Md. Linden et al., Factor V-LEIDEN and cardiopulmonary bypass: investigation of haemostatic parameters and the effect of aprotinin using an ex vivo model, PERFUSION-U, 16(6), 2001, pp. 476-484
It has been suggested that aprotinin results in significantly increased ris
k for perioperative thrombotic complications in patients with Factor V-LEID
EN (F5L) due to its ability to competitively inhibit activated protein C (A
PC) function in vitro. No clinical studies have been performed to assess th
e effect of aprotinin on APC function of F5L in vivo. We developed an ex vi
vo model to mimic the effects of cardiopulmonary bypass with the exclusion
of the patient in order to assess APC function. Blood from normal (n=2) and
F5L heterozygous donors (n=2) was treated with aprotinin or placebo (salin
e). The blood was heparinized, added to the prime and circulated at 21/min
through a modified cardiopulmonary bypass circuit. After 60 min of circulat
ion, the heparin was neutralized with protamine sulfate. Blood samples, dra
wn at specific time points, were analysed for APC ratio. Results showed a d
ecrease in APC ratio for both F5L and normal bloods with the addition of ap
rotinin (18% and 40%, respectively). APC ratios also decreased with the com
mencement of extracorporeal circulation for all bloods, resulting in an APC
ratio of 1.35 in normal placebo-treated blood and 0.67 in F5L placebo-trea
ted blood. The combined effect of aprotinin and extracorporeal circulation
resulted in APC ratios of 0.90 for normal blood and 0.63 for F5L blood, cor
responding to a severe dysfunction of APC intraoperatively (reference range
1.9-4.0). The data from this model predict an increased risk of perioperat
ive thrombosis due to inhibition of APC function in cardiac surgical patien
ts heterozygous for the F5L mutation. Aprotinin further compounds the sever
ity of APC dysfunction, though the effect is more severe in normal blood. T
he ex vivo model employed was an effective tool for the investigation of th
e haemostatic effect of aprotinin. This model may be exploited for other ap
plications such as the investigation of novel or emerging haemostatic agent
s prior to clinical trial.