Antiplatelet Agents and Anticoagulants

Chapter 22


Antiplatelet Agents and Anticoagulants


Stephan Moll



Physiology of Blood Clotting


Vascular injury leads to thrombus formation. As a first step, a platelet plug is formed, which is then surrounded and strengthened by a fibrin polymer meshwork. Several steps are involved in this process (Fig. 22-1):




1. Platelet adhesion: During the first step of hemostasis, von Willebrand factor multimers bind to exposed subendothelial collagen with one part of their structure and to the glycoprotein (GP)Ib receptor on the surface of platelets with another, thereby anchoring the platelet to the site of injury.


2. Platelet aggregation: Platelet adhesion leads to activation of the anchored platelet, which results in three major reactions:



• Release of platelet granules: Platelet granules contain platelet agonists such as thromboxane A2, adenosine diphosphate (ADP), and epinephrine. Thromboxane A2 is synthesized with the help of the enzyme cyclooxygenase (COX)-1. Once released into the bloodstream, the agonists bind to receptors on the surface of platelets trying to float by, thus activating and recruiting them to the site of injury. The platelet receptors for ADP are termed P2Y1 and P2Y12, and it appears both must be activated for platelet aggregation to take place.


• Activation of platelet surface GPIIb/IIIa receptors: Activation of the platelet leads to a change in shape of the GPIIb/IIIa receptor, enabling it to bind fibrinogen. One end of the fibrinogen molecule binds to the GPIIb/IIIa receptor of one activated platelet and the other to the receptor of another platelet, thus bridging platelets and creating a platelet plug.


• Flip-flop of phospholipids: In nonactivated platelets, phospholipids are located on the inner side of the cell membrane. Platelet activation leads to a flip-flop of these phospholipids to the outside of the platelet membrane, where then they can bind coagulation factors and calcium and facilitate the various reactions of the coagulation cascade that lead to formation of fibrin.


3. Plasmatic coagulation: Vascular injury brings tissue factor on extracellular cells (fibroblasts, monocytes) into contact with circulating coagulation factor VIIa, thereby initiating the coagulation cascade that leads to thrombin and eventually fibrin formation. Coagulation factor activation reactions require phospholipids, which are provided by platelets during the flip-flop mechanism that occurs during platelet aggregation. A fibrin meshwork forms around the platelets anchored at the site of vascular injury. A thrombus is formed.



Pathophysiology of Blood Clotting


Venous thrombosis occurs mostly via the plasma coagulation system, with only minor platelet participation. In contrast, platelets play a major role in arterial thrombus formation, with additional participation of the plasma coagulation system. This paradigm helps explain why drugs that block the plasmatic coagulation reaction (i.e., anticoagulants) are very active in preventing venous thrombosis and also effective in preventing arterial thrombosis, whereas antiplatelet drugs, which successfully prevent arterial thrombosis, are less or not at all effective in venous disease. Table 22-1 lists the important antiplatelet agents and anticoagulants, discussed in further detail in the following sections.



