Recombinant human, active site-blocked factor VIIa reduces infarct size and no-reflow phenomenon in rabbits

Abstract

Oxygen free radicals induce de novo synthesis of tissue factor (TF), the initiator of the extrinsic pathway of coagulation, within the coronary vasculature during postischemic reperfusion. In the present study we wanted to assess whether TF expression might cause myocardial injury during postischemic reperfusion. Anesthetized rabbits underwent 30 min of coronary occlusion followed by 5.5 h of reperfusion. At reperfusion the animals received 1) saline (n = 8), 2) human recombinant, active site-blocked activated factor VII (FVIIai, 1 mg/kg, n = 8), or 3) human recombinant activated FVII (FVIIa, 1 mg/kg, n = 8). FVIIai binds to TF as native FVII, but with the active site blocked it inhibits TF procoagulant activity. The area at risk of infarction (AR), the infarct size (IS), and the no-reflow area (NR) were determined at the end of the experiment. FVIIai resulted in a significant reduction in IS and NR with respect to control animals (28.1 +/- 11.3 and 11.1 +/- 6.1% of AR vs. 59.8 +/- 12.8 and 24.4 +/- 2.7% of AR, respectively, P < 0.01), whereas FVIIa resulted in a significant increase in IS and NR to 80.1 +/- 13. 1 and 61.9 +/- 13.8% of AR, respectively (P < 0.01). In conclusion, TF-mediated activation of the extrinsic coagulation pathway makes an important contribution to myocardial injury during postischemic reperfusion.

Is microvascular protection by cariporide and ischemic preconditioning causally linked to myocardial salvage?

“…On the other hand, if microvascular perfusion defects were the limiting factor for cardiomyocyte salvage during reperfusion in the rabbit, and if small border zones of the no-reflow area could be salvaged by diffusion of oxygen from the surrounding perfused tissue, one might expect exactly the observed relationship between anatomic no reflow and IS with a positive ordinate intercept and a slope of Ͻ1: small infarcts would be accompanied by proportionally larger noreflow zones, and as the diffusional component becomes negligible with lower surface-to-volume ratios of larger zones of microvascular obstruction, larger infarcts would be associated with proportionally smaller no-reflow zones. This causal chain between microvascular and myocardial damage would support studies that showed simultaneous reduction of anatomic no reflow and necrosis by interventions initiated at reflow (10) and suggest a contribution of no reflow to myocardial damage (9). However, a recent study in the canine that provided evidence for a quantitatively relevant transition of reversible cardiomyocyte injury to irreversible cardiomyocyte cell death during reperfusion emphasized that cardiomyocytes from no-reflow zones had already been dead at the time of initiation of reperfusion (28).…”

Coronary no-reflow is caused by shedding of active tissue factor from dissected atherosclerotic plaque

“…34 In more recent experimental work, recombinant human, active site-blocked factor VIIa reduced infarct size and NR in rabbits. 35,36 These observations support the view that clinical studies should be undertaken to investigate whether anti-TF agents are useful in the treatment of periinterventional slow-flow and NR.…”

Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy

“…6 Importantly, inhibition of either TF or thrombin significantly reduced the infarct size in rabbit models of cardiac I/R injury. 6,7 A recent study showed that the fibrin degradation fragment E1 contributes to inflammation after myocardial infarction by binding to vascular endothelial cadherin at cell-cell junctions in the endothelium and facilitating the recruitment of neutrophils into the myocardium. 8 Members of the protease-activated receptor (PAR) family of G-protein-coupled receptors are activated by proteolytic cleavage.…”