XVI.  Blood

 

The blood is the first part of the cardiovascular or circulatory system that will be considered.  In addition to the blood, the cardiovascular system consists of the heart and the blood vessels.  The heart causes the blood to circulate and the blood vessels conduct it to all parts of the body.  The continuous circulation of blood is essential for life.  When the heart stops, life ceases, not because of the failed heart, but because the blood is no longer supplying the tissues.  Blood is therefore, the functional part of the cardiovascular system.

 

A.  Functions of Blood ‑ Blood is considered to be a liquid connective tissue.  Its major functions include the following.

 

    l.  Transport ‑  The blood is the major highway for getting material to and from the cells.  These materials include

 

        a.  respiratory gases.

        b.  nutrients ‑ organic and inorganic.

        c.  wastes.

        d.  hormones and enzymes.

 

    2.  Water balance ‑ There  exists a dynamic balance between water in the blood and water in the cells and extracellular fluids.

 

    3.  Protection ‑ Many of the cells and substances found in the blood play a role in the protection of the body from foreign invasion.

 

    4.  Homeostasis ‑   Although the first three functions actually fall into this category, we are here concerned with chemical and physical regulation of the internal environment.

 

        a.  Chemical ‑ pH ‑ acid‑base balance.

        b.  Physical ‑ heat distribution.

 

B.  Blood  volumes    The total blood volume in males is about 5  ‑ 6 in males and 4 to 5 liters in females.   This represents about 67

    ml  per  kilogram of body weight in females and 75ml/kg in  males. The  reason  for  the lower ratio in females is that they have  a higher proportion of fat which is generally low in vascularization. About l0% of the total volume (l/2 liter) can be donated without harm.  A greater loss can prove fatal.  Blood volumes are regulated by complex  physiological processes which will be discussed later.

 

C.  Composition  of  blood ‑ Whole blood is composed of two 

    fractions,plasma,  which  is  the liquid portion,  and the formed elements or  cellular  component.   Normal  blood consists of  approximately 45%  formed elements and 55% plasma.

 

    l.  Plasma    This  is equal to the whole blood minus  the 

        formed elements.  The composition of plasma is as follows.

 

        a.  Water ‑ 90%

        b. Plasma  proteins ‑ These constitute 6 to 8%.   They are  the largest group of dissolved substances.  Fully 90% of the plasma proteins are produced by the liver. The principal groups  include

 

            (l) albumin  ‑ Increases the osmotic pressure of the 

               blood  and plays a role in water balance. These are the most abundant plasma proteins constituting 60% of the total amount.

            (2) globulins    There are two major categories here, the transport globulins which bind and transport other ions and molecules (alpha and beta globulins, and the antibodies (gamma globulins)which  play a  role in defense.

            (3) Fibrinogen ‑ This is the clotting protein.

            (4) Assorted enzymes and hormones.

 

        c.  Glucose (blood sugar) ‑ 0.1%

        d.  Amino and fatty acids.

        e.  Electrolytes ‑ Na, K, Cl, Ca, Mg, P04, etc.

        f.  Waste products ‑ Urea.

        g.  Dissolved gases ‑ 02, C02. N2.

 

    2.  Formed  elements    There are three  major  classes  of 

        formed elements,  erythrocytes  (red cells),  leukocytes    (white         cells), and thrombocytes (platelets).

 

        a.  Hemopoiesis ‑ This is the formation of blood cells. 

            Prior to  birth formed elements are produced by many tissues including the spleen, liver, thymus, bone marrow, and lymph nodes.  After birth, the source is the red bone marrow (myeloid tissue).  All of the formed elements have their origin from a primitive stem cell known  as a hemocytoblast. These cells give rise to the following types  of cells which in turn form the formed elements.

 

            (l) Proerythroblast ‑ Form red cells.

 

            (2) Myeloblasts ‑ Give rise to three types of leukocytes  known as granulocytes.

 

            (3) Lymphoblasts ‑ Give rise to a white cell known as a 

                lymphocyte.

 

            (4) Monoblasts ‑ Form a white cell known as a monocyte.

