AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

The bone marrow failure syndromes include a group of disorders than can be either inherited or acquired. These diseases are disorders of the hematopoietic stem cell that can involve either one cell line or all of the cell lines (erythroid for red cells, myeloid for white blood cells, megakaryocytic for platelets). The lymphocytes, which are involved in lymphoproliferative disorders, are usually spared. The inherited bone marrow failure syndromes include Fanconi anemia, dyskeratosis congenital, Diamond-Blackfan anemia, and other genetic disorders. The most common cause of acquired bone marrow failure is aplastic anemia.¹ Other diseases that can present in a manner similar to acquired bone marrow failure include myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, and large granular lymphocyte leukemia.

Pathophysiology

Bone marrow failure can be inherited or acquired. It can involve just 1 cell line or all 3 cell lines. The pathophysiology of these defects includes the following mechanisms of action: (1) a decrease in or damage to the hematopoietic stem cells and their microenvironment, resulting in hypoplastic or aplastic bone marrow; (2) maturation defects, such as vitamin B-12 or folate deficiency; and (3) differentiation defects, such as myelodysplasia.

Generally, hematopoietic stem cells are damaged by a congenital defect or exposure to a noxious substance or factor. Pathophysiologic mechanisms are (1) an acquired stem cell injury from viruses, toxins, or chemicals that leads to a quantitative or qualitative abnormality; (2) abnormal humoral or cellular control of hematopoiesis; (3) an abnormal or hostile marrow microenvironment; (4) immunologic suppression of hematopoiesis (ie, mediated by antibodies, T cells [or cellularly], or lymphokines); and (5) mutations in genes, causing inherited bone marrow failure syndromes. Identification of these relevant mutations has led to progress in defining the precise functions of the corresponding proteins in normal cells.

The genetic abnormalities in the inherited bone marrow failure syndromes (IBMFS) have been identified in the following:

• Fanconi anemia is inherited in either an autosomal recessive or X-linked fashion. Twelve Fanconi anemia (FANC) genes have been identified. These genes collaborate in a complicated pathway (FA pathway), which is responsible for the repair of DNA damage. One of these genes (FANCD1) is the breast/ovarian susceptibility gene (BRCA2).
• Dyskeratosis congenita is inherited in an X-linked recessive, autosomal dominant, or autosomal recessive manner. Patients with the X-linked form have mutations in DKC1 at band Xq28, a gene that encodes for dyskenin, in a protein involved in the telomere maintenance pathway. Other patients have mutations in band 3q26 in TERC, a part of the telomerase complex, and still others have mutations in the telomerase reverse transcription (TERT) enzyme.
• Shwachman-Diamond syndrome is an autosomal recessive disorder in which the majority of patients have a mutation in the Shwachman Bodian Diamond syndrome gene (SBDS) located at band 7q11.
• Amegakaryocytic thrombocytopenia is an autosomal recessive disorder with biallelic mutations in the thrombopoietin receptor, MPL, at the band 1p34 location.
• Diamond-Blackfan anemia is an autosomal dominant disease in which 25% of patients were found to have a mutation in the gene for small ribosomal protein (RPS19) located at band 19q13.2.
• Severe congenital neutropenia is associated with dominant mutations in neutrophil elastase (ELA2, located at band 19p13.3) in half of the patients, while a few patients have mutations in GFI-1.
• Thrombocytopenia absent radii syndrome has not been identified with any particular gene in this autosomal recessive disorder.

Frequency

United States

The prevalence of bone marrow failure resulting from hypoplastic or aplastic anemia is low in the United States and Europe (2-6 cases per million persons) compared to the prevalence of bone marrow failure resulting from acute myelogenous leukemia and multiple myeloma (27-35 cases per million persons). The frequency of myelodysplasia, on the other hand, has increased from 143 cases reported in 1973 to about 15,000 cases annually in United States. This is an underestimation of the actual prevalence, which is believed to be about 35,000-55,000 new cases a year.

International

Bone marrow failure occurs more frequently in the East than in the West. In Japan and the Far East, the frequency is at least 3 times higher than it is in the United States and Europe. Mexico and Latin America also have high occurrence rates, which are attributed to the liberal use of chloramphenicol. Environmental factors and pervasive use of insecticides have been implicated as a cause of this disease. The incidence of myelodysplasia was recently estimated to be around 4-5 per 100,000 population per year in Germany and Sweden.

Mortality/Morbidity

Bone marrow failure resulting in failure to produce 1, 2, or all 3 cell lines of the blood results in increased morbidity and mortality of the patients involved.

