10 Haemopoietic and lymphoreticular system
Haemopoiesis is the production of blood cells. In the fetus, blood is formed in the bone marrow, spleen and liver. At birth the marrow is the main site of haemopoiesis, but eventually the red marrow of the long bones is replaced by fat such that, in the adult, red marrow remains only in the axial skeleton, ribs and skull, and in the proximal ends of the humerus and femur.
Erythrocytes are non-nucleated blood cells which are biconcave and deformable. They are the most abundant blood cell and form 45% of the total blood volume, i.e. the haematocrit or packed-cell volume (PCV). Their function is to carry oxygen. About 1% of red cells stain purplish because of residual RNA. They are called reticulocytes. The proportion of these cells in the blood stream increases when bone marrow production of erythrocytes increases, e.g. after haemorrhage. Production of red cells in the bone marrow requires mitosis and maturation, the cells being derived from a pluripotent stem cell. The earliest red cell precursor is the proerythroblast, a large nucleated cell. By a series of divisions, the proerythroblast develops into a non-nucleated cell containing haemoglobin, i.e. an erythrocyte. At the stage of extrusion of the nucleus a reticulocyte is formed which contains remnants of RNA and ribosomes and continues to make haemo-globin. Reticulocytes mature for one or two days in the marrow before being released into the blood where, after a further one or two days, they lose their remaining ribosomes and become mature erythrocytes. Mature erythrocytes survive for 18–120 days in the circulation before being removed by macrophages in the spleen, and to a lesser extent in the bone marrow and liver. Within the macrophage the erythrocyte is broken down into haem and globin. The amino acids of the latter enter the general amino acid pool of the body, while the haem group is broken down with the release of iron which attaches to transferrin. Transferrin is an iron-binding beta-globulin responsible for iron transport and delivery to receptors on erythroblasts, or to iron stores. The remainder of the haem group is converted to bilirubin. Renal secretion of erythropoietin stimulates red cell production to keep pace with the rate of destruction. Erythropoietin is secreted by the kidneys in response to local hypoxia and acts on red marrow, causing an increased output of erythrocytes until the rise in haemoglobin concentration in the blood restores normal delivery of oxygen to the tissues. Erythropoiesis requires an adequate dietary intake of iron, vitamin B12 and folate. Depletion of stores of these will reduce erythropoiesis.
Anaemia is the reduction of the concentration of haemoglobin in the circulation below the normal range. There are three main causes of anaemia: blood loss, haemolysis, and impairment of red cell formation/function.
Immediately after acute haemorrhage the haemoglobin level is normal. In the absence of intravenous fluid replacement, there is a slow expansion in plasma volume over the next two to three days. The result is a normochromic, normocytic anaemia. There is also a reticulocytosis, which is maximal at one week, together with a mild neutrophil leucocytosis. Occasionally metamyeloyctes are present in the blood film. Chronic blood loss leads to hypochromic, microcytic, iron deficiency anaemia.
Haemolytic anaemias are a group of diseases in which red cell life span is reduced. Haemolysis is usually associated with increased erythropoiesis. Laboratory evidence of increased red cell destruction is demonstrated by: (i) increased serum unconjugated bilirubin; (ii) reduced serum haptoglobin; (iii) morphological evidence of red cell damage, e.g. spherocytes, red cell fragments, or sickled cells; (iv) reduced lifespan of red cells, e.g. demonstrated by tagging with radioactive chromium. Laboratory evidence of increased erythropoiesis depends on demonstrating a reticulocytosis in the peripheral blood and erythroid hyperplasia in the bone marrow.
These result from red cell destruction and compensatory erythropoiesis. Pallor and mild jaundice occur. Pigment stones may form in the gall bladder and bile ducts as a result of increased haemolysis, and spleno-megaly may occur. In congenital forms, erythroid hyperplasia causing expansion of marrow cavities with thinning of cortical bone may also occur. Frontal bossing of the skull may occur due to widening of the marrow space between inner and outer tables of the skull.
