[SUMMARY NOTES] ANEMIA OF BONE MARROW DISORDERS

▪ haematopoietically ACTIVE marrow

▪ Consists of developing blood cells & their
OUTLINE progenitors
I Introduction ▪ During infancy & early childhood, all
A Basic Anatomy & Physiology of Bone bones contain this red marrow
Marrow o Yellow marrow:
Pathophysiology of Bone Marrow Failure
▪
B
haematopoietically INACTIVE marrow
II Aplastic Anemia
A. Inherited Aplastic Anemia ▪ Consists of adipocytes, with
i. Fanconi Anemia (FA) undifferentiated mesenchymal cells &
ii. Dyskeratosis Congenita macrophages.
iii. Shwachman-Bodian-Diamond Syndrome ▪ Between 5 to 7 y/o, adipocytes become
B. Acquired Aplastic Anemia more abundant & begin to occupy the
i. Introduction to Secondary Aplastic Anemia spaces in the long bones previously
ii. Drugs and Chemicals dominated by active marrow
iii. Radiation (RETROGRESSION)
iv. Immune Mechanism ▪ Yellow marrow is able to revert back into
v. Miscellaneous Ethiologies active marrow (e.g., excessive blood loss
III Other Forms of Bone Marrow Failure or hemolysis)
A. Pure Red Cell Aplasia
B. Acquired Pure Red Cell Aplasia
C. Diamond-Blackfan Anemia
D. Congenital Dyserythropoietic Anemia
E. Myelophthisic Anemia
F. ANEMIA OF CHRONIC KIDNEY DISEASE

BASIC ANATOMY & PHYSIOLOGY OF BONE

MARROW
● Bone marrow
o is one of the largest organs in the body
o Location: Cavities of the cortical bones
o Trabeculae radiate out from the bone cortex
into the central space forming a three-
dimensional matrix resembling a honeycomb.
● 2 major components of normal bone marrow
o Red marrow

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 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

PATHOPHYSIOLOGY OF BONE MARROW FAILURE Table No. 1 Diagnostic Criteria for Severe Aplastic
● Bone marrow failure is the reduction or cessation Anemia
of blood cell production affecting one or more cell
lines.
● General Pathophysiology:
1. The destruction of hematopoietic stem cells
due to injury by drugs, chemicals, radiation,
viruses, or autoimmune mechanisms
2. Premature senescence and apoptosis of
hematopoietic stem cells due to genetic
mutations
3. Ineffective hematopoiesis due to stem cell
mutations or vitamin B12 or folate deficiency
4. Disruption of the bone marrow
microenvironment that supports
hematopoiesis
5. Decreased production of hematopoietic
growth factors or related hormones
6. The loss of normal hematopoietic tissue due Table No. 2 Etiologic Classification of Aplastic Anemia
to infiltration of the marrow space with
abnormal cells. ACQUIRED INHERITED
● Clinical consequences: •Idiopathic (70% of cases) 1. Fanconi anemia
o Depends on the extent & duration of • Secondary (10% to 15% of cases) 2. Dyskeratosis
cytopenias Dose dependent/predictable congenita
o Severe pancytopenia can be rapidly fatal if 1. Cytotoxic drugs 3. Shwachman-
2. Benzene Bodian-Diamond
untreated 3. Radiation syndrome
o Thrombocytopenia: result in bleeding and Idiosyncratic Drugs
increased bruising  Chemicals
o Decreased RBCs and hemoglobin: result in • Insecticides
• Cutting/Lubricating oils
fatigue, pallor, and cardiovascular
complications Viruses
o Sustained neutropenia: increases the risk of 1. Epstein-Barr virus
life threatening bacterial or fungal infections. 2. Hepatitis virus (non-A, non-B,
non-C, non-G)
3. Human immunodeficiency
APLASTIC ANEMIA virus
● Rare but potentially fatal bone marrow failure
syndrome Miscellaneous conditions
● First reported in 1888 by Erlich 1. Paroxysmal nocturnal
hemoglobinuria
● The name was given to the disease by Vaquez and
2. Autoimmune diseases
Aubertin in 1904 3. Pregnancy
● Characteristic features:
o Pancytopenia: decreased numbers of
INHERITED APLASTIC ANEMIA
circulating red blood cells (RBCs), white blood
● In comparison with acquired aplastic anemia,
cells (WBCs), and platelets
patients with inherited aplastic anemia present at
o Reticulocytopenia
an earlier age and may have characteristic physical
o Bone marrow hypocellularity
stigmata.
o Depletion of hematopoietic stem cells
● 80- 85% → Acquired Aplastic Anemia
● 15-29% → Inherited Aplastic Anemia

