Extensive Bone Marrow Necrosis Research Articles

5607225 ADDITION OF THERAPEUTIC PLASMA EXCHANGE TO RED CELL EXCHANGE IMPROVES OUTCOMES OF FAT EMBOLISM SYNDROME IN SICKLE CELL DISEASE

Background: Fat embolism syndrome (FES) is a severe but possibly underdiagnosed complication of sickle cell disease (SCD) associated with very high mortality and morbidity. It is the result of extensive bone marrow necrosis that leads to release of large amounts of fat droplets in the systemic circulation. These not only cause mechanical obstruction of the microvasculature but also act as a substrate for the generation of various pro-inflammatory cytokines that contribute to the development of multiorgan failure. FES predominantly affects non-homozygous patients and those with a previously mild course of their illness. Immediate red cell exchange (RCE) can be life-saving and it is currently the treatment of choice. However, despite its increasing use in recent years, mortality remains substantial while a large number of survivors is left with significant neurocognitive impairment. With that in mind, we have previously advocated the addition of therapeutic plasma exchange (TPE) to RCE in order to address the inflammatory environment and potentially improve outcomes. Aims: To compare outcomes from FES using standard treatment with RCE and combination of RCE and TPE. Methods: A systematic review of all cases published since 2012 where RCE was employed was performed, and outcomes were compared to cases where a combination of RCE and TPE was used. Results: The systematic review of the literature identified 39 cases treated with RCE since 2012. Mortality was 21%, 33% of patients were left with severe and 13% with mild neurological impairment while only 33% made a complete recovery (CR). We are aware (publications/ personal communication) of 11 cases (separate from the previous 39) treated with combination of RCE and TPE worldwide (8 UK, 2 Canada, 1 USA). 9 patients were adults and 2 patients were children. 5 patients had homozygous Hb SS disease, 5 Hb SC and 1 Hb Sβ+. All patients, irrespective of genotype, had previously a mild course of their illness. The number of TPE procedures performed varied greatly between cases (1-10). There was 1 death (9%), 2 patients (18%) suffered mild/moderate neurological impairment and 8 patients (73%) achieved CR. Both patients reported as suffering mild/moderate neurological impairment are patients who developed the complication recently, have fully recovered cognition but are still in rehabilitation improving from generalised weakness resulting from prolonged hospitalisation and are very likely to achieve CR eventually. One more 13-year old patient (not included in this analysis as the final outcome is yet unknown) is currently recovering in hospital having recently suffered severe FES with multiorgan failure requiring extracorporeal membrane oxygenation now extubated, recovering organ function and able to communicate appropriately. Interestingly, 2 patients had a cytotoxic lesion of the corpus callosum (CLOCC) on brain imaging. This further highlights the role of the inflammatory environment in the pathophysiology of FES as CLOCCs are known to be the result of direct cytotoxicity from proinflammatory cytokines, especially IL-1 and IL-6. TPE was well tolerated with no associated adverse events. Conclusion: These early data suggest a clear benefit from this approach, and as TPE is a low risk intervention, we recommend its addition to RCE as standard management for FES in SCD. Reference 1. Tsitsikas DA, Vize J, Abukar J. Fat Embolism Syndrome in Sickle Cell Disease. J Clin Med. 2020 Nov 8;9(11):3601.

Bone marrow necrosis and fat embolism syndrome in sickle cell disease during COVID-19 infection treated successfully with sequential red cell and plasma exchange.

Fat embolism syndrome (FES) is a rare life-threatening condition that is particularly seen in milder forms of sickle cell disease (SCD). Widespread systemic fat emboli are generated in the context of extensive bone marrow necrosis. Multi-organ failure with a high morbidity and mortality may quickly develop. Infection with Parvovirus B19 is a common precipitant. Here, the authors report the case of a 35-year-old Afro-Caribbean man with HbSC disease who presented with FES having tested positive for SARS-COV-2. He rapidly became critically ill and required admission to the intensive care unit for organ support. He was treated with red cell exchange and plasma exchange and made a good recovery to leave hospital at week 7.

Fat Embolism Syndrome in Sickle Cell Disease.

