scholarly journals A rare case of pancytopenia in a child with cystic fibrosis: Can copper cure it all?

2021 ◽  
Author(s):  
Maggie Seblani ◽  
Susanna McColley ◽  
Shawn Gong ◽  
Lee Bass ◽  
Sherif Badawy
Keyword(s):  
Cystic Fibrosis ◽  
Bone Marrow ◽  
Copper Deficiency ◽  
Intestinal Resection ◽  
Serum Copper ◽  
Nutritional Deficiencies ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Copper Supplementation ◽  
Treatment Considerations

Nutritional deficiencies such as iron, vitamin B12 and folate are recognized as etiologies for several cytopenias; although copper’s role in multiple metabolic enzymes is well-established, copper deficiency is often overlooked as a contributing entity. Frequently diagnosis is delayed, patients may undergo bone marrow investigations with findings overlapping a myelodysplastic process, which can lead to further testing and treatment considerations including hematopoietic stem cell transplant referral. We present a case of a young boy with cystic fibrosis with biliary dysplasia corrected with hepato-portoenterostomy and distal intestinal obstruction syndrome resulting in jejunal resection, with severe anemia and thrombocytopenia requiring transfusion support. Initial evaluation had been unremarkable, ongoing pancytopenia prompted bone marrow studies, which revealed vacuolated granulocytic and erythroid precursors and ring sideroblasts, suggestive of copper deficiency. Serum copper and ceruloplasmin were consistent with severe deficiency, attributed to insufficient absorption intestinal resection, chronic parenteral nutrition and prior zinc supplementation. Following enteral copper supplementation, anemia, leukopenia and thrombocytopenia significantly improved, however upon cessation, counts again worsened and has since been maintained on daily copper supplementation without further transfusion needs. Our experience exemplifies the importance of early consideration for copper deficiency in children with cytopenias, especially within context of intestinal malabsorption or inadequate nutritional intake which often occurs in children with cystic fibrosis.

scholarly journals Pancytopenia in a child with cystic fibrosis and severe copper deficiency: Insight from bone marrow evaluation

2021 ◽  
Author(s):  
Maggie D. Seblani ◽  
Susanna A. McColley ◽  
Shunyou Gong ◽  
Lee M. Bass ◽  
Sherif M. Badawy
Keyword(s):  
Cystic Fibrosis ◽  
Bone Marrow ◽  
Copper Deficiency ◽  
Bone Marrow Evaluation

scholarly journals The Platelet Millionaire: A Rare Cause of Thrombocytosis in an Adolescent

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5391-5391
Author(s):  
Ritika Walia ◽  
Theresa Sepulveda ◽  
Sharon Wretzel ◽  
Philip H Brandt
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Biopsy ◽  
Primary Care Physicians ◽  
Conflicts Of Interest ◽  
Abdominal Ultrasound ◽  
Cell Transplant ◽  
Peripheral Smear ◽  
Hematopoietic Stem ◽  
Marrow Fibrosis

Objectives: Primary myelofibrosis is rare in pediatrics, often manifesting as persistent idiopathic thrombocytosis.Transitions from pediatric to adult medical care can be complicated by workup requiring invasive procedures. J.M., an 18-year-old healthy male, presented for excessive gingival bleeding after wisdom tooth extraction. Workup revealed persistent thrombocytosis to 1,165K, prompting a referral to hematology-oncology. A peripheral smear was notable for many platelets but normal RBC morphology. He had splenomegaly on abdominal ultrasound and a decreased von-Willebrand's activity to antigen ratio, suggesting acquired vWD. A bone marrow biopsy was advised; however, J.M. became lost to follow up for over 9 months owing to self-reported anxiety about the procedure. He remained asymptomatic in this interim until he re-presented to clinic for easy bruising, with no other evidence of bleeding at the time. The biopsy was pursued, revealing hypercellular marrow for age with left shifted granulocytic and erythroid maturation, abnormal megakaryocytes, and 3% blasts. This was consistent with primary early myelofibrosis (PMF), positive for MF-1, CALR, and TP53 mutations and negative for JAK2 and BCR-ABL. He was transitioned to adult hematology, maintained on baby aspirin, and referred for potential allogeneic hematopoietic stem cell transplant (HSCT). PMF is characterized by marrow fibrosis due to secretion of fibroblast growth factor by clonally proliferative megakaryocytes. It is a disease of adulthood, with 67 years being the median age at diagnosis. Only 100 cases have been reported in children, most of which are secondary to AML, ALL or other malignancies.1 Most patients present with complications of extramedullary hematopoiesis or bleeding.2 Diagnosis is suggested by a leukoerythroblastic picture on peripheral smear and confirmed with a bone marrow biopsy "dry tap" revealing marrow fibrosis.3 Prognosis in pediatric PMF is difficult to predict but outcomes tend to be worse;4 TP53 mutation is rare and based on limited adult studies may portend a poorer prognosis.5 Our young patient with this rare mutation was therefore referred for HSCT evaluation. Further complicating this case was J.M.'s anxiety, which delayed definitive diagnosis by biopsy. He only agreed to it when, at the med-peds clinic, the concept of local pain management was discussed. Anticipation of upcoming procedures by primary care physicians and close follow-up is especially important for patients transitioning from pediatric to adult providers. Disclosures No relevant conflicts of interest to declare.

