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Approach to the Diagnosis and Classification of Blood Cell Disorders
Common presentations of haematological diseases
An abnormal blood count or blood cell morphology does not necessarily indicate a primary haematological problem because it may reflect an underlying nonhaematological condition or may be the result of therapeutic interventions. Anaemia occurs in many conditions, but a primary blood disease should be considered when a patient has splenomegaly, lymphadenopathy, a bleeding tendency or thrombosis and/or nonspecific symptoms characteristic of leukaemias and lymphomas such as malaise, sweats or weight loss.
As with any clinical problem, the first steps in determining the diagnosis include obtaining a careful clinical, travel and drug history and a thorough physical examination. The result of these, in combination with the patient’s age, sex, ethnic origin, social and family history and knowledge of the locally prevalent diseases, will determine subsequent laboratory investigations.
Initial screening tests
Although the range of haematological tests available to support clinical and public health services is broad, it is often the simplest investigations that are most useful in indicating the diagnosis. Even poorly resourced laboratories are usually able to provide an initial panel of tests such as haemoglobin concentration (Hb), white blood cell count (WBC) and platelet count ( Chapter 26 ) and examination of a peripheral blood film for a differential leucocyte count ( Chapter 3 ) and cellular morphology ( Chapter 5 ). These screening tests will often enable the underlying pathological processes to be suspected promptly and point to a few key diagnostic tests.
Interpretation of screening tests
Results of laboratory screening tests should always be interpreted with an understanding of the limitations of the tests and the physiological variations that occur with sex, age, ethnic group and conditions such as pregnancy and exercise. Physiological variations in cell counts are detailed in Chapter 2 . Abnormalities of red cells, white cells or platelets may be quantitative (increased or reduced numbers) or qualitative (abnormal appearance and/or function).
Quantitative abnormalities of blood cells
Increased numbers of cells
Increases affecting more than one cell line
A simultaneous increase in the cells of more than one cell line suggests overproduction of cells originating in an early precursor cell. This occurs in myeloproliferative neoplasms in which one cell type may predominate, e.g. platelets in essential thrombocythaemia and red cells in polycythaemia vera.
Erythrocytosis
Patients with a persistently (e.g. > 2 months) raised venous haematocrit (Hct) (> 0.52 males, > 0.48 females) should be assessed to determine the cause. Erythrocytosis can be relative or absolute and, if absolute, primary or secondary.
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Relative: normal total red cell volume with reduced plasma volume (e.g. dehydration).
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Absolute: males and females with Hct values above 0.60 and 0.56, respectively, can be assumed to have an absolute erythrocytosis and do not require confirmatory studies. However, the reason for the elevation of the Hct must still be elucidated.
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Primary: this is usually polycythaemia vera (PV), part of the spectrum of myeloproliferative neoplasms. The mutation JAK2 V617F is present in approximately 95% of patients with PV and mutations affecting exon 12 occur in many of those who lack the V617F mutation.
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Secondary: to chronic hypoxia (e.g. chronic lung disease, congenital heart disease, high-affinity haemoglobins) or aberrant erythropoietin production. Secondary polycythaemia can generally be excluded by the clinical history and examination, assessment of serum erythropoietin concentration and arterial oxygen saturation, haemoglobin electrophoresis or high performance liquid chromatography (HPLC) plus an oxygen dissociation curve and abdominal ultrasound examination. If initial screening tests are negative for a JAK2 mutation and there is no obvious secondary cause for the high Hct, then red cell mass studies are indicated ( Chapter 17 ).
Leucocytosis
Neutrophilia
Neutrophils are commonly increased during pregnancy and in acute infections, inflammation, alcohol intoxication, corticosteroid therapy and acute blood loss or red cell destruction. Additional findings on the full blood count can be helpful to identify the cause of neutrophilia. The combination of anaemia and neutrophilia occurs in chronic infection or inflammation, and also in malignant conditions; a high Hct with neutrophilia suggests polycythaemia vera. Neutrophilia with an increased platelet count occurs in infectious or inflammatory processes or malignant conditions and during marrow recovery. Neutrophilia with thrombocytopenia is classically seen in sepsis and occasionally in microangiopathic haemolytic anaemia. Examination of the peripheral blood film also provides additional clues to confirm or exclude a particular diagnosis. For example, neutrophilia with the neutrophils showing heavy cytoplasmic granulation (‘toxic’ granulation) is a common finding in severe bacterial infections. In the absence of any underlying cause, a high neutrophil count with immature myeloid cells suggests chronic myelogenous leukaemia (CML), and cytogenetic and molecular studies to look for t(9;22) and the BCR–ABL1 fusion gene are indicated ( Chapter 8 ).
Lymphocytosis
Lymphocytosis is a feature of certain infections, particularly infections in children. It may be especially marked in pertussis, infectious mononucleosis, cytomegalovirus infection, infectious hepatitis, tuberculosis and brucellosis ( Table 23-1 ). Elderly patients with lymphoproliferative disorders, including chronic lymphocytic leukaemia and lymphomas, often present with lymphadenopathy and a lymphocytosis. Morphology and immunophenotyping of the cells combined with histological examination of a bone marrow trephine biopsy specimen (and if necessary other tissue biopsy) are used to classify these disorders and to give an indication of management and prognosis. If lymph nodes are enlarged, a lymph node biopsy for histology and immunohistochemistry may be helpful in diagnosis. It is occasionally difficult to differentiate between a reactive and a neoplastic lymphocytosis. In this situation, immunophenotyping, to provide evidence of light chain restriction and polymerase chain reaction for immunoglobulin or T-cell receptor gene rearrangements, may indicate the presence of a monoclonal population of lymphocytes, thereby supporting a diagnosis of neoplastic, rather than reactive, lymphoproliferation.
