1

Pancytopenia

 Dr Abdifatah Ahmed
 Supervisor: Prof Silva
 September 2022
 Outline
2

1. Introduction

2. Etiology, epidemiology and pathogenesis

3. Clinical features

4. Diagnosis

5. Treatment

6. References
03/09/23
 Terminology

 Cytopenia: Reduction in either of the cellular component of

blood
 Bicytopenia: Reduction in any of the 2 two cell lines of blood
⚫ Anemia + Thrombocytopenia- 77.5%
⚫ Anemia + Leukopenia-17.3%
⚫ Thrombocytopenia + Leukopenia-5.5%*

 2
 Terminology

 Pancytopenia: Reduction in all 3 cell lines of blood.

 The values of the 3 components being:
⚫ Hb <13.5(M)/ 11.5(F) g/dl
⚫ TLC< 4000
⚫ Platelets <150,000
 Introduction

 Identifying the etiology of pancytopenia usually requires

microscopic examination of the peripheral blood smear, as
well as bone marrow biopsy and aspirate specimens to
assess overall cellularity and morphology.
 Introduction

 The 3 general categories of pancytopenia are related to bone

marrow pathologies and can frequently be differentiated
based on bone marrow findings.
The 3 general categories of pancytopenia

⚫ Pancytopenia with hypocellular bone marrow

⚫ Pancytopenia with cellular bone marrow
⚫ Pancytopenia with bone marrow infiltration
Introduction

 Pancytopenia with hypocellular bone marrow on biopsy

is seen with inherited bone marrow failure syndromes
(IBMFSs) with pancytopenia, acquired aplastic anemia of
varied etiologies, and the hypoplastic variant of
myelodysplastic syndrome (MDS).
Introduction

 Pancytopenia with cellular bone marrow is seen with

primary bone marrow disease (e.g., acute leukemia,
myelodysplasia) and secondary to autoimmune disorders
(e.g., autoimmune lymphoproliferative syndrome, systemic
lupus erythematosus), vitamin B12 or folate deficiency,
storage diseases (e.g., Gaucher, Niemann-Pick),
overwhelming infection, sarcoidosis, and hypersplenism.
Introduction

 Pancytopenia with bone marrow infiltration can be seen

in metastatic solid tumors, myelofibrosis, hemophagocytic
lymphohistiocytosis, and osteopetrosis. It is important to
note that exceptions exist with regard to this classification.
For example, IBMFSs can manifest as normocellular or
hypercellular bone marrow at early stages of presentation or
in cases where MDS develops.
Introduction
 Etiologies
 INHERITED  Familial aplastic anemias
 Fanconi's anemia
 Preleukemia (monosomy
 Dyskeratosis congenita
7, etc.)
 Shwachman-Diamond  Nonhematologic
syndrome
syndrome (Down,
 Amegakaryocytic Dubowitz, Seckel
thrombocytopenia
 Etiologies
 ACQUIRED-
 Immune diseases
 Radiation (Eosinophilic fasciitis,
 Drugs and chemicals Thymoma,
 Viruses (non-A, non-B, Hyperimmunoglobulinemia,
non-C Hepatitis, EBV, Graft-versus-host disease)
Parvovirus B19, HIV-1)  Idiopathic
FANCONI ANEMIA

Inherited Bone Marrow

Failure Syndromes With
Pancytopenia
 Fanconi anemia's

 Etiology and Epidemiology

 Fanconi anemia (FA) is a rare multisystem hereditary
disorder resulting in the development of bone marrow
failure in those affected and a predisposition to malignancy,
including myelodysplasia (MDS), acute myeloid leukemia
(AML), and epithelial cancers.
 Fanconi anemia's

 Individuals with FA often have congenital malformations

and high sensitivity to alkylatin agents and radiation.

 The estimated frequency of FA is 1 in 200,000 in most

populations but is higher in Ashkenazi Jews (1 : 30,000) and
Afrikaners (1 : 22,000).
 Clinical Manifestations

 The most common congenital anomalies in FA are skeletal

and include absence of radii and/or thumbs that are
hypoplastic, supernumerary, bifid, or absent.
 Anomalies of the feet, congenital hip dislocation, and leg
abnormalities can also be seen
Cont.
 Complications

 In addition to the low blood counts and physical anomalies,

patients with FA have a high risk of developing cancer.
 The most frequent solid tumors are squamous cell
carcinomas (SCCs) of the head and neck
 Benign and malignant liver tumors can occur (adenomas,
hepatomas) and are usually associated with androgen
therapy for aplastic anemia.
 Diagnosis

