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Information ⬇

Author: Deborah Hay

Pancytopenia may be due to inadequate or defective production of blood cells (bone marrow failure), increased destruction or complex mechanisms (see Table 100.10).

Priorities ⬆ ⬇

Outline

Immediate Clinical Assessment!!navigator!!

  • Assess for fever >37.5°C.
  • Assess for circulatory compromise (sepsis/symptomatic anaemia/occult haemorrhage – NB avoid rectal examination in neutropenic patients).
  • Assess for evidence of bleeding, for example petechiae, bruising, mucosal blood blisters.
  • Assess for lymphadenopathy, splenomegaly and hepatomegaly.
  • Assess for sources of infection, for example indwelling venous catheters.

Immediate Management and Urgent Investigation!!navigator!!

  • Alert the haematologist on-call (Figure 101.1).
  • Secure venous access and obtain blood samples for first-line investigation (see Table 101.2).
  • Fluid resuscitation if haemodynamically compromised.
  • Septic screen for patients with febrile neutropenia, including aseptic sampling of any indwelling lines for culture (Table 101.3).
  • Broad-spectrum empiric antibiotic treatment if neutropenic and febrile (>37.5°C). Agents are likely to include piperacillin/tazobactam as recommended by NICE guidelines, but will be determined by local hospital microbiology policy.
  • If haemorrhagic:
    • Adult therapeutic dose of platelets if count <50×109/L
    • Cryoprecipitate if fibrinogen<1g/L
    • Fresh frozen plasma (FFP) if PT and APTT >1.5× upper limit of normal

  • Packed red cells if symptomatically anaemic.

    NB: Some haematological malignancies and exposure to some chemotherapy agents necessitate the use of irradiated packed red cells and platelet concentrates (Table 101.4).

Patients Needing Admission!!navigator!!

  • Pancytopenia itself is not an absolute indication for admission: many patients who are receiving outpatient chemotherapy regimens will have intermittent and expected periods of pancytopenia that are safely managed in the community with regular attendance at day treatment units for blood product support. In this setting, platelets are typically given when the count falls to 10×109/L, and packed red cells when the haemoglobin falls below 80g/L.
  • Patients receiving myelosuppressive chemotherapy should be counselled by their coordinating physician to seek urgent medical attention if they develop a fever or any symptoms suggestive of infection. Regular and frequent follow-up is critical in this setting.
  • Admission is indicated for patients with febrile neutropenia (absolute neutrophil count <1×109/L, temperature >37.5°C), and these patients should be carefully monitored for signs of deterioration, especially while antibiotic treatment is empirical. Those with febrile neutropenia as a result of chemotherapy should be managed by their coordinating specialty team, but any delay in the administration of antibiotics should be avoided.
  • For patients with unexplained pancytopenia, admission is likely to be required to permit a comprehensive evaluation (see below, including Table 100.2).
    • Where the initial investigations suggest a primary haematological cause (e.g. acute leukaemia evident on the peripheral blood film) admission should be under the care of the haematologist.
    • Where no cause is identified from the first-line investigations, admission under the general medical service is appropriate, with haematological guidance for empirical management and further investigation.
  • Patients with mild pancytopenia in whom an indolent course can be clearly established from historic blood results may be suitable for discharge and further evaluation by the haematology service as an outpatient; seek advice from a haematologist.

Monitoring and Escalation of Care!!navigator!!

  • Intensive support should be requested for patients with febrile neutropenia who remain hypotensive or haemodynamically unstable despite aggressive fluid resuscitation and broad-spectrum antibiotic treatment.
  • Where patients have an indwelling tunnelled venous catheter (for the delivery of chemotherapy), consideration should be given to whether this constitutes the source of infection. Erythema along the line of the tunnel, discharge from the tunnel exit point and rigors on flushing of the line may all suggest local infection, and removal of the line is likely to be needed.
  • In patients where the cause of bone marrow failure is secondary to chemotherapy, close liaison with the coordinating specialty team is essential to establish long-term prognosis and appropriate ceilings of care.

Further Management ⬆ ⬇

Outline

Clinical Assessment!!navigator!!

Once the patient is stabilized, an initial assessment of the possible causes of pancytopenia can be undertaken. For those with a known likely explanation (e.g. recent chemotherapy) this should include:

  • Details of the diagnosis
  • The status of the disease (e.g. newly diagnosed, induction chemotherapy, in remission)
  • Duration of treatment
  • Nature of the chemotherapy given
  • Date of most recent treatment
  • Antimicrobial prophylaxis received

These factors will affect management by determining the choice of blood product and may also influence the antimicrobial agents used for the treatment of neutropenic fever.

Patients who have been exposed to prolonged and/or repeated periods of neutropenia may have fungal as well as bacterial infection.

In heavily immunosuppressed patients, the possibility of pneumocystis infection or CMV reactivation should also be considered.

For seriously ill or unstable patients, early liaison with the physicians coordinating the patient's care is vital to establish any previous history or infection, and any previously isolated organisms.

For patients with new or unexplained pancytopenia, the history should elicit the following:

  • Features to suggest occult malignancy: weight loss, fevers, night sweats, focal symptoms
  • Current and recently prescribed medications and over-the-counter treatments (Table 101.1)
  • Risk factors for blood-borne viruses (HIV, hepatitis B and C)
  • Travel history (e.g. leishmaniasis, malaria; see Chapter 33)
  • History of thrombosis (malignancy, paroxysmal nocturnal haemoglobinuria)
  • Features of haemoglobinuria (paroxysmal nocturnal haemoglobinuria)
  • Recent jaundice (hepatitis-associated aplasia)
  • Occupational history and exposure to toxins (e.g. solvents, pesticides)
  • Especially for children: family history of marrow failure, anaemia or malignancies

The features on physical examination of a patient with unexplained pancytopenia will include pallor, petechiae and bruising. However, features to suggest an underlying aetiology may be much more subtle. In cases where the pancytopenia arises due to accelerated consumption, there is likely to be splenomegaly; features suggesting an underlying cause for splenomegaly (e.g. liver disease, lymphoma, connective tissue diseases) must also be sought.

