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Aprotinin
General information
Because of increased mortality (see Death below), aprotinin was temporarily withdrawn worldwide in 2007, after consultation with the German Federal Institute for Drugs and Medical Devices (BfArM), the US Food and Drug Administration (FDA), Health Canada, and other health authorities, pending the final results from the Canadian BART trial; it was permanently withdrawn in May 2008 [ , ].
Aprotinin is a fibrinolytic agent, a naturally occurring serine protease inhibitor derived from bovine lung. It is a polypeptide of 58 amino acids, with a molecular weight of 6512, which inhibits the action of several serine proteases, including trypsin, chymotrypsin, plasmin, and kallikrein. It is extracted on a commercial basis from bovine lung. By inhibiting kallikrein, aprotinin inhibits the formation of activated factor XII indirectly. It thus inhibits the initiation of both coagulation and fibrinolysis induced by the contact of blood with a foreign surface. It does not affect platelet function. In cardiac surgery, aprotinin reduces the risk of bleeding [ , ].
Aprotinin is not effective after oral administration, but is administered intravenously as a loading dose followed by a continuous infusion. Its activity is expressed as kallikrein inactivation units (KIU). The conventional (Munich) dose regimen consists of an initial 2 × 10 6 KIU bolus, a similar initial dose to prime the bypass machine, and then 0.5 × 10 6 KIU/hour by continuous infusion thereafter. The half-life of aprotinin is about 2 hours. Plasma concentrations of 125 KIU/ml are necessary to inhibit plasmin, but a higher concentration of 300–500 KIU/ml is needed to inhibit kallikrein.
During normal fibrinolysis, inactive circulating plasminogen binds to fibrin through an active site that binds lysine. The bound plasminogen is then converted to plasmin by activators (such as tissue plasminogen activator, t-PA) and converted to plasmin, which breaks down the fibrin. Aminocaproic acid (EACA, 6-aminohexanoic acid, Amicar®) and tranexamic acid (Cyklokapron®) are structural analogues of lysine, which bind irreversibly to the lysine-binding sites on plasminogen, inhibiting binding to fibrin and thus the whole process of fibrinolysis [ , ]. These agents inhibit the natural degradation of fibrin and so stabilize clots.
Uses
Aprotinin has been widely used to inhibit fibrinolysis during cardiac surgery and orthotopic liver transplantation, and reduces the risk of bleeding [ , ]. In addition, it has been added as a constituent of several commercial formulations of fibrin sealants (“fibrin glues”), such as Quixil. The use of aprotinin in cardiopulmonary bypass surgery was pioneered by Royston, an anesthesiologist in London, who found that it reduced blood loss after both primary and repeat operations [ ]. It is also effective in operations normally characterized by particularly large blood losses, such as those in patients taking aspirin [ ] and patients undergoing cardiac transplantation [ ]. It has also been used to control blood loss in the setting of orthotopic liver transplantation [ , ], where accelerated fibrinolysis is an important component in the abnormalities of hemostasis, which can contribute to perioperative bleeding. Aprotinin controls hemorrhage associated with hyperplasminemia (which can, for example, occur after thrombolytic therapy or in association with promyelocytic leukemia). A combination of aprotinin with tranexamic acid can prevent or delay rebleeding after rupture of an intracerebral aneurysm. Clinical trials have not confirmed any benefit from the use of aprotinin in acute pancreatitis.
Organs and systems
Cardiovascular
The question of whether the use of aprotinin is associated with an increased risk of vein graft thrombosis in cardiac bypass surgery has not been resolved [ , ]. The use of aprotinin was not associated with an increased rate of early occlusion of saphenous vein or internal mammary artery grafts in controlled studies with coronary angiography [ ].
In a randomized, placebo-controlled, multicenter study of aprotinin in coronary artery bypass surgery, there was no increase in mortality or the incidence of myocardial infarction [ ].
There was no evidence of an increased risk of venous thromboembolism in patients receiving aprotinin in a small study after hip replacement [ ].
Of nine patients with severe end-stage heart failure caused by dilated cardiomyopathy who underwent external cardiopulmonary bypass, seven received intravenous heparin which was reversed with intravenous protamine sulfate, eight received aprotinin, and one received aminocaproic acid (total dose 25 g) [ ]. Of those who received aprotinin, four were given 1 ml (10 000 kallikrein inactivation units) as a test dose, 200 ml as a loading dose, and 50 ml/hour as a continuous infusion; at the start of the bypass an extra 200 ml was added to the priming fluid. In the other four patients, aprotinin was administered according to a weight-based protocol; the loading dose and priming dose were 100 ml each. Three of the eight patients who received aprotinin had had prior exposure to aprotinin, 3, 5, and 32 days earlier. Within minutes of protamine administration, pulmonary artery pressure increased dramatically. There was right ventricular distension and lack of right ventricular wall motion and eight of the nine patients died. At post-mortem there were multiple recent fibrin thrombi in the capillaries and small and medium pulmonary arterioles throughout both lungs. Three patients also had microthrombi in the epicardial and intramyocardial microvasculature.
Psychological, psychiatric
Psychotic reactions, including delirium, hallucinations, and confusion, have also been reported in patients given aprotinin, but it is possible that the symptoms were due to underlying pancreatitis [ ].
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