Chapter 19

Blood

Components
Formed elements
Living blood cells

Plasma
Non-living fluid matrix

While blood is a connective tissue, collagen & elastic fibers are absent.

Physical characteristics & volume

pH = 7.35-7.45 with high viscosity T = 100.4 (slightly higher than body T) Approx. 7% of total body weight
5-6-L volume in adult male (1.5 Gal) 4-5 L in adult female

Functions
Distribution
Oxygen/nutrients, waste, hormones

Regulation
T, pH (protein buffers), fluid volume (electrolytes)

Protection
Clotting (prevent blood loss), preventing infection (WBCs, antibodies)

Blood Plasma
Blood plasma contains 90% water & over 100 solutes, including:
Proteins albumin, globulins, clotting proteins, and others..plasma proteins ~8% plasma volume
Albumin is 60% of plasma protein Transport, buffer, osmotic pressure

Nonprotein nitrogenous substances lactic acid, urea, creatinine Organic nutrients glucose, carbohydrates, amino acids Electrolytes sodium, potassium, calcium, chloride, bicarbonate Respiratory gases oxygen and carbon dioxide

Fluid compartments

Plasma

Formed elements
Erythrocytes anucleate Leukocytes only complete cells Platelets cell fragments

Hematocrit-packed cell volume (PCV)

Percentage of RBCs in a sample of blood
Males 47% +/-5 Females 42% +/-5

Fractionation= the process of separating whole blood for clinical anaylsis

Erythrocytes
Biconcave discs (doughnuts)
High surface-to-volume ratio Predominately hemoglobin (transport of gases)

Lack nuclei (anucleate), mitochondria and ribosomes 2.5 trillion in average adult 4-6 million/mm3 Too little = anemia Too much = polycythemia

Figure 192d

RBC function
Dedicated solely to respiratory gas transport
Hemoglobin binds easily and reversibly w/ O2
Expressed as grams/100ml of whole blood (normal is 12-18g/dl) HEME is a red pigment/GLOBIN is a protein

Each hemoglobin can bind to 4 molecules of O2 A single RBC contains ~250 million hemoglobin moleculeseach RBC carries ~1 billion molecules of O2 ~20% CO2 transported in the blood combines w/hemoglobin
10% dissolves in plasma/70% converts to bicarbonate ions and is transported in plasma

Structure of Hemoglobin
Oxyhemoglobin Hb bound to oxygen
Oxygen loading takes place in the lungs

Deoxyhemoglobin Hb after oxygen diffuses into tissues (reduced Hb) Carbaminohemoglobin Hb bound to carbon dioxide
Carbon dioxide loading takes place in the tissues

Figure 193

Hemopoiesis
Occurs in red bone marrow (myeloid tissue)
Adults- axial skeleton (ilium/sternum), proximal humerus/femur

Marrow turns out ~1 ounce of blood every day (100 billion cells> 2-3 million/second) All formed elements arise from the same cell (hemocytoblast) before differentiating
Myeloid stem cellsbecome RBCs & some WBCs Lymphoid stem cellsbecome lymphocytes

Production/maturation of Erythrocytes: Erythropoiesis

Figure 195

Regulation and Requirements for Erythropoiesis

Circulating erythrocytes the number remains constant and reflects a balance between RBC production and destruction
Too few red blood cells leads to tissue hypoxia Too many red blood cells causes undesirable blood viscosity Immature RBCs are called reticulocytes Reticulocyte counts are used to assess RBC rates of production

Erythropoiesis is hormonally controlled and depends on adequate supplies of iron, amino acids, and B vitamins (especially B12, B6, and folic acid)

Hormonal control
Erythropoietin (EPO) is the primary stimulus for RBC production
Liver produces minimal amount Some circulates in blood at all times Primary production in kidneys
Hypoxic kidney cells release EPO

Key point to remember

Erythropoiesis is not controlled by the amount of erythrocytes but by their oxygen carrying ability!
Decrease # of RBCs Reduced availabilty of O2 (altitude/disease) Increase tissue demand for O2 (exercise)

