Monocyte chemotactic protein-1 as a potential biomarker for early anti-thrombotic therapy after ischemic stroke.

Inflammation following ischemic brain injury is correlated with adverse outcome. Preclinical studies indicate that treatment with acetylsalicylic acid + extended-release dipyridamole (ASA + ER-DP) has anti-inflammatory and thereby neuroprotective effects by inhibition of monocyte chemotactic protein-1 (MCP-1) expression. We hypothesized that early treatment with ASA + ER-DP will reduce levels of MCP-1 also in patients with ischemic stroke. The EARLY trial randomized patients with ischemic stroke or TIA to either ASA + ER-DP treatment or ASA monotherapy within 24 h following the event. After 7 days, all patients were treated for up to 90 days with ASA + ER-DP. MCP-1 was determined from blood samples taken from 425 patients on admission and day 8. The change in MCP-1 from admission to day 8 did not differ between patients treated with ASA + ER-DP and ASA monotherapy (p > 0.05). Comparisons within MCP-1 baseline quartiles indicated that patients in the highest quartile (>217-973 pg/mL) showed improved outcome at 90 days if treated with ASA + ER-DP in comparison to treatment with ASA alone (p = 0.004). Our data does not provide any evidence that treatment with ASA + ER-DP lowers MCP-1 in acute stroke patients. However, MCP-1 may be a useful biomarker for deciding on early stroke therapy, as patients with high MCP-1 at baseline appear to benefit from early treatment with ASA + ER-DP.

Dipyridamole in antithrombotic treatment.

The antithrombotic activity of dipyridamole was initially discovered in an in vivo experiment about half a century ago. At that time science had not appreciated the complexity of the regulation of local thrombus formation. Inhibition of platelets has been the main focus for the prevention of arterial thrombus formation. Unfortunately, established in vitro test systems have to take away several important components of the hemostatic system. Rather than directly inhibiting platelet aggregation, dipyridamole amplifies endogenous antithrombotic systems and modulates or downregulates prothrombotic processes. While for many years the main focus had been on preventing acute thrombus formation in the case of a rupture of an atherosclerotic plaque in large coronary arteries, it now has been appreciated that perfusion of tissue and patency of small vessels and capillaries is equally important for preventing further damage to the tissue. Here dipyridamole was experimentally shown to improve perfusion and function in chronic hypoperfused tissue unrelated to its vasodilatory properties. Recently, several clinical trials have shown the benefit of dipyridamole when given in a formulation that assures a sufficient plasma concentration. Its potential to scavenge particularly peroxy radicals, its direct reduction of innate inflammation, and a chronic elevation of interstitial adenosine seems to be of more importance for the prevention of vascular and tissue damage than its adenosine- and prostacyclin-mediated antithrombotic effect. In its extended-release preparation with the tartaric acid nucleus, not only does it not seem to add significantly to the risk of bleeding, but seems to hold potential for protecting tissue from oxidative and metabolic stress.

Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin.

Dabigatran is a highly selective, reversible, and potent thrombin inhibitor and is orally available as the prodrug, dabigatran etexilate. It has shown antithrombotic efficacy in animal models of thrombosis, with a rapid onset of action and predictable pharmacodynamic response. Peak plasma concentrations of dabigatran occur 1 to 2 hours after ingestion of the prodrug. The terminal half-life of dabigatran is 12 to 14 hours in elderly volunteers. Dabigatran is not metabolized by cytochrome P450 isoenzymes and does not interact with food. Dabigatran has a low potential for drug-drug interactions and is predominantly renally excreted. Dabigatran etexilate as chronic therapy effectively prevents the recurrence of venous thromboembolism and cardioembolic stroke. For the first time, it has been demonstrated clinically that there may be an effective and safe alternative to warfarin.

Accumulation of radiolabelled platelets and fibrin on the carotid artery of rabbits after angioplasty: effects of heparin and dipyridamole.

We investigated the dynamic accumulation of platelets and fibrin after balloon injury of the carotid arteries in rabbits in vivo. In addition, effects of heparin and dipyridamole treatment were also tested. Autologous (99m)Tc-labelled platelet and (123)I-labelled fibrin accumulation was measured at one minute intervals for 4 hours following balloon injury of the carotid artery. Platelet accumulation occurred rapidly, with an approximately 125% increase occurring within 30 min after injury. There was no further activity for up to 4 hours. This accumulation could be inhibited with an intravenous infusion of PGI2 (500 ng/kg/hr). Fibrin accumulation occurred slowly and continuously over the 4 hour measurement period. Injection of an anti-fibrin antibody inhibited fibrin accumulation. Heparin (25 U/kg/hr for 4 hrs) administration resulted in a significant 82 +/- 19% and 68 +/- 13% reduction in platelet and fibrin accumulation, respectively. This dose of heparin was associated with a 2-fold prolongation of the aPTT. Dipyridamole (0.45 mg/kg/hr for 4 hrs) resulted in a 46 +/- 12% and 70 +/- 25% reduction of platelet and fibrin accumulation, respectively. Thus, we demonstrated that the dynamics of platelet and fibrin accumulation following balloon injury in rabbits are very different. The vessel wall continues to be thrombogenic for fibrin up to 4 hours after injury even though platelet accumulation has ceased after one hour. We conclude that the local thrombotic events following balloon injury are complex and that not only platelets but also fibrin is important in regulating responses to injury.