Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ Antithrombotic agents are characterized separately as anticoagulants (including vitamin K antagonists, heparin or heparin derivatives, and directly acting thrombin or factor Xa inhibitors), antiplatelet agents, or fibrinolytic drugs (see Chap. 86), depending on their primary mechanism, although there is overlap in their activities. Anticoagulant therapy acts to decrease fibrin formation by inhibiting the formation and action of thrombin. Its most common use is in preventing systemic embolization in patients with atrial fibrillation, treatment of acute arterial thrombosis (eg, myocardial infarction or peripheral arterial thrombosis) and for treatment or (secondary) prevention of venous thromboembolism. Anticoagulant therapy is often monitored using coagulation testing because of marked biologic variation in effect. Antiplatelet agents act to inhibit platelet function, and their primary uses are in preventing thrombotic complications of cerebrovascular and coronary artery disease. They also have a role in treatment of acute myocardial infarction. They have no effect in preventing or treating venous thromboembolism. For many agents, the risk-to-benefit ratio is narrow, with the result that bleeding complications occur. Bleeding is the most common adverse effect of anticoagulation (Table 87–1). Consequently, the clinician should carefully weigh the risks and benefits for each patient when selecting treatment. The most common oral anticoagulants are vitamin K antagonists (coumarins). However, recently, new oral anticoagulants with specific antithrombin activity or anti–factor Xa activity have become available and are currently evaluated in clinical trials (see section, “Oral Antithrombin and Anti–factor Xa Agents” below). ++Table Graphic Jump LocationTABLE 87–1RISK FACTORS FOR HEMORRHAGIC COMPLICATIONSView Table||Download (.pdf) TABLE 87–1 RISK FACTORS FOR HEMORRHAGIC COMPLICATIONS Too high intensity of anticoagulation Simultaneous use of anticoagulants and antiplatelet agents Old age Initial phase of anticoagulation Cerebrovascular disease History of alcohol abuse Renal insufficiency Liver failure Use of nonsteroidal anti-inflammatory drugs (gastrointestinal bleeding) Polymorphisms in cytochrome 450 CYP2C9 gene Source: Williams Manual of Hematology, 8th ed, Chap. 88, Table 88–2. + VITAMIN K ANTAGONISTS Download Section PDF Listen +++ ++ Coumarins act by inhibiting vitamin K–dependent posttranslational γ-carboxylation of glutamic acid residues in the Gla domains of coagulation factors II, VII, IX, and X, and the anticoagulant proteins C and S. γ-Carboxylation requires the reduced form of vitamin K as a cofactor. During γ-carboxylation, vitamin K is oxidized. The enzymes vitamin K epoxide reductase and vitamin K reductase are required to recycle vitamin K back to its reduced form. Coumarins inhibit these reductases, thus depleting reduced vitamin K. A decrease in the number of γ-carboxyglutamate residues results in coagulation factors with impaired activity because they are unable to bind calcium and undergo necessary conformation changes. The production of affected coagulation factors stops promptly, but the anticoagulant effect is delayed until the previously formed coagulation factors are removed from the circulation. Factor VII has the shortest half-life at 6 hours, while the others range from 24 to 72 hours. +++ Pharmacokinetics ++ Warfarin, the most commonly used coumarin, has predictable oral absorption and a half-life of 35 to 45 hours. The pharmacokinetics appear to be dose-dependent. It is highly protein-bound and only the free compound is active. Warfarin is metabolized by hydroxylation in the liver and excretion of the hydroxylated derivative in the urine. Warfarin is not excreted in significant amounts in breast milk. Other frequently used coumarins are phenprocoumon (much longer half-life of 150 to 160 hours) or acenocoumarol (much shorter half-life of 8 to 12 hours). +++ Administration and Laboratory Monitoring ++ Dosages required for adequate anticoagulation range from about 1 to 20 mg per day, probably a result of differences in hydroxylation rates and target-organ sensitivity. There is a significant negative