Life Cycle of Red Blood Cells

Figure 194

RBC fate & destruction

Life span of 100-120 days
Anucleatecannot grow, divide, or synthesize proteins

Lose flexibility and become trapped in small circulatory channelsoften the spleen (~1% RBCs wear out/day) Heme splits from globinforms biliverdin (Fe stored for re-use)
Biliverdin (green pigment) degrades to bilirubin (yellow ) Bilirubin binds to albumin for transport to liver Liver cells pick up and secrete it (in bile) into intestinesfeces Globin broken down into AAs & released into circulation

RBC disorders
Anemias Low # Hemorrhagic/hemolytic/aplastic Low hemoglobin content Iron deficiency/pernicious (B12) Abnormal hemoglobin Thalassemia (mediterranean descent) sickle cell (black population1/400 U.S. newborns) Polycythemia (primary/secondary) Blood doping

RBC Tests

Human Blood Groups

RBC membranes have glycoprotein antigens on their external surfaces These antigens are:
Unique to the individual Recognized as foreign if transfused into another individual Promoters of agglutination and are referred to as agglutinogens

Presence or absence of these antigens is used to classify blood groups

ABO Blood Groups

The ABO blood groups consists of:
Two antigens (A and B) on the surface of the RBCs Two antibodies in the plasma (anti-A and anti-B)

An individual with ABO blood may have various types of antigens and spontaneously preformed antibodies Agglutinogens and their corresponding antibodies cannot be mixed without serious hemolytic reactions

ABO Blood Groups

Figure 196a

Rh Blood Groups
Presence of the Rh agglutinogens on RBCs is indicated as Rh+
Also called D antigen

Anti-Rh antibodies are not spontaneously formed in Rh individuals However, if an Rh individual receives Rh+ blood, antiRh antibodies form A second exposure to Rh+ blood will result in a typical transfusion reaction

Hemolytic Disease of the Newborn

Hemolytic disease of the newborn Rh+ antibodies of a sensitized Rh mother cross the placenta and attack and destroy the RBCs of an Rh+ baby Rh mother becomes sensitized when Rh+ blood (from a previous pregnancy of an Rh+ baby or a Rh+ transfusion) causes her body to synthesis Rh+ antibodies The drug RhoGAM can prevent the Rh mother from becoming sensitized Treatment of hemolytic disease of the newborn involves pre-birth transfusions and exchange transfusions after birth

Transfusion Reactions
Transfusion reactions occur when mismatched blood is infused Donors cells are attacked by the recipients plasma agglutinins causing:
Diminished oxygen-carrying capacity Clumped cells that impede blood flow Ruptured RBCs that release free hemoglobin into the bloodstream

Circulating hemoglobin precipitates in the kidneys and causes renal failure

Blood Typing
When serum containing anti-A or anti-B agglutinins is added to blood, agglutination will occur between the agglutinin and the corresponding agglutinogens Positive reactions indicate agglutination
Blood type being tested AB

RBC agglutinogens

Serum Reaction Anti-A Anti-B +

A and B

B
A O

B
A None

Blood Typing Test

Determines blood type and compatibility

Figure 197

Leukocytes
6,000-9,000/mm3 blood <1% of total blood volume Not confined to blood stream
Diapedesis = slip out of capillaries & move by amoeboid motion thru tissue spaces (loose CT/ lymphoid tissue) following chemical trail left by damaged cells or other WBCs called positive chemotaxis

Leukocytosisgood or bad?
>11,000

Never Let Monkeys Eat Bananas

Leukocytes from greatest [ ] to least
Neutrophils Lymphocytes Monocytes Eosinophils Basophils

Leukocytes, cont.
Granulocytes
Staining granules present Roughly spherical Lobed nuclei Are all phagocytic cells
Neutrophils Eosinophils Basophils

Agranulocytes
No noticeable staining granules Have spherical (lymphocytes) or kidneyshaped (monocytes) nuclei Lymphocytes Monocytes

Neutrophils
Lobulated nucleus
Polymorphonuclear cells (PMNs)

Most numerous WBC (50-70% of WBC population) Granules have lysosomal enzymes & bactericides Chemically attracted to sites of inflammation & are active phagocytes
Release prostaglandins/leukotrienes

Bacteria slayersincreased w/bacterial infections

Eosinophils
2-4% of all WBCs Function against parasitic worms too large to be phagocytized by other immune cells Lessen the severity of allergies with enzymes that counteract inflammatory effects of neutrophils and mast cells

