The Cardiovascular System:

Blood

The CV System
cardiovascular system
consists of three interrelated components:
Blood Heart Blood vessels.

Blood
Hematology
The study of blood, blood forming tissues, and the disorders associated with them

Blood contributes to homeostasis by:

Transporting respiratory gasses, nutrients, and hormones to and from your bodys cells. Helping to regulate body pH and temperature. Providing protection through its clotting mechanisms and immune defenses.

Characteristics of Blood
Blood is more dense and viscous (thicker) than water. Has a temperature of 38 deg C
1 deg C higher than oral or rectal body temp

Slightly alkaline
pH ranging from 7.35 7.45

Changes from dark to bright red depending on oxygen content Plasma volume constitutes roughly 25% of extracellular fluid (ECF)
Other 75% of ECF is interstitial fluid (ISF)

Average blood volume in:

Males = 5 to 6 liters (~1.5 gal) Females = 4 to 5 liters (~1.2 gal) Difference mainly due to body size

Blood
Blood is a type of connective tissue
Composed of:
Plasma Formed elements

Interstitial fluid (ISF)

Fluid that bathes body tissues Constantly renewed by blood
Discussed in more detail during blood vessels and hemodynamics lecture

Components of Blood
Plasma
A watery liquid extracellular matrix that contains dissolved substances. ~91.5% water and 8.5% solutes
The majority of the solutes in plasma are protiens
Specific proteins confined blood are called plasma proteins Most of the plasma proteins are produce by the liver These proteins have many functions but a very important one is a contribution to the maintenance of proper blood osmotic pressure

Other solututes include electrolytes, nutrients, gasses, regulatory substances, and waste products

Components of Blood
Formed Elements
3 principal components
Red Blood Cells (RBCs) White Blood Cells (WBCs) Platelets

Formed Elements
Hemopoiesis (hematopoiesis)
Process by which the formed elements of blood develop From late fetal development to death, red bone marrow is the primary site of hemopoiesis
All Blood cells arise from pluripotent stem cells found within the red marrow
The pluripotent stem cells give rise to 2 types of stem cells: Myeliod and lymphoid stem cells Lymphoid cells are named so due to their beginning development in the red bone marrow and ending in the lymphoid tissue Some of the myeloid stem cells give rise to progenitor cells The other myeloid stem cells, lymphatic stem cells, and progenitor cells give rise to precurser cells (blasts) which then differentiate into the blood cells

Regulation of Hemopoiesis
Hemopoietic growth factors
Hormones that regulate the differentiation and proliferation of particular progenator cells
Erythropoietin (EPO) increases the # of RBC precursers
EPO is primarily produced cells in the kidneys Renal failure leads to RBC defficiency Exogenous or synthetic EPO is also a banned substance in most professional sports

Thrombopoetin (TPO) stimulates formation of platelets from megakaryocytes

TPO is produced by the liver

Cytokines small glycoproteins that regulate the development of different blood cells
Typically produced by cells such as red bone marrow cells, leukocytes, macrophages, fibroblasts, and endothelial cells

Laboratory made hemopoietic growth factors have shown great promise in helping reduce some of the side effects of chemotherapy as well as treatment of particular disieases and genetic defficiencies

Formed Elements
Red Blood Cells (RBCs)
Also called erythrocytes make up the bulk of the blood cells
Hematocrit = the % of RBCs per unit blood volume
Normal Hct is around 45%

bi-concave discs
Allows for high surface area which is optimal for gas exchange Also allows RBCs to deform without rupturing
Very important in capillary circulation

Amongst many other membrane proteins, the RBC membrane contains glycolipid surface markers that designate ABO Rh blood type

Red Blood Cells (RBCs)

Developing RBCs lose their nucleus and many other organelles as they mature
When a maturing RBC loses its nucleus, it becomes a reticulocyte

The mature form is highly specialized for oxygen transport

Due to the lack of most organelles, the majority of their internal space is available for oxygen transport Cytosol of mature RBCs contain a high amount of hemoglobin
~33% of the cells weight

Each RBC contains about 280 million hemoglobin molecules Hemoglobin (Hgb) is a protein molecule adapted to carry O2 (and CO2 as well)
A Hgb molecule consists of 4 large globin proteins (2 alpha and 2 beta chains), each embedding an iron-containing heme center The iron binds oxygen

Red Blood Cells (RBCs)

Lack mitochondria
Generate ATP anaerobically so they do not use up the oxygen being transported

As previously stated, mature RBCs lack a nucleus or any protein making machinery
This means they cannot synthesize new components to repair damaged ones
Thus they are destined to die Average RBC life is about 120 days. ~1% of RBCs must be destroyed and replaced every day 250 billion cells per day!

Old RBCs a subject to bursting when passing through the narrow channels in the spleen
Ruptured RBCs are removed from circulation and destroyed by fixed phagocytotic macrophages in the spleen and liver Some of the breakdown products are recycled and others are excreted as shown in the following slide

In a sense, mature RBCs are not really cells, but remnants of cells with a very specific purpose to carry O2 to the tissues of the body

RBC Life Cycle

Circulation for about 120 days

3
Amino acids Reused for protein synthesis Fe3+ Fe3+ Transferrin

Globin

4 2 Heme
Transferrin

6
Ferritin Fe3+ + Globin + Vitamin B12 + Erythropoietin

9 1 Red blood cell

death and phagocytosis Kidney Biliverdin Bilirubin

Bilirubin

10
Bilirubin

11

Liver

Small intestine

13
Macrophage in spleen, liver, or red bone marrow Urine Urobilin

8 Erythropoiesis in
red bone marrow

12

Urobilinogen Stercobilin Feces

Bacteria

Key:
in blood in bile

Large 14 intestine

Abnormalities of Erythropoiesis
Anemia
A condition of insufficient RBCs or hemoglobin (quality or quantity) It is most often the result of low iron intake, hemolysis, autoimmune disease, blood loss, or lack of production in the bone marrow
a condition of excess number of RBCs per unit volume It occurs in response to:
Hypoxia Blood doping - receiving a transfusion of RBCs right before a sporting event to increase the bloods oxygen carrying capacity shots of EPO (illegal doping) smoking (COPD) dehydration
Natural blood doping is training at high altitude Condition in which the body or a region of the body is deprived of an adequate oxygen supply

Polycythemia

Anemias
Iron deficiency anemia is the most common anemia in the U.S., and affects primarily menstruating women
In the United States, 20% of all women of childbearing age have iron deficiency anemia, compared with only 2% of adult men

Hemorrhagic anemia is the result of precipitous blood loss, and results in an equal decrease in Hct, Hgb content, and RBC count

Anemias
Sickle-cell disease (SCD)
also called sickle-cell anemia An autosomal recessive disorder.
A genetic defect in the primary DNA sequence leads to production of a faulty Hgb chain, and RBCs that take on a rigid, sickle-shape People who only have one sickle-cell gene may experience mild symtoms People who have two copies of the sickle-cell gene may experience severe symptoms Decreased oxygen carrying capacity Easily ruptured RBCs Increased risk of stroke life expectancy is shortened Many others

Sickling decreases the cells' flexibility and results in a variety of complications;

May confer an advantage in malaria prone envoronments

People who inherit one copy of the mutated sickle-cell gene show increased resistance to infection and effects of the plasmodium parisite
http://en.wikipedia.org/wiki/File:Sickle_cell_ 01.jpg

Next Lecture
Lecture 1 part 2: Blood

Formed Elements
White Blood Cells (WBCs)
Also called leukocytes Function in immunity and defense Have nuclei and a full complement of other organelles do not contain the protein Hgb divided into two groups depending on whether they contain conspicuous chemical-filled cytoplasmic granules (when stained)
Granulocytes Agranulocytes

Leukocytes
Phagocytosis the process of engulphing a substance or another cell Chemicals released by microbes and inflamed tissues attract phagocytes, a phenomenon called chemotaxis This graphic shows a PMN phagocytizing (ingesting) a microbe for internal digestion and destruction
Monocytes (later termed macrophages when they differentiate) and neutrophills are active phagocytes

Granulocytes
Neutrophil
Also termed the polymorphonucleocyte (PMN) The most numerous WBC in normal blood (60-70% of circulating white cells) PMNs are granulocytes with a pinkish cytoplasm one of the two major phagocytes in the body their principal role is to fight bacterial infections Use a variety of chemicals destroy pathogens
Lysozyme (hydrolytic enzymes), superoxide anion (O2-), hydrogen peroxide, hypochlorite anion (much like bleach)

Granulocytes
Eosinophils
Characterized by their large red granules Involved in mediation of inflammation and phagocytosis of antigen-antibody complexes They are much less numerous than neutrophils (2-4% of circulating WBCs)
However, their numbers increase slightly with parasitic infection they have also been associated with the development of allergies

Granulocytes
Basophils
Contain large, dark blue, histamine containing granules Normally, they are the lowest number of circulating WBCs (only 0-1%), Play an important role in the escalation of inflammatory responses

Agranulocytes
Monocytes
Arise from the same immediate precursor cell as the 3 granulocytes (the myeloid stem cell) Along with neutrophils, monocytes are the other major group of phagocytic cells. Constitute only 3-8% of the circulating WBCs Differentiate into Macrophages in tissues Some become fixed (localized to a particular tissue) and others become wandering (roamers that congregate at sites of infection or inflammation)

Agranulocytes
Lymphocytes
Do not have granules or phagocytize The major soldiers in immune system battles Approximately 20-30% of circulating white cells Lymphocytes are the cornerstone of the specific immune response Continuosly move between blood and lymphatic tissue
Only spend up to a few hours at a time in blood

Develop into;
T-cells B-cells Natural killer cells

Leukocyte Movement
Emigratrion
Formally called diapedesis The process by which WBCs leave the blood stream
Usually due to a signal from infection or inflammation of that particular region or tissue

WBC Indices
WBCs are far less numerous than RBCs in the blood For diagnostic purposes, physicians measure the total number of circulating WBCs
Normal concentration ~5,000-10,000 cells/ml Leukocytosis
Increase in WBC count above 10,000 cells/ml Normal protective response due to stresses such as microbial infection, strenuous exercise, anesthesia , and surgery

Leukopenia
WBC count less than 5,000 cells/ml usually indicates a severe disease (AIDS, bone marrow failure, severe malnutrition, or chemotherapy)

WBC Indices
To enhance the diagnostic value of a WBC count, the percentages of each of the 5 types of WBCs is determined by using a machine to do a statistical analysis of the blood sample. This is called a WBC differential.

WBC Indices
Shifts in the normal percentages of circulating WBCs will often point towards a bacterial infection (elevated percentage of neutrophils) or a viral infection (elevated percentage of lymphocytes In this peripheral blood smear a patient with lymphocytic leukemia has a WBC >150,000 and 90% of the WBCs are cancerous lymphocytes!

Lymphocytic leukemia.

Formed Elements
Platelets
Also called thrombocytes Derived from megakaryocytes that splinter into 2000-3000 fragments Normal range = 150,000 400,000 platelets/ml Have many vesicles but are anucleate (no nucleus) Short life span
5 9 days

Form a platelet plug in damaged vessels and release chemicals that promote clotting

Hemostasis
Hemostasis
The sequence of responses that halts bleeding When blood vessels are damaged or ruptured, the hemostatic response must be quick, localized to the region of damage, and carefully controlled in order to be effective Requires clotting factors, and substances released by platelets and injured tissues Three mechanisms reduce blood loss
1. 2. 3.

Vascular spasm Formation of a platelet plug Blood clotting (coagulation)

Vascular Spasm
Vasoconstriction of damaged blood vessel Triggered by
Direct injury to vascular smooth muscle Chemicals released by endothelial cells (cells that line blood vessels) and platelets Pain reflexes

Formation of a Platelet Plug

Positive feedback cycle Damaged endothelium exposes collagen fibers
Platelets stick to collagen fibers via plasma protein von Willebrand factor Swell, become spiked and sticky, and release chemical messengers
ADP causes more platelets to stick and release their contents Serotonin and thromboxane A2 enhance vascular spasm and platelet aggregation

Coagulation
Reinforces platelet plug with fibrin threads
Thrombin: an enzyme that converts free fibrinogen (soluble) in the blood to fibrin threads (insoluble)

Blood transformed from liquid to gel-like substance Series of reactions that use clotting factors
# I XIII; most plasma proteins Vitamin K needed to synthesize 4 of them

Figure 17.13 Events of hemostasis.

Slide 1

Step 1 Vascular spasm Smooth muscle contracts, causing vasoconstriction.

Collagen fibers

Step 2 Platelet plug formation Injury to lining of vessel exposes collagen fibers; platelets adhere. Platelets release chemicals that make nearby platelets sticky; platelet plug forms.

Platelets

Fibrin
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Step 3 Coagulation Fibrin forms a mesh that traps red blood cells and platelets, forming the clot.

Clot Retraction
Clot retraction is the consolidation of the fibrin clot. As the clot retracts, it pulls the edges of the damaged vessel closer together, decreasing the risk of further damage
Actin and myosin in platelets contract Stabilizes clot new endothelial cells can then repair the vessel lining

Fibrinolysis
Because blood clotting involves amplification and positive feedback cycles, a clot has a tendency to enlarge, creating the potential for impairment of blood flow through undamaged vessels
The fibrinolytic system dissolves small, inappropriate clots
It also dissolves clots at a site of damage once the damage is repaired

Both body tissues and blood contain substances that can activate plasminogen to become plasmin, (the enzyme that actively dissolves clots)

Intravascular Clotting
Clotting in an unbroken blood vessel (usually a vein) is called thrombosis; the clot itself, called a thrombus
Embolus: thrombus freely floating in bloodstream Embolism: embolus obstructing a vessel
E.g., pulmonary and cerebral emboli Blocks blood supply to region and can result in tissue death

Risk factors atherosclerosis, infection, inflammation, slowly flowing blood or blood stasis from immobility

Anticoagulant Drugs
Aspirin
Antiprostaglandin that inhibits thromboxane A2

Heparin
Anticoagulant used clinically for pre- and postoperative cardiac care Helps antithrombin block thrombin formation and activity
Thrombin is involved in fibrin clot formation

Warfarin (Coumadin)
Interferes with action of vitamin K Works slower than heparin

Dabigatran directly inhibits thrombin

Next Lecture
Lecture 2 part 3: Blood type

Blood Transfusion
Blood transfusion Almost all donated blood in the U.S. is separated into its various components to make better use of it Whole blood is fractionated into units of;
Packed red blood cells (PRBCs) Fresh frozen plasma (FFP) Platelets WBCs The process of transferring blood or blood products from one person to another

Albumin, coagulation factors, and antibodies can be individually collected Serum - serum is just plasma without the clotting factors

Antigens and Antibodies

Red cells (and all cells in the body) have antigens on their surface which act as surface markers
Antigens can be;
Proteins Glycolipids = carbohydrate + lipid Glycoprotiens = carbohydrate + protein Proteolipids = protein + lipid

Anything perceived as foreign; generates an immune response

Antigens on foreign cells and particles generate these responses Promoters of agglutination (clumping); called agglutinogens Thus antigens are also called agglutinogens

Antigens and Antibodies

Antibody
Proteins produced by B-cells that are used by the immune system for identification and destruction of foreign objects Each antibody type is very specific for a particular antigen Antibodies are also called agglutinins

Human Blood Groups

Types A, B, AB, and O Based on presence or absence of two agglutinogens (A and B) on surface of RBCs Blood may contain preformed anti-A or anti-B antibodies (agglutinins)
Act against transfused RBCs with ABO antigens not present on recipient's RBCs

For instance, those with A antigens on their red cells have anti-B antibodies in their serum Anti-A or anti-B form in blood at about 2 months of age; adult levels by 8-10

Blood Groups
Blood typing for ABO status is done using single drops of blood mixed with different antisera
Agglutination with an antisera indicates the presence of that antigen on the RBC

Human Blood Groups

Rh antigen
Named due to its discovery in the blood of the Rhesus monkey Those with the Rh antigen are said to be Rh+ (positive) Those without the Rh antigen are Rh- (negative) Rh incompatibility can cause problems with any blood transfusion, so it is screened just as carefully as the ABO group

Anti-Rh antibodies not spontaneously formed in Rh individuals

Anti-Rh antibodies form if Rh individual receives Rh+ blood, or Rh mom carrying Rh+ fetus

Second exposure to Rh+ blood will result in typical transfusion reaction

Transfusion Reaction
Occur if mismatched blood infused Donor's cells
Attacked by recipient's plasma agglutinins Agglutinate and clog small vessels Rupture and release hemoglobin into bloodstream

Result in
Diminished oxygen-carrying capacity Diminished blood flow beyond blocked vessels Hemoglobin in kidney tubules renal failure

Table 17.4 ABO Blood Groups

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