Ganong's Review of Medical Physiology, 23rd Edition

534 SECTION VICardiovascular Physiology

resemblance to a Danish pastry of the same name. The kringles

are lysine-binding sites by which the molecule attaches to fibrin

and other clot proteins, and they are also found in prothrom-

bin. Plasminogen is converted to active plasmin when t-PA

hydrolyzes the bond between Arg 560 and Val 561.

Plasminogen receptors are located on the surfaces of many

different types of cells and are plentiful on endothelial cells.

When plasminogen binds to its receptors, it becomes acti-

vated, so intact blood vessel walls are provided with a mecha-

nism that discourages clot formation.

Human t-PA is now produced by recombinant DNA tech-

niques for clinical use in myocardial infarction and stroke.

Streptokinase, a bacterial enzyme, is also fibrinolytic and is

also used in the treatment of early myocardial infarction (see

Chapter 34).

CLINICAL BOX 32–3

Abnormalities of Hemostasis

In addition to clotting abnormalities due to platelet disorders,

hemorrhagic diseases can be produced by selective deficien-

cies of most of the clotting factors (Table 32–7). Hemophilia

A, which is caused by factor VIII deficiency, is relatively com-

mon. The disease has been treated with factor VIII-rich prepa-

rations made from plasma, or, more recently, factor VIII pro-

duced by recombinant DNA techniques. von Willebrand

factor deficiency likewise causes a bleeding disorder (von

Willebrand disease) by reducing platelet adhesion and by

lowering plasma factor VIII. The condition can be congenital

or acquired. The large von Willebrand molecule is subject to

cleavage and resulting inactivation by the plasma metallo-

protease ADAM 13 in vascular areas where fluid shear stress is

elevated. Finally, when absorption of vitamin K is depressed

along with absorption of other fat-soluble vitamins (see

Chapter 27), the resulting clotting factor deficiencies may

cause the development of a significant bleeding tendency.

Formation of clots inside blood vessels is called thrombo-

sis to distinguish it from the normal extravascular clotting of

blood. Thromboses are a major medical problem. They are

particularly prone to occur where blood flow is sluggish be-

cause the slow flow permits activated clotting factors to accu-

mulate instead of being washed away. They also occur in ves-

sels when the intima is damaged by atherosclerotic plaques,

and over areas of damage to the endocardium. They fre-

quently occlude the arterial supply to the organs in which

they form, and bits of thrombus (emboli) sometimes break

off and travel in the bloodstream to distant sites, damaging

other organs. An example is obstruction of the pulmonary ar-

tery or its branches by thrombi from the leg veins (pulmo-

nary embolism). Congenital absence of protein C leads to

uncontrolled intravascular coagulation and, in general, death

in infancy. If this condition is diagnosed and treatment is insti-

tuted, the coagulation defect disappears. Resistance to acti-

vated protein C is another cause of thrombosis, and this con-

dition is common. It is due to a point mutation in the gene for

factor V, which prevents activated protein C from inactivating

the factor. Mutations in protein S and antithrombin III may

less commonly increase the incidence of thrombosis.

Disseminated intravascular coagulation is another seri-

ous complication of septicemia, extensive tissue injury, and

other diseases in which fibrin is deposited in the vascular sys-

tem and many small- and medium-sized vessels are throm-

bosed. The increased consumption of platelets and coagula-

tion factors causes bleeding to occur at the same time. The

cause of the condition appears to be increased generation of

thrombin due to increased TPL activity without adequate tis-

sue factor inhibitory pathway activity.

FIGURE 32–14 The fibrinolytic system and its regulation by

protein C.

FIGURE 32–15 Structure of human plasminogen. Note the

Glu at the amino terminal, the Asn at the carboxyl terminal, and five

uniquely shaped loop structures (kringles). Hydrolysis by t-PA at the ar-

row separates the carboxyl terminal light chain from the amino terminal

heavy chain but leaves the disulfide bonds intact. This activates the mol-

ecule. (Modified and reproduced with permission from Bachman F, in: Thrombosis and

Hemostasis. Verstraete M et al [editors]. Leuven University Press, 1987.)

Endothelial cell

Thrombomodulin

Thrombin

Protein C Activated protein C (APC)

VIlIa Inactive VIIIa Va Inactive Va

Inactivates inhibitor of

tissue plasminogen activator (t-PA)

Plasminogen Plasmin

Lyses fibrin

+ Protein S

Thrombin

t-PA, u-PA

t-PA

Asn

Glu

Ser