correlation between age at start of therapy and dose. Requirement may decrease by 20% over 15 years. Warfarin resistance may be caused by impaired absorption, rapid clearance, or decreased affinity of the receptor, but poor compliance, excessive intake of vitamin K, and drug interactions must be ruled out. Many drugs interact with vitamin K antagonists, causing either an increased or decreased anticoagulant response (Table 87–2). Several mechanisms have been described for these interactions. Vitamin K antagonist therapy is monitored by the prothrombin time (PT). The sensitivity of the PT to anticoagulation varies with the source of thromboplastin in the assay. Interlaboratory variation is corrected for by using the international normalized ratio (INR) instead of the PT ratio. The International Sensitivity Index (ISI) is a correction factor established for each thromboplastin. The INR is determined by the formula INR = (patient PT/control PT)ISI. A target range of INR 2.0 to 3.0 has shown to be optimal for virtually all indications. Patients with prosthetic heart valves at high risk for thromboembolic complications may benefit from an INR range of 2.5 to 3.5. Also, in some patients with antiphospholipid syndrome and thrombosis, a higher range of 2.5 to 3.5 is recommended. In established venous thromboembolism, vitamin K antagonist therapy is given concomitantly with heparin because the antithrombotic effect of vitamin K antagonists is achieved only after 3 to 4 days. Some studies have indicated that patients with mechanical heart valves may be effectively treated with a combination of vitamin K antagonists to achieve an INR of less than or equal to 2.5 and an antiplatelet agent, but such regimens carry an increased risk of bleeding complications. Bioprosthetic valves also may cause thromboembolism (in particular in the initial phase), and prophylaxis with vitamin K antagonists is recommended to an INR of 2.0 to 3.0 during the first 3 months and continued indefinitely if there is atrial fibrillation, atrial thrombi, or a prior embolism. The risk of thromboembolism from cardioversion may be reduced by vitamin K antagonist therapy to an INR of 2.0 to 3.0 for 3 weeks before the procedure and 4 weeks after. ++Table Graphic Jump LocationTABLE 87–2EFFECT OF COMMONLY USED DRUGS ON WARFARIN RESPONSEView Table||Download (.pdf) TABLE 87–2 EFFECT OF COMMONLY USED DRUGS ON WARFARIN RESPONSE Potentiate Effect α-Methyldopa Indomethacin Acetaminophen Isoniazid Acetohexamide Ketoconazole Allopurinol Methimazole Androgenic and anabolic steroids Methotrexate Antibiotics that disrupt intestinal flora (tetracyclines, streptomycin, erythromycin, kanamycin, nalidixic acid, neomycin) Methylphenidate Nalidixic acid Nortriptyline Oxyphenbutazone Cephaloridine p-Aminosalicylic acid Chloral hydrate Paromomycin Chloramphenicol Phenylbutazone Chlorpromazine Phenyramidol Chlorpropamide Phenytoin Cimetidine Propylthiouracil Clofibrate Quinidine Diazoxide Salicylate Disulfiram Sulfinpyrazone Fluconazole Sulfonamides Glucagon Thyroid hormone Guanethidine Tolbutamide Depress Effect Antipyrine Glutethimide Azathioprine Griseofulvin Barbiturates Haloperidol Carbamazepine Phenobarbital Digitalis Prednisone Ethanol Rifampin Ethchlorvynol Vitamin K Source: Williams Hematology, 9th ed, Chap. 25, Table 25–2. +++ Adverse Effects and Reversal +++ Bleeding ++ The annual risk of major bleeding episodes has been estimated at between 1.2 and 7.0 per 100 patient-years. The wide variability exists because of differences in intensity of anticoagulation and patient populations and in the definition of “major bleeding.” The gastrointestinal tract is the most common site of bleeding. Gastrointestinal bleeding in anticoagulated patients may be caused by peptic ulcer or colon cancer. For this reason, detailed investigation to detect the source of bleeding should be carried out. Vitamin K antagonist treatment may be reversed by the administration of vitamin K (1–10 mg). However, it will take 6 to 8 hours after intravenous administration and 12 to 14 hours after oral administration of vitamin K before the effect is noticeable. Subcutaneous administration of vitamin K is less effective (more variable response) than oral