Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. The TAMI Study Group.

Abstract

Desire Collen, MD, PhD, and the TAMI Study Group Coagulation analysis was performed on blood samples from 386 patients with acute myocardial infarction drawn before, during, and after a continuous intravenous infusion of 150 mg recombinant tissue-type plasminogen activator (rt-PA) (Activase®). Plasma rt-PA rose to peak levels of 2.1±3.1 ,ug/ml (mean± SD). Fibrinogen levels measured by coagulation rate and by sulfite precipitation decreased from baseline levels of3.0±0.9 and 3.2+1.0 g/l, respectively, to nadir levels of 1.4±0.75 and 1.8±t0.92 g/l, respectively, and.were associated with peak levels in serum of fibrinogen-degradation products (FDP) of 230±470 ,g/ml. Forty percent of patients experienced a nadir functional-fibrinogen level of less than 1.0 g/l, whereas 20%o fell below 0.5 g/l. Nadir fibrinogen levels did not correlate with patency of the infarct-related coronary artery at 90 minutes or with risk of coronary vessel reocclusion within 7-10 days. However, the risk of coronary artery reocclusion was inversely related to the baseline functional fibrinogen level (p=0.0008), with the magnitude of its drop to nadir level (p=0.0003) as well as to peak levels of FDP (p=0.038). Quantitative blood loss correlated with all markers for systemic fibrinogenolysis including nadir fibrinogen level (r= -0.20,p=0.0011), percent decrease of fibrinogen (r=0.22,p=0.001), and peak FDP levels (r=0.14, p =0.020). Both patients who experienced intracranial hemorrhage presented with high baseline fibrinogen levels and experienced extensive degradation of coagulable fibrinogen. Overall, patients at greatest risk of systemic fibrinogenolysis tended to be relatively older women with lower body weight. Peak plasma levels of t-PA antigen were weakly correlated with nadir-fibrinogen levels (r=0.11,p=0.041) and peak FDP levels (r=0.12,p=0.020), and also tended to be higher in older women of lower body weight. Plasma levels of t-PA antigen were higher in nonoperated patients experiencing "major" bleeding (3.4 versus 2.2 ,g/ml, p=0.002). These results indicate that changes in coagulation parameters are highly variable in the setting of thrombolytic treatment with t-PA of acute myocardial infarction, precluding their use for predictive monitoring of therapy in individual patients. Nonetheless, the overall pattern of pharmacodynamic behavior of rt-PA within a given population and its correlation with selected major clinical outcomes, particularly with risk of reocclusion and bleeding, will be most useful for the design of alternative administration schemes.

Distinct dose-dependent effects of plasmin and TPA on coagulation and hemorrhage

“…In patients, this effect is indirectly reflected by the correlation of blood TPA concentration with bleeding risk. 30 Once the TPA infusion is terminated, the agent is rapidly cleared 31 and at these dosages, newly induced, postinfusion trauma sites do not bleed excessively (Figure 4). The effects of plasmin can now be explained as follows.…”

Alpha 2-antiplasmin supplementation inhibits tissue plasminogen activator-induced fibrinogenolysis and bleeding with little effect on thrombolysis.

“…Thus, we have demonstrated that the degradation products of crosslinked fibrin produced during the thrombolytic process can potentiate t-PA-induced plasminogen activation through their capacity to bind plasminogen and t-PA (7). While the major cause of t-PA-induced bleeding is likely to be lysis of fibrin within the hemostatic plug (8), the induction of the systemic lytic state may also be a contributing factor (3,4). Therefore, maneuvers that limit the systemic lytic state without impairing the thrombolytic effect of t-PA could be of potential clinical value.…”

“…Despite its affinity for fibrin, tissue-type plasminogen activator (t-PA) ' administration causes a systemic lytic state with fibrinogen proteolysis (1)(2)(3)(4). Although kinetic models predicted that high doses of t-PA would have this effect (5,6), recent studies suggest an additional mechanism through which even low doses of t-PA can produce fibrinogen breakdown.…”

Repeat Operation for Pseudoaneurysm of Left Ventricular Outflow in a Patient with Concomitant Takayasu’s Arteritis and Marfan Syndrome

“…Shiono et al 2) reported that the potential risk for anastomotic dehiscence is much higher in patients with Takayasu's arteritis than in those with dystrophic aneurysms of Marfan syndrome, even during the inactive phase of inflammation. Suzuki et al 7) emphasized the importance of reinforcing sutures around the aortic annulus and Carrel's button technique for reconstructing the coronary artery. They also recommended postoperative steroid therapy for active inflammation in patients with Takayasu's arteritis who have undergone several surgical procedures.…”

“…The translocated Bentall procedure might provide an alternative to composite graft detachment, 3,6,7) and might be helpful because it allows circumferential fixation outside the aortic wall and double fixation at the aortic annulus, and prosthetic valves do not apply direct pressure to the aortic annulus. Ando et al 6) noted that the pressure of valve function directly affects the rigid sewing ring in patients with AVR, which causes a higher detachment rate.…”