Kim Alyssa B.

Go UIC MLS3E
TOPIC 3 MIDTERMS: ANEMIA OF BONE
CLASSIFICATION OF APLASTIC ANEMIA ND
MARROW FAILURE SINGLE CYTOPENIA
KEZIAH AMOR S. CATULONG, RMT ● Acquired Aplastic Anemia
○ Secondary
■ Radiation
BONE MARROW FAILURE ■ Drugs and Chemicals
● Regular effects
Hypoproliferative Disorders ● Idiosyncratic reactions
- occurs as a result of decreased or absent ■ Viruses
production of hematopoietic cells in the bone ● Epstein-Barr virus
marrow. (infectious
- Disease Manifestations: mononucleosis)
a. Aplastic anemia, Fanconi Anemia ● Hepatitis (non-A, non-B,
(Congenital) non-C)
b. Pure Red Cell Aplasia, Diamond- ● Parvovirus B19
Blackfan Anemia (Congenital) (transient aplastic crisis,
c. Congenital dyserythropoietic Anemia pure red cell aplasia
d. Myelophthisic Anemia [PRCA])
e. Anemia resulting from chronic kidney ● HIV-1 (AIDS)
disease ■ Immune Diseases
● Eosinophilic fasciitis
● Hypoimmunoglobulinem
TABLE 1. DIFFERENTIAL DIAGNOSIS OF ia
PANCYTOPENIA ● Large granular
PANCYTOPENIA WITH HYPOCELLULAR BONE lymphocytosis (LGL)
MARROW ● Thymoma/thymic
carcinoma
● Acquired aplastic anemia ● Graft-versus-host
● Constitutional aplastic anemia (Fanconi disease in
anemia, dyskeratosis congenita, and others) immunodeficiency
● Hypocellular myelodysplastic syndrome
■ Paroxysmal nocturnal
● Rare aleukemic anemia
● Some acute lymphoid leukemia hemoglobinuria (PNH)
● Rare lymphomas of bone marrow ■ Pregnancy
● Copper deficiency ○ Idiopathic (Immune)