Fat embolism syndrome is a devastating complication of sickle cell disease resulting from extensive bone marrow necrosis and associated with high mortality rates, while survivors often suffer severe neurological sequelae. Despite that, the syndrome remains under-recognised and under-diagnosed. Paradoxically, it affects exclusively patients with mild forms of sickle cell disease, predominantly HbSC and HbSβ+. A significant number of cases occur in the context of human parvovirus B19 infection. We provide here a brief summary of the existing literature and describe our experience treating 8 patients in our institution. One patient had HbSS, 6 HbSC and 1 HbSβ+. All patients developed type I respiratory failure and neurological involvement either at presentation or within the first 72 h. The most striking laboratory abnormality was a 100-fold increase of the serum ferritin from baseline. Seven patients received emergency red cell exchange and 1 simple transfusion. Two patients (25%) died, 2 patients (25%) suffered severe neurological impairment and 1 (12%) mild neurological impairment on discharge, while 3 (38%) patients made a complete recovery. With long-term follow-up, 1 patient with severe neurological impairment and one patient with mild neurological impairment made dramatic improvements, making the long-term complete recovery or near complete recovery rate 63%. Immediate red cell exchange transfusion can be lifesaving and should be instituted as soon as the syndrome is suspected. However, as the outcomes remain unsatisfactory despite the increasing use of red cell exchange, we suggest additional therapeutic measures such as therapeutic plasma exchange and pre-emptive transfusion for high risk patients.

Bone Marrow Necrosis in a Child With Sepsis-Induced Macrophage Activation Syndrome

Bone marrow necrosis (BMN) is a rare condition, mostly described with hematological malignancies. Association of BMN with sepsis-induced macrophage activation syndrome (MAS) is rarely reported in the literature. Recently, we managed a 10-year-old girl with Staphylococcus aureus sepsis and MAS who had extensive BMN. Patient initially improved with antibiotics, source control, supportive care and immunomodulatory therapies (intravenous immunoglobulin and methylprednisolone). However, she succumbed to transfusion-related acute lung injury. Sepsis, MAS and BMN seem to represent increasing levels of immune dysregulation, hypercytokinemia and hyperinflammation. Int J Clin Pediatr. 2020;9(1):24-29 doi: https://doi.org/10.14740/ijcp346

Region specific Raman spectroscopy analysis of the femoral head reveals that trabecular bone is unlikely to contribute to non-traumatic osteonecrosis

Non-traumatic osteonecrosis (ON) of the femoral head is a common disease affecting a young population as the peak age of diagnosis is in the 40 s. The natural history of non-traumatic ON leads to a collapse of the femoral head requiring prosthetic replacement in a 60% of cases. Although trabecular bone involvement in the collapse is suspected, the underlying modifications induced at a molecular level have not been explored in humans. Here, we examine changes in the molecular composition and structure of bone as evaluated by Raman spectroscopy in human end-stage ON. Comparing samples from femoral heads harvested from 11 patients and 11 cadaveric controls, we show that the mineral and organic chemical composition of trabecular bone in ON is not modified apart from age-related differences. We also show that the molecular composition in the necrotic part of the femoral head is not different from the composition of the remaining ‘healthy’ trabecular bone of the femoral head. These findings support that quality of trabecular bone is not modified during ON despite extensive bone marrow necrosis and osteocyte death observed even in the ‘healthy’ zones on histological examination.

Multiple Myeloma: An Unusual Cause of Extensive Bone Marrow Necrosis.

Multiple Myeloma: An Unusual Cause of Extensive Bone Marrow Necrosis.

GATA1 mutation negative acute megakaryoblastic leukemia with acquired trisomy 21 presenting with extensive bone marrow necrosis in an adult: A case report and review of the literature

