Clinical

Approach to the Child with Pancytopenia

5
Scenario

Key Messages marrow failure or because the cells are being used
up at a greater rate than normal. This is also true of
1. Pancytopenia indicates a reduction of all
pancytopenia.
normal cellular elements – red blood cells
(RBCs), neutrophils, and platelets – in the
peripheral blood.
2. Understanding the causes of pancytopenia in Bone Marrow Failure
children and how to distinguish these causes The causes of bone marrow failure resulting in pan-
and make a diagnosis is a large part of cytopenia are listed in Table CS5.1. The key features
understanding clinical pediatric hematology. in the history, examination, and blood in the present-
3. There may be bone marrow causes – production ing child that alert to this diagnosis are given for each
failure – or there may be systemic causes – diagnosis.
consumption of formed cells. In order for the bone marrow to make blood,
4. Some of the causes of pancytopenia are  There must be physical space for bone marrow
inherited diseases, and some are acquired. stem and progenitor cells. Infiltration with
The differential diagnosis is different for malignant cells (leukemia) will reduce this
children of different ages. available space. (Note that solid-tumor marrow
involvement rarely causes pancytopenia; it might
5. In making a diagnosis, hematologists do it all,
cause anemia or there will commonly be primitive
and this is one of the joys of everyday clinical
cells on the smear including nucleated RBCs and
hematology. They take the history from
myelocytes, ie a leukoerythroblastic appearance.)
patients and their families. They examine
A rarer infiltrative cause is un-remodeled bone in
patients. They look at the peripheral blood
malignant infantile osteopetrosis (MIOP).
counts and blood smear. They take and
examine the bone marrow aspirate and smear.  Drugs may affect bone marrow function in either
a dose-related or dose-unrelated (idiosyncratic)
Once a diagnosis is made and explained, they
fashion. The most common cause of bone
manage the patients.
marrow failure in our hospitals is chemotherapy,
and for most chemotherapeutic agents, there will
Introduction be bone marrow failure if you give enough of
Pancytopenia indicates a reduction in the normal the drug.
cellular elements in the blood. It must not be confused  There must be adequate nutritional elements for
with aplastic anemia, which is a particular – and rare – the massive cellular proliferation that gives rise to
cause of pancytopenia. Pancytopenia may be life blood elements. This requires vitamin B12 and
threatening, and making a diagnosis as quickly as folate, and deficiency of these elements will give
possible is important. rise to pancytopenia.
The hematologist will make a diagnosis from his-  In aplastic anemia, there is a deficiency of
tory, examination, blood count with a blood film, and hematopoietic stem cells. This may be acquired or
bone marrow examination. All cytopenia – either single due to an inherited bone marrow failure
134 lineage or multilineage – is either because of bone syndrome.

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 Approach to the Child with Pancytopenia

