Hemostasis and Blood Coagulation pdf - Blood Cells and Immunity and Blood Clotting

and especially store large quantities of calcium ions; (3) mitochondria and

, that can cause the platelets to contract; (2) residuals of both the

to those found in muscle cells, and still another contractile protein,

, which are contractile proteins similar

they do not have nuclei and cannot reproduce. In their cytoplasm are such active

Platelets have many functional characteristics of whole cells, even though

per microliter.

after entering the blood, especially as they squeeze through capillaries. The

ocytes fragment into the minute platelets either in the bone marrow or soon

extremely large cells of the hematopoietic series in the marrow; the megakary-

, which are

eter. They are formed in the bone marrow from

we first discuss the nature of platelets themselves.

rather than by a blood clot. To understand this, it is important that

platelet plug,

If the cut in the blood vessel is very small—indeed, many very small vascular

Formation of the Platelet Plug

the processes of platelet plugging and blood coagulation can take place.

spasm. The spasm can last for many minutes or even hours, during which time

The more severely a vessel is traumatized, the greater the degree of vascular

thromboxane A

ing a vasoconstrictor substance,

vessels, the platelets are responsible for much of the vasoconstriction by releas-

vessels initiated by direct damage to the vascular wall. And, for the smaller

inate from the traumatized vessel or nearby tissues. However, even more vaso-

matized tissues and blood platelets, and (3) nervous reflexes. The nervous

results from (1) local myogenic spasm, (2) local autacoid factors from the trau-

taneously reduces the flow of blood from the ruptured vessel. The contraction

vessel wall itself causes the smooth muscle in the wall to contract; this instan-

Immediately after a blood vessel has been cut or ruptured, the trauma to the

Vascular Constriction

fibrous tissue into the blood clot to close the hole in the vessel permanently.

blood coagulation, and (4) eventual growth of

plug, (3) formation of a blood clot as a result of

vascular constriction, (2) formation of a platelet

hemostasis is achieved by several mechanisms: (1)

loss. Whenever a vessel is severed or ruptured,

The term

457

Hemostasis and Blood Coagulation

Events in Hemostasis

hemostasis means prevention of blood

reflexes are initiated by pain nerve impulses or other sensory impulses that orig-

constriction probably results from local myogenic contraction of the blood

holes do develop throughout the body each day—the cut is often sealed by a

Physical and Chemical Characteristics of Platelets

Platelets (also called thrombocytes) are minute discs 1 to 4 micrometers in diam-

megakaryocytes

normal concentration of platelets in the blood is between 150,000 and 300,000

factors as (1) actin and myosin molecules

throm-

bosthenin
endoplasmic reticulum and the Golgi apparatus that synthesize various enzymes

courses: (1) It can become invaded by

Once a blood clot has formed, it can follow one of two

Fibrous Organization or Dissolution

in this clot retraction, as is discussed later.

vessel still further. Platelets also play an important role

minutes to an hour, the clot retracts; this closes the

broken end of the vessel is filled with clot. After 20

vessel opening is not too large, the entire opening or

Within 3 to 6 minutes after rupture of a vessel, if the

important of the clotting factors.

shown in Figure 36–1, and Table 36–1 lists the most

clotting process. The physical events of this process are

cular wall, from platelets, and from blood proteins

minor. Activator substances from the traumatized vas-

severe, and in 1 to 2 minutes if the trauma has been

the blood clot. The clot begins to develop in 15 to 20

The third mechanism for hemostasis is formation of

Ruptured Vessel

Blood Coagulation in the

skin and throughout the internal tissues, but this does

form additional endothelial cell membrane. A person

daily. Indeed, multiple small holes through the

The platelet-plugging mechanism is extremely

Importance of the Platelet Mechanism for Closing Vascular

an unyielding plug.

These attach tightly to the platelets, thus constructing

cular opening is small. Then, during the subsequent

This is at first a loose plug, but

platelet plug.

selves attract more and more additional platelets, thus

vessel wall, the damaged vascular wall activates suc-

Therefore, at the site of any opening in a blood

activated platelets.

activate them as well, and the stickiness of these addi-

. The ADP

thromboxane A

from the plasma; they secrete large quantities of ADP;

von Wille-

factors; they become sticky so that they adhere to col-

swell; they assume irregular forms with numerous irra-

their own characteristics drastically. They begin to

wall, the platelets themselves immediately change

surface, especially with collagen fibers in the vascular

important functions of the platelet itself. When

trabeculae.

macrophage system. More than one half of the

weeks its functional processes run out. Then it is

life in the blood of 8 to 12 days, so that over several

Thus, the platelet is an active structure. It has a half-

in the blood-clotting process, as we discuss later.

addition, the platelet membrane contains large

exposed collagen from deep within the vessel wall. In

areas of the vessel wall, especially

The cell membrane of the platelets is also important.

eventually helps repair damaged vascular walls.

multiply and grow, thus causing cellular growth that

cells, vascular smooth muscle cells, and fibroblasts to

growth factor

we discuss later in relation to blood coagulation; and

, which

many vascular and other local tissue reactions; (5) an

, which are local hormones that cause

(ADP);

(4) enzyme systems that synthesize

(ATP) and

Blood Cells, Immunity, and Blood Clotting

458

Unit VI

enzyme systems that are capable of forming adenosine
triphosphate

adenosine diphosphate

prostaglandins

important protein called fibrin-stabilizing factor

(6) a

that causes vascular endothelial

On its surface is a coat of glycoproteins that repulses
adherence to normal endothelium and yet causes
adherence to injured
to injured endothelial cells and even more so to any

amounts of phospholipids that activate multiple stages

eliminated from the circulation mainly by the tissue

platelets are removed by macrophages in the spleen,
where the blood passes through a latticework of tight

Mechanism of the Platelet Plug

Platelet repair of vascular openings is based on several

platelets come in contact with a damaged vascular

diating pseudopods protruding from their surfaces;
their contractile proteins contract forcefully and cause
the release of granules that contain multiple active

lagen in the tissues and to a protein called
brand factor that leaks into the traumatized tissue

and their enzymes form

and thromboxane in turn act on nearby platelets to

tional platelets causes them to adhere to the original

cessively increasing numbers of platelets that them-

forming a
it is usually successful in blocking blood loss if the vas-

process of blood coagulation, fibrin threads form.