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 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

● The three inherited diseases for which bone CLINICAL PRESENTATION

marrow failure and pancytopenia are a consistent ● Higher frequency of:
feature are: o Skeletal abnormalities (thumb malformations,
1. Fanconi anemia radial hypoplasia, microcephaly, hip
2. Dyskeratosis congenita dislocation, and scoliosis)
3. Shwachman-Bodian-Diamond syndrome. o Skin pigmentation (hyperpigmentation,
hypopigmentation, café-au-lait lesions)
1. FANCONI ANEMIA (FA) o Short stature
● MOST COMMON among other inherited aplastic o Abnormalities of the eyes, kidneys & genitals.
anemia o Low birth weight and developmental delay
● Description: a pantocytopenic chromosome o Leukemia in childhood & solid tumors (e.g.,
instability disorder with a hyopoplastic to aplastic oral, esophageal, anogenital, cervical) in
bone marrow, physical abnormalities, & cancer adulthood
susceptibility. ● Symptoms: become apparent at 5 to 10 years of
age
ETIOLOGY & PATHOPHYSIOLOGY
● Dr. Guido Fanconi first described FA in 3 brothers LABORATORY FINDINGS & CORRELATION
with skin pigmentation, short stature, & ● HEMATOLOGY
hypogonadism in 1927. o Peripheral blood abnormalities generally don’t
● Rare; consanguinity (Ashkenazi Jews) manifest themselves until 5-10 yrs. after birth.
● Mode of Inheritance: Autosomal recessive o Macrocytic RBCs often detected first, followed
o EXCEPT for FANCB, which is X-linked recessive by anemia, neutropenia, & thrombocytopenia.
● 15 genes are associated with FA. o Anisocytosis & poikilocytosis
● FANCA gene has the highest frequency o Marked increased in Hb F and decreased in Hb
● FA cells are: A
o Highly susceptible to chromosomal breakage o Osmotic fragility & ESR is increased
o Accelerated telomere shortening & apoptosis, o Bone marrow is normocellular (diagnosed
a late S-phase cell cycle delay, hypersensitivity early) → hypoplastic→ aplastic anemia
to oxidants, and cytokine dysregulation
● FA pathway consists of: ● CYTOGENETICS
Nuclear core complex o Chromosomal breakage analysis: Diagnostic
▪ A, B, C, E, F, G, L, test for FA.
and M form ▪ Lymphocytes are cultured w/ DNA cross-
▪ Facilitates the linking agents diepoxybutane (DEB) or
monoubiquitylation mitomycin C (MMC)
& activation of the ▪ Results:
ID complex. - Multiple chromosomal abnormalities
Protein ID complex - Ring chromosomes
▪ D2 and I form - Translocations
▪ Localizes with - Spontaneous breaks
effector - Increased fragility
DNA repair proteins at
foci of DNA damage to TREATMENT, PROGNOSIS & MANAGEMENT
effect DNA ● Prognosis: POOR before the advent of androgen
▪ repair. therapy (Life expectancy: 2-4 yrs. after the
Effector proteins appearance of hematologic symptoms)
▪ D1, J, N, O, and P

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 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

