Pancytopaenia

Pancytopaenia refers to a decrease in all peripheral blood cell lines.

Pancytopaenia broadly refers to a decrease in the cell lines of the peripheral blood. It is said to occur when the laboratory values of the three major cell lines are low including red blood cells (RBCs), white blood cells (WBCs), and platelets. Haemoglobin and neutrophils are commonly used are surrogate markers of RBC and WBC lines, respectively.

Pancytopaenia is present when:

• Haemoglobin: < 115 g/L (women), < 130 g/L (men)
• Leucocytes: < 4.0 x10⁹/L OR Neutrophils: < 1.5 x 10⁹/L
• Platelets: < 150 x10⁹/L

NOTE: the exact values may differ depending on the laboratory normal values.

Pancytopaenia is concerning because it could be a sign of an underlying haematological malignancy. However, it is important to recognise there are many other causes that could account for this finding. An important aspect of the history, examination and investigations is about narrowing your differential diagnosis and excluding serious causes (e.g. malignancy) early in the diagnostic process.

There is a broad differential list for the cause of pancytopaenia.

Pancytopaenia may be caused by three broad mechanisms:

• Bone marrow suppression: the process of haematopoiesis is reduced preventing blood cell production.
• Bone marrow infiltration: the bone marrow is infiltrated (e.g. malignant cells, microorganisms) impairing its ability to conduct haematopoiesis.
• Blood cell destruction: there is an increased turnover of blood cells in the peripheral circulation due to destruction or sequestration in organs (e.g. spleen).

Abnormalities of the bone marrow are commonly implicated in pancytopaenia because it is the primary site of blood cell production (i.e. haematopoiesis). When the bone marrow is unable to produce new cells due to aplasia (i.e. failure of the organ to function properly) or infiltration (e.g. by malignant cells) the term ‘bone marrow failure’ is often used. This simply refers to the bone marrow being unable to carry out its normal function, which is accompanied by low blood cells line and corresponding clinical features of tiredness (due to anaemia), recurrent infections (due to leucopenia), and bruising (due to low platelets).

The causes of pancytopaenia can be divided into different categories:

• Haematological malignancies (e.g. leukaemia, lymphoma, multiple myeloma, myelodysplastic syndromes)
• Metastatic disease (e.g. lung, breast, and prostate carcinoma)
• Infections (e.g. tuberculosis, fungal infections, HIV, Parvovirus B19)
• Nutritional deficiencies (e.g. vitamin B12, folate, anorexia nervosa)
• Medications and toxins (e.g. Alcohol, chemotherapy, azathioprine, methotrexate, carbamazepine)
• Autoimmune disorders (e.g. aplastic anaemia, rheumatoid, SLE)
• Peripheral destruction (e.g. Disseminated intravascular coagulation)
• Peripheral sequestration (e.g. portal hypertension)
• Congenital (e.g. Wiskott Aldrich syndrome, Fanconi anemia).

Characteristic features include fatigue (anaemia), recurrent infections (leucopenia), and bruising (low platelets).

A thorough history is essential to determine the possible underlying cause of pancytopaenia. Patients will commonly have features associated with anaemia, low white cells, and low platelets.

Features secondary to low blood counts

The cardinal features of pancytopaenia include:

• Lethargy
• Weakness
• Pallor
• Bruising
• Bleeding
• Recurrent infections.

These presenting features are related to the fall in all three blood cell lines seen in pancytopaenia. You should consider the timing of onset (e.g. days, weeks, months), and determine whether there are any constitutional features of malignancy or chronic infection including weight loss, fever, and night sweats.

Features secondary to underlying disorder

The wider clinical history will help to determine the underlying cause of pancytopaenia.

