Treatment with hydroxyurea in thalassemia intermedia with paravertebral pseudotumors of extramedullary hematopoiesis

Excessive ineffective erythropoiesis in thalassemia intermedia may cause paravertebral pseudotumors of extramedullary hematopoiesis. Due to the proximity to the spinal canal, these paravertebral masses carry the risk of severe neurological damage. Treatment strategies include hypertransfusion, radiotherapy, and laminectomy. Hydroxyurea, stimulating fetal hemoglobin synthesis, may represent an alternative therapeutic approach. We report on a 26-year-old patient suffering from thalassemia intermedia with progressive anemia symptoms and presenting multiple intrathoracic paravertebral pseudotumors of extramedullary hematopoiesis. Hypertransfusion therapy and splenectomy were followed by regular transfusion (baseline hemoglobin 10 g/dl) and chelation with desferrioxamine. With this treatment, clinical symptoms disappeared, paravertebral hematopoietic masses did not progress, but severe hemosiderosis developed within a few years. Hydroxyurea therapy was initiated to increase the efficacy of erythropoiesis, thereby reducing the required transfusion volume but suppressing concomitantly further expansion of extramedullary hematopoiesis, and finally leading to a reduction of transfusional iron load. Treatment was started with 4 mg/kg per day and stepwise increased to 12.5 mg/kg per day. The fetal hemoglobin concentration increased from 4.5 to 5.5 g/dl after 1 year and to 9.9 g/dl after 2 years of treatment. The yearly transfusion volume was halved during the 1st year of treatment. At present, after 26 months of treatment, the patient has been transfusion-independent for 10 months. Serum ferritin levels decreased from 2844 to 1335 ng/ml. Size and shape of paravertebral hematopoietic pseudotumors remained stable. No side effects of hydroxyurea have been observed. In thalassemia intermedia patients with extramedullary hematopoiesis, hydroxyurea may lead to independence from regular transfusion therapy without further expansion of ectopic hematopoietic tissue.     

Développement d'un sarcome sur foyer ectopique hématopoïétique secondaire à une sphérocytose héréditaire : à propos d'un cas et revue de la littérature

IntroductionExtramedullary hematopoiesis is a complication of myeloproliferative neoplasms or of chronic hemolysis. The more frequent localizations are splenic, ganglionic or paraspinal. Rarely, extramedullary hematopoiesis is associated with solid cancer.Case reportWe report an original case of sarcoma located in an extramedullary hematopoiesis mass in a 72-year-old woman suffering from hereditary spherocytosis. An asymptomatic right paravertebral mass was found in 2004; the biopsy confirmed extramedullary hematopoiesis. In 2016, the patient was hospitalized due to paravertebral pain. Computed tomography showed the extension of the right paraspinal mass to pleura and mediastinum as well as vertebral bone lysis. Positron emission tomography showed an intense hypermetabolism. The biopsy showed undifferentiated sarcoma.ConclusionThis case report illustrates the risk of neoplastic transformation of extramedullary hematopoiesis, and the need for a biopsy when confronted to atypical aspect.     

Bulky extramedullary hematopoiesis is not a rare complication of congenital dyserythropoietic anemia

Bulky extramedullary hematopoiesis, usually detected in the thorax by imaging techniques, is a well-known complication in many types of congenital anemias. Here, we describe 12 cases of congenital dyserythropoietic anemia with extramedullary hematopoiesis which was always located in the paravertebral space of the thoracic spine and in other paraspinal regions in a few cases. All bulks were originally detected in chest radiographs and confirmed by imaging techniques such as computed tomography and/or magnetic resonance imaging. In some cases, thoracotomy was performed for suspected malignancy. Although the true prevalence is not known, paravertebral masses in patients with CDA of any type are not uncommon and should be the first differential diagnosis considered when masses adjacent to the spine are detected in this disorder.     

Marrow transplantation for juvenile osteopetrosis

Two children with the juvenile form of osteopetrosis were treated with marrow transplants from their HLA identical siblings. Following transplantation each child exhibited extensive bone resorption with a marked augmentation of osteoclastic function attributable to donor osteoclasts, including remodeling of bone with expansion of intramedullary hematopoiesis and correction of associated abnormalities of thymic factor and natural killer cells. Osteopetrosis ultimately recurred in one patient in whom engraftment of donor hematopoietic elements was not achieved. Our studies indicate that marrow transplantation will correct osteopetrosis but that permanent reconstitution necessitates sustained engraftment of marrow precursors of cells with osteoclastic activity.     

