Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 34. Drugs Used in Coagulation Disorders

Drugs Used in Coagulation Disorders: Introduction

The drugs used in clotting and bleeding disorders fall into 2 major groups: (1) drugs used to decrease clotting or dissolve clots already present in patients at risk for vascular occlusion and (2) drugs used to increase clotting in patients with clotting deficiencies. The first group, the anticlotting drugs, includes some of the most commonly used drugs in the United States. Anticlotting drugs are used in the treatment and prevention of myocardial infarction and other acute coronary syndromes, atrial fibrillation, ischemic stroke, and deep vein thrombosis (DVT). Within the anticlotting group, the anticoagulant and thrombolytic drugs are effective in treatment of both venous and arterial thrombosis, whereas antiplatelet drugs are used primarily for treatment of arterial disease.

High-Yield Terms to Learn

Activated partial thromboplastin time (aPTT) test Laboratory test used to monitor the anticoagulant effect of unfractionated heparin and direct thrombin inhibitors; prolonged when drug effect is adequate Antithrombin III An endogenous anticlotting protein that irreversibly inactivates thrombin and factor Xa. Its enzymatic action is markedly accelerated by the heparins Clotting cascade System of serine proteases and substrates in the blood that provides rapid generation of clotting factors in response to blood vessel damage Glycoprotein IIb/IIIa (GPIIb/IIIa) A protein complex on the surface of platelets. When activated, it aggregates platelets primarily by binding to fibrin. Endogenous factors including thromboxane A2, ADP, and serotonin initiate a signaling cascade that activates GPIIb/IIIa

Heparin-induced thrombocytopenia (HIT) A hypercoagulable state plus thrombocytopenia that occurs in a small number of individuals treated with unfractionated heparin LMW heparins Fractionated preparations of heparin of molecular weight 2000—6000. Unfractionated heparin has a molecular weight range of 5000—30,000 Prothrombin time (PT) test Laboratory test used to monitor the anticoagulant effect of warfarin; prolonged when drug effect is adequate



Anticoagulants inhibit the formation of fibrin clots. Three major types of anticoagulants are available: heparin and related products, which must be used parenterally; direct thrombin inhibitors, which also must be used parenterally; and the orally active coumarin derivatives (eg, warfarin). Comparative properties of the heparins and warfarin are shown in Table 34-1.

TABLE 34-1 Properties of heparins and warfarin.

Property Heparins Warfarin Structure Large acidic polysaccharide polymers Small lipid-soluble molecule Route of administration Parenteral Oral Site of action Blood Liver Onset of action Rapid (minutes) Slow (days); limited by half-lives of preexisting normal factors Mechanism of action Activates antithrombin III, which proteolyzes coagulation factors including thrombin and factor Xa Impairs post-translational modification of factors II, VII, IX and X Monitoring aPTT for unfractionated heparin but not LMW heparins Prothrombin time Antidote Protamine for heparin; unfractionated protamine reversal of LMW heparins is incomplete Vitamin K1 , plasma, prothrombin complex concentrates Use Mostly acute, over days Chronic, over weeks to months Use in pregnancy Yes No

aPTT, activated partial thromboplastin time; LMW, low molecular weight.



Heparin is a large sulfated polysaccharide polymer obtained from animal sources. Each batch contains molecules of varying size, with an average molecular weight of 15,000-20,000. Heparin is highly acidic and can be neutralized by basic molecules (eg, protamine). Heparin is given intravenously or subcutaneously to avoid the risk of hematoma associated with intramuscular injection.

Low-molecular-weight (LMW) fractions of heparin (eg, enoxaparin ) have molecular weights of 2000-6000. LMW heparins have greater bioavailability and longer durations of action than unfractionated heparin; thus, doses can be given less frequently (eg, once or twice a day). They are given subcutaneously. Fondaparinux is a small synthetic drug that contains the biologically active pentasaccharide present in unfractionated and LMW heparins. It is administered subcutaneously once daily.

