Bone Marrow failure – An issue of medical emergency

Abstract

Aim: To highlight hematological issues pertaining to bone marrow failure

Method: Various research papers were consulted and important information were retrieved on the Pathophysiology, clinical findings, laboratory findings, treatment and prognosis of cases pertaining to bone marrow failure.

Conclusion: Bone marrow failure is a medical emergency where pancytopenia should be immediately evaluated and must include the clinical findings as well as the laboratory findings and treatment will be based on the grade of pancytopenia. Further research is necessary to weigh the necessity of hematopoietic stem cell transplantation and or various recombinant therapies.

Keywords: Bone marrow, Pancytopenia, failure

Introduction

Bone marrow failure is the reduction or cessation of blood cell production affecting one or more cell lines. Pancytopenia or decreased numbers of circulating red blood cells(RBCs), White blood cells(WBCs) and platelets is seen in most cases of bone marrow failure, particularly in severe or advanced stages.

The Pathophysiology of bone marrow failure includes the following mechanisms;

• 1. Destruction of hematopoietic stem cells due to injury by drugs, chemicals, radiation, viruses or autoimmune mechanisms.

• 2. Premature senescene and apoptosis of stem cells due to inherited mutations.

• 3. Ineffective hematopoiesis owing to stem cell mutations or vitaminB12 or folate deficiency.

• 4. Disruption of the bone marrow microenvironment that supports hematopoiesis.

• 5. Decreased production of hematopoietic growth factors or related hormones.

• 6. Loss of normal hematopoietic tissue due to infiltration of the marrow space with abnormal cells.

The clinical consequences of bone marrow failure vary depending on the extent and duration of the cytopenias. Severe pancytopenia can be rapidly fatal if untreated. Some patients may present initially with no symptoms and their cytopenia is inadvertently detected during a routine examination. Thrombocytopenia can result in clinically significant bleeding. The decreased in RBCs and Hemoglobin( Hb) leads to symptoms of anemia including fatigue, pallor and cardiovascular complications sustained neutropenia increases the risk of bacterial or fungal infections that can be life-threatening. Because there are many mechanisms involved in the various bone marrow failure syndromes, accurate diagnosis is essential so that the appropriate treatment can be instituted.

Aplastic Anemia

Aplastic anemia is a rare but potentially fatal bone marrow failure syndrome. The characteristic features of Aplastic anemia include pancytopenia, reticulocytopenia, bone marrow hypocellularity and depletion of hematopoietic stem cells. Aplastic anemia may be acquired or inherited.

Acquired Aplastic anemia

Acquired Aplastic anemia is classified as idiopathic when the cause is unknown and secondary when the etiology cab be identified. The idiopathic type accounts for approximately 70% to 80% of Aplastic anemia cases Marsh JCW(2005). Clinical and laboratory findings are similar for idiopathic and secondary Aplastic anemia. Persons with Aplastic anemia initially may present with a normocytic or macrocytic anemia without reticulocytosis. Depending on the progression of the bone marrow failure, pancytopenia may develop slowly. More than half of Aplastic anemia progress at a rapid rate, however with complete cessation of erythropoiesis. Aplastic anemia can occur at any age but is more frequent in persons 10 to 25 years old and persons older than age 60 Marsh JCW et al (2003)

Etiology

The cause of bone marrow failure in idiopathic Aplastic anemia is unknown. Secondary Aplastic anemia is associated with exposure to certain drugs, chemicals, radiation, or infectious agents. Cytotoxic drugs, radiation and chemicals such as benzene suppress the bone marrow in a predictable, dose dependent manner Young & Maciejewski (2005). Depending on the dose and exposure time, the marrow generally recovers after withdrawal of the agent. About 90% of secondary Aplastic anemias occur secondary to idiosyncratic drug reactions or chemicals. In this aspect, the marrow failure is unpredictable and unrelated to dose and the bone marrow does not usually recover when the agent is withdrawn. Documentation of an identifiable factor or agent inducing Aplastic anemia in these cases is difficult because evidence is primarily circumstantial and symptoms may occur months or years after exposure.

Aplastic anemia as an idiosyncratic, adverse reaction to a drug , chemical or other agent is a rare event and is likely due to a combination of genetic and environmental factors in susceptible people. Acquired Aplastic anemia appears occasionally as a complication from infections. Viruses implicated in Aplastic anemia include Epstein- Barr virus, Human immunodeficiency virus(HIV), hepatitis virus and human parvovirusB19. A history of acute non-A, non-B, or non-C hepatitis 1 to 3 months before onset is found in 2% to 10% of patients with acquired Aplastic anemia Brown KE et al (1997).

