Requirement of heparin for arterial and venous thrombolysis with recombinant tissue-type plasminogen activator

Rapold, HJ; Lu, Hua-Rong; Wu, ZM; Nijs, H; Collen, D.

doi:10.1182/blood.v77.5.1020.bloodjournal7751020

Cited by 12 publications

(25 citation statements)

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“…Because of the small size of this study, little significance can be attached to the finding of rethrombosis in one of the t‐PA animals. However, this event is consistent with previous studies in t‐PA‐treated dogs [23], with clinical studies in which a 25–30% early coronary reocclusion incidence was reported with t‐PA [24], and with reports that the efficacy of percutaneous coronary intervention over t‐PA was related to a higher reocclusion rate with t‐PA [25]. By contrast, coronary reocclusion rates of only 0–5% were reported with proUK [2,26,27], and markers of thrombin generation in plasma were not induced by proUK [26], in contrast to t‐PA [28].…”

Section: Discussionsupporting

confidence: 94%

Thrombolysis vs. bleeding from hemostatic sites by a prourokinase mutant compared with tissue plasminogen activator

Gurewich

Pannell

Simmons-Byrd

et al. 2006

Journal of Thrombosis and Haemostasis

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Summary. Background: A single site mutant (M5) of prourokinase (proUK) was developed to make proUK less vulnerable to spontaneous activation in plasma. This was a problem that seriously compromised proUK in clinical trials, as it precluded proUK-mediated fibrinolysis at therapeutic concentrations. Methods and results: After completing dosefinding studies, 12 anesthetized dogs with femoral artery thrombosis were given either M5 (2.0 mg kg ) by i.v. infusion over 60 min (20% administered as a bolus). Two pairs of standardized injuries were inflicted at which hemostasis was completed prior to drug administration. Blood loss was quantified by measuring the hemoglobin in blood absorbed from these sites. Thrombolysis was evaluated at 90 min and was comparably effective by both activators. Rethrombosis developed in one t-PA dog. The principal difference found was that blood loss was 10-fold higher with t-PA (mean 40 mL) than with M5 (mean 4 mL) (P ¼ 0.026) and occurred at more multiple sites (mean 2.7 vs. 1.2). This effect was postulated to be related to differences in the mechanism of plasminogen activation by t-PA and M5 in which the latter is promoted by degraded rather than intact (hemostatic) fibrin. In addition, two-chain M5 was efficiently inactivated by plasma C1 inactivator, an exceptional property which helped contain its non-specific proteolytic effect. Conclusions: Intravascular thrombolysis by M5 was accompanied by significantly less bleeding from hemostatic sites than by t-PA. This was attributed to the proUK paradigm of fibrinolysis being retained at therapeutic concentrations by the mutation.

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Section: Discussionsupporting

confidence: 94%

Thrombolysis vs. bleeding from hemostatic sites by a prourokinase mutant compared with tissue plasminogen activator

Gurewich

Pannell

Simmons-Byrd

et al. 2006

Journal of Thrombosis and Haemostasis

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“…The pharmacologic actions of heparin include 1) facilitation of the effect of antithrombin by inhibiting thrombin activity 11 ; 2) attenuation of platelet aggregation"; 3) inhibition of conversion of fibrinogen to fibrin 12 ; 4)facilitation of release of plasminogen activator 13 ; 5) potentiation of thrombolysis by combination with thrombolytic agents 1415 ; and 6) increase in the blood level of tissue factor pathway inhibitor (TFP1), an exogenous inhibitor of coagulation derived from vascular endothelial cells. 16 Although heparin is not considered to have a direct thrombolytic action, Susawa 14 and Rapold et al 15 reported the usefulness of heparin in thrombolysis. In addition, Yamamoto et al 17 reported that the intravenous injection of heparin 5,000 U could support recanalization of the coronary arteries in an early phase, within 2 hr after the onset of myocardial infarction.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Bolus Infusion of Heparin for Circulatory Insufficiency after Finger Replantation