Mechanism and Effects

Unfractionated heparin binds to endogenous antithrombin III (ATIII) via a key pentasaccharide sequence. The heparin-ATIII complex combines with and irreversibly inactivates thrombin and several other factors, particularly factor Xa (Figure 34-1). In the presence of heparin, antithrombin III proteolyzes thrombin and factor Xa approximately 1000-fold faster than in its absence. Because it acts on preformed blood components, heparin provides anticoagulation immediately after administration. The action of heparin is monitored with the activated partial thromboplastin time (aPTT) laboratory test.


A model of the coagulation cascade, including its inhibition by the activated form of protein C. Tissue factor (TF) is important in initiating the cascade. Tissue factor pathway inhibitor (TFPI) inhibits the action of the VIIa-TF complex.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 34-2.)

LMW heparins and fondaparinux, like unfractionated heparin, bind ATIII. These complexes have the same inhibitory effect on factor Xa as the unfractionated heparin-ATIII complex. However, the short-chain heparin-ATIII and fondaparinux-ATIII complexes provide a more selective action because they fail to affect thrombin. The aPTT test does not reliably measure the anticoagulant effect of the LMW heparins and fondaparinux; this is a potential problem, especially in renal failure, in which their clearance may be decreased.

Clinical Use

Because of its rapid effect, heparin is used when anticoagulation is needed immediately (eg, when starting therapy). Common uses include treatment of deep vein thrombosis (DVT), pulmonary embolism, and acute myocardial infarction. Heparin is used in combination with thrombolytics for revascularization and in combination with glycoprotein IIb/IIIa inhibitors during angioplasty and placement of coronary stents. Because it does not cross the placental barrier, heparin is the drug of choice when an anticoagulant must be used in pregnancy. LMW heparins and fondaparinux have similar clinical applications.


Increased bleeding is the most common adverse effect of heparin and related molecules; the bleeding may result in hemorrhagic stroke. Protamine can lessen the risk of serious bleeding that can result from excessive unfractionated heparin. Protamine only partially reverses the effects of LMW heparins and does not affect the action of fondaparinux. Unfractionated heparin causes moderate transient thrombocytopenia in many patients and severe thrombocytopenia and thrombosis (heparin-induced thrombocytopenia or HIT) in a small percentage of patients who produce an antibody that binds to a complex of heparin and platelet factor 4. LMW heparins and fondaparinux are less likely to cause this immune-mediated thrombocytopenia. Prolonged use of unfractionated heparin is associated with osteoporosis.

Direct Thrombin Inhibitors

Chemistry and Pharmacokinetics

Direct thrombin inhibitors are based on proteins made by Hirudo medicinalis, the medicinal leech. Lepirudin is the recombinant form of the leech protein hirudin, while desirudin and bivalirudin are modified forms of hirudin. Argatroban is a small molecule with a short half-life. All 4 drugs are administered parenterally.

Mechanism and Effects

The protein analogs of lepirudin bind simultaneously to the active site of thrombin and to thrombin substrates. Argatroban binds solely to the thrombin-active site. Unlike the heparins, these drugs inhibit both soluble thrombin and the thrombin enmeshed within developing clots. Bivalirudin also inhibits platelet activation.

Clinical Use

Direct thrombin inhibitors are used as alternatives to heparin primarily in patients with heparin-induced thrombocytopenia. Bivalirudin also is used in combination with aspirin during percutaneous coronary angioplasty. Like unfractionated heparin, the action of these drugs is monitored with the aPTT laboratory test.


Like other anticoagulants, the direct thrombin inhibitors can cause bleeding. No reversal agents exist. Prolonged infusion of lepirudin can induce antibodies that form a complex with lepirudin and prolong its action, and it can induce anaphylactic reactions.

