Multiple Myeloma and Related Conditions

This heterogeneous group of conditions is associated with monoclonal immunoglobulin in serum or urine, and is characterized by disordered proliferation of monoclonal lymphocytes or plasma cells. The clinical phenotypes of these conditions are determined by the rate of accumulation, site and biological properties of both the ab- normal cells and the monoclonal protein.

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The Myelodysplastic Syndromes

Introduction

• The myelodysplastic syndromes (MDS) are a group of clonal haemopoietic disorders. They are characterized by:

• Ineffective haemopoiesis resulting in peripheral blood cytope- nias of all three lineages, but especially anaemia

• Increased risk (30%) of transformation to acute myeloid leukaemia

• MDS is mainly a disease of the elderly, with a median age at diag- nosis of 60–75 years. It does, however, affect younger adults also. MDS is rare in children, and is associated with genetic disorders such as Fanconi’s anaemia.

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Platelet Disorders

Platelets are small anucleate cells produced predominantly by the bone marrow megakaryocytes as a result of budding of the cytoplasmic membrane. Megakaryocytes are derived from the haemopoietic stem cell, which is stimulated to differentiate to mature megakaryocytes under the influence of various cytokines, including thrombopoietin. Platelets play a key role in securing primary haemostasis.

Once released from the bone marrow, young platelets are trapped in the spleen for up to 36 hours before entering the circulation, where they have a primary haemostatic role. Their normal lifespan is 7–10 days and the normal platelet count for all age groups is 150–450 × 10^9/L. The mean platelet diameter is 1–2 µm, and the normal range for cell volume (mean platelet volume; MPV) is 8–11 fL. Although platelets are non-nucleated cells, those that have recently been released from the bone marrow contain RNA and are known as reticulated platelets. They normally represent 8–16% of the total count and they indirectly indicate the state of marrow production.

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The Acute Leukaemias

Acute leukaemia is a malignant disorder of white cells caused by a failure of normal differentiation of haemopoietic stem cells and pro- genitors into mature cells. This results in the accumulation of primitive leukaemic cells within the bone marrow cavity, causing bone marrow failure, and as a consequence patients typically present with anaemia, thrombocytopenia or neutropenia (Box 6.1).

Much progress has been made in understanding the pathogenesis of the acute leukaemias, and it is now clear that they occur because of the acquisition of distinct genetic abnormalities in haemopoietic stem cells or committed progenitors. These molecular abnormalities frequently occur as the result of chromosomal translocations or the loss of chromosomal material. In addition, activating mutations in genes regulating cellular proliferation, such as tyrosine kinase genes, are commonly identified. Malignant transformation of primitive cells with the capacity to develop into cells of the myeloid lineage results in acute myeloid leukaemia (AML), while acquired genetic

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Chronic Myeloid Leukaemia

Chronic myeloid leukaemia (CML) is a clonal malignant myeloproliferative disorder believed to originate in a single abnormal haemopoietic stem cell. The progeny of this abnormal stem cell proliferate over months or years, so that, by the time the leukaemia is diagnosed, the bone marrow is grossly hypercellular and the number of leucocytes is greatly increased in the peripheral blood. Normal blood cell production is almost completely replaced by leukaemia cells, which, however, still function almost normally.

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Polycythaemia, Essential Thrombocythaemia and Myelofibrosis

Polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF), known collectively as the classic myeloproliferative disorders (MPDs), are clonal disorders originating from a neoplastic haemopoietic stem cell. They are most common in middle or older age, and share several features, including a potential to transform into acute leukaemia and into each other. Treatment of PV and ET can greatly influence prognosis, hence the importance

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The Hereditary Anaemias

Hereditary anaemias include disorders of the structure or synthesis of haemoglobin (Hb), deficiencies of enzymes that provide the red cell with energy or protect it from chemical damage and abnormalities of the proteins of the red cell’s membrane. Inherited diseases of haemoglobin (haemoglobinopathies) are by far the most important. The structure of human Hb changes during development (Fig.3.1). By the 12th week of gestation, embryonic haemoglobin is replaced by fetal haemoglobin (Hb F), which is slowly replaced after birth by the adult haemoglobins, Hb A and Hb A2. Each type of haemoglobin consists of two different pairs of peptide chains; Hb A has the structure α2β2 (namely, two α chains plus two β chains), Hb A2 has the structure α 2δ 2 and Hb F, α 2γ2.

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