Introduction

Pancytopenia is a reduction in the 3 lines of blood cells, (red blood cells, white blood cells, platelets). Many different diseases cause pancytopenia and these are grouped by the process through which they cause low cell counts; complications in haemopoiesis or increased peripheral destruction.

 

The effect that low haemoglobin levels have on the body is an increased heart rate in order to compensate for the hypoxia anaemia creates. Elderly people are less able to tolerate low haemoglobin levels because normal cardiovascular compensation diminshes with age, (coronary heart problems may be precipitated in many elderly people).

 

The effect that low white blood cell counts have on the body is that micro-organisms previously commensal become pathogenic, i.e. Staphylococcus epidermis or Gram negative organisms in the bowel. Leukopenia is most commonly caused by low numbers of neutrophils.

 

The significant reductions in the number of platelets, (thrombocytopenia), results in problems with repairs to damage in the body and abnormalities in haemostasis. 

 

 

Presentation

Patients with anaemia complain of shortness of breath, weakness, lethargy and palpitations. Examination reveals tachycardia, a strong pulse and a systolic heart murmur. More general signs include pallor of mucous membranes, (underneath eyelids), and skin. However, skin pallor is a less reliable measure. As mentioned above, symptoms of cardiac failure or angina pectoris are common in the elderly, so are an important differential for chest pain.

 

Signs indicating leukopenia would be frequent infections of the mouth and throat. In more severe cases, ulceration can also occur at these sites.

 

Mild thrombocytopenia presents as moderate haemorrhages after injury or easily bruising. In more severe cases, purpura and spontaneous haemorrhages from mucous membranes can occur too. There is also a risk of intracranial haemorrhages in severe cases but this risk is still relatively low.

 

 

Symptoms and Signs of Pancytopenia



Tests

Blood samples are taken to confirm the deficiencies in the cell types and grade the severity of them.

  • Haemoglobin levels, (g/L), below set boundaries are used to confirm anaemia.
  1. For a male adult it is < 135 g/L.
  2. For a female adult it is < 115 g/L.
  • A neutrophil count confirms and grades the neutropenia.
  1. Neutropenia is classified as a cell count < 1.5 x 10^9.
  2. Severe neutropenia is classified as a cell count <0.5 x 10^9. Pneumonia/Septicaemia are common at these levels and prophylactic antibiotics are given according to local hospital policies.
  • The platelet count confirms and grades thrombocytopenia.
  1. Mild thrombocytopenia is a count of 50-100 x 10^9, giving moderate haemorrhage after injury.
  2. Severe thrombocytopenia is a count of 20-50 x 10^9. At these levels haemorrhage occurs after injury and there are occasional bouts of purpura.
  3. Very severe thrombocytopenia is a count of <20 x10^9. For these cell counts, purpura is frequent and there are spontaneous haemorrhages from mucous membranes known as petechiae. However, intracranial haemorrhages are rare.

 

To differentiate between the different causes of pancytopenia an examination of the bone marrow is often necessary.

 

Bone marrow aspiration involves inserting a needle into the marrow and withdrawing the cellular contents. This method is quick, extracts the cells in proportion to their marrow contents and detects foreign cells, (i.e. cancerous cells). However, it does not give information on the bone marrow's stroma and does not provide all the cells inside the bone marrow, for example, lymphoma cells stick to the trabeculae. It is also a painful procedure.

 

Bone marrow trephine takes a bone marrow biopsy which is then examined histologically. This allows examination of the cells and the stroma but it takes longer than bone marrow aspirations.



Causes

Leukaemia

Leukaemia

Leukaemia is one of the commoner causes of pancytopenia. It is the uncontrolled production of white blood cells. The different types of leukaemia are classifed by whether they are acute or chronic diseases and whether the cell of origin is myeloid or lymphoid.

 

Pathophysiology

Mutations in blast cells cause them to avoid apoptosis and stops them differentiating. This results in overcrowding of the bone marrow, causing other stem cells to fail to create functional blood cells.

