Ch12.pdf

Alterations in Hemostasis

and Blood Coagulation

Mechanisms of Hemostasis

Vessel Spasm

Formation of the Platelet Plug

Blood Coagulation

Clot Retraction

Clot Dissolution

Hypercoagulability States

Increased Platelet Function

Increased Clotting Activity

Bleeding Disorders

Platelet Defects

Thrombocytopenia

Impaired Platelet Function

Coagulation Defects

Impaired Synthesis of Coagulation Factors

Hemophilia A

Von Willebrand Disease

Disseminated Intravascular Coagulation

Vascular Disorders

MECHANISMS OF HEMOSTASIS

Hemostasis is divided into five stages: vessel spasm, forma-

tion of the platelet plug, blood coagulation or development

of an insoluble fibrin clot, clot retraction, and clot dissolution

(Fig. 12-1).

Vessel Spasm

Vessel spasm is initiated by endothelial injury and caused by

local and humoral mechanisms. A spasm constricts the vessel

and reduces blood ﬂow. It is a transient event that usually lasts

less than 1 minute. Thromboxane A 2 (TXA 2 ), a prostaglandin

released from the platelets, contributes to the vasoconstric-

tion. A second prostaglandin, prostacyclin, released from the

vessel endothelium, produces vasodilation and inhibits plate-

let aggregation.

Formation of the Platelet Plug

The platelet plug, the second line of defense, is initiated as

platelets come in contact with the vessel wall. Small breaks in

the vessel wall are often sealed with a platelet plug and do not

require the development of a blood clot.

Platelets, also called thrombocytes, are large fragments from

the cytoplasm of bone marrow cells called megakaryocytes. They

are enclosed in a membrane but have no nucleus and cannot

reproduce. Their cytoplasmic granules release mediators for he-

mostasis. Although they lack a nucleus, they have many of the

characteristics of a whole cell. They have mitochondria and en-

zyme systems for producing adenosine triphosphate (ATP) and

adenosine diphosphate (ADP), and they have the enzymes

needed for synthesis of prostaglandins, which are required for

their function in hemostasis. Platelets also produce a growth

factor that causes vascular endothelial cells, smooth muscle

cells, and ﬁbroblasts to proliferate and grow.

The life span of a platelet is only 8 to 9 days. A protein called

thrombopoietin causes proliferation and maturation of mega-

karyocytes. 1 The sources of thrombopoietin include the liver,

kidney, smooth muscle, and bone marrow, which controls

platelet production. Its production and release are regulated by

the number of platelets in the circulation. The newly formed

The normal process of hemostasis is regulated by a com-

plex array of activators and inhibitors that maintain

blood ﬂuidity and prevent blood from leaving the vascular

compartment. Hemostasis is normal when it seals a blood ves-

sel to prevent blood loss and hemorrhage. It is abnormal when

it causes inappropriate blood clotting or when clotting is in-

sufﬁcient to stop the ﬂow of blood from the vascular compart-

ment. Disorders of hemostasis fall into two main categories:

the inappropriate formation of clots within the vascular system

( i.e., thrombosis) and the failure of blood to clot in response

to an appropriate stimulus ( i.e., bleeding).

205

CHAPTER

T he term hemostasis refers to the stoppage of blood ﬂow.

206

Unit Three: Alterations in the Hematologic System

Vessel spasm

of acute coronary myocardial infarction (see Chapter 17). In

addition, the platelet membrane contains large amounts of

phospholipids that play a role in activating several points in the

blood-clotting process.

Platelet plug formation involves adhesion and aggregation

of platelets. Platelet adhesion also requires a protein molecule

called von Willebrand factor (vWF). vWF, which is produced by

the endothelial cells of blood vessels, performs two important

functions: it aids in platelet adhesion, and it circulates in the

blood as a carrier protein for coagulation factor VIII.

