Blood Clotting

Normally, blood remains in its liquid form as long as it stays within its
vessels. If it is drawn from the body, however, it thickens and forms a
gel. Eventually, the gel separates from the liquid. The straw-colored liq-
uid, called serum, is simply blood plasma minus the clotting proteins.
The gel is called a blood clot. It consists of a network of insoluble pro-
tein fibers called fibrin in which the formed elements of blood are
trapped (Figure 19.10).
The process of gel formation, called clotting or coagulation
(kō-ag-u-LA
- -shun), is a series of chemical reactions that culminates
in formation of fibrin threads. If blood clots too easily, the result
can be thrombosis (throm-BO
- -sis; thromb- = clot; -osis = a condi-
tion of)—clotting in an undamaged blood vessel. If the blood takes
too long to clot, hemorrhage can occur.
Clotting involves several substances known as clotting (coagula-
tion) factors. These factors include calcium ions (Ca2+), several inactive
enzymes that are synthesized by hepatocytes (liver cells) and released
into the bloodstream, and various molecules associated with platelets
or released by damaged tissues. Most clotting factors are identified by
Roman numerals that indicate the order of their discovery (not neces-
sarily the order of their participation in the clotting process).
Clotting is a complex cascade of enzymatic reactions in which each
clotting factor activates many molecules of the next one in a fixed se-
quence. Finally, a large quantity of product (the insoluble protein fibrin)
is formed. Clotting can be divided into three stages (Figure 19.11):
1 Two pathways, called the extrinsic pathway and the intrinsic
pathway (Figures 19.11a, b), which will be described shortly,
lead to the formation of prothrombinase. Once prothrombinase
is formed, the steps involved in the next two stages of clotting
are the same for both the extrinsic and intrinsic pathways, and
together these two stages are referred to as the common pathway.
2 Prothrombinase converts prothrombin (a plasma protein formed
by the liver) into the enzyme thrombin.
3 Thrombin converts soluble fibrinogen (another plasma protein
formed by the liver) into insoluble fibrin. Fibrin forms the threads
of the clot.
The Extrinsic Pathway The extrinsic pathway of blood
clotting has fewer steps than the intrinsic pathway and occurs
rapidly—within a matter of seconds if trauma is severe. It is so named
because a tissue protein called tissue factor (TF), also known as
thromboplastin (throm′-bō-PLAS-tin), leaks into the blood from
cells outside (extrinsic to) blood vessels and initiates the formation
of prothrombinase. TF is a complex mixture of lipoproteins and
phospholipids released from the surfaces of damaged cells. In the
presence of Ca 2+, TF begins a sequence of reactions that ultimately
activates clotting factor X (Figure 19.11a). Once factor X is activated,
it combines with factor V in the presence of Ca 2+ to form the active
enzyme prothrombinase, completing the extrinsic pathway.
The Intrinsic Pathway The intrinsic pathway of blood
clotting is more complex than the extrinsic pathway, and it occurs more
slowly, usually requiring several minutes. The intrinsic pathway is so
named because its activators are either in direct contact with blood or
Tissue trauma
Tissue
factor
(TF)
Blood trauma
Damaged
endothelial cells
expose collagen
fibers
1
(a) EXTRINSIC PATHWAY (b) INTRINSIC PATHWAY
Activated XII
Ca 2+
Damaged
platelets
Ca 2 +
Platelet
phospholipids
Activated X
Activated
platelets
Activated X
PROTHROMBINASE
Ca 2+
V
Ca2+
Prothrombin
(II)
V
Ca 2 +
2
+
+
THROMBIN
Ca 2+
Loose fibrin
threads
STRENGTHENED
FIBRIN THREADS
Activated XIII
Fibrinogen
(I)
XIII
3
(c) COMMON
PATHWAY
FIGURE 19.11 The blood-clotting cascade. Green arrows represent
positive feedback cycles.
In blood clotting, coagulation factors are activated in sequence, resulting
in a cascade of reactions that includes positive feedback cycles.
Q What is the outcome of the first stage of blood clotting?
686 CHAPTER 1 9 The Cardiovascular System: The Blood
which release factor XIII and other factors, thereby strengthening and
stabilizing the clot. Permanent repair of the blood vessel can then
take place. In time, fibroblasts form connective tissue in the ruptured
area, and new endothelial cells repair the vessel lining.
Role of Vitamin K in Clotting
Normal clotting depends on adequate levels of vitamin K in the body.