• Morbidity and mortality from pancytopenia are caused by low levels of mature blood cells. Severe anemia can cause high-output cardiac failure and fatigue. Neutropenia can predispose individuals to bacterial and fungal infections. Thrombocytopenia can cause spontaneous bleeding and hemorrhage.
• The severity and extent of cytopenia determine prognosis. Severe pancytopenia is a medical emergency, requiring rapid institution of definitive therapy (ie, early determination of supportive care and bone marrow transplant candidates).

CLINICAL

Section 3 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
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• Follow-up
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• References

History

• Patients with bone marrow failure present with low blood counts.
• Low platelet counts predispose patients to spontaneous bleeding in the skin and mucous membranes. Neutropenia places the patient at risk for serious infections. Bleeding complications are usually the most alarming symptom, and infections prompt individuals to visit the emergency department.
• Weakness and fatigue resulting from anemia can develop slowly. Months may elapse before the patient seeks medical help with these symptoms.
• Family and personal medical histories can help distinguish inherited causes from acquired causes. Inherited bone marrow failure is usually diagnosed in young adults but may be missed until their fifth or sixth decades of life. These diseases should be considered if any of the following are present: subtle but characteristic physical anomalies, hematologic cytopenias, unexplained macrocytosis, myelodysplastic syndrome or acute myelogenous leukemia, or squamous cell cancer even in the absence of pancytopenia or a positive family history. Cases in which siblings of a patient with known Fanconi anemia who developed abnormal blood counts should be investigated.
• Exposure to toxins, drugs, environmental hazards, and recent viral infections (eg, hepatitis) should be noted.

Physical

The manifestations of bone marrow failure relate to the clinical effects of low blood counts.

• Patients with severe anemia may present with pallor and/or signs of congestive heart failure, such as shortness of breath.
• Bruising (eg, ecchymoses, petechiae) on the skin, gum bleeding, or nosebleeds frequently are associated with thrombocytopenia.
• Fever, cellulitis, pneumonia, or sepsis can be complications of severe neutropenia.
• Inherited bone marrow failure includes Fanconi anemia, which has characteristic physical developmental anomalies including absent thumbs, absent radius, microcephaly, renal anomalies, short stature, and abnormal skin pigmentation (ie, café-au-lait and hypopigmented or hyperpigmented spots). As many as half of patients with Fanconi anemia may not exhibit obvious developmental or skin manifestation, and it is increasingly clear that the diagnosis should be considered in adults with bone marrow failure, myelodysplastic syndrome, or early onset of epithelial cancer.

Causes

The main causes of bone marrow failure are congenital (ie, constitutional) in nature, or bone marrow failure may be acquired. Acquired bone marrow failure syndromes include single cytopenias and pancytopenias.

• Constitutional causes
• • Constitutional aplastic anemia is associated with chronic bone marrow failure, congenital anomalies, familial incidence, or thrombocytopenia at birth.
  • Fanconi anemia is characterized by familial aplastic anemia, chromosomal breaks, and in some cases, congenital anomalies of the thumb or kidneys.
  • Dyskeratosis congenita, another rare disorder, has a characteristic dermatologic manifestation of nail dystrophies and leukoplakia. These patients develop aplastic anemia in their second decade of life.
  • Shwachman-Diamond syndrome consists of exocrine pancreatic insufficiency and bone marrow failure. Occasionally, cartilage and hair hypoplasia can occur, resulting in short stature and dysostosis.
• Single cytopenias
• • Pure red cell aplasia may be secondary, caused by a thymoma. It may occur transiently, resulting from a viral infection such as with parvovirus B19. Pure red cell aplasia also may be permanent, as a result of viral hepatitis. Finally, it may be the result of lymphoproliferative diseases (eg, lymphomas, chronic lymphocytic leukemia) or collagen vascular diseases (eg, systemic lupus erythematosus, refractory anemia), or it may occur during pregnancy.
  • Amegakaryocytic thrombocytopenic purpura has been reported to occur as a result of causes similar to those for pure red cell aplasia.
  • Early forms of myelodysplastic syndrome initially can manifest as a single cytopenia or, more often, as a bicytopenia.
• Pancytopenia (decrease in all 3 cell lines)
• • This is the most common manifestation of bone marrow failure.
  • Aplastic or hypoplastic anemia can be idiopathic in nature, or it can develop from secondary causes. See Aplastic Anemia for further discussion.
  • Myelodysplastic anemia also can cause pancytopenia. See Myelodysplastic Syndrome for further details.
  • Myelophthisic anemia may result from marrow destruction because of tumor invasion or granulomas.