 

            (5) Megakaryoblasts  ‑ Give rise to cell fragments known

               as  platelets.

 

        b.  Erythrocytes ‑ These are the most abundant of the formed 

            elements.  It is the erythrocytes which give blood its color.  In males there are typically 4.5 to 6.3 million RBC per cubic millimeter of blood.  In females the numbers range from 4.2 to 5.5 million per cu mm.  Erythrocytes have the following general properties.

 

            (l) The shape is a biconcave disk.

            (2) They are very uniform in size, 7.5 ‑ 8.0 microns in 

                diameter.

            (3) Adult cells have no nucleus (anucleate).

            (4) The cells are flexible and elastic.  They can fold

               over  and therefore can squeeze through blood vessels

               which are smaller than their normal diameter.

            (5) The average life span is l15 days.

            (6) Red cells function to carry oxygen.  It is the red 

                pigment hemoglobin which actually combines with the 

                oxygen. Red cells are essentially sacs of hemoglobin.

            (7) Because red cells function to carry oxygen for other tissues, they lack mitochondria and therefore must  rely on anaerobic metabolism.  This keeps them from stealing oxygen for their own use.

            (8) The percentage of red cells in the blood is known as

                the hematocrit.  It is normally 46% in males and 

                42% in females.

 

        c.  Formation and regulation of red cells volumes.

 

            (l) Erythropoiesis (formation of red cells) ‑ The bone 

                marrow stem cell (hemocytoblast) differentiates into a  cell call the proerythroblast.  Hemoglobin synthesis   begins and the proerythroblast transforms into a cell  known as an erythroblast (normoblast).  When hemoglobin content reaches 34% the erythroblast extrudes its nucleus and becomes a reticulocyte.  It is in this form that it is released  into the general circulation. Within about l to 2 days  the reticulocytes become mature red blood cells. 

 

            (2) Control of erythropoiesis ‑ They kidneys produce a   glycoprotein known as erythropoietin (EPO).  This stimulates erythropoiesis by  the myeloid tissue.  Erythropoietin release in turn is regulated by  oxygen levels at the tissues. Decrease oxygen level stimulate erythropoietin release and hence increased red cell levels.  Male sex hormones seem to stimulate erythropoietin production while female hormones seem to depress it.  This is one reason that males have higher hematocrits than females.

 

            (3) Destruction of red cells ‑ Red cells circulate an     average of l20 days in males and l09 in females.  Worn and damaged cells are disposed of by special white cells known as macrophages.  These macrophages line certain vascular channels, especially those of the liver and spleen. Hemoglobin is broken down and the iron released.  The remainder is converted into a pigment known as biliverdin  which in turn is converted into bilirubin.   Bilirubin is absorbed from the plasma by the liver excreted into the intestinal tract with the liver bile.  Much of the iron is recycled. 

 

               (a) Because too much free iron is toxic, iron is usually bound to transport and storage proteins.  In the plasma it is bound to the protein known as transferin.

 

               (b) When transferin iron complexes become too high in the plasma, they are removed by the bone marrow and liver and the iron is stored bound to two proteins known as ferritin and hemosiderin.  This is why nutritionists consider liver to be  such a good source of iron in the diet.

 

         d.  Clinical conditions involving erythrocytes.

 

            (l) Anemia ‑ This is an abnormality which results when 

                there are decreased amounts of hemoglobin available

                for oxygen transport.  It may be due to

 

               (a) Low RBC counts.

               

               (b) Reduced amounts of hemoglobin per cell.

               

               (c) Reduced amounts of whole blood.

 

                There are several different types of anemia.

 

                (a) Hemorrhagic ‑ due to loss of whole blood.    

                (b) Nutritional ‑ Iron deficiency in diet.

                (c) Hemolytic ‑ Here the rate of red cell

                   destruction is increased due to fragile or defective cells.  Sickle cell anemia is of this type.

                (d) Pernicious ‑ This is due to an inability to

                   absorb  vitamin B12, a necessary maturation factor for RBCs.