TABLE 22-1


Antiplatelet Agents and Anticoagulants












































































































































































































































Generic Brand Name* Dosing
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitor
Aspirin   50-325 mg qd PO.
Phosphodiesterase Inhibitors
Dipyridamole Persantine 75-100 mg qid PO.
Dipyridamole + ASA Aggrenox 1 tablet (200 mg/25 mg) q12h PO.
Cilostazol Pletal 100 mg q12h PO.
ADP Receptor Blockers
Clopidogrel Plavix Loading dose 300 mg PO; then 75 mg qd PO.
Ticlopidine Ticlid Loading dose 500 mg PO; then 250 mg q12h PO.
Prasugrel Effient Loading dose 60 mg PO; then 10 mg qd PO.
Ticagrelor Brilinta Loading dose 180 mg PO; then 90 mg q12h PO.
Cangrelor   In development.
Elinogrel   Development stopped.
Glycoprotein IIb/IIIa Receptor Blockers
Abciximab ReoPro Bolus 0.25 mg/kg IV; then 0.125 µg/kg/min for 12 h IV.
Eptifibatide Integrilin Bolus 180 g/kg IV; then 0.5-2.0 µg/kg/min for up to 72 h IV.
Tirofiban Aggrastat 0.4 µg/kg/min × 30 min IV; then 0.1 µg/kg/min × 12-24 h IV.
Oral agents   Development stopped.
 Orbofiban  
 Sibrafiban  
 Xemilofiban  
Others
Pentoxifylline Trental 400 mg tid PO.
Anticoagulants
Heparins
Unfractionated heparin Various Various nomograms—APTT or anti-Xa adjusted.
Enoxaparin Lovenox Prophylaxis: various doses
  Clexane Full-dose: 1 mg/kg q12h or 1.5 mg/kg qd SQ.
Dalteparin Fragmin Prophylaxis: various doses; full-dose: 100 units/kg q12h SQ or 200 units/kg qd SQ.
Tinzaparin Innohep Prophylaxis: various doses; full-dose: 175 units/kg qd SQ.
Certoparin Monoembolex Prophylaxis: various doses.
Reviparin Clivarin Not approved for full-dose anticoagulant treatment.
Nadroparin Fraxiparin  
Anti-Xa Inhibitors
Pentasaccharides:
 Fondaparinux Arixtra Prophylaxis: 2.5 mg qd SQ; full-dose: 7.5 mg qd SQ; 10 mg qd if body weight above 100 kg.
 Idraparinux None yet In development.
Rivaroxaban Xarelto Atrial fibrillation with normal renal function: 20 mg qd PO.
VTE prevention: 10 mg qd; Acute DVT or PE: 15 mg q12h for 3 weeks, then 20 mg qd PO with normal renal function.
Apixaban Eliquis 2.5 mg q12h for VTE prevention. 5 mg bid for atrial fibrillation.
Edoxaban Lixiana 30 mg PO once daily for VTE prevention after orthopedic surgery.
Thrombin Inhibitors
Argatroban Acova No bolus.
  Novastan Continuous infusion: 2 µg/kg/min IV—APTT adjusted.
Lepirudin Refludan Bolus: 0.4 mg/kg IV.
    Continuous infusion: 0.15 mg/kg/h IV—APTT adjusted.
Desirudin Iprivask 15 mg q12h SQ.
  Revasc  
Bivalirudin Angiomax Bolus: 0.75 mg/kg IV.
    Continuous infusion: 1.75 mg/kg/h IV until 4 h after procedure; then 0.2 mg/kg/h for up to 20 h.
Danaparoid Orgaran Manufacturing discontinued.
Ximelagatran Exanta Withdrawn from market.
Dabigatran Pradaxa Atrial fibrillation with normal renal function: 150 mg q12h PO or 110 mg q12h.
Vitamin K Antagonists
Coumarins
Warfarin Coumadin Interindividual variability; dosing is INR adjusted.
  Jantoven
Phenprocoumon Marcumar
  Falithrom
  Phenpro
Acenocoumarol Sinthrome
Tioclomarol Apegmone
Indandiones
Fluindione Previscan
Anisindione Miradon
Phenindione Dindevan
  Pindione


image


image


ADP, Adenosine diphosphate; APTT, activated partial thromboplastin time; h, hour; INR, international normalized ratio; IV, intravenously; q, every; qd, once daily; tid, three times daily; PO, orally; SQ, subcutaneously; VTE, venous thromboembolism.


*Other products may exist.


Drug approval and dosing regimens may vary depending on indication, country of use, presence or absence of renal or liver dysfunction, and concomitant use of antiplatelet drugs or anticoagulants.


Specific agents printed in italics are investigational.



Antiplatelet Agents


Aspirin


Aspirin (acetylsalicylic acid) inhibits the enzyme COX-1, which is needed to form thromboxane A2 in platelets. Thromboxane A2 is normally released from platelet granules upon platelet adhesion and during platelet aggregation (see Fig. 22-1, B) and serves as an agonist to activate and thereby recruit other platelets to the platelet plug. Because platelets do not synthesize new cyclooxygenase and aspirin binds irreversibly to the enzyme, aspirin’s action lasts for the lifespan of a platelet (i.e., 7-10 days). Complete inactivation of platelet COX-1 is typically achieved with a daily aspirin dose of 160 mg. When used as an antithrombotic drug, aspirin is maximally effective at doses between 50 and 325 mg/day. Higher doses do not improve efficacy. However, there is considerable interindividual variability in aspirin’s ability to inhibit COX-1. “Aspirin resistance” is a laboratory phenomenon in which there is an inability of aspirin to inhibit one or more in vitro tests of platelet function, such as platelet aggregometry, the Platelet Function Analyzer (PFA-100), the VerifyNow Aspirin rapid platelet function assay, or measurement of thromboxane generation in vitro or in vivo via serum levels of thromboxane B2 or urinary levels of 11-dehydrothromboxane B2. “Aspirin failure” is a clinical observation of treatment failure. Aspirin resistance does not necessarily lead to treatment failure, nor is clinical aspirin failure necessarily due to aspirin resistance.



