Chapter Notes: The Blood
Blood is a specialised fluid connective tissue that circulates continuously throughout the body, providing communication and transport between distant tissues. It transports oxygen, nutrients, hormones, heat, protective substances and clotting factors. Blood normally consists of a clear, straw-coloured fluid called plasma in which different types of blood cells are suspended. Plasma constitutes about 55% of blood volume and the cellular fraction about 45%. Blood volume is approximately 7% of body weight (about 5.6 litres in a 70 kg man), less in women and greater in children. Continuous flow maintained by the heart helps preserve a stable internal environment for body cells and distributes heat produced by metabolically active organs.
Plasma
Plasma is about 90-92% water and contains dissolved and suspended substances including plasma proteins, inorganic salts (electrolytes), nutrients, waste products, hormones and gases. Plasma proteins constitute roughly 7% of plasma and are largely retained within the circulation because they are too large to cross capillary pores. They contribute to plasma osmotic pressure and viscosity.
Plasma proteins
Albumins (≈60% of plasma protein) maintain plasma osmotic pressure and act as carrier molecules for free fatty acids, some drugs and steroid hormones.
Globulins have several roles:
- as immunoglobulins (antibodies) produced by lymphocytes that bind and neutralise foreign antigens;
- as transport proteins for hormones and minerals (for example, thyroglobulin transports thyroxine, transferrin transports iron);
- as inhibitors of some proteolytic enzymes (e.g. α2-macroglobulin inhibits trypsin).
Clotting factors, the most abundant being fibrinogen, are responsible for coagulation. Serum is plasma from which clotting factors have been removed.
Electrolytes, nutrients, waste products, hormones and gases
Electrolytes (e.g. Na+, K+, Ca2+, Cl-, HCO3-, PO43-) are essential for muscle contraction, nerve impulse transmission and acid-base balance. Blood pH is tightly regulated between 7.35 and 7.45 by buffering systems.
Nutrients (glucose, amino acids, fatty acids, glycerol, minerals and vitamins) delivered from the alimentary tract supply energy, heat and material for repair and synthesis. Waste products (urea, creatinine, uric acid, carbon dioxide) are carried to excretory organs. Hormones produced by endocrine glands enter the blood and act at distant target tissues. Gases (oxygen, carbon dioxide, nitrogen) are transported dissolved in plasma and-in the cases of oxygen and carbon dioxide-also in combination with haemoglobin in red blood cells.
Cellular components of blood
The cellular components are erythrocytes (red blood cells), leukocytes (white blood cells) and platelets (thrombocytes). Blood cells are formed mainly in red bone marrow from pluripotent stem cells through separate developmental lineages (haemopoiesis). In adults, haemopoiesis occurs in flat and irregular bones and the epiphyses of long bones (sternum, ribs, pelvis, skull).
Erythrocytes (red blood cells)
Structure and function. Erythrocytes are biconcave discs about 7 µm in diameter, lack a nucleus and organelles, and contain haemoglobin. Their shape increases surface area for gas exchange and permits deformability to pass through narrow capillaries. Their principal role is transport of oxygen (most oxygen is carried bound to haemoglobin) and some carbon dioxide.
| Measure | Normal values |
|---|---|
| Erythrocyte count | Male: 4.5 × 1012/L to 6.5 × 1012/L Female: 3.8 × 1012/L to 5.8 × 1012/L |
| Packed cell volume (PCV, haematocrit) | 0.40-0.55 L/L |
| Mean cell volume (MCV) | 80-96 fL |
| Haemoglobin | Male: 13-18 g/100 mL; Female: 11.5-16.5 g/100 mL |
| Mean cell haemoglobin (MCH) | 27-32 pg/cell |
| Mean cell haemoglobin concentration (MCHC) | 30-35 g/100 mL of red cells |
Life span, formation and control
Erythrocytes live about 120 days and are produced by erythropoiesis in bone marrow from stem cells; the process takes roughly seven days. Immature cells (reticulocytes) are released into the bloodstream and mature within one to two days. The kidneys secrete the hormone erythropoietin in response to tissue hypoxia; erythropoietin stimulates bone marrow to increase erythrocyte production. When tissue oxygenation is restored, erythropoietin production falls (a negative feedback loop).