Holes.

important for closing minute ruptures in very small
blood vessels that occur many thousands of times

endothelial cells themselves are often closed by
platelets actually fusing with the endothelial cells to

who has few blood platelets develops each day liter-
ally thousands of small hemorrhagic areas under the

not occur in the normal person.

seconds if the trauma to the vascular wall has been

adhering to the traumatized vascular wall initiate the

of the Blood Clot

fibroblasts,

1. Severed vessel

2. Platelets agglutinate

3. Fibrin appears

5. Clot retraction occurs

4. Fibrin clot forms

Thomas, Publisher, Ltd., Springfield, IL.)

Seegers WH: Hemostatic Agents, 1948. Courtesy of Charles C

Clotting process in a traumatized blood vessel. (Modified from

Figure 36–1

form the clot itself.

fibrin fibers within another 10 to 15 seconds. Thus, the

thrombin to thrombin (Figure 36–2). Third, the throm-

, causes conversion of pro-

thrombin activator, in the presence of sufficient

to special substances in the blood. Second, the pro-

First, prothrombin activator is formed as a result of

Conversion of Prothrombin

of prothrombin to thrombin; then we will come back

blood clot itself is formed, beginning with conversion

enmesh platelets, blood cells, and plasma to form the

. (3) The thrombin acts as

The prothrombin activator catalyzes conversion of

. (2)

more than a dozen blood coagulation factors. The net

vessel or damage to the blood itself, a complex cascade

three essential steps: (1) In response to rupture of the

develop.

and override the anticoagulants, and then a clot does

from the area of tissue damage become “activated”

vessels. But when a vessel is ruptured, procoagulants

coagulants normally predominate, so that the blood

groups of substances. In the blood stream, the anti-

. Whether blood will

coagulation, called

procoagulants,

ulation, called

Basic Theory.

to dissolve the clot, as discussed later in the chapter.

usually become activated. These function as enzymes

not needed, special substances within the clot itself

Conversely, when excess blood has leaked into the

within about 1 to 2 weeks.

secreted by platelets). This continues

growth factor

sion by fibroblasts, beginning within a few hours after

the clot, or (2) it can dissolve. The usual course for a

Chapter 36

Hemostasis and Blood Coagulation

459

which subsequently form connective tissue all through

clot that forms in a small hole of a vessel wall is inva-

the clot is formed (which is promoted at least partially
by
to complete organization of the clot into fibrous tissue

tissues and tissue clots have occurred where they are

Mechanism of Blood
Coagulation

More than 50 important substances that

cause or affect blood coagulation have been found in
the blood and in the tissues—some that promote coag-

and others that inhibit

anticoagulants

coagulate depends on the balance between these two

does not coagulate while it is circulating in the blood

General Mechanism.

All research workers in the field of

blood coagulation agree that clotting takes place in

of chemical reactions occurs in the blood involving

result is formation of a complex of activated sub-
stances collectively called prothrombin activator

prothrombin into thrombin
an enzyme to convert fibrinogen into fibrin fibers that

clot.

Let us discuss first the mechanism by which the

to the initiating stages in the clotting process by which
prothrombin activator is formed.

to Thrombin

rupture of a blood vessel or as a result of damage

amounts of ionic Ca

bin causes polymerization of fibrinogen molecules into

rate-limiting factor in causing blood coagulation is
usually the formation of prothrombin activator and
not the subsequent reactions beyond that point,
because these terminal steps normally occur rapidly to

Platelets also play an important role in the con-

version of prothrombin to thrombin because much
of the prothrombin first attaches to prothrombin

Table 36–1

kininogen

(high-molecular-weight) kininogen

High-molecular-weight

Fitzgerald factor; HMWK

Prekallikrein

Fletcher factor

Factor XIII

Fibrin-stabilizing factor

Factor XII

Hageman factor

(PTA); antihemophilic factor C

Factor XI

Plasma thromboplastin antecedent

Factor X

Stuart factor; Stuart-Prower factor

(PTC); Christmas factor;

Factor IX

Plasma thromboplastin component

antihemophilic factor A

Factor VIII

Antihemophilic factor (AHF);

accelerator (SPCA); proconvertin;

Factor VII

Serum prothrombin conversion

Factor V

Proaccelerin; labile factor; Ac-globulin

Calcium

Factor IV

Tissue factor

Factor III; tissue thromboplastin

Prothrombin

Factor II

Fibrinogen

Factor I

Clotting Factor

Synonyms

Clotting Factors in Blood and Their Synonyms

(Ac-G)

stable factor

antihemophilic globulin (AHG);

antihemophilic factor B

Platelets

Thrombin

activated

Cross-linked fibrin fibers

Prothrombin

Thrombin

Fibrin fibers

Fibrinogen monomer

Fibrinogen

Prothrombin

activator

fibrin-stabilizing

factor

ization of fibrinogen to form fibrin fibers.