DIFFERENTIALS

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Other Problems to be Considered

Immune pancytopenias in connective tissue disorders (eg, systemic lupus erythematosus, refractory anemia)
Large granular lymphocyte leukemia

WORKUP

Section 5 of 10  

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• Clinical
• Differentials
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• Follow-up
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Lab Studies

• Laboratory features of bone marrow failure include a single cytopenia, as in pure red cell aplasia, and amegakaryocytic thrombocytopenic purpura or pancytopenia, as in aplastic anemia.
• Peripheral blood findings are as follows:
• • Anemia is common, and red cells appear morphologically normal. The reticulocyte count usually is less than 1%, indicating a lack of red cell production. Occasionally, the mean cell volume is elevated, with macrocytosis.
  • Platelet counts are lower than normal, with a paucity of platelets in the blood smear. Platelet size is normal, but a low platelet count may cause greater heterogeneity in size.
  • Agranulocytosis (ie, decrease in all granular white blood cells, including neutrophils, eosinophils, and basophils) and a decrease in monocytes are observed. A relative lymphocytosis occurs (ie, increased percentage) without an increase in numbers.
• The Ham test, or sucrose hemolysis test, result may be positive in a patient with underlying paroxysmal nocturnal hemoglobinuria, but a recent transfusion with packed RBCs may induce a false-negative test result (ie, testing normal transfused red cells). Folate, vitamin B-12, and serum erythropoietin levels usually are increased.
• Fanconi anemia should be considered in all young adults and children with hypoplastic or aplastic anemia² or cytopenias, unexplained macrocytosis, myelodysplastic syndrome, acute myelogenous leukemia, epithelial malignancies, or subtle but characteristic physical anomalies. The criterion standard screening test for Fanconi anemia is based on the characteristic hypersensitivity of Fanconi anemia cells to the crosslinking agents (eg, mitomycin C, diepoxy butane [DEB], cisplatin). Expose a culture of replicative cells (ie, phytohemagglutinin [PHA]–stimulated peripheral blood lymphocytes or skin fibroblasts) to low doses of mitomycin C or DEB. Then examine the cells in metaphase, looking for evidence of chromosomal breaks and radial chromosomes.
• Mutated genes can be identified by retroviral complement studies, by direct sequencing, or by denaturing high-performance liquid chromatography (DHLP), which are limited to research laboratories presently.
• Screening for dyskeratosis congenita (DC) should be considered in children and adults who have (1) bone marrow failure, acute myelogenous leukemia, or myelodysplastic syndrome; (2) negative mitomycin C and DEB test results, which rules out Fanconi anemia; and either (3) hypopigmented macules, reticulated hypopigmentation, dystrophic nails, or oral leukoplakia or (4) evidence in the family history of X-linked or autosomal dominant forms of DC by genomic DNA sequencing (DKC1-3).
• Diamond-Blackfan anemia (DBA) is a pure red cell aplasia and usually manifests in early infancy. Schwachman-Diamond syndrome is a syndrome of bone marrow failure (classically neutropenia), exocrine pancreatic insufficiency, and metaphyseal dysostosis that also manifests in early childhood.

Imaging Studies

• Bone marrow activity can be measured by radiographic methods. Ferrokinetic studies have been conducted using a radioactive label, such as iron-59 or indium-111, both of which are taken up by erythroid cells. Radioactive iron is no longer available in the United States.
• Magnetic resonance imaging (MRI) can be used to differentiate densities and intensity signals of bone marrow fat cells from densities and intensity signals of hematopoietic cells.
• Positron emission tomography (PET) scanning with radiolabeled oxygen can measure the metabolic activity difference between hypoplastic marrow and cellular marrow.

Procedures

• Bone marrow
• • An aspirate and biopsy should be performed to assess the cellularity and morphology of the residual cells. In general, the marrow is replaced with fat cells and stromal cells are replaced with lymphocytes, with very few hematopoietic cells. Occasionally, localized pockets of marrow are present (ie, from a sampling error), which can be misleading. To evaluate cellularity, the core biopsy specimen should be at least 1 cm long.
  • Residual erythroid cells may show evidence of dysplasia with nuclear-cytoplasmic maturation dissociation, which in the absence of a folate or vitamin B-12 deficiency, commonly is described as megaloblastoid features.

Histologic Findings

Bone marrow studies provide information to definitively diagnose failure, and the status of precursor cells of each cell line can be examined. Pure red cell aplasia characteristically affects erythroid progenitor cells; amegakaryocytic thrombocytopenia lacks megakaryocytes. A finding of hypoplastic bone marrow differentiates aplastic anemia from aleukemic leukemia, which produces blast cells in the marrow.

