Pancytopenia and its management

Introduction:
Pancytopenia is an important clinicohaematological entity encountered in our dayto-day clinical practice.Cytopenia is a reduction in the number of each type of peripheral blood cell. A reduction
in all 3 types of cellular components in peripheral blood is termed pancytopenia and this involves anaemia, neutropenia, and thrombocytopenia.Mild impairment in marrow function is inapparent.
It is apparent only during times of stress or increaseddemand (e.g., bleeding or infection).
Severe pancytopenia is defined as follows :
i) Absolute neutrophil count < 500/mm3
ii) Platelet count < 20,000/mm3
iii) Corrected reticulocyte count < 1%

Aetiopathogenesis:
Aplastic anaemia is one of the most serious causes of pancytopenia.Marrow failure leading to pancytopenia may result from immune-mediated or non-immune mediated damage or suppression of either pluripotent stem cells or committed progenitor cells.Interestingly, most cytotoxic drugs used in the treatment of malignancies exert their major effects on committed progenitor cells. Ablation of these cells result in marrow hypoplasia but recovery is still possible by regeneration from the pluripotent stem-cell compartment. Pancytopenia from bone marrow failure is also an important feature of acute leukaemias, the later stages of chronic leukaemias, myeloproliferative disorders, and myelodysplasias.

The different causes of pancytopenia due to bone
marrow failure are enumerated in Table I.
Causes of pancytopenia:
Primary Secondary
Idiopathic Drugs
Congenital/Familial Viral infections
Mycobacterial infections
Autoimmune disorders
Chemicals (benzene, arsenic)
Cytotoxics
Malignant infiltration
Paroxysmal nocturnal haemoglobinuria
Drugs causing pancytopenia:
A. Cytotoxics (by bone marrow suppression)
B. Chloramphenicol (by dose related effects)
C. Idiosyncratic response (immune mediated)
a. NSAIDs
b. Colchicine
c. Chloramphenicol
d. Sulfonamides
e. Phenothiazines
f. Thiazides
g. Anti-thyroid drugs
h. Anti-epileptics
i. Anti-diabetics
Viral infections causing pancytopenia:
1. Hepatitis B and C viruses
2. Cytomegalovirus
3. Epstein – Barr Virus
4. HIV
5. Hepatitis A virus(rare)
Clinical features:
The cardinal signs of moderate to severe pancytopenia are anaemia, bleeding, and infection.
Red blood corpuscles survive much longer than platelets or neutrophils. Thus, anaemia develops slowly.and the typical symptoms of tiredness, fatigue, puffiness of face, oedema, lassitude, and effort intolerance may not be striking in the initial phase.

The platelet count is first to be affected. Mucocutaneous bleeding is typical of thrombocytopenia with petechial haemorrhages in skin and mucous membranes.The presence of spontaneous bleeding with platelet count <20 x 109/l indicates severe marrow failure.Retinal bleeding is common and may lead to blindness.

Next to be affected is the myeloid series.Infections usually occur with commensal organisms of the skin or gastrointestinal tract.Early manifestation of neutropenia is often a sore throat or chest or soft tissue infection which typically show incomplete response to antibiotics.Thecommonest offending organisms include coliforms, klebsiella spp, pseudomonas
species, and staplylococci.


Investigations:

A. Pancytopenia and morphological changes in peripheral blood.
i) RBC changes:
Reticulocytes are markedly reduced or absent.
Stress in erythropoiesis may result in an increase in Haemoglobin F Increase in iron overload from multiple Increase in serum folate and vitamin B12 levels excludes other causes of macrocytic
anaemia.
ii) WBC changes
Blast cells may be evident in bone marrow of patients in whom pancytopenia is due to
malignant infiltration.
Morphological changes in neutrophils(absent granulation, nuclear abnormalities)
suggest preleukemia/myelodysplastic states.

iii) Platelet changes :
Mean volume of platelets (MVP) is normal.
B. Bone marrow examination :
It is indicated in all cases of pancytopenia where the underlying cause is not quite obvious. This is particularly needed to exclude leukaemia or other malignant infiltration. Routine aspiration smears may have to be combined with trephine biopsies as quite often aspiration might yield dry or bloody tap. Bone marrow examination shows diminished cellularity with increased fat cells,
reticulin cells, plasma cells, mast cells, and relative increase in lymphocytes. Trephine
biopsy better demonstrates increased fat spaces, elements of dyserythropoiesis, megaloblastosis, and nuclear cytoplasmic asynchrony.

