WRITTEN REPORT GROUP 2

BONE MARROW FAILURE

Bone marrow failure involves producing small amounts or cessation of the blood cell production in the
body, wherein pancytopenia is observed the decreasing in numbers of circulating red blood cells, white blood
cells and platelets.
The syndromes in both children and adults include a group of disorders which 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 cells, myeloid cells, megakaryocytic cells).
This bone marrow film at
demonstrates a complete

400X magnification
absence of hematopoietic cells

PATHOPHYSIOLOGY

INVOLVES:

1. Destruction of
to injury caused by drugs

hematopoietic stem cells due

and other chemicals.

2. Premature senescence
hematopoietic stem cells

and apoptosis of
due to genetic mutations

3. Ineffective
B12 deficiency.

hematopoiesis due to vitamin

4. Destruction of bone marrow microenvironment which supports hematopoiesis.

5. Decreased in amount of hematopoietic growth factors and other hormones.
6. Loss of normal hematopoietic tissue.
Bone marrow failure results in failure to produce one or more blood cell lines increases patient
morbidity and mortality.
Morbidity and mortality from pancytopenia are caused by low levels of mature blood cells. Severe
anemia can cause cardiac failure and fatigue. Neutropenia can prompt individuals to bacterial and fungal
infections. Thrombocytopenia can cause spontaneous bleeding and hemorrhage.

APLASTIC ANEMIA

Is a rare but potentially fatal bone marrow failure syndrome.

It is a condition that occurs when your body stops producing enough new blood cells. Aplastic anemia
leaves you feeling fatigued and with a higher risk of infections and uncontrolled bleeding.

Aplastic anemia can develop at any age. Aplastic anemia may occur suddenly, or it can occur slowly and
get worse over a long period of time. Treatment for aplastic anemia may include medications, blood
transfusions or a stem cell transplant.

In 1888, Ehrlich provided the first case report of Aplastic anemia, neutropenia and hypocellular marrow on
post-mortem examination (examination of a human body after death). The name aplastic anemia was given to
the disease by Vaquez and Aubertin in 1904.
Signs and symptoms:

o
o
o
o

Pallor
Headache
Palpitations, dyspnea
Fatigue
Foot swelling
Gingival bleeding, petechial rashes
Overt and/or recurrent infections
Oropharyngeal ulcerations
Low platelet counts can cause:
nose bleeds
bleeding in the gums
the skin to bruise easily
rash with small pinpoints
A. ACQUIRED APLASTIC ANEMIA

Acquired aplastic anemia is a rare, serious blood disorder, due to failure of the bone marrow failure to
produce blood cells. Bone marrow is the spongy substance found in the center of the bones of the body,
in adults mainly the spine, pelvis, and large bones of the legs. The bone marrow contains hematopoietic
stem cells. Stem cells can produce more stem cells (self-renewal) and also differentiate and proliferate,
giving rise to red blood cells (erythrocytes), white blood cells (leukocytes), and platelets.
Acquired aplastic anemia occurs occasionally as a complication of infection with Epstein-Barr virus,
human immunodeficiency virus (HIV), hepatitis virus and human parvovirus B19.
It is also associated with pregnancy.
It is classified into to two major categories: Idiopathic and Secondary.

1. Idiopathic acquired aplastic anemia has no know cause. It is a type of anemia in which your bone
marrow stops making new blood cells.
2. Secondary acquired aplastic anemia is associated with an identified cause. It is a failure of the bone
marrow to make enough blood cells. All blood cell types are affected.
Etiology:
Idiopathic aplastic anemia is unknown. Secondary Aplastic anemia is associated with exposure to certain drugs,
chemicals, radiation, or infection. Cytotoxic drugs, radiation and benzene are responsible for 10% of this type
and suppress the bone marrow in a predictable, dose-dependent manner. An idiosyncratic reaction to drugs or
chemicals causes approximately 70% of secondary aplastic anemia.

