Extramedullary Hematopoiesis in SCD Is More Prevalent Than Previously Recognized
Authors: Alan Sheinei , Bade Najeebah , Giri Upama , Fusisi Rania , Marti Sebasitan Mendez , Zik Chad , Ershler William B 
Published: June 2024

Abstract

Presentation Date: 6/8/2024
Presentation Start Time: 6:00:00 PM

Background
Sickle cell disease (SCD) is characterized by rapid red blood cell turnover and constant hematopoiesis. While the primary site of hematopoiesis is the bone marrow (BM); bone infarction, frequent vaso-occlusion and dysregulated marrow can result in release of hematopoietic stem cells into the periphery and establishment of hematopoiesis elsewhere in the body, also known as extramedullary hematopoiesis (EMH). The prevalence and mechanism of EMH in SCD is not yet established. EMH is considered to be rare in SCD. In patients with myelofibrosis, thalassemia and other diseases, EMH is thought to occur predominately in the spleen, liver and the lymph nodes rather than in the thoracic cavity. There are only a few case reports discussing EMH in SCD and interestingly, most sites of EMH were in the thoracic cavity rather than typical sites of EMH. There is little data regarding long term follow up, BM studies and further investigation. Herein, we demonstrate additional insight into EMH in SCD, by reporting on two patients with homozygous sickle cell disease (HbSS), and postulate that it might not be as rare as previously thought.

Methods
Of 179 active patients, two patients with HbSS were noted to have abnormal paraspinal masses on incidental computer topography (CT) imaging. While the literature did not suggest EMH based on rarity in SCD, given peculiar findings, both patients underwent magnetic resonance imaging (MRI) of the thoracic cavity to establish EMH. We used our electronic health record system to review the chronological development and progression of EMH as it relates to hematologic parameters and disease modifying therapy. In one of these patients, next generation sequencing (NGS), evaluation of JAK2V617F, CAL-R and MPL genes and BM studies were obtained.

Results
The first patient is a 33-year-old male with HbSS with a paraspinal mass at T9 and T10 of thoracic spine. No EMH lesions seen on imaging in 2016 but first noted in 2021 after CTA was performed for pulmonary embolism (PE); showing a 2.0 cm right paraspinal lesion. At that time, hemoglobin was 10g/dl and reticulocytes 0.7 x106/µL. Interestingly, between first CT in 2016 and CT in 2021, his hemoglobin was 7-8 g/dL with reticulocyte counts 0.1–0.4 x106/µL. His hemoglobin since 2022 has been 7-9 g/dL and reticulocytes 0.4–0.5 x106/µL. On thoracic MRI in 2023, these lesions measured 3.3 x 1.5 cm at T9 and 1.3 x 0.6 cm at T10. During this time, patient has been on monthly red cell exchanges as well as voxelotor but not hydroxyurea due to leg ulcers. These EMH lesions have not changed in size regardless of SCD treatments. He has not experienced any related respiratory or neurological issues.
Second patient is a 55-year-old male with HbSS and profound transfusion dependent anemia. CTA, obtained in 2021 to rule out PE, showed several paraspinal lesions consistent with EMH with largest being 5.3 x 4.2 cm at the level of T9. Patient underwent extensive testing to understand the EMH better. MRI of the thoracic spine showed several hypointense mass lesions in the lower thoracic region, the largest at 4.1x 5.8 cm at T9 consistent with EMH. BM biopsy demonstrated trilineage hematopoietic bone marrow with marked erythroid hyperplasia and progressive maturation. Flow cytometric studies were without immunophenotypic abnormalities. Peripheral blood NGS as well as JAK2V617F, JAK2 Exon 12, CAL-R, and MPL mutations were negative. These EMH lesions have not changed in size since initial CT scan of the chest from 2021 despite the interim treatment with darbepoetin alfa, voxelotor, and hydroxyurea.

Conclusions
The mechanism of extramedullary hematopoiesis in SCD is complex and multifactorial. Chronic hemolysis, vaso-occlusion, and ischemia-reperfusion injury contribute to the disruption of marrow function, leading to the expansion of hematopoietic activity in extramedullary sites. Our observation questions the present thought that EMH is rare in SCD and emphasizes the need for long-term follow-up and further elucidation. The persistent size of EMH lesions despite varied disease-modifying therapies raises questions about the contribution of current interventions in addressing EMH in SCD. Consequently, there is a pressing need for further research and larger studies to validate and extend our findings, paving the way for a more nuanced understanding of the prevalence, characteristics, and mechanisms of EMH in SCD.