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Lasting safe interruption of endarterectomy thrombosis by transiently
infused antithrombin peptide D-Phe-Pro-ArgCH2Cl in baboons
AB Lumsden, AB Kelly, PA Schneider, WC Krupski, T Dodson, SR Hanson and LA Harker
Department of Medicine, Emory University School of Medicine, Atlanta, GA
30322.
To evaluate the relative antithrombotic efficacy and hemostatic safety of
antithrombin therapy for vascular thrombus formation at sites of mechanical
vascular injury, we administered the potent and specific irreversible
synthetic antithrombin D-PHE-PRO-ARG chloromethyl ketone (D-FPRCH2Cl) after
performing carotid endarterectomies in baboons. The continuous intravenous
infusion of D-FPRCH2Cl, 100 nmol/kg per minute for 1 hour, abolished acute
carotid endarterectomy thrombosis for at least 48 hours. The plasma level
of D-FPRCH2Cl during the infusion was maintained steady at 7.2 +/- 0.9
mumol/L, but decreased rapidly after discontinuing its infusion (T50 17
minutes). Platelet deposition, measured in real time using autologous
111In-platelet scintillation camera imaging, was 1.51 +/- 0.40 x 10(8)
platelet/cm in the 14 treated animals 90 minutes postoperatively, compared
with 11.7 +/- 1.16 x 10(8) platelet/cm in 14 heparin-treated controls (P
< .002). The antithrombotic benefit was equivalent for treatment begun
either 5 minutes before (nine animals) or 15 minutes after (five animals)
reestablishing flow in the operated vessel, ie, 1.59 +/- 0.36 x 10(8)
platelet/cm versus 1.35 +/- 0.51 x 10(8) platelet/min, respectively; P >
.5. Endarterectomy thrombosis remained decreased for at least 48 hours
postoperatively, as determined by the ratio between net 111In- platelet
radioactivity at the endarterectomized site versus whole blood (ratio 0.82
+/- 0.25 in the treatment group v 3.03 +/- 0.51 in heparin controls at 90
minutes, P < .005; and 0.85 +/- 0.23 v 3.25 +/- 0.48 at 48 hours, P <
.002). The marked reduction in endarterectomy thrombosis in treated animals
at 48 hours was confirmed by scanning electron microscopy. Thrombin
activity formed rapidly and became immediately bound to thrombus on
thrombogenic segments in untreated control studies; treatment with
D-FPRCH2Cl irreversibly inactivated the thrombus-bound thrombin. Hemostatic
function, as measured by bleeding time (BT), activated partial
thromboplastin time (APTT), and prothrombin time (PT) was impaired
throughout the intravenous administration of D-FPRCH2Cl (BT > 30
minutes, APTT > 150 seconds, PT > 50 seconds); BT, APTT, and PT
values were normal 30 minutes after discontinuing the infusions. As
expected, blood loss into the surgical wound was substantial in nine
animals receiving therapy initiated before restoring flow in the operated
vessel (mean 95 mL, range 45 to 130 mL). By contrast, beginning D-FPRCH2Cl
therapy in five animals 15 minutes after restoring arterial flow, a time
when surgical hemostasis had been achieved, prevented excessive blood loss
(mean 15 mL, range 10 to 35 mL; P < .01 compared with earlier treatment)
without compromising the antithrombotic effects.(ABSTRACT TRUNCATED AT 400
WORDS)
Volume 81,
Issue 7,
pp. 1762-1770,
04/01/1993
Copyright © 1993 by The American Society of Hematology
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