NCLEX: Anticoagulants and Antiplatelet Agents

This chapter describes drugs that are useful in treating disorders of hemostasis. Thrombosis, the formation of an unwanted clot within a blood vessel, is the most common abnormality of hemostasis. Thrombotic disorders include acute myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE), and acute ischemic stroke. These conditions are treated with drugs such as anticoagulants and fibrinolytics. Bleeding disorders involving the failure of hemostasis are less common than thromboembolic diseases. These disorders include hemophilia, which is treated with transfusion of recombinant factor VIII, and vitamin K deficiency, which is treated with vitamin K supplementation.

 

Anticoagulants and Antiplatelet Agents

 

Anticoagulants and Antiplatelet Agents: THROMBUS VERSUS EMBOLUS

Focus topic: Anticoagulants and Antiplatelet Agents

A clot that adheres to a vessel wall is called a “thrombus,” whereas an intravascular clot that floats in the blood is termed an “embolus.” Thus, a detached thrombus becomes an embolus. Both thrombi and emboli are dangerous, because they may occlude blood vessels and deprive tissues of oxygen and nutrients. Arterial thrombosis most often occurs in medium-sized vessels rendered thrombogenic by atherosclerosis. Arterial thrombosis usually consists of a platelet-rich clot. In contrast, venous thrombosis is triggered by blood stasis or inappropriate activation of the coagulation cascade. Venous thrombosis typically involves a clot that is rich in fibrin, with fewer platelets than are observed with arterial clots.

Anticoagulants and Antiplatelet Agents: PLATELET RESPONSE TO VASCULAR INJURY

Focus topic: Anticoagulants and Antiplatelet Agents

Physical trauma to the vascular system, such as a puncture or a cut, initiates a complex series of interactions between platelets, endothelial cells, and the coagulation cascade. These interactions lead to hemostasis or the cessation of blood loss from a damaged blood vessel. Platelets are central in this process. Initially, there is vasospasm of the damaged blood vessel to prevent further blood loss. The next step involves the formation of a platelet–fibrin plug at the site of the puncture. The creation of an unwanted thrombus involves many of the same steps as normal clot formation, except that the triggering stimulus is a pathologic condition in the vascular system, rather than external physical trauma.

A. Resting platelets

Focus topic: Anticoagulants and Antiplatelet Agents

Platelets act as vascular sentries, monitoring the integrity of the vascular endothelium. In the absence of injury, resting platelets circulate freely, because the balance of chemical signals indicates that the vascular system is not damaged.

  • Chemical mediators synthesized by endothelial cells: Chemical mediators, such as prostacyclin and nitric oxide, are synthesized by intact endothelial cells and act as inhibitors of platelet aggregation. Prostacyclin (prostaglandin I2) acts by  binding to platelet membrane receptors that are coupled to thesynthesis of cyclic adenosine monophosphate (cAMP), an intracellular messenger. Elevated levels of intracellular cAMP are associated with a decrease in intracellular calcium. This prevents platelet activation and the subsequent release of platelet aggregation agents. Damaged endothelial cells synthesize less prostacyclin than healthy cells, resulting in lower prostacyclin levels. Since there is less prostacyclin to bind platelet receptors, less intracellular cAMP is synthesized, which leads to platelet aggregation.
  • Roles of thrombin, thromboxanes, and collagen: The platelet membrane also contains receptors that can bind thrombin, thromboxanes, and exposed collagen. In the intact, normal vessel, circulating levels of thrombin and thromboxane are low, and the intact endothelium covers the collagen in the subendothelial layers. The corresponding platelet receptors are, thus, unoccupied, and as a result, platelet activation and aggregation are not initiated. However, when occupied, each of these receptor types triggers a series of reactions leading to the release into the circulation of intracellular granules by the platelets. This ultimately stimulates platelet aggregation.

B. Platelet adhesion

Focus topic: Anticoagulants and Antiplatelet Agents

When the endothelium is injured, platelets adhere to and virtually cover the exposed collagen of the subendothelium. This triggers a complex series of chemical reactions, resulting in platelet activation.

C. Platelet activation

Focus topic: Anticoagulants and Antiplatelet Agents

Receptors on the surface of the adhering platelets are activated by the collagen of the underlying connective tissue. This causes morphologic changes in platelets and the release of platelet granules containing chemical mediators, such as adenosined iphosphate (ADP), thromboxane A2, serotonin, platelet activation factor, and thrombin. These signaling molecules bind to receptors in the outer membrane of resting platelets circulating nearby. These receptors function as sensors that are activated by the signals sent from the adhering platelets. The previously dormant platelets become activated and start to aggregate. These actions are mediated by several messenger systems that ultimately result in elevated levels of calcium and a decreased concentration of cAMP within the platelet.