o Idiosyncratic Reaction- also known as type B reactions are drug reactions that occur rarely and
unpredictably amongst the population. This is not to be mistaken with idiopathic, which implies that the
cause is not known.
Clinical Findings:
Symptoms vary in acquired aplastic anemia, ranging from asymptomatic to severe. Patients usually present with
symptoms of insidious-onset anemia with pallor, fatigue and weakness. Severe and prolonged anemia can result
in serious cardiovascular complications, including tachycardia, hypotension, cardiac failure and death.
Treatment and Diagnosis
This type of anemia requires immediate attention to prevent serious complications. Blood product replacement
should be given judiciously to avoid alloimmunization.
o Alloimmunization is defined as an immune response to foreign antigens after exposure to genetically
different cells or tissues.
Platelets should be not transfused at levels greater than 10,000/mL, unless the patient is bleeding.
One of the most important early decisions is determining whether the patient is a candidate for hematopoietic
stem cell transplantation (HCST) HSCT is the treatment of choice for patients who are younger than 40 years of
age and have a human leukocyte antigen (HLA) - identical siblings.
B. INHERITED APLASTIC ANEMIA

It is present at an earlier age and may have characteristic of physical stigmata. The three inherited
diseases for which bone marrow failure and pantocytopenia is a consistent feature of Fanconi anemia,
dyskeratosis congenital and Shwachman-Bodian-Diamond syndrome.

1. Fanconi anemia is a chromosome instability disorder characterized by aplastic anemia, physical

abnormalities and cancer susceptibility.
o In 1997, Dr. Guido Fanconi first describes this syndrome with three brothers with skin pigmentation,
short stature and hypoginadism.
o FA is the most common of the inherited aplastic anemias
o Fanconi anemia (FA) is one of the inherited anemias that lead to bone marrow failure (aplastic anemia).
It is primarily a recessive disorder: if both parents carry a defect (mutation) in the same FA gene, each of
their children has a 25% chance of inheriting the defective gene from both parents.
Clinical Findings
Physical malformations may are present at birth. Furthermore, only two thirds of patients have physical
malformations. These anomalies vary considerably, though there is higher frequency of skeletal abnormalities
(thumb malformation, radial hypoplasia, microcephaly, hip dislocation and scoliosis); skin pigmentation, short
stature and abnormalities of the eyes, kidneys and genitals. Low birth weight and developmental delay are also
common. Individual with FA have higher risk of cancer. This includes an increased incidence of leukemia in
childhood and solid tumors in adulthood.
2. Dyskeratosis Congenita (DKC) is a rare inherited bone marrow failure syndrome with fewer than 600
known cases.
o Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare, progressive
bone marrow failure syndrome characterized by the triad of reticulated skin hyperpigmentation, nail
dystrophy, and oral leukoplakia. Evidence exists for telomerase dysfunction, ribosome deficiency, and
protein synthesis dysfunction in this disorder. Early mortality is often associated with bone marrow
failure, infections, fatal pulmonary complications, or malignancy.

Clinical Findings
It is characterized by mucocutaneous abnormalities, bone marrow failure, and pantocytopenia.
3. Shwachman-Bodian-Diamond syndrome (SBDS) is an inherited multisystem disorder characterized by
pancreatic insufficiency, cytopenia, skeletal abnormalities and a predisposition for hematologic
malignancies.
Clinical Findings
Patient with SBDS have peripheral blood cytopenia and decreased pancreatic enzyme secretion.
o Skeletal abnormalities are another common feature of Shwachman-Diamond syndrome. Many affected
individuals have problems with bone formation and growth, most often affecting the hips and knees.
Low bone density is also frequently associated with this condition. Some infants are born with a narrow
rib cage and short ribs, which can cause life-threatening problems with breathing. The combination of
skeletal abnormalities and slow growth results in short stature in most people with this disorder.
o The complications of this condition can affect several other parts of the body, including the liver, heart,
endocrine system (which produces hormones), eyes, teeth, and skin. Additionally, studies suggest
that Shwachman-Diamond syndrome may be associated with delayed speech and the delayed
development of motor skills such as sitting, standing, and walking