Although vitamin K is not involved in actual clot formation, it is
required for the synthesis of four clotting factors. Normally produced
by bacteria that inhabit the large intestine, vitamin K is a fat-soluble
vitamin that can be absorbed through the lining of the intestine and
into the blood if absorption of lipids is normal. People suffering from
disorders that slow absorption of lipids (for example, inadequate
release of bile into the small intestine) often experience uncontrolled
bleeding as a consequence of vitamin K deficiency.
The various clotting factors, their sources, and the pathways of
activation are summarized in Table 19.4.
Homeostatic Control Mechanisms
Many times a day little clots start to form, often at a site of minor rough-
ness or at a developing atherosclerotic plaque inside a blood vessel.
Because blood clotting involves amplification and positive feedback
cycles, a clot has a tendency to enlarge, creating the potential for impair-
ment of blood flow through undamaged vessels. The fibrinolytic system
(fī-bri-nō-LIT-ik) dissolves small, inappropriate clots; it also dissolves clots
at a site of damage once the damage is repaired. Dissolution of a clot is
called fibrinolysis (fī-bri-NOL-i-sis). When a clot is formed, an inactive
plasma enzyme called plasminogen (plaz-MIN-o-jen) is incorporated into
the clot. Both body tissues and blood contain substances that can activate
plasminogen to plasmin or fibrinolysin (fī-brin-ō-LI
--sin), an active plasma
of a blood collection tube) activates clotting factor XII (Figure 19.11b),
which begins a sequence of reactions that eventually activates clotting
factor X. Platelet phospholipids and Ca 2+ can also participate in the
activation of factor X. Once factor X is activated, it combines with factor
V to form the active enzyme prothrombinase (just as occurs in the
extrinsic pathway), completing the intrinsic pathway.
The Common Pathway The formation of prothrombinase
marks the beginning of the common pathway. In the second stage of
blood clotting (Figure 19.11c), prothrombinase and Ca2+ catalyze the
conversion of prothrombin to thrombin. In the third stage, thrombin,
in the presence of Ca2+, converts fibrinogen, which is soluble, to loose
fibrin threads, which are insoluble. Thrombin also activates factor XIII
(fibrin stabilizing factor), which strengthens and stabilizes the fibrin
threads into a sturdy clot. Plasma contains some factor XIII, which is
also released by platelets trapped in the clot.
Thrombin has two positive feedback effects. In the first positive
feedback loop, which involves factor V, it accelerates the formation of
prothrombinase. Prothrombinase in turn accelerates the production
of more thrombin, and so on. In the second positive feedback loop,
thrombin activates platelets, which reinforces their aggregation and
the release of platelet phospholipids.
Clot Retraction Once a clot is formed, it plugs the ruptured
area of the blood vessel and thus stops blood loss. Clot retraction
is the consolidation or tightening of the fibrin clot. The fibrin threads
attached to the damaged surfaces of the blood vessel gradually
contract as platelets pull on them. As the clot retracts, it pulls the
edges of the damaged vessel closer together, decreasing the risk of
further damage. During retraction, some serum can escape between
the fibrin threads, but the formed elements in blood cannot. Normal
retraction depends on an adequate number of platelets in the clot,
TA B L E 1 9 . 4 Clotting (Coagulation) Factors
NUMBER* NAME(S) SOURCE
PATHWAY(S) OF
ACTIVATION
I Fibrinogen. Liver. Common.
II Prothrombin. Liver. Common.
III Tissue factor (thromboplastin). Damaged tissues and activated platelets. Extrinsic.
IV Calcium ions (Ca 2+). Diet, bones, and platelets. All.
V Proaccelerin, labile factor, or accelerator globulin (AcG). Liver and platelets. Extrinsic and
intrinsic.
VII Serum prothrombin conversion accelerator (SPCA), stable factor, or
proconvertin.
Liver. Extrinsic.
VIII Antihemophilic factor (AHF), antihemophilic factor A, or antihemophilic
globulin (AHG).
Liver. Intrinsic.
IX Christmas factor, plasma thromboplastin component (PTC), or
antihemophilic factor B.
Liver. Intrinsic.
X Stuart factor, Prower factor, or thrombokinase. Liver. Extrinsic and intrinsic.
XI Plasma thromboplastin antecedent (PTA) or antihemophilic factor C. Liver. Intrinsic.
XII Hageman factor, glass factor, contact factor, or antihemophilic factor D. Liver. Intrinsic.
XIII Fibrin-stabilizing factor (FSF). Liver and platelets. Common.
*There is no factor VI. Prothrombinase (prothrombin activator) is a combination of activated factors V and X.