Warfarin and Other Coumarin Anticoagulants

Chemistry and Pharmacokinetics

Warfarin and other coumarin anticoagulants are small, lipid-soluble molecules that are readily absorbed after oral administration. Warfarin is highly bound to plasma proteins (>99%), and its elimination depends on metabolism by cytochrome P450 enzymes.

Mechanism and Effects

Warfarin and other coumarins interfere with the normal post-translational modification of clotting factors in the liver, a process that depends on an adequate supply of reduced vitamin K. The drugs inhibit vitamin K epoxide reductase (VKOR), which normally converts vitamin K epoxide to reduced vitamin K. The vitamin K-dependent factors include thrombin and factors VII, IX, and X (Figure 34-1). Because the clotting factors have half-lives of 8-60 h in the plasma, an anticoagulant effect is observed only after sufficient time has passed for elimination of the normal preformed factors. The action of warfarin can be reversed with vitamin K, but recovery requires the synthesis of new normal clotting factors and is, therefore, slow (6-24 h). More rapid reversal can be achieved by transfusion with fresh or frozen plasma that contains normal clotting factors. The effect of warfarin is monitored by the prothrombin time ( PT ) test.

Clinical Use

Warfarin is used for chronic anticoagulation in all of the clinical situations described previously for heparin, except in pregnant women.


Bleeding is the most important adverse effect of warfarin. Early in therapy, a period of hypercoagulability with subsequent dermal vascular necrosis can occur. This is due to deficiency of protein C, an endogenous vitamin K-dependent anticoagulant with a short half-life. Warfarin can cause bone defects and hemorrhage in the developing fetus and, therefore, is contraindicated in pregnancy.

Because warfarin has a narrow therapeutic window, its involvement in drug interactions is of major concern. Cytochrome P450-inducing drugs (eg, carbamazepine, phenytoin, rifampin, barbiturates) increase warfarin's clearance and reduce the anticoagulant effect of a given dose. Cytochrome P450 inhibitors (eg, amiodarone, selective serotonin reuptake inhibitors, cimetidine) reduce warfarin's clearance and increase the anticoagulant effect of a given dose. Genetic variability in cytochrome P450 2C9 and VKOR affect responses to warfarin. Algorithms to determine initial warfarin dose based on cytochrome P450 2C9 and VKOR, age, body size, and concomitant medications are being tested.

Skill Keeper: Treatment of Atrial Fibrillation

(See Chapters 13 and 14)

Patients with chronic atrial fibrillation routinely receive warfarin to prevent the formation of blood clots in the poorly contracting atrium and to decrease the risk of embolism of such clots to the brain or other tissues. Such patients are also often treated with antiarrhythmic drugs. The primary goals of antiarrhythmic treatment are to slow the atrial rate and, most importantly, control the ventricular rate.

1. Which antiarrhythmic drugs are most appropriate for treating chronic atrial fibrillation?

2. Do any of these drugs have significant interactions with warfarin?

The Skill Keeper Answers appear at the end of the chapter.

Thrombolytic Agents

Classification and Prototypes

The thrombolytic drugs used most commonly are either forms of the endogenous tissue plasminogen activator (t-PA; eg, alteplase , tenecteplase, and reteplase) or a protein synthesized by streptococci (streptokinase). All are given intravenously.

Mechanism of Action

Plasmin is an endogenous fibrinolytic enzyme that degrades clots by splitting fibrin into fragments (Figure 34-2). The thrombolytic enzymes catalyze the conversion of the inactive precursor, plasminogen, to plasmin.


Diagram of the fibrinolytic system. The useful thrombolytic drugs are shown on the left. These drugs increase the formation of plasmin, the major fibrinolytic enzyme. Antiplasmin drugs are shown on the right. Aminocaproic acid and tranexamic acid inhibit plasmin formation.