Management :
The basic management of patients with pancytopenia involves identification and reversal of the underlying cause and adequate supportive care until normal counts are restored. It must be emphasised that bleeding and infection due to cytopenias is a medical emergency.
A. Supportive care :
This is the most important aspect of management of pancytopenia. Anaemia is corrected by transfusion of packed red cells to maintain haemoglobin (Hb) level above 8-9 gm/dl. It has been observed that retinal haemorrhage is likely to occur below this level. Blood should be administered cautiously to avoid circulatory overload. The previous concept of maintaining Hb
below 7 gm/dl to facilitate bone marrow stimulation is no longer valid. Intramuscular injections and teeth brushing should be avoided in thrombocytopenic patients. Active bleeding should be
promptly managed with the help of infusion of platelet concentrates in the form of
platelet packs from random donors (5.5 x 1010 platelet/unit) or single donor (3 to 4 x
1011 platelet/unit). It has been observed that each random donor platelet unit increases the platelet count by 10,000/ mm3 at 1 hour after infusion6. Platelet concentrates prepared from single donors using leukocyte filter is the ideal treatment with the aim to maintain platelet count
around 20,000/mm3. Bleeding in thrombocytopenic patients may be decreased by oral administration of eaminocaproic acid 50 mg/kg every 6 hours. In patients receiving large volumes of blood/blood component transfusions, irradiation of blood or blood products is
ideal to prevent transfusion-induced graft versus host disease (GVHD). Moreover, for
multiple transfusions (>50 transfusions) or when there are indications of iron overload.
(serum ferritin >500 mg/dl), iron chelation is needed. The scope of granulocyte tranfusions for the management of neutropenia is very limited as well as controversial because of
inconsistent rise in leucocyte count, prohibitive cost, unreliability in the homing of infused granulocytes at the sites of infection, possibility of allosensitisation, and GVHD. Its role has been further undermined with the availability of very effective and potent antimicrobials and
growth factors. Granulocyte transfusions are now only confined to desperate situations in which proven infection does not respond to appropriate antibiotic therapy.

B. Prevention of infection :

Reverse barrier isolation is one of the most cost-effective measures in the management
of pancytopenia. Careful maintenance of skin hygiene, good dental care, and rectal
hygiene is absolutely essential. Severe neutropenia by itself is not an indication
for hospitalisation as with each admission in the hospital the patient is exposed to the
risk of becoming colonised with antibiotic resistant micro organisms. Strict isolation
in a sterile environment (equipped with laminar flows) together with measures for
skin and gastrointestinal tract decontamination and consumption of
sterile food have been shown to reduce the episodes of infection but generally have
little impact on the eventual outcome of the underlying disorder.
For the past few years some centres are routinely using prophylactic oral antibiotics, such as ciprofloxacin or norfloxacin to reduce the incidence of gram negative sepsis. Both these drugs are very effective but carry the risk of inducing antibiotic resistance. Scrupulous hand washing by medical and health care.

Other management:

The availability of recombinant growth factors like granulocyte colony stimulating factor (GCSF)
or granulocyte macrophage colony stimulating factor (GM-CSF), and recombinant
erythropoietin (rhu EPO) have enabled more specific management with improved outcome
of the pancytopenic patients7,8. The exact role of newer cytokines like recombinant human
interleukin – 3 (IL-3) and interleukin-6 will gradually become better established in near
future. Although at present they are very expensive, yet may ultimately prove to be cost
effective, by reducing the cost of antimicrobials as well as transfusion requirements, thus reducing the total cost of supportive care9. Immunosuppressive therapy with anti
lymphocyte globulin (ALG) and/or cyclosporin has proved to be effective in achieving
remission in aplastic anaemia10. Bone marrow transplantation (BMT) is a therapeutic option
for suitable subsets of younger patients who have HLA matched siblings donors.