ContextAcute megakaryoblastic leukemia (AMKL) is a rare myeloid leukemia, occurring in 1%–5% of all adult acute myeloid leukemia (AML) cases. AMKL is characterized by a leukemic blast population positive for factor VIII, CD41a, CD42b, and/or CD61 with extensive myelofibrosis. Although various cytogenetic abnormalities are commonly reported, the association between constitutional trisomy 21 and AMKL has been of particular interest, because of the near universal presence of GATA1 mutation in such cases. Objective and DesignWe report a case of AMKL in an adult presenting with extensive bone marrow necrosis in which cytogenetic studies revealed three copies of chromosome 21 as part of a complex karyotype; however, sequencing of the GATA1 gene revealed no mutation. ResultsThe patient was an adult male who presented with extensive bone marrow necrosis, making definitive diagnosis difficult. Autopsy studies using a multimodality approach identified AMKL with a complex karyotype, including trisomy 21. Sanger sequencing of the GATA1 gene showed a germline configuration without a mutation. ConclusionsTo our knowledge, this is the first reported case of an adult with AMKL with acquired trisomy 21 in which the GATA1 mutation was investigated and the second reported case of AMKL presenting with extensive bone marrow necrosis. We will present a diagnostic approach to AMKL in which extensive bone marrow necrosis renders examination of the bone marrow difficult. Furthermore, we will examine the absence of the GATA1 mutation in a case of AMKL with trisomy 21 in an adult.

Extensive marrow necrosis due to miliary tuberculosis: A case report

Bone marrow necrosis (BMN) is a rare clinicopathologic entity caused by hypoxemia after the failure of microcirculation that frequently manifests with bone pain, fever, and peripheral cytopenia. In most reported cases of BMN resulting from extrapulmonary tuberculosis (TB), the presence of marrow granulomas, pulmonary infiltrates and/or extrapulmonary involvement are common. We report a case of an extensive BMN from miliary TB whose initial presentation was only mild anemia and multiple bone lesions.

P1-21-4 - Acute Myeloid Leukemia with Extensive Bone Marrow Necrosis

Background: Bone marrow necrosis, a rare condition, characterized by necrosis of the medullary stroma and myeloid tissues of the bone marrow. The etiology is diverse, including hematopoietic malignancies.Case report: A 54-year-old male arrived by ambulance with collapse and high fever. On clinical examination, he had numerous petechiae and ecchymoses in the mouth and on the limbs. Laboratory findings revealed anemia and thrombocytopenia (WBC 15,140/μl, Hb 4.7g/dl, Plt 3.8X104/μl). A blood culture was positive for Staphylococcus aureus, diagnosed as septic shock, complicated by disseminated intravascular coagulation (DIC). When his medical condition was improved after treatment, blood examination showed pancytopenia (WBC 2,170/μl, blast 1.5%, Hb 9.2g/dl, Plt 1.1X104/μl). Multiple bone marrow aspiration displayed only small amount of the cells, which were difficult to be classified and were negative for peroxidase. Bone marrow biopsy showed marked bone marrow necrosis. During being treated for DIC, the abnormal cells were appeared in the peripheral blood, which were analyzed by flow cytometry and cytogenetics and eventually he was diagnosed as AML (M0, FAB classification). The sudden appearance of consolidation in the lungs by chest X-ray indicated leukemic cells infiltration into the lungs. His physical status was allowed chemotherapy consisting of cytarabine and aclarubicin only for the first four days of the standard protocol. Laboratory findings were improved, however, he suffered from repeated hemoptysis. Thoracic CT scan demonstrated diffuse alveolar damage and possible pneumonia. Despite of supportive treatment, his condition was complicated with chemotherapy associated-febrile neutropenia and he expired four weeks after admission.Conclusion: Bone marrow necrosis prognosis is related to underlying diseases and is generally poor. Therefore, multiple bone marrow aspirations and biopsies are needed to achieve appropriate diagnosis.

Bone marrow necrosis and fat embolism syndrome in sickle cell disease: Increased susceptibility of patients with non-SS genotypes and a possible association with human parvovirus B19 infection

Fat embolism syndrome (FES) due to extensive bone marrow necrosis (BMN) in sickle cell disease (SCD) is a potentially under-diagnosed complication associated with severe morbidity and mortality. We identified 58 cases reported in the world literature to date. Typically, patients presented with a seemingly uncomplicated vaso-occlusive crisis (VOC) and subsequently deteriorated rapidly with a drop in their haemoglobin and platelets, development of respiratory failure, encephalopathy and varying degrees of involvement of other systems. Overall mortality in the reported cases was 64% but differed according to the use of transfusion and was 29%, 61% and 91% for patients receiving exchange, top-up or no transfusion respectively. Patients most at risk appear to be those with a “milder” form of SCD as 81% of patients had a genotype other than HbSS and the majority had no history of significant sickle-related complications. Human parvovirus B19 (HPV B19) infection was documented in 24% of cases.

