Principles of haematology 1 PRINCIPLES Platelets Like red cells, platelets lack nuclei. Platelets (thrombocytes) Haematology is the medical specialty concerned with the are derived from megakaryocytes, which derive from the study, diagnosis, treatment and prevention of diseases re- colony-forming unit megakaryocyte (CFU-Meg) progeni- lated to blood and is the subject of the first part of this book. tor cell. They play a pivotal role in haemostasis (Chapter 6). This chapter discusses blood cells, their production (hae- matopoiesis), bone marrow and the spleen. White blood cells White blood cells (leucocytes) are large unpigmented cells with primarily immune roles. They are also found in the BLOOD bloodstream, along with red blood cells and platelets. Leucocytes are further classified into granulocytes, mono- Blood is the fluid contained within the heart, arteries, capil- cytes/macrophages and lymphocytes. Each group fulfils laries and veins of the circulatory system. It delivers oxygen different immunological roles, participating in immune de- and nutrients to organs and tissues and carries carbon diox- fences against infection. ide and metabolic ‘waste’ products to excretory organs such as the kidneys, liver and lungs. Granulocytes Blood consists of several components: ‘Granulocytes’ is the collective term for white blood cells with • Plasma granules in their cytoplasm. The term encompasses neutro- • Cells (red cells, white cells, platelets) phils, eosinophils and basophils. The specific chemical content • Electrolytes (e.g., Na+, K+, Ca++) of the granules (and thus the cell’s function role) varies accord- • Proteins (including hormones and immunoglobulins) ing to subtype. Note that some clinicians misleadingly use the • Lipids term ‘granulocytes’ for neutrophils, which can cause confusion. • Glucose Neutrophils The cellular components of blood are synthesized in the Neutrophils (aka ‘polymorphs’) have multilobed nuclei. bone marrow in a process called ‘haematopoiesis’. Neutrophils (diameter 12–14 μm) comprise ≈60% of the bloodstream white cell population. They leave the bone marrow, where they are synthesized, and circulate in the bloodstream for ≤10 hours before entering tissues. BLOOD CELLS Neutrophils are an essential component of the innate immune system, due to their ability to phagocytose (en- This section discusses mature blood cells found in the gulf) microorganisms and kill them by releasing cytotoxic bloodstream. molecules from their granules. Once they arrive at the site of an infection or inflammation, they also recruit further Red blood cells immune cells with chemotactic mediators (see Chapter 9: Neutrophils). Neutrophils therefore represent a key com- Red blood cells (‘erythrocytes’) are derived from the eryth- ponent of the first-line defence against bacterial infections. roid blast-forming unit (BFU-E) progenitor cell. Red cells lack a nucleus and have a biconcave discoid shape. Eosinophils Their primary role is the transportation of oxygen Eosinophils (diameter 12–17 μm) have bilobed nuclei. (from lung to tissue) and carbon dioxide (from tis- They stain strongly with acidic dyes and comprise ≈1%– sue to lung). They contain haemoglobin, a specialized 6% of the bloodstream white cell population. Like other molecule that avidly binds these gases under condi- granulocytes, eosinophils release specific cytotoxic and tions of high partial pressure and releases them under messenger molecules. These are released directly into conditions of low partial pressure, thus allowing bulk the extracellular space by degranulation. Note how eo- transport of O2 and CO2 to proceed in the appropriate sinophils differ in this respect from neutrophils, which direction. Red blood cells are discussed in further detail phagocytose pathogens before releasing cytotoxic mole- in Chapter 2. cules. Eosinophils migrate into areas of inflammation or 1 Principles of haematology infection, particularly infection with multicellular par- HINTS AND TIPS asites, e.g., helminths (worms). They are also important in both innate (see Chapter 9: Eosinophils) and adaptive ‘CD’ DESIGNATION immunity and allergic responses. Cells can be classified according to the type of Basophils molecules expressed at their surface membranes. Basophils (diameter 14–16 μm) have bilobed nuclei and These are given numerical subdivisions with the granular cytoplasm, like eosinophils, but stain strongly with cluster of differentiation index. A CD4 ve cell, for basic dyes. Basophils represent ≤1% of the bloodstream’s + example, expresses CD4 surface receptors. Since white cell population. In concert with eosinophils and mast cells, they contribute strongly to innate and adaptive immu- the array of surface receptors in part governs the nity. Physiological histamine