This is due to the presence of a haemoglobin variant, HbS, in the red cells. Recurrent painful crises and chronic haemolytic anaemia occur relating to sickling of red cells on deoxygenation. Deoxygenated HbS is 50 times less soluble than deoxygenated HbA and polymerises on deoxygenation into long fibres which deform the red cell into the typical sickle shape. The presence of HbS is the result of a defect in the gene coding for glutamic acid, the latter being replaced by valine. When an individual is heterozygous for this defect, both HbA and HbS are formed, and they are individually said to have sickle cell trait. These individuals are usually haematologically normal and are usually asymptomatic. When only the trait is present the red cells do not usually sickle until the oxygen saturation falls below 40%, which is rarely reached in venous blood. In surgical practice the anaesthetist needs to be aware of the trait so that hypoxia is avoided intraoperatively. When the individual is homozygous, HbA is not formed. The red cells readily deform and sickle cell anaemia develops. Cells sickle at the oxygen tension normally found in venous blood. The increased rigidity of the cells causes them to plug small blood vessels, with resulting infarction and painful crises. Patients may develop acute abdominal and chest pain that mimics other intra-abdominal and thoracic catastrophes. Bone pain may occur and also the patient may develop priapism. The anaemic patient responds poorly to infection, and septicaemia and osteomyelitis may develop, the latter being attributable on occasions to Salmonella. The spleen may calcify and atrophy due to repeated infarction. Pigment gall stones may occur.
This is due to a defect in the red cell membrane. Clinical features include a family history, pallor, mild jaundice, and splenomegaly. Spherocytes are identified in the blood film. There is a raised serum bilirubin and an increased reticulocyte count. Cholecystitis may occur as a result of pigment stones. Splenectomy is the treatment of choice, being delayed until after the age of 10 years as postsplenectomy sepsis is less after this age. Splenectomy does not cure the spherocytosis but prevents the abnormally shaped cells being destroyed in the spleen. Following splenectomy the haemoglobin level rises, the jaundice disappears, and the lifespan of the red cells increases to near normal levels.
This may arise as a result of: (i) deficiency of essential haematinics, e.g. iron, folate, vitamin B12; (ii) chronic disorders, infections (TB), renal disease, liver disease, neoplasia, collagen disease; (iii) marrow infiltration, e.g. carcinoma, myeloma, lymphoma, myelofibrosis; (iv) endocrine disease, e.g. hypothyroidism; (v) cytotoxic and immunosuppressive agents.
Anaemias may be classified by the morphological appearance of erythrocytes in a stained blood smear. Normocytes are red cells with a normal diameter, microcytes are those with a reduced diameter, and macrocytes are those with an increased diameter. Normochromic is a term applied to normal staining of the red cell with a central area of pallor, while hypochromic indicates reduced staining with a larger central area of pallor. Classification also depends on other criteria. The haematocrit or PCV is expressed as the percentage of packed red cells in relation to the total volume of blood and is normally approximately 45%. Other important parameters in assessing anaemia are:
Polycythaemia is an increase in the concentration of red cells above the normal level. There is a rise in both total blood volume and PCV; the latter may be as high as 60%. The Hb concentration rises to about 18 g/dL and, because of the increased proportion of erythrocytes, blood viscosity is high. Polycythaemia may be a primary condition, i.e. polycythaemia rubra vera, or may be secondary or relative, or due to inappropriate secretion of erythropoietin (Box 10.1). Polycythaemia, especially the true and secondary forms, increases whole blood viscosity. This leads to sluggish blood flow through the heart, brain and limbs, leading to myocardial infarction, stroke and ischaemic limbs. The spleen is enlarged in about 75% of cases. Haemorrhagic lesions may be a feature especially in the gastrointestinal tract. Peptic ulceration is common in polycythaemia rubra vera, but the reason is unknown.