administration. Intramuscular injections of vitamin K should be avoided in anticoagulated patients. In patients with major hemorrhage, rapid reversal of anticoagulation can be achieved with replacement therapy using fresh-frozen plasma or prothrombin complex concentrates. It may be difficult to administer a sufficient volume of fresh-frozen plasma to replace the deficient coagulation factors, and therefore prothrombin complex concentrates may be more convenient. Reversal of anticoagulant treatment with vitamin K antagonists is only required in case of serious bleeding. A too high INR in the absence of bleeding does not require vitamin K administration (Table 87–3) and may make reanticoagulation particularly difficult. Minor bleeding (eg, epistaxis) may be managed by local measures if the INR is in the therapeutic range. ++Table Graphic Jump LocationTABLE 87–3REVERSING WARFARIN THERAPYView Table||Download (.pdf) TABLE 87–3 REVERSING WARFARIN THERAPY Indication Action INR < 6 Lower the dose, consider withholding 1 or more doses Recheck in 3–7 days INR 6–10 Lower the dose and withhold 1–3 doses Consider administering vitamin K, 1–2 mg orally Recheck INR in 24–48 h INR > 10 Withhold doses until INR in desired range and cause of elevation ascertained Give vitamin K, 2–4 mg orally Recheck INR in 24 h Serious bleeding and major overdose Administer four-factor prothrombin complex concentrate if available for rapid reversal. If four-factor prothrombin complex concentrate not available administer fresh-frozen plasma. Also give 5–10 mg vitamin K intravenously INR, international normalized ratio. Source: Williams Hematology, 9th ed, Chap. 25, Table 25–4. +++ Warfarin-Induced Skin Necrosis ++ A rare condition in which painful, discolored areas of skin, most often over fatty areas such as the buttocks, breasts, and thighs, appear, usually between the third and tenth day of warfarin therapy. Lesions progress to frank necrosis and eschar formation. The necrosis appears to be a result of more rapid decline of protein C and protein S levels than levels of factors II, IX, and X, thereby inducing a temporary hypercoagulable state. It may occur in patients with heparin-induced thrombocytopenia, in those with hereditary protein C or protein S deficiency, and in patients receiving large loading doses of warfarin. Treatment with warfarin should be stopped immediately and the anticoagulation should be reversed by administration of plasma, or administration of protein C concentrate if protein C deficiency is present. Prompt administration of vitamin K may stop the progress of skin necrosis. Anticoagulation should be continued with an alternative anticoagulant until healing of the lesions. +++ Purple Toe Syndrome ++ Patients receiving warfarin therapy may develop a syndrome of bilateral burning pain and dark blue discoloration of the toes and sides of the feet. The involved areas blanch with pressure. This condition occurs in patients with cardiac disease, diabetes mellitus, or peripheral vascular disease. It may be caused by cholesterol emboli. +++ Pregnancy ++ Vitamin K antagonists are contraindicated in pregnancy because they may induce midface and nasal hypoplasia, stippled epiphysis, hypoplasia of the digits, optic atrophy, and mental impairment in the fetus. These teratogenic effects are mostly associated with use of vitamin K antagonists during the second trimester of pregnancy; however, many believe that vitamin K antagonist should be avoided throughout pregnancy. Vitamin K antagonists are contraindicated in the last 4 weeks of pregnancy due to anticoagulation of the child and the risk of intracranial hemorrhage during vaginal delivery. +++ Perioperative Management of Anticoagulation ++ It appears that full anticoagulant therapy can be safely continued with cutaneous surgery, soft-tissue aspirations or injections, and pacemaker surgery. Oral surgery is also safe at an INR of less than 2.5, provided adequate local hemostasis and optionally use of tranexamic acid for irrigation at the time of the procedure and as a mouth rinse four times daily for a week postoperatively. For all other types of surgery on patients with high risk of thromboembolism, protocols have been developed for temporary