● Breakthrough & advancements: ▪ one or more mutation on the long arm of

o Androgens & Corticosteroids: maintain Hb X-chromosome on the DKC1 gene
level dyskerin
o Transfusions & administration of cytokines (G- ✓ DYSKERIN: ribonucleoprotein
CSF & GM-CSF) involved in RNA processing and it
o HSCT: ONLY curative treatment (preferably associates with TERC in the
from an HLA-identical sibling) telomerase complex
o Bone marrow transplant o Autosomal dominant:
o Gene therapy (unsuccessful) ▪ Dyskeratosis congenita, Scoggins type
▪ Mutation in the genes that encode TERC,
2. DYSKERATOSIS CONGENITA
TERT, or TINF2
ETIOLOGY & PATHOPHYSIOLOGY
o Autosomal recessive:
● Also known as Zinsser-Cole-Engman syndrome
▪ Mutations in TERT, NHP2, NOP10,
● LATIN: Dyskeratosis “irreversible degradation of
WRAP53 and CTC1
skin” Congenita “inborn”
● Rare inherited bone marrow failure syndrome with
CLINICAL PRESENTATION
fewer than 600 known cases worldwide.
TRIAD OF:
● Characterized by Mucocutaneous abnormalities,
A. Hyperpigmentation of skin: Lacy reticular
Bone marrow failure, Pancytopenia
pigmentation of the upper chest and/or neck.
● DKC chromosomes have short telomeres and
May be subtle or diffuse hyper- or
inherited defects in the telomerase complex
hypopigmentation
● SHORTENED TELOMERES IN DKC
B. Oral Leukoplakia: white patches in the mouth
o Cause premature death in the rapidly dividing
C. Nail dystrophy: ridging, flaking, or poor
cells in the bone marrow and epithelium
growth, or more diffuse with nearly complete
o Likely lead to genomic instability and
loss of nail
predisposition cancer
● MULTISYSTEM ABNORMALITIES
o Pulmonary fibrosis
o Liver disease
o Developmental delay
o Short stature
o Microcephaly
o Prematurely grey hair or hair loss

● MEDIAN AGE OF DIAGNOSIS

o 15 years old
o 30 years old (80-90% have bone marrow
abnormalities)
o 50 years old (40% have risk of cancer most
● INHERITED DEFECTS IN THE TELOMERASE commonly AML, MDS and epithelial
COMPLEX malignancies)
o 8 different genes can be inherited in 3
different patterns: X-linked recessive, LABORATORY FINDINGS & CORRELATIONS
Autosomal dominant and Autosomal ● Check family history
recessive ● Peripheral blood smear: Pancytopenia &
o X-linked recessive: Macrocytic RBC
▪ Zinsser-Cole-Engleman syndrome ● Fetal hemoglobin level: increased
● Complete blood count: abnormally low