TREATMENT

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Medical Care

• If clinically indicated, initiate a blood transfusion using specific cells, such as packed red cells for anemia and platelets for thrombocytopenia. Clinical indications for red cell transfusions are symptoms secondary to anemia and bleeding from thrombocytopenia. Supportive care gives only temporary relief of symptoms and does not treat the primary disease.
• Infections resulting in neutropenia should be treated as emergencies. Institute intravenous antibiotics that cover all possible organisms before culture results are available.
• Bone marrow transplantation (BMT) candidates are patients who are younger than 55 years who have severe disease and a matched related donor.³ With current BMT regimens, most patients with severe aplastic anemia have a 60-70% long-term survival rate. Survival rates of higher than 80% are reported for patients in more favorable subgroups. Using matched unrelated donors still is less favorable (11-20% survival rates). Patients with inherited bone marrow failure and a matched sibling are excellent candidates for hematopoietic stem cell transplantation (HSCT). A caveat is their extraordinary sensitivity to chemotherapeutic agents and radiation used in conditioning regimens, which must both be reduced to avoid fatal toxicities. Consider saving cord blood from healthy siblings when identified.
• Patients with severe aplastic anemia who receive antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) but do not receive BMT have a 41% response rate and a 1-year survival rate of 55%.⁴ The addition of androgens increases response rates to 70%, with a 1-year survival rate of 76%. Although their roles are unknown, ATG or ALG should be given with corticosteroids to prevent serum sickness.
• High-dose corticosteroids, using methylprednisolone (20 mg/kg/d with rapid taper), have been used in countries where ATG or ALG is expensive; response rates are 38%. Cyclosporine therapy at 200-400 mg/d (maintain serum trough levels at 100-250 ng/mL) has a reported 85% hematologic remission rate.
• Androgens were used in the past, but most are masculinizing and poorly tolerated by females and children. Danazol is a nonmasculinizing androgen that may be useful. The response rate is limited to approximately 45%, and results may require 6-10 months of therapy. Hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), may be useful in patients with neutropenia who have infections, without requiring a WBC transfusion.

Surgical Care

Splenectomy is no longer performed.

Consultations

• Hematologists should manage these patients.
• An infectious disease specialist may be necessary.
• In severe cases, early consideration for BMT should be initiated.

MEDICATION

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The approach to bone marrow failure depends on which mechanism is thought to predominate in the patient. If an immune mechanism is suspected, an immunosuppressive agent is used. Hematopoietic growth factors and androgens also have been tried in an effort to stimulate hematopoiesis.

Drug Category: Immunosuppressive agents

These are used to manipulate the bone marrow microenvironment and eliminate any immune-mediated bone marrow suppression. Intensive immunosuppression using a combination of ALG and cyclosporine has resulted in hematologic remission rates of 70-80% in patients with aplastic anemia.

Drug Category: Androgens

These agents push the resting hematopoietic stem cells into cycle, making them more responsive to differentiation by hematopoietic growth factors. They also stimulate endogenous secretion of erythropoietin

Drug Category: Immunosuppressive agents

These are used to address the immune mechanisms of bone marrow failure.