discontinuation of vitamin K antagonists and sustained perioperative anticoagulation with low-molecular-weight heparin (LMWH). Spinal or epidural anesthesia as well as local nerve block should be avoided. + HEPARIN AND HEPARIN DERIVATIVES Download Section PDF Listen +++ +++ Mechanism of Action ++ Unfractionated heparin consists of a heterogeneous mixture of sulfated glycosaminoglycans of different chain length with an average molecular mass of 15,000 daltons and an average chain length of 50 sugar residues. LMWH is prepared by depolymerization of unfractionated heparin by chemical or enzymatic means. The average molecular mass is 4000 to 6000 daltons, with a range of 1000 to 10,000 daltons. Heparin enhances the inactivation by antithrombin of thrombin and factors Xa and IXa. Inhibition of thrombin by heparin-antithrombin involves formation of a ternary complex, with heparin binding both thrombin and antithrombin. Formation of the ternary complex requires a heparin chain of at least 18 saccharide units. Inhibition of factor Xa by heparin-antithrombin does not require direct binding of heparin to factor Xa and therefore LMWHs have a relatively high anti–factor Xa over anti–factor IIa activity. Synthetic pentasaccharides (eg, fondaparinux) highly selectively bind to antithrombin and have only anti–factor Xa activity. Danaparoid is a mixture of glycosaminoglycans, containing heparan sulfate, dermatan sulfate, and chondroitin sulfate. The predominant anticoagulant effect is on factor Xa. Danaparoid is used for therapeutic anticoagulation in patients with acute heparin-induced thrombocytopenia or prophylactic anticoagulation in patients with a history of heparin-induced thrombocytopenia. +++ Pharmacokinetics ++ The pharmacokinetics of unfractionated heparin are compatible with saturable binding to endothelial cells and macrophages, combined with unsaturable renal excretion. The half-life of heparin increases with increased doses. In general, the half-life of unfractionated heparin at therapeutic dose is approximately 90 minutes. Therapeutic doses of unfractionated heparin are commonly administered by continuous intravenous infusion (after a single intravenous loading dose). Prophylactic unfractionated heparin can be given by twice daily subcutaneous injections. LMWHs have a more predictable systemic bioavailability after subcutaneous administration and a much longer half-life (12–24 hours). Hence, they are administered by once or twice daily subcutaneous injections, both therapeutically or prophylactically. +++ Laboratory Monitoring of Therapy ++ The activated partial thromboplastin time (aPTT) is the most frequently used test to monitor therapy with unfractionated heparin. In patients with venous thromboembolism and acute coronary syndromes, the aPTT response to a given heparin level is quite variable, and heparin dosages must be adjusted to achieve the desired aPTT range. Laboratory monitoring is not required for prophylactic subcutaneous heparin. LMWH does generally not require laboratory monitoring. However, in pregnant patients, critically ill patients, and patient with severe renal insufficiency (creatinine clearance < 30 mL/min) measurement of the anti–factor Xa activity in plasma is useful. LMWH cannot be monitored by the aPTT. +++ Clinical Use +++ Venous Thromboembolism ++ Unfractionated heparin administered at a dose of 5000 units every 8 to 12 hours is widely used for antithrombotic prophylaxis in patients undergoing surgery, in patients with ischemic stroke and leg paralysis, and in general medical patients. Alternatively, once daily subcutaneous low-dose LMWH is effective for antithrombotic prophylaxis as well (Table 87–4). Fondaparinux is more effective and safe compared with LMWH in patients undergoing major orthopedic surgery. Randomized clinical trials demonstrate that patients may be effectively treated for venous thromboembolism by heparin given intravenously at an initial loading dose of 5000 units intravenously, followed by maintenance therapy with 750 to 1500 U/h adjusted to the aPTT (aim: 1.5 to 2-fold prolongation of baseline aPTT). Venous thromboembolism can also be effectively treated with LMWH or fondaparinux (see Table 87–4). Adequate initial infusion rates