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 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS
SPECIAL TESTS
● FLUORESCENCE IN SITU HYBRIDIZATION (FISH)
TEST
o Diagnostic test for suspected DKC who lack
mutations in known genes
o cost-effective method to measure telomere
length in WBC subsets
o can identify very short telomeres in both
clinically apparent and silent disease
● SERIAL SINGLE-GENE TESTING
o Sequence analysis of the gene of interest is
performed first, followed by gene-
targeted deletion/duplication analysis if
no pathogenic variant is found.
o Targeted analysis for pathogenic variants can
be performed first in individuals of Ashkenazi
Jewish ancestry for the c.3791G> A
(p.Arg1264His) pathogenic variant in RTEL1.
● INVITAE DYSKERATOSIS CONGENITA PANEL
o analyzes genes associated with dyskeratosis
congenita (DC)
o Enables in the dentification of a disease-
causing variant
o PREFFERED SPECIMEN: 3mL whole blood in
EDTA (K2EDTA or K3EDTA)
o ALTERNATE SPECIMENS: Saliva, assisted
saliva, buccal swab, gDNA
o TURN AROUND TIME: 10-21 days
TREATMENT & MANAGEMENT
● Median survival for patients with DKC is 42 years
● Androgen therapy – transient response but does
not halt the progression of the bone marrow
failure. Can improve blood count
● Hematopoietic stem cell transplantation -only
long-term, curative treatment option for bone
marrow failure in DKC patients but does not
improve tissues affected by the condition.
GENERAL TREATMENT RECOMMENDATIONS
● Avoid smoking and alcohol to preserve the lungs
and liver
● Use Moisturizing creams to prevent damage to
the skin
● Good dental hygiene
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3. SHWACHMAN-BODIAN-DIAMOND SYNDROME
● Inherited multisystem disorder characterized by
pancreatic insufficiency, cytopenia, skeletal
abnormalities, and a predisposition for
hematologic malignancies.
● 8.5 cases / 1 million live births
ETIOLOGY & PATHOPHYSIOLOGY:
● Autosomal recessive disorder
o Biallelic mutations in SBDS gene (90%)
● SBDS gene:
o Chromosome 7 (7q11)
o Involved in ribosome metabolism and mitotic
spindle stability
o NOTE: SBDS gene is still under study
regarding its purposes
● Relationship to the disease manifestations is
currently unknown.
o Quantitative and qualitative deficiencies in
CD341 cells
o Dysfunctional bone marrow stromal cells
o Increased apoptosis and mitotic spindle
destabilization in hematopoietic cells
o Short telomeres in peripheral blood
granulocytes
CLINICAL PRESENTATIONS:
● Bone marrow malfunction
o Neutropenia
o Immune dysfunction
o Increased risk of severe infections
o Sepsis
o Higher chance of acquiring: (19% & 36%)
▪ Myelodysplastic syndrome (MDS)
▪ Acute myeloid anemia
▪ Leukemia
5
 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

● Pancreatic insufficiency NOTE: SBDS and Cystic Fibrosis may have the same
o Gastrointestinal malabsorption (early infancy) clinical presentations, thus the need for a differential
o Failure to thrive diagnosis.
o Short stature.
SPECIAL TESTS
● Skeletal abnormality ● SBDS Sequencing
o Delayed bone maturation
o Analysis of SBDS gene through a bi-directional
o Physical malformations sequencing of the coding regions and splice
o Low bone density sites of exons 1-5 of the SBDS gene.
o Uses next generation sequencing (NGS)
LABORATORY FINDINGS ● Specimen:
Table No. 3- 4 Laboratory Findings of Secondary o Whole blood
Aplastic Anemia o Buccal cell swab
● Volume:
o 1-5 mL or 2 swabs
● Interpretations:
o Positive: mutation detected
o Negative: no mutation detected

OTHER TESTS
● 72-hour fecal fat measurement
o Presence of steatorrhea
● Secretin-cholecystokinin quantitative stimulation
test
o Absence/decreased levels of trypsin, lipase,
colipase, and amylase
● Sweat test
o Differential diagnosis test for cystic fibrosis
● Vitamin A, D, E, and K levels
● Fetal hemoglobin levels
● MRI/CT Scan
● CBC

TREATMENT, PROGNOSIS, & MANAGEMENT

Table No. 5 Shwachman-Bodian-Diamond Syndrome
● IF NEEDED:
Vs. Cystic Fibrosis
o Supportive treatment
▪ G-CSF injection for neutropenia
▪ Transfusion support for anemia and
thrombocytopenia.
▪ Enzyme replacement for pancreatic
insufficiency.
▪ Allogeneic bone marrow transplantation
for severe pancytopenia, AML, and MDS.
o Curative treatment
o Hematopoietic stem cell transplantation
▪ Graft failure
▪ Transplant-related toxicities

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 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