19.8 Blood Groups and Blood Types 687
itself, called a thrombus (THROM-bus), may dissolve spontaneously. If it
remains intact, however, the thrombus may become dislodged and be
swept away in the blood. A blood clot, bubble of air, fat from broken
bones, or a piece of debris transported by the bloodstream is called an
embolus (EM-bō-lus; em- = in; -bolus= a mass). An embolus that breaks
away from an arterial wall may lodge in a smaller-diameter artery down-
stream and block blood flow to a vital organ. When an embolus lodges in
the lungs, the condition is called pulmonary embolism.
Checkpoint
18. What is hemostasis?
19. How do vascular spasm and platelet plug formation occur?
20. What is fibrinolysis? Why does blood rarely remain clotted inside
blood vessels?
21. How do the extrinsic and intrinsic pathways of blood clotting differ?
22. Define each of the following terms: anticoagulant, thrombus,
embolus, and thrombolytic agent.

Blood Groups and

19.8

Blood Types
OBJECTIVES
• Distinguish between the ABO and Rh blood groups.
• Explain why it is so important to match donor and recipient blood
types before administering a transfusion.
The surfaces of erythrocytes contain a genetically determined assort-
ment of antigens composed of glycoproteins and glycolipids. These
antigens, called agglutinogens (a-gloo-TIN-ō-jens), occur in characteris-
tic combinations. Based on the presence or absence of various anti-
gens, blood is categorized into different blood groups. Within a given
blood group, there may be two or more different blood types. There
are at least 24 blood groups and more than 100 antigens that can be
detected on the surface of red blood cells. Here we discuss two major
blood groups—ABO and Rh. Other blood groups include the Lewis, Kell,
Kidd, and Duffy systems. The incidence of ABO and Rh blood types var-
ies among different population groups, as indicated in Table 19.5.
enzyme. Among these substances are thrombin, activated factor XII, and
tissue plasminogen activator (t-PA), which is synthesized in endothelial
cells of most tissues and liberated into the blood. Once plasmin is formed,
it can dissolve the clot by digesting fibrin threads and inactivating sub-
stances such as fibrinogen, prothrombin, and factors V and XII.
Even though thrombin has a positive feedback eff ect on blood
clotting, clot formation normally remains localized at the site of dam-
age. A clot does not extend beyond a wound site into the general cir-
culation, in part because fibrin absorbs thrombin into the clot. An-
other reason for localized clot formation is that because of the disper-
sal of some of the clotting factors by the blood, their concentrations
are not high enough to bring about widespread clotting.
Several other mechanisms also control blood clotting. For example,
endothelial cells and white blood cells produce a prostaglandin called
prostacyclin (pros-ta-SI
--klin) that opposes the actions of thromboxane
A2. Prostacyclin is a powerful inhibitor of platelet adhesion and release.
In addition, substances that delay, suppress, or prevent blood clot-
ting, called anticoagulants (an′-tī-kō-AG-ū-lants), are present in blood.
These include antithrombin, which blocks the action of several factors,
including XII, X, and II (prothrombin). Heparin, an anticoagulant that is
produced by mast cells and basophils, combines with antithrombin
and increases its eff ectiveness in blocking thrombin. Another antico-
agulant, activated protein C (APC), inactivates the two major clotting
factors not blocked by antithrombin and enhances activity of plasmino-
gen activators. Babies that lack the ability to produce APC due to a ge-
netic mutation usually die of blood clots in infancy.
Intravascular Clotting
Despite the anticoagulating and fibrinolytic mechanisms, blood clots
sometimes form within the cardiovascular system. Such clots may be
initiated by roughened endothelial surfaces of a blood vessel resulting
from atherosclerosis, trauma, or infection. These conditions induce
adhesion of platelets. Intravascular clots may also form when blood
flows too slowly (stasis), allowing clotting factors to accumulate locally
in high enough concentrations to initiate coagulation. Clotting in an
unbroken blood vessel (usually a vein) is called thrombosis. The clot
Clinical Connection
Aspirin and Thrombolytic Agents
In patients with heart and blood vessel disease, the events of hemosta-
sis may occur even without external injury to a blood vessel. At low doses,
aspirin inhibits vasoconstriction and platelet aggregation by blocking syn-
thesis of thromboxane A2. It also reduces the chance of thrombus formation.
Due to these effects, aspirin reduces the risk of transient ischemic attacks
(TIA), strokes, myocardial infarction, and blockage of peripheral arteries.
Thrombolytic agents (throm′-bō-LIT-ik) are chemical substances that
are injected into the body to dissolve blood clots that have already formed to
restore circulation. They either directly or indirectly activate plasminogen.
