BONE MARROW FAILURE

SYNDROMES

MODERATOR- DR MAHENDRA SINGH

SPEAKER- DR SUNAINA SINGH
 Introduction
• Bone marrow failure syndrome is a group of disorders that may
manifest as single cytopenia or as bicytopenia or pancytopenia.
• There is inability of marrow to produce circulating mature cells due
to-
– Reduction in number of progenitors and subsequently paucity of
differentiated precursors(e.g. Aplastic anemia)
– Increased number of differentiated precursors but reduction of
mature cells in peripheral blood.
– Differentiation defects.
• The hallmark of BM failure is marrow hypoplasia.
Pancytopenia accompanied by reticulocytopenia in the absence of
organomegaly is characteristic feature of marrow hypoplasia.
 Pancytopenia
It is characterized by :
• Hemoglobin <9 g/dl
• Total leucocyte count <4 x 10^9/ L
• Platelet count <140 x 10^9/L

Neutropenia (absolute neutrophil count <1.5 x 10^9/L) is

more important than leucopenia.
 Etiology of Pancytopenia

Hypocellular Cellular
marrow marrow
•Aplastic anemia •Aleukemic leukemia
•Hairy cell leukemia
•Fanconi anemia •MDS
•Hypoplastic MDS •PNH
•Myelofibrosis
•Post chemotherapy •Def of B12, folic acid
•Diamond Schwachman •Hypersplenism
•Kala-azar
syndrome •SLE
•Severe sepsis •Metastatic solid tumor
Bone marrow failure syndromes can be either-

• inherited

• or acquired.
Pathogenesis of marrow failure syndrome
Mechanisms which result in marrow failure are:
• An acquired stem cell injury from viruses, toxins,
chemicals or radiation
• Abnormal humoral or cellular control of hematopoiesis
• Abnormal bone marrow microenvironment
• Immunologic suppresion of hemopoiesis mediated by T-
cells, lymphokines or by antibodies
• Mutations leading to marrow failure syndromes
 GATA2 Disorders
• Autosomal dominant disorder
• These are due to heterozygous mutation in the GATA2
genes resulting in marrow failure, MDS or AML
• BM is hypocellular with multilineage dysplasia especially
of megakaryocytes.
• Increase in reticulin fibrosis occurs in marrow.
 FANCONI ANEMIA
• It is a multigenic disorder with 20 genes currently
identified. Three affected genes are FANCA, FANCC and
FANCG
• Most common hereditary marrow failure disease
constituting 2/3rd of the cases and is associated with
chormosomal breaks.
• Mean age: in boys- 8 years
girls- 9 years
• It is believed to be premalignant since there is long term
risk of progression to MDS and AML.
Clinical features
• Short stature
• Microcephaly
• Broad nasal base
• Skeletal defects
• Syndactyly
• Strabismus
• Café-au-lait spots
• Mental retardation
• Renal malformation
Hematologic findings
• Anemia is normocytic normochromic with low reticulocyte
count.
• Bone marrow is hypocellular with increased fat and
infiltration by lymphocytes and plasma cells.
• Stress erythropoiesis is seen in patient pre-anemic and
anemic patients pr patients in remission.
• Diagnosis is made by- demonstration of increased
chromosomal breaks and radials on peripheral lymphocytes
after treatment with diepoxybutane and mitomycin C
Treatment
• Androgen therapy (oxymetholone) has been found to be
quite effective.
• Bone marrow transplantation
• Gene replacement therapy is a useful alternative
• HSCT is the treatment of choice.
• Long term follow up is essential since there is increased
risk of development of secondary malignancy.
Dyskeratosis congenita
• X linked recessive/ AD/ AR disorder
• Mutations are DKC1 at Xq28 which
encodes dyskerin. Some patients
have mutations in band 3q26 in
TERC, a part of telomerase
complex
• Physical findings: the
mucocutaneous triad-
– Leucoplakia
– Nail dystrophy
– Reticulated skin hyperpigmentation
 APLASTIC ANEMIA
• AA is characterized by marrow hypoplasia with failure to
form blood cells of all three lineages resulting in peripheral
cytopenia.
• May be- hereditary or acquired.
• Male to female incidence is equal.
• Age: it has 2 peaks. One at 15-25 years and other in old age
>58 years.
 Classification of Aplastic Anemia