Basophils
0.5% total WBCs Are functionally similar to mast cells Cells produce histamine (vasodilator)
Bind to IgE w/allergic reactions Initiate inflammation

Cells also contain heparin (anticoagulant)

Lymphocytes
2nd in WBC population
20-30% of WBCs

Some in blood/most in lymph

T Lymphocytes vs virus/tumor cells B Lymphocytes produce antibodies to be released to blood
Give rise to plasma cells

NK (natural killer) Cells immune surveillance

Monocytes
2-8% of WBCs Largest in size of all WBCs Differentiate into macrophages Increase w/ chronic infections, viruses, and some bacterial parasites Activate lymphocytes to mount immune response
Secrete substances that attract immune system cells and fibroblasts to injured area

Leukopoiesis
Hormonally regulated by cytokines 2 types
Interleukins & colony stimulating factors (CSFs)
Interleukins are numbered (e.g., IL-1, IL-2), whereas CSFs are named for the WBCs they stimulate (e.g., granulocyte-CSF stimulates granulocytes)

Macrophages & T lymphocytes are most important source (agranulocytes)

Released in response to specific chemical signals

Granulocyte:erythrocyte production = 3:1

Granulocytes live 0.5-9days

WBC disorders
Leukopenias vs leukemias Leukemia or leukocytosis?
Good or bad? Normal or abnormal?

Leukocytes Disorders: Leukemias

Leukemia refers to cancerous conditions involving white blood cells Leukemias are named according to the abnormal white blood cells involved
Myelocytic leukemia involves myeloblasts Lymphocytic leukemia involves lymphocytes

Acute leukemia involves blast-type cells and primarily affects children Chronic leukemia is more prevalent in older people

Leukemia
Immature white blood cells are found in the bloodstream in all leukemias Bone marrow becomes totally occupied with cancerous leukocytes The white blood cells produced, though numerous, are not functional Death is caused by internal hemorrhage and overwhelming infections Treatments include irradiation, antileukemic drugs, and bone marrow transplants

Platelets
Cell fragments from large cells called megakaryocytes
1 megakarycyte ~ 4000 platelets

Essential for clotting process Sometimes incorrectly called thrombocytes Degenerate in ~9-12 days Formation regulated by hormone called thrombopoietin (made in liver) 150,000-500,000/mm3 blood
Developmental pathway

Hemocytoblast

Megakaryoblast

Promegakaryocyte

Megakaryocyte

Platelets

Summary of Formed Elements

Hemostasis = blood stoppage

Blood will flow unimpeded thru intact endothelium of blood vessel walls If a wall is damagedfast, localized, controlled response to plug hole 3 phases of hemostasis:
1. Vascular spasm 2. Platelet plug formation 3. Coagulation

1. Vascular spasm
3 stimuli to cause vasospasm
1-direct injury to vascular smooth muscle 2-chemicals released by endothelial cells & platelets 3-reflexes initiated by local pain receptors

Spasm becomes more efficient with an increase in tissue damage.

Figure 1911a

2. Platelet plug formation

Platelets do not stick to themselves or to the smooth endothelial lining of BVs Platelets swell & form spikes once exposed to damaged endothelium and underlying exposed collagen Platelets become sticky and adhere to the collagen Then they release several chemicals like serotonin (to enhance vascular spasm), ADP (to attract more platelets), and some others. The platelet plug is limited to the immediate area of injury by prostacyclin (released by endothelial cells)

Platelet plug phase

Begins within 15 seconds after injury

Figure 1911b

3. Coagulation

Transforms blood from a liquid to a gel Begins 30 seconds or more after the injury

Figure 1912a

3. Coagulation
Involves 3 steps:

Detailed Events of Coagulation

Step 1.
2 pathways to prothrombinase: (extrinsic/intrinsic) Intrinsic can happen outside the body (test tube)
Only uses components found within blood itself

Extrinsic happens within body tissues

Uses TF (tissue factor) found outside the blood Ionic Ca activates a series of procoagulants that act as an enzyme to stimulate the next procoagulant in the series until production of the intermediate factor X Factor X combines w/ Ca to form prothrombinase Clot forms within 30 seconds

Step 2.
Common pathway to thrombin
Prothrombinase causes transformation of the plasma protein prothrombin to the active enzyme thrombin

