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factor) to activate Factor X. Factor VIII is the factor missing in people (chiefly males) who suffer from hemophilia (hence its name). Activated Factor X combines with Factor V and platelet phospholipids to form a complex which, in turn, quickly initiates the cleavage of prothrombin (an inactive enzyme) to thrombin.
The extrinsic pathway
The extrinsic pathway, initiated when blood comes into contact with damaged tissue, occurs in three basic steps (Fig. 13.11, top left):
prothrombin as described earlier for the intrinsic pathway.
The common end-point of both the intrinsic and extrinsic pathways for blood clotting is the conversion of prothrombin to thrombin. In the next step the thrombin brings about the polymerization of the soluble plasma protein fibrinogen to form long strands of the insoluble protein fibrin. These strands of fibrin form a mesh-like structure which traps the blood constituents (plasma and formed elements) to form the clot and bind the edges of the damaged vessel together.
Following the coagulation of blood, the clot gradually shrinks as serum is extruded from it. The exact mechanism of this process is not understood but it is believed to be initiated by the action of thrombin on platelets. One idea is that thrombin causes the release of intracellularly stored calcium into the platelet cytoplasm. This calcium then triggers the contraction of contractile proteins within the platelets by a process resembling the
Fig. 13.11 The extrinsic and intrinsic pathways leading to the formation of a blood clot. Note the central roles played by Factor Xa and thrombin in the process of blood coagulation.
13 The properties of blood
contraction of muscle. The contractile process may then cause the extrusion of pseudopodia from the platelets. These stick to the fibrin strands within the clot and, as they contract, the fibrin strands are pulled together, at the same time squeezing out the entrapped fluid as serum.
Dissolution of the clot
Once the wall of the damaged blood vessel is repaired, the blood clot is removed by lysis. Activated Factor XII stimulates the production of a substance in the plasma known as kallikrein. In turn, kallikrein promotes the conversion of inactive plasminogen into active plasmin, an enzyme that digests fibrin and thus brings about dissolution of the clot.
Various other plasminogen activators are used clinically to promote the dissolution of clots. These include streptokinase, a substance produced naturally by certain bacteria, and an endogenous substance called tissue plasminogen activator (TPA) which can now be produced commercially by genetic engineering. These substances can be injected either into the general circulation or into a specific blood vessel that contains a clot to promote lysis of the clot.
The role of calcium in hemostasis
As Fig. 13.11 shows, calcium ions are required for each step in the clotting process except for the first two reactions of the intrinsic pathway. Adequate levels of calcium ions are therefore necessary for normal clotting. In reality, plasma calcium levels never fall low enough to impair the clotting processes since death would have resulted from other causes (most notably tetany of the respiratory muscles) long before. It is, however, possible to prevent the coagulation of blood removed from the body and stored in vitro by reducing the calcium ion concentration of the plasma. This may be achieved by the addition of substances such as EDTA (ethylenediaminetetraacetic acid) or citrate, which bind calcium.
Inappropriate clotting of blood is prevented by endogenous anticoagulants
Normally, blood is prevented from clotting inappropriately by a variety of mechanisms. The preceding account showed that clotting is initiated when blood comes into contact with an abnormal or damaged tissue surface. By contrast, undamaged vascular endothelial cells generally prevent clotting by releasing substances that inhibit coagulation—anticoagulants. These are:
thrombm complex activates protein С which inhibits the actions of Factors Va and Villa. In addition, protein С stimulates the production of the proteolytic enzyme plasmin from plasminogen. Plasmin disperses any clors that have begun to form by dissolving fibrin.
Clot formation at inappropriate sites within the circulation is potentially lethal
It is clearly highly undesirable for blood clots to form in the circulation at inappropriate sites. If such a clot does occur it is known as a thrombus and may block the vessel in which it forms. If a thrombus forms or lodges within a coronary artery the result is a heart attack, where a part of the heart muscle becomes ischemic (i.e. receives insufficient blood to meet its oxygen requirements) and dies. A clot forming in one of the blood vessels supplying the brain gives rise to a stroke. The area of brain tissue supplied by that vessel is deprived of oxygen during a stroke and will suffer ischemia. This will result in some degree of brain damage.