Treatment and Prognosis

No treatment of hematologic features is required. However, if needed, a treatment consist of G-CSF for
neutropenia, transfusion support for anemia and thrombocytopenia and enzyme replacement for pancreatic
insufficiency.
Differential Diagnosis
A distinction must be made between acquired aplastic anemia, inherited aplastic anemia, and other causes of
pantocytopenia, including PNH, MDS, megaloblastic anemia and leukemia. The importance of a correct
diagnosis is clear, as diagnostics conclusion dictate the therapeutic management and prognosis.
PURE RED CELL APLASIA
Pure red cell aplasia (PRCA) or erythroblastopenia refers to a type of anemia affecting the precursors to red
blood cells but not to white blood cells. In PRCA, the bone marrow ceases to produce red blood cells. Patients
present with severe anemia, Reticulocytopenia, and a normal WBC and Platelet count. It can be acquired or
congenital. The anemia due to PRCA is usually normocytic but can be macrocytic.
In adults, most cases of chronic PRCA are idiopathic. Secondary PRCA occurs in patients with conditions such
as autoimmune disorders, thymomas, systemic lupus erythematosus, hematologic malignancies, and solid
tumors.
The life expectancy of patients with idiopathic PRCA is about 1-2 decades. The survival of patients with
congenital PRCA is limited. The lifespan of patients with secondary PRCA depends on the course of the
underlying disorder.
Acquired PRCA

May occur in children or adults, can be acute or chronic .Primary may be idiopathic or autoimmune
related. Secondary may occur association with an underlying hematologic malignancy, solid tumor
infection, chronic hemolytic anemia, collagen vascular disease, or drug induced or chemicals. Therapy
involves treatment of the underlying condition and immunosuppression.
Acquired form of PRCA in children is also known as Transient erthroblastopenia of childhood
(TEC). Is a selflimiting, benign disorder, A history of a recent viral infection is usually noted.

Acquired primary (idiopathic) PRCA is the most common form of red cell aplasia in adults.
PRCA can also be secondary to and is associated with the following:

Thymoma
Hematological malignancies (e.g., B- and T-cell chronic lymphocytic leukemia)
T-cell large granular lymphocyte leukemia and solid tumors
Infections
Drugs
Pregnancy
Systemic lupus erythematosus
Renal failure
PRCA can occur following ABO-mismatched marrow transplantation.
CONGENITAL PRCA OR DIAMOND-BLACKFAN ANEMIA

Diamond-Blackfan syndrome is a rare congenital PRCA that is usually detected at birth, or later during the first
18 months of childhood. Affected individuals usually have a macrocytic anemia. The expression of hemoglobin
F and surface I antigen in erythrocytes is increased, indicating erythrocyte immaturity
About one third of these patients have developmental defects, including cleft palates, macroglossia, craniofacial
defects, thumb or upper limb abnormalities, cardiac defects, and urogenital malformations. Growth is often
retarded. A modest increased risk for leukemia and neoplasms is noted.
Karyotype normal, WBC are normal or slightly decreased, platelet normal or slightly increased,
Therapy includes transfusion and corticosteroids, Stem cell transplantation may be considered for patients with
severe anemia and an HLA-identical sibling.
CONGENITAL DYSERTHROPOIETIC ANEMIA
Congenital dyserythropoietic anemia (CDA) is an inherited blood disorder that affects the development of red
blood cells. This disorder is one of many types of anemia, which is a condition characterized by a shortage of
red blood cells. This shortage prevents the blood from carrying an adequate supply of oxygen to the body's
tissues. The resulting symptoms can include tiredness (fatigue), weakness, pale skin, and other complications.
There are three major types of CDA:
A. Type I is characterized by moderate to severe anemia. This condition also causes the body to absorb too
much iron, which builds up and can damage tissues and organs. In particular, iron overload can lead to an
abnormal heart rhythm (arrhythmia), congestive heart failure, diabetes, and chronic liver disease (cirrhosis).
Most often involving the fingers and/or toes.