Phosphodiesterase Inhibitors


Dipyridamole (Persantine)


Dipyridamole inhibits platelet aggregation by two mechanisms: (1) it inhibits cyclic nucleotide phosphodiesterase, and (2) it attenuates uptake of adenosine into platelets. Both these actions lead to an increase in intraplatelet cyclic adenosine monophosphate (cAMP), which inhibits platelet aggregation induced by several agonists. However, dipyridamole by itself has little or no effect as an antithrombotic drug. Its platelet aggregation inhibitory effect is reversible. The combination of aspirin (25 mg) and dipyridamole (200 mg) is available as Aggrenox. Dipyridamole also has vasodilator effects and should therefore be used with caution in patients with severe coronary artery disease, in whom episodes of angina may increase as a result of the steal phenomenon. The most common side effects of Aggrenox are gastrointestinal complaints and headaches. The major indication for Aggrenox is secondary stroke prevention.





Adenosine Diphosphate Receptor Antagonists


Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor, and Others


Clopidogrel (Plavix), ticlopidine (Ticlid), and Prasugrel (Effient) inhibit the platelet ADP receptor P2Y12 by irreversibly altering its structure. Clopidogrel and ticlopidine are closely related, but clopidogrel has a more favorable side-effect profile, with less frequent thrombocytopenia and leukopenia, and has largely replaced ticlopidine. Prasugrel is more rapid in onset and leads to less variable platelet response and more complete inhibition of platelet function than clopidogrel. Because maximal inhibition of platelet aggregation with all three drugs is not seen for a few days after starting therapy, loading doses of are often given to achieve a more rapid onset of action. Inhibition of platelet aggregation persists for the lifespan of the platelet. In all indications, clopidogrel appears to be equally effective as aspirin, except in peripheral arterial disease, where it has been shown to be slightly more effective than aspirin for prevention of ischemic events. Ticagrelor (Brilinta), Cangrelor, and Elinogrel are also inhibitors of the platelet P2Y12 ADP receptor, but their action is reversible. Prasugrel or ticagrelor given together with aspirin have been shown to be more efficacious than clopidogrel plus aspirin in certain acute coronary syndromes and percutaneous coronary interventions. Cangrelor is being studied in patients who require percutaneous coronary intervention. Development of Elinogrel was terminated in 2012.



Glycoprotein IIb/Ill Receptor Antagonists


The platelet GPIIb/IIIa receptors (also termed integrin αIIbβ3) are the sites where fibrinogen binds during platelet aggregation (see Fig. 22-1, B), leading to cross-linking of platelets and platelet plug formation. Several inhibitors of this receptor have been developed for clinical use.



Abciximab (ReoPro)


Abciximab is the Fab fragment of a chimeric human-murine monoclonal antibody against the IIb/IIIa receptor. The drug is given as a bolus followed by continuous infusion for 12 hours or longer. Unbound drug is cleared from the circulation with a half-life of about 30 minutes. Drug bound to the IIb/IIIa receptor inhibits platelet aggregation for 18 to 24 hours as measured in vitro, but bound drug is demonstrable in the circulation for up to 10 days. Ex vivo platelet clumping in ethylenediamine tetra-acetic acid (EDTA)-containing blood tubes can be seen in patients treated with the drug, and such clumping can lead to pseudothrombocytopenia when platelets are counted with an automatic blood cell counter. This phenomenon is clinically irrelevant and does not require discontinuation of the drug. However, true thrombocytopenia also occurs and, if severe enough, can require drug discontinuation.





Dec 23, 2015 | Posted by in INTERVENTIONAL RADIOLOGY | Comments Off on Antiplatelet Agents and Anticoagulants
Premium Wordpress Themes by UFO Themes