Long-term follow-up of two children with a variant of mild autosomal recessive osteopetrosis undergoing bone marrow transplantation

Malignant autosomal recessive (AR) osteopetrosis represents an absolute indication for bone marrow transplantation (BMT). Over the last 15 years, almost 100 BMTs for osteopetrosis have been reported. The median age at transplant of most patients is 4 months. Very few cases of mild AR osteopetrosis have been described. Here, we report the good outcome of two cases of mild AR osteopetrosis with a follow-up of 5 and 6 years, respectively, after an HLA-identical sibling transplant undergone at 5 and 12 years of age, respectively. At the time of BMT, severe visual impairment was present in both children. Bone biopsy demonstrated hypermineralization with virtual obliteration of the medullary spaces, rare microfoci of hematopoiesis and marked deficiency in osteoclastic activity. Successful engraftment was complicated by hypercalcemia, controlled by a combination of bisphosphonate, phosphate infusions, vigorous hydration and calcitonin. Following BMT, radiological and histological findings showed extensive bone resorption with marked augmentation of the osteoclasts in normalized marrow. No improvement was observed in visual acuity, despite complete remodeling of skeletal abnormalities. We conclude that allogeneic BMT is the only chance of curing mild AR osteopetrosis.     

Existence of cord compression in extramedullary hematopoiesis due to beta thalassemia intermedia

Extramedullary hematopoiesis (EMH) is a rare disorder, characterized by the appearance of hematopoietic elements outside of the bone marrow, which occurs in patients with chronic myeloproliferative disorders or congenital hemolytic anemias. We report a case with thalassemia intermedia, EMH in spinal cord and a paravertebral mass. We report the case of a 20 year old female who initially presented with back pain and leg weakness was found to have paravertebral mass in the spinal cord.     

Transudative Pleural Effusion Associated with Extramedullary Hematopoiesis

The authors report a case of transudative pleural effusion associated with extramedullary hematopoiesis due to the presence of a myeloproliferative neoplasm, which was unclassified. A 71-year-old man presented with right pleural effusion during an exacerbation of thrombocytosis. The pleural effusion was transudative, although there was no history of cardiac failure or hypoalbuminemia, and treatment with diuretics failed. Extramedullary hematopoiesis was diagnosed in bilateral paravertebral soft tissue and the liver on ¹¹¹In bone marrow scintigraphy. The administration of hydroxyurea simultaneously reduced peripheral blood platelet count and pleural effusion within 2 weeks. The possible cause of transudative pleural effusion in association with extramedullary hematopoiesis is discussed.     

Hematopoiesis in the human spleen

To assess the capacity of the human spleen to function as a hematopoietic organ, spleen mononuclear cells from patients undergoing splenectomy were cultured to assay CFU-E, BFU-E, and CFU-C. Although the peripheral blood from cases of hereditary spherocytosis, Gaucher disease, Thalassemia major, and idiopathic thrombocytopenic purpura yielded 3–20 BFU-E/5 × 10⁵ cells plated and 1–7 CFU-C/5 × 10⁵, suspensions of spleen cells failed to grow colonies. Histologically these spleens did not show extramedullary hematopoiesis. In contrast, peripheral blood from a patient with osteopetrosis (marble bone disease) yielded 130 BFU-E/5 × 10⁵, 40 CFU-E/5 × 10⁵, and 9 CFU-C/5 × 10⁵. The spleen had extensive extramedullary hematopoiesis on microscopy and grew 180 BFU-E/10⁵, 210 CFU-E/10⁵, and 25 CFU-C/10⁵. We conclude that spleens from patients without extramedullary hematopoiesis do not contain committed hematopoietic progenitors in spite of normal precursors in the blood. In osteopetrosis the spleen contained stem cells in a concentration comparable to bone marrow, and the embryonic role of the spleen in blood formation appeared to continue in postnatal life.     

An interesting presentation of intrathoracic extramedullary hematopoiesis in a patient with thalassemia intermedia

Extramedullary hematopoiesis (EMH) occurs as a compensatory mechanism for bone marrow dysfunction in severe thalassemia. In addition to the more common locations, such as liver, spleen and lymph nodes, a mass of EMH may occasionally occur in the thorax. Intrathoracic EMH is usually asymptomatic. A 69-year-old woman who initially presented with hematuria, dysuria, and left inguinal pain was found to have paravertebral masses in the thorax. Histopathologic examination of a CT-guided needle aspiration biopsy of the masses showed the presence of trilineage hematopoiesis. We present this unusual case, in which EMH was diagnosed by chance in an elderly patient with no symptoms related to thalassemia.     