Haemoglobin and oxygen transport
Haemoglobin is a tetrameric protein with four globin chains and four haem groups, each haem containing one iron atom that can bind one O2 molecule. Thus one haemoglobin molecule can carry up to four O2 molecules. An average erythrocyte contains ~280 million haemoglobin molecules.
Haemoglobin binds oxygen reversibly to form oxyhaemoglobin. The affinity of haemoglobin for oxygen is influenced by
- pH (Bohr effect): low pH (acidic, e.g. in actively metabolising tissues) promotes oxygen release;
- PO2: low oxygen tension in tissues favours oxygen release, while high PO2 in the lungs favours oxygen binding;
- temperature: higher temperature (active tissues) promotes oxygen release.
Destruction and recycling
Aged erythrocytes are removed mainly by phagocytic cells of the spleen, liver and bone marrow. Iron released from haem is recycled and used in new haemoglobin synthesis; the haem portion is converted to biliverdin and then bilirubin, transported to the liver, conjugated and excreted in bile.
Blood groups
Red cell membranes carry inherited surface antigens that determine blood groups. Transfusion of incompatible blood leads to immune-mediated destruction of donor cells (transfusion reactions). The two clinically most important systems are the ABO system and the Rhesus (Rh) system.
The ABO system
Individuals have A antigens, B antigens, both (AB) or neither (O) on their red cells. Corresponding antibodies (anti-A and anti-B) are present in the plasma according to the genotype: for example, group A individuals have anti-B, group B have anti-A, group AB have neither, and group O have both anti-A and anti-B. Because of these antibodies:
- AB is often called a universal recipient (no anti-A or anti-B);
- O is often called a universal donor (no A or B antigens on red cells).
These terms are limited because other antigen systems may cause incompatibility; cross-matching before transfusion is essential.
The Rhesus (Rh) system
The most important Rh antigen is the D antigen. People with the antigen are Rh positive (Rh+); those lacking it are Rh negative (Rh-). Rh- individuals can be sensitised to produce anti-Rh antibodies after exposure to Rh+ red cells (for example during pregnancy or after transfusion). Maternal anti-Rh antibodies can cross the placenta and destroy fetal red cells in subsequent Rh+ pregnancies, producing haemolytic disease of the newborn; this can be prevented by giving an Rh- mother anti-Rh immunoglobulin shortly after delivery of an Rh+ baby.
Leukocytes (white blood cells)
Leukocytes provide defence and immunity. They contain nuclei and are larger than erythrocytes but make up only about 1% of blood volume. There are two broad classes: granulocytes (neutrophils, eosinophils, basophils) and agranulocytes (monocytes and lymphocytes).
| Cell type | Number (× 109/L) | Percentage of total leukocytes |
|---|---|---|
| Neutrophils | 2.5-7.5 | 40-75% |
| Eosinophils | 0.04-0.44 | 1-6% |
| Basophils | 0.015-0.1 | <1% |
| Monocytes | 0.2-0.8 | 2-10% |
| Lymphocytes | 1.5-3.5 | 20-50% |
| Total leukocytes | 5-9 | 100% |
Granulocytes
Granulocytes develop through a common myeloid lineage and contain cytoplasmic granules and multilobed nuclei. Their names reflect staining properties.
Neutrophils
Neutrophils are rapid responders and primary defenders against bacterial infection. They migrate to sites of infection by chemotaxis, pass through capillary walls by diapedesis and kill microbes by phagocytosis and intracellular digestion using lysosomal enzymes. They typically live 6-9 hours in the bloodstream; pus is largely composed of dead neutrophils, microbes and cell debris.
Eosinophils
Eosinophils participate in defence against multicellular parasites (e.g. worms) and modulate allergic inflammation by releasing toxic granular contents and enzymes such as histaminase. They accumulate in allergic tissues such as asthmatic airways and skin lesions.
Basophils
Basophils contain granules rich in histamine and heparin and are important in allergic reactions. They are activated when allergens bind to IgE-type receptors. Mast cells (tissue counterparts of basophils) release granules rapidly on allergen exposure and mediate immediate allergic symptoms.