Sometimes small clots (emboli) break off from larger thrombi and travel to other parts of the circulation where they may block small vessels. Such a block is called an embolism. Clots that form in the systemic vessels often travel to the lungs where they lodge in pulmonary vessels to produce pulmonary emboli.
There are a number of conditions in which the formation of clots within blood vessels is favored. These include damage to the vascular wall, sluggish blood flow (stasis), and alterations in one or more of the components of blood which renders it more easily coagulated. One of the most common causes of thrombosis is a condition known as atherosclerosis. It is characterized by the formation of fibro-fatty lesions (plaques) in the intimal lining of large or medium-sized arteries such as the aorta, the coronaries, and the large vessels that supply the brain. As the lesions increase in size, they gradually occlude the vessel, causing a reduction in blood flow and a predisposition to thrombus formation. Major risk factors in atherosclerosis (apart from genetic factors, being male, and getting older) appear to include cigarette smoking, high blood pressure, and a high blood cholesterol level.
Failure of the normal clotting mechanisms may result from a reduction
in the number of platelets or from a deficiency of one of the clotting factors
Bleeding disorders or failure of coagulation may result from defects in any of the factors that are involved in the normal process of hemostasis, i.e. platelets, clotting factors, or vascular integrity. These will be considered briefly in turn.
Thrombocytopenia is a decrease in the number of circulating platelets. The depletion of platelets must be relatively severe before problems with clotting are seen. Hemorrhagic tendencies become evident when the platelet count falls to around
13.9 Blood transfusions and the ABO system of blood groups
20 X 109 I"1 as compared with the normal 150-300 X 109 H. Characteristics of the condition include the appearance of bruised areas and tiny reddish spots on the arms and legs (petechiae), and bleeding from the mucous membranes of the nose, mouth, and gastrointestinal tract.
Certain drugs as well as pathological states can result in thrombocytopenia. Aplastic anemia (where bone marrow function is impaired) or invasion of the bone matrow by malignant cells—as in leukemia—results in decreased production of platelets.
In addition to a reduction in platelet numbers, impairment of the clotting process may result from a deficiency of platelet function—thrombocytopathia. Such a defect may be inherited, as with the disorder of platelet adhesion known as von Willebrand's disease, or acquired following disease or drug treatment.
Hereditary disorders of blood clotting— the hemophilias
As may be deduced from the cascade mechanism of clotting illustrated in Fig. 13-11, impairment of blood coagulation can result from deficiencies in one or more of the clotting factors involved. Such disorders may be inherited or may arise from a reduction in synthesis of one or more of the clotting factors.
Although there are known to be hereditary defects associated with each of the clotting factors, most are extremely rare. By far the most common fotms of hemophilia, each affecting 1 in 10 000 males, are Factor VIII deficiencies and von Willebrand's disease (in which there is a loss of Factor VIII associated with a loss of platelet adhesion).
Hemophilia is a sex-linked recessive trait primarily affecting males, although many cases are thought to arise as new mutations. The disease may be mild or severe in form. In severe cases, spontaneous bleeding into soft tissues, joints, and the gastrointestinal tract occurs and can lead to serious disability. In such cases, Factor VIII replacement therapy is essential. Recent advances in recombi-nant DNA technology have enabled pure Factor VIII to be produced, thereby eliminating the risk of disease transmission from Factor VIII extracted from donated blood.
Impaired synthesis of clotting factors
Prothrombin, fibrinogen, and Factots V, VII, IX, X, XI, and XII are all synthesized in the liver. Furthetmore, the activity of Factors VII, IX, and X, and prothrombin requires the presence of vitamin K. Vitamin К deficiency or liver disease may therefore result in a loss of factors or a loss of activity. Either of these will produce impairment of the clotting mechanism, with abnormal bleeding.