and frequent determination of the aPTT in the first 24 hours reduce the frequency of delayed adequate heparinization. Use of a validated heparin treatment protocol makes it more likely that adequate early heparinization will be achieved. Long-term treatment of venous thromboembolism in pregnant patients or for others for whom warfarin is unsatisfactory can be achieved by adjusted-dose subcutaneous heparin. ++Table Graphic Jump LocationTABLE 87–4LOW-MOLECULAR-WEIGHT HEPARIN REGIMENS*View Table||Download (.pdf) TABLE 87–4 LOW-MOLECULAR-WEIGHT HEPARIN REGIMENS* Drug† Regimen Prophylaxis of VTE General surgery Low risk Dalteparin 2500 U, 1 or 2 h preoperation and daily Enoxaparin 40 mg, 2 h preoperation and daily Fondaparinux 2.5 mg daily (start 6–8 h postoperation) Nadroparin 2850 anti-Xa U once daily High risk Dalteparin 5000 U, 10–14 h preoperation and daily 2500 U, 1–2 h preoperation and after 12 h; then 5000 U daily (with malignancy) Enoxaparin 40 mg, 2 h preoperation and daily Fondaparinux 2.5 mg daily (start 6–8 h postoperation) Orthopedic surgery Dalteparin 2500 U, 4–8 h postoperation and 5000 U daily; or 2500 U, 2 h preoperation and 2500 U, 4–8 h postoperation and 5000 U daily; or 5000 U, 10–14 preoperation and 5000 U daily Enoxaparin 30 mg BID starting 12–24 h postoperation; 40 mg 9–15 h preoperation and once daily Fondaparinux 2.5 mg daily (start 6–8 h postoperation) Medical patients Enoxaparin 40 mg once daily Nadroparin 2850 anti-Xa U once daily Treatment of VTE Fondaparinux weight < 50 kg: 5 mg daily; 50–100 kg: 7.5 mg daily; > 75 kg: 10 mg daily Dalteparin (VTE with cancer) 200 U/kg daily × 1 month; then, 150 U/kg daily for up to 6 months Enoxaparin 1 mg/kg q12h; 1.5 mg/kg daily Tinzaparin 175 U/kg daily Acute coronary syndrome Dalteparin 120 U/kg (max 10,000 U) q12h Enoxaparin STEMI: 30 mg IV bolus plus 1mg/kg SQ q12h (older than age 75 y: initial 0.75 mg/kg with no IV bolus) Enoxaparin Unstable angina and non-STEMI: 1 mg/kg 12 h STEMI, ST-segment elevation myocardial infarction; VTE, venous thromboembolism. *Consult package insert for more detailed dosing information. Only FDA approved-indications are included. †Drug brand names: dalteparin, Fragmin; enoxaparin, Lovenox; fondaparinux, Arixtra; tinzaparin, Innohep; nadroparin, Fraxiparine. Source: Williams Hematology, 8th ed, Chap. 23, Table 23–5, p. 358. +++ Acute Coronary Syndromes ++ Heparin therapy is given to patients with acute coronary syndromes to reduce the risk of death, myocardial infarction, mural thrombosis, systemic embolism, and recurrent ischemia (see Table 87–4). In patients with unstable angina, combined use of intravenous heparin and aspirin is the preferred therapy. Low-dose, subcutaneous heparin is widely used in patients with acute myocardial infarction to prevent venous thromboembolism. Many patients with acute myocardial infarction receive more intensive heparin therapy either as an adjunct to fibrinolytic therapy or because they are at high risk for mural thrombosis and systemic thromboembolism. Patients requiring long-term anticoagulation because of high risk for mural thrombosis and systemic embolism are usually transferred to therapy with vitamin K antagonists. +++ Side Effects ++ The principal side effects of heparin therapy are bleeding and thrombocytopenia. Heparin-induced thrombocytopenia is discussed in Chap. 90. Thrombocytopenia is less likely to occur with LMWH than with unfractionated heparin. However, LMWH is not recommended for patients who have developed thrombocytopenia while receiving unfractionated heparin. Long-term treatment with unfractionated heparin, usually for more than 3 months, may cause osteoporosis. Clinically significant osteoporosis may occur less frequently with LMWH than with unfractionated heparin. Heparin may cause elevation of serum transaminase levels, which return to normal when heparin treatment is discontinued. Rare side effects are hypersensitivity; skin reactions, including necrosis; alopecia; and hyperkalemia due to hypoaldosteronism. +++ Antidote to Heparin ++ The anticoagulant effect of unfractionated heparin can be neutralized by intravenous administration of protamine sulfate, which should be considered for use in heparinized patients