Tissue Plasminogen Activator

t-PA is an enzyme that directly converts plasminogen to plasmin (Figure 34-2). It has little activity unless it is bound to fibrin, which, in theory, should make it selective for the plasminogen that has already bound to fibrin (ie, in a clot) and should result in less danger of widespread production of plasmin and spontaneous bleeding. In fact, t-PA's selectivity appears to be quite limited. Alteplase is normal human plasminogen activator. Reteplase is a mutated form of human t-PA with similar effects but a slightly faster onset of action and longer duration of action. Tenecteplase is another mutated form of t-PA with a longer half-life.


Streptokinase is obtained from bacterial cultures. Although not itself an enzyme, streptokinase forms a complex with endogenous plasminogen; the plasminogen in this complex undergoes a conformational change that allows it to rapidly convert free plasminogen into plasmin. Unlike the forms of t-PA, streptokinase does not show selectivity for fibrin-bound plasminogen.

Clinical Use

The major application of the thrombolytic agents is as an alternative to percutaneous coronary angioplasty in the emergency treatment of coronary artery thrombosis. Under ideal conditions (ie, treatment within 6 h), these agents can promptly recanalize the occluded coronary vessel. Very prompt use (ie, within 3 h of the first symptoms) of t-PA in patients with ischemic stroke is associated with a significantly better clinical outcome. Cerebral hemorrhage must be positively ruled out before such use. The thrombolytic agents are also used in cases of severe pulmonary embolism.


Bleeding is the most important hazard and has about the same frequency with all the thrombolytic drugs. Cerebral hemorrhage is the most serious manifestation. Streptokinase, a bacterial protein, can evoke the production of antibodies that cause it to lose its effectiveness or induce severe allergic reactions on subsequent therapy. Patients who have had streptococcal infections may have preformed antibodies to the drug. Because they are human proteins, the recombinant forms of t-PA are not subject to this problem. However, they are much more expensive than streptokinase and not much more effective.

Antiplatelet Drugs

Platelet aggregation contributes to the clotting process (Figure 34-3) and is especially important in clots that form in the arterial circulation. Platelets appear to play a central role in pathologic coronary and cerebral artery occlusion. Platelet aggregation is triggered by a variety of endogenous mediators that include the prostaglandin thromboxane, adenosine diphosphate (ADP), thrombin, and fibrin. Substances that increase intracellular cyclic adenosine monophosphate (cAMP; eg, the prostaglandin prostacyclin, adenosine) inhibit platelet aggregation.


Thrombus formation at the site of the damaged vascular wall (EC, endothelials cell) and the role of platelets and clotting factors. Platelet membrane receptors include the glycoprotein (GP) Ia receptor, binding to collagen (C); GP Ib receptor, binding von Willebrand factor (vWF); and GP IIb/IIIa, which binds fibrinogen and other macromolecules. Antiplatelet prostacyclin (PGI2 ) is released from the endothelium. Aggregating substances released from the degranulating platelet include adenosine diphosphate (ADP), thromboxane A2 (TXA2), and serotonin (5-HT).

(Modified and reproduced, with permission, from Katzung BG, Masters SB, and Trevor AT editors: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 34-1.)

Classification and Prototypes

Antiplatelet drugs include aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), glycoprotein IIb/IIIa receptor inhibitors ( abciximab, tirofiban, and eptifibatide ), antagonists of ADP receptors ( clopidogrel and ticlopidine ), and inhibitors of phosphodiesterase 3 ( dipyridamole and cilostazol ).

Mechanism of Action

Aspirin and other NSAIDs inhibit thromboxane synthesis by blocking the enzyme cyclooxygenase (COX; Chapter 18). Thromboxane A2 is a potent stimulator of platelet aggregation. Aspirin, an irreversible COX inhibitor, is particularly effective. Because platelets lack the machinery for synthesis of new protein, inhibition by aspirin persists for several days until new platelets are formed. Other NSAIDs, which cause a less persistent antiplatelet effect (hours), are not used as antiplatelet drugs and, in fact, can interfere with the antiplatelet effect of aspirin when used in combination with aspirin.

