Survival of 83 AA patients, aged 14 to 40 years, treated with ISA was not statistically significant from that of 61 adult AA patients who underwent BMT (6-year survival rate, 65% and 79%, respectively). Chiu ML, Hsu YL, Chen CJ, Li TM, Chiou JS, Tsai FJ, Lin TH, Liao CC, Huang SM, Chou CH, Liang WM, Lin YJ. Such an approach, if successful in AA, would extend the indication spectrum of BMT for older patients. Infusion of haploidentical hematopoietic stem cells combined with mesenchymal stem cells for treatment of severe aplastic anemia in adult patients yields curative effects. Immunoregulatory cytokine polymorphisms in Italian patients affected by paroxysmal nocturnal haemoglobinuria and aplastic anaemia. Aplastic anemia is a rare but potentially life-threatening disease that may affect older patients. Your risk increases if you: Are exposed to toxins Take certain medicines Have a disease such as hepatitis or HIV What are the symptoms of aplastic anemia? Clearly, the diagnosis of inherited bone marrow (BM) failure is of most significance in pediatric AA, but appropriate testing may also be indicated in younger adults, given that genetic factors may constitute a propensity to develop the disease even in non-pediatric patients. Anemia, aplastic. Flow cytometry should be used to rule out lymphoproliferative syndromes such as large granular lymphocytic (LGL) leukemia as well as occult lymphoid malignancies, especially hairy cell leukemia, which can mimic AA. Unable to load your collection due to an error, Unable to load your delegates due to an error. Int J Gen Med. Jaiswal et al. Aplastic anemia is a rare but serious disorder. In children, a better outcome was reported for those patients who were transplanted following the initial ATG failure.25 In addition to repeated ATG courses, new agents such as Campath-1H or anti-CD3 mAb could be used in the context of a clinical trial. The disorder tends to get worse over time, unless its cause is found and treated. The survival rate is higher for younger people. Fanconi anemia is different from Fanconi syndrome, a rare kidney disorder. Delaying BMT may decrease the chance of its success, but this concern is not well supported in adults,26 and high treatment-related mortality of BMT in older patients may justify all attempts at remission induction. Symptoms result from anemia, thrombocytopenia (petechiae, bleeding), or leukopenia (infections). Clearly, children and young adults with a matched sibling donor should be offered BMT as a first therapeutic option. Your body may reject the transplant, leading to life-threatening complications. acquired aplastic anemia is that a dysregulated immune system destroys HPSCs. In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation. Multicenter prospective study of clonal complications in adult aplastic anemia patients following recombinant human granulocyte colony-stimulating factor (lenograstim) administration. There are different forms of sideroblastic anemia, and all forms are defined by the presence of ring sideroblasts in the bone marrow. We offer novel therapies, participate in . There are between 300-600 new cases of aplastic anemia in the United States each year. Refractory anemias. Novel immunosuppressive and immunomodulatory agents and constantly improving results of allogeneic BMT will further improve the survival rate of adult patients with AA. . In: Ferri's Clinical Advisor 2020. Earlier in pregnancy, supportive measures are most commonly used, but ATG has been also administered to women with severely depressed counts, especially low ANC. myelodysplasi; a Aplastic Anemia MUST KNOW THAT CARBAMAZEPINE CAN CAUSE APLASTIC ANEMIA. Only a sufficient observation period (> 3 months) with chronically and not progressively depressed counts warrants the diagnosis of moderate AA. High-dose cyclophosphamide has been suggested to provide an IS modality that prevents subsequent relapses. Young Adults GVHD Patient - Support Group ; Products . In a study involving 98 children and adults with aplastic anemia, . The overall incidence of UC appears to be on the decline, but death rates have remained stable.1,2 Stage IV metastatic disease is associated with only a 5% survival rate at 5 years.2 Gemcitabine . Mortality rate is 51% In one non-randomized study 6-year survival was 69% and 79% for IS and BMT, respectively.18 Comparable survival was obtained for older adults when the data from the European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia (WPSAA) were