmal nocturnal hemoglobinuria. Blood 1982;60(1):20-3. [PubMed]

10. Röth A, Dührsen U. Treatment of paroxysmal nocturnal hemoglobinuria in the era of eculizumab. Eur J Haematol 2011;87(6):473-9. [PubMed]

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