Massive mediastinal extramedullary hematopoiesis in hereditary spherocytosis: a case report

A case of extramedullary hematopoiesis (EMH) with a massive mediastinal mass in a 72-year-old woman with hereditary spherocytosis is reported. Several cases of EMH have been described in nonsplenectomized adults with hereditary spherocytosis, and it is thought to be a consequence of long-term stimulation of erythropoiesis. The exact mechanism remains controversial. EMH should be considered in the differential diagnosis of an asymptomatic paravertebral mass.     

Extramedullary Hematopoiesis in Hereditary Spherocytosis Deficient in Ankyrin: A Case Report

Hereditary spherocytosis (HS) is a common inherited hemolytic anemia due to red cell membrane defects. Extramedullary hematopoiesis is a compensatory response to insufficient bone marrow blood cell production. The preferred sites of extramedullary hematopoietic involvement are the spleen, liver, and lymph nodes, but in HS the posterior paravertebral mediastinum is also commonly involved. A nonsplenectomized 74-year-old man with mild HS, with primary deficiency in ankyrin, was found by magnetic resonance imaging to have thoracic paravertebral hematopoietic masses. The patient showed high serum levels of erythropoietin, which may have played a role in the development of extramedullary hematopoietic masses through a continuous hematopoietic stimulus to erythroid cells in the propositus. The long-standing history of respiratory infections and of hypoxia in the propositus may have been an additional etiological factor.     

Presacral and intrathoracic extramedullary hematopoiesis in a patient with β thalassemia minor

Extramedullary hematopoiesis (EMH) is a rare disease characterized by the presence of hematopoietic elements outside the bone marrow as a compensatory phenomenon in several hematological diseases, including thalassemia. We report a 64‐year‐old man with epigastric pain of 3‐months' duration radiated to the back. Imaging workup showed multiple paravertebral, retrosternal and presacral masses. Cytology findings obtained by CT‐guided FNAC were compatible with the diagnosis of EMH. Peripheral blood smear confirmed the presence of β‐thalassemia.     

Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis

Expression of the Src-family kinases--Src, Hck, and Fgr--increases dramatically during myeloid cell development. Src-deficient mice exhibit functional abnormalities in only one myeloid cell type, the osteoclast, resulting in impaired bone remodeling and osteopetrosis, while hck-/- or fgr-/- mice have few and subtle myeloid cell deficiencies. To determine whether these limited phenotypes are due to the coexpression of multiple Src-family kinases with overlapping functions, we have intercrossed src-/- mice to hck-/- and fgr-/- mutants to produce double mutants. Two thirds of hck-/- src-/- double mutants die at birth; surviving animals develop a severe form of osteopetrosis, resulting in extreme levels of splenic extramedullary hematopoiesis, anemia, and leukopenia. These hematopoietic defects are caused by abnormalities in the bone marrow environment because hck-/- src-/- mutant stem cells reconstitute a normal hematopoietic system in irradiated wild-type mice. In contrast, fgr-/- src-/- double mutants have no defects beyond those observed in src-/- animals. Cultured normal murine osteoclasts express abundant amounts of Src, Hck, and Fgr and Hck levels are increased in src-/- osteoclasts. These observations suggest that Hck and Src serve partially overlapping functions in osteoclasts and that the expression of Hck in src-/- osteoclasts ameliorates their functional defects.     

Massive hemothorax due to intrathoracic extramedullary hematopoiesis in a patient with hereditary spherocytosis

 Extramedullary hematopoiesis (EMH) is a rare disorder, characterized by the appearance of hematopoietic elements outside of the bone marrow, which occurs in patients with chronic myeloproliferative disorders or congenital hemolytic anemias. We report on a 64-year-old man with hereditary spherocytosis, who presented with anemia, jaundice, intrathoracic EMH, and massive hemothorax. The diagnosis of EMH was established after computer tomography (CT)-guided punctuation of the paravertebral mass. The patient underwent splenectomy and thoracic drainage. After 1 year, the patient is in good health, with normal hemoglobin values, and hemothorax has not recurred. Received: 23 December 1999 / Accepted: 31 May 2000     

Osteoclasts are not crucial for hematopoietic stem cell maintenance in adult mice