Agranulocytes
Monocytes and macrophages
Monocytes are the largest circulating leukocytes; some circulate and phagocytose, others migrate into tissues and become macrophages. Macrophages synthesise and release cytokines (e.g. interleukin-1), play central roles in inflammation and immunity, and link innate and adaptive responses. Collections of tissue macrophages (reticuloendothelial system) include Kupffer cells in the liver, alveolar macrophages in the lung, microglia in the brain and osteoclasts in bone.
Lymphocytes
Lymphocytes are central to specific immunity. They originate from stem cells in bone marrow and lymphoid tissue and differentiate into B-lymphocytes and T-lymphocytes, which have distinct roles in humoral and cell-mediated immunity, respectively.
Platelets (thrombocytes) and haemostasis
Platelets are small (2-4 µm) anuclear cytoplasmic fragments derived from megakaryocytes. They contain granules with substances that promote clotting and haemostasis. Normal platelet count: 200 × 109/L to 350 × 109/L (200 000-350 000/mm3). Platelet life span is 8-11 days; about one third are stored in the spleen as an emergency reserve. Thrombopoietin from the liver stimulates platelet production.
Stages of haemostasis
When a vessel is damaged haemostasis proceeds through overlapping steps:
- Vasoconstriction: platelets adhering to exposed subendothelium release vasoconstrictors (e.g. serotonin), reducing blood loss;
- Platelet plug formation: adherent platelets become sticky, release ADP and other agonists to recruit and aggregate more platelets, forming a temporary plug (usually within minutes);
- Coagulation (clot formation): a cascade of clotting factors leads to generation of thrombin, which converts fibrinogen to insoluble fibrin threads that stabilise the platelet plug into a firm clot;
- Clot retraction and repair: platelets contract to reduce clot size and draw vessel edges together;
- Fibrinolysis: plasminogen trapped in the clot is activated to plasmin, which digests fibrin and removes the clot as healing proceeds.
| Factor | Name / Alternative names |
|---|---|
| I | Fibrinogen |
| II | Prothrombin |
| III | Tissue factor (thromboplastin) |
| IV | Calcium (Ca2+) |
| V | Labile factor (proaccelerin) |
| VII | Stable factor (proconvertin) |
| VIII | Antihaemophilic globulin (AHG, factor VIII) |
| IX | Christmas factor (factor IX) |
| X | Stuart-Prower factor (factor X) |
| XI | Plasma thromboplastin antecedent |
| XII | Hageman factor |
| XIII | Fibrin stabilising factor |
Vitamin K is required for synthesis of factors II, VII, IX and X. The coagulation cascade can be initiated by the intrinsic pathway (contact activation on damaged endothelium) or the extrinsic pathway (tissue factor released by damaged tissue); both pathways converge on a final common pathway culminating in fibrin formation.
Control of coagulation
Because coagulation is self-amplifying, several anticoagulant mechanisms limit clot formation to the site of injury: an intact smooth endothelium prevents platelet adhesion; natural anticoagulants such as antithrombin III and heparin-like molecules inhibit activated clotting factors; and fibrinolytic pathways remove clots after repair.
Erythrocyte disorders
Anaemia is a deficiency in the oxygen-carrying capacity of blood, usually due to reduced haemoglobin concentration or defective haemoglobin. Classification may be by cause (reduced production, blood loss, increased destruction) or by red cell morphology (size and haemoglobin content).
| Term | Meaning |
|---|---|
| Normochromic | Normal cell colour |
| Normocytic | Normal cell size |
| Microcytic | Cells smaller than normal |
| Macrocytic | Cells larger than normal |
| Hypochromic | Paler than normal cells (reduced haemoglobin) |
| Haemolytic | Increased rate of cell destruction |
| Megaloblastic | Large, immature red cells due to impaired DNA synthesis |
Common features of anaemia include tachycardia, breathlessness on exertion and palpitations due to inadequate oxygen delivery. The specific signs and red cell morphology help identify the cause.