Abciximab is a monoclonal antibody that reversibly inhibits the binding of fibrin and other ligands to the platelet glycoprotein IIb/IIIa receptor, a cell surface protein involved in platelet cross-linking. Eptifibatide and tirofiban also reversibly block the glycoprotein IIb/IIIa receptor.

Clopidogrel and the older drug ticlopidine are converted in the liver to active metabolites that irreversibly inhibit the platelet ADP receptor and thereby prevent ADP-mediated platelet aggregation.

Dipyridamole and the newer cilostazol appear to have a dual mechanism of action. They prolong the platelet-inhibiting action of intracellular cAMP by inhibiting phosphodiesterase enzymes that degrade cyclic nucleotides, including cAMP, an inhibitor of platelet aggregation, and cyclic guanosine monophosphate (cGMP), a vasodilator (see Chapter 19). They also inhibit the uptake of adenosine by endothelial cells and erythrocytes and thereby increase the plasma concentration of adenosine. Adenosine acts through platelet adenosine A2 receptors to increase platelet cAMP and inhibit aggregation.

Clinical Use

Aspirin is used to prevent further infarcts in persons who have had 1 or more myocardial infarcts and may also reduce the incidence of first infarcts. The drug is used extensively to prevent transient ischemic attacks (TIAs), ischemic stroke, and other thrombotic events.

The glycoprotein IIb/IIIa inhibitors prevent restenosis after coronary angioplasty and are used in acute coronary syndromes (eg, unstable angina and non-Q-wave acute myocardial infarction).

Clopidogrel and ticlopidine are effective in preventing TIAs and ischemic strokes, especially in patients who cannot tolerate aspirin. Clopidogrel is routinely used to prevent thrombosis in patients who have received a coronary artery stent.

Dipyridamole is approved as an adjunct to warfarin in the prevention of thrombosis in those with cardiac valve replacement and has been used in combination with aspirin for secondary prevention of ischemic stroke. Cilostazol is used to treat intermittent claudication, a manifestation of peripheral arterial disease.


Aspirin and other NSAIDs cause gastrointestinal and CNS effects (Chapter 36). All antiplatelet drugs significantly enhance the effects of other anticlotting agents. The major toxicities of the glycoprotein IIb/IIIa receptor-blocking drugs are bleeding and, with chronic use, thrombocytopenia. Ticlopidine is used rarely because it causes bleeding in up to 5% of patients, severe neutropenia in about 1%, and very rarely thrombotic thrombocytopenic purpura (TTP), a syndrome characterized by the disseminated formation of small thrombi, platelet consumption, and thrombocytopenia. Clopidogrel is less hematotoxic. The most common adverse effects of dipyridamole and cilostazol are headaches and palpitations. Cilostazol is contraindicated in patients with congestive heart failure because of evidence of reduced survival.

Drugs Used in Bleeding Disorders

Inadequate blood clotting can result from vitamin K deficiency, genetically determined errors of clotting factor synthesis (eg, hemophilia), a variety of drug-induced conditions, and thrombocytopenia. Treatment involves administration of vitamin K, preformed clotting factors, or antiplasmin drugs. Thrombocytopenia can be treated by administration of platelets or oprelvekin, the recombinant form of the megakaryocyte growth factor interleukin-11 (see Chapter 33).

Vitamin K

Deficiency of vitamin K, a fat-soluble vitamin, is most common in older persons with abnormalities of fat absorption and in newborns, who are at risk of vitamin K deficiency bleeding. The deficiency is readily treated with oral or parenteral phytonadione (vitamin K 1). In the United States, all newborns receive an injection of phytonadione. Large doses of vitamin K1 are used to reverse the anticoagulant effect of excess warfarin.