Schema for conversion of prothrombin to thrombin and polymer-

Figure 36–2

feedback) to promote more clotting. One of the most

That is, the clot itself initiates a vicious circle (positive

Once a blood clot has started to develop, it normally

Vicious Circle of Clot Formation

further to the ultimate state of hemostasis.

vessel are pulled together, thus contributing still

As the clot retracts, the edges of the broken blood

platelets.

endoplasmic reticulum, and Golgi apparatus of the

into a smaller mass. The contraction is activated and

fibrin. This also helps compress the fibrin meshwork

bosthenin, actin, and myosin molecules, which are all

addition, the platelets themselves contribute directly

cross-linking bonds between adjacent fibrin fibers. In

fibrin-stabilizing factor, which causes more and more

substances, one of the most important of which is

different fibers together. Furthermore, platelets

might be low. Electron micrographs of platelets in

Therefore, failure of clot retraction is an indication

Platelets are necessary for clot retraction to occur.

factors.

plasma. Serum cannot clot because it lacks these

have been removed; in this way, serum differs from

60 minutes. The fluid expressed is called

clot is formed, it begins to contract and usually

Within a few minutes after a

opening and thereby prevents further blood loss.

fore, the blood clot becomes adherent to any vascular

adhere to damaged surfaces of blood vessels; there-

blood cells, platelets, and plasma. The fibrin fibers also

The clot is composed of a meshwork of

linkages between adjacent fibrin fibers, thus adding

fibrin monomer molecules, as well as multiple cross-

covalent bonds

Then this activated substance operates as an enzyme

mation also activates the fibrin-stabilizing factor.

activated. The same thrombin that causes fibrin for-

can have an effect on the fibrin fibers, it must itself be

entrapped in the clot. Before fibrin-stabilizing factor

This involves a substance called

ease. But another process occurs during the next few

fibers are not cross-linked with one another; therefore,

covalent hydrogen bonding, and the newly forming

In the early stages of polymerization, the fibrin

Therefore,

It acts on fibrinogen to remove four low-molecular-

with weak proteolytic capabilities.

Thrombin

Action of Thrombin on Fibrinogen to Form Fibrin.

ordinarily do not coagulate. Yet, when the permeabil-

tial factors in the coagulation process, interstitial fluids

stitial fluids, and because fibrinogen is one of the essen-

Because of its large molecular size, little fibrinogen

tration of prothrombin, pointed out above.

tration of circulating fibrinogen, as it does the concen-

the liver, and liver disease can decrease the concen-

quantities of 100 to 700 mg/dl. Fibrinogen is formed in

Fibrinogen is a high-molecular-weight

Conversion of Fibrinogen to Fibrin—

results.

prothrombin level so low that a bleeding tendency

few other clotting factors. Therefore, either lack of

Vitamin K is required by the liver for normal for-

bin, in a day or so prothrombin concentration in

blood clotting. If the liver fails to produce prothrom-

Prothrombin is formed continually by the liver, and

, which has a molecular weight of 33,700,

can split easily into smaller compounds, one of which

tration of about 15 mg/dl. It is an unstable protein that

of 68,700. It is present in normal plasma in a concen-

protein, an alpha2-globulin, having a molecular weight

damaged tissue.

Blood Cells, Immunity, and Blood Clotting

460

Unit VI

receptors on the platelets already bound to the

Prothrombin and Thrombin.

Prothrombin is a plasma

is thrombin
almost exactly one half that of prothrombin.

it is continually being used throughout the body for

the plasma falls too low to provide normal blood
coagulation.

mation of prothrombin as well as for formation of a

vitamin K or the presence of liver disease that pre-
vents normal prothrombin formation can decrease the

Formation of the Clot

Fibrinogen.

protein (MW

= 340,000) that occurs in the plasma in

normally leaks from the blood vessels into the inter-

ity of the capillaries becomes pathologically increased,
fibrinogen does then leak into the tissue fluids in suf-
ficient quantities to allow clotting of these fluids in
much the same way that plasma and whole blood can
clot.

is a protein enzyme

weight peptides from each molecule of fibrinogen,
forming one molecule of fibrin monomer that has the
automatic capability to polymerize with other fibrin
monomer molecules to form fibrin fibers.
many fibrin monomer molecules polymerize within
seconds into long fibrin fibers that constitute the retic-
ulum of the blood clot.

monomer molecules are held together by weak non-

the resultant clot is weak and can be broken apart with

minutes that greatly strengthens the fibrin reticulum.

fibrin-stabilizing

factor that is present in small amounts in normal
plasma globulins but is also released from platelets

to cause

between more and more of the

tremendously to the three-dimensional strength of the
fibrin meshwork.

Blood Clot.

fibrin fibers running in all directions and entrapping

Clot Retraction—Serum.

expresses most of the fluid from the clot within 20 to

serum because

all its fibrinogen and most of the other clotting factors

that the number of platelets in the circulating blood

blood clots show that they become attached to the
fibrin fibers in such a way that they actually bond

entrapped in the clot continue to release procoagulant

to clot contraction by activating platelet throm-

contractile proteins in the platelets and cause strong
contraction of the platelet spicules attached to the

accelerated by thrombin as well as by calcium ions
released from calcium stores in the mitochondria,

extends within minutes into the surrounding blood.

from the

. This factor is

. Traumatized tissue

lowing steps, as shown in Figure 36–3:

come in contact with the blood. This leads to the fol-

The extrinsic pathway for initiating the formation of

to indicate the activated state of Factor VIII.

added after the Roman numeral, such as Factor VIIIa

the activated form of the factor, a small letter “a” is

36–1, are designated by Roman numerals. To indicate

Most of the clotting factors, which are listed in Table

cessive, cascading reactions of the clotting process.

the active forms, their enzymatic actions cause the suc-

forms of proteolytic enzymes. When converted to

play major roles. Most of these are

In both the extrinsic and the intrinsic pathways, a

that begins in the blood itself.

pathway

sic pathway

interact constantly with each other: (1) by the

formed in two ways, although, in reality, the two ways

steps.