D. Platelet aggregation

Focus topic: Anticoagulants and Antiplatelet Agents

The increase in cytosolic calcium accompanying activation is due to a release of sequestered stores within the platelet.This leads to 1) the release of platelet granules containing mediators, such as ADP and serotonin that activate other platelets; 2) activation of thromboxane A2 synthesis; and 3) activation of glycoprotein (GP) IIb/IIIa receptors that bind fibrinogen and, ultimately, regulate platelet–platelet interaction and thrombus formation. Fibrinogen, a soluble plasma GP, simultaneously binds to GP IIb/IIIa receptors on two separate platelets, resulting in platelet cross-linking and platelet aggregation. This leads to an avalanche of platelet aggregation, because each activated platelet can recruit other platelets.

E. Formation of a clot

Focus topic: Anticoagulants and Antiplatelet Agents

Local stimulation of the coagulation cascade by tissue factors released from the injured tissue and by mediators on the surface of platelets results in the formation of thrombin (factor IIa). In turn, thrombin, a serine protease, catalyzes the hydrolysis of fibrinogen to fibrin, which is incorporated into the clot. Subsequent cross-linking of the fibrin strands stabilizes the clot and forms a hemostatic platelet–fibrin plug.

F. Fibrinolysis

Focus topic: Anticoagulants and Antiplatelet Agents

During clot formation, the fibrinolytic pathway is locally activated. Plasminogen is enzymatically processed to plasmin (fibrinolysin) by plasminogen activators in the tissue. Plasmin limits the growth of the clot and dissolves the fibrin network as wounds heal.

Anticoagulants and Antiplatelet Agents

Anticoagulants and Antiplatelet Agents

Anticoagulants and Antiplatelet Agents: PLATELET AGGREGATION INHIBITORS

Focus topic: Anticoagulants and Antiplatelet Agents

Platelet aggregation inhibitors decrease the formation of a platelet-rich clot or decrease the action of chemical signals that promote platelet aggregation. The platelet aggregation inhibitors described below inhibit cyclooxygenase-1 (COX-1) or block GP IIb/IIIa or ADP receptors, thereby interfering with the signals that promote platelet aggregation. Because these agents have different mechanisms of actions, synergistic or additive effects may be achieved when agents from different classes are combined. These agents are beneficial in the prevention and treatment of occlusive cardiovascular diseases, in the maintenance of vascular grafts and arterial patency, and as adjuncts to thrombin inhibitors or thrombolytic therapy in MI.

Anticoagulants and Antiplatelet Agents

A. Aspirin

  • Mechanism of action: Stimulation of platelets by thrombin, collagen, and ADP results in activation of platelet membrane phospholipases that liberate arachidonic acid from membrane phospholipids. Arachidonic acid is first converted to prostaglandin H2 by COX-1. Prostaglandin H2 is further metabolized to thromboxane A2, which is released into plasma. Thromboxane A2 promotes the aggregation process that is essential for the rapid formation of a hemostatic plug. Aspirin [AS-pir-in] inhibits thromboxane A2 synthesis by acetylation of a serine residue on the active site of COX-1, thereby irreversibly inactivating the enzyme. This shifts the balance of chemical mediators to favor the antiaggregatory effects of prostacyclin, thereby preventing platelet aggregation. The inhibitory effect is rapid, and aspirin-induced suppression of thromboxane A2 and the resulting suppression of platelet aggregation last for the life of the platelet, which is approximately 7 to 10 days. Repeated administration of aspirin has a cumulative effect on the function of platelets. Aspirin is the only antiplatelet agent that irreversibly inhibits platelet function.
  • Therapeutic use: Aspirin is used in the prophylactic treatment of transient cerebral ischemia, to reduce the incidence of recurrent MI, and to decrease mortality in the setting of primary and secondary prevention of MI. Complete inactivation of platelets occurs with 75 mg of aspirin given daily. The recommended dose of aspirin ranges from 50 to 325 mg daily.
  • Pharmacokinetics: When given orally, aspirin is absorbed by passive diffusion and quickly hydrolyzed to salicylic acid in the liver. Salicylic acid is further metabolized in the liver, and some is excreted unchanged in the urine. The half-life of aspirin ranges from 15 to 20 minutes and for salicylic acid is 3 to 12 hours.
  • Adverse effects: Higher doses of aspirin increase drug-related toxicities as well as the probability that aspirin may also inhibit prostacyclin production. Bleeding time is prolonged by aspirin treatment, causing complications that include an increased incidence of hemorrhagic stroke and gastrointestinal (GI) bleeding, especially at higher doses of the drug. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, inhibit COX-1 by transiently competing at the catalytic site. Ibuprofen, if taken within the 2 hours prior to aspirin, can obstruct the access of aspirin to the serine residue and, thereby, antagonize platelet inhibition by aspirin. Therefore, immediate release aspirin should be taken at least 60 minutes before or at least 8 hours after ibuprofen. Although celecoxib (a selective COX-2 inhibitor, does not interfere with the antiaggregation activity of aspirin, there is some evidence that it may contribute to cardiovascular events by shifting the balance of chemical mediators in favor of thromboxane A2.