Blood films show pancytopenia and sometimes leukaemic blast cells. However, there is difficulty distinguishing between immature myeloid and lymphoid blast cells purely on morphology.

Several additional tests are used to discern the type of leukaemia.

Cytochemistry uses special stains to distinguish between the different lines of white blood cells.

Immunophenotyping uses CDs, (Clusters of Differentiation/surface antigens), unique to different white blood cell types at different stages of the cell's development. These identify the stage at which differentiation errors occur.

Cytogenetic tests reveal chromosomal abnormalities, providing valuable prognostic information about the sub-type of that specific leukaemia.

 

Acute Myeloid Leukaemia (AML)

AML starts with a mutation that causes a cancerous change in a myeloid precursor cell. It usually occurs early in development of a cell but can happen at any stage. The incidence increases with age and most cases occur over the age of 60.

Symptoms suggesting anaemia, neutropenia or thrombocytopenia may be present but there is no classical presentation; patients can be relatively asymptomatic or severely unwell. Common signs include gum infiltration, skin deposits, hepatosplenomegaly and lymphadenopathy.

Blood tests show reduced counts of red blood cells and platelets whilst white cell counts are normally raised, sometimes up to as much as 200x10⁹/L. Leukaemic blast cells are normally present on the blood film but not always and cells from the blood and bone marrow stain positive with sudan black and is positive for myeloperoxidase. This is in contrast to Acute Lymphoblastic Leukaemia which stains negative and is negative for myeloperoxidase.

The aim of chemotherapy is complete remission which is defined as less that 5% blasts cells in the bone marrow. Induction involves a combination of anthracycline and cytosine arabinoside. For consolidation, increased doses of cytosine are used. Other drugs such as thioguanine or etoposide can be used in either induction or consolidation. In younger patients, 80-90% achieve complete remission but many relapse and the cure rate is only around 45%. Older patients achieve much less success and have a worse prognosis.

 

Acute Lymphoblastic Leukaemia (ALL)

ALL starts with a malignant change in a lymphoid precursor cell, typically during the early stages of lymphocyte development. 80% of the time the malignant change happens in a B-lymphocyte precursor, 20% of the time it occurs in a T-lymphocyte precursor. The peak incidence of ALL is in children with a small rise in incidence in the elderly as well.

The symptoms of ALL are variable but may include symptoms suggesting anaemia, neutropenia or thrombocytopenia. Patients may have additional symptoms such as anorexia, back pain or joint pain. T-Cell ALL can cause dyspnoea which is from pleural effusions and large nodal masses in the mediastinum. CNS involvement is more common in ALL compared to AML and symptoms suggesting raised intracranial pressure may be present, (vomiting, headache, cranial nerve palsies). On examination the patients may have lymphadenopathy or moderate hepatosplenomegaly.

Blood tests typically show reduced numbers of red blood cells or platelets whilst white blood cells can be raised, normal or low. T-Lymphocyte ALL typically stains positive for acid phosphatase in contrast to B- Lymphocyte ALL which stains negative.

Chemotherapy consists of induction, consolidation, (intensification), and maintenance. Induction is usually a combination of vincristine, prednisolone and asparaginase. Induction may also include the anthracycline daunorubicin. During consolidation cyclophosphamide, methotrexate and cytosine arabinoside are added. Consolidation is started early in the treatment programme so that the leukaemic cell population is decreased quickly, lowering the probability of drug resistance. The final stages of therapy are completed with a maintenance period of methotrexate and mercaptopurine. The prognosis is good for children with almost 90% having a 5 year disease free survival in response to chemotherapy. In contrast, adults have a relatively poor prognosis, with less than 40% becoming long term survivors.

 

Chronic Myeloid Leukaemia (CML)

CML is a disease where neutrophils and their precursor cells are produced in excess. It has 3 phases; a chronic benign phase, an accelerated phase and a blast crisis phase, (resembling acute leukaemia). It is most common between the ages of 40-60.