, which then causes prothrombin

vessel. In each instance, this leads to the formation of

adjacent tissues, (2) trauma to the blood, or (3) contact

initiate clotting in the first place. These mechanisms

Now that we have discussed the clotting process itself,

of Prothrombin Activator

ceases.

and more and more thrombin to be formed; thus,

Once a critical amount of thrombin is formed, a vicious

VIII, IX, X, XI, and XII and aggregation of platelets.)

graphs, include acceleration of the actions of Factors

activator. (These effects, discussed in subsequent para-

more thrombin, and it acts on some of the blood-clot-

on prothrombin itself, tending to convert this into still

For instance, thrombin has a direct proteolytic effect

Chapter 36

Hemostasis and Blood Coagulation

461

important causes of this is the fact that the proteolytic
action of thrombin allows it to act on many of the
other blood-clotting factors in addition to fibrinogen.

ting factors responsible for formation of prothrombin

circle develops that causes still more blood clotting

the blood clot continues to grow until blood leakage

Initiation of Coagulation: Formation

we must turn to the more complex mechanisms that

are set into play by (1) trauma to the vascular wall and

of the blood with damaged endothelial cells or with
collagen and other tissue elements outside the blood

prothrombin activator
conversion to thrombin and all the subsequent clotting

Prothrombin activator is generally considered to be

extrin-

that begins with trauma to the vascular

wall and surrounding tissues and (2) by the intrinsic

series of different plasma proteins called blood-
clotting factors

inac-

tive

Extrinsic Pathway for Initiating Clotting

prothrombin activator begins with a traumatized vas-
cular wall or traumatized extravascular tissues that

1. Release of tissue factor

releases a complex of several factors called tissue
factor or tissue thromboplastin
composed especially of phospholipids
membranes of the tissue plus a lipoprotein
complex that functions mainly as a proteolytic
enzyme.

Tissue trauma

Tissue factor

VIIa

Vll

Thrombin

Prothrombin

Activated X (Xa)

Prothrombin

Activator

Platelet

phospholipids

(1)

(2)

(3)

Figure 36–3

Extrinsic pathway for initiating blood clotting.

. Trauma

Blood trauma causes (1) activation of Factor XII

series of cascading reactions shown in Figure 36–4.

vessel wall. Then the process continues through the

ting,

thrombin activator, and therefore for initiating clot-

The second mechanism for initiating formation of pro-

process once it begins.

acting through Factor V, to accelerate the entire

positive feedback

a vehicle that further accelerates the process. Note

protease activity, and platelet phospholipids act as

activated Factor V greatly accelerates this

Factor X is the actual protease that causes

final prothrombin activator complex, activated

accelerator of prothrombin activation. Thus, in the

V. This then becomes an additional strong

the proteolytic action of thrombin activates Factor

prothrombin activator complex is inactive, but

explained. At first, the Factor V in the

), this splits prothrombin to form thrombin,

few seconds, in the presence of calcium ions

Within a

prothrombin activator.

platelets as well as with Factor V to form the

activated Factor X combines immediately with

. The

prothrombin activator—role of Factor V

Effect of activated Factor X (Xa) to form

Factor X

acts enzymatically on Factor X to form

Factor VII and, in the presence of calcium ions,

. The lipoprotein complex of tissue

Activation of Factor X—role of Factor VII and

Blood Cells, Immunity, and Blood Clotting

462

Unit VI

tissue factor
factor further complexes with blood coagulation

activated

(Xa).

tissue phospholipids that are part of tissue factor
or with additional phospholipids released from

complex called

(Ca

and the clotting process proceeds as already

once clotting begins and thrombin begins to form,

splitting of prothrombin to form thrombin;

especially the

effect of thrombin,

Intrinsic Pathway for Initiating Clotting

begins with trauma to the blood itself or exposure

of the blood to collagen from a traumatized blood

and (2) release of platelet phospholipids
to the blood or exposure of the blood to vascular

Activated X (Xa)

Activated XI (XIa)

XII

Activated XII (XIIa)

(1)

(2)

(3)

(4)

(5)

Activated IX (IXa)

(HMW kininogen, prekallikrein)

VIII

Thrombin

VIIIa

Thrombin

Thrombin

Prothrombin

Prothrombin

Activator

Platelet

phospholipids

Blood trauma or

contact with collagen

Platelet

phospholipids

Figure 36–4

Intrinsic pathway for initiating
blood clotting.

blood and, therefore, prevents excessive spread of the

adsorbed to the fibrin fibers as they develop. This helps

While a clot is forming, about 85 to 90 per cent of

are those that remove thrombin from the blood. The

subendothelial collagen, the activation is even more

Factor XII and platelets come in contact with the

thus setting off the intrinsic pathway of clotting. If

which activates both Factor XII and the platelets,

When the endothelial wall is damaged, its smooth-

activated Factors V and VIII.

, that acts as an anticoagulant by

process by removing thrombin, but the thrombomod-

which binds thrombin. Not only does the binding of

with the endothelial membrane,

venting activation of clotting; and (3) a protein bound

which repels clotting factors and platelets, thereby pre-

sic clotting system; (2) a layer of

surface, which prevents contact activation of the intrin-

in the Normal Vascular System

Prevention of Blood Clotting

minutes to cause clotting.

is much slower to proceed, usually requiring 1 to 6

occur in as little as 15 seconds. The intrinsic pathway

in the blood. With severe tissue trauma, clotting can

tissues and by the quantities of Factors X, VII, and V

can be explosive; once initiated, its speed of

pathway

wall initiates the intrinsic pathway.