PANCYTOPENIA WITH CELLULAR BONE

MARROW
● Inherited/Constitutional Aplastic Anemia
Primary bone marrow Secondary to systemic ○ Fanconi Anemia
disease diseases ○ Dyskeratosis congenita/telomere
● Myelodysplastic ● Systemic lupus disease
syndromes erythematosus
○ Shwachman-Diamond syndrome
● Paroxysmal ● Hypersplenism
nocturnal ● B12’ folate ○ Familial aplastic anemia/leukemia
hemoglobinuria deficiency predisposition syndromes: GATA2,
● Myelofibrosis ● Copper RUNX1, CTLA4, and others
● Aleukemic deficiency ○ Nonhematologic syndromes (Down,
Leukemia ● Alcohol Dubowitz, Seckel)
● Myelophthisis ● HIV infection
Bone marrow lymphoma ● Brucellosis
Hairy cell leukemia ● Sarcoidosis
● Tuberculosis
● Leishmaniasis
● Sepsis GENERAL PATHOPHYSIOLOGY OF BONE MARROW
FAILURE
 Kim Alyssa B. Go UIC MLS3E
1. Destruction of hematopoietic stem cells due ○ Idiopathic Acquired Aplastic Anemia
to direct damage (e.g. drugs, viruses) or immune ■ AAA that has an unknown
mediated (e.g. cytotoxic lymphocyte activation) cause
2. Genetic mutations causing premature ■ 70% of cases of aplastic
senescence and apoptosis of hematopoietic anemia
stem cells ○ Secondary Acquired Aplastic Anemia
3. Ineffective hematopoiesis due to stem cell ■ Associated with an identified
mutations or Vit. B12 or folate deficiency non-hereditary cause
4. Destruction of the BM microenvironment that ● 10-15% of cases of
supports hematopoiesis aplastic anemia
5. Decrease production of hematopoietic ■ associated with:
growth factors and/or hormones ● Cytotoxic drugs
6. Infiltration of bone marrow spaces with ● Chemicals
abnormal cells that leads to loss of normal ● Radiation
hematopoietic tissue ● Infections
● Some drugs and Chemicals Associated with
Aplastic Anemia:
○ Agents that regularly produce marrow
depression as major toxicity is
commonly use doses or normal
exposures:
■ Cytotoxic drugs used in cancer
chemotherapy: alkylating
agents,antimetabolites,
antimitotics, some antibiotics
○ Agents that frequently but not inevitably
produce marrow aplasia:
APLASTIC ANEMIA ■ Benzene
● Characterized by pancytopenia associate with ○ Agents associated with aplastic anemia
severe reduction in the number of hematopoietic but with a relatively low probability:
tissues in the absence of bone marrow ■ Chloramphenicol
infiltrative process ■ Insecticides
● 2 forms: ■ Antiprotozoals: quinacrine and
a. Hereditary (15-20% of cases) chloroquine, mepacrine
- inherited gene mutations, ■ Nonsteroidal anti-inflammatory
shortened telomeres drugs (including
b. Acquired (80-85%) phenylbutazone, indomethacin,
1. Direct damage ibuprofen, sulindac, aspirin)
2. Immune-mediated ■ Anticonvulsants (hydantoins,
● Clinical features: carbamazepine, phenacemide,
1. Pancytopenia felbamate)
2. Reticulocytopenia ■ Heavy metals (gold, arsenic,
3. Bone marrow hypocellularity bismuth, mercury)
4. Depletion of hematopoietic stem cells ■ Sulfonamides: some antibiotics,
antithyroid drugs (methimazole,
methylthiouracil,
ACQUIRED APLASTIC ANEMIA propylthiouracil), anti-diabetes
● Characterized with markedly decreased CD34+ drugs (tolbutamide,
cell in the bone marrow chlorpropamide), carbonic
● cells are observed to have increased expression anhydrase inhibitors
of Fas receptors (acetazolamide and
● leads to increased cell apoptosis methazolamide)
● Two major categories:
 Kim Alyssa B. Go UIC MLS3E
■ Antihistamines (cimetidine,
chlorpheniramine)
a. Complete Pancytopenia with increased
■ D-Penicillamine Blood Count or normal MCV
■ Estrogens (in pregnancy and in Blood picture:
high doses in animal) Normocytic/Normochromic
○ Agents whose association with aplastic Ineffective erythropoiesis:
anemia is more tenuous: Decreased RPI
■ Other antibiotic (streptomycin,
b. Bone Marrow Hypocellular bone marrow
tetracycline, methicillin,
examination Blasts and abnormal cells
mebendazole, are absent
trimethroprim/sulfamethoxazole, Bone Marrow aspirate shows
flucytosine) prominent fat cells
■ Sedatives and tranquilizers
(chlorpromazine, c. Flow Test for Paroxysmal
Cytometric Nocturnal Hemoglobinuria
prochlorperazine,
analysis (PNH) lacks CD55 and CD59
piperacetazine, on RBC surface, CD24 and
chlordiazepoxide, CD14 in WBC
meprobamate, methyprylon)
■ Allopurinol d. Cytogenetic Interphase fluorescence in
■ Methyldopa Analysis situ hybridization - perform to
■ Quinidine differentiate for inherited
aplastic anemia
■ Lithium
■ Guanidine
■ Potassium perchlorate
■ Thiocyanate INHERITED APLASTIC ANEMIA
■ Carbimazole a. Fanconi Anemia (Congenital Aplastic
● Mechanisms: Anemia)
1. Direct damage to stem cells: DNA injury ● Characterized by aplastic anemia,
after exposure to cytotoxic drugs (e.g. physical abnormalities, and cancer
chloramphenicol) benzene, radiation, susceptibility
and viruses (e.g. Epstein-Barr virus, ● FANCA mutation - most common
Hepatitis Virus, HIV), and miscellaneous ● chromosomes are susceptible to
conditions (e.g. PNH) breakage and the cell may not be able
2. Immune-mediated: autoimmune to repair DNA damage
cytotoxic T-cell destruction of stem cells ● cells also show accelerated telomere
and progenitor cells shortening and apoptosis
● Clinical Features: ● with skeletal abnormalities (e.g. thumb
○ Pallor malformation, radial hypoplasia,
○ Fatigue microencephaly, hip dislocation,
○ Bleeding scoliosis), skin pigmentation and short
○ Recurrent Infection stature
○ Typically absent hepatomegaly and ● Diagnostic Test: Chromosomal
splenomegaly Breakage Test

