Adenine nucleotide metabolism in human blood – important roles for leukocytes and erythrocytes

Abstract

Summary. Adenosine diphosphate (ADP) released into blood induces platelet aggregation and contributes to hemostasis and thrombosis. Released ATP can also induce platelet aggregation and there is evidence that blood leukocytes and also erythrocytes play important roles in this. Rapid metabolism of ADP and ATP by endothelial cells is important in protecting platelets from their effects. Here we have performed a systematic investigation of adenine nucleotide metabolism in human blood and the involvement of blood cells. Conversion of ATP to ADP in blood was due almost exclusively to the presence of leukocytes; plasma, platelets and erythrocytes made little or no contribution. Mononuclear leukocytes (MNLs) and polymorphonuclear leukocytes (PMNLs) were equally effective. Conversion of ADP to AMP was also promoted by leukocytes, with no involvement of platelets or erythrocytes. Some ADP was also converted to ATP in blood, apparently via an enzyme present in plasma, but ATP was then rapidly removed by the leukocytes. Conversion of AMP to adenosine occurred via a plasma enzyme with little or no contribution from any cellular element. As expected, in blood the adenosine produced was removed very rapidly by erythrocytes and then converted to inosine and then hypoxanthine. In the absence of erythrocytes plasma supported only a slow conversion of adenosine to inosine and hypoxanthine, which was not influenced by platelets or leukocytes. This study has demonstrated that leukocytes and erythrocytes play a major role in adenine nucleotide metabolism in blood and that these cells, as well as endothelial cells, may be important determinants of the effects of ATP and ADP on platelets.

Pharmacokinetic Study of the Structural Components of Adenosine Diphosphate-Encapsulated Liposomes Coated with Fibrinogenγ-Chain Dodecapeptide as a Synthetic Platelet Substitute

“…1), indicating that the H12-(ADP)-liposomes circulate in the bloodstream without any leakage of ADP. In addition, we also realized that the nonliposomal ADP was immediately eliminated from blood (unpublished data), because ADP released into blood was metabolized by leukocytes, erythrocytes, and endothelial cells (Marcus et al, 2003;Heptinstall et al, 2005). This means that ADP encapsulated in the vesicle has advantages that are not only specific delivery ADP to injury site but also improvement of the blood retention of ADP.…”

Alterations of Adenine Nucleotide Metabolism and Function of Blood Platelets in Patients With Diabetes

“…Large pools of ATP/ADP are sequestered in secretory granules during platelet formation, and the release of ADP from activated platelets is one of the important signals stimulating their aggregation. Furthermore, ATP coreleased with ADP from dense granules may increase platelet aggregation in whole blood because of its cleavage to ADP by ecto-ATPases present on the surface of leukocytes (11,12). In addition, platelet exocytosis and aggregation require metabolic energy in the form of ATP (13).…”

Myocardial necrosis in patients with thrombotic thrombocytopenic purpura: pathophysiology and rationale for specific therapy

“…ATP can be converted into ADP in the presence of leukocytes (35). ADP is a potent stimulus for platelet aggregation.…”

“…However, not all studies have reported success with ASA plus dipyridamole (51) and, furthermore, these studies have not examined the effect of treatment on troponin levels. From a theoretical standpoint, dipyridamole has several advantages: it exerts antiplatelet activity by inhibiting platelet phosphodiesterase and also has a vasodilating effect by inhibiting the uptake of adenosine into red cells, endothelial cells and platelets by blocking the equilibrative nucleoside transporters (35). Subsequent binding of adenosine to the A2 adenosine receptor leads to elevated intracellular levels of cAMP, which results in anti-platelet activity and vasodilation.…”