Factor XII and platelets with collagen in the vascular

initiates the extrinsic pathway, whereas contact of

occurs by both pathways simultaneously. Tissue factor

sic systems that after blood vessels rupture, clotting

and Intrinsic Pathways—Summary

oxalate ion

threshold level for clotting, either by deionizing the

from a person, it can be prevented from clotting by

kinetics of blood clotting. But, when blood is removed

In the living body, the calcium ion concentration

pathway does not occur.

the absence of calcium ions, blood clotting by either

tion of all the blood-clotting reactions. Therefore, in

Except for the first two steps in the intrinsic pathway,

earlier.

into motion the final clotting process, as described

prothrombin to form thrombin, thereby setting

. The prothrombin activator

combines with Factor V and platelet or tissue

the extrinsic pathway. That is, activated Factor X

. This step in the

activator—role of Factor V

Action of activated Factor X to form prothrombin

this step is deficient. Factor VIII is the factor that

either Factor VIII or platelets are in short supply,

platelets, activates Factor X. It is clear that when

activated Factor VIII and with the platelet

The activated Factor IX, acting in concert with

Activation of Factor X—role of Factor VIII

on Factor IX to activate this factor also.

The activated Factor XI then acts enzymatically

Activation of Factor IX by activated Factor XI

HMW (high-molecular-weight) kininogen

intrinsic pathway. This reaction also requires

factor as well, which is the second step in the

acts enzymatically on Factor XI to activate this

. The activated Factor XII

Activation of Factor XI

subsequent clotting reactions.

, which also plays a role in

in other ways), and this releases platelet

Simultaneously, the blood trauma also damages

enzyme called “activated Factor XII.”

such as glass, it takes on a new molecular

Factor XII is disturbed, such as by coming into

in the blood: Factor XII and the platelets. When

Chapter 36

Hemostasis and Blood Coagulation

463

wall collagen alters two important clotting factors

contact with collagen or with a wettable surface

configuration that converts it into a proteolytic

the platelets because of adherence to either
collagen or a wettable surface (or by damage

phospholipids that contain the lipoprotein called
platelet factor 3

and is

accelerated by prekallikrein.

phospholipids and factor 3 from the traumatized

is missing in a person who has classic hemophilia,
for which reason it is called antihemophilic factor.
Platelets are the clotting factor that is lacking in
the bleeding disease called thrombocytopenia.

intrinsic pathway is the same as the last step in

phospholipids to form the complex called
prothrombin activator
in turn initiates within seconds the cleavage of

Role of Calcium Ions in the Intrinsic and
Extrinsic Pathways

calcium ions are required for promotion or accelera-

seldom falls low enough to significantly affect the

reducing the calcium ion concentration below the

calcium by causing it to react with substances such as
citrate ion or by precipitating the calcium with sub-
stances such as

Interaction Between the Extrinsic

of Blood-Clotting Initiation

It is clear from the schemas of the intrinsic and extrin-

An especially important difference between the

extrinsic and intrinsic pathways is that the extrinsic

completion to the final clot is limited only by the
amount of tissue factor released from the traumatized

—

Intravascular Anticoagulants

Endothelial Surface Factors.

Probably the most important

factors for preventing clotting in the normal vascular
system are (1) the smoothness of the endothelial cell

glycocalyx on the

endothelium (glycocalyx is a mucopolysaccharide
adsorbed to the surfaces of the endothelial cells),

thrombomodulin,

thrombin with thrombomodulin slow the clotting

ulin-thrombin complex also activates a plasma protein,
protein C

inactivating

ness and its glycocalyx-thrombomodulin layer are lost,

powerful.

Antithrombin Action of Fibrin and Antithrombin III.

Among

the most important anticoagulants in the blood itself

most powerful of these are (1) the fibrin fibers that
themselves are formed during the process of clotting
and (2) an alpha-globulin called antithrombin III or
antithrombin-heparin cofactor.

the thrombin formed from the prothrombin becomes

prevent the spread of thrombin into the remaining

clot.

disease). Lack of bile prevents adequate fat digestion

ciency is failure of the liver to secrete bile into the gas-

the blood along with the fats.

fats from the gastrointestinal tract. The reason is that

ciency often occurs as a result of poor absorption of

However, in gastrointestinal disease, vitamin K defi-

tinal tract by bacteria, so that vitamin K deficiency

Vitamin K is continually synthesized in the intes-

dencies.

K, subsequent insufficiency of these coagulation

. In the absence of vitamin

, and

Factor X

Factor

Factor VII

factors by the liver is vitamin K deficiency. Vitamin K

greatly that the patient develops a severe tendency to

acute yellow

, and

factors are formed by the liver. Therefore, diseases of

With few exceptions, almost all the blood-clotting

by Vitamin K De

(3) thrombocytopenia (platelet deficiency).

caused by (1) vitamin K deficiency, (2) hemophilia, and

to the greatest extent are discussed here: bleeding

one of the many blood-clotting factors. Three particu-

Excessive bleeding can result from deficiency of any

nism. Thus, an especially important function of the

fact, many small blood vessels in which blood flow has

turn removes the remaining unnecessary blood clot. In

eventually converts plasminogen to plasmin, which in

days later, after the clot has stopped the bleeding,

(t-PA) that a few

until it is activated. The injured tissues and vascular

This will not become plasmin or cause lysis of the clot

is trapped in the clot along with other plasma proteins.

When a clot is formed, a large amount of plasminogen

Activation of Plasminogen to Form Plasmin: Then Lysis of Clots.

factors, thereby sometimes even causing hypocoagula-

Therefore, whenever plasmin is formed, it can cause

Factor V, Factor VIII, prothrombin, and Factor XII.

pancreatic secretion. Plasmin digests fibrin fibers and

) that, when activated,

The plasma proteins contain a euglobulin called

Lysis of Blood Clots

growth of the clots.

blood; sufficient formation of heparin prevents further

ies of the liver. It is easy to understand why large quan-

mast cells, release small quantities of heparin into

blood, which are functionally almost identical to the

into the circulatory system. The

nective tissue throughout the body. These cells contin-

body, but especially large quantities are formed by the

Factors XII, XI, X, and IX.

ness of anticoagulation. The others include activated

addition to thrombin, further enhancing the effective-

The complex of heparin and antithrombin III

antithrombin III is almost instantaneous.

