The Blood

I. plasma - liquid portion

A. mostly water with dissolved substances:

electrolytes, gases (O₂, CO₂), nutrients, wastes, regulatory molecules.

B. Plasma proteins:

1) albumin - the most abundant protein (~65%), responsible for blood osmolarity and viscosity.

2) fibrinogens or clotting proteins - prothrombin, fibrinogen and others.

3) globulins - found as antibodies, as well as storage and transport proteins

Albumin and the clotting proteins are made by the liver, as are some transport proteins. Some storage or transport proteins are made by other cells such as in the thyroid. Antibodies are produced by lymphocytes.

II. The formed elements: these are blood cells and cell derivatives. All the formed elements are originally derived from a pleuripotential (multiple potential) stem cell known as a hemocytoblast. These cells are derived from mesenchyme cells which give rise to other types of connective tissue as well. Pleuripotential stem cells are also known as colony forming units (CFU) because their presence in marrow and other locations permits the formation of all types of blood cells.

A. erythrocytes - red blood cells, carry hemoglobin and certain other substances, 5 to 6 X 10⁶/mm³.

B. leucocytes (also leukocytes) - white blood cells, part of defense and immune mechanisms, 5 to 10 X 10³/mm³.

C. thrombocytes - platelets, instrumental in the intrinsic blood clotting pathway, 150 to 200 X 10³ /mm³.

Biconcave disks whose shape optimizes both volume and surface area.

They have no nuclei or other organelles and only rudimentary enzyme systems. But they do produce certain substances of importance, for example carbonic anhydrase. RBCs carry hemoglobin which carries oxygen and carbon dioxide.

 See also:

Hb + O₂ <-----> HbO₂. (Deoxyhemoglobin + oxygen yields oxyhemoglobin in a reversible reaction. The reaction goes left to right in the lungs where oxygen is in abundance from respiration. The reaction goes from right to left in the systemic tissues where oxygen is being constantly used by cells. If all iron atoms on all hemoglobin molecules were carrying oxygen we would say hemoglobin is 100% saturated. In oxygenated blood at sea level hemoglobin is about 98% saturated.

98% of oxygen is transported attached to the iron in hemoglobin.

2% is dissolved as a gas in the plasma.

Iron will also bind to carbon monoxide (CO) in competition with oxygen. The strength of the bond with CO (called carboxyhemoglobin) is about 10 times that of the bond with oxygen. CO comes from polluted air resulting from incomplete combustion such as autos, woodstoves, etc. Removal of CO requires breathing clean air, or high concentration oxygen, or being placed in a hyperbaric (high pressure) chamber of pure oxygen.

7% of CO2 is carried dissolved in the plasma.

23% is carried attached to globin - carbaminohemoglobin.

70% is carried as a result of the following chemical reaction:

CO₂ + H₂O <---> H₂CO₃(carbonic acid) <---> H⁺ + HCO₃^-

The reaction of carbon dioxide with water requires carbonic anhydrase, an enzyme in the red blood cell. Carbonic acid is a weak acid and partially dissociates into hydrogen and bicarbonate ions. The reaction goes from left to right in the systemic tissues where carbon dioxide is produced, and right to left in the lungs where it is eliminated through respiration. Because the concentration of hydrogen ions (H⁺) fluctuates the pH decreases slightly in the tissues and increases slightly in the lungs. The pH range of blood is 7.35 to 7.45 and is maintained by the buffering action of the dissociation products of H₂CO₃ as well as by the blood's protein buffers.

RBCs enter the blood at a rate of about 2 million cells per second. The stimulus for erythropoiesis is the hormone erythropoietin, secreted mostly by the kidney. RBCs require Vitamin B12, folic acid, and iron. The lifespan of RBC averages 120 days. Aged and damaged red cells are disposed of in the spleen and liver by macrophages. The globin is digested and the amino acids released into the blood for protein manufacture; the heme is toxic and cannot be reused, so it is made into bilirubin and removed from the blood by the liver to be excreted in the bile. The red bile pigment bilirubin oxidizes into the green pigment biliverdin and together they give bile and feces their characteristic color. Iron is picked up by a globulin protein (apotransferrin) to be transported as transferrin and then stored, mostly in the liver, as hemosiderin or ferritin. Ferritin is short term iron storage in constant equilibrium with plasma iron carried by transferrin. Hemosiderin is long term iron storage, forming dense granules visible in liver and other cells which are difficult for the body to mobilize.

Some iron is lost from the blood due to hemorrhage, menstruation, etc. and must be replaced from the diet. On average men need to replace about 1 mg of iron per day, women need 2 mg. Apotransferrin (transferrin without the iron) is present in GI lining cells and is also released in the bile. It picks up iron from the GI tract and stimulates receptors on the lining cells which absorb it by pinocytosis. Once through the mucosal cell iron is carried in blood as transferrin to the liver and marrow. Iron leaves the transferrin molecule to bind to ferritin in these tissues. Most excess iron will not be absorbed due to saturation of ferritin, reduction of apotransferrin, and an inhibitory process in the lining tissue.