▪ Recurrent leukemia concentrations and vacuolation of the ma

● Prognosis: rrow erythroblasts.
o 5-year overall survival is 60% to 65% o How does Chloramphenicol causes Aplastic
▪ severe infections and malignancy Anemia?
▪ It may cause bone marrow suppression
INTRODUCTION OF SECONDARY APLASTIC during treatment; this is a direct toxic
ANEMIA effect of the drug on human mitochondria.
● Secondary aplastic anemia is associated with an This effect manifests first as a fall in
identified cause hemoglobin levels, which occurs quite
● Approximately 70% of all aplastic anemia is predictably once a cumulative dose of 20g
IDIOPATHIC has been given to the patient.
● Whereas 10% to 15 percent in Secondary Aplastic ● Cytotoxic drugs (alkylating agents,
Anemia antimetabolites, antimitotics, some antibiotics)-
● Which is also known for Secondary acquired Agents that regularly produce marrow depression
aplastic anemia as major toxicity in commonly employed doses or
● Is associated with an identified cause normal exposures
● exposure of certain drugs, radiation, chemicals, or ● Other drugs and chemicals include:
infection. o Benzene
● Viruses ▪ Agents that frequently but not inevitably
o Epstein-Barr Virus produce marrow aplasia
o Hepatitis Virus (Non-A, non-B, non-C, non-G) ▪ Benzene causes harmful effects on
o HIV the bone marrow and can cause a
o Parvovirus B19 decrease in red blood cells, leading to
● Idiosyncratic anemia. It can also cause excessive
o Drugs bleeding and can affect the immune
o Chemicals system, increasing the chance for
o Insecticides infection.
o Cutting/lubricating oils
▪ Benzene derivatives, hydantoins,
● Dose dependent
sulfonamides, and gold preparations.
o Cytotoxic drugs
Pesticides/ Insecticides such as chlordane,
o Benzene
chlorophetanol and gamma benzene
o Radiation
hexachloride

● Miscellaneous conditions
RADIATION
o Paroxysmal nocturnal hemoglobinuria
● Long term exposure to radiation could lead to
o Autoimmune diseases
Aplastic Anemia
o Pregnancy
● It can damage stem cells or the hematopoietic
microenvironment
DRUGS AND CHEMICALS
● Marrow aplasia can be an acute sequel to
● Chloramphenicol- usual drug associated with
radiation.
Aplastic Anemia
● Nuclear accidents power plant workers,
o What is the effect of Chloramphenicol?
employees of hospitals, laboratories, and industry
▪ Due to its ability to reversibly inhibit (food sterilization, metal radiography) are
mitochondrial protein susceptible to it.
synthesis and ferrochelatase found on the ● MDS and leukemia, but probably not aplastic
inner membrane of mitochondria. The anemia, are late effects of radiation.
hematologic effects occur in sequence.
Initially, increased serum iron

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 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

