Blood

Overview of Blood Circulation

Blood leaves the heart via arteries that branch repeatedly until they become capillaries

Oxygen (O2) and nutrients diffuse across capillary walls and enter tissues

Carbon dioxide (CO2) and wastes move from tissues into the blood

Overview of Blood Circulation

Oxygen-deficient blood leaves the capillaries and flows in veins to the heart

This blood flows to the lungs where it releases CO2 and picks up O2

The oxygen-rich blood returns to the heart

Composition of Blood Blood is a connective fluid tissue It is composed of liquid plasma and formed

elements Formed elements include:

Erythrocytes, or red blood cells (RBCs)Leukocytes, or white blood cells (WBCs)Platelets

Hematocrit – the percentage of RBCs out of the total blood volume

Components of Whole Blood

Physical Characteristics and Volume Blood is a sticky, opaque fluid with a

metallic taste Color varies from scarlet to dark red The pH of blood is 7.35–7.45 Temperature is 38C Blood accounts for approximately 8% of

body weight Average volume: 5–6 L for males, and 4–5

L for females

Functions of Blood

Blood performs a number of functions dealing with:Substance distributionRegulation of blood levels of particular

substancesBody protection

Distribution

Blood transports:Oxygen from the lungs and nutrients from

the digestive tractMetabolic wastes from cells to the lungs and

kidneys for eliminationHormones from endocrine glands to target

organs

Regulation

Blood maintains:Appropriate body temperature by absorbing

and distributing heatNormal pH in body tissues using buffer

systemsAdequate fluid volume in the circulatory

system

Protection

Blood prevents blood loss by:Activating plasma proteins and platelets Initiating clot formation when a vessel is

broken Blood prevents infection by:

Activating complement proteinsActivating WBCs to defend the body against

foreign invaders

Blood Plasma Blood plasma contains over 100 solutes,

including:Proteins – albumin, globulins, clotting

proteins, and othersLactic acid, urea, creatinineOrganic nutrients – glucose, carbohydrates,

amino acidsElectrolytes – sodium, potassium, calcium,

chloride, bicarbonate Respiratory gases – oxygen and carbon

dioxide

Formed Elements

Erythrocytes, leukocytes, and platelets make up the formed elementsOnly WBCs are complete cellsRBCs have no nuclei or organelles, and

platelets are just cell fragments Most formed elements survive in the

bloodstream for only a few days Most blood cells do not divide but are

renewed by cells in bone marrow

Components of Whole Blood

Erythrocytes (RBCs)

Biconcave discs, anucleate, essentially no organelles

Filled with hemoglobin (Hb), a protein that functions in gas transport

Contain the plasma membrane protein spectrin and other proteins that:Give erythrocytes their flexibilityAllow them to change shape as necessary

Erythrocytes (RBCs)

Erythrocytes (RBCs)

Erythrocytes are an example of the complementarity of structure and function

Structural characteristics contribute to its gas transport functionBiconcave shape has a huge surface area

relative to volumeErythrocytes are more than 97%

hemoglobinATP is generated anaerobically, so the

erythrocytes do not consume the oxygen

they transport

Erythrocyte Function RBCs are dedicated to respiratory gas

transport Hb reversibly binds with oxygen and most

oxygen in the blood is bound to Hb Hb is composed of the protein globin, made up

of two alpha and two beta chains, each bound to a heme group

Each heme group bears an atom of iron, which can bind to one oxygen molecule

Each Hb molecule can transport four molecules of oxygen

Structure of Hemoglobin

Hemoglobin (Hb)

Oxyhemoglobin – Hb bound to oxygenOxygen loading takes place in the lungs

Deoxyhemoglobin – Hb after oxygen diffuses into tissues (reduced Hb)

