Pancytopenia – a common clinical problem that puts a strain on blood transfusion services

to a low maintenance dose with excellent response; no more blood transfusions were needed.

This case of pancytopenia illustrates a common clini­cal problem that clinicians may encounter everywhere but that in areas with limited resources poses major dif­ficulties. It is difficult to accurately diagnose the under­lying condition, and management is often empirical, frequently resulting in repeated blood transfusions.

Definition

Pancytopenia means that all three cell lineages in the peripheral blood (red cells, white cells and platelets) are reduced below the reference range. For each cell line, a reference standard has been published by WHO[1]:

Pathogenesis

The main (groups of) underlying conditions are listed in Table 1. The most common causes may vary according to the region.[2] Bone marrow aplasia may be the result of damage to the haematopoietic stem cells. Another term that is often used is aplastic anaemia which is actually a misnomer as not only the red cells are affected but also white cells and platelets are involved.[3] Bone marrow aplasia may be caused by virus infections such as HIV or HIV-associated viruses. Drugs are another important cause. Antibiotics such as chloramphenicol are widely used in LMICs and may lead to irreversible bone marrow destruction in 1:20,000-40,000 cases, and there are many more examples of other drugs.[4] Autoimmune antibod­ies against any of the cell lineages may also occur, and this may also be the case in our patient in the context of SLE.[5]

Alternatively, the bone marrow may not be damaged as such but the cell lines may be displaced by infiltration by a massive infection such as tuberculosis or malignan­cies such lymphomas. In such cases the bone marrow may recover after treatment of the underlying condition.

The other causes, blood cell destruction and sequestra­tion, are less common, are more difficult to diagnose, and may not easily be recognized in clinical practice. Se­questration of blood cells in a massively enlarged spleen may occur for example in the context of liver cirrhosis and portal hypertension, or in visceral leishmaniasis.[6]

Clinical presentation

The clinical presentation depends on the underlying condition and the resulting anaemia (fatigue, heart failure, ischaemic heart disease), risk of infection (fever, night sweats, yellowing of eyes) and bleeding tendency (bruising, bleeding). Simi­larly, on examination, lymphadenopathy, hepatomegaly and splenomegaly, jaundice or stigmata of liver disease may be found. There is a long differential diagnosis, and it is use­ful to distinguish between the main groups. (see Table 1)

Diagnosis

With regard to pancytopenia

In most settings, a full blood count should be pos­sible leading to the diagnosis of pancytopenia as a syndrome. Reticulocyte count is helpful to assess pro­duction of red cells; it will be raised in the case of in­creased peripheral destruction and low in the case of reduced production of red cells in the bone marrow.

A peripheral blood smear may show abnormal cells such as lymphoblasts or myeloblasts in leukemia, or atypi­cal lymphocytes in infectious mononucleosis.

Further analysis should be done at a tertiary referral setting.

A bone aspirate or biopsy would then be the next step and is essential to differentiate between the two main causes: destruction of bone marrow (few haematopoietic cells, empty space filled by fatty cells) and infiltration (e.g. malignant cells in lymphoma, positive Ziehl-Neelsen stain in tuberculosis).[7]

In advanced settings, flow cytometry and other molecular tests would be done to type any abnormal cell to make a firm diagnosis.

With regard to underlying condition

The clinical assessment may provide clues to an underlying condition. Tuberculosis may be suspected in a patient present­ing with cough, pleural effusion, ascites or lymphadenopa­thy; many patients will be HIV positive and an HIV test is always indicated. Diffuse lymphadenopathy with hepato- and splenomegaly may point malignant lymphoma. In addi­tion to clues for a primary tumour, severe weight loss and localized matted lymph nodes may point to malignancy.

Additional tests to diagnose viral infections or to dem­onstrate autoimmune antibodies or other markers of as­sociated diseases are often not available. Vitamin B12 or folate deficiency may be suspected if the red cells show macrocytosis; in vitamin B12 deficiency, glossitis and subacute combined neuropathy should be looked for.

Depending on the quality of the laboratory, a firm diagnosis may be made, but often the exact cause remains unclear.

Management

In case of an underlying condition, the bone marrow usu­ally recovers with normalization of the cell lineages. In case of bone marrow destruction, e.g. by a viral infection or drug toxicity, damage may be permanent. In addition to recurrent infections and bleeding tendency, recurrent severe anaemia with a clinical presentation of fatigue, shortness of breath, oedema or overt heart failure is common; repeated blood transfusions are needed that are not always safe and available.

Learning point

In the case described, it was not possible to make a further diagnosis in Malawi due to a lack of diagnostic capacity. Nu­merous repeated blood transfusions were given with all their associated risks of infection, fluid overload and transfusion reactions, including dangerous delays in transfusion because of lack of availability. Referral to South Africa in this case was possible. This may be done through a government-funded scheme or at the patient’s own initiative. The assessment in the South African hospital revealed a treatable underlying condi­tion in this case that responded well to appropriate therapy and no further blood transfusions were needed.[8] Upgrad­ing of laboratory facilities at least at the central level should be considered to diagnose any treatable underlying condi­tion and to avoid unnecessary life-long blood transfusions.

Acknowledgment

This case was kindly provided by Professor Johnstone Kumwenda, College of Medicine, Blantyre, Malawi.

References

1. Valent P. Low blood counts: immune mediated, idiopatic, or myelodyspla­sia. Hematology. Am Soc Hematol Educ Program 2012;2012;485-491.
2. Jain A, Naniwadekaf M. An etiological appraisal of pancytopenia-largest series reported to data from a single tertiary care teaching hospital. BMC Hematol 2013;13:10.
3. Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and man­agement of adult aplastic anaemia. Br J Haematology 2016;172:187-207.
4. DB, Cochran JB, Tecklenburg FW. Chloramphenicol Toxicity Revisited: A 12-Year-­Old Patient With a Brain Abscess J Pediatr Pharmacol Ther. 2012;17: 182-188.
5. Newman K, Owlia MB, El-Hemaidi I, Akhtari M. Management of im­mune cytopenias in patients with systemic lupus erythemato­sus – Old and new. Autoimmun Rev. 2013;12:784-791.
6. al-Jurayyan NA, al-Nasser MN, al-Fawaz IM, al Ayed IH, al Herbish AS, al-­Mazrou AM, al Sohaibani MO. The haematological manifestations of visceral leishmaniasis in infancy and childhood. J Trop Pediatr. 1995; 41:143-148.
7. Weinzierl EP, Arber DA. Bone marrow evaluation in new-on­set pancytopenia. Hum Pathol. 2013;44:1154-1164.
8. Gormezano NW, Kern D, Pereira OL, Esteves GC, Sallum AM, Aikawa NE, Pereira RM, Silva CA, Bonfá E. Autoimmune hemolytic anemia in systemic lupus erythematosus at diagnosis: differences between pediatric and adult patients. Lupus 2017;26:426-430.