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Chapter: Modern Medical Toxicology: Cardiovascular Poisons: Anticoagulants and Related Drugs

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Aprotinin - Antifibrinolytic Cardiovascular Poison

Aprotinin is a basic proteinase inhibitor obtained from bovine organs, and is given intravenously to reduce peri-operative blood loss in open heart surgeries.

Antifibrinolytics

Examples

Aprotinin, epsilon-aminocaproic acid, ancrod, hirudin, tranexamic acid.

Aprotinin

Aprotinin is a basic proteinase inhibitor obtained from bovine organs, and is given intravenously to reduce peri-operative blood loss in open heart surgeries. It is also useful in the management of traumatic, haemorrhagic, pancreatogenic, and endotoxic shock. Aprotinin acts as an inhibitor of multiple mediators (e.g. kallikrein, plasmin). It is able to modulate the systemic inflammatory response associated with cardiopul-monary bypass surgery, thus decreasing the risk of bleeding.

Aprotinin is also combined with other components to be applied topically as a fibrin glue for wound haemostasis, suture support, and tissue adhesion or sealing. In May 1998, the United States FDA approved the use of fibrin sealants containing aprotinin in multi-ingredient products. These sealants are freeze-dried concentrates which are reconstituted separately as solutions of fibrinogen and thrombin. Because sealants contain ingredients derived from pooled human plasma, procedures are in place to reduce possible viral transmission (donor screening and product pasteurisation). Up until the present time, no cases of viral infection have been reported.

Aprotinin has been withdrawn from the Italian market based on concerns that it may transmit a bovine spongiform encephalopathy and/or a new variant Creutzfeldt-Jakob disease.

During therapeutic use with aprotinin, the following have occurred infrequently: anaphylactic or anaphylactoid reactions which can range from mild to life-threatening symptoms and may not appear until the second or third dose. However, severe symptoms have been reported in a few individuals following a test dose. Anaphylaxis is not considered an uncommon response to intravenous therapy, but is a relatively rare response following fibrin sealant use.

Haematologic and lymphatic disorders have been reported during therapy: thrombosis (which may include the central nervous system, cardiovascular and pulmonary occlusions and/ or emboli), leukocytosis, thrombocytopenia, and coagulation disorders. In controlled US trials with aprotinin, an incidence between 1% and 2% was reported for the following: throm-bocytopenia, leukocytosis, coagulation disorders (including disseminated intravascular coagulation). High IV doses can lead to decrease in arterial pressure and metabolic acidosis.

Coronary and arterial thrombosis have been reported in patients following the use of aprotinin during cardiac surgery, as well as, other types of surgery and/or disease processes. Sudden episodes of hypotension have been (rarely) reported in trauma victims following the use of fibrin glue containing bovine thrombin and cryoprecipitate. This may be secondary to bovine impurities or relatively high concentrations of glue.

Treatment involves the use of noradrenaline, steroids, and sodium bicarbonate. Obtain a CBC with differential following a significant exposure or as indicated in symptomatic patients. Monitor for signs or symptoms of bleeding. Monitor CBC, PT or INR, PTT, bleeding time in patients with evidence of bleeding. In the immediate hours following surgery, elevations in the partial thromboplastin time (PTT) and celite activated Clotting Time (celite aCT) are anticipated due to circulating aprotin. The celite aCT is considered a more accurate deter-mination of whole blood clotting time in the presence of apro-tinin. Monitor blood pressure and respiratory function. Airway management may be indicated in patients with symptoms of anaphylaxis.

Decontamination is NOT indicated; aprotinin is inacti-vated in the gastrointestinal tract. Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta agonists, corticosteroids or adrenaline. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, adrenaline, ECG monitoring, and IV fluids. If hypotensive, give 500 to 2000 ml crystalloid initially (20 ml/kg in children), and titrate to desired effect (stabilisation of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension. Dopamine may be used in refractory cases unresponsive to repeated doses of adrenaline, and after vigorous intravenous crystalloid rehydration.

 

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