Intestinal ischemia in paroxysmal nocturnal hemoglobinuria with associated aplastic anemia: a rare and challenging association (case report)

¹Department of Internal Medicine, Faculty of Medicine and Pharmacy of Oujda, Oujda, Morocco, ²Department of Radiology, University Hospital of Mohammed VI, Oujda, Morocco

^&Corresponding author
Ismail Belefqih, Department of Internal Medicine, Faculty of Medicine and Pharmacy of Oujda, Oujda, Morocco

Introduction    

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematological disorder that has 3 classical presentations: hemolysis, thrombosis, and aplastic anemia. While the first two are managed with complement inhibitors, aplastic anemia is managed with triple immunosuppressive therapy or allogeneic stem cell transplant. Thrombosis may represent the major cause of death in PNH [1], but it is rarely reported in association with aplastic anemia, which would make management more challenging.

Patient and observation     

Patient information: we report the case of a 24-years-old woman, with no underlying comorbidities, who was diagnosed with severe aplastic anemia associated with paroxysmal nocturnal hemoglobinuria (PNH). The diagnosis was made on the basis of a severe pancytopenia, a bone marrow biopsy revealing a very low cellularity, and the detection of a clonal PNH-affected white blood cells at 25 percent. Laboratory results did not show signs of hemolysis, nor did the clinical finding suggest a potential thrombosis. The patient did not have a compatible donor for a potential allogeneic stem cells transplant, and therefore was put on triple immunosuppressive therapy (IST) consisting of cyclosporine at a dose of 150 mg twice a day, eltrombopag 100 mg once a day, and horse antithymocyte globulin which she received four months after the diagnosis, and which was complicated by a hepatic cytolysis that required the discontinuation of eltrombopag for a period of a month until the transaminases levels were back to normal. The cyclosporine serum level was monitored every month and was within the therapeutic range of 200 to 400 ng/mL. Despite the triple IST, there were no signs of improvement as the number and frequency of blood products transfusions remained the same. Eight months following the diagnosis the patient reported an acute diffuse abdominal pain with vomiting.

Clinical findings: physical evaluation found a hemodynamically, respiratory and neurologically stable patient, a mild tachycardia at 110 beats per minute, a fever at 38.2°C, and a tender abdominal palpation with no other clinical findings.

Diagnostic assessment: laboratory findings revealed a pancytopenia with hemoglobin level at 6 g/dl, thrombocytopenia at 14000 elements/mm³, neutropenia at 750 element/mm³, C-Reactive Protein (CRP) level was 250 mg/l, and lipase level was normal. A contrast enhanced computed tomography (CT) scan revealed jejunal ischemia with signs of pre-perforation (Figure 1).

Therapeutic interventions: the patient was managed conservatively with oral feeding stoppage, hydration with isotonic saline, parenteral feeding, anticoagulation with enoxaparin at a dose of 2500 UI once a day and antibiotics consisting of imipenem and metronidazole.

Informed consent: the patient provided a clear and well informed written consent for the publication of the case.

Discussion     

Paroxysmal nocturnal hemoglobinuria is a rare but potentially fatal hematological disorder. It is due to an acquired genetic mutation in phosphatidylinositol glycan anchor biosynthesis, class A (PIGA) gene [2]. The PIGA gene is responsible for the synthesis of glycosylphosphatidylinositol (GPI) anchor, which links proteins to the surface of plasma membranes. CD55 and CD59 are surface cell proteins that inhibit complements and prevent it from attacking the cell. As both the complement inhibitors require a GPI anchor, the mutation in PIGA gene is responsible for a lack of complement inhibitors on cell surface, that manifest as intravascular and extravascular hemolysis [2]. Paroxysmal nocturnal hemoglobinuria can have different manifestations, classical hemolysis, thrombosis, aplastic anemia. For the first two presentations, hemolysis and thrombosis, complement inhibitors, such as eculizumab and ravulizumab have proven their efficacy, unlike in the aplastic anemia presentation where the treatment relies on triple immunosuppressive therapy or allogeneic stem cell transplantation [3].

Only a handful of cases have reported intestinal ischemia in PNH [4-7], most of which were reported in the pre-complement inhibitors era.In these cases, there were two different approaches, while some underwent surgery with resection of necrotic intestinal segments, some used a more conservative approach consisting of oral feeding cessation, hydration, anticoagulation and antibiotics. Both approaches have reported a high risk of recurrence [6,7]. Cases where surgery was performed showed on histological findings hemorrhagic infarcts with focal necrosis [4,5].

Most of these cases were of patients with either hemolytic or thrombotic manifestations that might have required a complement inhibitor therapy. In our case, the patient presentation was purely of a severe aplastic anemia for which she received a triple immunosuppressive therapy. As the major cause of mortality in PNH is thrombosis, this raises the question as whether a complement inhibitors treatment in a severe aplastic anemia might prove beneficial in preventing thrombosis, especially considering the management challenge that aplastic anemia presents as both surgery and anticoagulation become infeasible due to the deep thrombocytopenia.

Conclusion     

Paroxysmal nocturnal hemoglobinuria associated aplastic anemia is a disorder where complement inhibitors have not shown efficacy, and where the management relies on either allogeneic stem cell transplant or triple immunosuppressive therapy. However, our case showed that this presentation might still be followed by a thrombotic manifestation, that may be fatal considering its location and the potentially severe thrombocytopenia that may render surgery or anticoagulation infeasible or dangerous. As complement inhibitors have proven their efficacy in preventing thrombosis and hemolysis, their use in aplastic anemia might be beneficial in preventing life threatening ischemia.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Patient management: Ismail Belefqih, Houda Bachir, Imane Kamaoui, Khalid Serraj. Manuscript revision: Houda Bachir, Siham Hamaz, Habiba Alaoui, Khalid Serraj. All the authors have read and agreed to the final manuscript.

Figure     

Figure 1: abdominal CT scan showing a markedly thickened jejunal wall with discontinued mucosal enhancement

References