Clotting Factors and Desmopressin

The most important agents used to treat hemophilia are fresh plasma and purified human blood clotting factors, especially factor VIII (for hemophilia A) and factor IX (for hemophilia B), which are either purified from blood products or produced by recombinant DNA technology. These products are expensive and carry a risk of immunologic reactions and, in the case of factors purified from blood products, infection (although most known blood-borne pathogens are removed by chemical treatment of the plasma extracts.)

The vasopressin V2 receptor agonist desmopressin acetate (see Chapter 37) increases the plasma concentration of von Willebrand factor and factor VIII. It is used to prepare patients with mild hemophilia A or von Willebrand disease for elective surgery.

Antiplasmin Agents

Antiplasmin agents are valuable for the prevention or management of acute bleeding episodes in patients with hemophilia and others with a high risk of bleeding disorders. Aminocaproic acid and tranexamic acid are orally active agents that inhibit fibrinolysis by inhibiting plasminogen activation (Figure 34-2). Adverse effects include thrombosis, hypotension, myopathy, and diarrhea.

Skill Keeper Answers: Treatment of Atrial Fibrillation

(See Chapters 13 and 14)

1. The  adrenoceptor-blocking drugs (class II; eg, propranolol, acebutolol) and calcium channel-blocking drugs (class IV; eg, verapamil, diltiazem) are useful for atrial fibrillation because they slow atrioventricular (AV) nodal conduction and thereby help control ventricular rate. Though rarely used, digoxin can be effective by increasing the effective refractory period in AV nodal tissue and decreasing AV nodal conduction velocity. If symptoms persist in spite of effective rate control, other class I or class III antiarrhythmic drugs (eg, amiodarone, procainamide, flecainide, sotalol) can be used in an attempt to provide rhythm control.

2. With warfarin, one is always concerned about pharmacodynamic and pharmacokinetic drug interactions. A metabolite of amiodarone inhibits the metabolism of warfarin and can increase the anticoagulant effect of warfarin. None of the other antiarrhythmic drugs mentioned appears to have significant interactions with warfarin.


When you complete this chapter, you should be able to:

 List the 3 major classes of anticlotting drugs and compare their usefulness in venous and arterial thromboses.

 Name 3 types of anticoagulants and describe their mechanisms of action.

 Explain why the onset of warfarin's action is relatively slow.

 Compare the oral anticoagulants, standard heparin, and LMW heparins with respect to pharmacokinetics, mechanisms, and toxicity.

 Give several examples of warfarin's role in pharmacokinetic and pharmacodynamic drug interactions.

Diagram the role of activated platelets at the site of a damaged blood vessel wall and show where the 4 major classes of antiplatelet drugs act.

 Compare the pharmacokinetics, clinical uses, and toxicities of the major antiplatelet drugs.

 List 3 drugs used to treat disorders of excessive bleeding.

Drug Summary Table: Drugs Used for Anticoagulation and for Bleeding Disorders

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Anticoagulants Heparins Unfractionated heparin Complexes with antithrombin III irreversibly inactivates the coagulation factors thrombin and factor Xa Venous thrombosis, pulmonary embolism, myocardial infarction, unstable angina, adjuvant to percutaneous coronary intervention (PCI) and thrombolytics Parenteral administration Bleeding (monitor with aPTT, protamine is reversal agent); thrombocytopenia; osteoporosis with chronic use LMW heparins (enoxaparin, dalteparin, tinzaparin): More selective anti-factor X activity, more reliable pharmacokinetics with renal elimination, protamine reversal only partially effective, less risk of thrombocytopenia Fondaparinux: Effects similar to LMW heparins Direct thrombin inhibitors Lepirudin Binds to thrombin's active site and inhibits its enzymatic action Anticoagulation in patients with heparin-induced thrombocytopenia (HIT) IV administration Bleeding (monitor with aPTT); anaphylactic reactions Oral anticoagulants Warfarin Inhibits vitamin K epoxide reductase and thereby interferes with production of functional vitamin K-dependent clotting and anticlotting factors Venous thrombosis, pulmonary embolism, prevention of thromboembolic complications of atrial fibrillation or cardiac valve replacement Oral administration; delayed onset and offset of anticoagulant activity; many drug interactions Bleeding (monitor with PT, vitamin K1 is a reversal agent); thrombosis early in therapy due to protein C deficiency; teratogen Thrombolytic drugs Alteplase, recombinant human tissue plasminogen activator (t-PA) Converts plasminogen to plasmin, which degrades the fibrin in thrombi Coronary artery thrombosis, ischemic stroke, pulmonary embolism Parenteral administration Bleeding especially cerebral hemorrhage Reteplase, tenecteplase: Similar to alteplase but with a longer half-life Streptokinase: Bacterial protein that forms a complex with plasminogen that rapidly converts plasminogen to plasmin. Subject to inactivating antibodies and allergic reactions Antiplatelet drugs COX inhibitor Aspirin Nonselective, irreversible COX inhibitor; reduces platelet production of thromboxane A2, a potent stimulator of platelet aggregation

