Albumin Therapy Augments the Effect of Thrombolysis on Local Vascular Dynamics in a Rat Model of Arteriolar Thrombosis

Abstract

Background and Purpose-Results of our recent pilot clinical trial suggest that the efficacy of thrombolytic therapy in acute ischemic stroke may be enhanced by the coadministration of high-dose albumin. Here, we explored the microvascular hemodynamic effects of this combined therapy in a laboratory model of cortical arteriolar thrombosis. Methods-We studied the cortical microcirculation of physiologically monitored rats in vivo by two-photon laser-scanning microscopy after plasma-labeling with fluorescein-dextran. We induced focal thrombosis in 30-to 50-m cortical arterioles by laser irradiation and measured arteriolar flow velocity by repeated line-scanning. At 30 minutes post-thrombosis, we treated animals with the thrombolytic agent, reteplase, which was coadministered with either human albumin, 2 g/kg, or with saline control. Results-Baseline arteriolar flow velocity averaged 3.8Ϯ0.7 mm/s, was immediately reduced by thrombosis to 22% to 25% of control values, and remained unchanged before treatment. Subthrombolytic doses of reteplase combined with saline led to a median increase in flow velocity to 37% of control distal to the thrombus (Pϭnonsignificant versus pretreatment). By contrast, reteplase combined with albumin therapy resulted in a prompt, highly significant increase of median flow velocity to 58% of control levels (Pϭ0.013 versus reteplaseϩsaline), which remained significantly higher than the reteplaseϩsaline group at multiple time-points over the subsequent hour. Conclusions-The

Serum Albumin in Ischemic Stroke Patients: The Higher the Better

“…Albumin reverses stagnation and thrombosis in the postcapillary microcirculation during the recanalization phase [2]. In addition to the above mechanisms, albumin is shown to have a prothrombolytic effect explained by its capability to maintain vascular patency after successful thrombolysis or by preventing postthrombolytic reocclusion [10, 11]. …”

Multifunctional Actions of Approved and Candidate Stroke Drugs

“…92 Recently, high-dose human albumin (doses between 0.63 g/kg and 2.5 g/kg) was studied in animal models of focal cerebral ischemia. [93][94][95][96] Albumin reduced infarct size and improved functional recovery after permanent and temporary cerebral ischemia. 94,97 Preclinical studies included a dose-response relationship evaluation and a time window investigation (up to 4 hours).…”

In vivo real-time two-photon microscopic imaging of platelet aggregation induced by selective laser irradiation to the endothelium created in the beta-actin-green fluorescent protein transgenic mice

“…Using TPLSM acquires ability to observe much deeper tissue for the longer time course compared to the confocal microscopy because of TPLSM characteristic. Although there have been recent reports of thrombus research using TPLSM [7,[9][10][11], detailed thrombus formation involving vessel wall components remains obscure. Even though recent studies have developed some excellent thrombus visualizations using single-photon microscopy and other visualization systems, the advantages of TPLSM for thrombus investigation have not previously been reported [12,13].…”

“…10µm 10µm Previous laser-induced thrombosis models include induction by high-power laser irradiation of blood vessel components, and thrombosis begins with the onset of extravasation [7,10,15]. Analysis of a thrombus due to extravasation, which can induce swelling or rupture of the vessel wall at the site of irradiation and may also partly involve the other side of the vessel wall, could be inaccurate.…”