Antifibrinolytics (Lysine Analogs and Aprotinin)
Antifibrinolytics are frequently used in patients placed on CPB.
The two available lysine analogs, epsilon-aminocaproic acid and tranexamic 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,[199]
decrease mediastinal
bleeding,[200]
[201]
and depending on the study, may[201]
or may not
[202]
decrease transfusion requirements.
Aprotinin is 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.
[203]
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.
[204]
Moreover, some evidence suggests that antibody
levels change over time and are highest and the risk greatest if re-exposure occurs
within 6 months.[205]
Aprotinin is excreted by the kidney, and one study[206]
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.[207]
Concern regarding
the prothrombotic effects of aprotinin remains unresolved, but the preponderance
of clinical data suggests that such concern may not be justified.[208]
However, recent laboratory data suggest that aprotinin may inhibit endothelial NOS
in the coronary circulation.[209]
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.[210]
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. The influence of
aprotinin on ACT measurements has already been discussed.
