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13.7 Major disorders of the red and white blood
Proliferative disorders of the white blood cells
In addition, a very small amount of carbon dioxide is carried in the blood combined with a-amino groups on plasma proteins in the form of carbamino compounds formed by the general reaction:
R-NH, + CO,
The reactions involved in the carriage of carbon dioxide in the form of both bicarbonate ions and carbamino compounds are illustrated diagrammatically in Fig. 13.9.
To summarize, each deciliter of arterial blood has a Pco2 of 5.3 kPa (40 mmHg) and contains about 2.8 ml of CO2 in solution, 43.9 ml as bicarbonate and 2.3 ml as carbamino com-
Fig 13.9 A schematic representation of CO2 and O2 transport in the blood, (a) The exchange of CO2 and O2 that occurs between the blood and the tissues; and (b) the exchange that occurs in the lungs between the blood and the alveolar air.
pounds, making a total of 49 ml dl l. Mixed venous blood has a Pco2 of 6.1 kPa (46 mmHg) and each deciliter contains approximately 3.2 ml of CO2 in solution, 47 ml as bicarbonate and 3.8 ml as carbamino compounds (mainly carbaminohemoglobin), equivalent to a total of 54 ml CO, per deciliter.
The carbon dioxide dissociation curve
The amount of carbon dioxide present in solution depends on the PCO2 and this in turn will determine the amount of bicarbonate and carbamino compounds that will be formed in the blood. The relationship between the PCO2 (in kPa or mmHg) and the total CO2 (mlCO2dl~1 blood) is called the CO2 dissociation curve. It differs from the oxyhemoglobin dissociation curve in that it does not become saturated even at high PCO2 (Fig. 13.10). Across the physiological range of PCO2 for whole blood (5.3 kPa (40 mmHg) in arterial blood to 6.13 kPa (46 mmHg) in mixed venous blood) the CO2 dissociation curve is roughly linear. The quantity of CO2 carried in the blood is, however, dependent on the degree of oxygenation of hemoglobin. This is called the Haldane effect and is also illustrated in Fig. 13.10.
Two main factors are responsible for the changes in carbon dioxide affinity of the blood seen when HbO2 levels vary:
H2O + CO2 ^ HCOj + H+
to the right and encouraging more CO2 to be carried as bicarbonate ion.
Fig. 13.10 The carbon dioxide dissociation curve for whole blood and the Haldane effect. Point a is for arterial blood and v is the value for mixed various blood.
In the lungs, where about 97 per cent of the hemoglobin is in the form of oxyhemoglobin, the carbon dioxide content of
13 The properties of blood
the blood is relatively lower than it is in the tissues where oxyhemoglobin makes up around 75 per cent of the total Hb. In other words, more carbon dioxide may be carried when HbO2 is low. This makes good sense physiologically, as a major purpose of blood gas transport is to load the blood with CO2 in the tissues and unload it for expiration in the lungs.
This section focuses on the consequences arising from changes in the rate of production or destruction of the cellular elements of the blood. Broadly, blood cell disorders fall into two categories, proliferative disorders (where there is an excess of cells, often with abnormal function) and deficiency disorders (where there are too few cells). Red and white cells will be considered here, while abnormalities of platelet function will be considered in Section 13.8.
Red cell abnormalities
This term covers a variety of blood disorders characterized by a reduced number of red cells, a reduced hemoglobin concen-
tration, or both. All types of anemia result in a reduction in the oxygen-carrying capacity of the blood. Anemia may arise for a number of reasons:
13.8 Mechanisms of hemostasis 249
This condition is the tesult of overstimulation of red blood cell production. It brings about an increase in the hematocrit value (to as much as 60—80 per cent) and a rise in blood viscosity. It is often seen in people living at high altitude who experience chronic hypoxia as a result of the low prevailing atmospheric oxygen tension (see Chapter 30 for further details), although it can also arise under other circumstances. The increase in red blood cell numbers increases the oxygen-carrying capacity of the blood but, at the same time, it increases the viscosity of the blood and this places an extra load upon the heart. Over time, the heart hypertrophies (enlarges) to adapt to the increased work load.
White cell abnormalities
As with the red cells, disorders of the leukocytes fall into two broad categories; deficiency disorders and proliferative disorders.
This term describes an absolute reduction in the numbers of white blood cells. It may affect any of the different types of leukocyte but most often involves the neutrophils, which are the predominant type of granulocyte. In this case the disorder is known as neutropenia. It can result from defective neutrophil production or from an increase in the rate of removal of neutrophils from the circulation. The former may arise as part of a genetic impairment of the regulation of neutrophil production, aplastic anemia, in which all the myeloid stem cells are affected, or as a result of certain types of chemotherapy. It may also be a consequence of the overgrowrh of neoplastic cells characteristic of some forms of leukemia, which suppresses the function of the neutrophil precursor cells.
Occasionally, leukopenia arises as a result of an accelerated rate of neutrophil removal from the circulation rather than a reduction in the rate of production. This is most usually a consequence of chemotherapy but may also be seen in certain infections or autoimmune disorders in which neutrophils are destroyed. The neutrophils are essential in the inflammatory response. Infections are, therefore, common in people with neutropenia and these may be severe or even life-threatening.
Malignant proliferative diseases of the blood include the leukemias, lymphomas, and myelomas. Self-limiting proliferative disorders such as infectious mononucleosis (glandular fever) can also occur.
