Last updated: 03/04/2015
Anitfibrinolytics are frequently used in patients placed on CPB. The two available lysine analogs,ε-aminocaproic acidandtranexamic acid, bind to lysine binding sites on plasminogen and fibrinogen and thereby inhibit plasminogen activator and plasmin release. When administered before CPB, these agents clearly inhibit fibrinolysis, decrease mediastinal bleeding, and depending on the study, may or may not decrease transfusion requirements.
Aprotininis a nonspecific protease inhibitor, and its inhibitory action includes the intrinsic coagulation cascade, complement activation, fibrinolysis, and bradykinin and kallikrein formation. It is a naturally occurring compound extracted from beef lung and as such has the potential to induce antibody formation. Aprotinin clearly decreases bleeding and transfusion requirements. However, it is not used as widely as it might be because of cost, immunogenicity, and possible side effects.
IgG antibody formation has been demonstrated after aprotinin exposure. However, this does not necessarily translate into a clinical problem. A recent study in pediatric patients demonstrated reactions to protamine in 1% of patients on first exposure and 1.3% of patients on re-exposure. Moreover, some evidence suggests that antibody levels change over time and are highest and the risk greatest if re-exposure occurs within 6 months.
Aprotinin is excreted by the kidney, and one study of patients subject to deep hypothermic circulatory arrest suggested that aprotinin had a negative impact on renal function. However, their controls were historical, and lesser doses of heparin were used in the patients who received aprotinin. Recent studies suggest that aprotinin does not have a negative influence on renal function. Concern regarding the prothrombotic effects of aprotinin remains unresolved, but the preponderance of clinical data suggests that such concern may not be justified. However, recent laboratory data suggest that aprotinin may inhibit endothelial NOS in the coronary circulation. In contrast to concerns regarding thrombosis in the coronary circulation, aprotinin may exert a salubrious effect on neurologic injury. Pooled, double-blind, multicenter data in 1721 patients demonstrated a reduction in the stroke rate from 2.4% in the control group to 1% in the aprotinin group. If real, the underlying mechanisms responsible for this decrease are likely to extend beyond aprotinin’s effects on the coagulation and fibrinolytic cascades. A “high-dose” regimen of aprotinin was used in this study, and it is likely that to derive maximal effect from this nonspecific protease inhibitor, one should use a higher dose to inhibit pathways that have very different affinities and binding properties for this protein. As a corollary, it is possible to demonstrate a benefit from lower doses of aprotinin, depending on the specific end point one measures.”
In regards to the safety of aprotinin,a 2006 prospective study of over 4000 patientsby Mangano, et al published in the NEJMdemonstrated increased adverse outcomes when aprotinin was used in cardiac surgery. Specifically, they observed a doubling in the risk of renal failure requiring dialysis, a 55% increase in the risk of MI or heart failure, and a 181 percent increase in risk of stroke or encephalopathy when aprotinin was used as compared with aminocaproic acid, tranexamic acid, or no antifibrinolytic therapy. This study influenced many subsequent clinical practices, and the routine use of aprotinin in cardiac surgery has since fallen out of favor.
- Dennis T Mangano, Iulia C Tudor, Cynthia Dietzel, Multicenter Study of Perioperative Ischemia Research Group, Ischemia Research and Education Foundation The risk associated with aprotinin in cardiac surgery. N. Engl. J. Med.: 2006, 354(4);353-65 Link
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