Therefore, in the presence of excess heparin, removal

a thousandfold, and thus it acts as an anticoagulant.

antithrombin III, the effectiveness of antithrombin III

anticoagulant properties, but when it combines with

conjugated polysaccharide. By itself, it has little or no

The heparin molecule is a highly negatively charged

prevent intravascular clotting.

it have significant anticoagulant effects. However,

but its concentration in the blood is normally low, so

during the next 12 to 20 minutes.

fibers soon combines with antithrombin III, which

The thrombin that does not adsorb to the fibrin

Blood Cells, Immunity, and Blood Clotting

464

Unit VI

further blocks the effect of the thrombin on the fi-
brinogen and then also inactivates the thrombin itself

Heparin.

Heparin is another powerful anticoagulant,

that only under special physiologic conditions does

heparin is used widely as a pharmacological agent in
medical practice in much higher concentrations to

for removing thrombin increases by a hundredfold to

of free thrombin from the circulating blood by

removes several other activated coagulation factors in

Heparin is produced by many different cells of the

basophilic mast cells located in the pericapillary con-

ually secrete small quantities of heparin that diffuse

basophil cells of the

the plasma.

Mast cells are abundant in tissue surrounding the

capillaries of the lungs and to a lesser extent capillar-

tities of heparin might be needed in these areas
because the capillaries of the lungs and liver receive
many embolic clots formed in slowly flowing venous

—Plasmin

plasminogen (or profibrinolysin
becomes a substance called plasmin (or fibrinolysin).
Plasmin is a proteolytic enzyme that resembles trypsin,
the most important proteolytic digestive enzyme of

some other protein coagulants such as fibrinogen,

lysis of a clot by destroying many of the clotting

bility of the blood.

endothelium very slowly release a powerful activator
called tissue plasminogen activator

been blocked by clots are reopened by this mecha-

plasmin system is to remove minute clots from millions
of tiny peripheral vessels that eventually would
become occluded were there no way to clear them.

Conditions That Cause
Excessive Bleeding in
Human Beings

lar types of bleeding tendencies that have been studied

Decreased Prothrombin, Factor VII,
Factor IX, and Factor X Caused

ficiency

the liver such as hepatitis, cirrhosis
atrophy can sometimes depress the clotting system so

bleed.

Another cause of depressed formation of clotting

is necessary for liver formation of five of the impor-
tant clotting factors: prothrombin,

IX,

protein C

factors in the blood can lead to serious bleeding ten-

seldom occurs in the normal person as a result of
vitamin K absence from the diet (except in neonates
before they establish their intestinal bacterial flora).

vitamin K is fat-soluble and ordinarily is absorbed into

One of the most prevalent causes of vitamin K defi-

trointestinal tract (which occurs either as a result of
obstruction of the bile ducts or as a result of liver

blood vessels, where small quantities of thrombin and

when it flows very slowly

or trauma—is likely to initiate the clotting process. (2)

—as may be caused by arteriosclerosis, infection,

twofold: (1) Any

The causes of throm-

brain, kidneys, or elsewhere. Emboli that originate in

. Also, emboli that originate in

are known as

the clot to flow with the blood; such freely flowing clots

developed, continued flow of blood past the clot is

. Once a clot has

Thrombi and Emboli.

Thromboembolic Conditions

helpful, sometimes effecting almost complete cure

large numbers of platelets. Also,

effected in a patient with thrombocytopenia by

unknown reasons, specific antibodies have formed and

of these people, it has been discovered that for

means thrombocytopenia of unknown cause. In most

, which

Most people with thrombocytopenia have the

because, as pointed out earlier, clot retraction is nor-

thrombocytopenia if the person’s blood fails to retract,

blood, sometimes one can suspect the existence of

than the normal 150,000 to 300,000. Levels as low as

l, rather

Ordinarily, bleeding will not occur until the number

capillaries and other small vessels.

. As stated earlier, platelets are

purplish blotches, giving the disease the name

tissues. The skin of such a person displays many small,

from larger vessels as in hemophilia. As a result, small

from many small venules or capillaries, rather than

do hemophiliacs, except that the bleeding is usually

with thrombocytopenia have a tendency to bleed, as

numbers of platelets in the circulating blood. People

Thrombocytopenia means the presence of very low

human blood and only in extremely small quantities.

VIII. The cost of Factor VIII is high, and its availabil-

that is truly effective is injection of purified Factor

severe prolonged bleeding, almost the only therapy

When a person with classic hemophilia experiences

ferent characteristics, called von Willebrand’s disease,

philia. Another bleeding disease with somewhat dif-

of this part of Factor VIII that causes classic hemo-

the intrinsic pathway for clotting, and it is deficiency

230,000. The smaller component is most important in

Factor VIII has two active components, a large com-

For instance, bleeding can often last for days after

bleeding may be so mild that it is hardly noticeable.

except after trauma, but in some patients, the degree

genetic deficiency. Bleeding usually does not occur

degrees of severity, depending on the character of the

The bleeding trait in hemophilia can have various

half of her female offspring.

