FACTOR*	COMMON SYNONYM	DEPENDENT ON VITAMIN K^†
I	Fibrinogen	No
II	Prothrombin	Yes
III	Tissue thromboplastin	No
IV	Calcium	No
V	Proaccelerin	No
VII	Proconvertin	Yes
VIII	Antihemophilic factor	No
IX	Plasma thromboplastin component	Yes
X	Stuart factor	Yes
XI	Plasma thromboplastin antecedent	No
XII	Hageman factor	No
XIII	Fibrin stabilizing factor	No

^*Factor VI is no longer considered to be a coagulation factor.

^†Proteins C and S, which are endogenous anticoagulants that inactivate factors Va and VIIIa and promote fibrinolysis, are also dependent on vitamin K.

Pathologic Thrombus Formation

The processes leading to thrombosis and embolism are complex and not completely understood.

Atherosclerosis and other abnormalities affecting the vascular endothelium can serve as stimuli for platelet aggregation and blood coagulation in arteries. Venous pooling, sluggish blood flow, and inflammation of veins may permit inappropriate platelet adhesion and coagulation in vessels. Platelet aggregation appears to have a larger role in the formation of arterial thrombi (white thrombi), whereas coagulation predominates in the formation of venous thrombi (red thrombi). Platelet aggregation followed by coagulation, however, occurs both in arteries and in veins, and the processes differ only in the degree of contribution by platelets or coagulation to the thrombus.

An arterial or venous thrombus can become dislodged from the vessel wall and form an embolus that travels through the circulation and eventually occludes a smaller vessel in the lungs or brain, thereby causing pulmonary embolism or a cerebrovascular occlusion (stroke), respectively.

Anticoagulant Drugs

Anticoagulants are drugs that impede blood coagulation and prevent the occurrence or expansion of a thrombus. The anticoagulants are classified according to their mechanism of action and include vitamin K antagonists, drugs that potentiate antithrombin III, and drugs that directly inhibit thrombin or active factor X. Table 16-2 compares the properties of various anticoagulant drugs.

TABLE 16-2

Comparison of the Pharmacologic Properties of Selected Anticoagulants

PROPERTY	WARFARIN	HEPARIN AND RELATED DRUGS	DABIGATRAN ETEXILATE	RIVAROXABAN
Mechanism	Vitamin K antagonist	Potentiator of antithrombin III	Direct thrombin inhibitor	Active factor X inhibitor
Active in vitro	No	Yes	No (a prodrug)	Yes
Route of administration	Oral	Parenteral	Oral	Oral
Onset of action	Delayed	Immediate	Immediate	Immediate
Safe to take during pregnancy	No	Yes	Unknown	Use with caution
Antidote	Phytonadione (vitamin K₁)	Protamine sulfate	Unknown	Active factor VII or prothrombin complex concentrate

Warfarin

Chemistry and Mechanisms

Coumarin compounds such as warfarin were originally identified as the substances in spoiled clover hay that caused hemorrhagic disease in cattle. These compounds were subsequently developed as anticoagulants and rodenticides.

Warfarin and other coumarin derivatives are structurally related to vitamin K. These drugs inhibit the synthesis of coagulation factors II (prothrombin), VII, IX, and X, whose carboxylation is dependent on a reduced form of vitamin K. As shown in Figure 16-3, warfarin blocks the reduction of oxidized vitamin K and thereby prevents the posttranslational (following protein synthesis) carboxylation of these four factors. Warfarin also inhibits the synthesis of proteins C and S, which are endogenous anticoagulants that inactivate factors V and VIII and promote fibrinolysis. It is possible that the inhibition of proteins C and S contributes to a transient procoagulant effect when warfarin is first administered.

FIGURE 16-3 Mechanisms of action of warfarin. Warfarin blocks the reduction of oxidized vitamin K (vitamin K epoxide) and thereby prevents vitamin K–dependent carboxylation of clotting factors.

Pharmacokinetic and Pharmacologic Effects

Warfarin is well absorbed from the gut and extensively metabolized before being excreted in the urine. Unlike heparin and related anticoagulants, warfarin crosses the placenta and can cause fetal hemorrhage.

Warfarin has a delayed onset of action owing to the time required to deplete the pool of circulating clotting factors after synthesis of new factors is inhibited. The half-life of circulating vitamin K–dependent clotting factors ranges from 6 hours (factor VII) to 50 hours (factor II). Therefore the maximal effect of warfarin is not observed until 3 to 5 days after therapy is started. Patients with acute thromboembolic disorders can be initially treated with a low-molecular-weight heparin (LMWH) plus warfarin, and the LMWH is then withdrawn after warfarin becomes effective. A period of several days is also required for coagulation factor levels to return to normal after warfarin has been discontinued. The recovery of clotting factors can be accelerated by administration of phytonadione (vitamin K₁), as described later.

Adverse Effects and Interactions

The most common adverse effect of warfarin is bleeding (Table 16-3), which can range in severity from mild nosebleed to life-threatening hemorrhage. Patients should be instructed to report any signs of bleeding, including hematuria and bleeding into the skin (ecchymoses).