Presentation normally occurs in the chronic phase with symptoms of anaemia, anorexia and weight loss. Abdominal pain, bloating and increased satiety are also common symptoms resulting from the splenomegaly. Acceleration follows the chronic phase and it is a gradual worsening of the patient’s health as well as a decrease in response to treatment controlling white blood cell count and spleen size. As the patients transition into the blast crisis stage they start to develop signs of acute leukaemia.

White blood cell counts are very high, frequently greater than 100x10⁹/L. Blood films show increased numbers of myeloid cells with the largest increase in the number of neutrophils and myelocytes. The Philadelphia chromosome is the result of a chromosomal translocation, t(9;22) (q34;q11) and it is important to the diagnosis of CML. Patients without this chromosome are reviewed carefully as they could be another disease. During the accelerated phase, the number of immature cells in the peripheral blood increases and the blast crisis is characterised by presence of myeloblasts or lymphoblasts in the blood.

During the chronic phase, treatment consists of imatinib, (a tyrosine kinase inhibitor), 400mg daily. This drug has a good response with high levels of progression free survival. Stem Cell Transplant is the only proven cure for CML but the success rate is only around 60%. Therefore, patients with poor responses to imatinib are best suited for Stem Cell Transplants. Hydroxycarbamide is sometimes used initially to reduce a high white blood cell count. In advanced diseases, combination chemotherapy used in acute leukaemia’s may produce remission. However, these are brief and ultimately the prognosis is poor.

 

Chronic Lymphblastic Leukaemia (CLL)

CLL is the commonest leukaemia in the western hemisphere and the vast majority of patients are over 50 years old. It is an overproduction of mature B-lymphocytes. CLL is a diverse disease that can be divided into 2 subgroups based on the possession of a mutation in the immunoglobulin heavy variable region (IgVH) gene. Patients without this mutation typically have worse prognosis as their form of leukaemia is more aggressive.

Most patients experience minimal symptoms for long periods of time but unfortunately some patients have a fast progression of their disease with bone marrow failure, lymphadenopathy and hepatosplenomegaly. The common symptoms patients complain of are lymphadenopathy, persistent/severe infections, weight loss or suggest anaemia. On examination, the patient may have lymphadenopathy or splenomegaly. During the advanced stages, the diseases spreads to other tissues such as the gastrointestinal system, the skin, the lungs, the CNS, the kidneys and the bone may occur.

The lymphocyte count in the blood is more than 5x10⁹/L and may reach levels equal to or greater than 500x10⁹/L. The cells look very similar to normal lymphocytes if only slight bigger.  To confirm the diagnosis flow cytometry is used to show that the cells have antigens typical of B-Lymphocytes.

The aim of treatment is to prolong life and control the symptoms of the disease. Treatment is usually started when: the patient is experiencing significant symptoms, their disease is deteriorating or they have advanced disease. Treatment in the early stages does not produce a long term improvement in survival. It consists of fludarabine, (a purine analogue), separately or in a combination. Fludarabine is preferred because it has a high rate of clinical responses and is likely to produce a clinical remission. Radiotherapy may be used for enlarged lymph nodes or splenomegaly as palliative treatment or a splenectomy can be beneficial if there is significant pain.

 

Myelodysplasia

This disease is characterised by ineffective haemopoiesis. It is an uncommon cause of Pancytopenia with an incidence of 33 cases per million.

 

Pathophysiology

The ineffective haemopoiesis results in the accumulation of immature stem cells that are unable to develop their full function. Thus, the bone marrow is hypercellular and the peripheries have reduced cell counts.

 

Qualitative abnormalities of the blood cells are also present and it is important to note that some subtypes of Myelodysplasia progress to Acute Myeloid Leukaemia, (AML). These two diseases are distinguished through the blast cell precentages in the bone marrow aspirations; percentages greater than 20 are classified as AML.