It is caused by mutation in CDAN1 gene on chromosome 15. CDAN1 codes for codanin-1 important for
nuclear envelope integrity. RBC are macrocytic and may exhibit basophilic stippling and cabot rings.
Treatment: Interferon-a and iron depletion.
B. Type II most common type and is autosomal recessive. The gene associated with CDA type II maps to
chromosome 20. The anemia can range to mild to severe .The Hb is usually 8-11g/dL, RBC are normocytic with
anisocytosis, poikilocytosis and basophilic stippling. It results in mutations in SEC23B gene
C. Type III the least common, a familial autosomal dominant form was found in three families and is mapped
to the chromosome 15: the non-familial or sporadic for is extremely rare .Signs and symptoms are milder.
Patients are transfusion independent and clinical iron is not observed.\
Causes of PRCA include:

Autoimmune disease
Thymoma
Viral infections such as HIV, herpes, parvovirus B19 (Fifth disease), or hepatitis

Treatment
PRCA is considered an autoimmune disease as it will respond to immunosuppressant treatment such
as ciclosporin in many patients, though this approach is not without risk.
It has also been shown to respond to treatments with Rituximab and Tacrolimus.

MYELOPHTHISIC ANEMIA
Myelophthisis is a form of bone marrow failure that results from the destruction of bone marrow
precursor cells and their stroma, which nurture these cells to maturation and differentiation. It is the infiltration
of abnormal cells into the bone marrow and subsequent destruction and replacement of the normal
hematopoietic cells.
The most common causes of infiltrative myelopathy are metastatic carcinomas (eg, lung, breast, and
prostate cancer), lymphoproliferative malignancies (eg, lymphomas), disseminated granulomatous diseases (eg,
miliary tuberculosis),and rare diseases (eg, Gaucher disease).

This bone marrow film at 400X magnification demonstrates carcinoma

metastasis. Bone marrow cells are completely replaced by large
carcinoma cells with clear nucleoli.

It is suspected in patients with normocytic anemia, particularly when splenomegaly or a potential

underlying disorder is present. Its causes include tumors, granulomatous disorders, and lipid storage diseases.
Marrow fibrosis often occurs. Splenomegaly may develop that later may result Myeloid metaplasia.,

If it is suspected, a peripheral smear should be obtained, a typical findingsshows teardrop erythrocytes

and nucleated RBCs, presence ofmegakaryote fragments and giant platelets exhibiting immature myeloid cells
or what so called leukoerythroblastic pattern, suggests myelophthisic anemia. Anemia, usually moderately
severe, is characteristically normocytic but may be slightly macrocytic. RBC morphology may show extreme
variation (anisocytosis and poikilocytosis) in size and shape. The WBC count may vary. The platelet count is
often low, and platelets are often large and bizarre in shape. Reticulocytosis often occurs. It may be caused by
premature release of reticulocytes from the marrow or extramedullary sites and thus does not always indicate
increased blood regeneration.

This blood film at 1000X magnification demonstrates a leukoerythroblastic blood picture with the presence of
precursor cells of the myeloid and erythroid lineage. In addition, anisocytosis, poikilocytosis, and
polychromasia can be seen.

