Analysis of coagulation and fibrinolysis during intravenous infusion of recombinant human tissue-type plasminogen activator in patients with acute myocardial infarction.

Collen, D.; Bounameaux, H; Cock, F De; Lijnen, H. Roger; Verstraete, Marc

doi:10.1161/01.cir.73.3.511

Cited by 155 publications

(51 citation statements)

References 27 publications

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“…Their infusion at these doses in patients is unavoidably associated with moderate (with t-PA and scu-PA) to extensive (with urokinase) systemic activation of the fibrinolytic system and fibrinogen breakdown.6 19 Provided the present observations can be extrapolated to man, the combined use of synergic thrombolytic agents may allow significant reduction of total doses, with resultant elimination of systemic fibrinolytic activation and its undesirable breakdown of the hemostatic system.…”

Section: Discussionmentioning

confidence: 77%

Synergism of thrombolytic agents in vivo.

Collen¹,

Stassen²,

Stump³

et al. 1986

Circulation

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119

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The existence of significant synergism between tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA), and between t-PA and urokinase in thrombolysis in vivo is described. In a quantitative preparation of thrombolysis, consisting of rabbits in which a blood clot was induced in the jugular vein with`251-labeled fibrin, intravenous infusion over 4 hr of t-PA, scu-PA, or urokinase in amounts of 0.5, 1.0, or 2.0 mg/kg body weight resulted in significant thrombolysis (30% to 60%). The simultaneous infusion of t-PA and scu-PA or of t-PA and urokinase had a significantly greater (p < .001) thrombolytic effect than could be anticipated on the basis of the added effects of each agents alone. However, no synergism was observed between scu-PA and urokinase. The observed a2-antiplasmin consumption and fibrinogen breakdown after urokinase at higher doses did not occur with the equivalent thrombolytic combinations of t-PA and urokinase. The combined use of synergic thrombolytic agents in patients may permit a significant reduction in total administered doses, probably with elimination of the systemic activation of the fibrinolytic system and the concomitant fibrinogen breakdown that is unavoidable with the currently used thrombolytic doses of each agent. Circulation 74, No. 4, 838-842, 1986. ONE APPROACH to the treatment of thromboembolic disease is the use of pharmacologic agents that activate the fibrinolytic system in blood. During activation of this system, the inactive zymogen plasminogen is converted to the active enzyme plasmin, a proteolytic enzyme with relatively low fibrin specificity. When plasmin circulates freely in the blood, it degrades a number of proteins, including fibrinogen and the blood coagulation factors V and VIII. Plasma does, however, contain a fast-acting plasmin inhibitor, a2-antiplasmin, which reacts extremely rapidly with free plasmin but only slowly with plasmin generated on the fibrin surface. Clot-specific fibrinolysis therefore requires generation of plasmin at the fibrin surface, out of reach of a2-antiplasmin.'One promising approach to obtaining specific thrombolysis is the use of thrombolytic agents, the action of which is stimulated by the presence of fibrin. Indeed, streptokinase and urokinase, which have no

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Section: Discussionmentioning

confidence: 77%

Synergism of thrombolytic agents in vivo.

Collen¹,

Stassen²,

Stump³

et al. 1986

Circulation

Self Cite

119

View full text Add to dashboard Cite

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“…TPA caused bleeding regardless of the plasma concentration of antiplasmin, fibrinogen, or factor VIII (Figure 6), consistent with prior observations that show minimal effect of TPA on coagulation 23 and no predictive value of laboratory coagulation assays for a bleeding event caused by TPA. 2,[24][25][26] By contrast, plasmin caused no excessive bleeding when fibrinogen and factor VIII were present, but induced excessive bleeding when the factors were absent (below the limit of quantification). Thus, for the first time, a clear profile of plasma coagulation assays is linked to protection from bleeding on administration of a thrombolytic agent, albeit only with plasmin.…”

Section: Discussionmentioning

confidence: 97%

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

Stewart

Kong

Novokhatny

et al. 2003

Blood

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All thrombolytic agents in current clinical usage are plasminogen activators. Although effective, plasminogen activators uniformly increase the risk of bleeding complications, especially intracranial hemorrhage, and no laboratory test is applicable to avoid such bleeding. We report results of a randomized, blinded, dose-ranging comparison of tissue-type plasminogen activator (TPA) with a directacting thrombolytic agent, plasmin, in an animal model of fibrinolytic hemorrhage. This study focuses on the role of plasma coagulation factors in hemostatic competence. Plasmin at 4-fold, 6-fold, and 8-fold the thrombolytic dose (1 mg/kg) induced a dose-dependent effect on coagulation, depleting antiplasmin activity completely, then degrading fibrinogen and factor VIII. However, even with complete consumption of antiplasmin and decreases in fibrinogen and factor VIII to 20% of initial activity, excessive bleeding did not occur. Bleeding occurred only at 8-fold the thrombolytic dose, on complete depletion of fibrinogen and factor VIII, manifest as prolonged primary bleeding, but with minimal effect on stable hemostatic sites. Although TPA had minimal effect on coagulation, hemostasis was disrupted in a dose-dependent manner, even at 25% of the thrombolytic dose (1 mg/kg), manifest as rebleeding from hemostatically stable ear puncture sites. Plasmin degrades plasma fibrinogen and factor VIII in a dose-dependent manner, but it does not disrupt hemostasis until clotting factors are completely depleted, at an 8-fold higher dose than is needed for thrombolysis. Plasmin has a 6-fold margin of safety, in contrast with TPA, which causes hemorrhage at thrombolytic dosages. (Blood.

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“…This property distinguishes rt-PA from streptokinase, urokinase, and APSAC, which require systemic fibrinolytic activation for thrombolytic efficacy.28 A significant relation between coronary patency and the extent of fibrinogen breakdown was observed in the European cooperative studies; however, these were carried out with two-chain rt-PA and the correlation was weak. 13 The role of fibrinogen degradation in the process of reocclusion appears to be more complex. Although no significant difference was observed between levels of nadir fibrinogen by either method, both the relative drop in functional fibrinogen and levels of peak fibrinogen-degradation products were significantly greater in patients with sustained coronary patency.…”

Section: Discussionmentioning

confidence: 99%

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.

et al. 1989

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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.

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Analysis of coagulation and fibrinolysis during intravenous infusion of recombinant human tissue-type plasminogen activator in patients with acute myocardial infarction.

Cited by 155 publications

References 27 publications

Synergism of thrombolytic agents in vivo.

Synergism of thrombolytic agents in vivo.

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

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.

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