analyzed.19. Aplastic anemia affects males and females equally. Some patients will show an improvement of neutropenia with G-CSF, but severe neutropenia due to typical AA is mostly refractory. The most common IS regimens combine horse (ATGam at 20 mg/kg per day for 4 days) or rabbit ATG (Thymoglobulin at 3.5 mg/kg per day for 5 days) with CsA (1215 mg/kg in a divided dose bid) given usually for 6 months. See this image and copyright information in PMC. For those who received an allogenic bone marrow transplant, it was 62%. It remains unclear whether AA patients who developed PNH did have minor PNH clones detectable at presentation or whether their PNH developed truly de novo. According to the National Cancer Institute, the percentage of deaths by age group is as follows: Kojima S, Inaba J, Yoshimi A, et al. Socie G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli A. Horowitz MM. Haematologica. Aplastic anemia may appear at any age but is diagnosed more often in children and young adults. Hematology/Oncology Clinics of North America. Transfused red blood cells contain iron that can accumulate in your body and can damage vital organs if an iron overload isn't treated. among older adults,15 correlating with . Before The overall five-year survival rate is about 80% for patients under age 20 . Why?. Therapeutically, this distinction may not be essential, as responses to immunosuppression (IS) have been reported in patients with abnormal cytogenetics in the context of MDS as well as AA. Front Pharmacol. The procedure requires a lengthy hospital stay. Estimates vary, but between 1.5 and about seven cases are diagnosed per million people each year. Young NS, Kaufman DW. However, prolonged cytopenia resulted in excessive toxicity related to neutropenic complications in randomized trials between ATG/CsA and cyclophosphamide/CsA, resulting in a termination of the trials.23 Long-term follow-up of patients treated with cyclophosphamide showed that relapse and clonal disease can occur after this type of therapy.23 It seems that high-dose cyclophosphamide does not constitute advancement over ATG/CsA and should be used only in very selected cases or as a part of a controlled experimental trial with a narrowly defined indication spectrum. Up to 90% of those who are diagnosed with this disease will get better. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Aplastic anemia is a heterogeneous disease, with great diversity in possible causes. The MDS are a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias. Selected results of immunosuppression with antithymocyte globulin (ATG) + cyclosporine (CsA) for aplastic anemia (AA).14,17,19. It has been hypothesized that the autoimmune attack responsible for the stem cell depletion in AA generates permissive conditions under which an otherwise dormant PNH clone can evolve, as the stem cells may show differential insensitivity to T cell-mediated inhibition of stem cell function.10 Patients with AA in whom a PNH clone has been identified can be classified as having AA/PNH syndrome. Olson TS. [35] Survival rates for stem cell transplants vary depending on the age and availability of a well-matched donor. What's the most likely cause of my symptoms? . Frank dysplasia was observed in a large proportion of patients, but in many patients there were no morphologic changes suggestive of MDS.33 While the entity of AA with cytogenetic abnormalities may exist, the new appearance of an abnormal clone in the course of AA warrants the change of diagnosis from AA to MDS. fever. In the U.S., the overall five-year survival rate for patients diagnosed with lung cancer is 25%, which is a 21% improvement over the last five years. 2013 Jul 23;2013(7):CD006407. Am J Med Sci. Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia. -, Kaufman DW, Kelly JP, Jurgelon JM, et al. Flow cytometric analysis of red cells and granulocytes should be performed to establish the presence of a PNH clone. Aplastic anemia is a rare but serious blood condition that occurs when your bone marrow cannot make enough new blood cells for your body to work normally. Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS. The symptoms of hemorrhagic diathesis and the tendency to infection with a serious outcome is usually observed. This latter condition may not become clinically obvious until adulthood and shows a variable penetrance. Accessed Nov. 16, 2019. 