with major bleeding. Dosage is usually calculated assuming 1 mg of protamine sulfate will neutralize 100 units of heparin. The maximum recommended dose is 50 mg. Heparin is rapidly cleared from the plasma and calculation of the dose of protamine required must consider this important variable. LMWH is incompletely neutralized by protamine sulfate, but protamine may still be of benefit in treating bleeding caused by LMWH. + DIRECT THROMBIN AND FACTOR XA INHIBITORS Download Section PDF Listen +++ +++ Hirudin and Derivatives ++ Hirudin is a 65–amino acid peptide produced in the salivary gland of the leech. Hirudin is the most potent, naturally occurring, specific inhibitor of thrombin. Hirudin directly inactivates thrombin by forming a 1:1 complex. Hirudin for clinical use is produced by recombinant DNA technology. Recombinant hirudin is not sulfated on the tyrosine residue and consequently has markedly reduced affinity for thrombin, compared with native hirudin (Table 87–5). Bivalirudin is a 20–amino acid peptide analog of hirudin that produces transient, albeit potent, inhibition of thrombin. Lepirudin is a recombinant form of hirudin approved for use in patients with heparin-induced thrombocytopenia. Hirudin has been clinically evaluated in patients with acute coronary syndromes and does not appear to be a major advance. Bivalirudin has been compared with heparin in patients who have angina. It was not more effective than heparin in reducing the cluster outcome of death in the hospital, myocardial infarction, or abrupt vessel closure. All hirudin derivatives are cleared by the kidney and have a markedly prolonged half-life in case of renal insufficiency. Hirudin derivatives carry a high risk of bleeding and currently there is no antidote available. ++Table Graphic Jump LocationTABLE 87–5CLINICAL INDICATIONS AND USE OF DIRECT THROMBIN INHIBITORSView Table||Download (.pdf) TABLE 87–5 CLINICAL INDICATIONS AND USE OF DIRECT THROMBIN INHIBITORS Agent Clinical Indication Regimen Monitoring Lepirudin HIT 0.4 mg/kg bolus, then 0.15 mg/kg/h aPTT Bivalirudin Angioplasty, PCI with HIT 0.75 mg/kg/bolus; then 1.75 mg/kg/h ACT Argatroban HIT 2 μg/kg/min aPTT HIT with PCI 350 μg/kg/min bolus, then 15 to 400 μg/kg/min ACT ACT, activated clotting time; aPTT, activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary intervention. Source: Williams Hematology, 8th ed, Chap. 23, Table 23–6, p. 359. +++ Argatroban ++ Argatroban is a small-molecule arginine derivative that reversibly inhibits thrombin by binding directly to the active catalytic site. Argatroban is approved for treatment and prophylaxis of heparin-induced thrombocytopenia and for percutaneous interventions in patients with heparin-induced thrombocytopenia. It also shows some benefit in patients with thrombotic stroke in clinical trials (see Table 87–5). The anticoagulant effect can be assessed with the aPTT, which correlates well with plasma concentrations of the drug. Metabolism is primarily hepatic, and the clearance and half-life are prolonged in patients with hepatic functional abnormalities requiring dose reduction. Renal function has less effect on argatroban pharmacokinetics. As with other direct thrombin inhibitors, the main side effect is bleeding, and no specific agent is available to reverse its action. + ORAL ANTITHROMBIN AND ANTI–FACTOR XA AGENTS Download Section PDF Listen +++ ++ The oral direct-acting antithrombin agent dabigatran was shown to be as effective or superior to vitamin K antagonists in patients with atrial fibrillation and for prevention and treatment of venous thromboembolism. The oral direct-acting anti–factor Xa agents—rivaroxaban, apixaban, and edoxaban—were also shown to be as effective or superior to vitamin K antagonists in patients with atrial fibrillation and for prevention and treatment of venous thromboembolism. The new oral antithrombin and anti–factor Xa agents were not effective in preventing thromboembolism in patients with prosthetic heart valves. Dabigatran, rivaroxaban, apixaban, and edoxaban do not need laboratory monitoring, although data in elderly patients and patients with renal insufficiency are limited. The anti–factor Xa inhibitors can be monitored with the prothrombin time (PT), but not with the INR, and with anti–factor Xa assays. Dabigatran can only be accurately monitored with an ecarin clotting time, which may not be routinely available. The anticoagulant effect of dabigatran may be reversed by the administration of a Fab fragment that binds dabigatran (idarucizumab) based on preliminary trial data. The anticoagulant effect of the oral factor Xa inhibitors may be reversed by a modified inactive factor Xa molecule (Andexanet). Also, prothrombin complex concentrate may be able to reverse the anticoagulant effect of Xa inhibitors. + ANTIPLATELET DRUGS Download Section PDF Listen +++ ++ The properties that make platelets useful in the arrest of hemorrhage also allow platelets to form thrombi in vessels, and on heart valves, artificial membranes, and prosthetic devices, in particular in situations with high shear stress. Drugs that inhibit platelet function may, therefore, have clinical application in the treatment and prevention of arterial thrombosis (Table 87–6). Drugs that inhibit platelet function include aspirin, nonsteroidal anti-inflammatory drugs, dipyridamole, thienopyridine derivatives (ticlopidine, clopidogrel and prasugrel), and inhibitors of the platelet glycoprotein (GP) IIb/IIIa receptor. ++Table Graphic Jump LocationTABLE 87–6ANTIPLATELET AGENTS BY MECHANISM OF ACTION AND CLINICAL USEView Table||Download (.pdf) TABLE 87–6 ANTIPLATELET AGENTS BY MECHANISM OF ACTION AND CLINICAL USE Agent and Indications Dosages Cyclooxygenase inhibitors Aspirin Coronary and cerebrovascular disease 75–650 mg daily VTE secondary prevention Agents that increase cAMP Dipyridamole Coronary, cerebrovascular, peripheral arterial disease 75–100 mg QID Pentoxifylline Peripheral arterial disease 400 mg BID Cilostazol Peripheral arterial disease 100 mg BID ADP receptor blockers Ticlopidine Cerebrovascular disease 250 mg BID Clopidogrel Coronary, cerebrovascular disease, PCI 75 mg daily, loading dose 300 mg Prasugrel ACS, PCI 10 mg daily, 60-mg loading dose Ticagrelor ACS 90 mg BID, 180-mg loading dose ADP mimetic Cangrelor PCI 30 mcg/kg IV bolus, then 4 mcg/kg/min αIIbβ3 inhibitors Abciximab ACS, PCI 0.25 mg/kg, then 10 mcg/kg/min Eptifibatide ACS, PCI ACS 180 mcg/kg, then 2 mcg/kg/min PCI 180 mcg/kg, then 2 mcg/kg/min with 180 mcg/kg at 10 min Tirofiban ACS, PCI 0.4 mcg/kg/min × 30 min, then 0.1 mcg/kg/min Thrombin receptor blocker Vorapaxar Coronary disease, peripheral arterial disease 2.08 mg daily ACS, acute coronary syndrome; ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; PCI, percutaneous coronary intervention; VTE, venous thromboembolism. Source: Williams Hematology, 9th ed, Chap. 25, Table 25–6. +++ Aspirin ++ Aspirin inhibits prostaglandin synthesis by irreversibly acetylating a critical serine residue in cyclooxygenase, thereby blocking the formation of thromboxane A2 (TXA2). Because platelets cannot synthesize new enzymes, the inhibition is permanent for the life span of the platelet. This agent inhibits collagen-induced platelet aggregation and secondary aggregation to weak agonists, such as ADP and epinephrine. Effects on aggregation last about 7 days after a single oral dose. Inhibition of the synthesis of the potentially antithrombotic prostaglandin, PGI2 (prostacyclin), occurs in endothelial cells, but the inhibition is short-lived because endothelium can synthesize new enzyme. A dose of aspirin that inhibits TxA2 but not PGI2 production has not been found, and the optimal dose of aspirin has not been defined for any specific indication. The dose used for a specific indication should take into account efficacy, as determined by clinical trials, and adverse effects, which include, most importantly, gastrointestinal bleeding and hemorrhagic stroke. +++ Nonsteroidal Anti-inflammatory Drugs ++ These drugs appear to work by a mechanism similar to aspirin, but as the effect on cyclooxygenase is reversible, the effects are of much shorter duration. +++ Dipyridamole ++ This is a phosphodiesterase inhibitor with vasodilator effects. Mechanisms of action may include increasing platelet cyclic AMP levels, or indirectly increasing the plasma levels of adenosine. This agent does not inhibit aggregation of platelets in platelet-rich plasma in