Practical Approach to Pancytopenia

Introduction

Pancytopenia is defined as reduction in the number of blood cell count below the age adjusted normal reference ranges in the peripheral blood. ² In other words, this is a condition where anaemia, leucopenia and thrombocytopenia are present in combination.

Before we discuss the possible causes and approach to patients with pancytopenia, let us review the following two clinical scenarios.

Patient A: Patient A is a 23 year old administrative assistant who presented with fever, sore throat and tender enlarged glands in his neck and axilla. Blood count revealed Hb 12.5 g/dL, total white cells 3.4 x 10⁹/L and platelets 109 x 10⁹/L. Absolute neutrophil count was 0.9 x 10⁹/L. Monospot or rapid antibody test for EBV was positive. Liver function tests were mildly deranged.

Patient was given anti-pyretics for fever and was advised to rest well with good hydration. Symptoms resolved after 1 week. Follow-up blood count after 2 weeks’ time showed resolution of previously noted pancytopenia.

Patient B: Patient B is a 72 year old gentleman with progressive fatigue, loss of interest in food and increased bruising. He also had two courses of oral antibiotics for lower respiratory tract infection and urinary tract infection 3 weeks apart.

Patient C’s blood count showed Hb 7.8 g/dL, WBC 2.1 x 10⁹/L, Platelets 47 x 10⁹/L and absolute neutrophil count 0.9. Patient’s blood counts were normal 10 months ago. Blood film showed dysplastic features. Patient was referred to haematology straightaway for further investigations. Patient was diagnosed with myelodysplastic syndrome after extensive work-up and remained under the care of the haematology team for further management.

Who needs a referral?

Any unexplained and significant pancytopenia requires a review by haematology. Significant pancytopenia reflects severely low blood counts, in general where there is

• white cell count is less than 0.5 x 10⁹/L and/or absolute neutrophil count <0.5 x 10⁹/L
• platelet count <20 x 10⁹/L
• Severe symptomatic anaemia ^2,3

Pancytopenia in the presence of circulating immature blast cells or severely low reticulocyte count should be referred urgently.

There are serious clinical implications with severe pancytopenia such as life-threatening sepsis, significant bleeding and cardiovascular compromise, hence an urgent haematology review is warranted.

If patient has a mild pancytopenia for the first time and asymptomatic, a repeat blood count may be performed again in 2 weeks. Some patients may have transient pancytopenia arising from a reversible cause such as medications. These patients do not require haematology review if their cytopenia recovered after discontinuation of medications. Unexplained pancytopenia which is either persistent or progressive warrants further investigations and a referral to haematology will be necessary.

Aetiology

This review will focus mainly on adult patients. However, in children and young adults, inherited disorders of bone marrow such as Fanconi’s syndrome, dyskeratosis congenital and lysosomal storage disorders such as Gaucher’s disease should be considered in the correct clinical context. Inherited bone marrow failure syndromes are usually accompanied by unique clinical features (growth retardation, skeletal and skin abnormalities, etc.) in addition to pancytopenia.

Majority of pancytopenia are acquired in aetiology and may be due to decreased bone marrow production or bone marrow failure, increased peripheral destruction or sequestration or combination of both.³ Common causes for pancytopenia are summarised in Table 1.

CMV- cytomegalo virus, EBV- Ebstein-Barr virus, SLE- systemic lupus erythematosis

Table 1: Summary of common causes for pancytopenia

Decreased bone marrow function

Medications: Drug-induced pancytopenia can be related todirect toxic effects of medications to haematopoietic stem cells or immune-mediated destruction. Many different medications are described but most commonly cytotoxic chemotherapy, antiepileptics, anti-psychotics, NSAIDs, some antimicrobial drugs, etc. Patients are expected to recover from pancytopenia within 1-2 weeks after exposure to chemotherapy. If cytopenia does not recover after 2 weeks or as expected, further investigations should be considered.