                (e) Aplastic ‑ This is due to a shutdown of the red

                    marrow.  It can be caused by radiation, 

                  antibiotics, and toxic chemicals.

 

            (2) Polycythemia ‑  This is an over production of red cells leading to elevated hematocrits.  Primary

               polycythemia  is usually due to myeloid tumors.  Secondary polycythemia is due to an over production of erythropoietin.  This is frequently physiological in

                nature, be brought about by chronic exposure to

               reduced oxygen levels such as exist at high altitudes.

 

        e.  Leukocytes ‑ These cells are present in far fewer numbers   than are red cells.  A healthy white count will show 5 to l0 thousand white cells per cu mm of blood.  During disease the white count rises as all white cells play a role in body  defense.  All leukocytes are ameboid cells.  They can move around and are found in the circulation and in the tissues. Some are phagocytic while others produce antibodies against foreign substances.  There are two major classes of white cells and a total of 5 different white cells in these  groups.

 

            (l) Granular leukocytes ‑ These are characterized by 

                granules in their cytoplasm which stain heavily. 

               They are formed in the red bone marrow from myeloblasts.

 

               (a) Neutrophils ‑ These are the most abundant of

                   the  leukocytes constituting 60 to 70% of the total white cell count.  Because of their variable  multilobed nuclei they are sometimes called polymorphonuclear cells or PMN's.  They are active phagocytic cells which can leave the circulation and congregate in the tissues at the sites of  infection where they phagocytize foreign  materials.

 

                (b) Eosinophils ‑ These constitute  2 ‑ 4% of the      white cells.  They have a reddish color when 

                    stained and exhibit a pronounced bilobed

                   nucleus.  Eosinophils target objects that have been coated by antibodies.  While they are phagocytic, they primarily attack by  releasing toxic compounds such as NO and enzymes on to the target objects.  They are important in defense against large multicellular parasites such as worms.  They also rise during allergic responses.

 

                (c) Basophils ‑ These constitute 0.5% of the total 

                    white cells.  They stain very heavily.  These 

                    release vasoactive substances such as histamine

                    and heparin.  These substances can alter blood 

                    flow.

 

            (2) Agranular leukocytes ‑ These cells lack large secretory granules and have nuclei which are either round or indented.While these cells initially form in the bone marrow from lymphoblasts and monoblasts, they can secondarily  divide and proliferate in the lymphoid tissues  throughout the body.

 

                (a) Lymphocytes ‑ These constitutes 20 to 25% of

                   the  total white cells and therefore are the second most abundant white cell.  Lymphocytes function in immune reactions.

 

                (b) Monocytes ‑ These account for 2 to 6% of the

                   total white cells.  They form in the bone marrow and then leave circulation where they become 

                     macrophages, large phagocytic cells that

                   cleanse  the tissues of microorganisms and other

                   materials.

 

        f.  Clinical aspects involving white cells.

 

            (1) Leucocytosis - This refers to a white count above normal healthy levels.  A moderate leucotyosis normally occurs during infection.

           

            (l) Leukemia ‑ This results in a highly elevated white     counts (100,000 or more).  It is due to cancer of either the myeloid  tissue or lymphoid tissue.

 

            (2) Leukopenia ‑ This is a reduction in white cell

               count.  It may be due to exposure to radiation or chemical agents.  Individuals suffering from these disease are very liable to infection.

       

        g.  Control of leukocyte production

 

            (1) Leukocyte production is controlled by hormones known as colony stimulating factors (CSF)).

 

            (2) Most CSFs are produced by macrophages and T-lymphocytes.

 

            (3) Production of CSFs are tied to infection and other defense responses of the body which will be discussed later.

 

            (4) Granulocyte production and maturation occurs completely in the bone marrow (myeloid tissue).  The life span of granulocytes is about one half to nine days.  Granulocytes are stored in the bone marrow which usually contains 10 to 20 times the number which are found in the blood.

 

            (5) Prolymphocytes leave the bone marrow and travel to the lymphoid tissues where final maturation occurs.  Lymphocytes live anywhere from a few days to decades. 

           

            (6) Monocytes begin maturation in the bone marrow,  enter the circulation, and then complete development when they become free macrophages in the tissues.

