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Bone Marrow failure – An issue of medical emergency




Enviado por Dr. Peter Ubah Okeke



  1. Abstract
  2. Introduction
  3. Aplastic Anemia
  4. Acquired Aplastic anemia
  5. Etiology
  6. Pathophysiology
  7. Clinical Findings
  8. Laboratory Findings
  9. Treatment and Prognosis
  10. Acquired Pure Red cell
    Aplasia
  11. Myelophthisic Anemia
  12. Anemia of chronic Renal
    Insufficiency
  13. References

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

 

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