Note: b. Dyskeratosis Congenita

a. Environmental exposures may cause alteration ● rare inherited bone marrow failure
of self-proteins, induce expression of abnormal syndrome with mucocutaneous
or novel antigens or induce an immune abnormalities, BM failure and
response that cross-reacts with self-antigens pancytopenia
b. Patients of acquired aplastic anemia were ● Clinical presentation- triad of abnormal
observed with short telomeres skin pigmentation, dystropic nails, and
oral leukoplakia
LABORATORY DIAGNOSIS
 Kim Alyssa B. Go UIC MLS3E
● DC chromosomes have very short ○ Acquired form of PRCA in young
telomeres and inherited defects in the children
telomerase complex ○ Viral infection is found in half of the
● Mutations in long arm of the X- patients
chromosome on the DKC1 gene coding ● b. Diamond-Blackfan Anemia (Congenital
for dyskerin Pure Red Cell Aplasia)
○ most common PRCA
○ congenital erythroid hypoplasia
c. Schwachman-Bodian-Diamond Syndrome ○ mutation at RPS19 (25%), RPS7,
● Multisystem disorder characterized by RPS10, RPS17, RPS24 and RPS26 in
pancreatic insufficiency, cytopenia, the 40s subunit - mutation at RPL5,
skeletal abnormalities, and a RPL11, and RPL35A in the 60s subunit
predisposition for hematologic ○ Half of patients have characteristic
malignancies physical anomalies (craniofacial
● Biallelic mutations in the SBDS gene dysmorphisms, short stature and neck
which is involved in the ribosome and thumb malformations)
biogenesis and mitotic spindle stability ● CLASSIFICATION OF PURE RED CELL
● Autosomal recessive disorder leading to APLASIA
neutropenia and/or anemia and ○ Self limited
thrombocytopenia ■ Transient erythroblastopenia of
● Patients have decreased pancreatic childhood
enzymes secretion ■ Transient aplastic crisis of
○ because of pancreatic hemolysis (acute B19
insufficiency, 72-hr fecal fat parvovirus infection)
testing shows increased fat ○ Fetal red blood cell aplasia
excretion ■ Nonimmune hydrops fetalis (in
● Treatment: utero B19 parvovirus infection)
a. Hematopoietic Stem Cell ○ Constitutional pure red cell aplasia
Transplantation - for <40 yrs. ■ Congenital pure red cell aplasia
old patients with HLA identical (Diamond-Blackfan anemia)
sibling ○ Acquired pure red cell aplasia
b. Immunosuppressive Therapy ■ MDS (5q-syndrome)
- for >40 yrs.old patients without ■ Cancer
HLA identical sibling ● Thymoma
● Lymphoid malignancies
(and more rarely other
PURE RED CELL APLASIA hematologic diseases)
● Rare disorder of erythropoiesis characterized by ● Paraneoplastic to solid
selective and severe decrease in erythroid tumors
precursors in an otherwise normal bone marrow ■ Connective tissue with
● With severe anemia, reticulocytopenia, and immunologic abnormalities
normal WBC and platelet counts ● Systemic lupus
● a. Acquired erythematosus, juvenile
○ Primary is idiopathic or autoimmune rheumatoid arthritis,
○ Secondary is usually associated with rheumatoid arthritis
tumors, infection (Parvo B Virus), drugs ● Multiple endocrine
(Chloramphenicol), Chemicals gland insufficiency
(Benzene) ■ Viruses
● Persistent B19
parvovirus, hepatitis,
● Transient Erythroblastopenia of Childhood adult T-cell leukemia
(TEC) virus, Epstein-Barr virus
■ Pregnancy
 Kim Alyssa B. Go UIC MLS3E
■ Drugs ■ Myelofibrosis is remarkable for
● Especially phenytoin, pancytopenia despite very large
azathioprine, numbers of circulating
chloramphenicol, hematopoietic progenitor cells
procainamide, isoniazid ■ Anemia is dominant in
■ Antibodies to erythropoietin secondary myelofibrosis, usually
■ Idiopathic (immune) normocytic and normochromic
● C. Congenital Dyserythropoietic Anemia ■ The diagnosis is suggested by
(CDA) the characteristic
○ heterogenous group of rare disorders leukoerythroblastic smear.
characterized by refractory anemia, ■ Erythrocyte morphology is
reticulocytopenia, hypercellular bone highly abnormal, with circulating
marrow with markedly ineffective nucleated RBCs, teardrops,
erythropoiesis and distinctive dysplastic and shape distortions. WBC
changes in BM erythroblasts] numbers are often elevated,
○ Granulopoiesis and thrombopoiesis are sometimes mimicking a
normal leukemoid reaction, with
circulating myelocytes,
promyelocytes, and myeloblasts
■ Platelets may be abundant and
are often of giant size
■ Inability to aspirate the bone
marrow, the characteristic “dry
tap” can allow a presumptive
diagnosis in the appropriate
setting before the biopsy is
decalcified
■ The course of secondary
myelofibrosis is determined by
its etiology, usually a metastatic
**CDA II is the most common CDA; CDA III is the
tumor or an advanced
least common
hematologic malignancy.
Treatable causes must be
● d. Myelophthisic Anemia
excluded, especially
○ Infiltration of abnormal cells (metastatic
tuberculosis and fungus.
solid tumors e.g. lung, breast, and
Transfusion support can relieve
prostate) into the bone marrow and
symptoms
subsequent destruction and
replacement of normal hematopoietic
● d. Anemia of Chronic Kidney Disease
cells
○ individuals suffer anemia due to
○ Myelophthisis or secondary
inadequate renal production of
myelofibrosis, is reactive
erythropoietin
○ Pathophysiology has three distinct
○ Red cells are typically normocytic and
features:
normochromic, and reticulocytes are
■ proliferation of fibroblasts in the
decreased
marrow space (myelofibrosis)
■ The extension of hematopoiesis
into the long bones and into
extramedullary sites, usually the
spleen, liver, and lymph nodes
(myeloid and metaplasia);
■ Ineffective erythropoiesis 1. inability to produce adequate erythropoietin due
○ Clinical features: to kidney problem
 Kim Alyssa B. Go UIC MLS3E
2. anemia due to chronic inflammation (of kidney),
cytokines are produced, induce hepcidin, inhibits
ferroportin, decreased iron absorption
3. Uremia (inhibit EPO) (presence of Burr Cell
/Echinocytes)
4. Frequent renal dialysis and frequent blood
draws