 

        h.  Thrombocytes (platelets) ‑ These are cell fragments which

            are derived from megakaryocytes.  There are normally 250

            to 400 thousand platelets per cu mm.  They function in blood clotting. Platelet production is stimulated by Thrombopoietin (TP0), a protein hormone produced by the kidneys.  Several other factors also stimulate platelet production.

 

D.  Hemostasis ‑ This is the prevention of loss of blood from the 

    circulatory system.  It involves several different processes.

 

    1.  Vascular spasm ‑ This is a localized  vasoconstriction

        upstream  from the vessel break.  It results in a reduction of flow to the torn area. During the vascular spasm, change occur in the endothelium that lines the blood vessel.  Endothelial cells release a number of chemical factors that promote the spasm and initiate the next phases of the hemostasis process.

 

    2.  Formation of platelet plug ‑ At the site of damage platelets    begin to aggregate.  Under the influence of ADP they become     swollen, sprout long sticky projections, and stick together.    They also release substances which attract other platelets to   the growing pile.  Layers build up forming a plug.  This process seals small tears that occur during daily activities and trigger coagulation. 

 

        a.  Platelets also release a number of factors involved in promoting hemostasis. Some such as serotonin promote continued vasoconstriction. Others such as Thromboxane A2 and calcium promote further aggregation of platelets.  Still others, procoagulants, are important in the clotting process.  Finally, platelets release platelet-derived growth factor (PDGF).  This peptide promotes vascular repair.  It stimulates division of the epithelial cells, smooth muscle cells, and fibroblasts.

 

    3.  Clot formation ‑  This is an extremely complex process involving eleven different proteins (procoagulants) and calcium that react with one another in a cascading fashion.  There are two variations on the process which are activated by different triggers.

 

        a. Extrinsic mechanism ‑ This is activated by tears in

            vessels or tissue damage.  Damaged cells release  tissue factor (TF).  Tissue factor reacts with calcium and another procoagulant to form an enzyme known as tissue thromboplastin which activates factor X.  Activated factor X along with other substances converts the plasma protein prothrombin into thrombin.  Thrombin is an active enzyme which converts soluble fibrinogen into insoluble fibrin.  Fibrin forms long sticky strands which traps cells and plasma forming a  gelatinous clot.

 

        b.  Intrinsic mechanism ‑ This begins when factor XII is 

            activated.  This activation does not require ruptured 

            vessels but can be initiated by roughness inside of the 

            vessel or exposure to underlying collagenous fibers found

            in the walls of blood vessels.  Activated factor XII plus  calcium and other factors derived from platelets combine to form  tissue thromboplastin which   will activate factor X and the pathway is then the same as in the extrinsic mechanism.

 

        Clotting has a positive feedback component which makes the process very rapid.  Thrombin when it forms not only stimulates formation of fibrin, but it also stimulates further formation of thromboplastin, thereby amplifying the process.

 

    4.  Clot retraction ‑ After the initial clot forms a contraction 

        process begins.  This is brought about by an actomyosin like 

        protein which is found in platelets trapped within the fibrin

        meshwork.  This pulls the edges of the tear together and

        makes the healing process more efficient.

 

    5.  Clot dissolution ‑ This is brought about by the enzyme

        plasmin. It forms from the plasma protein known as plasmogen. This is converted into active plasmin by substances released from the damaged cell.  Plasmin eventually dissolves the clot away.

 

    6.  Anticoagulants ‑ Clotting is normally prevented inside of 

        vessels by the following mechanisms.

 

        a.  The endothelium which lines the vessels is very smooth

            and in addition has a layer of negatively charged protein

            which repels clotting factors.

 

        b.  Antithrombin III, an antibody against thrombin,

            neutralizes small quantities of thrombin which may spontaneously form.

 

        c.  Heparin is a substance released by most cells, but 

            especially Mast cells and basophils.  This accelerates

            the activity of antithrombin III.  Outside of the body, as in blood banking, blood is prevented from clotting by adding chelating agents which sequester all of the calcium.  As calcium is essential to the clotting process this prevents the clotting process but does not adversely effect other components of the blood. Such an agent is  citratephosphate dextrose (CPD).