Inherited Acquired
•Fanconi •Idiopathic AA
•Secondary-
•drug idiosyncrasy
anemia •Ionizing radiation
•chemical exposure
•Dyskeratosis • infections- hepatitis, EBV,
Parvovirus B19, Influenza, HIV

congenita
• Immune mediated
•Associated with PNH, MDS
Chloramphenicol-

This drug has two types of effects on bone marrow

which manifest in 1 to 5 months of therapy

• Reversible erythroid hypoplasia

• Irreversible aplasia of the marrow

BM smear demonstrate vacuolization of nucleus and

cytoplasm of proerythroblasts and later on of
promyelocytes.
 Pathophysiology of AA
In majority of cases, AA is an immune mediated disease.
Overexpression of HLA-DR2 and polymorphism in genes like T-bet, PRF1 and TNF2

T cells get activated

Increased production of IL-2 leads to polygonal expansion of T cells which secrete

IFN-gamma and TNF-α

TNF-α and IFN-gamma affect hemopoietic stem cells and progenitor cells.

Stem cells undergo apoptosis and thus diminish in bone marrow

 Clinical features:

• Fatigue, lethargy
• Bleeding tendency- bleeding gums, epistaxis, petechiae
• Fever – due to neutropenia
• Severe infections may result in bronchopneumonia or skin
infections.
• Splenomegaly is uncommon.
 Criteria for diagnosis of AA
• Severe Aplastic Anemia(SAA):
1. Granulocyte count < 500/ ul
2. Platelet count< 20,000/ ul
3. Absolute reticulocyte count <1 %, < 40,000/ul
In addition, bone marrow biopsy must contain <25% of the
normal cellularity.
• Very severe aplastic anemia(VSAA):
Same as SAA with granulocyte count <200/ ul

• Non severe aplastic anemia:

patients who don’t fulfill the criteria for SAA and have
<30% cellularity of bone marrow with depression of >= 2
hematopoietic cell lines and absence of pancytopenia.
Blood findings:

• Hb, absolute neutrophil and platelet count are

decreased
• Reticulocyte count <1%
• PBS- pancytopenia with normocytic normochromic
or macrocytic red cells.
• ESR is almost invariably
increased.
 Bone marrow findings:

• The marrow aspirate typically contains numerous spicules

with empty, fat-filled spaces, and relatively few
hematopoietic cells.
• Lymphocytes, plasma cells, macrophages, and mast cells
may be present.
• Marrow biopsy is essential to confirm the overall
hypocellularity as a poor yield of spicules and cells occurs in
marrow aspirates in other disorders, especially if fibrosis is
present.
 Management of AA
• Identification and elimination of exposure to causative agent
• Stem cell transplantation: 1st line of management in young
patients with severe/ very severe AA.
• Immunosuppressive therapy:
i. ATG/ALG are effective, more so in older patients.
ii. Cyclosporin (CYA) is being used extensively and results are similar
as ATG/ALG
iii. Combination of ATG+ CYA
• Androgens : oxymetholone or danazol
• Eltrombopag: recently approved by FDA. It is
thrombopoietin agonist and acts on C-MPL receptor.
• Blood products, transfusions.
CONGENITAL DYSERYTHROPOIETIC ANEMIAS

• Rare Autosomal recessive disorder

• There is failure of terminal erythropoiesis
• Characterized by-
– anemia, mild jaundice,
– reduced red cell survival,
– ineffective erythropoiesis and abnormal red cell precursors
in the marrow.
 Type I Type II Type III