, transmitting the disease to half of

If one of her X chromosomes is deficient, she will be

two X chromosomes will have the appropriate genes.

female chromosome. Therefore, almost never will a

is caused by deficiency of Factor IX. Both of these

per cent of hemophilia patients, the bleeding tendency

United States has classic hemophilia. In the other 15

. About 1 of every 10,000 males in the

abnormality or deficiency of Factor VIII;

exclusively in males. In 85 per cent of cases, it is caused

are at least one-half normal in function, sufficient

before performing the surgical procedure. Ordinarily,

Because of this, vitamin K is injected into all surgical

absorption and because of the diseased liver cells.

absorption as well. Thus, liver disease often causes

and absorption and, therefore, depresses vitamin K

Chapter 36

Hemostasis and Blood Coagulation

465

decreased production of prothrombin and some other
clotting factors both because of poor vitamin K

patients with liver disease or with obstructed bile ducts

if vitamin K is given to a deficient patient 4 to 8 hours
before the operation and the liver parenchymal cells

clotting factors will be produced to prevent excessive
bleeding during the operation.

Hemophilia

Hemophilia is a bleeding disease that occurs almost

by an

this

type of hemophilia is called hemophilia A or classic
hemophilia

factors are transmitted genetically by way of the

woman have hemophilia because at least one of her

a hemophilia carrier
her male offspring and transmitting the carrier state to

of trauma required to cause severe and prolonged

extraction of a tooth.

ponent with a molecular weight in the millions and a
smaller component with a molecular weight of about

results from loss of the large component.

ity is limited because it can be gathered only from

Thrombocytopenia

punctate hemorrhages occur throughout all the body

throm-

bocytopenic purpura
especially important for repair of minute breaks in

of platelets in the blood falls below 50,000/

10,000/

ml are frequently lethal.

Even without making specific platelet counts in the

mally dependent on release of multiple coagulation
factors from the large numbers of platelets entrapped
in the fibrin mesh of the clot.

disease known as idiopathic thrombocytopenia

react against the platelets themselves to destroy them.
Relief from bleeding for 1 to 4 days can often be

giving fresh whole blood transfusions that contain

splenectomy is often

because the spleen normally removes large numbers
of platelets from the blood.

in the Human Being

An abnormal clot that develops in

a blood vessel is called a thrombus

likely to break it away from its attachment and cause

emboli

large arteries or in the left side of the heart can flow
peripherally and plug arteries or arterioles in the

the venous system or in the right side of the heart gen-
erally flow into the lungs to cause pulmonary arterial
embolism.

Cause of Thromboembolic Conditions.

boembolic conditions in the human being are usually

roughened endothelial surface of a

vessel

Blood often clots

through

other procoagulants are always being formed.

for 1 hour or more. The reason for this delay is that

siliconized containers

glass test tube normally clots in about 6 minutes, blood

Prevention of Blood Coagulation

coumarin therapy.

factors already present in the plasma. Normal coagu-

In other words, the coagulation process is not blocked

to about 20 per cent of normal by the end of 24 hours.

farin, the coagulant activity of the blood decreases to

of prothrombin and the other three clotting factors,

on liver formation of these compounds. Warfarin

VII, IX, and X, all formed by the liver, begin to fall,

patient, the plasma levels of prothrombin and Factors

When a coumarin, such as

Coumarins as Anticoagulants

The action of heparin lasts about 1.5 to 4 hours. The

time occurs instantaneously, thereby immediately pre-

more minutes. Furthermore, this change in clotting

1 mg/kg of body weight, causes the blood-clotting time

Injection of relatively small quantities, about 0.5 to

have been developed for this purpose. The ones most

delay the coagulation process. Various anticoagulants

In some thromboembolic conditions, it is desirable to

to bleed. The reason for this is that so many of the

85 per cent or more of patients.

septicemic shock

that leads to or exacerbates circulatory shock. It is

activate the clotting mechanisms. Plugging of

endotox-

with widespread septicemia, in which either circulat-

eral blood vessels. This occurs especially in patients

ous, and they plug a large share of the small periph-

the blood. Frequently, the clots are small but numer-

. This often results from the presence of

vated in widespread areas of the circulation, giving rise

a lifesaver.

the pulmonary vessels. But, again, t-PA therapy can be

pulmonary artery is blocked, death may not occur, or

the same time, immediate death ensues. If only one

. If the clot is large

cause massive blockage of the pulmonary arteries,

about 1 time out of every 10, a large part of the clot

the common iliac vein and inferior vena cava. Then,

moving venous blood, sometimes growing the entire

the clot grows, mainly in the direction of the slowly

one or more of the leg veins for hours at a time. Then

body, the immobility of patients confined to bed plus

Femoral Venous Thrombosis and

damage.

coronary artery, the heart is often spared serious

some intravascular clots. For instance, if used within

plasminogen to plasmin, which in turn can dissolve

area through a catheter, it is effective in activating

available. When delivered directly to a thrombosed

engineered t-PA (tissue plasminogen activator) is

Use of t-PA in Treating Intravascular Clots.

Blood Cells, Immunity, and Blood Clotting

466

Unit VI

Genetically

the first hour or so after thrombotic occlusion of a

Massive Pulmonary Embolism

Because clotting almost always occurs when blood
flow is blocked for many hours in any vessel of the

the practice of propping the knees with pillows often
causes intravascular clotting because of blood stasis in

length of the leg veins and occasionally even up into

disengages from its attachments to the vessel wall and
flows freely with the venous blood through the right
side of the heart and into the pulmonary arteries to

called massive pulmonary embolism
enough to occlude both of the pulmonary arteries at

the embolism may lead to death a few hours to several
days later because of further growth of the clot within

Disseminated Intravascular
Coagulation

Occasionally the clotting mechanism becomes acti-

to the condition called disseminated intravascular
coagulation
large amounts of traumatized or dying tissue in the
body that releases great quantities of tissue factor into

ing bacteria or bacterial toxins—especially
ins—
small peripheral vessels greatly diminishes delivery of
oxygen and other nutrients to the tissues—a situation

partly for this reason that

is lethal in

A peculiar effect of disseminated intravascular

coagulation is that the patient on occasion begins

clotting factors are removed by the widespread clot-
ting that too few procoagulants remain to allow
normal hemostasis of the remaining blood.