Iron deficiency anaemia
This is the commonest form worldwide. Dietary iron (from meat and certain vegetables) is absorbed slowly; daily requirement is ~1-2 mg for men and ~3 mg for women (menstrual losses and pregnancy increase requirements). Features include microcytic, hypochromic red cells with reduced MCH (<27 pg/cell).="" causes:="" insufficient="" dietary="" intake,="" increased="" requirement="" (pregnancy,="" growth),="" chronic="" blood="" loss="" (peptic="" ulcer,="" heavy="" menstruation,="" gi="" malignancy),="" or="" malabsorption="" (e.g.="" following="" gastrectomy,="" reduced="" gastric="" acidity="" from="" antacid="">
Vitamin B12 and folic acid deficiency (megaloblastic anaemias)
Deficiency of vitamin B12 or folate impairs DNA synthesis during erythropoiesis and produces large, immature red cells (megaloblasts) with elevated MCV (>94 fL). Haemoglobin per cell may be normal or increased, but total cell numbers fall. Cells are fragile and lifespan is shortened.
Vitamin B12 deficiency
Pernicious anaemia is an autoimmune condition in which intrinsic factor and parietal cells are destroyed, impairing vitamin B12 absorption. Dietary deficiency is rare except in strict vegans. Other causes: gastrectomy, terminal ileal disease or resection (Crohn's), chronic gastritis. Neurological complications (subacute combined degeneration of the spinal cord) can be irreversible if untreated.
Folic acid deficiency
Folate deficiency causes a megaloblastic anaemia similar to vitamin B12 deficiency but without the neurological damage. Causes include poor diet, increased requirements (pregnancy), malabsorption (coeliac disease, tropical sprue), and certain drugs (anticonvulsants, cytotoxics).
Aplastic (hypoplastic) anaemia
Bone marrow failure reduces production of erythrocytes, leukocytes and platelets (pancytopenia). Causes include ionising radiation, cytotoxic drugs, benzene exposure, certain viral infections (e.g. hepatitis) and sometimes inherited predisposition. Clinical features include anaemia, recurrent infections and bleeding/bruising.
Haemolytic anaemias
Haemolytic anaemias result from premature destruction of erythrocytes. Destruction may be intravascular or extravascular (spleen, liver). Mild haemolysis can be compensated by increased marrow production; when compensation fails, anaemia develops. Jaundice and splenomegaly are common.
Congenital haemolytic anaemias
Genetic defects produce abnormal haemoglobin or membrane instability.
- Sickle cell anaemia: a mutation in β-globin produces haemoglobin that polymerises on deoxygenation, distorting cells into a sickle shape. Sickle cells haemolyse early and obstruct microcirculation, causing vaso-occlusive crises, ischaemia, infarction, pain and chronic organ damage. Heterozygotes have some protection against malaria.
- Thalassaemia: inherited reduction or absence of one globin chain causes ineffective erythropoiesis and haemolysis; presentation ranges from mild to severe transfusion-dependent anaemia. Chronic transfusion can cause iron overload.
Haemolytic disease of the newborn
Occurs when an Rh- mother is sensitised by Rh+ fetal red cells and produces anti-Rh antibodies that cross the placenta in subsequent pregnancies and cause fetal haemolysis. Prophylaxis by giving anti-Rh immunoglobulin to the Rh- mother within 72 hours of delivery of an Rh+ infant prevents maternal sensitisation.
Acquired haemolytic anaemias
Causes include chemical agents and drugs (sulphonamides, lead, arsenic), microbial toxins (e.g. Clostridium perfringens), autoimmune haemolysis (autoantibodies to red cell antigens), and transfusion reactions from incompatible blood leading to intravascular haemolysis, acute kidney injury and shock.
Polycythaemia
Polycythaemia denotes an excessive erythrocyte mass, which increases blood viscosity and risk of thrombosis and ischaemia.
Relative polycythaemia results from reduced plasma volume (e.g. dehydration or fluid losses), giving an apparent increase in red cell concentration. True polycythaemia can be physiological (long-term hypoxia at high altitude, chronic lung or cardiac disease, heavy smoking) stimulating erythropoietin production, or pathological (polycythaemia vera or secondary to tumours that produce erythropoietin).