Prevention and treatment of arterial thrombosis Dose required for antithrombotic effect is lower than anti-inflammatory dose (see Chapter 36); duration of activity is longer than pharmacokinetic half-life due to irreversible action Gastrointestinal toxicity, nephrotoxicity; hypersensitivity reaction due to increased leukotrienes; tinnitus, hyperventilation metabolic acidosis, hyperthermia, coma in overdose Glycoprotein IIb/IIIa inhibitor (GP IIb/IIIa)Abciximab Inhibits platelet aggregation by interfering with GPIIb/IIIa binding to fibrinogen and other ligands Used during PCI to prevent restenosis; acute coronary syndrome Parenteral administration Bleeding, thrombocytopenia with prolonged use Eptifibatide, tirofiban: Reversible GP IIb/IIIa inhibitors of smaller size than abciximab ADP receptor antagonists Clopidogrel Active metabolite irreversibly inhibits platelet ADP receptor Acute coronary syndrome, prevention of restenosis after PCI, prevention and treatment of arterial thrombosis Oral administration Bleeding, gastrointestinal disturbances, hematologic abnormalities Ticlopidine: Older ADP receptor antagonist with more toxicity, particularly leukopenia and thrombotic thrombocytopenic purpura Dipyridamole Dipyridamole Inhibits adenosine uptake and inhibits phosphodiesterase enzymes that degrade cyclic nucleotides (cAMP, cGMP) Prevention of thromboembolic complications of cardiac valve replacement; combined with aspirin for secondary prevention of ischemic stroke Oral administration Headache, palpitations, contraindicated in congestive heart failure Cilostazol: Similar to dipyridamole Drugs used in bleeding disorders Reversal agents Vitamin K1 (phytonadione) Increases supply of reduced vitamin K, which is required for synthesis of functional vitamin K-dependent clotting and anticlotting factors Vitamin K deficiency, reversal of excessive warfarin anticlotting activity Oral or parenteral administration Severe infusion reaction when given IV or IM Protamine: Acidic protein administered parenterally to reverse excessive anticlotting activity of unfractionated heparin Clotting factors Factor VIII Key factor in the clotting cascade Hemophilia A Parenteral administration Infusion reaction, hypersensitivity reaction Plasma and purified human clotting factors: These are available to treat other forms of hemophilia Desmopressin: Vasopressin V2 receptor agonist increases concentrations of von Willebrand factor and factor VIII (see Chapter 37) Antiplasmin drugsAminocaproic acid Competitively inhibits plasminogen activation Excessive fibrinolysis Oral or parenteral administration Thrombosis, hypotension, myopathy, diarrhea Tranexamic acid: Analog of aminocaproic acid

aPTT, activated partial thromboplastin time; cAMP. cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; COX, cyclooxygenase; GP, glycoprotein; PCI, percutaneous coronary intervention.

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