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 block multiple steps in the coagulation cascade;
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); and
vitamin K, which is required for the biosynthesis of key coagulation factors.
ACT: activated clotting time
ADP: adenosine diphosphate
aPTT: activated partial thromboplastin time
CNS: central nervous system
CPR: cardiopulmonary resuscitation
CrCL: creatinine clearance
CYP: cytochrome P450
EDTA: ethylenediaminetetraacetic acid
EPCR: endothelial protein C receptor
Gla: γ-carboxyglutamic acid
Glu: glutamic acid
INR: international normalized ratio
IP3: inositol 1,4,5-trisphosphate
LMWH: low-molecular-weight heparin
NO: nitric oxide
PAI: plasminogen activator inhibitor
PAR: protease-activated receptor
PGI2: prostaglandin I2 or prostacyclin
PLC: phospholipase C
PT: prothrombin time
TF: tissue factor
TFPI: tissue factor pathway inhibitor
t-PA: tissue plasminogen activator
TxA2: thromboxane A2
u-PA: urokinase plasminogen activator
USP: U.S. Pharmacopeia
VKOR: vitamin K epoxide reductase
VKORC1: C1 subunit of vitamin K epoxide reductase
vWF: von Willebrand factor
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 ...