Platelet Release Occurs in the Bone Marrow Sinusoids and Spleen but Not in the Lungs Following Hematopoietic Stem Cell Transplant in the Mouse.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1710-1710
Author(s):  
Deanna Kreinest ◽  
Martha Sola ◽  
Xiao-Miao Li ◽  
Ronald Sanders ◽  
Marda Jorgensen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Platelet Release

Abstract The steps that lead to platelet production are poorly understood. Current theories suggest that megakaryocytes mature under the influence of contact with sinusoidal endothelium, and release platelets either in the sinusoids or in the lungs. We hypothesized that platelet release would be accentuated following hematopoietic stem cell transplant, and that sites of platelet release would be apparent during the period of platelet recovery. We transplanted highly purified hematopoietic stem cells based on lack of expression of markers for mature lineages (Linneg) and expression of Sca-1, c-kit, and Thy-1.1 (KTSL cells), and subfractionated these cells based on low expression of Rhodamine 1-2-3, into lethally irradiated hosts expressing an allelic version of glucose phosphate isomerase to identify donor and host-derived platelets. We collected bones, lungs, livers and spleens on day 7, 14, 21, and 28 post-tranplant, and stained formalin/fixed tissue with anti-Von Willebrand Factor antibody to identify megakaryocytes (5–10 animals per cohort, 2 separate experiments). We scored megakaryocytes based on their location relative to endothelial cells, and whether they were releasing platelets based on extension of proplatelet processes into the vascular spaces. Almost every megakaryocyte was associated with the endothelium during the period of platelet recovery, and we did not identify megakaryocytes that were migrating to the endothelium. We saw numerous megakaryocyte releasing platelets in both the bone marrow and the spleen during the time of platelet recovery, which occurred on days 13–28 following transplant of purified stem cells. Some of these megakaryocytes had disrupted the endothelium and were incorporated into the sinusoidal wall. Others were completely within the sinusoidal spaces. Between 30 and 50% of megakaryocytes were releasing platelets in the spleen and bone marrow at any given time following transplant, and platelet release did not correlate with the platelet counts. These levels were similar to levels of platelet release seen in healthy control mice. In contrast, we saw no identifiable megakaryocytes in the liver and lung during the period of platelet recovery. Our results suggest that in the mouse, the bone marrow and spleen, and not the lung, are major sites of platelet release following stem cell transplant.

The Role of Telomerase Activity and Telomere Length in Cellular Sensitivity to DNA Damaging Agents.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4192-4192
Author(s):  
Greg T. Rice ◽  
Michael A. Beasley ◽  
Ike I. Akabogu ◽  
Erik R. Westin ◽  
Dale A. Winnike ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Telomere Length ◽  
Bone Marrow Failure ◽  
Skin Pigmentation ◽  
Cytotoxic Agents ◽  
Cell Surface Expression ◽  
Cell Transplant ◽  
Telomere Shortening ◽  
Hematopoietic Stem ◽  
Increased Sensitivity

Abstract Dyskeratosis congenita (DC) is a premature aging syndrome characterized by progressive bone marrow failure, abnormal skin pigmentation and nail dystrophy. We have described an autosomal dominant form of DC (AD DC) in a large three-generation kindred that is due to a mutation in the gene encoding human telomerase RNA (hTR). While telomere shortening is a normal consequence of the aging process, DC patients display extremely short telomeres in many somatic cell types, including hematopoietic cells, and they often suffer from bone marrow failure. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy for marrow failure in DC. However, HSCT in DC is generally poorly tolerated and associated with significant morbidity, perhaps as a consequence of increased sensitivity of dividing cells to cytotoxic agents during myeloablative therapy. To test this hypothesis, we characterized lymphocytes from various AD DC patients and age matched controls that had been placed in long term culture following in vitro exposure to irradiation (137Cs) and varying doses of Taxol, Adriamycin, and Etoposide. Cell proliferation and viability were quantified by direct visual counting on a hemocytometer, and flow cytometry was employed to assess apoptosis and cell surface expression of senescent markers. In addition to DC lymphocytes having a decreased proliferative capacity and higher basal apoptotic levels, an increased sensitivity to irradiation, Taxol, Adriamycin, and Etoposide was noted. These results suggest that telomere shortening may be an important factor in determining cellular tolerance to cytotoxic therapy and support the concept of reduced intensity HSCT regimens in both aged individuals and DC patients. Further studies have been initiated to determine whether reconstitution of telomere length in DC cells alters response to cytotoxic agents.

Excelent Option Therapy of BONE Marrow Failure in Fanconi Anemia Patients Withouth Full Match Donnor

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5075-5075 ◽  
Author(s):  
Lisandro L Ribeiro ◽  
Samantha Nichele ◽  
marco Antonio Bitencourt ◽  
Ricardo Petterle ◽  
Gisele Loth ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Hematological Parameters ◽  
Severe Neutropenia ◽  
Cell Transplant ◽  
Variable Degree ◽  
Duration Of Treatment ◽  
Hematopoietic Stem ◽  
Hematological Response

Abstract The main cause of morbidity and mortality of FA pts is bone marrow failure (BMF), which usually arises in the first decade of life and progresses to transfusion dependence and severe neutropenia. Androgen treatment has been recommended for FA pts with BMF for whom there is no acceptable hematopoietic stem cell transplant donor. Oxymetholone and Danazol are frequently used in these pts. We retrospectively analyzed data on 67 FA pts who received oxymetholone or danazol for the treatment of their BMF. The starting dose was approximately 1mg/kg for oxy and 2-4mg/kg for danazol. The hematological parameters at the initiation of treatment were hemoglobin (Hb) < 8 g/dL and/or thrombocytes < 30.000/μl. Patients were diagnosed between 01.2005 and 01.2016. The median age was 10.5 ys (2.9 - 40ys). Gender: 39M/27F. The median duration of treatment was 18m (3m - 95m). Fifty-three patients (79%) showed hematological response and became transfusion independence at a median of 3 months after beginning oxymetholone (2-9m) and 5 months after danazol (4-7m). Two adult pts treated with danazol achieved total hematological response with 2.5mg/kg. Seven pts are stable after tapering and stopping androgen with a median follow up of 4 ys (6m-8.5ys). Fourteen pts did not respond to treatment (21%). Eleven pts received an HSCT and seven are alive and well. Three pts were not transplanted and two are alive but transfusion dependent and one pt died from CNS bleeding. All patients developed variable degree of virilization but it was more evident with oxymetholone therapy. Older age at starting therapy was related to less virilization. Conclusion: This study shows the largest number of FA pts treated with androgen up till now. Androgen is an effective and well-tolerated treatment option for FA pts who develop BMF with 79% of them showing transfusion free after 3-5 months. This response may give us time to search for better donors. Disclosures No relevant conflicts of interest to declare.

scholarly journals Plasma EDA Fibronectin in Primary Myelofibrosis Correlates with Bone Marrow Fibrosis and Predicts Splenomegaly

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1688-1688
Author(s):  
Alessandro Malara ◽  
Cristian Gruppi ◽  
Margherita Massa ◽  
Vittorio Rosti ◽  
Giovanni Barosi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Costal Margin ◽  
Cell Transplant ◽  
Healthy Controls ◽  
Hematopoietic Stem