Box 10.1 Causes of polycythaemia
White blood cells form part of the body’s defence mechanism. They are divided into two main groups: phagocytes, which engulf and destroy bacteria and foreign matter, and lymphocytes, which are responsible for the immune response. Granulocytes and monocytes develop in red bone marrow from a common stem cell. The granulocyte precursor is a myeloblast which subsequently differentiates and matures, acquiring characteristic granules, to become either a neutrophil, basophil, or eosinophil granulocyte. Precursors do not normally circulate but may do so in case of bone marrow disease or severe infections.
Neutrophils have a scavenging function and are most important in defence against bacter-ial infection. They possess a segmented nucleus and abundant cytoplasmic granules containing enzymes e.g. alkaline phosphatase and lysosyme. They spend 14 days in the bone marrow, whereas their half-life in the blood is only 6–12 h. They enter tissues by pene-trating the endothelium.
Leucocytosis is an increase in the number of circulating white cells. The normal reference range is shown in Table 10.2. It may involve any of the white cells, but a polymorphonuclear leucocytosis is the most common, i.e. neutrophilia (Table 10.3).
|Total white cell count
Leucopaenia is a reduction in circulating leucocytes. In practice the most common form is neutropaenia – a deficiency of neutrophil granulocytes. Neutropaenia may be selective or part of a pancytopaenia (Table 10.4).
Neutropaenia with counts of less than 0.5 × 109/L may result in severe sepsis, e.g. oral and oesophageal candida, septicaemia, opportunistic infection. This type of disease is seen in patients receiving chemotherapy for malignant disease or immunosuppressive therapy for organ transplantation.
Platelets are discoid non-nucleated granule-containing cells that are formed in the bone marrow by fragmentation of the cytoplasm of megakaryocytes. Their concentration in normal blood is 160–450×109/L. They survive in the circulation for 8–10 days. Platelets are contractile and adhesive cells which are import-ant in haemostasis. They adhere to exposed subendothelial tissues, aggregate, and form a haemostatic plug. Platelets may also take part in the repair process after vascular injury. Platelet-derived growth factor is mitogenic for smooth muscle and fibroblasts; it may also be involved in the development of atheroscler-osis. The function of platelets is discussed further in the section on haemostasis. A reduction in the number of platelets is called thrombocytopaenia (Table 10.5).
|Decreased platelet survival
|Sequestration of platelets
Following injury to the vessel wall, loss of endothelium exposes subendothelial collagen, allowing adhesion of platelets to the damaged area and activation of the intrinsic pathway of coagulation. Damaged endothelial cells release von Willebrand factor, which is necessary for platelet adhesion, and also release tissue thromboplastin which activates the intrinsic pathway of coagulation. Simultaneously platelet granules release ADP, which initiates platelet aggregation.
The end-stage of blood coagulation is the conversion of soluble fibrinogen to insoluble fibrin by the protease thrombin. The coagulation mechanism is complex and involves two interacting systems: the intrinsic and extrinsic pathways. Activation of factor X is the result of preceding enzyme reactions in the two pathways. The intrinsic pathway involves normal blood compon-ents; the extrinsic pathway requires tissue thromboplastin released by damaged cells. The pathways are shown in Fig. 10.1. All the soluble coagulation factors are manufactured in the liver with the exception of Factor VIII (endothelium), calcium, platelet factors and thromboplastin.
During the repair process in blood vessels and healing wounds, fibrin is removed by the fibrinolytic system (Fig. 10.2). Fibrin is broken down to soluble fibrin degradation products by plasmin. Plasmin is derived from the inactive precursor plasminogen by the action of plasminogen activators. Tissue plasminogen activator is released from endothelial cells. Control of the activation of plasminogen is provided by plasminogenactivator inhibitor I, which is released by endothelial cells and rapidly inactivates tissue plasminogen activator.
The normal range is 160–450× 109/L. Thrombocytopaenia exists with counts of less than 100×109/L. Counts of 70×109/L are usually adequate for surgical haemostasis. Spontaneous bleeding usually occurs with counts of less than 20×109/L.