Radiotherapy: Likewise, radiotherapy can also damage stem cells hence resulting pancytopenia. It may take several weeks to months for marrow function to recover after exposure to radiation.

Megaloblastic anaemia: Deficiency in Vitamin B12 and/or Folic acid not only cause megaloblastic anaemia but can also be presented with leucopenia and thrombocytopenia. In some cases, peripheral blood findings may also mimic acute leukemia or haemolytic anaemia.

Viral infections: Acute viral infections are one of the commonest causes for pancytopenia and usually reversible within a short number of weeks. Certain Infection such as acute HIV, CMV, EBV, HHV-8 can also present with pancytopenia. Parvovirus infections in patients with sickle cell anaemia or congenital spherocytosis also cause pure red cell aplasia causing severe anaemia with leucopenia and thrombocytopenia.

Other common causes include acute alcohol excess (direct marrow toxicity), severe sepsis and antibiotic use. Rare causes include heavy metal poisoning, anorexia nervosa and patients with transfusion associated graft versus host disease.

Acquired bone marrow failure

Clonal haematopoiesis: The commonest acquired marrow failure results from abnormal clonal haematopoiesis characterised by ineffective haematopoiesis, reduced survival of blood cells and resultant peripheral cytopenia with dysplastic features. This disorder is recognised as Myelodysplastic syndromes (MDS), typically presents with progressive cytopenia in older age (usually >70 years) with risk of evolution to acute myeloid leukemia.^5,6 MDS is also associated with specific chromosomal and molecular aberrations with variable prognosis based on same.

Acquired Aplastic anaemia: Non-inherited Aplastic anaemia is an acquired bone marrow failure syndrome characterised by immunologically mediated destruction of haematopoiesticstem cells leading to hypoplastic marrow with pancytopenia in peripheral blood. Absolute reticulocytopenia is one of the hall marks of disease. Acquired aplastic anaemia may co-exists with PNH (Paroxysmal Nocturnal Haemglobinuria).

Bone marrow infiltration

Primary haematological neoplasms: This includes acute and chronic leukemia of myeloid or lymphoid lineages, lymphoproliferative disorders, plasma cell disorders (myeloma, amyloidosis) and myelofibrosis. Primary haematological neoplasms are usually manifested by other symptoms and signs relevant to each disorder. The degree of cytopenia is variable but with abnormal cells or features on the peripheral blood smears. Many patients may also have B symptoms (unintentional weight loss of >10% over 6 months, drenching night sweats, unexplained fever), recurrent infections, lymphadenopathy or hepatosplenomegaly.

Marrow infiltration by systemic diseases: secondary metastatic disease to the bone marrow, non-neoplastic infiltration such as tuberculosis.

Increased destruction or sequestration

Autoimmune-mediated pancytopenia is noted in patients with systemic lupus erythematosus (SLE) and autoimmune lymphoproliferative syndrome (ALPS). Splenic sequestration due to splenomegaly is a common cause for pancytopenia in patients with chronic liver disease in our clinical practice. These patients generally have normal haematopoiesis in the absence of abnormal infiltrative disease.

Other conditions such as acute and chronic infections that can result in splenomegaly (brucellosis, malaria, Leishmaniasis). Autoimmune mediated pancytopenia is also observed with some medications such as sulphur containing drugs, methotrexate and quinine, where antibodies with cross reactivity to the drug and haematopoietic stem cells are responsible for low blood counts^.7

Combination of above causes

Many conditions associated with pancytopenia result from a combination of decreased bone marrow production and increased destruction or sequestration of blood cells. They include:

• Connective tissue disorders (most commonly rheumatoid arthritis and systemic lupus erythematosus)
• Acute cytomegalovirus infection
• Mycobacterial infection
• Infectious mononucleosis
• HIV
• Felty’s syndrome (rheumatoid arthritis, splenomegaly, and neutropenia).

Practical Approach

History

As mentioned above, causes of pancytopenia are diverse, especially for children and adults. A thorough history taking on symptoms and effects of pancytopenia on individual patients, medications, and travel history, social and personal history are equally important. In children and young adults, particular attention should be given to family history for inherited disorders of bone marrow.

