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WhIte cell couNtS
compiled by dr N holland
This newsletter deals with an approach to increased toxic granulation and vacuolation, the presence white cell counts. All reference levels mentioned of dohle bodies and left shift. Rarely, organisms can be visualised within the neutrophils. In cases which are not clear, reactive markers such as CRP, Is an increased white blood cell count a clonal
procalcitonin and ESR may be useful in confirming (malignant) or reactive increase?
This question is often asked, and in most cases tissue infarction/necrosis
the increase is reactive in nature. But be aware of the possibility of malignancy so that a potential y For example, myocardial infarction, burns and serious condition is not overlooked.
When a raised white cell count is detected, the chronic inflammation
differential count should always be evaluated to determine the significance of the high count. If Numerous chronic inflammatory conditions can be the raised count is due to the presence of blasts associated with chronic neutrophilia, for example, or primitive mononuclear cel s, particularly with associated cytopaenias, urgent evaluation by a haematologist is necessary. drugs and toxins
A neutrophilia is one of the most common abnormal findings on the full blood count. This is defined as • Growth factor administration: e.g. neupogen a neutrophil count greater than 8x109/l. There are numerous reactive causes of neutrophilia: Steroid/stress response
• Chronic cigarette smoking: common cause of Conditions associated with steroid and stress- hormone release can cause a rapid, usual y transient, neutrophilia, for example, pain, exercise, underlying carcinoma or lymphoma
seizures and emotional stress such as anger. This is primarily the result of redistribution of cel s from Certain carcinomas, particularly adenocarcinomas vascular beds (e.g. the spleen) to the circulating that have metastasised, can result in raised neutrophil counts, possibly through release of growth factors. This can be a cause of particularly Infection
Bacterial infection, particularly, is a common More rarely lymphomas, for example Hodgkin’s cause of neutrophilia. Associated changes to lymphoma, may stimulate a reactive increase in the neutrophil morphology may be noted on review of the peripheral smear. These include less common causes
• Persistent neutrophilia may be detected post- Vasculitides and connective tissue disease are less common causes. In the case of malignant disease eosinophilia may be reactive to underlying non- haemopoietic tumours or lymphoma (e.g. Hodgkin’s lymphoma). Clonal T cell populations have been • Rebound fol owing agranulocytosis.
identified in a subset of patients with otherwise unexplained eosinophilia.
clonal/malignant increase in the neutrophil
clonal causes of eosinophilia
This is far more rare than reactive causes. A clonal These are uncommon. Clonal eosinophilia may increase in a differentiated myeloid cel , such as be seen in the context of myeloid and lymphoid the neutrophil, may occur in the myeloproliferative neoplasms. Reactive causes should be excluded. neoplasms. Findings that may increase suspicion In certain cases no reactive cause or evidence of of a myeloid malignancy include the presence of clonality can be identified to explain a persistent a significant left shift (neutrophil precursors in the eosinophilia. These cases have been label ed as peripheral blood), an associated increase in the idiopathic hypereosinophilic syndrome. This is an basophil count, normal reactive markers, increased unexplained eosinophilia of >1.5x109/l that lasts for patient age, very high white cell counts (although there is no absolute cut off to distinguish reactive from clonal states), the presence of splenomegaly BaSophIlIa
and accompanying thrombocytosis and/or polycythaemia. If there is concern, review of the This is a basophil count greater than 0.2x109/l. An increase in the basophil count can be noted in al ergy and in inflammatory conditions such as eoSINophIlIa
ulcerative colitis. Viral infection, notably chickenpox and influenza, may have an associated basophilia.
An eosinophilia is defined as an eosinophil count above 0.5x109/l. A wide range of conditions can Basophilia can be seen in clonal myeloid disorders. be associated with eosinophilia, some common, Importantly, CML (chronic myeloid leukaemia) is others less so. Eosinophilia may be reactive to almost invariably associated with an increase in an underlying condition or clonal (i.e. represent the basophil count. This can provide a clue to the part of a malignant clone). A persistent significant diagnosis in patients with a neutrophil leucocytosis eosinophilia can result in end organ infiltration and damage. The causes of eosinophilia are as fol ows: MoNocYtoSIS
A monocytosis is defined as a blood monocyte This is the most common cause of eosinophilia count greater than 1x109/l. An acute mild increase worldwide. Helminthic parasitic infestation is a in the monocyte count can be recorded fol owing particularly common cause and can be associated acute physical and/or emotional stress (probably with very high while blood cell counts.
secondary to catecholamine release). This is as a result of demargination (redistribution from allergic disease
areas such as spleen, pulmonary capil aries). The increase is transient and is mirrored by an increase In the developed world, eosinophilia is more frequently seen secondary to atopic disease such as seasonal rhinitis, asthma and atopic dermatitis.