 

    7.  Intravascular clots ‑ It sometimes occurs that in spite of 

        safeguards, intravascular clots do form.  This is frequently

        due to damaged vessel lining.  An intravascular clot which does not  move is termed a thrombus.  A clot that breaks loose and begins to move is termed an embolus.  Intravascular clots can impede blood flow and can therefore prove dangerous. Intravascular clots may be treated by giving substances that convert plasminogen into plasmin which breaks down the clot.  Such substances include tissue plasminogen activator (t-PA), streptokinase, and urokinase.

 

E.  ABO blood groups ‑ Each individual has a genetically determined 

    blood type.  Different types cannot be usually be mixed because

    of an agglutination reaction which is a clumping of the cells.  This is  because the red blood cells have complex molecules on their membrane surface which are termed antigens.  These antigens will react with globulin protein molecules found in the plasma which are termed antibodies or immunoglobulins.  The antibodies act like glue, sticking to the antigens and clumping the red cells together.  There are four different ABO blood groups.

 

    l.  Blood types, antigens, and antibodies.

 

        Blood type        Surface Antigen        Antibody found in

                                                 plasma

 

        A                 A                      Anti B

 

        B                 B                      Anti A

 

        AB                A and B                neither

 

        O                 neither                Anti A and Anti B

 

    Note that it would be impossible for a person to have the same 

    antigen  and antibody as their blood would agglutinate in their 

    vessels.  Note that O type has no antigen and consequently can be

    mixed with all other types.  This is why it is termed the

    universal donor.  Type AB has not antibody and therefore can receive any other  type.  It is termed a universal acceptor.

 

    2.  Distribution of blood groups ‑ In the United States the ABO

        blood groups are distributed as follows.

 

        a.  Type O ‑ 46%

 

        b.  Type A ‑ 40%

 

        c.  Type B ‑ l0%

 

        d.  Type AB ‑ 4%

 

    3.  Genetics of the ABO blood groups ‑ In the population there

        exists three different genes for the blood antigens: Ia (A antigen),Ib (B antigen), and Io (no antigen).  Every person has two of these.

 

        a.  Ia and Ib are both dominant to Io and co-dominant to one 

            another.

 

        b.  Consequently, a person with type A blood might be IaIa or

            IaIo.  The same would be true for type B.  Type O can

            only be IoIo.  IaIb yields type AB.

 

        c.  When two people have a child, the child will receive one

            gene from each parent.  It is a 50/50 chance which gene from each parent will be received by the child.  Thus, by knowing the blood type of the child and mother, it is sometime impossible to determine the blood type of the father (but not always).

 

F.  Rh factor ‑ This is another antigen system found on the red blood cells.  People who possess the Rh antigen are said to be Rh positive while people who do not have this antigen are said to be Rh negative.  In blood typing the Rh factor is indicated by a + or ‑ sign following the ABO type such as A+.

 

    l.  Rh negative individuals do not automatically have antibody

        against the Rh antigen.  They must develop such antibody by exposure to Rh positive blood.

 

    2.  Such exposure may be due to a mismatched transfusion or in

        the case of an Rh negative mother, the bearing of an Rh positive child.

 

    3.  Rh incompatibility problems can arise when a mother is

        negative and the father is positive.  If the first pregnancy results in an Rh positive child it is possible that the mother may be exposed to the baby's Rh positive blood at the time of birth.  This can cause her to develop antibody against the Rh antigen.  If she has a subsequent pregnancy with another Rh positive fetus, antibody which she developed during the earlier pregnancy will now cross the placenta and cause agglutination of the baby's red cell. This is the "Rh baby" or more correctly, erythroblastosis fetalis.

 

    4.  Rh incompatibility problems can now be controlled by means of

        the Rhogam shot which is given in suspected cases within 24 hours of the child's birth.  This shot consists of antibody against the Rh antigen and will agglutinate and clear any stray fetal blood cells  before the mother has time to develop antibody against them.