FOLLOW-UP

Section 8 of 10  

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Further Inpatient Care

• Supportive care is essential for patient survival. In patients with bone marrow failure, the resulting cytopenia can lead to life-threatening symptoms.
• Anemia can cause fatigue and can impair the patient's ability to function in daily activities. Impaired heart function can be aggravated into congestive heart failure by increasing oxygen demands on the heart and other tissues.
• • Transfuse packed red cells to maintain hemoglobin levels of 7-10 g/dL. Patients with coronary artery disease may need to be maintained at 10-12 g/dL if they are symptomatic at lower levels of hemoglobin.
  • The benefits of this therapy are limited to 1 month because the life span of transfused red blood cells is limited to the average life span of collected cells.
  • Also, each unit of transfused packed red cells introduces unwanted iron, which over time, accumulates in the patient.
  • Although minimal, the risk of infection still is present (eg, HIV, hepatitis C).
• Bleeding/hemorrhage resulting from thrombocytopenia is a major problem and may be life threatening if it occurs intracranially.
• • Platelet transfusions are effective for stopping acute bleeding. Unfortunately, the platelet life span is short; the effects may last 2-4 days. This treatment temporarily stops bleeding, but it is not a practical maintenance therapy. Development of alloantibodies can make the patient refractory to platelet transfusions.
  • Mucosal bleeding from the nose, gums, or teeth may be easily controlled by oral aminocaproic acid (Amicar 500-mg tab or 500 mg/mL elix). The dose of aminocaproic acid can be as high 6-8 g/d, in divided doses, every 6-8 hours. Hypotension is the dose-limiting symptom. Disseminated intravascular coagulation (DIC) and clots in the urinary tract are contraindications. This therapy is useful in the long-term maintenance of severe thrombocytopenia in patients with bone marrow failure.
• Sepsis, pneumonias, urinary tract infections, and cellulitis with bacterial organisms are common complications of neutropenia. The risk is moderate with actual or total neutrophil counts of 500-1000, and the risk is high at levels below 500.
• • After blood is drawn and other cultures are taken, broad-spectrum antibiotics should be started empirically in the presence of febrile neutropenia. Coverage for the most common gram-positive and gram-negative organisms should be considered. With the new broad-spectrum antibiotics, a single antibiotic generally is sufficient. The choice can be altered later, depending on the results of sensitivity tests from positive cultures.
  • The addition of antifungal agents should be considered in the presence of persistent fever despite adequate antibacterial coverage. Liposomal amphotericin B is indicated if renal dysfunction is present because of toxicity resulting from the drug in another form.

Complications

• Over time, the transfusion of packed red cells increases the total iron load to the patient.
• • Measure iron stores in the form of ferritin.
  • Increased levels of iron are toxic to various organs, including the heart.
  • Iron toxicity can cause arrhythmia by blocking the bundle of His, diabetes by damaging the islets of Langerhans in the pancreas, liver cirrhosis, and bronze color in fair-skinned individuals.
  • Administering a chelating agent is an effective method of removing excess iron. Chelating agents are composed of molecules that bind tightly with free iron and remove the iron by carrying it as the agent is excreted from the body.
  • Desferrioxamine is the iron chelator available in parenteral form. If given intravenously, its activity is short and it is excreted rapidly by the kidneys. A subcutaneous infusion given continuously by a portable pump for 3-4 hours every 12 hours is the preferred method. It optimizes the binding of the chelator to the free iron. As more free iron is excreted, storage iron is mobilized into the free form. This treatment can be performed in an outpatient setting.
• Monitoring serum ferritin levels and measuring total iron urinary excretion can determine effectiveness of therapy.
• Most tissue damage can be reversed with timely chelation, except for cirrhosis of the liver (once it has set in).

Prognosis

• The prognosis of bone marrow failure depends on the duration of the marrow function abnormality.
• Most inherited forms of bone marrow failure, such as Fanconi anemia, are associated with transformation into leukemia several years later.
• Viral causes, such as parvoviruses, are usually self-limiting.
• Acquired idiopathic aplastic anemia is usually permanent and life threatening. Half the patients die during the first 6 months.

Patient Education

For excellent patient education materials, please see eMedicine's Blood and Lymphatic System Center. For information specific to anemia, see the article Anemia.

MULTIMEDIA

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Media file 1:  This bone marrow film at 400X magnification demonstrates a complete absence of hemopoietic cells. Most of the identifiable cells are lymphocytes or plasma cells. Photographed by U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland (http://www.aum.iawf.unibe.ch/).
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Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
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1. Young NS. Acquired bone marrow failure. In: Handin RI, Stossel TP, Lux SE, eds. Blood: Principles and Practice of Hematology. Philadelphia, Pa: JB Lippincott; 1995:293-365.
2. Alter BP. Bone marrow failure: a child is not just a small adult (but an adult can have a childhood disease). Hematology Am Soc Hematol Educ Program. 2005;96-103. [Medline].
3. Grewal SS, Kahn JP, MacMillan ML, Ramsay NK, Wagner JE. Successful hematopoietic stem cell transplantation for Fanconi anemia from an unaffected HLA-genotype-identical sibling selected using preimplantation genetic diagnosis. Blood. Feb 1 2004;103(3):1147-51. [Medline].
4. Molldrem JJ, Leifer E, Bahceci E, Saunthararajah Y, Rivera M, Dunbar C, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med. Aug 6 2002;137(3):156-63. [Medline].
5. Marmont AM. Introduction: autoimmune myelopathies. Semin Hematol. Oct 1991;28(4):269-74. [Medline].
6. Tichelli A, Gratwohl A, Würsch A, Nissen C, Speck B. Late haematological complications in severe aplastic anaemia. Br J Haematol. Jul 1988;69(3):413-8. [Medline].

Article Last Updated: Jan 4, 2008