is derived in part from baso- behaviour and therefore function of the cell, it is philic granules. an appropriate mechanism to subclassify cells, particularly leucocytes. CD-type surface molecules Monocytes/macrophages are expressed by all haemopoietic cells. Monocytes and macrophages are larger than granulo- cytes (diameter ≤25 μm). They have a large eccentri- cally placed reniform (kidney-shaped) nucleus. In the Natural killer cells bloodstream, they are called monocytes and account These large granular lymphocytes are also cytotoxic lym- for ~2%–10% of the white cell population. They circu- phocytes, like T cells, but natural killer (NK) cells are larger. late for 1–3 days, then leave the circulation and enter the Their behaviour differs from that of T cells in that they do tissues, where they differentiate further, developing into not require major histocompatibility complex (MHC) or macrophages. antibody-bound antigen complexes to recognize and de- Macrophages comprise the reticuloendothelial system stroy foreign or infected cells. They are thus prominent in and are found in tissues throughout the body. They phago- the innate immune response (Chapter 9). cytose cellular debris and pathogens and produce various cytokines. They also process and present antigens to lym- phocytes as part of the adaptive immune response (see HAEMATOPOIESIS Chapter 10: MHC processing). Lymphocytes Haematopoiesis is the formation and development of blood These white blood cells are small and have a relatively large, cells. The haematopoietic system is composed of the bone round nucleus relative to their nongranular, basophilic marrow, spleen, liver, lymph nodes and thymus. cytoplasm volume. They all originate from the lymphoid lineage. Pluripotent haemopoietic stem cells B lymphocytes All blood cells originally derive from a population of plu- ripotent, CD34 ve haemopoietic stem cells, residing in These cells are small lymphocytes (diameter 6–9 μm) express- + ing the B cell receptor. They secrete immunoglobulins (anti- haematopoietic tissues. These stem cells may either: bodies). A large proportion of B lymphocytes reside in lymph • Remain as pluripotent stem cells, dividing to form identical node germinal centres, where they are known as memory B daughter cells, maintaining the haemopoietic population cells. Some B lymphocytes also mature further into plasma cells. • Differentiate into specific progenitor cells, which ultimately Plasma cells are larger than B lymphocytes and have a develop into specific cellular components of blood strongly basophilic cytoplasm and an eccentric round nu- After initially differentiating into either a myeloid or lym- cleus. They are mainly seen in the bone marrow, but a few phoid progenitor cell, further developmental changes fol- may be seen circulating in the peripheral blood. low. As cells progress down their respective development T lymphocytes pathways, they sequentially acquire characteristic recep- tors and functions, ultimately forming a mature blood cell These cells are small lymphocytes (diameter 6–9 μm) (Fig. 1.1) with characteristics specific to the cell type. expressing the T cell receptor. T cells are subclassified by type of surface glycoproteins they express, indicated Progenitor cells by the CD prefix. Cytotoxic T cells (CD8 +ve) medi- ate destruction of cells infected by intracellular organ- The pluripotent stem cells can differentiate into one of the isms, while T helper cells (CD4 +ve) release cytokines two multipotent progenitors: to regulate and assist in the adaptive immune response • Myeloid lineage progenitor cell (Chapter 10). • Lymphoid lineage progenitor cell 2 Haematopoiesis 1 Bone marrow Identical division Pluripotent HSC Lymphopoiesis Myelopoiesis Common lymphoid Common myeloid progenitor progenitor aka CFU-GEMM Pro T cell Pro B cell BFU-E CFU-MEG CFU-BASO CFU-EOS CFU-GM CFU-GCFU-M T cell B cell NK cell Thymus Erythrocyte Megakaryocyte Basophil Eosinophil Neutrophil Monocyte (red blood cell) T cell Plasma cell Platelets Blood Erythropoiesis Thrombopoiesis Granulopoiesis CD4 CD8 Other T cell T cell T cells Tissue Basophil Eosinophil Macrophage Fig. 1.1 Overview of haemopoiesis. Note the four relevant zones: bone marrow, blood, tissues and thymus. For information on growth factors important for various specific maturations, please see Table 1.2. HSC, haematopoietic stem cell Myeloid lineage multipotent progenitor cell HINTS AND TIPS The CFU generating myeloid cells (CFU-GEMM) multi- potent stem cell subsequently further differentiates into COLONY-FORMING UNITS (CFU) either: CFU describes a progenitor cell committed • Red cell progenitor (BFU-E) to the development of a particular blood • Platelet progenitor (CFU-Meg) cell. For example, CFU-Baso is a progenitor • Eosinophil