Platelets are attracted to a damaged vessel wall, become

activated, and change from smooth disks to spiny spheres,

exposing receptors on their surfaces. Adhesion to the vessel

subendothelial layer occurs when the platelet receptor binds

to vWF at the injury site, linking the platelet to exposed colla-

gen ﬁbers (Fig. 12-2A). The process of adhesion is controlled

by local hormones and substances released by platelet gran-

ules. As the platelets adhere to the collagen ﬁbers on the dam-

aged vessel wall, they begin to release large amounts of ADP

and TXA 2 . Platelet aggregation and formation of a loosely or-

ganized platelet plug occur as the ADP and TXA 2 cause nearby

platelets to become sticky and adhere to the original platelets.

Stabilization of the platelet plug occurs as the coagulation

Formation of platelet plug,

platelet adhesion, and

aggregation

Formation of the insoluble

fibrin clot

Activation of the intrinsic

or extrinsic coagulation pathway

Clot retraction

Collagen

von Willebrand

factor (vWf)

Clot dissolution

Factor

VIII

■ FIGURE 12-1 ■ Steps in hemostasis.

Thromboxane A 2

Platelet

ADP

VIIIa

vWf/ fVIII

platelets that are released from the bone marrow spend as long

as 8 hours in the spleen before they are released into the blood.

The cell membrane of the platelet is important to its func-

tion. The outside of the platelet membrane is coated with

glycoproteins that repulse adherence to the normal vessel en-

dothelium, while causing adherence to injured areas of the ves-

sel wall, particularly the subendothelial layer. 2 The platelet

membrane also has glycoprotein receptors that bind ﬁbrinogen

and link platelets together. Glycoprotein receptor antagonists

have been developed and are selectively used in the treatment

X a

Clotting

cascade

Endothelial

cells

Sub-

endothelium

Platelet

aggregation

Collagen

Intrinsic

pathway

PROTHROMBIN

Fibrin

degradation

products

THROMBIN

X Xa

Extrinsic

pathway

Activated

protein

THROMBIN

Plasmin

KEY CONCEPTS

HEMOSTASIS

Tissue factors

Fibrinogen

Plasminogen

activators

Plasminogen

Fibrin

■

Hemostasis is the orderly, stepwise process for stop-

ping bleeding that involves vasospasm, formation of

a platelet plug, and the development of a ﬁbrin clot.

Collagen

■ FIGURE 12-2 ■ ( A ) The platelet plug occurs seconds after vessel

injury. Von Willebrand’s factor, released from the endothelial

cells, binds to platelet receptors, causing adhesion of platelets to

the exposed collagen. Platelet aggregation is induced by release of

thromboxane A 2 and adenosine diphosphate. ( B ) Coagulation

factors, activated on the platelet surface, lead to the formation of

thrombin and ﬁbrin, which stabilize the platelet plug. ( C ) Control

of the coagulation process and clot dissolution are governed by

thrombin and plasminogen activators. Thrombin activates pro-

tein C, which stimulates the release of plasminogen activators. The

plasminogen activators in turn promote the formation of plasmin,

which digests the ﬁbrin strands.

■

The blood clotting process requires the presence

of platelets produced in the bone marrow, von

Willebrand factor generated by the vessel endothe-

lium, and clotting factors synthesized in the liver,

using vitamin K.

■

The ﬁnal step of the process involves ﬁbrinolysis or

clot dissolution, which prevents excess clot

formation.

Chapter 12: Alterations in Hemostasis and Blood Coagulation

207

pathway is activated on the platelet surface and ﬁbrinogen is

converted to fibrin, thereby creating a fibrin meshwork that

cements together the platelets and other blood components

(see Fig. 12-2B).

Defective platelet plug formation causes bleeding in persons

who are deﬁcient in platelet receptor sites or vWF. In addition

to sealing vascular breaks, platelets play an almost continuous

role in maintaining normal vascular integrity. They may supply

growth factors for the endothelial cells and arterial smooth

muscle cells. Persons with platelet deﬁciency have increased

capillary permeability and sustain small skin hemorrhages

from the slightest trauma or change in blood pressure.

curs by way of the intrinsic or the extrinsic coagulation path-

ways (Fig. 12-4). The intrinsic pathway, which is a relatively

slow process, begins in the blood itself. The extrinsic pathway,

which is a much faster process, begins with tissue or vessel

trauma and the subsequent release of a complex of several fac-

tors, called tissue factor, or tissue thromboplastin. The terminal

steps in both pathways are the same: the activation of factor X,

the conversion of prothrombin to thrombin, and the conver-

sion of fibrinogen to fibrin. Prothrombin is an unstable

plasma protein, which is easily split into smaller parts, one of

which is thrombin. Thrombin, in turn, acts as an enzyme to

convert fibrinogen to fibrin.