IMMUNE MECHANISM LABORATORY FINDINGS & CORRELATIONS

● Autoimmune mechanism
● Patients with aplastic anemia were condition with
cyclophosphamide which leads to
immunologic mechanism
● Lymphocytes from patients with aplastic anemia
suppresses growth of normal marrow cells in vitro
● Anti-thymocyte globulin - an anti for lymphocyte
to suppress normal marrow cell in vivo
● Human natural killer cells or HNK cells
● Abnormal composition of t cell subsets in the
bone marrow (Tac+,T3+, and T11+)
● Humoral inhibitor of stem cells growth that may
lead either idiopathic or associated with Systemic
Lupus Erythromatosus, Quinidine,
Cryoglobulinemia
MISCELLANEOUS ETHIOLOGIES
● Aplastic anemia associated diseases:
o Non-A & non-b Hepatitis
o military tuberculosis, brucellosis, and parasitic
infection
o Pancytopenia that leads to hypersplenism
o myeloid disorders (paroxysmal nocturnal
hemoglobinuria)
o Leukemia due to hypoplastic marrow with
peripheral blood pancytopenia
o Rarely seen in pregnant, if it is present, it will
disappear after the pregnancy
CLINICAL PRESENTATION
● Directly related to Pancytopenia
● Important Note: NO SPLENOMEGALY
● Insidious-onset Anemia
o Pallor
o Fatigue
o Weakness
● Severe and Prolonged
o Cardiovascular Complications
o Death
● Neutropenia
o High Bacterial Infection
o No Viral Infection
o Fever
● Thrombocytopenia
● Petechiae & Bruising
● Epistaxis & Mucosal Bleeding
● Menorrhagia
● Acquired pancytopenia = anemia, leukopenia and
thrombocytopenia
● The cytopenia= fatigue, cardia failure, infection,
and bleeding
● Peripheral blood smear:
o Decreased total leukocytes
o Lymphocytes is normal to slightly decreased
o Normal red cell morphology
o Decreased reticulocyte count in PB
o No immature cells in PB
● Bone marrow:
o Hypoplastic/Aplastic
o Lymphocyte and Plasma cells are present
or o Megakaryocytes are absent
o No increase number of immature cells
o With patchy areas of cellularity
SPECIAL HEMATOLOGY TESTS
● Hemoglobin F = elevated
● Kleihauer-Betke acid elution test = unevenly
distributed in red cells
● Leukocyte alkaline phosphatase (LAP) score =
elevated
● Ham acid-serum test = may be positive in aplastic
anemia
CHEMISTRY
● Serum iron = elevated
● Plasma iron = delayed – patient has adequate iron
stores but decreased uptake of iron
DIFFERENTIAL DIAGNOSIS
● A distinction must be made between acquired
aplastic anemia, inherited aplastic anemia, and
other causes of pancytopenia.
● Diagnostic conclusions dictate therapeutic
management and prognosis.
● Alternative diagnoses include lymphoma,
myelofibrosis, and mycobacterial infections.
● Physical findings- generally rule out aplastic
anemia including splenomegaly or
lymphadenopathy
● Radiographic studies- necessary to rule out
primary or metastatic bone tumors or other focal
lesions
● Immature erythrocytes/ leukocyte- rule out
aplastic anemia and indicates other disorder

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 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

Table No. 6 Differentiation of Aplastic Anemia from Table No. 8 Differential Diagnosis of Pancytopenias
other Causes of Pancytopenia

OTHER FORMS OF BONE MARROW FAILURE

PURE RED CELL APLASIA (PRCA)
● Description: rare disorder of erythropoiesis
characterized by a selective and severe decrease
in erythrocyte precursors in an otherwise normal
bone marrow.
● Patients have severe anemia (usually normocytic),
reticulocytopenia, and normal WBC and platelet
Table No. 7 Key Characteristics of Inherited/Congenital
counts
Bone Marrow Failure Anemias
● May be acquired or inherited
o Note: It is important to distinguish b/n
acquired & congenital forms, as they require
different therapeutic approaches

ACQUIRED PURE RED CELL APLASIA

● Transient erythroblastopenia of childhood (TEC)
o Acquired form of PRCA in children
● Primary PRCA
o Idiopathic
o Autoimmune-related
▪ Immunoglobulin inhibitor of erythroid
precursors
▪ Antinuclear Ab
● Secondary PRCA: may occur in association with:
o Thymoma (most significant)
o Hematologic malignancy
o Solid tumor
o Infection
o Chronic hemolytic anemia
o Collagen vascular disease
o Exposure to drugs or chemicals
CLINICAL PRESENTATION
● Anemia develops insidiously, meaning in gradual,
subtle way, but with harmful effects
● EXTREME PALLOR: the only constant finding

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 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

