Bone Marrow failure

KLIENSTAR CIARA MAGBOO, RMT, MLS (ASCPI)

 Pathophysiology of Bone marrow failure
• Reduction or cessation of blood cell production affecting
one more cell lines.
• Pancytopenia, or decreased numbers of circulating red
blood cells, white blood cells, and platelets.
2. Premature senescence and apoptosis of hematopoietic
stem cells (Mutation of Stem Cells)
3. Ineffective hematopoiesis due to stem cell
a. Deficiency in Vit B12 (maturation of RBC and Hemoglobin)

1. Destruction of hematopoietic Stem cells 4. Disruption of the bone marrow microenvironment that
a. Presence of Drugs supports hematopoiesis
b. Chemicals
5. Decreased production of hematopoietic growth factors or
c. Radiations
related hormones;
d. Viruses b. Erythropoietin
e. Autoimmune Mechanism. c. Thrombopoietin

6. Loss of normal hematopoietic tissue due to infiltration of

the marrow space with abnormal cells
Different forms of Bone Marrow Failure
1. Aplastic anemia
2. Pure red cell aplasia
3. Congenital Dyserythropoietic anemia
4. Myelophthisic anemia
5. Myelodysplastic syndrome
6. Anemia Chronic Kidney Disease
Aplastic anemia
•Rare but potentially fatal bone marrow failure syndrome
•1888 Ehrlich provided the first case report of aplastic anemia
•The name came from Vaquez and Aaubertin in 1904
•80%- 85% cases are acquired and 15% to 20% are inherited /
congenital
Aplastic Anemia
● The characteristic features of aplastic anemia include:
◦ Pancytopenia
◦ Reticulocytopenia
◦ Bone marrow hypocellularity
◦ Depletion of hematopoietic stem cells.
● Acquired or Hereditary
● Only a Manifestation of a Bone Marrow Failure but it’s not a final
diagnosis
 Acquired Aplastic anemia
2 categories:
Idiopathic acquired aplastic anemia
 Has no known cause
 70% of cases

Secondary aplastic anemia

 Associated with an identified cause
 10%-15% of cases
 Exposure to drugs, chemicals, radiation or infections

Have the same clinical and laboratory findings

May present with macrocytic or normocytic anemia and reticulocytopenia
Pancytopenia may develop slowly or progress at a rapid rate with complete cessation of hematopoiesis
Occurs occasionally as a complication of infection with Epstein-Barr virus, HIV, hepatitis virus and human
parvovirus B19
Acquired Aplastic anemia
Laboratory findings:
◦ Pancytopenia
◦ Red cell are macrocytic or normocytic
◦ Serum iron level and Percent transferrin saturation are increased
◦ Liver function test results may be abnormal if the pancytopenia was preceded by hepatitis
◦ Biopsy samples are required for an accurate quantitative assessment of the Marrow cellularity, and
Severe Hypocellularity is a characteristic feature

● Important Early Decisions that must be made, weather the patient candidate of Bone Marrow
Transplantation is having a Aplastic Anemia
● For this case we are gonna be needing a Bone Marrow Transplantation (Pancytopenia)
● Classified as: Normocytic, Normochromic Anemia (mostly)
Inherited/Congenital Bone marrow
Failure syndrome
•Present at an early age and may have characteristic physical
stigmata
•3 most common congenital bone marrow failure:
1. Fanconi anemia
2. Dyskeratosis congenita
3. Shwachman-Bodian-Diamond syndrome
Fanconi Anemia
•A chromosome instability disorder characterized by aplastic
anemia, physical abnormalities, and cancer susceptibility
•In 1927 Dr. Guido Fanconi first described this syndrome in 3
brothers with skin pigmentation, short stature, and
hypogonadism
•1 to 5 per million people
•Most common of the inherited bone marrow failure
syndromes
 Fanconi anemia
Mutation or deletions of 21 genes: FANCI
FANCA-has the highest frequency FANCJ
FANCB
FANCL
FANCC- mutations in this gene experience bone marrow
failure at a particular young age and have the poorest FANCM
survival
FANCN
FANCD1
FANCO
FANCD2
FANCP
FANCE
FANCF
FANCQ

