Page 161 - Cardiac Nursing

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C HAPTER 6 / Hematopoiesis, Coagulation, and Bleeding 137
(formerly factor III), is a membrane glycoprotein that is partic- the plasminogen molecule. Activators of plasminogen are found
ularly prevalent in tissues, where it plays a vital role in the pre- in various tissues, blood, and urine. The best-known endogenous
vention of hemorrhage. Tissue factor is exposed to and binds to activators are tPA and urokinase, which is a urinary activator of
factor VII, which is activated to factor VIIa. Factor VIIa is a po- plasminogen. Some exogenous plasminogen activators are related
tent enzyme that activates factor X to Xa. The reactions from to types of bacteria such as streptokinase and staphylokinase. 5
this step on are referred to as the common pathway. Calcium Drugs have been developed to mimic the activity of these kinases
plays a significant role in each step leading to the formation of to dissolve clots. Fragments of the fibrin clot, known as fibrin
thrombin. 5 degradation products (FDP), are released into the circulation as
theclot is broken down. FDP are potent inhibitors of coagula-
Intrinsic Pathway tion. They act by binding to thrombin, thus inhibiting its action,
Because the intrinsic pathway is initiated by a separate set of and by interfering with the binding of fibrin threads to form the
factors that is not degraded by rapid-acting inhibitors, the fibrin clot. Except in some abnormal situations, FDP are present
process may proceed more slowly and the results may last in such small numbers that their anticoagulant effect is not clin-
longer and be more pronounced than those initiated by the ex- ically important. Plasminogen is then converted back to plasmin
trinsic pathway. The function of the intrinsic pathway is com- and neutralized by a number of antiplasmin and inhibitor sys-
monly analyzed by the partial thromboplastin time (PTT). In- tems. All these reactions that occur in the coagulation cascade
trinsic activation is initiated when blood is exposed to a and fibrinolytic system are time dependent and can be monitored
negatively charged surface, such as the site of blood vessel in- using laboratory testing as listed in Table 6-3.
jury. The negative charge, along with collagen and endotoxin,
attracts factor XII, which binds to the surface and autoactivates Natural Anticoagulant Systems
to factor XIIa. Factor XIIa converts prekallikrein to kallikrein,
which in turn converts circulating factor XII to its activated Coagulation is regulated by three major mechanisms: the elimi-
form, XIIa. Both the activated form of factor XII and kallikrein nation of activated clotting factors, the protease inhibitors (in-
catalyze the activation of factor XI into XIa. Factor XIa, to- hibitors of coagulation), and the destruction of the fibrin clot.
gether with ionized calcium, cleaves factor IX at two sites to There must be a balance between coagulation and anticoagulation
produce factor IXa. Factor IXa, together with factor VIII, phos- processes in the body to maintain homeostasis. The natural anti-
pholipid, and ionized calcium convert factor X to its activated coagulant systems include antithrombin III, heparin cofactor II,
form, factor Xa. As discussed previously, factor X can also be ac- and protein C and its cofactor, protein S.
tivated through the extrinsic pathway. From here, the coagula- Antithrombin III is an 2-globulin glycoprotein, which is con-
tion process proceeds along the common pathway, regardless of sidered the major inhibitor of coagulation. It slowly inactivates
whether initiation was extrinsic or intrinsic. 5 thrombin as well as factors Xa, IXa, XIa, and XIIa. In the presence
of heparin, antithrombin III–thrombin binding is increased sig-
Common Pathway and Fibrin Formation nificantly. This is thought to be the main mechanism for heparin’s
The final common sequence involves the combination of factors anticoagulation ability and its interaction with antithrombin III
Xa and V, phospholipid, and ionized calcium into a complex that and tissue factor pathway inhibitor.
converts prothrombin to thrombin. The thrombin formed subse- Heparin cofactor II is a heparin-dependent thrombin inhibitor
quently cleaves the long molecule fibrinogen to fibrin. The fibrin whose activity is also accelerated by the presence of heparin. This
monomer is able to polymerize spontaneously to form a loose web cofactor not only inhibits thrombin but also thrombin-induced
of fibers that is capable of stopping the bleeding in small- and platelet aggregation and release. 5
medium-sized arteries and veins. The fibrin clot is eventually sta- Protein C and protein S are major natural anticoagulants in
bilized and thickened by the action of factor XIII, which is acti- the body and have a powerful role in anticoagulation. Deficiency
vated by the presence of ionized calcium and thrombin. Fibrin in either of these proteins can lead to the development of throm-
forms a loose covering over the injured area and reinforces the bus. Protein C is a vitamin K-dependent protein, which is syn-
platelet plug. After a short period of time, the clot begins to re- thesized in the liver and circulates as a zymogen, an inactive pre-
tract. This process is thought to be a reaction of the platelets, cursor form in the blood. Activation occurs faster when
which send out cytoplasmic processes that attach to the fibrin and thrombin, in the presence of thrombomodulin, assists with pro-
5
pull the fibers closer. Plasminogen and other components of the teolytic cleavage that converts protein C to its active enzymatic
fibrinolytic mechanism are incorporated into the fibrin clot as it form, activated protein C (APC). Protein S must also be present
solidifies. to help APC proteolytically cleave factors Va and VIIIa, which
will decrease the conversion of prothrombin to thrombin, and
Fibrinolysis acts as a regulatory feedback loop to balance coagulation. The
dual role of thrombin in both coagulation and anticoagulation is
The removal of clots when the site of vessel injury has healed is exemplified here. Protein C also has a function in promoting fib-
as important as the formation of the clot itself. Fibrinolysis is the rinolysis by neutralizing the inhibitors of tPA, which allows the
physiological process that removes insoluble fibrin deposits by conversion of plasminogen to plasmin. Inactivation of APC is a
5
enzymatic digestion of the stabilized fibrin polymers. The slower process with a plasma protease inhibitor that has a short
process of fibrinolysis re-establishes blood flow. Plasmin dissolves half-life intimating that other unidentified direct cell mecha-
5
clots by digesting fibrin and fibrinogen using hydrolysis. Plas- nisms. The properties of protein C have been applied clinically
minogen is a glycoprotein and an inactive form of plasmin, with the development of the medication, Drotrecogin alfa.
which is synthesized by the liver. It is activated to plasmin by the Drotrecogin alfa is a recombinant intravenous (IV) form of APC,
activity of proteolytic enzymes, the kinases that cleave a bond on which is used in severely ill patients with sepsis to decrease