Abnormal bleeding may occur from vessels that are structurally weak or that have been damaged by inflammation or immune responses. Examples include vitamin С deficiency (scurvy) in
which the vessels become ffagile due to a lack of adhesion between the endothelial cells, and Cushing's disease, in which the excess corticosteroid hormones cause a loss of protein and reduction in support for the vascular tissue.
13.9 Blood transfusions and the ABO system of blood groups
Early attempts to restore heavy loss of blood by transfusion of blood from another person were frequently disastrous. The transfused cells aggregated together in clumps which were sufficiently large to block minor blood vessels. This clumping is known as agglutination. Following the agglutination reaction, the red cell membranes broke down and hemoglobin was liberated into the plasma (this is known as hemolysis). The liberated hemoglobin was converted to bilirubin by the liver and this resulted in jaundice (yellowish skin coloration). In addition, the high plasma levels of bilirubin adversely affected urine production by the kidney. When such clinical signs follow the transfusion of blood the transfused blood is said to be incompatible with that of the recipient. Death frequently occurred as a result of the transfusion of incompatible blood.
13 The properties of blood
Fig. 13.12 The agglutination reaction of incompatible blood types. Drops of anti-A and anti-B serum are placed in shallow wells on a porcelain plate as shown in the figure. A drop of the test sample of blood is added to each well and mixed. If the blood is compatible, the mixed blood sample appears uniform bur, if the blood is incomparible with the serum, it aggregates and precipitates as shown.
What is the basis of this incompatibility and why is some blood compatible while other blood is not? It is now known that agglutination results from an antibody—antigen interaction. Normal human plasma (and the corresponding serum) may contain antibodies that cause red cells to stick together in large clumps (i.e. ro agglutinate; Fig. 13.12). The antibodies that cause the reaction are known as agglutinins. Unlike most other antibodies, the agglutinins have not arisen as a result of a specific antibody reaction. They occur naturally and are inherited by mendelian laws. Clearly, if red cells agglutinate in response to a particular kind of plasma or serum, they must possess the corresponding antigen, which is known as an agglutinogen.
To account for the known cross-reactivity of blood from different people, Landsteiner proposed that two kinds of agglutinogen are present on human red cells. These agglutinogens are called A and В and they may be present separately, together, or be completely absent, so giving rise to four groups: А, В, АВ and О (Table 13.5). In addition, human plasma may contain antibodies to one or both agglutinogens. The plasma antibodies are known as anti-A and anti-B or as agglutinins a and /3. Where the blood contains red cells with a particular agglutinogen, the corresponding agglutinin is absent from the plasma. Thus people with agglutinogen A on their red cells do not have anti-A in their plasma as they do not agglutinate their own blood. Nevertheless, this group of people do have anti-B in rheir plasma. Conversely, group В have agglutinogen В on their red cells but anti-A in their plasma. Group AB have both agglutinogens A and В on their red cells but no agglutinins in their plasma and group О have neither agglutinogen but both anti-A and anti-B agglutinins. Table 13.5 gives the relationships between the different groups and their approximate frequency of occurrence in the general population of the United Kingdom and United Sates.
The rhesus blood group system
In 1940 Landsteiner and Wiener found that the serum of rabbits that had been immunized against the blood of rhesus monkeys could agglutinate human blood. Using this antibody they identified two groups in rhe general population. Those whose blood could be agglutinated by this serum, now known as rhesus (or Rh) positive (about 85 per cent of the population), and those whose blood could not be agglutinated—Rh-negative. Rh-positive persons have a specific antigen on their red cells known as the D-antigen (also known as the rhesus factor).