● Significant number of patients have ● Marked growth retardation & failure of secondary
splenomegaly, hepatomegaly, or both sexual maturation (>14y/o)
(consequence of hemosiderosis) ● Craniofacial dysmorphisms, short stature, and
neck & thumb malformations
LABORATORY FINDINGS & CORRELATION LABORATORY FINDINGS & CORRELATION
● HEMATOLOGY ● Severe macrocytic anemia with reticulocytopenia
o Blood picture: severe normocytic, o Characteristic peripheral blood finding
normochromic anemia with reticulocyte count ● WBC & platelet count
greatly depressed or 0%. o Normal or slightly increase
o Platelet & wbcs counts (& differentials) are ● Bone marrow examination
normal (or mildly depressed) o Distinguish DBA from the hypocellular marrow
o Bone marrow is normal except for the extreme in aplastic anemia
decrease in or even absence of erythroid o DBA has normal cellularity of myeloid cells &
precursors. megakaryocytes BUT hypoplasia in erythroid
● CHEMISTRY cells.
o Serum iron & % transferrin saturation are ● Karyotyping
increased because of multiple red cell o Normal
transfusion ● Hb F & erythrocyte adenosine deaminase
o EPO levels are increased o Increased
o While normal in TEC
TREATMENT, PROGNOSIS, & MANAGEMENT
● Red cell transfusion DIFFERENTIAL DIAGNOSIS
● Androgens Table No. 10 Distinguishing Characteristics of
Diamond-Blackfan Anemia & Transient
DIAMOND-BLACKFAN ANEMIA (DBA) Erythroblastopenia of Childhood
● Congenital hypoplastic anemia or inherited PRCA
(1938) TEST RESULT DBA TEC
● Blood picture: Normochromic, normocytic Erythrocyte ADA 85% 5%
anemia increased at
o with normal leukocyte & platelet counts & diagnosis
marked decreased in marrow erythroblast MCV increased at 80% 5%
diagnosis
ETIOLOGY & PATHOPHYSIOLOGY MCV increased in 80% 0%
● Mode of Inheritance: Autosomal dominant (50% remission
cases) Hb F increased at 50%–85% 1%–2%
● Mutations in 9 genes that disrupts the ribosome diagnosis
biogenesis in DBA: Hb F increased in 50%–85% 0%
1. RPS7 remission
2. RPS10
3. RPS17
4. RPS19 (25%)
5. RPS24
6. RP26
7. RPL5
8. RPL11
9. RPL35A

CLINICAL PRESENTATION

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 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

Table No. 11 Principal Clinical & Laboratory Factors for

Differentiation of Congenital Disorders Causing Bone
Marrow Failure
CLINICAL/LAB FANCONI DIAMOND-
FEATURES ANEMIA BLACKFAN
ANEMIA
Hematologic Aplastic anemia Pure red cell
classification aplasia
Brown skin Common Uncommon
pigmentation
Thumb abnormalities Common Uncommon
Renal abnormalities Common Uncommon
Onset of hematologic 5 to 10 <1 ● Common Findings
abnormalities (years o Jaundice
of age) o Cholelithiasis
Bone marrow biopsy Hypoplastic to Cellular
o Splenomegaly
aplastic
Peripheral blood Pancytopenia Decrease in ▪ CDA do not progress to Aplastic Anemia or
RBC; Normal Hematologic malignancies
WBC & platelets
Cytogenetics Multiple No associated
MYELOPHTHISIC ANEMIA
chromosomal abnormalities
abnormalities in ● is due to the infiltration of abnormal cells into the
many tissues bone marrow and subsequent destruction and
replacement of normal hematopoietic cells.
TREATMENT, PROGNOSIS, & MANAGEMENT ● Metastatic solid tumor cells, leukemic cells,
• RBC transfusion (every 3-6 weeks) fibroblasts, and inflammatory cells have been
• Corticosteroids implicated.
• Prognosis: ● Most often a hypoproliferative anemia – anemia
o POOR (Steininger) of chronic inflammation
o Rodak’s: overall survival is 75% at 40 years ● With disruption of normal bone marrow
(Rodak’s architecture by the infiltrating cells, the marrow
releases immature hematopoietic cells.
▪ Bone marrow transplant increase the
● progenitor cells migrate to the spleen and liver -
overall survival to 90% in patients younger
establish extramedullary hematopoietic sites; also
than 10 years old transplanted with a
release immature cells
matched-related donor
● sometimes used interchangeably with
▪ 80% overall survival to those transplanted
leucoerythroblastic reaction; not synonymous
with a matched unrelated donor.
● Leucoerythroblastic reaction – presence of
circulating nucleated red blood cells (NRBC),
CONGENITAL DYSERYTHROPOIETIC ANEMIA
immature leukocytes, and may not be associated
● Is a heterogenous group of rare disorders
with anemia. If anemia is present, the quantity of
characterized by:
NRBC is much greater than expected.
o Refractory Anemia
● Severity of anemia – mild to moderate
o Reticulocytopenia
● normocytic erythrocytes and reticulocytopenia
o Hypercellular Bone Marrow w/ markedly
● Peripheral blood findings:
ineffective erythropoiesis
o teardrop erythrocytes
o Distinctive dysplastic changes in the bone
o nucleated RBCs
marrow erythroblast
o immature myeloid cells
o megakaryocyte fragments