Leucocytes are produced in two cell lines: those from the marrow, the myeloid cells, and those from the lymph tissue. Myeloid cells include the following:

1) granulocytes - these cells have observable granules in their cytoplasm. Their origin is the myeloid tissue in the red bone marrow. The granules contain digestive enzymes and all the granulocytes can act as phagocytes.

a) neutrophils - the most numerous wbc, making up about 65% of normal white count. These cells are the most important phagocytic cell in the circulation. Also called PMN (polymorphonuclear) neutrophils because of their nuclear shape. These cells spend 8 to 10 days in the circulation making their way to sites of infection etc. where they engulf bacteria, viruses, infected cells, debris and the like. They have two types of granules: the most numerous are specific granules which contain bactericidal agents such as lysozyme; the azurophilic granules are lysosomes containing peroxidase and other enzymes.

b) basophils- rare except during infections where these cells mediate inflammation by secreting histamine and heparan sulfate (related to the anticoagulant heparin). Histamine makes blood vessels permeable and heparin inhibits blood clotting. Basophils are functionally related to mast cells. 

c) eosinophils - also rare except during allergic reactions, these cells counteract the action of the basophils by secreting an anti-histamine (histaminase) and other enzymes which combat inflammation in allergies, they help to remove antigen-antibody complexes, and also are high during defense against multicellular parasites.

2) agranulocytes - (a.k.a. mononuclear leucocytes) these cells have no observable granules.

a) monocytes - also originate in marrow, spend up to 20 days in the circulation, then travel to the tissues where they become macrophages. Macrophages are the most important phagocyte outside the circulation. Monocytes are about 9% of normal wbc count.

The following are the lymphoid cells:

b) lymphocytes - about 25% of wbc, these cells come in B and T cell types (see Immune System Notes) and are responsible for the specific immune response. Lymphocytes acquire immunocompetence in the thymus and other areas and subsequently proliferate by cloning in the lymph nodes. They circulate between the lymph, circulation, lymph and back again for long periods of time. [Small Lymphocyte] [Large Lymphocyte]

Thrombocytes are cellular derivatives from megakaryocytes which contain factors responsible for the intrinsic clotting mechanism. They represent fragmented cells (See Figure 17.12) which contain residual organelles including rough endoplasmic reticulum and Golgi apparati. They are only 2-microns in diameter, are seen in peripheral blood either singly or, often, in clusters, and have a lifespan of 10 days.

Hemostasis - the "stopping of the blood". Triggered by a ruptured vessel wall it occurs in several steps: (See Figure 17.13).

1) vascular spasm - most vessels will constrict strongly when their walls are damaged. This accounts for individuals not bleeding to death even when limbs are crushed. It also can help to enhance blood clotting in less severe injuries.

2) platelet plug - platelets become sticky when they contact collagen, a protein in the basement membrane of the endothelium exposed when the vessel wall is ruptured. As they stick together they can form a plug which will stem the flow of blood in minor vessels.

3) Formation of the Blood Clot:

A) release of platelet factors - as platelets stick together and to the vascular wall some are ruptured releasing chemicals such as thromboxane, PF3, ADP and other substances. These become prothrombin activators (see below). Thromboxane also makes the platelets even stickier, and increases the vascular constriction. These reactions are self perpetuating and become a cascade which represents a positive feedback mechanism.

B) prothrombin activators (the chemicals above plus collagen, See Figure 18.13) cause the following reaction: prothrombin (already in the blood) is split into smaller products including thrombin, an active protease.

C) thrombin splits soluble fibrinogen, already present in the plasma, into monomers which then polymerize to produce insoluble fibrin threads. The fibrin threads weave the platelets and other cells together to form the actual clot. This occurs within four to six minutes when the injury is severe and up to 15 minutes when it is not. After 15 minutes the clot begins to retract as the fibrin threads contract, pulling the broken edges of the injury together and smoothing the surface of the clot causing the chemical processes to cease. Eventually the clot will dissolve due to enzymes such as plasmin also present in the blood.

The extrinsic pathway: when tissues are damaged the damaged cells release substances called tissue thromboplastin which also acts as a prothrombin activator. This enhances and speeds coagulation when tissue damage is involved.

Anti-thrombin III - this factor helps to prevent clotting when no trigger is present by removing any thrombin present. Its function is magnified many times when heparin is present. Therefore heparin is used clinically as a short-term anticoagulant.

Vitamin K - stimulates the production of clotting factors including prothrombin and fibrinogen in the liver. This vitamin is normally produced by bacteria in the colon. Coumarin (or coumadin) competes with Vitamin K in the liver and is used clinically for long-term suppression of clotting.

Several factors important to clotting are known to be absent in forms of hemophilia. These factors are produced by specific genes which are mutated in the deficient forms. The factors are (see Table 17.3) VIII, IX, and XI.

Calcium is necessary for blood clotting and its removal from the blood by complexing with citrate will prevent the blood from clotting during storage.