Step 3.
Common pathway to fibrin mesh
Thrombin catalyzes polymerization of fibrinogen (plasma protein made in liver) Fibrinogen molecules line up into hairlike, insoluble fibrin Plasma becomes gel-like and traps formed elements as they try to pass through
W/ Ca, thrombin activates factor XIII (fibrin stabilizing factor) to bind fibrin tight and strengthen the clot W/ rapid, extrinsic pathwayclot formation can occur w/in 30 seconds

Clot retraction & repair

Clot retraction occurs w/in 30-60 minutes Platelets contain actin & myosin and contract in much the same way as mm cells
Platelets pull on surrounding fibrin strand & squeezes serum out of the mass Serum = plasma minus clotting proteins

As clot is compacted fibroblasts (stimulated by plateletderived growth factor -PDGF) rebuild the wall while endothelial cells (stimulated by vascular endothelial growth factor -VEGF) multiply to restore the lining

Fibrinolysis
Plasmin (fibrin-digesting enzyme) is made from activating plasminogen (blood protein)
Presence of the clot causes endothelial cells to release tissue plasminogen activator Fibrinolysis begins w/in 2 days and continues slowly over several days until the clot is dissolved

Factors limiting clot growth

1. Swift removal of clotting factors 2. Inhibition of activated clotting factors
Fibrin acts as an anticoagulant by binding thrombin and preventing its:
Positive feedback effects of coagulation Ability to speed up the production of prothrombin activator Acceleration of the intrinsic pathway by activating platelets

Heparin a natural anticoagulant found in the granules of basophils and mast cells and is produced by endothelial cells thereby inhibiting thrombin
Secreted in small amounts into plasma

Prevention of Undesirable Clots

Substances used to prevent undesirable clots include:
Aspirin an antiprostaglandin that inhibits thromboxane A2 Heparin an anticoagulant used clinically for preand postoperative cardiac care Warfarin used for those prone to atrial fibrillation

Hemostasis Disorders: Thromboembolytic Conditions

Thrombus a clot that develops and persists in an unbroken blood vessel
Thrombi can block circulation, resulting in tissue death Coronary thrombosis thrombus in blood vessel of the heart

Embolus a thrombus freely floating in the blood stream

Pulmonary emboli can impair the ability of the body to obtain oxygen Cerebral emboli can cause strokes

Hemostasis/Bleeding Disorders
Thrombocytopenia condition where the number of circulating platelets is deficient
Patients show petechiae (small purple blotches on the skin) due to spontaneous, widespread hemorrhage Caused by suppression or destruction of bone marrow (e.g., malignancy, radiation) Platelet counts less than 50,000/mm3 is diagnostic for this condition Treated with whole blood transfusions

Hemostasis/Bleeding Disorders
Inability to synthesize procoagulants by the liver results in severe bleeding disorders Causes can range from vitamin K deficiency to hepatitis and cirrhosis Inability to absorb fat can lead to vitamin K deficiencies as it is a fat-soluble substance and is absorbed along with fat Liver disease can also prevent the liver from producing bile, which is required for fat and vitamin K absorption

Hemostasis/Bleeding Disorders
Hemophilias hereditary bleeding disorders caused by lack of clotting factors
Hemophilia A most common type (83% of all cases) due to a deficiency of factor VIII Hemophilia B results from a deficiency of factor IX Hemophilia C mild type, caused by a deficiency of factor XI

Symptoms include prolonged bleeding and painful and disabled joints Treatment is with blood transfusions and the injection of missing factors

Diagnostic Blood Tests

Laboratory examination of blood can assess an individuals state of health Microscopic examination:
Variations in size and shape of RBCs predictions of anemias Type and number of WBCs diagnostic of various diseases
CBC & Differential Count

Chemical analysis can provide a comprehensive picture of ones general health status in relation to normal values

Developmental Aspects
Before birth, blood cell formation takes place in the fetal yolk sac, liver, and spleen By the seventh month, red bone marrow is the primary hematopoietic area The fetus forms HbF, which has a higher affinity for oxygen than adult hemoglobin Age-related blood problems result from disorders of the heart, blood vessels, and the immune system Increased leukemias are thought to be due to the waning deficiency of the immune system Abnormal thrombus and embolus formation reflects the progress of atherosclerosis