Table CS5.1 Bone Marrow Causes of Pancytopenia

Infiltration with  Examination might show evidence of infiltration elsewhere, including lymph nodes, skin,
leukemia (most and spleen.
common cause  Blast cells may be present in the blood film.
perhaps) (see  Diagnosis is made on bone marrow aspirate.
Chapters 36 and 37)
Infiltration with  There might be a family history, and the illness is more common in a consanguineous
trabecular bone family.
(malignant infantile  There are features of extramedullary hematopoiesis on examination – including
osteopetrosis) (see splenomegaly.
Chapter 25)  There is evidence of bone compression elsewhere beyond the marrow. There will
frequently be clinical blindness or roving-eye movements (compression of the optic
nerve by excess bone as the nerve passes through the optic foramen).
 There may be associated developmental delay.
 The blood film is leukoerythroblastic and without blast cells. This reflects disruption of the
bone marrow–blood architecture and the extramedullary hemopoiesis.
 The abnormal cortical bone is visible on plain x-ray of the long bones or ribs.
Nutritional deficiency  There might be an appropriate dietary history.
(vitamin B12 and folate)  In infants, there will be associated developmental delay (TCII deficiency or infant of a
(see Chapter 14) deficient mother).
 There will be blood features with macrocytes, circulating megaloblastic RBC precursors,
and hypersegmented neutrophils.
 The bone marrow aspirate is cellular and megaloblastic with giant metamyelocytes.
 The exact diagnosis will follow appropriate testing.
Drug-related causes:  The cause is clearly evident on the history.
a. Dose related –  Note that whole-body radiotherapy will also cause dose-related pancytopenia, and this is
chemotherapy also used with high-dose chemotherapy in bone-marrow transplantation.
b. Dose unrelated –  Remember that some drugs that might cause bone marrow failure are used beyond the
idiosyncratic hematology ward (e.g. azathioprine in autoimmune or transplant medicine).
 Altered renal or liver function or inherited polymorphisms affecting drug metabolism
may sensitize patients to hematologic toxicity from these drugs.
 A drug history should be taken in all patients admitted with pancytopenia.
Chloramphenicol is the best-known idiosyncratic drug cause of bone marrow failure and
pancytopenia.
Acquired aplastic  There is no evidence of extramedullary hematopoiesis – no spleen or nodes, etc.
anemia (see Chapter 11)  There is frequently macrocytosis on the full blood count (FBC) and smear.
 There are no primitive cells in the blood smear.
 Definitive diagnosis is made by marrow aspirate and trephine biopsy.
Inherited bone marrow  There might be a family history, and most of these disorders are autosomal recessive and
failure syndrome therefore more common where there is consanguinity.
(see Chapter 10)  There might be associated features of disease such as short stature, skin abnormalities
(DKC and FA), and skeletal abnormalities (FA and SDS).
 There might be macrocytosis in the blood.
 There are no primitive RBCs in the blood smear.
 The marrow might not be as hypoplastic as in acquired aplastic anemias (there is an
element of ineffective blood cell production).
 There may be dysplastic features in the bone marrow aspirate.
 Definitive diagnosis will test for the specific condition (e.g. chromosome fragility testing
for FA).
 Pearson’s anemia is an important but rare cause of inherited bone marrow failure (see
Chapter 12) 135

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 Approach to the Child with Pancytopenia

Table CS5.1 (cont.)

Immune causes (e.g.  HLH is an important cause of pancytopenia in infancy.

HLH) (see Chapter 24)  This is often a genetic illness, and this is more common where there is parental
consanguinity, and there may be a family history of HLH or death in infancy.
 The affected child is often ill, and there is usually fever (one of the diagnostic criteria).
 There is frequently splenomegaly (another of the diagnostic criteria).
 The blood film does not show circulating blast cells.
 A comprehensive, systematic search for the diagnostic criteria should be initiated. The
genetic causes should be sought.
 There may be many contributors to pancytopenia: bone marrow suppression by
hypercytokinemia, hemophagocytosis of formed cellular elements, and splenomegaly
and hypersplenism.
 Urgent treatment may be needed in this condition.

Table CS5.2 Consumptive Causes of Pancytopenia

Splenomegaly  The presence of splenomegaly in itself is neither an adequate cause of pancytopenia nor
does it necessarily imply that bone marrow function is normal.
 Some bone marrow causes of pancytopenia are usually associated with hypersplenism
(see Table CS5.1, ‘Infiltration with leukemia’). MIOP and HLH are associated with
splenomegaly.
 A cause for splenomegaly must be ascertained. It might be thalassemia or another
hematologic condition, a metabolic illness, chronic liver disease with portal hypertension,
or an immunologic cause.
 The pancytopenia of hypersplensim is rarely severe, and splenectomy is rarely indicated.
Immune causes (see  Many of the inherited primary immune deficiencies (PIDs) are associated with either
Chapter 23) humoral or cellular autoimmune cytopenia, which might be pancytopenia.
 HLH is a PID that is also associated with pancytopenia (see ‘bone marrow causes’ above).
 Systemic lupus erythematosus (SLE) may cause pancytopenia.
 Rheumatologic illness may be associated with pancytopenia that is mutifactorial and
includes macrophage activation syndrome (MAS), which is part of the spectrum of HLH.
Infection (see  Severe infection may cause pancytopenia.
Chapter 16)  Activation of the coagulation cascade and disseminated intravascular coagulation (DIC)
may contribute to the thrombocytopenia of severe infection.
 The hematologist must distinguish bone marrow failure and pancytopenia as a cause of
infection, from pancytopenia as a consequence of infection.

Peripheral Consumption
The peripheral causes of pancytopenia are usually
obvious and are given in Table CS5.2. Important
comments for each cause are given as well.

136

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