Inheritance Autosomal recessive Autosomal recessive Autosomal

dominant or
Autosomal recessive

Mutation CDAN1 gene SEC23B 15q22- KIF23

Red cells Macrocytes Normocytes Large macrocytes

Erythroblasts: L/M Megaloblastic; Normoblastic; 10-35% Megaloblastic; giant

internuclear bridges binucleate late multinucleate
(dumb-bell shaped) erythroblasts, erythroblasts
Pseudogaucher cells+/- (gigantoblasts)
Erythroblasts: E/M Spongy(swiss cheese) Peripheral double Non specific changes
Appearance of membrane like intranuclear
heterochromatin with clefts, karyorrhexis
pore in the nuclear
membrane

Serology
Hams/ HEMPAS Negative Positive in 30% control Negative
Anti-i Normal /strong Strong Normal /strong
 PURE RED CELL APLASIA
• Anemia with marked reduction or absence of erythroid
precursors in the bone marrow along with normal
myelopoiesis and megakaryopoeisis.
• Characterized by:
– Normocytic normochromic anemia
– Reticulocytopenia
– Almost complete absence of erythroblast from BM (< 1%).

• May be inherited or acquired

 Diamond- Blackfan Anemia
• Mostly AD, while others are AR
• Defect in ribosome synthesis
• C/F: short stature, mental retardation, microcephaly, cleft
palate, cardiac septal defects, urogenital defects and
thumb deformities.
• Bone marrow: selective deficiency of erythroblast few
proerythroblast may be seen.
• S. iron, ferritin, folic acid and B12 are increased.
• Treatment: transfusion and corticosteroids
 Parvovirus B19 infection PRCA
• Parvovirus B19 directly infects erythroid progenitors
through P antigen on erythroblast surface.
• Bone marrow: reveals giant proerythroblasts with
basophilic cytoplasm ‘dogear’ like cytoplasmic projections,
stippled chromatin and inclusion like nucleoli.
• Giant proerythroblasts- positive with Ki67.
 Acquired PRCA

• PRCA is associated with autoimmune disorder such as

thymoma, SLE, rheumatoid arthritis, chronic active hepatitis
and chronic lymphoproliferative disorders.
• Erythropoiesis is restored after thymomectomy in 25% of
cases.
• Treated with steroids and immunosuppresive drugs.
 Management of PRCA

• If associated with infective disorder, treat the disease

• For parvovirus b19 PRCA, IVIg is required
• Rituximab is effective for PRCA associated with CD20
positive lymphoproliferative disorders.
• Cyclosporin A is effective drug when PRCA is primary or
secondary acquired.
 Approach to diagnosis
History
• Age, sex, occupation, diet
• Exposure to chemicals, drugs, or radiation
• Bone pain
• Fever, night sweats, malaise, weight loss, pruritus
• Symptoms of disorders causing major splenic enlargement
Physical examination
• Lymph node enlargement
• Splenomegaly, Hepatomegaly
• Bone tenderness, deformity, or tumour
• Gum hypertrophy
• Signs of disorders causing hypersplenism, especially portal hypertension·
• Evidence of primary malignancies often associated with metastasis to
bone, especially breast, prostate and lung
ROUTINE LAB INVESTIGATION:
• CBC ( TLC, DLC, PLT, GBP) & RETIC COUNT
• LFT, LDH, URIC ACID, Sr FOLIC ACID & VIT B12
BONE MARROW ASPIRATION AND BIOPSY
OTHER SPECIFIC TEST:
• Fetal hemoglobin level and DNA stability test as markers of
Fanconi anemia
• Immunophenotyping of red and white cells, especially for CD55,
CD59 to exclude PNH
• Screening tests for hepatitis viruses A, B, and C
• Screening tests for EBV, cytomegalovirus (CMV), and HIV
• Marrow cell cytogenetics to evaluate hypoplastic MDS.
• Serum iron, iron-binding capacity, and ferritin as a baseline prior
to chronic transfusion therapy
Thank you