Important and relevant aspect of history taking is to assess the severity and impact of cytopenia on patient. Symptoms of anaemia including exercise tolerance, performance status to features of cardiovascular compromise should be assessed. Infections including fevers, rigors, mucositis to specific infective symptoms should be explored. History and severity of skin and mucocutaneous bleeding episodes need to be checked.

Physical examination

Thorough general and systemic examination is absolutely essential in assessing the patient for underlying causes including signs of infections, bleeding or bruising, features of congenital/inherited syndromes, lymphadenopathy, hepatosplenomegaly or autoimmune disorders. ³ Figure 1

Fig 1: Summary of physical examination for assessing patients with pancytopenia

Laboratory Investigations

Not every clinician will have equal access to a range of laboratory tests in real life clinical practice. A summary of clinical diagnostic tests will be described in two groups; initial investigations which should be widely available to primary care physicians (first line investigations) and specialised tests to be considered in secondary and tertiary care settings. Table 2.

PT – prothrombin time, APTT- activated partial thromboplastin time, LDH- lactate dehydrogenase, PNH- paroxysmal nocturnal haemoglobinura

Table 2: Outline of Investigations in general for pancytopenia

Examination of bone marrow is almost always indicated in patients with pancytopenia except in cases where the underlying cause is apparent such as portal hypertension.4,8,9 The diagnostic yield from bone marrow examination also depends on technique in performing the procedure so that adequate sample is available for interpretation. Viability of the sample is also important for performing specialised tests such as immunophenotyping or cytogenetic analysis.

Morphological assessment of marrow aspirate smears and trephine biopsy provides valuable information such as cellularity, megaloblastic changes, dysplastic features, abnormal infiltrates, infections such as Leishmaniasis, CMV, TB, etc.

Immunophenotyping enables more accurate characterisation of abnormal infiltrates if present. Specific cytogenetic and molecular analysis provide confirmation of diagnosis, prognostic information and may also be useful as markers for disease monitoring during treatment. These are specialised tests with potentially longer turn-around times. Some haematological disorders such as acute leukemias can be diagnosed readily by examination bone marrow aspirate smears and treatment can be initiated without delay. In some cases, a repeat marrow may be required to consolidate the findings. It is important to reassure patients and families that it is necessary to perform and review all relevant tests so that accurate diagnosis can be made and most appropriate treatment pathway can be recommended for them.

References

1. Desai AV, P. M. (2017). Clinical assessment and diagnosis of germline predisposition. Front Pediatr, 252.
2. Gnanaraj J, P. A. (2018). Approach to pancytopenia: diagnostic algorithms for clinical haematologists. Blood Reviews, 361-367.
3. JM., L. (2024). Assessment of Pancytopenia. BMJ Best Practice, https://bestpractice.bmj.com/topics/en-gb/1024/aetiology.
4. NS, Y. (2018). Aplastic anemia. N Engl J Med, 1643-56.
5. Roman E, S. A. (2016). Myeloid malignancies in the real-world: occurrence, progression. Cancer Epidemiol, 186-98.
6. Sekeres MA, T. J. (2022). Diagnosis and treatment of myelodysplastic syndromes: a review. JAMA, 872-80.
7. Vanni KMM, L. H. (2020). Cytopenias among patients with rheumatic diseases using. Rheumatology (Oxford), 709-17.
8. Weinzierl EP, A. D. (2013). The differential diagnosis and bone marrow evaluation of new-onset. Am J Clin Pathol, 9-29.
9. Williams DA, B. C. (2014). Diagnosis and treatment of pediatric acquired aplastic. Pediatr Blood Cancer, 869-74.

Author Information
Su W Maung
Clinical Lecturer/Adjunct Professor in Haematology, School of Medicine, University College Dublin
MBBS, MRCP (UK), FRCPI, FRCPath, MD
Consultant Haematologist, Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland