Download Chapter 1. Circulatory System

Chapter 1. Circulatory System
- Blood
Reading: Vander, Sherman, and Luciano, Human Physiology, pp. 395-402, 741-749
Objectives:
1. Describe blood constituents and their functions
2. Describe the oxygen carrying capacity of blood vs. plasma.
3. Describe the roles of leukocytes and monocytes in the nonspecific
immune response.
4. Describe the major steps and key factors in hemostasis.
I. Introduction
A. Total blood volume in an average person is~5.5 liters
B. Plasma volume is 58-55% of total blood volume (TBV), or ~3 liters
1. 90% of plasma volume is water
2. organic solutes (plasma proteins) comprise 7% of plasma weight
3. inorganic solutes (electrolytes) comprise 1% of plasma weight
C. The hematocrit, or packed erythrycyte voume, is 42-45% of TBV
1. RBC count = 5,000,000/mm3 (mm3 = ul)
2. Hemoglobin content is 14-16g /dl
D. Leukocytes and platelets represent less than 1% of TBV
1. Leukocyte count = 7,000/mm3 (~ one WBC to every 700 RBCs)
a. Neutrophils = 50-70% of total leukocytes
b. Lymphocytes = 20-40% of total leukocytes
c.
Eosinophils 1-4%, Basophils 0.1%, Monocytes 2-8% of total WBCs
2. Platelet count = 250,000/mm3
II. Blood constituents and their functions
Constituents Functions
Plasma
1. Water Transport medium; carries heat
2. Electrolytes Membrane excitability; osmotic distribution of fluid between extracellular and
intracellular fluid; buffering of pH changes
3. Nutrients, wastes, Transported in blood; the blood gas CO2 plays a role in acid-base
balance
4. Gases, hormones
5. Plasma proteins
In general: exert osmotic effect that is important in distribution of extracellular fluid
between vascular and intersititial compartments; buffering pH changes
Albumins : Transports many substances; make greatest contribution to colloid osmotic
pressure
Globulins:
1) Alpha and beta : Transport many substances; clotting factors;
inactive precursor molecules
2) Gamma Antibodies
3) Fibrinogen Inactive precursor for fibrin meshwork of clot
Cellular Elements
1. Erythrocytes Transport O2 and CO2 (mainly O2)
2. Leukocytes :
1) Neutrophils Phagocytes that engulf bacteria and debris and participte in the
inflammatory response
2) Eosinophils Attack parasitic worms; important in allergic reactions
3) Basophils Release histamine, which is important in allergic reactions, and heparin,
which helps clear fat from blood and functions as an anticoagulant
4) Monocytes In transit to become tissue macrophages
5) Lymphocytes
i)
B lymphocytes Production of antibodies
ii)
T lymphocytes Cell-mediated immune responses
3. Platelets : Hemostasis
(Adapted from Human Physiology, From Cells to Systems, 2nd ed., Lauralee Sherwood)
Human Red Blood Cells, Platelets and T-lymphocyte (erythocytes = red; platelets = yellow; Tlymphocyte = light green) (SEM x 9,900).
III. Erythrocytes and oxygen
A.
Plasma-membrane-enclosed sac of hemoglobin, containing 200-300 million
hemoglobin (Hgb) molecules in each RBC
1.
Each Hgb molecule contains four subunits; each subunit consists of a heme
group and a polypeptide chain; all four polypeptide groups are collectively called
globin
2.
A single hemoglobin molecule can bind four molecules of oxygen (fully
saturated); oxygen binds to the iron atom of heme molecule. When fully saturated,
each gram of Hgb can bind 1.34 ml of O2. Thus, assuming 100% saturation:
O2 content of blood = 16g/100ml x 1.34 ml O2/g = 21.44 ml O2/100ml blood
3.
Dissolved oxygen in plasma ( at a normal PO2 of 100mm Hg) will supply only
0.3ml O2/100ml blood
IV. Leukocytes and Immunity
A. Leukocytes are the mobile units of the body's immune defense system.
B. Immune responses are classified as nonspecific or specific responses, depending
on the degree of selectivity of the defense mechanism
C. Nonspecific immune responses are defense responses that non-selectively defend
against foreign or abnormal material of any type, even upon initial expose to it.
1. Inflammation is a one of several nonspecific immune responses that occurs
in response to foreign invasion, tissue damage, or both.
a. Goal of inflammation is to
1) isolate, destroy, or inactivate the invaders
2) remove debris
3) prepare for subsequent healing
b. Phagocytic (engulfment and breakdown of foreign particles and
debris) leukocytes, the neutrophils and monocytes, play a major role in
the inflammatory response, undergoing
1)
Chemotaxis--directed migration of leukocytes by their attraction
to certain chemical mediators released by injured tissue
2)
Margination--adhesion (sticking) of blood-borne leukocytes to
the inner endothelial lining of capillaries and venules.
3)
Diapedesis--leukocyte cell spreading and projection of
pseudopods through vessel pores.
4)
Migration--leukocyte travels through tissue to site of injury
5)
Resident tissue macrophages (matured monocytes) are first on
the scene of injured tissue, followed by blood-borne leukocytes
(hour) and then by blood-borne monocytes (8-12 hours).
D. Specific immune responses are targeted against particular foreign material to which
the body has previously been exposed
1. These specific responses are mediated by the lymphocytes, which upon
ubsequent exposure to the same offending agent, recognize and discriminately defend
against it (to be covered in depth in Blood II Lec)
V. Hemostasis
A. Three major steps of hemostasis
1. Vascular spasm
2. Formation of platelet plug
3. Blood coagulation (clotting)
B. Vascular spasm
1. Cut or torn blood vessel immediately constricts as a response to injury
causing a sympathetically induced vasoconstriction resulting in decreased
blood flow; decreased flow minimizes blood loss
2. As opposing endothelial surfaces of the vessel are pressed together by this
initial vascular spasm, they become sticky and adhere to each other, further
sealing off the damaged vessel.
C. Formation of platelet plug
1. Platelets attach to exposed collagen of injured vessel
2. Enhanced platelet aggregation
a. Adenosine diphosphate (ADP), serotonin (in granules)--causes
surfaces of other circulating platelets to become sticky so they adhere
to the first layer of platelets
b. Thromboxane A2 (TXA2) (synthesized from arachidonic acid in
platelet plasma membrane)--enhances platelet aggregation and
triggers the release of more ADP
3. Platelet plug contracts via actin-myosin, to strengthen and compact the plug
4. Platelet plug releases vasoconstrictors (serotonin, epinephrine, TXA2),
reinforcing the initial, self-induced vascular spasm
5. Platelet plug releases other chemicals that enhance blood clotting, the next
step in hemostasis
6. Endothelial cell production of prostaglandin I2 prevents platelet aggregation
on adjacent, noninjured surface
D. Blood coagulation
1. A triggered chain reacton involving clotting factors in the plasma results in
blood coagulation
2. Blood coagulation is the transformation of blood from a liquid into a gel
3. The clotting cascade may be triggered by the intrinsic pathway or the
extrinsic pathway
a) In the body, the extrinsic pathway is usually the initiator of clotting
(initiated by an element "outside the blood", therefore extrinsic)
1) A tissue factor (Factor III, or tissue thromboplastin) released
by the injured tissue initiates the clotting cascad
b) The instrinsic pathway may be activated when blood elements come
into contact with exposed collagen or to foreign surfaces such as glass
test tubes (all elements are "insidethe blood", therefore intrinsic)
1) Factor XII (Hageman factor) in the blood initiates the
cascade
4. The final common steps for both pathways include:
a) conversion of prothrombin (Factor II) to thrombin
b) thrombin, in turn
1) converts fibrinogen to a fibrin (loose network)
2) activates Factor XIII which acts to stabilize the fibrin
meshwork
3) activates more prothrombin into thrombin in positivefeedback mechanism
4) enhances platelet aggregation
5) thrombin produced by the extrisic pathway (in-vivo) activates
an early step in the intrinsic pathway, amplifying the process
4.
Plasminogen->plasmin->fibrin clot breakdown
VI. Wound healing
A. Trauma : Open cut
B. Inflammatory response
1. Vasodilation
2. Early invasion of neutrophils
3. Later invasion of monocytes\macrophages
C. Fibroblast : Produce proteins needed for revascularization
D. Revascularization : New capillaries are formed to supply needed nutrients
VII. Blood Vessel
A
B
Vasculogenesis and Angiogenesis
Further Reading
How do scientists make artificial blood? How effective is it compared with the real thing?
The concept of 'artificial blood' sounds simple, but it isn't. When William Harvey first described the
circulation of blood in 1616, scientists starting thinking about whether blood could be removed and
replaced by other liquids, such as wine and milk, for example. They thought that by doing so, diseases
could be cured and even that personalities could be changed. Obviously, there were some interesting but
disappointing experiments!
Modern efforts to produce artificial blood were spurred on by the military in World Wars I and II and,
more recently, by the discovery in the early 1980s that HIV could be transmitted by blood transfusion.
Blood is now safe, thanks to improved collection and screening by blood banks. But it still has to be
cross-matched and can be stored for only a few weeks before it has to be discarded. If a solution that
could replace blood were immediately available, if it were completely safe, and if it could be stored for
long periods, it would be extremely useful in emergencies, disaster and wars--not to mention in countries
where blood is not collected and stored as it is in the U.S and western Europe.
Blood does many things, of course, and artificial blood is designed to do only one of them: carry
oxygen and carbon dioxide. No substitutes have yet been invented that can replace the other vital
functions of blood: coagulation and immune defense. Therefore, the replacement solutions being
developed today are more accurately described as oxygen carriers. There are basically two types of
oxygen carriers, which differ in the way they transport oxygen. One is based on perfluorochemicals, the
other on hemoglobin.
Perfluorochemicals are inert materials that can dissolve approximately 50 times more oxygen than
blood plasma, the liquid that surrounds the red cells. Perfluorochemicals are cheap to produce and are
completely free of biological materials so there is no risk of infectious agents contaminating them. In
order to work, however, they must be combined with other materials that enable them to mix in with the
bloodstream. These companion materials are fatty compounds known as lipids. They take the form of an
emulsion, a suspension of extremely small particles in a liquid that can be injected into a patient. One
such lipid product was approved by the Food and Drug Administration, but it has not proved successful,
because the amount that can be administered is not enough to achieve a significant benefit. Improved
versions of perfluorocarbon emulsions are being developed but have not yet reached the market.
Hemoglobin-based oxygen carriers (HBOCs) utilize the same oxygen-carrying protein molecule found
in blood. Oxygen bonds chemically to the hemoglobin, whereas it dissolves only into the perfluorocarbon
emulsions. HBOCs differ from red blood cells in that the hemoglobin is not contained within a membrane.
The membrane of a red blood cell contains the antigen molecules that determine the 'type' of the blood (A,
B, AB or O). Because HBOCs have no membranes, they do not need to be cross-matched by type and can
be given to any patient without previous testing. In addition, these artificial oxygen carriers can be stored
for long periods, greatly simplifying the work of the blood bank. Best of all, HBOCs can be used in
situations and locations where real blood is not available, as at disaster sites, underdeveloped countries or
battle zones.
Two main problems arise when hemoglobin is removed from the red blood cells; these problems
account for the large amount of scientific research that has been conducted so far in this area. First, the
red cell membrane protects hemoglobin from degradation and protects tissues from the toxic effects of
free hemoglobin. Second, when oxygen is being delivered by a cell-free carrier instead of red blood cells,
complex biological mechanisms alter the flow through the smallest blood vessels (the arterioles and
capillaries). Major advances have been made in overcoming both of these problems, and several HBOC
products are now in advanced human trials. It is anticipated that in the next one to two years the first of
these products will become available to physicians for use in patients.
The second part of the question, regarding the efficacy of oxygen carriers, is difficult to answer. From
the discussion above, it is clear that real blood and artificial blood are not strictly comparable, so
controlled comparisons are tricky. The Food and Drug Administration and the National Institutes of
Health have held two major conferences to address how these new products should be developed. A
provisional answer is that if the artificial product can reduce the use of blood, it will achieve a useful goal.
But based on animal studies, many of us working in the field believe that HBOCs will perform their
specialized function--delivery of oxygen to tissues--even better than blood.
Hemoglobin-Based Red Cell Substitutes. Robert M. Winslow. Johns Hopkins University
Press, 1992.
Blood Substitutes--A Moving Target. Robert M. Winslow in Nature Medicine, Vol. 1,
No. 11, pages1212-1215; 1995.
Blood Substitutes. Robert M. Winslow in Science & Medicine, Vol. 4, No. 2, pages 5463; 1996.