Both the intrinsic and extrinsic pathways are needed for nor-

mal hemostasis, and many interrelations exist between them.

Each system is activated when blood passes out of the vascular

system. The intrinsic system is activated as blood comes in con-

tact with collagen in the injured vessel wall and the extrinsic

system when blood is exposed to tissue extracts. Bleeding,

when it occurs because of defects in the extrinsic system, usu-

ally is not as severe as that which results from defects in the in-

trinsic pathway.

With few exceptions, almost all the blood-clotting factors

are synthesized in the liver. Vitamin K is required for the syn-

thesis of prothrombin, factors VII, IX, X, and protein C. Cal-

cium (factor IV) is required in all but the ﬁrst two steps of the

clotting process. The body usually has sufﬁcient amounts of

calcium for these reactions. Inactivation of the calcium ion pre-

vents blood from clotting when it is removed from the body.

The addition of citrate to blood stored for transfusion purposes

prevents clotting by chelating ionic calcium. Another chelator,

EDTA, is often added to blood samples used for analysis in the

clinical laboratory.

Coagulation is regulated by several natural anticoagulants.

Antithrombin III inactivates coagulation factors and neutral-

izes thrombin, the last enzyme in the pathway for the con-

version of fibrinogen to fibrin. When antithrombin III is

complexed with naturally occurring heparin, its action is

accelerated and provides protection against uncontrolled

thrombus formation on the endothelial surface. Protein C, a

plasma protein, acts as an anticoagulant by inactivating fac-

tors V and VIII. Protein S, another plasma protein, accelerates

the action of protein C. Plasmin breaks down fibrin into fib-

rin degradation products that act as anticoagulants. It has

been suggested that some of these natural anticoagulants may

play a role in the bleeding that occurs with disseminated in-

travascular coagulation (DIC; discussed later).

The anticoagulant drugs heparin and warfarin are used to

prevent venous thrombi and thromboembolic disorders, such

as deep vein thrombosis and pulmonary embolism. Heparin is

naturally formed by basophilic mast cells located at the pre-

capillary junctions in tissues throughout the body. These cells

continuously secrete small amounts of heparin, which is re-

leased into the circulation. Pharmacologic preparations of he-

parin, extracted from animal tissues, are available for treatment

of coagulation disorders. Heparin binds to antithrombin III,

causing a conformational change that increases the ability of

antithrombin III to inactivate factor Xa, thrombin, and other

clotting factors. By promoting the inactivation of clotting fac-

tors, heparin ultimately suppresses the formation of ﬁbrin.

Heparin is unable to cross the membranes of the gastrointes-

tinal tract and must be given by injection. Warfarin acts by

Blood Coagulation

Blood coagulation is controlled by many substances that pro-

mote clotting ( i.e., procoagulation factors) or inhibit it ( i.e., anti-

coagulation factors). Each of the procoagulation factors, iden-

tiﬁed by Roman numerals, performs a speciﬁc step in the

coagulation process. The action of one coagulation factor or

proenzyme is designed to activate the next factor in the se-

quence ( i.e., cascade effect). Because most of the inactive pro-

coagulation factors are present in the blood at all times, the

multistep process ensures that a massive episode of intravascu-

lar clotting does not occur by chance. It also means that ab-

normalities of the clotting process occur when one or more of

the factors are deﬁcient or when conditions lead to inappro-

priate activation of any of the steps.