1 Over the past years, bone marrow transplantation. The presence of PNH clones has been associated with a good response to IS. As a normal karyotype common in MDS and some elderly cases of AA may represent misdiagnosed MDS, clues to the recognition of MDS include micromegakaryocytes, myeloid dysplasia and residual blasts. Choudhry VP, Gupta S, Gupta M, Kashyap R, Saxena R. Pregnancy associated aplastic anemiaa series of 10 cases with review of literature. HHS Vulnerability Disclosure, Help Aplastic; anemia. At least one third of patients with AA will harbor PNH clones of various sizes.3 It is likely that some of these patients may develop clinically significant PNH in the course of their disease, but the factors determining this complication remain unknown. A stem cell transplant carries risks. Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. In addition, it is more common in Asian Americans. 1987;70(6):17181721. Wang H, Chuhjo T, Yasue S, Omine M, Nakao S. Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome. Fermo E, Bianchi P, Barcellini W, et al. There are two types of aplastic anemia: Inherited aplastic anemia occurs because of a random gene mutation. Make a donation. Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition. There is controversy as to the cut-off values used for the flow cytometric diagnosis of the PNH clones, and some investigators believe that, by using the proper technology, even very tiny PNH clones can be identified and have prognostic value.4 Of note is that PNH clones have been found also in apparently healthy individuals.5, Several novel tests may be helpful in assessment of immune responsiveness. G-CSF in combination with other agents has been used as salvage therapy in the refractory setting and their prolonged administration has been associated with recovery of counts in some patients. Aplastic anemia. So far a systematic experience in AA has not been published; however, historically conditioning regimens utilized for AA patients undergoing BMT have been less intense than those adopted for patients with malignancy. Careers. However, in many reports, cases of AA with abnormal cytogenetics have often been included. Copyright 2023 by American Society of Hematology, Clinical Features of Aplastic Anemia in Adults, https://doi.org/10.1182/asheducation-2005.1.110, Abbreviations: ANC, absolute neutrophil count; ARC, absolute reticulocyte count; MAA, moderate AA, ARC < 40,000/L in anemic/tranfusion-dependent patients, Diagnosis of chronic MAA requires persistent moderately depressed counts > 3 months, Abbreviations: Dx, diagnosis; SAA, severe AA; MAA, moderate AA; ALG, antilymphocyte globulin; CsA, cyclosporine; ATG, antithymocyte globulin; G-CSF, granulocyte colony-stimulating factor, Abbreviations: mAb, monoclonal antibody; TNF, tumor necrosis factor; IFN, interferon, Abbreviations: TAI, thoracoabdominal irradiation; Cy, cyclophosphamide; ATG, antithymocyte globulin; GVHD, graft-versus-host disease; CsA, cyclosporine; MTX, methotrexate, 59% at 16 y for TAI/Cy 95% at 4.4 y for ATG/Cy, 89% at 20 y without GVHD 69% at 20 y with GVHD, Actuarial survival 77% for patients 68% for patients 1740 y 54% for patients > 40 y, 94% at 8 y with CsA/MTX 78% at 7 y with CsA, 5 y survival: 75% for patients 20 y 68% for patients 2040 y 35% for patients > 40 y. Most experts believe that the presence of karyotypic abnormalities at presentation is only consistent with the diagnosis of MDS. In primary MDS, the proportion of patients with a normal karyotype is 40%60%, and by analogy, it is possible that also in post-AA, MDS can evolve without an overt chromosomal change. Aplastic anemia (AA) is a rare disease occurring in all age groups but with two peak incidences from 10 to 20 years and over 60 years. Causes of treatment failure and relapse in aplastic anemia. eCollection 2021. Cochrane Database Syst Rev. Conceptually, in analogy to the therapy of malignant disorders, intense IS with ATG may be viewed as induction treatment, which may require a prolonged maintenance period with CsA or even the reinduction. This rare, life-threatening anemia occurs when your body doesn't produce enough red blood cells. Bacigalupo A, Brand R, Oneto R, et al. 2020 Jan 14;41(1):80-83. doi: 10.3760/cma.j.issn.0253-2727.2020.01.016. Evolution of clonal hematopoietic diseases such as PNH and MDS has been recognized as a serious late complication in conservatively treated patients. Overall survival rates at day 180 post transplant were 98% for patients treated with abatacept and standard of care compared with 75% for those treated with standard of