 

Diagnosis

Blood films show abnormal cells which help lead to a diagnosis. Red blood cells show macrocytosis or anisopoikilocytosis (a variation in cell shape and size that is completely irregular between cells) and neutrophils display hypogranulation and pseudo-pelger-huet malformation (hyposegmentation). Also, platelets can appear abnormally large or small.

 

Bone aspiration reveals defects in the developing haemopoietic cells. Sideroblasts are commonly found, (atypical erythroblasts with iron granules built up in their perinuclear mitochondria). Additionally, erythroblasts are commonly found with multinuclearity or nuclear budding. Myeloid cells display hypogranulation or increased numbers of the blast cells and megakaryocytes typically show as micronuclear, binuclear or polynuclear forms and can appear abnormally small or large.

 

Treatment

Treatment of this disease varies with the risk of progression to AML. Low risk subtype treatment focuses on improving peripheral blood cell counts through transfusions and haemopoietic growth factors. High risk subtypes have treatments focused on increasing long term survival by delaying progression to AML. This is achieved through chemotherapy and in younger patients, stem cell transplants.

Please see below for the FAB and WHO classifications of Myelodysplasia, released 1975 and 2008 respectively. (Please note that the CMML was removed and placed into the category of Myelodysplasia-Myeloproliferative syndrome by the World Health Organisation).

 

FAB Classification of Myelodysplasia



WHO Classification of Myelodysplasia



Myelofibrosis

Myelofibrosis is a disease where abnormally high amounts of collagen are laid down in the bone marrow. It has an incidence of around 4-14 cases per million.

 

Pathophysiology

Megakaryocytes secrete the cytokintes PDGF and TGF-β. These cytokines stimulate fibroblasts in the bone marrow to proliferate and deposit excessive amounts of collagen. This impedes the bone marrow's ability to produce blood cells, leading to extramedullary haematopoiesis.

 

Diagnosis

A diagnosis is made through a bone marrow aspiration, which gives a dry tap, only drawing up peripheral blood cells and no marrow. Additionally, bone marrow trephines show dense reticulin fibres, fibroisis and osteosclerosis. Any X-rays taken also indicate osteosclerosis as they will appear more radiopaque (whiter) than normal.

 

Treatment

Treatment is palliative as there is no cure available. Regular blood transfusions are used to improve blood cell counts. Splenectomy is indicated when splenomegaly causes discomfort, thrombocytopenia, portal hypertension, excessive transfusion requirements or hypermetabolism.

 

 

Aplastic Anaemia

Aplastic Anaemia is a significant reduction in the haemopoietic pluripotential stem cells. This can be primary or secondary. It has an incidence of around 2 cases per million in Europe. However, it is a lot commoner in Asia.

 

Pathophysiology

Primary aplastic anaemia can be immune-mediated. Drugs or infectious agents alter the stem cell's antigens and an immune response targets these new surface antigens. Activated Th1 cells produce the cytokines Interferon-ϒ and TNF which suppress and kill the cells. Genetic diseases can also cause Aplastic Anaemia; Faconi's disease is the most common example. It is an autosomal recessive disease involving 13 different genes that usually work together to protect cells from genetic damage.

 

Secondary causes include whole body irradiation which can destroy the bone marrow's stem cells in a dose dependent fashion. Sometimes chemotherapy and other immunosuppressants can also cause aplastic anaemia, as can viruses such as Epstein Barr virus.

 

Diagnosis

The patient typically presents with easy bruising or blood blisters in the mouth. Additionally, infections in the mouth are also quite common.

 

Blood tests will reveal a decreased count in all blood cell lines and there will be an almost complete absence of reticulocytes. However, a bone marrow trephine is necessary to prove there is decreased cellularity in the bone marrow, (increased fat spaces are often seen as well).