vitro, but does inhibit aggregation of platelets in the presence of erythrocytes, as measured by whole-blood aggregometry. Other agents that increase cyclic adenosine monophosphate (cAMP) are pentoxifylline and cilostazol. +++ Thienopyridine Derivatives (Ticlopidine, Clopidogrel, and Prasugrel) ++ These antiplatelet drugs prolong bleeding time and inhibit aggregation induced by ADP and low concentrations of collagen or thrombin. Antiplatelet effects are caused by metabolites. The drugs appear to exert their antiplatelet effects by inhibiting the binding of ADP to platelets. Drugs are given orally and are fully effective only after 2 to 3 days. Loading doses may accelerate the onset of action. The usual dose of clopidogrel is 50 to 100 mg daily. Adverse effects include diarrhea and rash. Neutropenia may be severe but is usually reversible. Aplastic anemia and thrombotic thrombocytopenic purpura may occur, in particular with ticlopidine. +++ Inhibitors of the Platelet GP IIb/IIIa Receptor ++ Platelets with absence or blockade of the receptor function of GP IIb/IIIa will not aggregate with any physiologic agonist. Blockade of GP IIb/IIIa can be achieved with monoclonal antibodies or with peptide or nonpeptide agonists. Abciximab is a human-mouse chimeric antibody fragment that inhibits platelet aggregation almost completely when 80% of GP IIb/IIIa receptors are blocked and that also inhibits the prothrombinase activity of platelets. The platelet count has been reported to be reduced to less than 100 × 109/L in approximately 2% to 6% of patients and to less than 50 × 109/L in 1% to 2%. Cyclic peptides (eptifibatide) containing the arginine-glycine-aspartic acid (RGD) sequence or the lysine-glycine-aspartic acid (KGD) sequence bind with high affinity to GP IIb/IIIa and are relatively resistant to enzymatic breakdown. Nonpeptide agents (tirofiban) inhibit the binding of adhesive proteins to GP IIb/IIIa, presumably because they mimic the structural features of the RGD sequence. + ANTIPLATELET DRUGS IN CLINICAL MEDICINE Download Section PDF Listen +++ +++ Ischemic Heart Disease ++ Aspirin therapy is widely used for both primary and secondary prevention of acute coronary syndromes and other forms of ischemic heart disease. Aspirin is also useful alone, or in combination, in treating unstable angina and acute myocardial infarction, and as an adjunct in managing patients after thrombolytic therapy, percutaneous coronary interventions, or coronary artery bypass surgery. Thienopyridine derivatives are useful in combination with aspirin in unstable angina and in the prevention of acute occlusion after coronary stenting. GP IIb/GP IIa antagonists in combination with other drugs favorably influence unstable angina and evolving myocardial infarction, and prevent ischemic vascular complications following percutaneous coronary interventions. +++ Valvular Heart Disease ++ Oral anticoagulant therapy is generally recommended for patients with prosthetic heart valves, but the addition of aspirin is recommended for patients who have systemic thromboembolism despite adequate anticoagulation. +++ Cerebrovascular Disease ++ Antiplatelet therapy is effective in preventing cerebrovascular events in patients with either prior cerebrovascular events or prior cardiac events. In most studies, aspirin has been used in doses ranging from 38 to 100 mg/d, but the optimal dose has not been determined. Low doses appear to be as effective as higher doses but have fewer adverse effects. +++ Peripheral Vascular Disease ++ Aspirin treatment may decrease the need for vascular surgery without affecting the pattern of stable intermittent claudication, suggesting that antiplatelet therapy decreases the incidence of thrombotic complications without affecting the basic disease process. The role of antiplatelet therapy in preventing graft occlusion after peripheral artery reconstruction is controversial. ++ For a more detailed discussion, see Gregory C. Connolly and Charles W. Francis: Principles of Antithrombotic Therapy, Chap. 25 in Williams Hematology, 9th ed.
For a more detailed discussion, see Gregory C. Connolly and Charles W. Francis: Principles of Antithrombotic Therapy, Chap. 25 in Williams Hematology, 9th ed.