Extensive bone marrow necrosis and sickle cell disease

A 24-years old Gabonese women with sickle cell disease had a severe vaso-occlusive crisis, which was treated by exchange transfusion. Then, she developed an extended bone marrow necrosis and needed repeated blood transfusion. The aim of this article is to relate an rare sickle cell disease complication.

Acute myeloid leukaemia with mutated NPM1 presenting with extensive bone marrow necrosis and Charcot–Leyden crystals

Here, we report an unusual case of acute myeloid leukaemia with mutated NPM1 presenting with pancytopenia and leukoerythroblastosis, without circulating blasts and bone marrow necrosis with numerous Charcot-Leyden crystals, but no eosinophilia.

Precursor T-cell acute lymphoblastic leukemia presenting with bone marrow necrosis: a case report

IntroductionBone marrow necrosis is a clinicopathological condition diagnosed most often at postmortem examination, but it is also seen during the course of malignancy and is not always associated with a poor prognosis. The morphological features of bone marrow necrosis are disruption of the normal marrow architecture and necrosis of myeloid tissue and medullary stroma. Non-malignant conditions associated with bone marrow necrosis are sickle cell anemia, infections, drugs (sulfasalazine, interferon α, all-trans retinoic acid, granulocyte colony-stimulating factor and fludarabine), disseminated intravascular coagulation, antiphospholipid antibody syndrome and acute graft versus host diseases. The malignant causes are leukemia, lymphoma and metastatic carcinomas. Herein we report the case of a patient with precursor T-cell acute lymphoblastic leukemia and bone marrow necrosis at initial presentation.Case presentationA 10-year-old Kurdish boy was presented with generalized bone pain and fever of 1 month’s duration which was associated with sweating, easy fatigability, nose bleeding, breathlessness and severe weight loss. On examination, we observed pallor, tachypnea, tachycardia, low blood pressure, fever, petechial hemorrhage, ecchymoses, tortuous dilated veins over the chest and upper part of abdomen, multiple small cervical lymph node enlargements, mildly enlarged spleen, palpable liver and gross abdominal distention. Blood analysis revealed pancytopenia and elevated lactate dehydrogenase and erythrocyte sedimentation rate. Imaging results showed mediastinal widening on a planar chest X-ray and diffuse focal infiltration of the axial bone marrow on magnetic resonance imaging of the lumbosacral vertebrae. Bone marrow aspiration and biopsy examination showed extensive bone marrow necrosis. Immunophenotyping analysis of the bone marrow biopsy confirmed T-cell acute lymphoblastic leukemia, as CD3 and terminal deoxynucleotidyl transferase markers were positive and CD10, CD20 and CD79a markers were negative.ConclusionThe aggressive initial clinical presentation of our patient with huge mediastinal widening, development of superior vein cava syndrome and extensive bone marrow necrosis as initial signs made the diagnosis of the case difficult. The necrotic hematopoietic cells gave inconclusive results on the initial immunohistochemistry tests. The prognosis of bone marrow necrosis is better secondary to acute lymphoblastic leukemia in the pediatric age group compared with adults and those with underlying solid tumors. Despite the aggressive behavior at initial presentation, the patient responded to chemotherapy and necrosis disappeared at day 28 after the start of the therapeutic regimen.

Microangiopathic Hemolytic Anemia as the First Manifestation of Metastatic Signet Ring Cell Carcinoma of Unknown Origin: A Case Report and Review of Literature

Microangiopathic hemolytic anemia (MAHA) occurs occasionally as a paraneoplastic syndrome in some solid tumors, but MAHA accompanied by signet ring cell carcinoma of an unknown origin is very rare. In this study, we present the case of an 80-yr-old man who was admitted to the hospital because of a 1-month history of lower back pain and dyspnea. He was diagnosed with MAHA on the basis of the laboratory findings that revealed anemia with schistocytes, decreased haptoglobin levels, and a negative direct Coombs' test. Bone marrow examination, which was performed because of the progression of anemia, revealed bone marrow metastases of signet ring cell carcinoma with extensive bone marrow necrosis. However, the primary origin of this signet ring cell carcinoma was not found. When the cause of progressive MAHA is unknown, the possibility of cancer-associated MAHA must be excluded by performing additional tumor workup, including the detection of tumor markers, gastric and colorectal endoscopic examinations, bone marrow examinations, and positron emission tomography-computed tomography or bone scans.