ANEMIA OF CHRONIC KIDNEY DISEASE

Richard Bright in 1836 first observed that anemia was a complication of a renal failure. Robert
Christison further described renal anemia. In 1977, Miyake purified and identified erythropoietin. In December
2, 1985, the first human use of EPO was devised by Eschbach.
Anemia refers to an absolute reduction of the total number of circulating red blood cells (RBCs).It is
linked to left ventricular dysfunction, heart failure, reduced exercise tolerance and reduced quality of life. It is a
condition wherein the number RBCs or their carrying capacity is insufficient to meet physiologic needs which
may vary by age, sex, attitude, smoking and pregnancy status. (WHO)
Anemia in CKD is typically normocytic, normochromic, and hypoproliferative. The demonstration of a
circulating factor responsible for stimulating erythropoiesis, and the kidney as the main source of erythropoietin
(EPO) in the 1950s.Although generally normal or slightly increased in anemia of CKD, EPO levels are
considered inappropriately low relative to the degree of anemia, because similarly anemic patients with normal
kidney function have 10100 times higher EPO levels.One important limitation of such assays is that they
measure all immunogenic EPO fragments, which do not all correlate with biologic activity.
When kidneys are diseased or damaged, they do not make enough erythropoietin (EPO). As a result, the
bone marrow makes fewer red blood cells, causing anemia. The major cause of the anemia in CKD is the
inadequate production of erythropoietin by the kidneys or. Without erythropoietin, the bone marrow is unable to
increase RBC production in response to tissue hypoxia, and anemia ensues. Other factors may also contribute.
Anemia in CKD is usually normocytic and normochromic, with normal or decreased reticulocytes. Burr cells
may be present as a result of uremia. Anemia in CKD can lead to cardiovascular complications, faster

progression to kidney failure. The other effects of anemia in CKD is the acceleration of progression of kidney
disease by oxygen depriviation, increased risk of bacteremia (11% increased risk for every 1g/dL fall in Hb) and
detrimental effects on brain and cognitive functions. The causes of anemia in CKD are relative EPO deficiency,
shortened RBC survival, bone marrow suppression, other vitamin deficiencies (B12 and folic acid), iron
deficiency, inflammation, and blood loss and hypoparathyroidism.
For diagnosis and further evaluation Hb values according to NKF guidelines:

<13.5 g/dL in adult males

<12.0 g/dL in adult females

This definition represents the mean Hb of lowest fifth percentile of the sex specific general adult population.
Treatment of anemia resulting from CKD involves administration of recombinant human erythropoietin
or other erythropoiesis stimulationg agents or ESAs with goal keeping the hemoglobin generally between
11g/dL and 12 g/dL. Hemoglobin above 13 g/dL is not recommended because of an increase in the risk of
cardiovascular and thromboembolitic complications. Successful ESA therapy requires adequate iron stores,
plasma ferritin level and percent transferrin saturation are also monitored. Iron is administered with ESA
therapy to maintain the transferrin saturation above 20% and the plasma ferritin level above 100 ng/mL for
hemodialysis dependent CKD patients. Iron therapy is not routinely recommended if the ferritin level is above
500 ng/mL.
Patient may becomehyporesponsive to ESA therapy due to functional iron deficiency. The transferrin
saturation remains below 20% but the serum ferritin level is either normal or increased which indicates adequate
iron stores. Patients bearing FID are unable to reach or maintain target hemoglobin. However, they may be able
to reach the target hemoglobin after intravenous iron therapy. Some other causes of hyporesponsiveness to ESA
therapy include chronic inflammatory disease, infection, malignancy, aplastic anemia, antibody mediated
PRCAA, thalassemia, multiple myeloma and presence of Hb H or Hb S.
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WebMD LLC. (2016). Bone marrow failure. Retrieved September 15, 2016
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GROUP MEMBERS:
ABELLA, CRISTINA
ABULE, MARY GRACE
ARPON, MA. ROANN
BAUTISTA, JOHN KOBE
BUENCONSEJO, DIANA ROSE
DOMINGO, AARON
LARDIZABAL, JASMIN ANN
MAGALONA, GEMELA
MIRAFLOR, ANGEL
ORIAL, PAULA LIZA
SAN PEDRO, JOHN ELLISON