A platelet target for venous thrombosis? P2Y1 deletion or antagonism protects mice from vena cava thrombosis.

Abstract

A role for platelets in the pathogenesis of venous thrombosis was suggested by clinical and preclinical studies. However, examination of the platelet receptor, P2Y1, in this area has been limited. The goal of the current study was to examine effects of P2Y1 deletion, or selective antagonism with MRS2500, in oxidative venous thrombosis in mice. The P2Y12 antagonist, clopidogrel, was included as a reference agent. Anesthetized C57BL/6 or genetically modified mice underwent 3.5 or 5 % FeCl(3)-induced vena cava thrombosis. Pharmacokinetic properties of MRS2500 were defined for dose selection. Platelet aggregation and renal or tail bleeding times (BT) were measured to put antithrombotic effects into perspective. P2Y1 deletion significantly reduced (p < 0.001) venous thrombus weight by 74 % in 3.5 % FeCl(3) injury compared to P2Y1(+/+) littermates. MRS2500 (2 mg/kg, i.v.) significantly decreased (p < 0.001) thrombus weight 64 % in C57BL/6 mice. In the more severe 5 % FeCl(3)-induced injury model, thrombus weight significantly (p < 0.001) decreased 68 % in P2Y1(-/-) mice versus P2Y1(+/+) mice, and MRS2500 (2 mg/kg) was also beneficial (54 % decrease, p < 0.01). Renal BT doubled in P2Y1(-/-) versus P2Y1(+/+) mice, and increased threefold with MRS2500 compared to vehicle. Tail BT was markedly prolonged in P2Y1(-/-) mice (7.9X) and in C57BL/6 mice given MRS2500. The current study demonstrates that P2Y1 deletion or antagonism significantly reduced venous thrombosis in mice, suggesting that P2Y1 receptors play a role in the pathogenesis of venous thrombosis, at least in this species. However as with many antithrombotic agents the benefit comes at the potential price of an increase in provoked bleeding times.

• Authors: J Eileen Bird, Xinkang Wang, Patricia L Smith, Frank Barbera, Christine Huang, William A Schumacher
• Journal: Journal of thrombosis and thrombolysis (J Thromb Thrombolysis) Vol. 34 Issue 2 Pg. 199-207 (Aug 2012) ISSN: 1573-742X [Electronic] Netherlands
• PMID: 22588534 (Publication Type: Journal Article)

Chemical References

• 2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate
• Chlorides
• Deoxyadenine Nucleotides
• Ferric Compounds
• Noxae
• Platelet Aggregation Inhibitors
• Receptors, Purinergic P2Y1
• ferric chloride

Topics

• Animals
• Blood Platelets (metabolism)
• Chlorides (adverse effects, pharmacology)
• Deoxyadenine Nucleotides (pharmacology)
• Ferric Compounds (adverse effects, pharmacology)
• Gene Deletion
• Mice
• Mice, Knockout
• Noxae (adverse effects, pharmacology)
• Platelet Aggregation (drug effects, genetics)
• Platelet Aggregation Inhibitors (pharmacology)
• Receptors, Purinergic P2Y1 (genetics, metabolism)
• Venae Cavae
• Venous Thrombosis (chemically induced, drug therapy, genetics)