A sustained increase is more significant. Conditions associated with monocytosis include infectious drug reaction
and other inflammatory disorders and malignant disease. A monocytosis can be reactive to the Many drugs may be implicated and the eosinophil malignant disease or may be part of the abnormal count returns to normal once the drug has clone. Reactive causes will be discussed first.
been withdrawn. The drugs often involved are carbamazepine and minocycline. Infection
• Subacute/chronic: tuberculosis, bacterial • Chronic inflammation can result in a persistent increase, e.g. autoimmune disease Inflammatory conditions
• Hypersensitivity reactions: drug reactions, Col agen vascular disease: systemic lupus erythematosus, rheumatoid arthritis etc.
reactive to underlying malignancy
• Stress (acute) lymphocytosis: similar causes Monocytosis may be a marker of underlying malignancy and a reactive increase is seen in up Malignant/Monoclonal lymphocytosis
Clinical features which can suggest a lympho- Up to 25% of Hodgkin’s lymphoma is associated proliferative disorder include lymphadenopathy, with a monocytosis. It can also be noted in other hepatomegaly or splenomegaly, an isolated mass lymphoproliferative disorders including multiple or findings such as unexplained skin lesions. If the morphology is unhelpful, the lymphocytosis persists or the clinical suspicion is high, flow cytometric analysis can be performed on a peripheral blood sample. This al ows more definitive assessment of neutropaenia or the early stages of drug-induced agranulocytosis may be B cel /T cell and NK cell lymphoproliferative disorders can be associated with a lymphocytosis.
clonal increase in monocytes (haemopoietic
An increase in monocytes may be seen in certain acute myeloid leukaemias and chronic disorders such as particular myeloproliferative neoplasms and myelodysplastic syndromes. In some situations the monocyte count may be very high. Peripheral blood findings, including the presence of cytopaenias and clinical features such as splenomegaly provide valuable clues in the investigation of an unexplained monocytosis. Assessment of inflammatory markers (e.g. CRP) should be considered. In certain cases a bone marrow investigation will be of value.
This is an absolute lymphocyte count of greater than 4x109/l. The increase may be reactive (polyclonal) or monoclonal. Clinical history and thorough physical examination, as well as assessment of the peripheral smear, are useful in differentiating between these two states.
The presence of a population of blasts or primitive mononuclear cel s in the blood is usual y a cause reactive causes of lymphocytosis
for concern. Please note that circulating blasts can be seen in the context of a reactive neutrophil left • Infectious mononucleosis type syndromes: shift, but the number is usual y small in comparison Epstein-Barr virus, cytomegalovirus, HIV, to the presence of maturing granulocytic elements. If blasts or an abnormal primitive population are identified in the peripheral blood, flow cytometric analysis can be performed on this sample to further characterise the cel s. coNcluSIoN
The presence of a raised white cell count should not be assessed in isolation. The component of the differential that is increased should be established. The presence of cytopaenias or other cytoses may provide additional information. Assessment of the peripheral blood smear by a haematologist or an experienced technologist may be of value in situations in which the cause of the increased count is not clear. Clinical y, hepatosplenomegaly, lymphadenopathy and other abnormal masses should be excluded. In certain situations, a bone marrow investigation may be required. When an unexplained lymphocytosis is detected or blasts are present in the peripheral blood, flow cytometric analysis can be performed on a peripheral blood sample to investigate a possible haemopoietic/lymphoid malignancy.
Hoffbrand AV, Catovsky D & Tuddenham EGD (2005) Postgraduate Haematology, 5th edition. Blackwell Publishing. Oxford.
Beutler E, Lichtman M, Col er BS, Kipps TJ & Seligsohn U (2001) Wil iams Hematology, 6th edition. McGraw-Hil , Medical Publishing Division. New York.
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Adriano B. L. Tort . Oscar P. Dall ’ Igna . Ricardo V. de Oliveira . Carlos E. A. Mantese . Paulo Fett . Márcio W. S. Gomes . Juliana Schuh . Diogo O. Souza . Diogo R. LaraAtypical antipsychotic profile of flunarizine in animal modelsReceived: 12 April 2004 / Accepted: 29 May 2004 / Published online: 28 July 2004Abstract Rationale: Flunarizine is known as a calciumchannel blocker commonly u