The chemical events in the blood coagulation process

involve a number of essential steps that result in the conver-

sion of fibrinogen, a circulating plasma protein, to the fibrin

strands that enmesh platelets, blood cells, and plasma to form

the clot (Fig. 12-3). The initiation of the clotting process oc-

■ FIGURE 12-3 ■ Scanning electron micrograph of a blood clot

( × 3600). The ﬁbrous bridges that form a meshwork between red

blood cells are ﬁbrin ﬁbers. (© Oliver Meckes, Science Source/

Photo Researchers)

208

Unit Three: Alterations in the Hematologic System

Intrinsic system

XII

XIIa

XIa

Extrinsic system

IXa

VIIa

Antithrombin III

Prothrombin

Thrombin

■ FIGURE 12-4 ■ Intrinsic and extrinsic coagula-

tion pathways. The terminal steps in both path-

ways are the same. Calcium, factors X and V, and

platelet phospholipids combine to form prothrom-

bin activator, which then converts prothrombin to

thrombin. This interaction causes conversion of

ﬁbrinogen into the ﬁbrin strands that create the in-

soluble blood clot. Prothrombin and factors VII,

IX, and X require vitamin K for synthesis.

Fibrinogen

Fibrin (monomer)

Fibrin (polymer)

decreasing prothrombin and other procoagulation factors. It

alters vitamin K such that it reduces its availability to partici-

pate in synthesis of the vitamin K-dependent coagulation fac-

tors in the liver. Warfarin is readily absorbed after oral admin-

istration. Its maximum effect takes 36 to 72 hours because of

the varying half-lives of preformed clotting factors that remain

in the circulation.

Two naturally occurring plasminogen activators are tissue-

type plasminogen activator and urokinase-type plasminogen

activator. The liver, plasma, and vascular endothelium are the

major sources of physiologic activators. These activators are

released in response to a number of stimuli, including vaso-

active drugs, venous occlusion, elevated body temperature,

and exercise. The activators are unstable and rapidly inacti-

vated by inhibitors synthesized by the endothelium and the

liver. For this reason, chronic liver disease may cause altered

Clot Retraction

After the clot has formed, clot retraction, which requires large

numbers of platelets, contributes to hemostasis by squeezing

serum from the clot and joining the edges of the broken vessel.

Plasminogen activators

(liver and vascular endothelial factors)

Clot Dissolution

The dissolution of a blood clot begins shortly after its forma-

tion; this allows blood ﬂow to be re-established and permanent

tissue repair to take place (see Fig. 12-2C). The process by

which a blood clot dissolves is called ﬁbrinolysis. As with clot

formation, clot dissolution requires a sequence of steps con-

trolled by activators and inhibitors (Fig. 12-5). Plasminogen,

the proenzyme for the ﬁbrinolytic process, normally is present

in the blood in its inactive form. It is converted to its active

form, plasmin, by plasminogen activators formed in the vas-

cular endothelium, liver, and kidneys. The plasmin formed

from plasminogen digests the ﬁbrin strands of the clot and cer-

tain clotting factors, such as ﬁbrinogen, factor V, factor VIII,

prothrombin, and factor XII. Circulating plasmin is rapidly

inactivated by

Plasminogen

Plasmin

A 2 plasmin

inhibitor

Inhibitors of

plasminogen and

activators

Digestion of fibrin

strands, fibrinogen,

Factors V and VIII.

α 2 -plasmin inhibitor, which limits ﬁbrinolysis

to the local clot and prevents it from occurring in the entire

circulation.

■ FIGURE 12-5 ■ Fibrinolytic system and its modiﬁers. The solid

lines indicate activation, and the broken lines indicate inactivation.

Chapter 12: Alterations in Hemostasis and Blood Coagulation

209

fibrinolytic activity. A major inhibitor, plasminogen activator

inhibitor-1, in high concentrations has been associated with

deep vein thrombosis, coronary artery disease, and myocar-

dial infarction. 3

sclerotic plaques disturb ﬂow, cause endothelial damage, and

promote platelet adherence. Platelets that adhere to the ves-

sel wall release growth factors that can cause proliferation of

smooth muscle and thereby contribute to the development of

atherosclerosis. Smoking, elevated levels of blood lipids and

cholesterol, hemodynamic stress, diabetes mellitus, and im-

mune mechanisms may cause vessel damage, platelet adher-

ence, and, eventually, thrombosis. Some cancers and other dis-

eases are associated with high platelet counts and the potential

for thrombosis. The term thrombocytosis is used to describe

platelet counts greater than 1,000,000/mm 3 . This occurs in

some malignancies and inﬂammatory states and after splenec-

tomy. Myeloproliferative disorders that result in excess platelet

production may predispose to thrombosis or, paradoxically,

bleeding when the rapidly produced platelets are defective.