TABLE 16-3

Adverse Effects and Drug Interactions of Anticoagulant, Antiplatelet, and Fibrinolytic Drugs

DRUG	COMMON ADVERSE EFFECTS	COMMON DRUG INTERACTIONS
Anticoagulants
Warfarin	Birth defects and bleeding	Serum levels altered by drugs that induce or inhibit cytochrome P450, by drugs that inhibit gut absorption, and by drugs that directly increase or decrease the anticoagulant effect.
Rivaroxaban	Bleeding	Serum levels increased by cytochrome P450 3A4 inhibitors and by drugs that inhibit P-glycoprotein (Pgp) drug transport.
Dalteparin, enoxaparin	Bleeding and thrombocytopenia	Risk of bleeding increased by salicylates.
Heparin	Bleeding, hyperkalemia, and thrombocytopenia	Same as dalteparin.
Hirudin and related drugs	Bleeding	Same as dalteparin.
Antiplatelet Drugs
Abciximab	Bleeding, bradycardia, hypotension, and thrombocytopenia	Unknown.
Aspirin	Gastrointestinal irritation and bleeding, hypersensitivity reactions, and tinnitus	Increases hypoglycemic effect of sulfonylureas. Increases risk of gastrointestinal bleeding and ulceration associated with methotrexate, valproate, and other drugs. Inhibits uricosuric effect of probenecid.
Dipyridamole	Gastrointestinal distress, headache, mild and transient dizziness, and rash	Decreases metabolism of adenosine. Increases risk of bradycardia associated with β-adrenergic receptor antagonists.
Clopidogrel	Bleeding, diarrhea, gastrointestinal pain, increased cholesterol and triglyceride levels, nausea, and neutropenia	Increases levels of drugs metabolized by liver microsomal enzymes.
Fibrinolytic Drugs
Streptokinase*	Bleeding, hypersensitivity reactions, and reperfusion arrhythmias	Increases risk of bleeding associated with anticoagulant and antiplatelet drugs.

^*Also alteplase, urokinase, anistreplase, reteplase, and tenecteplase.

Warfarin is contraindicated in pregnancy because of its potential to cause fetal hemorrhage and various structural malformations referred to as the fetal warfarin syndrome. These malformations are partly a result of antagonism of vitamin K–dependent maturation of bone proteins during a process in which these proteins are carboxylated in the same manner as the nascent clotting factors. Warfarin and other vitamin K antagonists block this process and can cause bone deformities and various birth defects that are listed in Table 4-6.

Warfarin interacts with many drugs that either induce or inhibit cytochrome P450 (CYP) enzymes, but a few of its interactions result from antagonism or potentiation of its anticoagulant effect. The most serious interactions are with drugs that increase the anticoagulant effect and place the patient at risk of hemorrhage. Because the number of drugs that interact with warfarin is large, patients who are taking this drug should be instructed to consult a health care provider before starting or discontinuing any other medication.

High doses of salicylates and some third-generation cephalosporins directly reduce prothrombin levels and thereby increase the anticoagulant effect of warfarin. In contrast, treatment with rifampin or barbiturates induces CYP enzymes that metabolize warfarin and decreases its anticoagulant effect. Cholestyramine inhibits the absorption of warfarin from the gut. Amiodarone, cimetidine, erythromycin, fluconazole, gemfibrozil, isoniazid, metronidazole, sulfinpyrazone, and other drugs inhibit the metabolism of warfarin and increase the risk of bleeding. The prothrombin time (PT) should be monitored when adding or discontinuing drugs that interact with warfarin.

Phytonadione (vitamin K₁) directly antagonizes the effect of warfarin on clotting factor synthesis and is used to treat hemorrhage caused by anticoagulant activity.

Indications

Warfarin has been primarily used in the long-term treatment of patients who have a thromboembolic disorder such as deep vein thrombosis (DVT) and patients who have atrial fibrillation or an artificial heart valve (Table 16-4). It has also been used with a heparin-type anticoagulant for the treatment of MI. The goals of warfarin therapy are to prevent thrombus formation or expansion and to prevent embolization and other potentially fatal consequences of thrombosis.

TABLE 16-4

Clinical Uses of Antithrombotic Agents

CLINICAL USE	PRIMARY DRUGS
Venous Thromboembolism
Acute	LMWH, fondaparinux
Surgical prophylaxis	LMWH, fondaparinux, or rivaroxaban
Long-term prophylaxis	Warfarin or rivaroxaban
Pulmonary embolism	Heparin, fibrinolytic drug
Acute Coronary Syndromes
Unstable angina and non-STE ACS	Aspirin ± clopidogrel or prasugrel; eptifibatide or tirofiban; LMWH or fondaparinux
STEMI	Fibrinolytic drug, aspirin, and LMWH
Percutaneous coronary interventions*	LMWH or bivalirudin ± abciximab, or eptifibatide; also aspirin, clopidogrel, or prasugrel
Stroke, Thrombotic
Acute	Fibrinolytic drug or aspirin
Prophylaxis, including transient ischemic attacks	Aspirin and dipyridamole combined; clopidogrel or prasugrel
Atrial fibrillation	Heparin or LMWH followed by warfarin, dabigatran, or rivaroxaban
Artificial heart valve	Warfarin, aspirin