Bone marrow necrosis and sickle cell crisis associated with double heterozygosity for HbS and HbOARAB
Authors: Pascal Rossi, Marielle Curiel, Anne Laurence Demoux, Denis Bagneres, Régis Costello, Kathia Chaumoitre, Fanny Bernard, Yves Frances, Brigitte Granel
Journal: American Journal of Hematology (2010)

A 39-year-old male from Maghreb, professional wrestler, with no family medical history, had been in perfect health until he developed muscular, back, and joints pain with fever and fatigue. The conjunctiva and the skin exhibited icterus; lumbar spine and knees were painful, and muscles were markedly tender. No other abnormalities were found during the examination. He had a regenerative anaemia (haemoglobin, 79 g/L; reticulocytes, 145 giga/L) with microcytosis (mean corpuscular volume, 72 fL), and mild thrombocytopenia (platelets, 110 × 109/L). The white blood cell count was 30,280/mm3 with 21,500/mm3 neutrophils and myelemia. The peripheral blood smear showed anisopoikilocytosis and target cells; schistocytes or sickle cells were absent. Total bilirubin was 56 μmol/L (normal range (NR) <22 μmol/L) of which 50% was conjugated, lactic dehydrogenase was 10,296 UI/L (NR, 100–620), and haptoglobin was undetectable. Haemoglobin (Hb) electrophoresis revealed an abnormal band migrating, corresponding to haemoglobin S and Hb O-Arab, amounting to 79% of the total haemoglobin, with foetal Hb of 8%, and the solubility test for HbS was positive. Investigations for infectious process were negative. Bone marrow biopsy showed extensive necrosis with aplasia and no evidence of vasculitis or thrombosis. Thoraco-abdomino CT scan only demonstrated an atrophy of the spleen. MRI showed diffuse bone marrow medulla abnormalities on both diaphysis and metaphysis involving long bones (upper arm bone, femur, tibia, ribs, and clavicle), thoracic and lumbar spine (vertebral body, spinous process, and transverse process), sternum and pelvic bone (Images 1 and 2). Despite the unremarkable personal, familial history and the age of the patient, we concluded to bone marrow necrosis (BMN) secondary to sickle-cell crisis in a patient double heterozygote for HbS and HbOARAB. After hyperhydratation, oxygenotherapy, and prophylactic antibiotherapy, the evolution was favorable despite a persistent mild anaemia with stable haemoglobin around 100 g/L on the six-month follow-up. Owing to the splenic atrophy, both long term antibioprophylaxis by oracilline and anti-pneumococcal vaccine were prescribed. Whole body MRI using “fluid sensitive” STIR sequences (Short Tau Inversion Reconvery) without gadolinium showing diffuse hyperintense involvement of the bone marrow spine (a and c) (even spinous process, c) and pelvic lesions (sacrum, ilium, ischium) with sharp margins and serpentine borders in favor of bone infarcts. There is also vertebral body endplate collapse. Whole body MRI showing bone infarcts on coronal STIR sequence concerning femoral heads (a), femoral and tibial diaphysis and metaphysis (b and c). These lesions are located at sites of residual hematopoietic marrow. Concerning the femoral lesions, there is the classical “double line sign” with an inner bright T2 line representing granulation tissue and an outer dark line representing sclerotic bone. This sign is specific and is reported in up to 80% of osteonecrosis. BMN is a rare but life-threatening syndrome. Whereas malignancy, especially from haematopoietic origin, represents 90% of all causes of BMN, some non-malignant conditions increasing susceptibility to blood vessel occlusion can be associated. BMN was first described in 1941 by Wade and Stevenson in a patient with sickle cell disease (SCD) [1] although representing only 2% of all BMN reported cases [2]. Our report is the first of BMN as manifestation of sickle cell-like crisis in a patient double heterozygote for HbS and HbOARAB. Few cases of BMN in heterozygotes for HbSC, HbSD, HbSE, HbSβ+-thalassemia, and HbSβ0-thalassemia have been reported [3] but, to our knowledge, never as a heralding manifestation of the hemoglobinopathy. Among the patients with HbOARAB mutation (β globin chains: 121 Glu→Lys), HbOARAB heterozygotes show no related clinical manifestations whereas homozygotes present a mild haemolysis with borderline splenomegaly. The double heterozygoty for HbS and HbOARAB (Hb S/O-Arab) is rare and results in a severe sickling hemoglobinopathy as homozygous sickle cell anemia [4]. The enhancing role of the HbO-Arab on the sickling effect of HbS is driven by electric charge modifications of the erythrocytes' membrane resulting in denser and more spherical erythrocytes, a dysfunction of K:Cl co-transport system leading to erythrocyte's dehydration and intracellular HbS polymerization enhancement and stabilization [5]. In this patient, the high level of HbF, well known to modulate clinical severity in SCD by reducing the sickling process, may explain the late diagnosis of hemoglobinopathy.