eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Bone Marrow Failure

Author: Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Coauthor(s): Ulrich Woermann, MD, Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland
Contributor Information and Disclosures

Updated: Jan 4, 2008

Introduction

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

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.

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