Since the D-antigen is inherited like the AB agglutinogens, anti-Rh antibody can occur in the serum of Rh-negative mothers who have had Rh-positive children. During pregnancy a Rh-negative mother may form anti-Rh antibodies in response to the leakage of fetal red cells into her circulation. This immunization of the mother by the baby's red cells may occur at any time during pregnancy but is most likely to occur when the placenta is separating from the wall of the uterus while the mother is giving birth. For this reason anti-Rh antibodies generally arise
after the first or second pregnancy. The anti-Rh antibodies are IgG antibodies of about 150 kDa and are sufficiently small to pass across the placenta into the fetal circulation. If this happens, they may cause a severe agglutination reaction. The resulting disorder is known as hemolytic disease of the newborn and, in the absence of suitable preventative measures, it occurs about 1 in every 160 births. As indicated above, this problem usually arises during a woman's second or third pregnancy. About half of the affected babies will require a partial replacement of their blood by transfusion. This problem can be avoided by injecting Rhesus negative mothers with anti-D immunoglobulin immediately after delivery. This neutralizes any Rhesus positive fetal red cells that may be present in the maternal circulation.
Although hemolytic disease can occur as a result of an anti-A antibody in the blood of group О mothers, ABO blood group incompatibility generally causes no problems during pregnancy. This reflects the fact that the plasma agglutinins are IgM antibodies of high molecular weight (about 900 kDa) and proteins of this size do not readily cross the placenta.
Other blood group types
The blood group antigens (agglutinogens) are found on the surface of the red cell membrane and many kinds of antigen have been discovered in addition to the fundamental ABO system. For example, soon after the original description of the ABO system of blood groups it was discovered that group A could be further subdivided into two groups: Al and A2. Other blood groups such as the M, N, P, and Lewis groups are also known. Nevertheless, the Aj and A2 subdivisions and other blood groups are not generally of significance in blood transfusion.
Blood must be cross-matched for safe transfusions
To prevent the problems of blood group incompatibility, blood for transfusion is cross-matched to that of the recipient. In this process, serum from the recipient is tested against the donor's cells. If there is no reaction to the cross-match test, the transfusion will be safe. Note that this test screens for all serum agglutinins and not just those of the ABO system. Although correct matching of blood groups of both donor and recipient is preferable, in emergencies group О blood can be transfused into people of other groups because group О red cells have neither A nor В antigens. For this reason a group О person is sometimes called a universal donor. As the plasma of group AB has neither anti-A nor anti-B antibodies other blood groups can be transfused into a group AB patient. Such a patient is known as a universal recipient. The plasma agglutinins present in the blood of a donor do not generally cause adverse reactions because they become diluted in the recipient's circulation.
Biochemistry of hemoglobin and myoglobin
Stryer, L. (1995). Biochemistry, (4th edn), Chapter 7, pp. 147-180. Freeman, New York.
Hematopoesis and histology
Alberts, В., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson, J. D. (1989). Molecular biology of the cell, (3rd edn), Chaptet 22, pp. 1161-75. Garland, New York.
Junquieira, L. C, Carneiro, J., and Kelley, R. O. (1995). Basic histology, (8th edn), Chaptets 12 and 13. Prentice-Hall, London.
Physiology of gas transport
Levitzky, M. G. (1991). Pulmonary physiology, (3rd edn), Chapter 7. McGtaw-Hill, New York.
Pharmacology of the blood
Rang H. P., Dale, M. M., and Ritter, J. M. (1995). Pharmacology, (3rd edn), Chapters 16 and 23. Chutchill-Livingstone, Edinburgh.
Hematology and immunology
Austyn, J. M. and Wood, K. J. (1993). Principles of cellular and molecular immunology, Chapter 1. Oxford University Press, Oxford.
Hoffbrand, A. V. and Pettit, J. E. (1993). Essential hematology, (3rd edn). Blackwell Scientific, Oxford.
Linen, D. C. (1997). Hematological disordets. In Textbook of medicine, (3rd edn), (ed. R. L. Souhami and J. Moxham), Chaptet 25. Churchill-Livingstone, Edinburgh.
Each statement is either true or false. The answers are given below.
1. The plasma of a normal adult:
a. Accounts for 10 per cent of body weight;
b. Has an osmolality of about 290 mOsm kg"1;
с Has about I40mmoles I"1 of sodium;
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