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 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

Criteria for FID in CKD:

• Decreased reticulocyte hemoglobin
content
• Increased soluble transferrin receptor
• Greater than 10% hypochromic RBCs in
the peripheral blood.

Other causes of ESA (Erythropoietin Stimulating

Agents)
Hyporesponsiveness
Infection
Malignancy
Aplastic anemia
DIFFERENTIAL DIAGNOSIS Thalassemia
● Carcinomas that most likely to metastasize: Multiple myeloma
o Breast, prostate, lung, neuroblastoma, adrenal Presence of hemoglobin
cortex, thyroid, kidney, gastrointestinal tract, H or hemoglobin S variants
genitourinary tract and malignant melanoma.
● Marrow biopsy – best method
● Marrow aspirate TREATMENT
● It’s important to do both biopsy and an aspirate, ● Treatment includes recombinant human
when searching for metastatic carcinoma erythropoietin or other erythropoiesis-stimulating
agents (ESAs), with a goal hemoglobin range of 11
ANEMIA OF CHRONIC KIDNEY DISEASE g/dL to 12 g/dL.
● Anemia is a common complication of chronic ● Successful ESA therapy requires adequate iron
kidney disease (CKD), with a positive correlation stores, so plasma ferritin level and percent
between anemia and renal disease severity. transferrin saturation should also be monitored.
● Causes of Anemia: ● Iron is administered with ESA therapy to maintain
o Inadequate renal production of the transferrin saturation above 20% and the
erythropoietin. plasma ferritin level above 100 ng/mL for non-
o Uremia- inhibits erythropoiesis and increases dialysis-dependent patients and above 200 ng/mL
RBC fragility. for hemodialysis-dependent patients.
o Chronic inflammation and a restricted diet ● Iron therapy is not routinely recommended for
● Approximately 26 million adults over 20 years of ferritin levels above 500 ng/mL
age in the United States had CKD ● Patients may become hyporesponsive to ESA
● Anemia of CKD is normocytic and normochromic therapy because of functional iron deficiency
with reticulocytopenia. (FID).
● Anemia in CKD can lead to cardiovascular ● The transferrin saturation remains below 20%, but
complications, kidney failure, and suboptimal the serum ferritin level is normal or increased,
quality of life. indicating adequate iron stores.
● Annual hemoglobin testing in patients with CKD ● Patients with FID are unable to reach or maintain
and investigation of the anemia if the hemoglobin the target hemoglobin

LEGARTA, ALEMPANG, ASUNTO, BAQUIA, CARO, GOZALO, LIWANAG, LOMOCSO, SACRO | MLS3D 12
 SUMMARY NOTES: ANEMIA OF BONE MARROW DISORDERS

REFERENCES

Rodak, B. F., Fritsma, G. A., & Keohane, E. M. (2012).

Hematology: Clinical Principles and applications. 4th
Ed. St. Louis, Mo.: Elsevier Saunders

Lotspeich-Steininger, C. A., Stiene-Martin, E. A., &

Keopke, J. A. (1992). Clinical hematology: Principles,
procedures, correlations. Philadelphia: Lippincott

LEGARTA, ALEMPANG, ASUNTO, BAQUIA, CARO, GOZALO, LIWANAG, LOMOCSO, SACRO | MLS3D 13