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INTRODUCTION

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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.

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This chapter reviews the agents commonly used for controlling blood fluidity, including

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  • 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.

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ABBREVIATIONS

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Abbreviations

ACT: activated clotting time

ADP: adenosine diphosphate

α2-AP: α2-antiplasmin

aPTT: activated partial thromboplastin time

CNS: central nervous system

COX: cyclooxygenase

CPR: cardiopulmonary resuscitation

CrCL: creatinine clearance

CYP: cytochrome P450

EDTA: ethylenediaminetetraacetic acid

EPCR: endothelial protein C receptor

GI: gastrointestinal

Gla: γ-carboxyglutamic acid

Glu: glutamic acid

GP: glycoprotein

INR: international normalized ratio

IP3: inositol 1,4,5-trisphosphate

KGD: lysine-glycine-aspartate

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

RGD: arginine-glycine-aspartate

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

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OVERVIEW OF HEMOSTASIS: PLATELET FUNCTION, BLOOD COAGULATION, AND FIBRINOLYSIS

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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.

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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.

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The processes of platelet activation and ...

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