Where there is inadequate marrow production due to marrow infiltration, there may be physical evidence to suggest a primary malignancy (with prostate, breast, lung and renal tumour being typical primary sites for marrow metastases). Clonal haematological disorders suppressing normal haemopoiesis may also give signs on examination, including lymphadenopathy and splenomegaly. Rarely, hypopituitarism can give rise to marrow aplasia, and it is worth considering features due to both hormone deficiency and local effects in the region of the pituitary fossa.

Patients presenting (typically in childhood) with the rare congenital and inherited bone marrow failure syndromes may also have characteristic features on clinical examination, including skeletal abnormalities, short stature and changes in skin pigmentation.

In many cases, however, the clinical examination will yield no clues to the cause of pancytopenia, and the ultimate diagnosis will require specific haematological investigation.

Investigation

After the first-line investigations described above, specialized haematological input is needed. Clues on the peripheral blood film may guide a working differential (Table 101.5), but patients with persistent pancytopenia of unknown aetiology are very likely to require examination of the bone marrow in order to obtain a diagnosis. An opinion on the morphological appearance of the marrow aspirate may be available as soon as one hour following the bone marrow biopsy. A more detailed evaluation of any abnormal cell population seen in either the peripheral blood or marrow aspirate can be obtained using immunophenotyping by flow cytometry.

A bone marrow trephine offers complementary information, and allows assessment of a more representative section of marrow including the distribution of cells and the presence or absence of fibrosis. Detailed immunostaining protocols allow the identification of haemopoietic and infiltrating cell types, even when their appearance is atypical. However, since these samples require extensive laboratory manipulation and specialist interpretation, information from a trephine will not be available to inform immediate management.

Lymphadenopathy is best assessed by cross-sectional imaging such as CT, or PET-CT, which may provide additional information about the site and nature of malignant disease.

Problems!!navigator!!

Artefacts

Occasionally, samples are reported as pancytopenic simply because a clot is present in the tube. Drawing blood from a site proximal to an intravenous infusion is another potential error that might lead to the false impression of pancytopenia (though here, biochemical results would also be markedly abnormal). An urgent repeat plus blood film is always warranted – although where the clinical picture fits there should be no delay in emergency management.

Acute infection

Infections that have been termed the ‘mononucleosis syndromes’ – including acute EBV and CMV infection – can sometimes produce a clinical picture of alarming severity, especially in adults. Complications may include haemolysis, immune thrombocytopenia and immune neutropenia, and the combination of pancytopenia with atypical lymphocytes in the peripheral blood film can raise concerns of high-grade haematological malignancy. Many cases also feature lymphadenopathy and splenomegaly, and it is easy to expose the patient to a bone marrow examination that is both unnecessary and potentially very easy to misinterpret. The monospot test is useful, especially in adults, but not uncommonly gives false negative results in children with acute EBV infection; consequently, specific viral serology and PCR testing are indicated where these infections form part of the differential diagnosis.

Acute promyelocytic leukaemia (APML)

Although rare, this subtype of acute myeloid leukaemia is worth particular mention due to its association with disseminated intravascular coagulation. Patients may present with signs of haemorrhage, including widespread purpura, gum bleeding, epistaxis and intracranial bleeding. It is for the emergency diagnosis of this condition above all others that a haematologist will review the blood film of a pancytopenic patient urgently, at any time of day or night.

APML is the consequence of a chromosomal translocation that involves the retinoic acid receptor gene (RARα). For this reason, treatment with all-trans retinoic acid (ATRA) can promote differentiation of the leukaemic cells, reducing the risk of haemorrhage. For any patient in whom APML is considered after inspection of the peripheral blood film, immediate treatment with ATRA is indicated.

Macrophage-activating syndrome

This umbrella term refers to a constellation of clinical features, including persistent fever, cytopenias, consumptive coagulopathy, deranged liver function, gross hyperferritinaemia and hypertriglyceridaemia. The underlying pathophysiology is most clearly defined in the rare familial haemophagocytic syndrome where perforin or Munc gene mutations result in dysregulation of cytotoxic immune functions. However, acquired haemophagocytic syndrome is also described, and can be triggered by infections such as HIV, EBV and CMV, and by malignancies, notably aggressive lymphomas. It is also seen in association with connective tissue disorders. The uncontrolled T cell proliferation and macrophage activation that characterize this syndrome are associated with a high mortality. Although rare, this syndrome and its associated disorders should be considered in patients with persistent pancytopenia and unremitting fevers, despite appropriate antimicrobials.

Further Reading ⬆

Klastersky J, deNaurois J, Rolston B, et al. (2016) Management of febrile neutropaenia. ESMO Clinical Practice Guidelines. Ann Oncol 27 (suppl 5), v111–v118. https://annonc.oxfordjournals.org/content/27/suppl_5/v111.full.pdf+html.

Weinzierl EP, Arber DA (2013) The differential diagnosis and bone marrow evaluation of new-onset pancytopenia. Am J Clin Pathol 139, 9–29. http://ajcp.oxfordjournals.org/content/ajcpath/139/1/9.full.pdf