care only. The .gov means its official. and survival in severe aplastic anemia. Mild or moderate aplastic anemia may not need immediate treatment. Gerull S, Stern M, Apperley J, Beelen D, Brinch L, Bunjes D, Butler A, Ganser A, Ghavamzadeh A, Koh MB, Komarnicki M, Krger N, Maertens J, Maschan A, Peters C, Rovira M, Sengelv H, Soci G, Tischer J, Oneto R, Passweg J, Marsh J. Haematologica. National Library of Medicine Low-grade, longterm blood loss eventually results in iron-deficiency anemia. Alternative-donor hematopoietic stem-cell transplantation for severe aplastic anemia. High-dose cyclophosphamide has been advocated as an effective first-line therapy in AA.24 High response rates were associated with prevention of relapse and also clonal disease. However, BMT also has several sequelae including an increased frequency of solid tumors. Deeg HJ, Leisenring W, Storb R, et al. In some patients the clonal size does not change, while clinical PNH can evolve in up to 10% of AA patients over a period of 10 years. shortness of breath when exercising or being active. Untreated, severe aplastic anemia has a high risk of death. Causes of death were as follows: nine infections (38%), four hemorrhagic complications (17%), five deaths in palliative care or after active treatment had finished (21%), two cases involving unknown etiologies (8%), one case of clonal evolution to acute myeloid leukemia, one case of multi-metastatic breast cancer, one case of hypercalcemia, and one cardiac arrest. 2019 Feb;104(2):215-216. doi: 10.3324/haematol.2018.207167. The https:// ensures that you are connecting to the In aplastic anemia all three of these blood cell levels are low. However, this notion has not been confirmed. Dashed lines represent confidence intervals (CI95%). Haematologica. The following tests can help diagnose aplastic anemia: Once you've received a diagnosis of aplastic anemia, you might need other tests to determine the cause. In some instances, rabbit ATG can be used instead of horse ATG, but it is unclear whether this measure helps to avoid more violent allergic reactions. Current status of allogeneic bone marrow transplantation in acquired aplastic anemia. Hepatitis is associated with jaundice. Mayo Clinic does not endorse companies or products. . "Mayo," "Mayo Clinic," "MayoClinic.org," "Mayo Clinic Healthy Living," and the triple-shield Mayo Clinic logo are trademarks of Mayo Foundation for Medical Education and Research. In kittens, this is often caused by parasites (for example, fleas, lice, or intestinal worms), but in older cats, bleeding from stomach ulcers or tumors is more common. with a long-term survival rate of more than 90% among young children 61,62 and more than 80% among adolescents 63 and a low . Having aplastic anemia weakens your immune system, which leaves you more prone to infections. A theoretical argument can be made for early therapy as a measure to prevent progressive stem cell loss due to an unopposed autoimmune process. Although the appearance of PNH clones is often already observed at first presentation of BM failure,3 manifest PNH develops in a much smaller but significant proportion of patients. More recently, T cell receptor (TCR) variable beta chain (VB) genotyping has been used to identify oligoclonal skewing of the TCR repertoire within cytotoxic T cells. Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia (see the image below). doi: https://doi.org/10.1182/asheducation-2005.1.110. Symptoms may include: Headache Dizziness There is often a pronounced rise in transaminases and there may even be fulminant liver failure. Your risk increases if you: Are exposed to toxins Take certain medicines Have a disease such as hepatitis or HIV What are the symptoms of aplastic anemia? Aplastic anemia is a disorder of the hematopoietic stem cell that results in a loss of blood cell precursors, hypoplasia or aplasia of bone marrow, and cytopenias in two or more cell lines (red blood cells, white blood cells, and/or platelets). 2018; doi:10.1016/j.hoc.2018.04.001. 