 FA should be considered in all children and young adults

with unexplained cytopenias.
 Abnormal hematologic findings and characteristic physical
anomalies suggest the diagnosis, which can be confirmed
with lymphocyte chromosomal breakage study done with
and without the addition of cross-linking agents such as
DEB and MMC.
 Diagnosis

 Chromosome breakage testing — The hallmark of FA is

defective DNA repair that causes extreme sensitivity to
DNA interstrand crosslinking agents. Screening for FA
involves exposure of cells to diepoxybutane (DEB)
or mitomycin C (MMC) followed by assessment for
chromosomal breakage.
 Diagnosis

 This screening should be performed with peripheral blood

rather than bone marrow; in some cases (described below),
chromosome breakage testing should use skin fibroblasts.
 Diagnosis

 Genetic testing — Next-generation sequencing (NGS) is

required to confirm the diagnosis of FA and to identify the
specific molecular defect. NGS testing should be performed
for all individuals with a positive chromosomal breakage
test. 
 Treatment

 If hematologic abnormalities are mild to moderate and

stable and there is no transfusion requirement, patients can
be observed closely with peripheral blood counts every 3
mo and bone marrow aspiration surveillance every year for
clonal cytogenetic abnormalities, MDS, and AML.
 Treatment

 Bone marrow biopsy might also be intermittently done

during bone marrow testing to evaluate changes in
percentage of cellularity and fibrosis.

 More frequent monitoring can be applied when deemed

necessary, as when a decline in blood counts occurs.
 Treatment

 Glucose levels should be performed annually or biannually,

depending on the degree of hyperglycemia found on initial
testing.
 Screening for hypothyroidism should be performed yearly.

 Patients should be assessed for solid tumors at least

annually
 Treatment

 Beginning at menarche, female patients should be screened

annually for gynecologic cancer.

 Hematopoietic stem cell transplantation (HSCT), is the only

curative therapy for the hematologic abnormalities
observed in FA patients.
 Treatment

 The overall survival of FA patients transplanted with a fully

matched unrelated donor is 65–70%.
 Those transplanted before they receive multiple transfusions
or develop clonal and malignant myeloid transformation
(MDS or AML) do better.
 Survival rates are higher for patients who undergo transplant
at <10 yr of age.
 Treatment

 Androgens produce a response in approximately 70% of

patients, heralded by reticulocytosis and a rise in
hemoglobin within 1-2 mo.

 White blood cell (WBC) counts may increase next, followed

by platelet counts.
 Treatment

 The potential for recombinant growth factor (cytokine)

therapy for FA has not been defined.
 Granulocyte colony-stimulating factor (G-CSF) can usually
induce an increase in the absolute neutrophil count;
however, there may be a heightened risk of expansion of
bone marrow cells with clonal cytogenetic abnormalities
such as monosomy 7.
 Prognosis

 Improvements in supportive care, careful surveillance of

known complications, prompt intervention, and improved
transplant techniques have resulted in patients with FA
surviving into their 30s.

 Unfortunately, there is an increased risk of solid tumors

after HSCT.
 Prognosis

 The cumulative incidence of malignancy 20 yr after

transplant is 35–40%.

 Some of the increased risk might be attributed to the use of

DNA-damaging agents or the occurrence of graft-versus-
host disease (GVHD).
 SHWACHMAN-DIAMOND
SYNDROME
 Etiology and Epidemiology
 Shwachman-Diamond syndrome (SDS) is inherited in an
autosomal recessive manner and occurs in all racial and
ethnic groups. As with FA, SDS is a multisystem disorder.
However, the nonhematologic manifestations of SDS are
substantially different and usually include exocrine
pancreatic insufficiency and skeletal abnormalities such as
metaphyseal dysplasia
 Cont.

 SDS is a ribosomopathy, and the underlying defect is in

ribosome assembly. There is no increased chromosomal
breakage after DEB testing of SDS lymphocytes.
 Clinical Manifestations

 Most patients with SDS have symptoms of fat

malabsorption from birth that are caused by pancreatic
insufficiency, but steatorrhea is not always obvious.
 Approximately 50% of patients appear to exhibit an
improvement in pancreatic enzyme secretion as they age.
 The clinical picture can be dominated by complications
from anemia, neutropenia, or thrombocytopenia.
 Clinical Manifestations

 Bacterial and fungal infections secondary to neutropenia,

neutrophil dysfunction, and immunodeficiency can occur.
Short stature is a consistent feature of SDS.