Pathophysiology

The primary lesion in acquired Aplastic anemia is a quantitative and qualitative deficiency of hematopoietic stem cells rather than a defect of the bone marrow stroma or a deficiency of growth factors. The hematopoietic stem cell and early progenitor cell compartment is identified by expression of CD34 surface antigens. When measured by flow cytometry, the CD34 cell population in the bone marrow of patients with Aplastic anemia can be 10 times lower compared with normal individuals Maciejewski JP et al (1996).

There is an increase in apoptotic CD34 cells in aplastic anemia and they have an increased expression of fas receptors that mediate apoptosis Philpott NJ (1995) and also persons with Aplastic anemia have elevated levels of growth factors in their serum such as erythropoietin Koijima S (1998).

Clinical Findings

Symptoms vary in acquired Aplastic anemia from very severe to mild or asymptomatic. Patients usually present with symptoms typical of insidious onset anemia, pallor, fatigue and weakness. Severe anemia can result in serious cardiac complications or even cardiac failure and death, petechiae, bruising, epistaxis, bleeding gums, menorrhagia, retinal hemorrhages, intestinal bleeding and sometimes intracranial bleeding may occur secondary to thrombocytopenia. Fever and bacterial or fungal infections are unusual at initial presentation but may occur after prolonged periods of neutropenia. Splenomegaly and hepatomegaly are absent.

Laboratory Findings

Pancytopenia is typical, the absolute neutrophil count is decreased, Hb is less than 10g/dl, mean cell volume(MCV) is normal or increased and absolute reticulocytopenia is seen. On a peripheral blood films, Neutrophils, monocytes and platelets are all decreased and the RBCs are normocytic or macrocytic. Blasts and other immature blood cells are absent. Serum iron and percentage transferring saturation are increased reflecting the decreased use of iron for erythropoiesis. Liver function tests may be abnormal if the pancytopenia was preceded by hepatitis. Almost one third of Aplastic anemia patients develop Paroxysmal Nocturnal Hemoglobinuria(PNH) Socie G et al (2000). Bone marrow aspirates and biopsy specimens have prominent fat cells with areas of patchy cellularity. Biopsy samples are required for an accurate quantitative assessment of the marrow cellularity and severe hypocellularity is a prominent finding or feature. Erythroid, granulocytic and megakaryocytic cells are decreased or absent. New Techniques of Fluorescent In Situ Hybridization(FISH) using DNA probes for specific chromosomes have a greater sensitivity in the detecting karyotype chromosomes abnormalities in Aplastic cases.

Treatment and Prognosis

Severe Aplastic anemia requires immediate treatment to prevent the consequences of serious pancytopenia. If a potential causative agent is suspected, it should be discontinued. One of the most important early decisions that must be made is whether a patient is a candidate for hematopoietic stem cell transplantation. Hematopoietic stem cell transplant is the treatment of choice for patients with severe Aplastic anemia who are younger than age 40 and have an Human Leucocyte Antigen(HLA) identical sibling.

For patients older than age 40 or of any age without an HLA identical sibling, immunosuppressive therapy, consisting of antithymocyte globulin with cyclosporine is the preferred therapy. Recombinant humanized antibody to interleukin-2 receptor is under evaluation as a possible therapy Maciejewski JP et al(2003). Over the course of the disease, 10% to 25% of patients treated with immunosuppression develop PNH and 10% to 20% progress to myelodysplastic syndrome or leukemia Kearns WG et al(2004).

Inherited Aplastic Anemia

Patients with inherited Aplastic anemia usually present at an early age and may have associated congenital malformations. The two inherited diseases with bone marrow failure and pancytopenia as a consistent feature and they are Fanconi anemia and Dyskeratosis congenital.

Pure Red Cell Aplasia

Pure red cell aplasis (PRCA) is a rare disorder of erythroplasia characterized by a selective and severe decrease in erythrocyte precursors in an otherwise normal bone marrow. Patients present with severe anemia, reticulocytopenia and a normal WBC and platelet count. PRCA may be acquired or congenital Dessypris EN (2005).

Acquired Pure Red cell Aplasia

Acquired PRCA may occur in children or adults and can be acute or chronic. Primary PRCA may be idiopathic or autoimmune related. Secondary PRCA may occur in association with an underlying hematologic malignancy solid tumor infection, chronic hemolytic anemia, collagen vascular disease or exposure to drugs or chemicals. Therapy involves treatment of the condition and immunosuppression. The acquired form of PRCA in children also is known as transient erythroblastopenia of childhood. A history of viral infection is found in half of patients and an immune mechanism is involved in its etiology.

The anemia is normocytic and HbF levels are normal. Transfusions are the initial therapy and restoration of normal erythropoiesis occurs in the most patients Freedman MH(2005)

Congenital Dyserythropoietic Anemia

The congenital dyserythropoietic anemias (CDAs ) are a heterogeneous group of rare disorders characterized by refractory anemia, reticulocytopenia, hypercellular bone marrow with markedly ineffective erythropoiesis and distinctive dysplastic changes in the bone marrow erythroblasts, including giantism, multinuclearity and karyorrhexis.