Iron Overload Accelerates Development of Leukaemia: Evidence From a Mouse Model

AbstractAbstract 122 Introduction:Transfusion-related iron overload is common in MDS. Iron catalyzes, via the Fenton reaction, excess production of reactive oxygen species (ROS), which are known to cause cell senescence and death, promote DNA damage and accelerate carcinogenesis. In addition to the well characterized effects of iron overload on the heart, liver, and endocrine organs, clinical data have suggested iron also causes haematopoietic toxicity in MDS, since iron chelation can lead to dramatic reduction in transfusion requirements and in large registry studies leukaemia-free survival is inversely related to serum ferritin. These observations have led to controversy since they are supported by no mechanistic or animal model data. Hypothesis:We have demonstrated that iron overload increases intracellular ROS (iROS) in early haematopoietic cells in MDS. We hypothesize that iron, via increased iROS, promotes accumulation of DNA damage in MDS HSCs and thus, in the context of the genomic instability of the MDS clone, accelerates progression of MDS to AML. Here we report the results of experiments that establish the biological and mechanistic plausibility of this hypothesis. Results:To establish that the B6D2F1 mouse model, which has been used in studies of cardiac and hepatic iron overload, is also a suitable model of bone marrow iron overload, mice (n=5 per cohort) were given iron dextran (0-150 mg i.p.) and sacrificed 3 days later. Severe weight loss was noted in the iron-loaded animals. Iron deposition was confirmed by Prussian Blue staining in the bone marrow, liver, myocardium, and the red pulp of the spleen.The cardiac effects of this degree of iron overload compromise survival, preventing assessment of longer-term effects of iron on haematopoiesis. We therefore evaluated the effects of lower doses of iron dextran (0, 5, 10, or 20 mg; n=5 per cohort) over 3 months. Increased iROS was seen in lineage negative (lin−) CD45+ bone marrow cells for animals that received 5 mg iron. However, iROS levels decreased progressively from the 10–20 mg treated animals, possibly representing an increase in apoptosis in early haematopoietic cells exposed to the greatest oxidative stress. Consistent with this, we observed increased apoptosis in early erythroid progenitors for the 20 mg iron treated animals (p<0.05).We adapted the chronic iron overload mouse model to evaluate the effect of iron overload on leukaemogenesis. B6D2F1 mice were sublethally irradiated (300 cGy) followed by s.c. injection of 0.5 mg dexamethasone, a protocol which induces a pre-leukaemic state leading, in SJL mice, to AML in 50–75% with a 12 month latency. These mice were then loaded with 0 or 5 mg I.P. iron dextran, n=6 per cohort). Three mice from each cohort were sacrificed and analyzed 3 months after iron loading. Expansion of the splenic white pulp was observed in iron loaded mice and flow cytometric analysis of the bone marrow cells revealed expansion of the lin− CD45+ early haematopoietic population. Furthermore, in one iron loaded mouse we observed a lin− CD45lo population with size and complexity similar to that of haematopoietic progenitors, suggesting blast accumulation. The remaining mice (n=3 per cohort) continued to be observed. One mouse in the iron loaded cohort died eight months after iron loading. Post-mortem examination revealed severe hepatomegaly and splenomegaly, massive splenic and hepatic infiltration by leukaemic blasts, and extensive bone marrow necrosis, fibrosis, and substantial blast accumulation.To establish a plausible mechanism for the promotion of leukaemia development by iron, we tested the ability of iron to cause DNA damage in a haematopoietic cell line. HL60 cells line were treated with ferric ammonium sulfate (10 or 100 μ M) and DNA damage was assessed by flow cytometry for γH2AX, an indicator of DNA double-strand breaks. Elevated γH2AX was observed in HL60 cells 2 hours after iron loading, and sustained DNA damage was noted till the end of the experiment at day 4. Conclusions:Our observations demonstrate that iron is mutagenic in haematopoietic cells and can promote progression of a pre-leukaemic state to frank AML. We postulate that iron is not itself leukaemogenic, but, by causing DNA damage, promotes clonal evolution in MDS. Further evaluation in animal models and in clinical trials is necessary to elucidate the clinical implications of these observations, especially in regard to the deployment of iron chelation therapy. Disclosures:No relevant conflicts of interest to declare.