 Most patients show normal growth velocity, yet remain

consistently below the 3rd percentile for height and weight.
 Clinical Manifestations

 The occasional SDS adult achieves the 25th percentile for

height.

 Although skeletal abnormalities are variable, classic

findings are metaphyseal dysplasia, osteopenia, delayed
appearance of secondary ossification centers, short or flared
ribs, and thoracic dystrophy.
 Clinical Manifestations

 Some patients have hepatomegaly and elevations of liver

enzymes.
 Most patients have dental abnormalities and poor oral
health.
 Many have neurocognitive problems and poor social skills.
39
 Laboratory findings

 CBC
 Anemia

 Thrombocytopenia

 Leukopenia

 Neutropenia is observed in about 70% of patients with SDS

at presentation and is seen in almost 100% of patients on
follow-up.
 Laboratory findings

 Ultrasound or CT scan can visualize fatty replacement of

pancreatic tissue.
 Decreased serum trypsinogen and pancreatic isoamylase
levels.
 Decreased levels of IgG levels
 Decreased or absent of B-lymphocytes
 Treatment

 Oral pancreatic enzyme replacement.

 Supplemental fat-soluble vitamins.
 Daily subcutaneous G-CSF for profound neutropenia is
effective in inducing a sustained increase in neutrophils.
 Cure is Hematopoietic stem cell transplantation
 Complications

 Patients with SDS are predisposed to MDS and leukemic

transformation.

 Prognosis

 The accurate life expectancy of SDS patients is unknown;

analysis of published cases revealed a median survival of 35 yr.

 Cont.

The Acquired Pancytopenia's

 Epidemiology

 The overall incidence of acquired aplastic anemia is

relatively low, with an approximate incidence in both
children and adults in the United States and Europe of 2-6
cases per 1 million population per year.
 The incidence is higher in Asia, with as many as 14 cases
per 1 million per year in Japan.
Cont.
 Pathology and pathogenesis

 The hallmark of aplastic anemia is peripheral pancytopenia,

coupled with hypoplastic or aplastic bone marrow.

 The severity of the clinical course is related to the degree of

myelosuppression.
 Pathology and pathogenesis

 Severe aplastic anemia is defined as a condition in which

≥2 cell components have become seriously compromised
(absolute neutrophil count <500/mm3, platelet count
<20,000/mm3, reticulocyte count <1% after correction for
hematocrit) in a patient whose bone marrow biopsy material
has <30% cellularity.
 Cont.

 Approximately 65% of patients who first present with

moderate aplastic anemia (absolute neutrophil count 500-
1,500/mm3, platelet count 20,000-100,000/mm3,
reticulocyte count <1%) eventually progress to meet the
criteria for severe disease, if they are simply observed.
 Diagnosis

 Careful examination of the peripheral blood smear for RBC,

leukocyte, and platelet morphologic features is important.

 In children the possibility of congenital pancytopenia must

always be considered, and chromosomal breakage analysis
should be performed to evaluate for Fanconi anemia
 Diagnosis

 Bone marrow examination should include both aspiration

and biopsy, and the marrow should be carefully evaluated
for morphologic features, cellularity, and cytogenetic
abnormalities.
 Treatment

 The treatment of children with acquired pancytopenia requires

comprehensive supportive care coupled with an attempt to treat the
underlying marrow failure.
 For patients with a human leukocyte antigen–matched family
member donor, allogeneic hematopoietic stem cell transplantation
(HSCT) offers a 90% chance of long-term survival.
 Treatment

 For patients without a sibling donor, the major form of

therapy is immunosuppression with horse ATG and
cyclosporine, with a response rate of 70–80%.
 Treatment

 As many as 30% of patient responders experience relapse

after discontinuation of immunosuppression, and some
patients must continue cyclosporine for several years to
maintain a hematologic response.
 Among those who relapse after immunosuppression,
approximately 50% show response to a second course of
ATG and cyclosporine.
 Complications

 The major complications of severe pancytopenia are predominantly

related to the risk of life-threatening bleeding from prolonged
thrombocytopenia or to infection secondary to protracted neutropenia.
 Patients who have been transfused with RBCs regularly over a long
period are at increased risk of developing alloantibodies to RBC
antigens and may require iron chelation therapy for transfusional iron
overload.
 Prognosis

 Spontaneous recovery from pancytopenia rarely occurs.

 If left untreated, severe pancytopenia has an overall
mortality rate of approximately 50% within 6 mo of
diagnosis and of >75% overall, with infection and
hemorrhage being the major causes of morbidity and
mortality.
 References

 Nelson pediatrics 21st edition

 Uptodate 2022
 Medscape