The first thrombolytic agent, approved in 1982 for dissolving clots in the
coronary arteries of the heart, was streptokinase, which is produced by
streptococcal bacteria. A genetically engineered version of human tissue
plasminogen activator (tPA) is now used to treat victims of both heart
attacks and brain attacks (strokes) that are caused by blood clots.
TABLE 19.5 Blood Types in the United States
BLOOD TYPE (PERCENTAGE)
POPULATION GROUP O A B AB Rh+
European-American 45 40 11 4 85
African-American 49 27 20 4 95
Korean-American 32 28 30 10 100
Japanese-American 31 38 21 10 100
Chinese-American 42 27 25 6 100
Native American 79 16 4 1 100
688 CHAPTER 1 9 The Cardiovascular System: The Blood
severe hemorrhage), or to improve immunity. However, the normal
components of one person’s RBC plasma membrane can trigger dam-
aging antigen–antibody responses in a transfusion recipient. In an
incompatible blood transfusion, antibodies in the recipient’s plasma
bind to the antigens on the donated RBCs, which causes agglutina-
tion (a-gloo-ti-NA
- -shun), or clumping, of the RBCs. Agglutination is an
antigen–antibody response in which RBCs become cross-linked to
one another. (Note that agglutination is not the same as blood clot-
ting.) When these antigen–antibody complexes form, they activate
plasma proteins of the complement family (described in Section
22.6). In essence, complement molecules make the plasma mem-
brane of the donated RBCs leaky, causing hemolysis (hē-MOL-i-sis) or
rupture of the RBCs and the release of hemoglobin into the blood
plasma. The liberated hemoglobin may cause kidney damage by clog-
ging the filtration membranes. Although quite rare, it is possible for
the viruses that cause AIDS and hepatitis B and C to be transmitted
through transfusion of contaminated blood products.
Consider what happens if a person with type A blood receives a
transfusion of type B blood. The recipient’s blood (type A) contains A
antigens on the red blood cells and anti-B antibodies in the plasma.
The donor’s blood (type B) contains B antigens and anti-A antibodies.
In this situation, two things can happen. First, the anti-B antibodies in
the recipient’s plasma can bind to the B antigens on the donor’s eryth-
rocytes, causing agglutination and hemolysis of the red blood cells.
Second, the anti-A antibodies in the donor’s plasma can bind to the A
antigens on the recipient’s red blood cells, a less serious reaction be-
cause the donor’s anti-A antibodies become so diluted in the recipi-
ent’s plasma that they do not cause significant agglutination and he-
molysis of the recipient’s RBCs.
People with type AB blood do not have anti-A or anti-B antibodies
in their blood plasma. They are sometimes called universal recipients
because theoretically they can receive blood from donors of all four
ABO Blood Group
The ABO blood group is based on two glycolipid antigens called A
and B (Figure 19.12). People whose RBCs display only antigen A have
type A blood. Those who have only antigen B are type B. Individuals
who have both A and B antigens are type AB; those who have neither
antigen A nor B are type O.
Blood plasma usually contains antibodies called agglutinins (a-
GLOO-ti-nins) that react with the A or B antigens if the two are mixed.
These are the anti-A antibody, which reacts with antigen A, and the
anti-B antibody, which reacts with antigen B. The antibodies present
in each of the four blood types are shown in Figure 19.12. You do not
have antibodies that react with the antigens of your own RBCs, but
you do have antibodies for any antigens that your RBCs lack. For ex-
ample, if your blood type is B, you have B antigens on your red blood
cells, and you have anti-A antibodies in your blood plasma. Although
agglutinins start to appear in the blood within a few months aft er
birth, the reason for their presence is not clear. Perhaps they are
formed in response to bacteria that normally inhabit the gastrointes-
tinal tract. Because the antibodies are large IgM-type antibodies
(see Table 22.3) that do not cross the placenta, ABO incompatibil-
ity between a mother and her fetus rarely causes problems.
Transfusions
Despite the differences in RBC antigens reflected in the blood group
systems, blood is the most easily shared of human tissues, saving
many thousands of lives every year through transfusions. A transfu-
sion (trans-FU
- -zhun) is the transfer of whole blood or blood compo-
nents (red blood cells only or blood plasma only) into the bloodstream
or directly into the red bone marrow. A transfusion is most often given
to alleviate anemia, to increase blood volume (for example, aft er a
TYPE B
B antigen
TYPE A
A antigen
TYPE O
Neither
A nor B antigen
TYPE AB
Both A and B antigens
BLOOD TYPE
Red blood cells
Plasma
Both anti-A and
anti-B antibodies
Neither
antibody
Anti-A
antibody
Anti-B
antibody
FIGURE 19.12 Antigens and antibodies of the ABO blood types.