Severe Extensive Bone Marrow Necrosis From Miliary Tuberculosis Without Granulomas and Pulmonary Presentations

Bone marrow necrosis (BMN) is a rare clinicopathologic entity caused by hypoxemia after failure of the microcirculation, which frequently manifests with bone pain, fever, and peripheral cytopenia. In most reported cases of BMN resulting from miliary tuberculosis (TB), the presence of marrow granulomas, pulmonary infiltrates and/or extrapulmonary involvement is common. We report a female patient with extensive BMN from miliary TB, whose initial presentation was only severe peripheral cytopenia with extensive marrow necrosis, with neither evident pulmonary manifestations nor granulomas in the marrow biopsy. Serial Ziehl-Neelsen stains and Mycobacterium tuberculosis cultures were negative. The diagnosis of suspected miliary TB was made by consecutive positive results from polymerase chain reaction analysis for TB of marrow samples at 2 separate examination time points and a good treatment response to anti-TB therapy. Magnetic resonance imaging showed a geographic pattern of multiple signal abnormalities, indicating bone infarcts over the bilateral iliac bones and T-L-spine vertebral bodies, compatible with extensive BMN. The unusual presentation of extensive BMN with severe peripheral cytopenia in the absence of granulomas or pulmonary presentations should alert clinical physicians in epidemic areas. We discuss the use of polymerase chain reaction analysis for TB and magnetic resonance imaging for diagnosis of these patients.

Extensive Bone Marrow Necrosis with Recovery

Extensive Bone Marrow Necrosis with Recovery

Letter to the Editor

Letter to the Editor

The 3-week sulphasalazine syndrome strikes again

A 34-year-old lady developed a constellation of dermatitis, fever, lymphadenopathy and hepatitis, beginning on the 17th day of a course of oral sulphasalazine for sero-negative rheumatoid arthritis. Cervical and inguinal lymph node biopsies showed the features of severe necrotising lymphadenitis, associated with erythrophagocytosis and prominent eosinophilic infiltrates, without viral inclusion bodies, suggestive of an adverse drug reaction. A week later, fulminant drug-induced hepatitis, associated with the presence of anti-nuclear autoantibodies (but not with other markers of autoimmunity), and accompanied by multi-organ failure and sepsis, supervened. She subsequently died some 5 weeks after the commencement of her drug therapy. Post-mortem examination showed evidence of massive hepatocellular necrosis, acute hypersensitivity myocarditis, focal acute tubulo-interstitial nephritis and extensive bone marrow necrosis, with no evidence of malignancy. It is thought that the clinico-pathological features and chronology of this case bore the hallmarks of the so-called “3-week sulphasalazine syndrome”, a rare, but often fatal, immunoallergic reaction to sulphasalazine.

Membranous Obstruction of the Inferior Vena Cava and Extensive Bone Marrow Necrosis Associated with Catastrophic Antiphospholipid Syndrome

The catastrophic antiphospholipid syndrome is a rare and devastating manifestation of the antiphospholipid syndrome. It is associated with acute multi-organ failure involving three or more end organs in patients with antiphospholipid antibodies. A precipitating event can be found in some cases, and mortality rates have approached 60%. This article describes a case of catastrophic antiphospholipid syndrome in a patient who presented with Budd-Chiari syndrome from membranous obstruction of the inferior vena cava and extensive bone marrow necrosis shortly after a surgical procedure. These and other clinical manifestations of multi-organ failure (including low-grade disseminated intravascular coagulation) were associated with high titers of immunoglobulin M anticardiolipin antibodies. The patient fully recovered after being treated with percutaneous transluminal angioplasty and aggressive anticoagulation. The pathogenesis of catastrophic antiphospholipid syndrome in this patient may well have resulted from in situ thrombus formation around an intravascular coagulation web (congenital or acquired) from a patient predisposed to a hypercoagulable state from anticardiolipin antibodies and a recent surgical procedure.