Table 23-1
Causes of lymphocytosis
| Infections |
|
| Stress and Postsplenectomy |
| Smoking |
| Hypersensitivity Reactions |
| Autoimmune Disorders |
| Thymoma |
| Clonal |
|
Monocytosis
A slight to moderate monocytosis may be associated with some protozoal, rickettsial and bacterial infections including malaria, typhus and tuberculosis. Monocytosis associated with neutrophilia is suggestive of chronic myelomonocytic leukaemia. High levels of monocytes (monocyte count > 1 × 10 9 /l) in an elderly patient suggest chronic myelomonocytic leukaemia or sometimes, atypical chronic myeloid leukaemia. These conditions fall into the myelodysplastic/myeloproliferative neoplasm group of disorders, so the diagnosis is supported by finding splenomegaly, quantitative and qualitative abnormalities in other cell lines or a clonal cytogenetic abnormality.
Eosinophilia
Eosinophilia is typically associated with parasitic infections, skin diseases and allergic disorders. Eosinophils have a tendency to infiltrate and damage tissues such as the heart, lungs and gut, so in patients with eosinophilia, assessment of these organs is necessary. In most cases, the cause of the eosinophilia is indicated by the clinical history, which should include details of all medications and foreign travel, and by examination of the stool and urine for parasites, cysts and ova. Other causes of eosinophilia are given in Table 23-2 .
Table 23-2
Causes of eosinophilia ,
| Parasitic Infections – Especially with Helminths |
| Neoplastic Diseases |
|
| Allergic Disorders |
|
| Immunodeficiency Disorders |
|
| Connective tissue/rheumatology disorders |
Ig, immunoglobulin.
Basophilia
Basophilia as an isolated finding is unusual. However, it is a common feature of myeloproliferative neoplasms, and basophils may be particularly prominent in CML. In this condition, an increasing basophil count may be the first indication of accelerated phase disease. Endocrinopathies such as myxoedema and oestrogen abnormalities, infections and allergic diseases – and rarely, other haematological malignancies – can also cause basophilia.
Thrombocytosis
Thrombocytosis can be primary or secondary (reactive) to surgery, infectious and inflammatory conditions, hyposplenism, blood loss and malignancy, and can occur as a rebound phenomenon following recovery from marrow suppression. Spurious thrombocytosis can also occur in severe burns and cryoglobulinaemia because the size of the red cell fragments or cryoglobulin particles is similar to that of platelets. A moderately increased platelet count (e.g. 450–800 × 10 9 /l) often does not indicate a primary haematological disorder. When there is isolated persistent thrombocytosis in a myeloproliferative neoplasm the diagnosis is essential thrombocythaemia (providing that the presence of a BCR – ABL1 fusion gene has been excluded). Thrombotic or haemorrhagic complications can occur with thrombocytosis but often the diagnosis is made incidentally. Individuals with essential thrombocythaemia have been noted to have JAK2 V617F (50%), MPL (10%) or CALR mutations, with the JAK2 mutation being associated with an increased risk of thrombosis.
Reduced numbers of cells
Reductions in more than one cell line
A reduction in cell numbers occurs because of increased destruction, reduced production or increased pooling in the spleen or other organs. Reduced production of cells may be the result of aplastic anaemia, a lack of haematinics such as folate or cobalamin or interference with normal haemopoiesis by infiltration (e.g. leukaemia), infection (e.g. human immunodeficiency virus (HIV) infection, tuberculosis, leishmaniasis) or exposure to toxins (e.g. alcohol) or myelosuppressive drugs (e.g. hydroxycarbamide or methotrexate). Certain myeloid neoplasms, e.g. primary myelofibrosis and myelodysplastic syndromes (MDS), are characterised by cytopenias, which are at least in part the result of ineffective haemopoiesis. Cytopenia is also sometimes a feature of acute myeloid leukaemia (AML), when it is due both to ineffective haemopoiesis and to replacement of normal haemopoietic stem cells by leukaemic cells. A relatively common cause of a global reduction in circulating cells is pooling of the cells in a markedly enlarged spleen (hypersplenism), which may be secondary to conditions such as primary myelofibrosis and portal hypertension. Examination of a bone marrow aspirate and trephine biopsy specimen is often helpful in determining the cause of cytopenias for which no obvious cause is apparent.
Anaemia
The mechanisms which result in anaemia are decreased production, reduced red cell lifespan, blood loss and splenic pooling. Anaemia is broadly divided into three types: microcytic (low mean cell volume (MCV)), macrocytic (high MCV) and normocytic (normal MCV). The choice of investigations is guided by the MCV and red cell morphology in addition to clinical features. Figures 23-1 to 23-3 are flow charts that provide an orderly sequence of investigations for the different types of anaemia on the basis of these indices. Examination of a blood film will usually suggest the quickest route to the diagnosis, though confirmation may require more specific tests. The presence of basophilic stippling with microcytic red cells suggests thalassaemia trait or, much less often, lead poisoning. A dimorphic blood film is typical of congenital sideroblastic anaemia but is more often the result of iron deficiency responding to treatment. Pappenheimer bodies suggest that a microcytic anaemia is the result of sideroblastic erythropoiesis.
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