Leukocyte disorders
Leukopenia is leukocyte count < 4 × 109/L and predisposes to infection. Granulocytopenia (neutropenia) refers to reduced granulocytes/neutrophils and may result from drugs, marrow suppression, irradiation, severe infections or splenic sequestration. Extreme deficiency is agranulocytosis and may lead to severe sepsis.
Leukocytosis is a protective increase in leukocyte count commonly seen in infections and some inflammations. Sustained pathological leukocytosis (>11 × 109/L) may indicate malignancy or other disease.
Leukaemia
Leukaemia is malignant proliferation of white blood cell precursors in bone marrow, leading to uncontrolled production of leukocytes or precursors, bone marrow crowding, anaemia, thrombocytopenia and reduced functional immunity. Leukaemic cells are often immature (blast) cells released into blood.
Causes
Known risk factors include ionising radiation, certain chemicals (benzene), some cytotoxic drugs, viral agents and genetic predisposition. Many cases, however, have no identifiable cause.
Classification and clinical features
Leukaemias are classified by the predominant cell line and by disease course.
- Acute leukaemias: rapid onset, affect poorly differentiated blast cells. Acute myeloblastic leukaemia (AML) involves myeloblasts and is common in adults; acute lymphoblastic leukaemia (ALL) primarily affects children and originates from lymphoid precursors.
- Chronic leukaemias: slower course with more differentiated cells. Chronic myeloid leukaemia (CML) may progress to an acute phase; chronic lymphocytic leukaemia (CLL) commonly affects older adults and often follows an indolent course.
Haemorrhagic diseases
Disorders that impair haemostasis cause a tendency to bleeding. Important causes include thrombocytopenia, vitamin K deficiency, disseminated intravascular coagulation and inherited clotting factor defects.
Thrombocytopenia
Defined as platelet count < 150 × 109/L; spontaneous bleeding is uncommon until counts fall below ~30 × 109/L. Causes include reduced production (marrow failure, marrow infiltration, radio- or cytotoxic therapy) and increased destruction (disseminated intravascular coagulation, immune thrombocytopenic purpura).
Autoimmune thrombocytopenic purpura is characterised by antiplatelet antibodies that mark platelets for removal, producing purpura (skin and mucosal bleeding) and variable severity from mild bruising to life-threatening haemorrhage.
Vitamin K deficiency
Vitamin K is required for hepatic synthesis of clotting factors II, VII, IX and X. Deficiency occurs in liver disease, biliary obstruction (impaired fat absorption), prolonged antibiotic therapy that suppresses gut flora, and in newborns (limited placental transfer and immature gut flora). Newborns are routinely given vitamin K to prevent haemorrhagic disease of the newborn.
Disseminated intravascular coagulation (DIC)
DIC is a pathological activation of coagulation within the vasculature causing widespread fibrin deposition and microthrombi, consumption of clotting factors and platelets and a paradoxical tendency to severe bleeding. Common triggers include severe infection (sepsis), major trauma, obstetric complications (e.g. placental abruption), acute pancreatitis, advanced malignancy and massive transfusion.
Congenital clotting disorders
The haemophilias are X-linked inherited deficiencies of specific clotting factors. Haemophilia A (factor VIII deficiency) and haemophilia B (factor IX deficiency, Christmas disease) cause prolonged and excessive bleeding, spontaneous haemarthroses and deep tissue haemorrhages. Female carriers rarely express full disease unless homozygous or by X-chromosome inactivation anomalies.
von Willebrand disease is an autosomal bleeding disorder caused by deficiency or dysfunction of von Willebrand factor, leading to reduced platelet adhesion and reduced factor VIII levels; it affects males and females equally.
Summary: Blood comprises plasma and cellular elements (erythrocytes, leukocytes, platelets). Plasma proteins and cells together maintain transport, defence and haemostasis. Disorders of blood arise from deficiencies or excesses in these components, from inherited defects or from acquired insults (nutritional deficiency, infection, immune reactions, toxins or marrow failure). Understanding normal blood physiology and the mechanisms of haemostasis and immunity is essential to recognise, classify and manage common haematological conditions.