FANCG FANCT
FANCV FANCU
Fanconi Anemia
Laboratory findings:
•Hematologic abnormalities may not appear until older childhood or adulthood
•Same as acquired aplastic anemia
•Macrocytic RBCs are often the first detected abnormality and thrombocytopenia
usually precedes the development of the other cytopenias
•Hemoglobin F is strikingly elevated and alpha fetoprotein is also increased
•Chromosomal breakage analysis is the diagnostic test for Fanconi anemia
o Compared to normal lymphocytes, FA cells have greater number of characteristic
chromosome breaks and ring chromosomes indicating increased fragility
Fanconi Anemia
Treatment and prognosis:
•More than 90% FA patients develop bone marrow failure by 40 years
of age
•1/3 of px develop MDS and/or acute myeloid leukemia by a median
age of 14 years, 25% develop solid tumorsby a median age of 26
years.
•Patients have an increased risk of developing vulvar cancer (4300
fold), esophageal cancer (2300 fold) AML (800 fold) and head/neck
cancer (700 fold)
Dyskeratosis Congenita
•Rare inherited bone marrow failure syndrome with an
incidence of approximately 4 cases per million per year.
•Characterized by mucocutaneous abnormalities, bone
marrow failure and pancytopenia
•Clinical presentation involves a triad of abnormal skin
pigmentation, dystrophic namil and oral leukoplakia
•Pulmonary fibrosis, liver disease, developing mental delay,
immunodeficiency, dental caries, and periodontal disease
Dyskeratosis Congenita
Genetics and pathophysiology:
DC chromosomes have a very short telomeres and inherited defects in the telomerase complex
Have mutation to 11 genes:
 TERC
 TERT
 TINF2
 RTEL1
 ACD
 CTC1
 NHP2
 NOP10
 PARN
 WRAP53
Dyskeratosis Congenita
Laboratory findings:
Pancytopenia and macrocytic RBCs
Fetal hemoglobin is increased
Treatment and prognosis:
Median survival : 42 years
Poor prognosis
 Shwachman-Bodian-Diamond syndrome
• A multisystem disorder characterized by pancreatic insufficiency, cytopenia, skeletal abnormalities and a
predisposition for hematologic malignancies.
• 8.5 cases per 1 million live births
• Have a peripheral blood cytopenia and decreased and pancreatic enzyme secretion
• Patients have neutropenia and immune dysfunction thus they are at risk of severe infection and sepsis
• Have delayed bone maturation and approx. 50% have failure to thrive and short stature
• SBDS gene is involved in ribosome biogenesis and mitotic spindle stability
• 72 hour fecal fat shows increased fat excretion and serum trypsinogen and isoamylase levels are
decreased compared with age-related reference intervals
• Have normal sweat test compared to cystic fibrosis
• No treatment available
Other forms of Bone marrow failure
1. Pure Red Cell Aplasia
Rare disorder of erythropoiesis characterized by a selective and
severe decrease in erythroid precursors in an otherwise normal bone
marrow.
Patients have severe anemia, reticulocytopenia and a normal WBC
and platelet counts.
May be acquired or congenital
1. Pure red cell aplasia
Acquired Pure Red cell Aplasia
May occur in children or adults
Primary PRCA: may be idiopathic or autoimmune related
Secondary PRCA: : may occur in association with an underlying thymoma,
hematologic malignancy, solid tumor, infection, chronic hemolytic anemia,
collagen vascular disease or exposure to drugs or chemicals
Transient erythroblastopenia of childhood: acquired form of PRCA in young
children
1. Pure red cell aplasia
Congenital Pure red cell aplasia
Diamond Blackfan Anemia
• Is a congenital erythroid hypoplastic disorder of early infancy with an estimated incidence of
7 to 10 cases per million live births
• Mutations to 17 genes: those encoding structural ribosome proteins and GATA1, a
transcription factor important for hematopoiesis
o Mutations to RPS19 has the highest frequency followed by RPL11 and RPS26
• Has a severe macrocytic anemia with reticulocytopenia
• WBC count is normal or slightly decreased and platelet count is normal or slightly increased
• Hb F is increased and RBC adenosine deaminase
• Therapy with RBC transfusions and corticosteroids responds to 50 to 75% patients although
side effects can be severe with long term use.
2. Congenital dyserythropoietic
anemia
•Heterogenous group of rare disorders characterized by
refractory anemia, reticulocytopenia, hypercellular bone
marrow with markedly ineffective erythropoiesis and
distinctive dysplastic changes in bone marrow erythroblasts.
•Iron overload develops even in the absence of blood
transfusions
•Jaundice, cholelithiasis and splenomegaly are the common
findings
3. Myelophthisic anemia
•Due to the infiltration of abnormal cells into the bone marrow and subsequent
destruction and replacement of normal hematopoietic cells
•Metastatic solid tumor cells, fibroblasts and inflammatory cells have been
implicated
•Cytopenia was seen with disruption of normal bone marrow architecture by the
infiltrating cells, the marrow releases immature hematopoietic cells
•The severity of anemia is mild to moderate, with normocytic erythrocytes and
reticulocytopenia
•Dacryocytes and nRBS with immature myeloid cells and megakaryocyte
fragments
4. Anemia of chronic Kidney disease
•Common complication of chronic kidey disease with a positive correlation
between anemia and renal disease severity
•The primary cause of anemia in CKD is inadequate renal production of
erythropoietin and chronic inflammation
•Uremia also inhibits erythropoiesis and increases RBC fragility.
•Hemodialysis and frequent blood draws results to chronic blood loss
•Normocytic, normochromic with reticulocytopenia
•Burr cells are common peripheral blood film
•Can lead to cardiovascular complication, cognitive impairment and suboptimal
quality of life.