Blood must remain fluid within the vasculature and yet clot quickly when exposed to subendothelial surfaces at sites of vascular injury. Under normal circumstances, a delicate balance between coagulation and fibrinolysis prevents both thrombosis and hemorrhage. Alteration of this balance in favor of coagulation results in thrombosis. Thrombi, composed of platelet aggregates, fibrin, and trapped red blood cells, can form in arteries or veins. Antithrombotic drugs used to treat thrombosis include antiplatelet drugs, which inhibit platelet activation or aggregation; anticoagulants, which attenuate fibrin formation; and fibrinolytic agents, which degrade fibrin. All antithrombotic drugs increase the risk of bleeding.
This chapter reviews the agents commonly used for controlling blood fluidity, including:
The parenteral anticoagulant heparin and its derivatives, which activate antithrombin, a natural inhibitor of coagulant proteases
The coumarin anticoagulants, which lower the functional levels of multiple coagulation factors
The direct oral anticoagulants, which inhibit factor Xa or thrombin
Fibrinolytic agents, which degrade fibrin
Antiplatelet agents, which attenuate platelet activation (aspirin, clopidogrel, prasugrel, ticagrelor, and vorapaxar) or aggregation (glycoprotein IIb/IIIa inhibitors)
Vitamin K, which is required for the biosynthesis of key coagulation factors
ACT: activated clotting time
aPTT: activated partial thromboplastin time
CrCL: creatinine clearance
CYP: cytochrome P450
EPCR: endothelial protein C receptor
Gla: γ-carboxyglutamic acid
Glu: glutamic acid
INR: international normalized ratio
LMWH: low-molecular-weight heparin
PAI: plasminogen activator inhibitor
PAR: protease-activated receptor
PT: prothrombin time
TF: tissue factor
TFPI: tissue factor pathway inhibitor
t-PA: tissue plasminogen activator
TxA2: thromboxane A2
u-PA: urokinase plasminogen activator
VKOR: vitamin K epoxide reductase
OVERVIEW OF HEMOSTASIS: PLATELET FUNCTION, BLOOD COAGULATION, AND FIBRINOLYSIS
Hemostasis is the cessation of blood loss from a damaged vessel. Platelets first adhere to macromolecules in the subendothelial regions of the injured blood vessel, where they become activated. Adherent platelets release substances that activate nearby platelets, thereby recruiting them to the site of injury. Activated platelets then aggregate to form the primary hemostatic plug.
Vessel wall injury also exposes tissue factor (TF), which initiates the coagulation system. Activated platelets enhance activation of the coagulation system by providing a surface onto which clotting factors assemble and by releasing stored clotting factors. This results in a burst of thrombin (factor IIa) generation. Thrombin converts soluble fibrinogen to fibrin, activates platelets, and feeds back to promote additional thrombin generation. The fibrin strands tie the platelet aggregates together to form a stable clot.
The processes of platelet activation and aggregation and blood coagulation are summarized in Figures 36–1 and 36–2 (see also the animation on the Goodman & Gilman site on AccessMedicine.com). Coagulation involves a series of zymogen activation reactions, as shown in Figure 36–2. At each stage, a precursor protein, or zymogen, is converted to an active ...