Effects of SolCD39, a novel inhibitor of Platelet Aggregation, on Platelet Deposition and Aggregation after PTCA in a Porcine Model.
BACKGROUND
This study evaluated CD39 in a porcine model of balloon angioplasty and in plasma of patients undergoing percutaneous intervention. CD39 (E-NTPDase1), is the endothelial ecto-ADPase inhibiting platelet function via hydrolysis of released platelet ADP.


RESULTS
A recombinant soluble form of CD39 (solCD39) given intravenously to pigs had an elimination half life of 5--7 days, increased the bleeding time to an extent similar to aspirin, and inhibits platelet aggregation by>90%. Platelet counts and clot retraction remained normal following solCD39 administration. In a pig model of acute coronary balloon injury, solCD39 resulted in non-statistically significant decreases in platelet (7.7+/-1.4 versus 11.7+/- 3.4) and fibrin (3.5+/- 0.4 versus 4.2+/- 0.7) deposition ratios. Adding ex vivo to human platelet rich plasma (PRP) solCD39 produced nearly 100% inhibition of ADP-induced platelet aggregation. A dose-response effect of solCD39 on platelet aggregation induced by collagen or a thrombin receptor activating peptide (TRAP(SFLLRN)) was noted in PRP obtained from volunteers and patients receiving aspirin, clopidogrel or ticlopidine. SolCD39 also provided additional and complete inhibition of TRAP-induced platelet aggregation in PRP from patients who had received abciximab, aspirin and clopidogrel.


CONCLUSIONS
SolCD39, a novel inhibitor of platelet activation and recruitment with a relatively long half-life appears to be well tolerated and is a potent inhibitor of ADP-, collagen-, or TRAP-induced platelet activation. Its potential use in percutaneous coronary intervention requires further study. ABBREVIATED ABSTRACT: E-NTPDase1/CD39 is the endothelial ecto-ADPase responsible for inhibition of platelet function. A recombinant soluble form (solCD39) had an elimination half life of 5-7 days in pigs, elevated bleeding times similar to aspirin, did not affect clot retraction, and inhibited platelet aggregation by > 90%. When combined with standard heparin therapy in a pig model of acute coronary balloon injury, solCD39 resulted in a trend toward a decrease in platelet and fibrin deposition. SolCD39 added ex vivo to human platelet rich plasma yielded nearly 100% inhibition of ADP-induced platelet aggregation and provided further inhibition when combined with standard therapy.
Buergler
John M
JM
Section of Cardiology, Department of Medicine, Baylor College of Medicine, The Methodist DeBakey Heart Center, Houston, TX 77030, USA. dwebb@tmh.tmc.edu
Maliszewski
Charles R
CR
Broekman
M Johan
MJ
Kaluza
Grzegorz L
GL
Schulz
Daryl G
DG
Marcus
Aaron J
AJ
Raizner
Albert E
AE
Kleiman
Neal S
NS
Ali
Nadir M
NM
D000244:Adenosine Diphosphate / Q000494:pharmacology; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology* / Q000627:therapeutic use; D001081:Apyrase / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001780:Blood Coagulation Tests; D003094:Collagen / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D023421:Models, Animal; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D018179:Receptors, Thrombin; D012995:Solubility; D013552:Swine
D015703:Antigens, CD; D010975:Platelet Aggregation Inhibitors; D018179:Receptors, Thrombin; D000244:Adenosine Diphosphate; D003094:Collagen; D001081:Apyrase; C067869:CD39 antigen