Carbaminohemoglobin – Hb bound to carbon dioxide It binds to globin’s amino acidsCarbon dioxide loading takes place in the

tissues

Production of Erythrocytes

Hematopoiesis – blood cell formation Hematopoiesis occurs in the red bone

marrow of the:Axial skeleton and girdlesEpiphyses of the humerus and femur

Hemocytoblasts give rise to all formed elements

Production of Erythrocytes: Erythropoiesis A hemocytoblast is transformed into a

proerythroblast Proerythroblasts develop into early

erythroblasts

Production of Erythrocytes: Erythropoiesis The developmental pathway consists of three

phases1 – ribosome synthesis in early erythroblasts2 – Hb accumulation in late erythroblasts and

normoblasts3 – ejection of the nucleus from normoblasts

and formation of reticulocytes Reticulocytes then become mature erythrocytes

1-2% of RBC in health people

Production of Erythrocytes: Erythropoiesis

Regulation and Requirements for Erythropoiesis

Circulating erythrocytes – the number remains constant and reflects a balance between RBC production and destructionToo few RBCs leads to tissue hypoxiaToo many RBCs causes undesirable blood

viscosity Erythropoiesis is hormonally controlled and

depends on adequate supplies of iron, amino acids, and B vitamins

Hormonal Control of Erythropoiesis Erythropoietin (EPO) release by the

kidneys is triggered by:Hypoxia due to decreased RBCs or

hemoglobin contentDecreased oxygen availabilityIncreased tissue demand for oxygen

Enhanced erythropoiesis increases the: RBC count in circulating bloodOxygen carrying ability of the blood

Homeostasis: Normal blood oxygen levels

IncreasesO2-carryingability of blood

Erythropoietinstimulates redbone marrow

Reduces O2 levelsin blood

Kidney (and liver to a smallerextent) releases erythropoietin

Enhancederythropoiesisincreases RBC count

Stimulus: Hypoxia due todecreased RBC count,decreased amount of hemoglobin, or decreased availability of O2

Start

Erythropoietin Mechanism

Erythropoiesis requires:Proteins, lipids, and carbohydratesIron, vitamin B12, and folic acid

The body stores iron in Hb (65%), the liver, spleen, and bone marrow

Intracellular iron is stored in protein-iron complexes such as ferritin and hemosiderin

Circulating iron is loosely bound to the transport protein transferrin

Dietary Requirements of Erythropoiesis

Fate and Destruction of Erythrocytes The life span of an erythrocyte is 100–120

days Old RBCs become rigid and fragile, and

their Hb begins to degenerate Dying RBCs are engulfed by macrophages Heme and globin are separated and the

iron is salvaged for reuse

Fate and Destruction of Erythrocytes

Heme is degraded to a green pigment biliverdin

Biliverdin is converted to a yellow pigment called bilirubin

The bilirubin is picked up by the liver and secreted into the intestines as bile

Fate and Destruction of Erythrocytes The intestines metabolize it into

urobilinogen and stercobilinogen These degraded pigments leave the body

in feces and urine, in a pigment called stercobilin and urobilin

Fate and Destruction of Erythrocytes Globin is metabolized into amino acids

and is released into the circulation Hb released into the blood is captured by

haptoglobin and phagocytized

Hemoglobin

Erythropoietin levelsrise in blood.

Erythropoietin and necessaryraw materials in blood promoteerythropoiesis in red bone marrow.

New erythrocytesenter bloodstream;function about120 days.

Low O2 levels in blood stimulatekidneys to produce erythropoietin.

Aged and damaged redblood cells are engulfed bymacrophages of liver, spleen,and bone marrow; the hemoglobinis broken down.

1

2

3

4

5

Hemoglobin

Aminoacids

Globin

Raw materials aremade available inblood for erythrocytesynthesis.

Iron is bound to transferrin and released to blood from liver as needed for erythropoiesis

Food nutrients,including aminoacids, Fe, B12,and folic acidare absorbedfrom intestineand enter blood

Heme

Circulation

Iron storedas ferritin,hemosiderin

Bilirubin

Bilirubin is picked up fromblood by liver, secreted intointestine in bile, metabolizedto stercobilin by bacteriaand excreted in feces

Erythropoietin levelsrise in blood.

Erythropoietin and necessaryraw materials in blood promoteerythropoiesis in red bone marrow.

New erythrocytesenter bloodstream;function about120 days.

Low O2 levels in blood stimulatekidneys to produce erythropoietin.

Aged and damaged redblood cells are engulfed bymacrophages of liver, spleen,and bone marrow; the hemoglobinis broken down.

1

2

3

4

5

6

Anemia Low RBC count or Hemoglobin content

Low oxygen-carrying capacityIt is a symptom rather than a disease itselfBlood oxygen levels cannot support normal

metabolismSigns/symptoms include fatigue, paleness,

shortness of breath, and chills

Erythrocyte Disorders

Anemia: Insufficient Erythrocytes Hemorrhagic anemia – result of acute or

chronic loss of blood Hemolytic anemia – prematurely ruptured

RBCs Aplastic anemia – destruction or inhibition

of red bone marrow

Iron-deficiency anemia results from:A secondary result of hemorrhagic anemiaInadequate intake of iron-containing foodsImpaired iron absorption

Pernicious anemia results from:Deficiency of vitamin B12

Lack of intrinsic factor needed for absorption of B12

Treatment is intramuscular injection of B12

Anemia: Decreased Hemoglobin Content

Anemia: Abnormal Hemoglobin

Thalassemias – absent or faulty globin chain in Hb RBCs are thin, delicate, and deficient in Hb

Sickle-cell anemia – results from a defective gene coding for an abnormal Hb called hemoglobin S (HbS)HbS has a single amino acid substitution in

the beta chainThis defect causes RBCs to become sickle-

shaped in low oxygen situations

Polycythemia

Polycythemia – excess RBCs that increase blood viscosity

Three main polycythemias are:Polycythemia veraSecondary polycythemiaBlood doping

Leukocytes (WBCs) Leukocytes, the only blood components

that are complete cells:Are less numerous than RBCsMake up 1% of the total blood volumeCan leave capillaries via diapedesisMove through tissue spaces

Leukocytes (WBCs)

Leukocytosis – WBC count over 11,000 / mm3

Normal response to bacterial or viral invasion

Leukopenia – WBC count under 4,000/mm3

Percentages of Leukocytes

Granulocytes

Granulocytes – neutrophils, eosinophils, and basophilsContain cytoplasmic granules that stain

specifically (acidic, basic, or both) with Wright’s stain

Are larger and usually shorter-lived than RBCs

Have lobed nucleiAre all phagocytic cells

Neutrophils

Neutrophils have two types of granules that:Take up both acidic and basic dyesGive the cytoplasm a lilac colorContain peroxidases, hydrolytic enzymes,

and defensins (antibiotic-like proteins) Neutrophils are our body’s bacteria slayers

Respiratory burst – by metabolizing oxygen they produce substances that pierce holes in the germ’s membrane

Eosinophils account for 1–4% of WBCs Have red-staining, bilobed nuclei connected

via a broad band of nuclear materialHave red to crimson (acidophilic) large,

coarse, lysosome-like granulesLead the body’s counterattack against

parasitic wormsLessen the severity of allergies by

phagocytizing immune complexes

Eosinophils

Account for 0.5% of WBCs and:Have U- or S-shaped nuclei with two or

three conspicuous constrictionsHave large, purplish-black (basophilic)

granules that contain histamineHistamine – inflammatory chemical that

acts as a vasodilator and attracts other WBCs (antihistamines counter this effect)

Mast cellsAre functionally similar to basophils

Basophils

Agranulocytes – lymphocytes and monocytes:Lack visible cytoplasmic granulesAre similar structurally, but are functionally

distinct and unrelated cell typesHave spherical (lymphocytes) or kidney-

shaped (monocytes) nuclei

Agranulocytes

Account for 25% or more of WBCs and:Have large, dark-purple, circular nuclei with

a thin rim of blue cytoplasmAre found mostly enmeshed in lymphoid

tissue (some circulate in the blood) There are two types of lymphocytes: T

cells and B cellsT cells function in the immune response B cells give rise to plasma cells, which

produce antibodies

Lymphocytes

Monocytes account for 4–8% of leukocytes They are the largest leukocytesThey have abundant pale-blue cytoplasmsThey have purple-staining, U- or kidney-

shaped nucleiThey leave the circulation, enter tissue, and

differentiate into macrophages

Monocytes

Macrophages:Are highly mobile and actively phagocyticActivate lymphocytes to mount an immune

response

Macrophages

Leukocytes

Summary of Formed Elements

51

Summary of Formed Elements

52

Leukopoiesis is stimulated by interleukins and 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 and T cells are the most important sources of cytokines

Many hematopoietic hormones are used clinically to stimulate bone marrow

Production of Leukocytes

Formation of Leukocytes All leukocytes originate from

hemocytoblasts Hemocytoblasts differentiate into myeloid

stem cells and lymphoid stem cells Myeloid stem cells become eosinophilic,

basophilic and neutrophilic myeloblasts or monoblasts

Lymphoid stem cells become lymphoblasts

Formation of Leukocytes

The myeloblasts develop into eosinophils, neutrophils, and basophils

Monoblasts develop into monocytes Lymphoblasts develop into lymphocytes

56

Leukocytes Disorders: Leukemias Leukemia refers to cancerous conditions

involving WBCs Leukemias are named according to the

abnormal WBCs involvedMyelocytic leukemia – involves myeloblastsLymphocytic leukemia – involves

lymphocytes Acute leukemia involves blast-type cells and

primarily affects children Chronic leukemia is more prevalent in older

people

Leukemia Immature WBCs are found in the bloodstream

in all leukemias Bone marrow becomes totally occupied with

cancerous leukocytes The WBCs 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 are fragments of megakaryocytes with a blue-staining outer region and a purple granular center

Their granules contain serotonin, Ca2+, enzymes, ADP, and platelet-derived growth factor (PDGF)

Platelets function in the clotting mechanism by forming a temporary plug that helps seal breaks in blood vessels

Platelets not involved in clotting are kept inactive by NO and prostacyclin

Platelets

Stem cell Developmental pathway

Hemocytoblast Megakaryoblast Promegakaryocyte Megakaryocyte Platelets

Genesis of Platelets The stem cell for platelets is the

hemocytoblast The sequential developmental pathway is

as shown.

Hemostasis

A series of reactions for stoppage of bleeding

During hemostasis, three phases occur in rapid sequenceVascular spasms – immediate

vasoconstriction in response to injuryPlatelet plug formationCoagulation (blood clotting)

Hemostasis

Vascular spasms because of:Direct injury to the smooth muscle layer of

the blood vesselChemicals released by the platelet and

endothelial cellsReflexes initiated by local pain receptors

Hemostasis

Platelet Plug Formation Platelets do not stick to each other or to blood

vessels in normal conditions Upon damage to blood vessel endothelium the

exposed collagen will cause platelets to swell and become sticky :With the help of von Willebrand factor

(VWF) secreted by the endothelial cells .Stick to exposed collagen fibers and form a

platelet plug

Hemostasis

Release serotonin and ADP, which attract still more platelets and promote vascular spam

Release thromboxane A2 that promotes further platelet aggregation

The platelet plug is limited to the immediate area of injury by prostacyclin secreted by endothelial cells

Coagulation A set of reactions in which blood is

transformed from a liquid to a gel Coagulation follows intrinsic and extrinsic

pathways

Hemostasis

Coagulation

67

Detailed Events of Coagulation

Coagulation

May be initiated by either the intrinsic or extrinsic pathwayTriggered by tissue-damaging eventsInvolves a series of procoagulantsEach pathway cascades toward factor X

Coagulation

Prothrombin is transformed into thrombin Thrombin converts fibrinogen into fibrin Fibrin becomes part of the clot

It causes plasma to become a gel-like trap

Clot Retraction and Repair

Clot retraction – stabilization of the clot by squeezing serum from the fibrin strands

Restoration of the blood vessel wallPlatelet will stimulate

smooth muscle cells mitosis fibroblast multiplication endothelial cells division

Fibrinolysis

The process of removal of clots after healing has occurred

Plasminogen is activated by Tissue plasminogen activator (tPA)

released by many tissuesThrombin

Plasminogen is converted into plasmin Plasmin will then digest the clot

Factors Limiting Clot Growth or Formation

Two homeostatic mechanisms prevent clots from becoming largeBlood flow

Wash away activated clotting factors Hinder further grow of forming clot

Factors Limiting Clot Growth or Formation

Mechanisms that prevents thrombin actionFibrin binds thrombin preventing its:

Positive feedback effects of coagulation

Fast inactivation of thrombin that escapes into blood circulation by:

Antithrombin III

Prevention of clotting in the normal vascular system The presence of a smooth and intact

endothelial surface The presence of circulating antithrombin

factorsAntithrombin III

also inhibits steps of the intrinsic pathwayProtein C

inhibits steps of the intrinsic pathway

Heparin increases the action of antithrombin III

Vitamin E a potent anticoagulant

Prevention of clotting in the normal vascular system

Hemostasis Disorders:Thromboembolytic Conditions

Thrombus – a clot that develops and persists in an unbroken blood vesselThrombi can block circulation, resulting in

tissue deathCoronary thrombosis – thrombus in blood

vessel of the heart

Hemostasis Disorders:Thromboembolytic Conditions

Embolus – a thrombus freely floating in the blood streamPulmonary emboli can impair the ability of

the body to obtain oxygenCerebral emboli can cause strokes

Substances used to prevent undesirable clots:Aspirin – an antiprostaglandin that inhibits

thromboxane A2

Heparin – an anticoagulant used clinically for pre- and postoperative cardiac care

Warfarin – competes with vitamin K in the production of some procoagulants

Prevention of Undesirable Clots

Disseminated Intravascular Coagulation (DIC): widespread clotting in intact blood vessels

Residual blood cannot clot Blockage of blood flow and severe

bleeding follows Most common as:

A complication of pregnancyA result of septicemia or incompatible blood

transfusions

Hemostasis Disorders

Thrombocytopenia – condition where the number of circulating platelets is deficientPatients show petechiae 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 conditionTreated with whole blood transfusions

Hemostasis Disorders: 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 Disorders: Bleeding Disorders

Hemophilias – hereditary bleeding disorders caused by lack of clotting factorsHemophilia A – most common type (83% of

all cases) due to a deficiency of factor VIIIHemophilia B – due to a deficiency of factor

IXHemophilia C – mild type, due to a

deficiency of factor XI

Hemostasis Disorders: Bleeding Disorders

Hemostasis Disorders: Bleeding Disorders Symptoms include prolonged bleeding and

painful and disabled joints Treatment is with blood transfusions and

the injection of missing factors

Blood Transfusions

Whole blood transfusions are used: When blood loss is substantial In treating thrombocytopenia

Packed red cells (cells with plasma removed) are used to treat anemia

RBC membranes have glycoprotein antigens on their external surfaces

These antigens are:Unique to the individual Recognized as foreign if transfused into

another individualPromoters of agglutination and are referred

to as agglutinogens Presence or absence of these antigens is

used to classify blood groups

Human Blood Groups

Humans have 30 varieties of naturally occurring RBC antigens

The antigens of the ABO and Rh blood groups cause vigorous transfusion reactions when they are improperly transfused

Other blood groups (M, N, Dufy, Kell, and Lewis) are mainly used for legalities

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) ABO blood groups may have various types

of antigens and preformed antibodies Agglutinogens and their corresponding

antibodies cannot be mixed without serious hemolytic reactions

ABO Blood Groups

ABO Blood Groups

There are eight different Rh agglutinogens, three of which (C, D, and E) are common

Presence of the Rh agglutinogens on RBCs is indicated as Rh+

Anti-Rh antibodies are not spontaneously formed in Rh– individuals

However, if an Rh– individual receives Rh+ blood, anti-Rh antibodies form

A second exposure to Rh+ blood will result in a typical transfusion reaction

Rh Blood Groups

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 exposure to Rh+ blood causes her body to synthesize Rh+ antibodies

Hemolytic Disease of the Newborn 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 occur when mismatched blood is infused

Donor’s cells are attacked by the recipient’s plasma agglutinins causing:Diminished oxygen-carrying capacityClumped cells that impede blood flowRuptured RBCs that release free

hemoglobin into the bloodstream

Transfusion Reactions

Transfusion Reactions

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

RBC agglutinogens Serum Reaction

Anti-A Anti-B

AB A and B + +

B B – +

A A + –

O None – –

Blood Typing

Plasma Volume Expanders

When shock is imminent from low blood volume, volume must be replaced

Plasma or plasma expanders can be administered

Plasma Volume Expanders

Plasma expandersHave osmotic properties that directly

increase fluid volumeAre used when plasma is not availableExamples: purified human serum albumin,

plasminate, and dextran Isotonic saline can also be used to replace

lost blood volume

Diagnostic Blood Tests

Laboratory examination of blood can assess an individual’s state of health

Microscopic examination:Variations in size and shape of RBCs –

predictions of anemiasType and number of WBCs – diagnostic of

various diseases Chemical analysis can provide a

comprehensive picture of one’s 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

Blood cells develop from mesenchymal cells called blood islands

The fetus forms HbF, which has a higher affinity for oxygen than adult hemoglobin

Developmental Aspects

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