Leukemia is characterized by greatly increased numbers of abnormal white blood cells circulating in the blood. There are several different types of leukemia, classified according to their cells of origin (lymphocytic or myelocytic) and whether the disease is acute or chronic. Lymphocytic leukemias are most commonly seen in children and involve the lymphoid precursors that originate in the bone marrow. Cancerous production of lymphoid cells then spreads to other tissues such as the spleen,
lymph nodes, and CNS. Myelocytic disease, which is more common in adults, involves the pluripotent myeloid stem cells in the bone marrow. The maturation of all the blood cell types, including granulocytes, erythrocytes, and thrombocytes is affected.
Leukemic cells are usually nonfunctional and therefore cannot provide the normal protection associated with white blood cells. Common consequences of the disease include the development of infections, severe anemia, and an increased tendency to bleed, as a result of a lack of platelets (thrombocytopenia). Furthermore, the leukemic cells of the bone marrow may grow so rapidly that they invade the surrounding bone itself. This causes pain and an increased risk of fractures.
Almost all forms of leukemia spread to other tissues, particularly those which are highly vascular, such as the spleen, liver, and lymph nodes. As they invade these regions the growing cancerous cells cause extensive tissue damage and place heavy demands on the metabolic substrates of the body, especially amino acids and vitamins. The energy reserves of the patient are thus depleted and the body protein broken down. Weight loss and excessive fatigue are characteristic symptoms of leukemia.
3- An important consequence of all types of anemia is a reduction in the oxygen-carrying capacity of the blood.
13.8 Mechanisms of hemostasis
When a blood vessel is damaged by mechanical injury of some kind, excessive blood loss from the wound is prevented by a process called bemostasis. This involves a series of events— vasoconstriction, platelet aggregation, and blood coagulation (clot fotmation). Later, blood-vessel repair, clot retracrion, and dissolution complete the healing process.
13 The properties of blood
When the vascular endothelium (Section 15.9) is damaged, there is a localized contractile response by the vascular smooth muscle, causing the vessel to narrow. This may be mediated by humoral factors or directly by mechanical stimulation, and in arterioles and small arteries closure may be virtually complete. However, this response lasts for only a short time and, to prevent serious loss of blood, further hemostatic mechanisms are initiated.
The role of platelets
Within seconds of a vascular injury, platelets start to build up and adhere to the site of damage. This process is self-perpetuating as the adhering platelets secrete ADP and 5-hydroxytryptamine. They also synthesize arachidonic acid and thromboxane A2. These factors trigger a change in the surface characteristics of the platelets (see also Sections 5.5 and 5.7) which causes them to adhere to the walls of damaged vessels and to each other. This process results in the formation of я platelet plug, which may be sufficient to stem the flow of blood from minor wounds.
In addition to sealing damaged vessels, the platelets play a continuous role in maintaining normal vascular integrity. This is illustrated by the increased capillary permeability seen in people suffering from platelet deficiency (thrombocytopenia). Such individuals often develop spontaneous tiny hemorrhages in the skin and mucous membranes (petechiae), giving the patient a curious blotchy appearance, with further bleeding into subcutaneous
This is the process by which fibrin strands create a mesh that binds blood components together to form a blood clot. It is a complex process that involves the sequential activation of a number of factors that are normally present in the blood in an inactive form. A cascade of reactions occurs by which one activated factor activates another according to the following scheme:
Many clotting factors are synthesized in the liver and their manufacture is dependent upon vitamin K. The major reactions in the clotting process are shown in Fig. 13.11, from which it is evident that there are two pathways which may lead to the formation of a fibrin clot. These are the intrinsic and extrinsic pathways, both are needed for normal hemostasis and both involve a number of enzyme factors. Throughout the medical and scientific literature these enzymes are known by a variety of names and/or Roman numerals (Table 13.4). In this account the factors are assigned the nomenclature by which they are most commonly known.
Table 13.4 The nomenclature of the clotting factors of blood
Note that factors I-IV are generally known by their names while factors V-XIII are generally referred to by their Roman numeral. Activated factors are designated by the letter 'a' after the numeral, e.g. activated Factor X is called Xa.
Both systems are activated when blood passes out of the vascular system. The intrinsic system (which is the slower of the two) is activated as blood comes into contact with the injured vessel wall, while rhe extrinsic system is activated when blood is exposed to the products of damaged tissue—specifically tissue factor or thromboplastin. The intrinsic pathway is so-called because all of the elements required to activate it are present in normal blood while the extrinsic pathway is activated by a factor from outside the blood, i.e. tissue factor. Both pathways lead to the formation of activated Factor X (Factor Xa) at the end of the first stage of coagulation. Further steps in the clotting reaction are common to both pathways and involve the enzymatic conversion of inactive prothrombin to thrombin. This then initiates the polymerization offibrinogen to fibrin strands within which plasma and blood cells are trapped to form a clot.
The intrinsic pathway
The initial step in this series of reactions is dependent upon a plasma protein called Factor XII (Hageman factor). When there is vascular damage and blood comes into contact with collagen, Factor XII is converted to 'activated Factor Х1Г. At the same time, platelets release phospholipid which plays a role in subsequent steps of the process.
Activated Factor XII converts Factor XI to 'activated Factor XI' which subsequently converts Factor IX (Christmas factor) to 'activated Factor IX' by a calcium-dependent process. Activated Factor IX then acts together with the phospholipids from the traumatized platelets and with Factor VIII ( antihemophilic
13.8 Mechanisms of hemostosis
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