Anticoagulants and Antiplatelet Agents

Anticoagulants and Antiplatelet Agents

B. Ticlopidine, clopidogrel, prasugrel, and ticagrelor

Ticlopidine [ti-KLOE-pi-deen], clopidogrel [kloh-PID-oh-grel], prasugrel [PRA-soo-grel], and ticagrelor [tye-KA-grel-or] are P2Y12 ADP receptor inhibitors that also block platelet aggregation but by a mechanism different from that of aspirin.

  • Mechanism of action: These drugs inhibit the binding of ADP to its receptors on platelets and, thereby, inhibit the activation of the GP IIb/IIIa receptors required for platelets to bind to fibrinogen and to each other. Ticagrelor binds to the P2Y12 ADP receptor in a reversible manner. The other agents bind irreversibly. The maximum inhibition of platelet aggregation is achieved in 1 to 3 hours with ticagrelor, 2 to 4 hours with prasugrel, 3 to 4 days with ticlopidine, and 3 to 5 days with clopidogrel. When treatment is suspended, the platelet system requires time to recover.
  • Therapeutic use: Clopidogrel is approved for prevention of atherosclerotic events in patients with a recent MI or stroke and in those with established peripheral arterial disease. It is also approved for prophylaxis of thrombotic events in acute coronary syndromes (unstable angina or non–ST-elevation MI). Additionally, clopidogrel is used to prevent thrombotic events associated with percutaneous coronary intervention (PCI) with or without coronary stenting. Ticlopidine is similar in structure to clopidogrel. It is indicated for the prevention of transient ischemic attacks (TIA) and strokes in patients with a prior cerebral thrombotic event. However, due to life-threatening hematologic adverse reactions, ticlopidine is generally reserved for patients who are intolerant to other therapies. Prasugrel is approved to decrease thrombotic cardiovascular events in patients with acute coronary syndromes (unstable angina, non–ST-elevation MI, and ST-elevation MI managed with PCI). Ticagrelor is approved for the prevention of arterial thromboembolism in patients with unstable angina and acute MI, including those undergoing PCI.
  • Pharmacokinetics: These agents require loading doses for quicker antiplatelet effect. Food interferes with the absorption of ticlopidine but not with the other agents. After oral ingestion, the drugs are extensively bound to plasma proteins. They undergo hepatic metabolism by the cytochrome P450 (CYP) system to active metabolites. Elimination of the drugs and metabolites occurs by both the renal and fecal routes. Clopidogrel is a prodrug, and its therapeutic efficacy relies entirely on its active metabolite, which is produced via metabolism by CYP 2C19. Genetic polymorphism of CYP 2C19 leads to a reduced clinical response in patients who are “poor metabolizers” of clopidogrel. Tests are currently available to identify poor metabolizers, and it is recommended that other antiplatelet agents (prasugrel or ticagrelor) be prescribed for these patients. In addition, other drugs that inhibit CYP 2C19, such as omeprazole and esomeprazole, should not be administered concurrently with clopidogrel.
  • Adverse effects: These agents can cause prolonged bleeding for which there is no antidote. Ticlopidine is associated with severe hematologic reactions that limit its use, such as agranulocytosis, thrombotic thrombocytopenic purpura (TTP), and aplastic anemia. Clopidogrel causes fewer adverse reactions, and the incidence of neutropenia is lower. However, TTP has been reported as an adverse effect for both clopidogrel and prasugrel (but not for ticagrelor). Prasugrel is contraindicated in patients with history of TIA or stroke. Prasugrel and ticagrelor carry black box warnings for bleeding. Additionally, ticagrelor carries a black box warning for diminished effectiveness with concomitant use of aspirin doses above 100 mg.

