Blood S-J Tsai Department of Physiology

Composition Composed of cells (erythrocytes, leukocytes, and platelets) and plasma (the liquid in which the cells are suspended).cells The total blood volume of an average person is about 7% of his/her body weight.

Plasma and Serum Plasma contains proteins (albumins, globulins, and fibrinogen), nutrients, metabolic end products, hormones, and mineral electrolytes. Plasma proteins, unlike other plasma constituents, normally are not taken up by cells. Serum is plasma from which fibrinogen and other coagulation proteins have been removed as a result of clotting. Table 14-1 lists the constituents of plasma.

Erythrocytes(I) Make up more than 99% of blood cells (5,000,000/mm 3 ) Contain hemoglobin, an oxygen-binding protein consisting of heme and globin. Each hemoglobin molecule is made up of four subunits and each subunit has an iron- containing molecule group, heme. Each of the four heme groups in a hemoglobin molecule can bind one molecule of oxygen

Erythrocytes (II) Produced in the bone marrow and enter the blood when mature (losing their nuclei). Destroyed in the spleen and liver with an average life span approximately 120 days. The major breakdown product of heme is bilirubin, which gives plasma its color.

Iron Balance Iron, folic acid, and vitamin B12 are essential for erythrocyte formation.

Leukocytes & Platelets Leukocytes & Platelets Leukocytes (7,000/mm 3 ) include polymorphonuclear granulocytes (neutrophils, eosinophils, and basophils), monocytes, and lymphocytes. Essential for defenses against foreign matter. Platelets (250,000/mm 3 ) fragments from megakaryocytes. Essential for blood clotting.

Major hematopoietic factors Erythropoietin: erythrocytes Colony-stimulating factors (CSFs): granulocytes and monocytes Interleukins: various leukocytes Thrombopoietin: Platelets (from megakaryocytes) Stem cell factor: many blood-cell types

Regulation of blood cell production Erythopoietin is produced by the kidneys in response to low O 2 supply, stimulates erythrocyte differentiation and production by the bone marrow.

Major Causes of Anemia Dietary deficiencies of iron (iron-deficiency anemia), VitB12, or folic acid Bone marrow failure due to toxic drugs or cancer Blood loss from the body (hemorrhage) leading to iron deficiency Inadequate secretion of erythropoietin in kidney disease Excessive destruction of erythrocytes (sickle- cell anemia)

Hemostasis (elimination of bleeding ) Most effective in dealing with injuries in small vessels Initial response: vasoconstriction and the sticking together of the opposed endothelial surfaces. This process may be initiated by injured vascular cells. The other early event is formation of a platelet plug followed by blood coagulation (clotting).

Formation of a Platelet Plug Platelets adhere to exposed collagen in a damaged vessel and release the procoagulant contents of their secretory vesicles (granules). These released substances help cause platelet aggregation, which uses fibrinogen as the bridge molecule between platelets. These processes are also enhanced by von Willebrand factor (secreted by activated endothelial cells) and by thromboxane A2 (produced by activated platelets).

Formation of a Platelet Plug

Prostaglandin and Nitroc Oxide The platelet plug does not spread along normal endothelium because the latter secretes prostacyclin (PGI 2 ) and nitric oxide (NO), both of which inhibit platelet activation

Blood Coagulation: Clot Formation Blood is transformed into a solid gel when, at the site of vessel damage, plasma fibrinogen is converted into fibrin molecules, which bind to each other to form a mesh. This reaction is catalyzed by the enzyme thrombin, which also activates factor XIII, a plasma protein that stabilizes the fibrin meshwork.

Blood Coagulation

Clotting Pathway In the body, the cascade usually begins via the extrinsic clotting pathway when tissue factor from cells in injured tissue forms a complex with factor VIIa. This complex activates factor X, which then catalyzes the conversion of small amounts of prothrombin to thrombin. This thrombin then recruits the intrinsic pathway by activating factor XI and factor VIII, as well as platelets, and this pathway generates large amounts of thrombin.

Clotting Pathway

Anticlotting Systems Clotting is limited by three events: –1) Tissue factor pathway inhibitor inhibits the tissue-factor VIIa complex; –2) protein C, activated by thrombin, inactivates factors VIIIa and Va; and –3) antithrombin III, a heparin-binding protein, inactivates thrombin and several other clotting factors. Clots are dissolved by the

Fibrinolytic System Tissue plasminogen activator is secreted by endothelial cells and is activated by fibrin in a clot. Plasminogen activator Plasminogen Plasmin Fibrin Soluble fibrin fragments

Anticlotting roles of endothelial cells Synthesize and release PGI 2 and NO to inhibit platelet activation; Bind thrombin, which then activates protein C to inactivate clotting factors VIIIa and Va; Display heparin molecules on their surfaces to activate antithrombin III which inhibits thrombin; Synthesize and secrete tissue plasminogen activator to catalyze the formation of plasmin, the clot-dissolving enzyme.

Anticlotting Drugs Aspirin inhibits the cyclooxygenase enzyme in the eicosanoid pathways that generate prostaglandins and thromboxanes. Low doses of aspirin may inhibit platelet COX but not endothelial COX. Oral anticoagulants interfere with the action of vitamin K, which is required for liver synthesis of clotting factors. Heparin, the naturally occurring endothelial- cell cofactor for antithrombin III, can be administered as a drug. Plasminogen activators are often used to dissolve clots after they are formed.

Blood Cells

Regulation of blood cell production