In summary, hemostasis is designed to maintain the in-

tegrity of the vascular compartment. The process is divided

into ﬁve phases: vessel spasm, which constricts the size of the

vessel and reduces blood ﬂow; platelet adherence and forma-

tion of the platelet plug; formation of the ﬁbrin clot, which

cements together the platelet plug; clot retraction, which

pulls the edges of the injured vessel together; and clot disso-

lution, which involves the action of plasmin that dissolves the

clot and allows blood ﬂow to be re-established and tissue

healing to take place. Blood coagulation requires the stepwise

activation of coagulation factors, carefully controlled by acti-

vators and inhibitors.

Increased Clotting Activity

Increased clotting activity results from factors that increase the

activation of the coagulation system, including stasis of blood

ﬂow and alterations in the coagulation components of the

blood ( i.e., an increase in procoagulation factors or a decrease

in anticoagulation factors). Stasis of blood ﬂow causes the ac-

cumulation of activated clotting factors and platelets and pre-

vents their interactions with inhibitors. Slow and disturbed

ﬂow is a common cause of venous thrombosis in the immobi-

lized or postoperative patient. Heart failure also contributes to

venous congestion and thrombosis. Elevated levels of estrogen

tend to increase hepatic synthesis of many of the coagulation

factors and decrease the synthesis of antithrombin III. 4 The in-

cidence of stroke, thromboemboli, and myocardial infarction

is greater in women who use oral contraceptives, particularly

after age 35 years, and in heavy smokers. Clotting factors are

also increased during normal pregnancy. These changes, along

with limited activity during the puerperium (immediate post-

partum period), predispose to venous thrombosis. A hyper-

coagulability state is also common in cancer and sepsis. Many

tumor cells are thought to release tissue factor molecules that,

along with the increased immobility and sepsis seen in patients

with malignant disease, contribute to increased risk of both

venous and arterial thrombosis.

A reduction in anticoagulants such as antithrombin III,

protein C, and protein S predisposes to venous thrombosis. 5

HYPERCOAGULABILITY STATES

Hypercoagulability represents hemostasis in an exaggerated

form and predisposes to thrombosis. Arterial thrombi caused

by turbulence are composed of platelet aggregates, and venous

thrombi caused by stasis of ﬂow are largely composed of

platelet aggregates and ﬁbrin complexes that result from excess

coagulation. There are two general forms of hypercoagulability

states: conditions that create increased platelet function and

conditions that cause accelerated activity of the coagulation

system. Chart 12-1 summarizes conditions commonly associ-

ated with hypercoagulability states.

Increased Platelet Function

Increased platelet function predisposes to platelet adhesion,

formation of a platelet or blood clot, and disturbance of blood

ﬂow. The causes of increased platelet function are disturbances

in ﬂow, endothelial damage, and increased sensitivity of plate-

lets to factors that cause adhesiveness and aggregation. Athero-

CHART 12-1 Conditions Associated

With Hypercoagulability States

Increased Platelet Function

Atherosclerosis

Diabetes mellitus

Smoking

Elevated blood lipid and cholesterol levels

Increased platelet levels

KEY CONCEPTS

HYPERCOAGULABILITY STATES

■

Hypercoagulability states increase the risk of clot or

thrombus formation in either the arterial or venous

circulations.

Accelerated Activity of the Clotting System

Pregnancy and the puerperium

Use of oral contraceptives

Postsurgical state

Immobility

Congestive heart failure

Malignant diseases

■

Arterial thrombi are associated with conditions that

produce turbulent blood ﬂow and platelet

adherence.

■

Venous thrombi are associated with conditions that

cause stasis of blood ﬂow with increased concentra-

tions of coagulation factors.

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