Myelophthisic Anemia

Myelophthisic anemia is the infiltration o abnormal cells into the bone marrow and subsequent destruction and replacement of normal hematopoietic cells. Metastatic solid tumor cells (particularly lung, breast, prostate), leukemic cells, fibroblasts and inflammatory cells found in military tuberculosis and fungal infections are implicated Makoni & Laber (2004). Cytokines, growth factors and other substances are released that suppress hematopoiesis or destroy stem, progenitor or stromal cells resulting in peripheral cytopenias.

Myelophthisic anemia is typically mild to moderate with normocytic erythrocytes. The typical findings on peripheral blood films are teardrop erythrocytes and nucleated RBCs, but immature myeloid cells (Leukoerythroblastic), Megakaryocyte fragments and giant platelets also may be present Prchal JT (2006).

Although, myelophthisic anemia is distinguished from Aplastic by the presence of normocytic RBCs with teardrop forms, a leukoerythroblastic blood picture and abnormal cells in the bone marrow aspiration or biopsy.

Anemia of chronic Renal Insufficiency

The major cause of the anemia in chronic renal disease is the inadequate production of erythropoietin by the kidneys. Without erythropoietin, the bone marrow is unable to increase RBC production in response to tissue hypoxia and anemia ensues. The anemia occurs even in moderate impairment of renal function Caro J(2006). Other factors also contribute to anemia in renal disease. Patients on dialysis experience chronic blood loss (and iron loss) and folate depletion as a result of the dialysis procedure itself. Waste products accumulate secondary to renal excretory failure and shorten the life span of the erythrocytes and chronic inflammatory conditions and poor diet may limit the iron available for erythropoiesis. The anemia in chronic renal disease is normocytic and normochromic with normal or decreased reticulocytes. Treatment of anemia resulting from chronic renal disease involves the administration of recombinant human erythropoietin with a goal to maintain the hemoglobin level.

Conclusion: Bone marrow failure is a medical emergency where pancytopenia should be immediately evaluated and must include the clinical findings as well as the laboratory findings and treatment will be based on the grade of pancytopenia. Further research is necessary to weigh the necessity of hematopoietic stem cell transplantation and or various recombinant therapies.

References

Brown KE et al (1997); Hepatitis- associated Aplastic anemia. New Eng J Med 336:1059

Caro J (2006); Anemia of chronic renal failure. . In Lichtman MA et al (eds): Williams Hematology 7 th edn New York: Mcgraw –Hill .

Dessypris EN(2005); Pure red cell aplasia. In Hoffman R. et al (eds): Hematology: Basic principles and practice 4th edn. Philadelphia.

Freedman MH(2005); Inherited forms of bone marrow failure. In Hoffman R et al (eds) :Hematology: Basic principles and practice 4th edn. Philadelphia.

Kearns WG et al (2004); Genomic instability in bone marrow failure syndromes. Am J Hematol 76:220-224

Koijima S(1998); Hematopoietic growth factors and marrow stroma in Aplastic anemia. Int J Hematol 68:19-28.

Maciejewski JP et al (1996); A severe and consistent deficit in marrow and circulating primitive hematopoietic cells in acquired Aplastic anemia. Blood 88:1983-1991

Maciejewski JP et al (2003); Recombinant humanized anti-IL-2 receptor antibody produces response in patients with moderate Aplastic anemia.102:3584

Makoni SN & Laber DA (2004); Clinical spectrum of myelophthisis in cancer patients. Am J Hematol 76:92-93.

Marsh JCW et al (2003);Guide lines for the diagnosis and management of acquired Aplastic anemia .Br J Hematol 123:782-801.

Marsh JCW(2005); Management of acquired Aplastic anemia. Blood Rev. 19:143-151.

National Kidney Foundation (2001); K/DoQ1 clinical practice guidelines for anemia of chronic kidney disease. Am J Kidney Dis. 37(suppl1): S182-238

Philpott NJ et al (1995); Increased apoptosis in Aplastic anemia bone marrow progenitor cells: Possible pathophysiologic significance. Exp Hematol 23:1642

Prchal JT (2006); Anemia associated with marrow infiltration. In Lichtman MA et al (eds): Williams Hematology 7 th edn New York: Mcgraw –Hill .

Socie G et al (2000); Late clonal diseases of treated Aplastic anemia. Semin Hematol 37:91-101.

Young NS & Maciejewski JP(2005);Aplastic anemia: In Hoffman R et al edn; Hematology: Basic principles and practice, 4th edn. Philadephia 318

Autor:

Dr. Peter Ubah Okeke