Introduction: Primary myelofibrosis (PMF) is a Philadelphia chromosome negative myeloproliferative neoplasm with adverse prognosis characterized by bone marrow (BM) fibrosis and extramedullary hematopoiesis. Fibronectin (FN) is an extracellular matrix glycoprotein that plays vital roles during tissue repair and regeneration. It exists in different forms. Plasma FN is synthesized by hepatocytes and secreted into the blood plasma, where circulates at a concentration of 300-600 μg/ml in a soluble, compact form. Differently, cellular FN is synthesized by several cell types, such as fibroblasts, endothelial cells, chondrocytes and myocytes. The alternative splicing of EDA and EDB and more complex splicing of the V domain, during transcription of FN1 gene, allows different isoforms of FN to be expressed in a tissue-dependent and temporally regulated manner. Very low levels (1.3-3 μg/ml) of FN containing EDA and/or EDB are present in plasma. Although its function is not well understood, EDA containing FN (EDA-FN) is known to agonize Toll like receptor 4 (TLR4), resulting in NF-κβ-dependent cytokine release; to induce myofibroblast differentiation during wound healing; and to increase agonist-induced platelet aggregation and thrombus formation in vivo. We previously showed that EDA-FN levels are increased in plasma and BM biopsies of PMF patients. Mechanistically, BM EDA-FN sustains megakaryocyte proliferation through TLR4 binding and confer a pro-inflammatory phenotype to cell niches promoting fibrosis progression in Romiplostim-treated mice. In this work we measured the plasma levels of EDA-FN in 104 well characterized patients with PMF to determine whether elevated levels of EDA-FN predict the occurrence of disease-related events. Methods: Plasma circulating EDA FN was measured with an enzyme linked immunosorbent assay developed at the University of Pavia, by our group. We obtained plasma EDA-FN concentration values and health care data of persons with PMF from the data-base of the Centre for the Study of Myelofibrosis at the IRCCS Policlinico S. Matteo Foundation in Pavia. We sequentially excluded persons treated with disease-modifying drugs at any time before or on the date of base-cohort entry, and those who had been splenectomized or had received a stem cell transplant. We also excluded persons with acute inflammatory diseases, autoimmune diseases, other neoplasms, and severe liver or renal dysfunction. For this study we selected everyone giving written informed consent and the study was approved by the local Ethic Committee. Immunofluorescence was performed on spleen sections from PMF patients who underwent splenectomy either because of anemia or symptomatic splenomegaly, or both; and healthy controls that were splenectomized following traumatic lesion of the spleen. Data were analyzed using STATISTICA software. Results: A homozygous JAK2V617F genotype was the major determinant of elevated plasma EDA-FN. Elevated EDA-FN levels were associated with anemia, increased levels of high-sensitivity C-reactive protein, BM fibrosis and splanchnic vein thrombosis at diagnosis. We interpreted these associations as reflecting the role EDA-FN plays in tissue remodeling, inflammation and vascular injury. Interestingly, EDA-FN levels resulted also associated with spleen size, and elevated levels of EDA-FN at diagnosis predicted large splenomegaly (more than 10 cm from the left costal margin) outcome. The evidence that plasma EDA-FN levels were not associated with the CD34+ hematopoietic stem cells mobilization, drove us to hypothesize that EDA-FN could reflect spleen endothelial cell activation and/or neoangiogenesis. Immunofluorescence analysis of spleen specimens from PMF patients and healthy controls revealed that high levels of EDA-FN were present in pathological spleens in strong association with endothelial neoangiogenesis. Conclusions: Quantification of EDA-FN level in PMF strongly correlates with BM fibrosis and may be the first marker of an altered spleen microvasculature that contributes to splenomegaly. Understanding the role of this FN isoform in PMF would be useful for testing new mechanisms of disease progression and new hypotheses about the treatment of splenomegaly in PMF. Disclosures No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation for Children and Adolescents with Acute Myeloid Leukemia in Brazil: A Multicentric Retrospective Study

2020 ◽  
Vol 29 ◽  
pp. 096368972094917
Author(s):  
Ana Luiza de Melo Rodrigues ◽  
Carmem Bonfim ◽  
Adriana Seber ◽  
Vergilio Antonio Rensi Colturato ◽  
Victor Gottardello Zecchin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Acute Myeloid

The survival rates of children with high-risk acute myeloid leukemia (AML) treated with hematopoietic stem cell transplant (HSCT) range from 60% to 70% in high-income countries. The corresponding rate for Brazilian children with AML who undergo HSCT is unknown. We conducted a retrospective analysis of 114 children with AML who underwent HSCT between 2008 and 2012 at institutions participating in the Brazilian Pediatric Bone Marrow Transplant Working Group. At transplant, 38% of the children were in first complete remission (CR1), 37% were in CR2, and 25% were in CR3+ or had persistent disease. The donors included 49 matched-related, 59 matched-unrelated, and six haploidentical donors. The most frequent source of cells was bone marrow (69%), followed by the umbilical cord (19%) and peripheral blood (12%). The 4-year overall survival was 47% (95% confidence interval [CI] 30%–57%), and the 4-year progression-free survival was 40% (95% CI 30%–49%). Relapse occurred in 49 patients, at a median of 122 days after HSCT. There were 65 deaths: 40 related to AML, 19 to infection, and six to graft versus host disease. In conclusion, our study suggests that HSCT outcomes for children with AML in CR1 or CR2 are acceptable and that this should be considered in the overall treatment planning for children with AML in Brazil. Therapeutic standardization through the adoption of multicentric protocols and appropriate supportive care treatment will have a significant impact on the results of HSCT for AML in Brazil and possibly in other countries with limited resources.