Anticoagulants for
Clinical Use

useful clinically are heparin and the coumarins.

Heparin as an Intravenous
Anticoagulant

Commercial heparin is extracted from several differ-
ent animal tissues and prepared in almost pure form.

to increase from a normal of about 6 minutes to 30 or

venting or slowing further development of a throm-
boembolic condition.

injected heparin is destroyed by an enzyme in the
blood known as heparinase.

warfarin, is given to a

indicating that warfarin has a potent depressant effect

causes this effect by competing with vitamin K for
reactive sites in the enzymatic processes for formation

thereby blocking the action of vitamin K.

After administration of an effective dose of war-

about 50 per cent of normal by the end of 12 hours and

immediately but must await the natural consumption
of the prothrombin and the other affected coagulation

lation usually returns 1 to 3 days after discontinuing

Outside the Body

Although blood removed from the body and held in a

collected in

often does not clot

preparing the surfaces of the containers with silicone

thrombin concentration to prothrombin time, such as

seconds. In each laboratory, a curve relating pro-

centration. The normal prothrombin time is about 12

of the time

. The

pathway. The time required for coagulation to take

The excess calcium nullifies the effect of the oxalate,

into thrombin. Then, a large excess of calcium ion and

thrombin time is the following.

thrombin time. The method for determining pro-

tration of prothrombin in the blood. Figure 36–5 shows

Prothrombin Time

using sophisticated chemical procedures.

ments of the clotting factors themselves are made,

is no longer used in many clinics. Instead, measure-

depending on the method used for measuring it, so it

Unfortunately, the clotting time varies widely,

determining clotting time more accurately.

the normal clotting time is 6 to 10 minutes. Procedures

seconds until the blood has clotted. By this method,

blood clotting times. The one most widely used is to

Clotting Time

of platelets.

the bleeding time, but it is especially prolonged by lack

the finger or ear lobe at the time of the test. Lack of

for 1 to 6 minutes. The time depends largely on the

of the finger or lobe of the ear, bleeding ordinarily lasts

When a sharp-pointed knife is used to pierce the tip

Bleeding Time

Blood Coagulation Tests

the level of calcium ion in the blood, which can result

the citrate can, under these conditions, greatly depress

citrate ion may not be removed quickly enough, and

given too rapidly (within fractions of a minute), the

without dire consequences. But if the liver is damaged

Consequently, 500 milliliters of blood that has been

into glucose or metabolized directly for energy.

injection, the citrate ion is removed from the blood

tities of citrate can be injected intravenously. After

oxalate is toxic to the body, whereas moderate quan-

coagulation. Citrate anticoagulants have an important

compound, and the lack of

. The citrate ion combines with

, or

is especially valuable for this purpose, mixed with

prevent coagulation. The negatively charged

oxalate

instance, a soluble

the body. For

Various substances that

blood outside the body as well as in the body. Heparin

XII, with rapid development of clots.

ers allow contact activation of the platelets and Factor

ting mechanism. Conversely, untreated glass contain-

prevents contact activation of platelets and Factor XII,

Chapter 36

Hemostasis and Blood Coagulation

467

the two principal factors that initiate the intrinsic clot-

Heparin can be used for preventing coagulation of

is especially used in surgical procedures in which the
blood must be passed through a heart-lung machine
or artificial kidney machine and then back into the
person.

decrease the concentration

of calcium ions in the blood can also be used for pre-
venting blood coagulation outside

compound mixed in a very

small quantity with a sample of blood causes precipi-
tation of calcium oxalate from the plasma and thereby
decreases the ionic calcium level so much that blood
coagulation is blocked.

Any substance that deionizes the blood calcium will

citrate ion

blood usually in the form of sodium, ammonium
potassium citrate
calcium in the blood to cause an un-ionized calcium

ionic calcium prevents

advantage over the oxalate anticoagulants because

within a few minutes by the liver and is polymerized

rendered incoagulable by citrate can ordinarily be
transfused into a recipient within a few minutes

or if large quantities of citrated blood or plasma are

in tetany and convulsive death.

depth of the wound and the degree of hyperemia in

any one of several of the clotting factors can prolong

Many methods have been devised for determining

collect blood in a chemically clean glass test tube and
then to tip the tube back and forth about every 30

using multiple test tubes have also been devised for

Prothrombin time gives an indication of the concen-

the relation of prothrombin concentration to pro-

Blood removed from the patient is immediately

oxalated so that none of the prothrombin can change

tissue factor is quickly mixed with the oxalated blood.

and the tissue factor activates the prothrombin-to-
thrombin reaction by means of the extrinsic clotting

place is known as the prothrombin time

shortness

is determined mainly by prothrombin con-

6.25

12.5

25.0

50.0

Concentration (per cent of normal)

100

Prothrombin time

(seconds)

Relation of prothrombin concentration in the blood to “prothrom-

Figure 36–5

bin time.”

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tate the concentration of the factor.

prolonged. The time itself can then be used to quanti-

factor being tested is deficient, the coagulation time is

in the same manner as for prothrombin time. If the

Then the time required for coagulation is determined

are added to oxalated blood all at once.

clotting factors. In each of these tests, excesses of

Tests similar to that for prothrombin time have been

that shown in Figure 36–5, is drawn for the method

Blood Cells, Immunity, and Blood Clotting

468

Unit VI

used so that the prothrombin in the blood can be quan-
tified.

devised to determine the quantities of other blood

calcium ions and all the other factors besides the one
being tested

References

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toward a molecular understanding of disorders of platelet

2004.