• History of presenting complaint: you should complete a full systems review to determine any potential underlying condition. If a relevant symptom is present (e.g. joint pain), ensure you fully explore that symptom thinking about timing of onset, severity, distribution, and associated symptoms.
• Past medical history: consider any prior history of malignancy or autoimmune disorders. Has the patient previously needed replacement of vitamins (e.g. B12/folate) and do they have any conditions that may influence the nutritional status (e.g. Crohn’s)? Could they have an underlying condition causing portal hypertension (e.g. liver disease / cirrhosis)? Have they recently suffered from an infection?
• Medications: Ensure you determine the current medications, any new drugs, and any dose changes. Make sure you establish the temporal association (e.g. one week or one month before symptom onset). Certain medications are more likely to cause pancytopaenia (e.g. azathioprine) that usually warrant monitoring cell counts whilst on treatment. Remember drug doses as some medications have a dose-dependent effect whereas others are related to an idiosyncratic reaction (i.e. unpredictable reaction).
• Family history: ask about any family history of autoimmune conditions, bleeding disorders or malignancy.
• Social history: occupation and travel history are really important to exclude exposure to toxins (e.g. organic solvents) and specific infections (e.g. hepatitis viruses, HIV, TB, malaria). Simple factors such as drug and alcohol use are important as they can be toxic to the bone marrow.

Look for signs of an underlying haematological malignancy (e.g. lymphadenopathy, organomegaly).

Always perform a full clinical examination, specially looking for any features of an underlying malignancy, liver disease, or autoimmune disorder. The examination may provide clues to the presence of anaemia (e.g. conjunctival pallor, pale nail beds) and thrombocytopaenia (e.g. bleeding, bruising, petechiae, purpura).

Features to consider:

• Lymphadenopathy
• Organomegaly (e.g. splenomegaly, hepatomegaly)
• Scleral findings: pale, jaundiced
• Oral findings: ulcers, thrush (e.g. as immunocompromised)
• Features of cardiac failure (e.g tachypnoea, raised JVP, crackles on auscultation, peripheral oedema): due to symptomatic anaemia
• Skin findings: pale, jaundiced, bruising, petechiae, purpura
• Other: joint pain or swelling, sarcopenia, active bleeding

A full blood count and peripheral blood film are essential to make the diagnosis and look for a potential cause.

Pancytopaenia is confirmed based on a full blood count that will provide values for the haemoglobin, white cell count (and differentials), and platelets. Once it has been confirmed, other investigations are crucial to determine the underlying cause of pancytopaenia as the presence of reduced cell lines by itself is not a diagnosis.

Peripheral blood film

The peripheral blood film is a simple investigation that involves looking at a drop of blood under the microscope. This allows the assessment of blood cell quantity and morphology. A peripheral blood film is mainly a test to determine if there is an underlying haematological process (e.g. malignancy), but subtle findings can suggest other causes (e.g. atypical lymphocytes in viral infections).

Some important features to look for on a blood film include:

• Circulating blasts (i.e. immature white blood cells): suggestive of leukaemia
• Abnormal / dysplastic white cells: suggestive of myelodysplastic syndrome
• Immature white blood cells: suggestive of myeloproliferative disorder
• Hypersegmented neutrophils: suggestive of megaloblastic anaemia (e.g. B12 deficiency)
• Schistocytes (fragmented red blood cells): suggestive of peripheral destruction

Abnormal findings on a blood film are usually followed up with more specialist laboratory tests to confirm the diagnosis. These can include bone marrow aspirate and biopsy, flow cytometry, cytogenetic testing, and molecular studies. A bone marrow biopsy is particularly important in patients with a suspected primary haematological disorder.

Basic investigations

• Full blood count
• Peripheral blood film
• Liver function tests
• Iron studies
• Haematinics: vitamin B12 and folate
• Bone profile
• Uric acid
• Renal function
• Coagulation
• Lactate dehydrogenase
• Reticulocyte count

Specialist investigations

More specialist tests depend on the suspected underlying cause and results of initial testing. These can include:

• Autoimmune / vasculitis screen
• Malaria screen
• Viral screen (e.g. HIV, hepatitis B/C)
• Serological tests for infections
• Bone marrow biopsy
• Lymph node biopsy
• CT-PET

It is essential to exclude an underlying haematological malignancy in patients presenting with pancytopaenia.

Pancytopaenia may be associated with a serious underlying disorder that requires urgent treatment. Always consider the need for urgent inpatient management and discussion with a haematologist in the following situations:

• New diagnosis of neutropenia (esp. with fever)
• Symptomatic anaemia
• Severe thrombocytopaenia (e.g. < 10 x10^9/L or < 50×10^9/L with bleeding)
• Suspected disseminated intravascular coagulation
• Abnormal blood film (e.g. blasts)
• Severe pancytopaenia (i.e. significantly low blood counts of all lines)
• A suspected metabolic emergency in the context of pancytopaenia (e.g. tumour lysis syndrome)