Outcomes of Patients with Engraftment Syndrome (ES) Following Nonmyeloablative Hematopoietic Stem Cell Transplant (SCT) for Hematologic Malignancy(HM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3661-3661 ◽  
Author(s):  
Erica Linden ◽  
Steven L. McAfee ◽  
Bimalangshu R. Dey ◽  
Karen Ballen ◽  
Susan Saidman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Weight Gain ◽  
Pulmonary Edema ◽  
Renal Dysfunction ◽  
Acute Gvhd ◽  
Hepatic Dysfunction ◽  
Mixed Chimerism ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Donor Chimerism

Abstract ES may accompany hematologic recovery following SCT and is characterized by fever and rash, in addition to one of the following clinical syndromes: noncardiogenic pulmonary edema, hepatic dysfunction, renal dysfunction, weight gain, or transient encephalopathy. A retrospective analysis was performed to evaluate the incidence of ES using a published clinical definition (Spitzer TR, Bone Marrow Transplant2001; 27:893–898), the use of corticosteroids in the peri-engraftment period, the relationship of ES to the development of GVHD, and the fate of the patient’s chimerism. Seventy-three patients with a HM (NHL, n=45; HD, n=9; AML, n=6; ALL, n=1; CLL, n=6; MDS, n=1; MM, n=4) who were treated with a nonmyeloablative conditioning regimen consisting of cyclophosphamide, antithymocyte globulin, thymic irradiation, cyclosporine, and hematopoietic SCT (bone marrow, n =57; peripheral blood stem cells, n =15) were analyzed. Chimerism was assessed weekly for the first 100 days, then q6 months by VNTR/STR analysis and/or flow cytometry. In the absence of full donor chimerism (FDC) or evidence of acute GVHD, donor leukocyte infusions (DLI) were given beginning 5 weeks post-transplant to convert mixed chimerism (MC) to FDC and thus maximize a graft-versus-tumor effect. Thirty-five (50%) patients met the clinical definition of ES, presenting with fever and rash (100% of ES patients), hepatic dysfunction (74.3%), fluid retention/weight gain (60%), noncardiogenic pulmonary edema (22.9%), renal dysfunction (22.9%), and transient encephalopathy (5.7%). Three (4.1%) patients never engrafted and thus were censored from the population. Median time to engraftment was 13 (range 9 to 18) days in ES patients and 14 (range 9 to 21) days in non-ES patients. The incidence of significant (≥ grade II) aGVHD was 45.7% in ES patients versus 22.9% in non-ES patients. The incidence of chronic GVHD was similar in both groups (63.6% in ES patients vs. 68.0% in non-ES patients). Loss of donor chimerism (LDC) was seen at a lower rate in ES patients (15.2%) vs. non-ES patients (36.4%). Conversely, full donor chimerism (FDC) was higher in ES patients (48.5%) versus non-ES patients (36.4%). Corticosteroids were administered based on clinical suspicion of ES. Thirty two (91.4%) of ES patients and nineteen (54.3%) of non-ES patients received steroids. Resolution of clinical abnormalities occurred in twenty seven (84.4%) of ES patients and eighteen (94.7%) of patients who did not fulfill the criteria for ES. In conclusion, patients with ES had a higher propensity to develop clinically significant acute GVHD, suggesting that ES may represent early GVHD. However, those who developed LDC and ES had indistinguishable clinical presentations of their ES. Thus, ES represents heterogeneous populations of patients with diverse immunologic alloreactivity (either GVH or HVG reactivity). The high incidence of ES (and of both GVHD and LDC) in this population of patients suggests that competing GVH and HVG alloreactivity following nonmyeloablative conditioning (and in all likelihood the occurrence of a “cytokine storm”) might be responsible for the clinical manifestations of this syndrome.

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