8600 Rockville Pike The survival curve (solid line) was obtained using the Kaplan Meier estimator. Accessed Nov. 16, 2019. Three-year survival was 74.7% (median 7.36 years). Ades L, Mary JY, Robin M, et al. The definition of moderate AA is difficult as it may represent a transition stage to severe AA. 2021 Jul 15;14:3529-3537. doi: 10.2147/IJGM.S310844. Sideroblastic anemia is a type of anemia that results from abnormal utilization of iron during erythropoiesis. A stem cell transplant, also called a bone marrow transplant, is generally the treatment of choice for people who are younger and have a matching donor most often a sibling. Bacigalupo A, Hows J, . A bone marrow biopsy is often done at the same time. Syngeneic transplantation in aplastic anemia: pre-transplant conditioning and peripheral blood are associated with improved engraftment: an observational study on behalf of the Severe Aplastic Anemia and Pediatric Diseases Working Parties of the European Group for Blood and Marrow Transplantation. While the low numbers of reported patients preclude generalization, no individual abnormality predicted unresponsiveness. Aplastic anemia is a life-threatening condition with very high death rates (about 70% within 1 year) if untreated. dizziness. Affected patients typically present with infections due to neutropenia, bleeding due to thrombocytopenia, and/or fatigue due to anemia. In addition to the possibility of clonal evolution and progression to significant hemolytic disease, the finding of a large proportion of PNH cells complicates administration of ATG, which may precipitate a major hemolytic episode. Growth factors are often used with immune-suppressing drugs. Blood counts provide a distinction between severe and moderate AA and, consequently, the assessment of the urgency of therapy (Table 1). Results and follow-up of a phase III randomized study of recombinant human-granulocyte stimulating factor as support for immunosuppressive therapy in patients with severe aplastic anaemia. Vaht K, Gransson M, Carlson K, Isaksson C, Lenhoff S, Sandstedt A, Uggla B, Winiarski J, Ljungman P, Brune M, Andersson PO. sharing sensitive information, make sure youre on a federal The development of MDS in the setting of AA has been described in several studies, but these vary significantly in design and especially in case definition,32 exemplifying diverse views with regard to the criteria required for the diagnosis of both MDS and AA. Risitano AM, Maciejewski JP, Green S, et al. At this time, there is no way to prevent aplastic anemia. Aplastic anemia - About the Disease - Genetic and Rare Diseases Information Center National Center for Advancing Translational Sciences Browse by Disease About GARD Contact Us We recently launched the new GARD website and are still developing specific pages. Some conditions may mimic AA in all or some of its features. All but 2 deaths were related to AML.33 Response to IS in patients with aplasia and an abnormal karyotype may be as high as 50%,34 and certain karyotypic abnormalities (Trisomy 8, 13q) may favorably respond to IS. Takahashi Y, McCoy JP, Jr., Carvallo C, et al. Who might get aplastic anemia? The primary therapeutic approach to acquired aplastic anemia (AA) in older adults differs from the primary approach used in children and younger adults because in the former group, the results of allogeneic bone marrow transplantation (BMT) are less favorable. is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a 4 cm), II, or IIIA NSCLC. the combination of ATG and CSA is significantly better than CSA alone in respect of response rate and disease-free survival. Although effective, these drugs further weaken your immune system. Although not a cure for aplastic anemia, blood transfusions can control bleeding and relieve symptoms by providing blood cells your bone marrow isn't producing. government site. In one study of patients refractory to horse ATG, rabbit ATG resulted in a 50% response rate and excellent long-term survival.13 No good prognostic factors are available with regard to the response to ATG with the exception of the presence of HLA-DR*15 alleles and PNH clones, which both correlated with responsiveness to IS4 but the correlation was not absolute. Aplastic anemia is a life-threatening condition with very high death rates (about 70% within 1 year) if untreated. Similarly, Campath-1H is currently being tested in a refractory setting to assess its potential usefulness as an IS agent (Table 3). Summary Aplastic anemia is a rare serious disease (2-6 cases/1 million/year), which can be diagnosed also in pregnant women. The age limit for the primary choice of BMT has not been fully established, and in patients older than 3035 years, intense IS may be selected as a first attempt, with BMT used as salvage therapy for non-responders. With today's standard treatments, around 7 of every 10 patients with aplastic anemia improves. National Heart, Lung, and Blood Institute. Various methods, including modified conditioning regimens and T cell depletion, have been used to improve the results. Routine testing is not available and suspected cases should be referred to specialized centers. Acquired aplastic anemia occurs because of an immune system problem. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO) 14. Data regarding the treatment of aplastic anemia in this ageing population remains scarce. History consistent with drug-induced AA (e.g., gold) or infection-associated AA (hepatitis-associated AA) does not preclude response to IS treatments. Etiology of AA includes auto immunity, toxins, infection, ionizing radiation, drugs and rare genetic disorders, but in the majority of cases no cause can be identified. Multicenter randomized study comparing cyclosporine-A alone and antithymocyte globulin with prednisone for treatment of severe aplastic anemia. Treatment, by drugs or stem cell transplant, has a five-year survival rate of about 70%, . Marsh J, Schrezenmeier H, Marin P, et al. headache. Symptoms may include: Headache Dizziness . Acquired SAA is regarded as the result of an immune-mediated destruction of hematopoietic cells, at least in a proportion of patients. Causes After the transplant, you'll receive drugs to help prevent rejection of the donated stem cells. Graft failure has also been described, and in some cases such patients may benefit from autologous reconstitution of hematopoiesis. For many women, pregnancy-related aplastic anemia improves once the pregnancy ends. 2021 Oct 8;12:730776. doi: 10.3389/fphar.2021.730776. For example, flow cytometric determination of IFN- expression, as well as serum levels of these cytokines, are indicative of a reversed TH1/TH2 ratio and correlate with response to IS (for review see 6). Refractory patients constitute a significant challenge and their prognosis is poor. Bone Marrow Failure . red or purple spots on the skin caused by bleeding under the skin. In a series involving 122 patients treated with intensive IS consisting of ATG and CsA, the risk of MDS evolution was about 21% at 10 years.33 In 100 patients from the GITMO (Gruppo Italiano Trapianto di Midollo Osseo) and EBMT study involving antilymphocyte globulin (ALG), CsA, prednisone and G-CSF, 11 patients developed cytogenetic abnormalities during a median follow-up of 5 years.35 The differences in the diagnostic criteria are obvious, such as in a recent analysis by the EBMT AA Working Party, in which karyotypic abnormalities occurred in 23 of 170 patients, but in 4 cases chromosomal changes were present at first diagnosis36 and would be classified as MDS at other institutions. Bacigalupo A, Bruno B, Saracco P, et al. weakness. Clearly, the diagnosis of MDS in the course of AA has prognostic significance. After clonal evolution, marrow morphology was characterized by predominance of hypercellularity (41%) and patchy biopsy cellularity (27%), while continued hypocellularity was found in 33% of the patients. This content does not have an Arabic version. The mechanism that triggers AA in pregnancy remains unclear, but AA often resolves with the termination of pregnancy and can recur during subsequent pregnancies. A doctor uses a needle to remove a small sample of bone marrow from a large bone in your body, such as your hipbone. Typical acquired aplastic anemia (AA) is a disease of young adults, but a second peak in incidence has been reported in the fifth or sixth decade of life. Each person's symptoms may vary. 5 1996;602330. Certain karyotypic abnormalities such as trisomy 8 may be more common in these cases, and cytogenetic evaluation may show only a portion of affected metaphases and likely may just reflect oligoclonal hematopoiesis. What are the survival rates for aplastic anemia? Zhonghua Xue Ye Xue Za Zhi. Recent long-term allogeneic bone marrow transplantation (BMT) results.18,;26,;28,30. This leads to abnormally small red blood cells and a lack of hemoglobin. You don't want the infection to get worse, because it could prove life-threatening. Even better results were reported in children, in whom BMT appears to be more effective in improving survival than IS.27,Table 5 summarizes recently reported results.18,26,28,30 However, a typical decrease in the overall survival is observed with increasing age of the recipient, making the therapeutic decision for older patients a challenge. Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. This second procedure removes a small piece of bone tissue and the enclosed marrow.