The osteoclast is vital for establishment of normal hematopoiesis in the developing animal. However, its role for maintenance of hematopoiesis in adulthood is more controversial. To shed more light on this process, we transplanted hematopoietic stem cells from two osteopetrotic mouse models, with lack of osteoclasts or defective osteoclast function, to normal adult mice and examined the bone phenotype and hematopoiesis in the recipients. B6SJL mice were lethally irradiated and subsequently transplanted with oc/oc, Receptor Activator of Nuclear Factor Kappa B knockout or control fetal liver cells. Osteoclasts derived from the recipient animals were tested in vitro for osteoclastogenesis and resorptive function. Bone remodeling changes were assessed using biomarkers of bone turnover and micro-CT. Hematopoiesis was assessed by flow cytometry and colony formation, and hematopoietic stem cell function by secondary competitive transplantations and cell cycle analysis. After transplantation, a donor chimerism of 97–98% was obtained, and by 15 weeks mild osteopetrosis had developed in recipients of cells from osteopetrotic mice. There were no alterations in the number of bone marrow cells. Colony formation was slightly reduced in Receptor Activator of Nuclear Factor Kappa B knockout recipients but unchanged in oc/oc recipients. Phenotypically, stem cells were marginally reduced in recipients of cells from osteopetrotic mice, but no significant difference was seen in cell cycle status and in competitive secondary transplantations all three groups performed equally well. Our results indicate that osteoclast function is not crucial for hematopoietic stem cell maintenance in adult mice.     

Radiotherapy combined with erythropoietin for the treatment of extramedullary hematopoiesis in an alloimmunized patient with thalassemia intermedia

 We report a patient with thalassemia intermedia who developed a mediastinal syndrome due to the growth of paravertebral hematopoietic masses in the posterior mediastinum. Because the patient did not receive blood transfusions due to alloimmunization, she was first treated with human recombinant erythropoietin (escalating low-moderate doses) to recover hemoglobin levels, then in association with radiotherapy to prevent a worsening of her anemia. The mean Hb level dramatically increased and peaked at week 11, to 83 g/l, and remained unchanged before and after radiotherapy (81 versus 78 g/l). Immediately after radiotherapy extramedullary hematopoiesis volume decreased by 16.4%. Received: 12 December 1995 / Accepted: 7 March 1996     

骨硬化症研究进展

骨硬化症是一类以骨密度增高,破骨细胞吸收功能障碍为主要特点的遗传性骨病,根据临床表现和致病基因可分为常染色体显性遗传骨化症(ADO)、常染色体隐性遗传骨硬化症(ARO)和罕见X连锁遗传骨硬化症(XLO)。本文对该病的临床分型和致病基因做一综述。     

Myonecrosis caused by Edwardsiella tarda: a case report and case series of extraintestinal E. tarda infections.

Edwardsiella tarda is an unusual human pathogen. It is primarily associated with gastrointestinal disease, although recent reports of extraintestinal disease are broadening the current understanding of the clinical spectrum of E. tarda. A series of 11 cases of extraintestinal E. tarda infection is presented, including the first reported case of myonecrosis in an immunocompetent patient. Wound infections were the most common manifestation, and 3 of 5 patients with infected wounds had been exposed to a marine environment. One patient had bacteremia, and the remaining 5 patients developed abscesses that required surgical drainage. Four patients had E. tarda isolated in pure culture, including the patient with myonecrosis. Although it is often difficult to ascertain the contribution of E. tarda to infection when it is isolated as part of a mixed culture, this case series suggests that E. tarda is singularly capable of causing limb- and life-threatening infections.     

The Physiology and Pathophysiology of the Osteoclast

The osteoclast is the giant cell of bone phylogenically evolved to resorb the bone matrix. It contributes to both the bone modeling and remodeling processes through a complex extracellular mechanism, termed bone resorption, which removes the mineral and the organic bone matrix components. Primary osteoclast pathologies occur both in children and adults, and are very common in elderly. Reduced bone resorption is typically responsible of osteopetrosis, in which both bone modeling and remodeling are altered, and the primary bone persists reducing strength and causing spontaneous fractures, failure in hematopoiesis and impairment of sensory and motor systems. In children, bone resorption can be increased secondary to other pathological conditions due for instance to mechanical failure or inflammatory diseases. Excess bone resorption over formation is typical of post-menopausal women and elderly men, and the net result of this unbalanced bone cell activity is osteoporosis, which affects millions of people worldwide with high costs for management. This article will expand the concepts associated with the pathophysiology of the osteoclasts, providing up-to-date information on their function and involvement in bone diseases.     

A case of sepsis caused by Edwardsiella tarda complicated panophthalmitis and pyogenic spondylitis

Edwardsiella tarda (E. tarda) is gram negative enterobacteriaceae which has been found generally in animal hosts and occasionally in human feces. We have reported a case of sepsis caused by E. tarda, complicated panophthalmitis and pyogenic spondylitis. A 39-year old patient suffered from fever, polyarthralgia and lumbago. We performed blood culture, from which E. tarda was isolated. Spinal CT scan showed destruction and osteogenesis of the fourth and fifth lumbar vertebral body and cranial CT scan showed destruction of the right lens. So we diagnosed sepsis with pyogenic spondylitis and panophthalmitis. We suspected that chronic ethanol administration reduced the resistance to infection of E. tarda which caused sepsis.