Human Physiology, 14th edition (2016)

Blood, Heart, and Circulation 417

by the extrinsic pathway. This function is aided by activated

platelets. As platelets become activated and form a platelet

plug, a molecule called phosphatidylserine becomes exposed

at their surfaces. The phosphatidylserine anchors factor VIII

and factor V complexes ( fig. 13.9 ) to the platelet surface, which

greatly increases the formation of thrombin.

Dissolution of Clots

As the damaged blood vessel wall is repaired, activated factor

XII promotes the conversion of an inactive molecule in plasma

into the active form called kallikrein. Kallikrein, in turn, cata-

lyzes the conversion of inactive plasminogen into the active

molecule plasmin. Plasmin is an enzyme that digests fibrin

into “split products,” thus promoting dissolution of the clot.

of blood vessels (in the tunica media and tunica externa; see
fig.  13.26 ) and the cells of the surrounding tissues. When a
blood vessel is injured, tissue factor then becomes exposed
to factor VII and VIIa in the blood and forms a complex with
factor VIIa. By forming this complex, tissue factor greatly
increases (by a factor of two million) the ability of factor VIIa
to activate factor X and factor IX.
The extrinsic clotting pathway (shown on the left side of
fig. 13.9 ) is now believed to initiate clot formation in vivo. Cur-
rent evidence suggests that the intrinsic clotting pathway plays
an amplification role, increasing the clotting cascade initiated

CLINICAL APPLICATION

Hemophilia A is a hereditary disease, inherited as an

X-linked recessive trait, which has been prevalent in the royal

families of Europe. In hemophilia A, a defect in one subunit

of factor VIII prevents this factor from participating in the

intrinsic clotting pathway. Von Willebrand’s disease, involv-

ing a defect in another subunit of factor VIII, is also inherited

as an X-linked recessive trait. This produces defective von

Willebrand factor, a large glycoprotein needed for rapidly cir-

culating platelets to adhere to collagen at the site of vascular

injury (see fig. 13.7 ), which contributes to difficulty in clot for-

mation. Hemophilia B, also known as Christmas disease, is

caused by a deficiency of factor IX and, like factor VIII defi-

ciency in hemophilia A, is inherited as an X-linked trait. This

disorder has recently been successfully treated with gene

therapy. Some acquired and inherited defects in the clotting

system are summarized in table 13.5.

Table 13.5 | Some Acquired and Inherited Clotting Disorders and a Listing
of Anticoagulant Drugs

Category Cause of Disorder Comments

Acquired clotting disorders Vitamin K deficiency Inadequate formation of prothrombin and other

clotting factors in the liver

Inherited clotting disorders Hemophilia A (defective factor VIIIAHF) Recessive trait carried on X chromosome; results

in delayed formation of fibrin

von Willebrand’s disease (defective factor VIIIVWF) Dominant trait carried on autosomal chromosome;

impaired ability of platelets to adhere to

collagen in subendothelial connective tissue

Hemophilia B (defective factor IX); also called

Christmas disease

Recessive trait carried on X chromosome; results

in delayed formation of fibrin

Anticoagulants

Aspirin Inhibits prostaglandin production, resulting in a defective platelet release reaction

Coumarin Inhibits activation of vitamin K

Heparin Inhibits activity of thrombin

Citrate Combines with Ca^21 , and thus inhibits the activity of many clotting factors

CLINICAL APPLICATION

Thrombolytic agents are drugs that function as protease

enzymes to convert plasminogen to plasmin, thereby pro-

moting the dissolution of blood clots. Recombinant DNA

technology has allowed the production of tissue plas-

minogen activator ( t-PA, or alteplase; there is also r-P A,

or reteplase ), but products derived from Streptococcus

bacteria— urokinase and streptokinase —are also used.

These can promote the dissolution of blood clots in the

treatment of such conditions as deep vein thrombosis,

stroke, coronary thrombosis, and pulmonary embolism.

Thrombolytic agents must be used carefully because of the

risk of hemorrhage.