 

Treatment

Treatment is either immunosuppression with drugs such as Anti-Thymocyte Globulin, Ciclosporin and Oxymethalone. Another treatment option is a stem cell transplant; this is recommended for younger patients with more severe cases.

 

 

Haemophagocytic Syndrome

Haemophagocytic syndrome is inappropriate ingestion of the body's blood cells by macrophages. It has an incidence of around 1.2 cases per million.

 

Pathophysiology

High levels of cytokines induce this inappropriate macrophage activation. Excess cytokines are caused by impaired secretion of toxic granules by natural killer cells and cytotoxic T-lymphocytes to induce apoptosis in the target cell. This causes prolonged activation of these cells and thus their continual release of cytokines.

 

The impaired secretory process can be due to a primary cause. This can be genetic, such as the autosomal recessive disease haemophagocytic lymphohistiocytosis.  It can also be through a secondary cause such as viral infections or cancer.

 

Diagnosis

Haemophagocytic syndrome presents with prolonged fever and cytopenias. Activated white blood cells can infiltrate organs like the liver, brain and spleen. Thus patients often present with splenomegaly and neurological problems as well.

 

For diagnosis to be made either a genetic defect must be found or 5 of the following 8 criteria must be met:

  1. Fever
  2. Splenomegaly
  3. Cytopenia (of at least 2 lines)
  4. Hypertryglyceridemia (Fasting>265mg/dL)/Hyperfibrinogenemia (<150mg/L)
  5. Haemophagocytosis in Bone Marrow/CSF/Lymph nodes
  6. Proven decrease/absence of Natural Killer Cell activity
  7. Ferritin > 500 ug/L
  8. Soluble CD25 >2400 U/ml

 

Treatment

Short term treatment involves

  • suppressing the cytokine response (dexamethasone)
  • inhibiting activated T-Cells (Cyclosporin-A)
  • killing overstimulated macrophages (Etoposide)

 

 It is also important to remove any triggering agents like neoplasms or infections. Stem cell therapy is recommended for cases where the cause is a genetic defect.



Hypersplenism

Hypersplenism is an enlargement of the spleen, (splenomegaly), with reductions in one or more blood cell lines. It is a fairly common cause of pancytopenia.

 

There are many different diseases that cause splenomegaly and these diseases can be grouped under the following headings; haematological, portal hypertension, glycogen storage diseases, systemic diseases, infections or tropical.

 

Pathophysiology

Pancytopenia can be caused through sequestration of large amounts of blood cells in the spleen, with phagocytosis of these blood cells by the spleen's resident macrophages.

 

Diagnosis

A diagnosis is made through full blood count confirming reductions in the cell lines, increased reticulocytes due to increased marrow output and palpation revealing an enlarged spleen.

 

Treatment

The standard treatment for hypersplenism is treatment of the underlying cause. A splenectomy may be necessary.

 

 

Drugs that can induce Pancytopenia

There are numerous drugs that can cause Pancytopenia. Rather than discuss each drug individually, they are listed in the table to the right. This table was taken from reference 6 where more information can be found.







References

  1. Kumar V, Abbas A, Fausto N, Aster J. Robbins and Cotran Pathologic Basis of Disease. 8th Ed. 2010. Saunders Elsevier.
  2. Hoffbrand AV, Moss PAH. Essential Haematology. 6th Ed. 2008. Wiley-Blackwell.
  3. Howard M, Hamilton P. Haematology- An Illustrated Colour Text. 3rd Ed, pg 38-52, Churchill Livingstone Elsevier.
  4. Kumar P, Clark M. Kumar & Clark's Clinical Medicine. 7th Ed. Saunders Elsevier.
  5. "Haemophagocytosis in adults". Brady Miller. http://depts.washington.edu/hemeweb/seminars-conferences/HemophagocyticSyndromeFinal.pdf
  6. Kar, M., Ghosh, A. Pancytopenia. JIACM 2002; 3(1):29-34.
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