Thromboembolic diseases are treated by antithrom-botic drugs. Antithrombotic agents include antiplatelet drugs, anticoagulant drugs, and thrombolytic drugs. Antiplatelet drugs prevent platelet activation and aggregation and are most effective in the treatment of the arterial diseases. Anticoagulant drugs inhibit thrombin and fibrin formation and are used commonly for the treatment of venous thrombosis. Thrombolytic drugs are used to break down fibrin clots, to restore vascular function, and to prevent loss of tissues and organs.
There are numerous agents used against platelets. Aspirin (acetylsalicylic acid) is an antiplatelet drug that irreversibly affects platelet function by inhibiting the cyclooxygenase (COX) enzyme and thereby the formation of thromboxane A2 (TXA2). TXA2 is a potent platelet-activating substance released from the activated platelets. Aspirin is rapidly absorbed from the gastrointestinal tract and the plasma concentration is at peak 1 hour after aspirin ingestion.1 The effect of aspirin on platelets starts 1 hour after ingestion and lasts for the entire platelet life span (approximately 1 week).1 Aspirin is effective in the treatment of angina, acute MI, transient ischemic attack, stroke, arterial fibrillation, and prostatic heart valve. The minimum effective dosage for these conditions is 75 to 325 mg/day.1 Aspirin toxicity includes gastrointestinal discomfort, blood loss, and the risk of systemic bleeding. A low dose of aspirin (30 to 75 mg/day) has shown to have an antithrombotic effect.1 Some patients may develop aspirin resistance. Patients who become resistant to aspirin have a higher rate of heart attacks and strokes. Aspirin resistance can be evaluated by platelet aggregation tests.
Other antiplatelet drugs include dipyridamole, thienopyridines, ticlopidine, and clopidogrel.1
Table 19.4 O Conditions That
Require Evaluation for Hypercoagulable States
• Recurrent thrombosis in patients <45 years old
• Patients with a positive family history
• Recurrent spontaneous thromboses
• Thrombosis in unusual sites
• Heparin resistance
• Proteins C and S deficiency
• Thrombosis associated with pregnancy and estrogen therapy
• Unexplained recurrent pregnancy loss
Table 19.5 O Screening Laboratory Tests for Hyper-coagulable State
• Activated protein C resistance
• Functional assays for antithrombin, protein C, and protein S
• Prothrombin G20210A by polymerase chain reaction
• APTT, DRVVT, mixing studies, and confirmatory test for lupus anticoagulant
• Enzyme-linked immunosorbent assays for anticardi-olipin antibody
• Factor VIII activity
Anticoagulant drugs are used for the prevention and treatment of thromboembolic disorders. Short-term anticoagulant drugs such as heparin are administered by intravenous infusion or subcutaneous injection. Long-term anticoagulant drugs such as Coumadin are orally administered.
Heparin is present in human tissue as naturally occurring highly sulfated glycosaminoglycan. Commercially unfractionated heparin (UFH) is isolated from bovine lung or porcine intestine. It contains a mixture of polysaccharide chains with a molecular weight of 4000 to 30,000 daltons.1 Heparin sulfate is a heparin-like substance made by the vascular endothelium. The anticoagulant activity of heparin is enhanced by binding to AT. Heparin-AT complex inactivates thrombin and factor Xa (see Fig. 19.2).
The half-life of heparin is dose dependent. Heparin is cleared from the circulation by the reticu-loendothelial system and metabolized by the liver.1 Heparin is given in a weight-adjusted dosage with an initial bolus (high dose) followed by continuous infusion (lower dose).
Heparin dosage is monitored by aPTT value to range from 1.5 to 2.5 times the mean of the laboratory normal ranges. This level of aPTT is equivalent to heparin levels of 0.3 to 0.7 U/mL that can be measured by factor Xa activity assay.1,8
The adverse effects of heparin include bleeding, HIT, and heparin resistance. Heparin resistance may occur as a result of nonspecific binding of heparin to plasma proteins, platelets, and endothelial cells or as a result of AT deficiency
Low-molecular-weight heparin (LMWH) is derived from the UFH via enzymatic digestion to produce smaller and low-molecular-weight glycosaminoglycan molecules. The mean weight of LMWH is about 5000 daltons.1 LMWH has a higher half-life and has low affinity to bind to plasma proteins and endothelial cells.1,9 The half-life of the drug is not dose dependent. LMWH is administered subcutaneously, once or twice daily based on the body's weight, and does not require monitoring.1 LMWH has a higher inhibitory effect on factor Xa than on factor IIa.9 LMWH is cleared by the kidney. The adverse reaction of LMWH includes bleeding, HIT, or sensitivity to LMWH. The LMWH drugs available in the United States, which are approved
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