Anticoagulants and Antiplatelet Agents

 C. Abciximab, eptifibatide, and tirofiban

  • Mechanism of action: The GP IIb/IIIa receptor plays a key role in stimulating platelet aggregation. A chimeric monoclonal antibody, abciximab [ab-SIKS-eh-mab], inhibits the GP IIb/IIIa receptor complex. By binding to GP IIb/IIIa, abciximab blocks the binding of fibrinogen and von Willebrand factor and, consequently, aggregation does not occur. Eptifibatide [ep-ti-FIB-ih-tide] and tirofiban [tye-roe-FYE-ban] act similarly to abciximab, by blocking the GP IIb/IIIa receptor. Eptifibatide is a cyclic peptide that binds to GP IIb/IIIa at the site that interacts with the arginine–glycine–aspartic acid sequence of fibrinogen. Tirofiban is not a peptide, but it blocks the same site as eptifibatide.
  • Therapeutic use: These agents are given intravenously, along with heparin and aspirin, as an adjunct to PCI for the prevention of cardiac ischemic complications. Abciximab is also approved for patients with unstable angina not responding to conventional medical therapy when PCI is planned within 24 hours.
  • Pharmacokinetics: Abciximab is given by IV bolus, followed by IV infusion, achieving peak platelet inhibition within 30 minutes. The metabolism of abciximab is unknown. After cessation of abciximab infusion, platelet function gradually returns to normal, with the antiplatelet effect persisting for 24 to 48 hours. When IV infusion of eptifibatide or tirofiban is stopped, both agents are rapidly cleared from the plasma. Eptifibatide and its metabolites are excreted by the kidney. Tirofiban is excreted largely unchanged by the kidney and in the feces.
  • Adverse effects: The major adverse effect of these agents is bleeding, especially if used with anticoagulants.

Anticoagulants and Antiplatelet Agents

Anticoagulants and Antiplatelet Agents

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D. Dipyridamole

Dipyridamole [dye-peer-ID-a-mole], a coronary vasodilator, increases intracellular levels of cAMP by inhibiting cyclic nucleotide phosphodiesterase, thereby resulting in decreased thromboxane A2 synthesis. The drug may potentiate the effect of prostacyclin to antagonize platelet stickiness and, therefore, decrease platelet adhesion to thrombogenic surfaces. Dipyridamole is used for stroke prevention and is usually given in combination with aspirin. Dipyridamole has variable bioavailability following oral administration. It is highly protein bound. The drug undergoes hepatic metabolism, as well as glucuronidation, and is excreted mainly in the feces. Patients with unstable angina should not use dipyridamole because of its vasodilating properties, which may worsen ischemia (coronary steal phenomenon). Dipyridamole commonly causes headache and can lead to orthostatic hypotension (especially if administered IV).

E. Cilostazol

Cilostazol [sill-AH-sta-zole] is an oral antiplatelet agent that also has vasodilating activity. Cilostazol and its active metabolites inhibit phosphodiesterase type III, which prevents the degradation of cAMP, thereby increasing levels of cAMP in platelets and vascular tissues. The increase in cAMP levels in platelets and the vasculature prevents platelet aggregation and promotes vasodilation of blood vessels, respectively. Cilostazol favorably alters the lipid profile, causing a decrease in plasma triglycerides and an increase in high-density lipoprotein cholesterol. The drug is approved to reduce the symptoms of intermittent claudication. Cilostazol is extensively metabolized in the liver by the CYP 3A4, 2C19, and 1A2 isoenzymes. As such, this agent has many drug interactions that require dose modification. The primary route of elimination is via the kidney. Headache and GI side effects (diarrhea, abnormal stools, dyspepsia, and abdominal pain) are the most common adverse effects observed with cilostazol. Phosphodiesterase type III inhibitors have been shown to increase mortality in patients with advanced heart failure. As such, cilostazol is contraindicated in patients with heart failure.

Anticoagulants and Antiplatelet Agents: BLOOD COAGULATION

Focus topic: Anticoagulants and Antiplatelet Agents

The coagulation process that generates thrombin consists of two interrelated pathways, the extrinsic and the intrinsic systems. The extrinsic system is initiated by the activation of clotting factor VII by tissue factor (also known as thromboplastin). Tissue factor is a membrane protein that is normally separated from the blood by the endothelial cells that line the vasculature. However, in response to vascular injury, tissue factor becomes exposed to blood. There it can bind and activate factor VII, initiating the extrinsic pathway. The intrinsic system is triggered by the activation of clotting factor XII. This occurs when blood comes into contact with the collagen in the damaged wall of a blood vessel.

A. Formation of fibrin

Focus topic: Anticoagulants and Antiplatelet Agents

Both the extrinsic and the intrinsic systems involve a cascade of enzyme reactions that sequentially transform various plasma factors (proenzymes) to their active (enzymatic) forms. [Note: The active form of a clotting factor is denoted by the letter “a.”] Ultimately, factor Xa is produced, which converts prothrombin (factor II) to thrombin (factor IIa,.Thrombin plays a key role in coagulation, because it is responsible for generation of fibrin, which forms the mesh-like matrix of the blood clot. If thrombin is not formed or if its function is impeded (for example, by antithrombin III), coagulation is inhibited.

B. Inhibitors of coagulation

Focus topic: Anticoagulants and Antiplatelet Agents

It is important that coagulation is restricted to the local site of vascular injury. Endogenously, there are several inhibitors of coagulation factors, including protein C, protein S, antithrombin III, and tissue factor pathway inhibitor. The mechanism of action of several anticoagulant agents, including heparin and heparin-related products, involves activation of these endogenous inhibitors (primarily antithrombin III).

Anticoagulants and Antiplatelet Agents

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