The antibodies in your plasma do not react with the antigens on your red blood cells.
Q Which antibodies are usually present in type O blood?
19.8 Blood Groups and Blood Types 689
blood types. They have no antibodies to attack antigens on donated
RBCs. People with type O blood have neither A nor B antigens on their
RBCs and are sometimes called universal donors because theoreti-
cally they can donate blood to all four ABO blood types. Type O per-
sons requiring blood may receive only type O blood ( Table 19.6). In
practice, use of the terms universal recipient and universal donor is
misleading and dangerous. Blood contains antigens and antibodies
other than those associated with the ABO system that can cause
transfusion problems. Thus, blood should be carefully cross-matched
or screened before transfusion. In about 80% of the population, solu-
ble antigens of the ABO type appear in saliva and other body fluids, in
which case blood type can be identified from a sample of saliva.
Rh Blood Group
The Rh blood group is so named because the Rh antigen, called Rh
factor, was first found in the blood of the Rhesus monkey. The alleles
of three genes may code for the Rh antigen. People whose RBCs have
Rh antigens are designated Rh+ (Rh positive); those who lack Rh anti-
gens are designated Rh − (Rh negative). Table 19.5 shows the inci-
dence of Rh+ and Rh− in various populations. Normally, blood plasma
does not contain anti-Rh antibodies. If an Rh− person receives an Rh+
blood transfusion, however, the immune system starts to make anti-
Rh antibodies that will remain in the blood. If a second transfusion of
Rh+ blood is given later, the previously formed anti-Rh antibodies will
cause agglutination and hemolysis of the RBCs in the donated blood,
and a severe reaction may occur.
Typing and Cross-Matching Blood
for Transfusion
To avoid blood-type mismatches, laboratory technicians type the
patient’s blood and then either cross-match it to potential donor blood
or screen it for the presence of antibodies. In the procedure for ABO
blood typing, single drops of blood are mixed with diff erent antisera,
TA B L E 1 9 . 6 Summary of ABO Blood Group Interactions
BLOOD TYPE
CHARACTERISTIC A B AB O
Agglutinogen
(antigen) on RBCs
A B Both A
and B
Neither
A nor B
Agglutinin (antibody)
in plasma
Anti-B Anti-A Neither
anti-A nor
anti-B
Both anti-A
and anti-B
Compatible donor
blood types (no
hemolysis)
A, O B, O A, B, AB, O O
Incompatible donor
blood types
(hemolysis)
B, AB A, AB — A, B, AB
Clinical Connection
Hemolytic Disease of the Newborn
The most common problem with Rh incompatibility, hemolytic disease
of the newborn (HDN), may arise during pregnancy (Figure 19.13). Nor-
mally, no direct contact occurs between maternal and fetal blood while a
woman is pregnant. However, if a small amount of Rh + blood leaks from
the fetus through the placenta into the bloodstream of an Rh − mother, the
mother will start to make anti-Rh antibodies. Because the greatest possi-
bility of fetal blood leakage into the maternal circulation occurs at delivery,
the firstborn baby usually is not affected. If the mother becomes pregnant
again, however, her anti-Rh antibodies can cross the placenta and enter
the bloodstream of the fetus. If the fetus is Rh −, there is no problem, be-
cause Rh− blood does not have the Rh antigen. If the fetus is Rh+, however,
agglutination and hemolysis brought on by fetal–maternal incompatibility
may occur in the fetal blood.
An injection of anti-Rh antibodies called anti-Rh gamma globulin
(RhoGAM®) can be given to prevent HDN. Rh − women should receive
RhoGAM® before delivery, and soon aft er every delivery, miscarriage, or
abortion. These antibodies bind to and inactivate the fetal Rh antigens
before the mother’s immune system can respond to the foreign antigens
by producing her own anti-Rh antibodies.
(a) (b) (c)
Rh–
mother
Rh+
antigens
Anti-Rh
antibodies Second
Rh +
fetus
First
Rh +
fetus
First
pregnancy
Second
pregnancy
Between
pregnancies
Placenta
FIGURE 19.13 Development of hemolytic disease of the newborn
(HDN). (a) At birth, a small quantity of fetal blood usually leaks across
the placenta into the maternal bloodstream. A problem can arise when
the mother is Rh− and the baby is Rh+, having inherited an allele for the
Rh antigens from the father. (b) On exposure to Rh antigen, the mother’s
immune system responds by making anti-Rh antibodies. (c) During a
subsequent pregnancy, the maternal antibodies cross the placenta into the
fetal blood. If the second fetus is Rh+, the ensuing antigen–antibody reac