Noguchi¹,

Matsusaki²,

Yamamoto³

1999

J reconstr Microsurg

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When heparin 2,500 to 5,000 U was administered by intravenous bolus infusion to 13 fingers that had developed arterial thrombosis after replantation, complete survival was achieved in seven of 13 fingers. If fingers demonstrating partial necrosis were included, survival was obtained in 11 of 13 fingers. In nine fingers in which survival was obtained and follow-up observation was possible, sensory recovery was favorable, and there was no limitation in the use of the affected fingers, although mild atrophy of the pulp and nail deformity were noted in fingers with partial necrosis. Using a model of arterial thrombosis created in the carotid arteries of Sprague-Dawley rats, the authors investigated how the intravenous bolus infusion of heparin affected thrombolysis. During the early phase of arterial thrombosis when the thrombus is fragile, the intravenous bolus of heparin affected the balance between coagulation and fibrinolysis, facilitating the thrombolytic process, and increasing the rate of recanalization of the occluded arteries. Since an intravenous bolus injection of heparin is an easy procedure, without the risk of any severe side effects, this method should be considered in such cases of arterial thrombosis, with attention paid to the general condition of the patient.

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“…The aim of our study was to evaluate the thrombolytic and haemorrhagic effects of a bolus of rt-PA and K2tu-PA, a chimeric tissue-type and urokinase-type plasminogen activator with prolonged half life. We found that the two agents are equally effective in lysing pre-formed fibrin but (32,33). Such doses would not be used in humans because of the high risk of bleeding.…”

Section: Discussionmentioning

confidence: 89%

Thrombolytic and Haemorrhagic Effects of Bolus Doses of Tissue-Type Plasminogen Activator and a Hybrid Plasminogen Activator with Prolonged Plasma Half-Life (K2tu-PA: CGP 42935)

et al. 1993

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SummaryK2tu-PA is a hybrid plasminogen activator linking the kringle 2 domain of tissue-type plasminogen activator (t-PA) to the catalytic protease domain of single-chain urokinase-type plasminogen activator (scu-PA). K2tu-PA, as t-PA has high affinity for fibrin and is activated by fibrin but has a longer plasma half-life (over 30 min). The aim of this study was to compare the effects of bolus doses of recombinant t-PA (rt-PA) and K2tu-PA, on: 1) lysis of preformed thrombi (fibrinolysis), 2) accretion of new fibrin on pre-existing thrombi during fibrinolysis (thrombus growth), 3) thrombolysis as assessed by reduction of thrombus weight and 4) systemic plasma proteolysis and blood loss from a standard wound. A jugular vein thrombosis model and an ear bleeding model were adopted in rabbits. Saline produced 11 ± 2% fibrinolysis. rt-PA, 0.2 mg/kg, 0.4 mg and 0.8 mg/kg produced 35 ± 4%, 54 ± 4% and 78 ± 6% fibrinolysis, respectively. K2tu-PA, at the same doses, produced 39 ± 5%, 57 ± 6% and 83 ± 6% fibrinolysis, respectively. Thus, no differences in the fibrinolytic activity of rt-PA and K2tu-PA were observed. Injection of saline was followed by an accretion of 56.4 ± 5.9 μg of radioactive new fibrin on the thrombi. The injection of the three increasing doses of rt-PA was followed by an accretion of 54.9 ± 5.3 μg, 49.1 ± 6.1 μg and 47.2 ± 4.8 μg. The injection of three increasing doses of K2tu-PA was followed by an accretion of 38.1 ± 3.4 μg, 29.6 ± 2.5 μg and 17.1 ± 3.4 μg. At each of the three doses, K2tu-PA was more effective than rt-PA in reducing the accretion of new fibrin on the thrombi (p <0.01) and, as a consequence, in reducing thrombus weight (p <0.01). The two lower doses of rt-PA and K2tu-PA did not produce systemic proteolysis and bleeding. The highest dose of K2tu-PA produced a statistically significant more intense systemic proteolysis and bleeding than the highest dose of rt-PA.This study demonstrates that bolus doses of K2tu-PA and rt-PA produce a similar degree of fibrinolysis. Due to its longer half-life K2tu-PA is more efficient than rt-PA in inhibiting accretion of new fibrin on the thrombi during thrombolysis so that the thrombus size is more efficiently reduced. As a consequence the concomitant use of heparin might not be necessary. The potential increased risk of bleeding with bolus of high doses of K2tu-PA has to be seen in view of the advantage of avoiding the concomitant use of heparin.

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Requirement of heparin for arterial and venous thrombolysis with recombinant tissue-type plasminogen activator

Cited by 12 publications

References 0 publications

Thrombolysis vs. bleeding from hemostatic sites by a prourokinase mutant compared with tissue plasminogen activator

Thrombolysis vs. bleeding from hemostatic sites by a prourokinase mutant compared with tissue plasminogen activator

Intravenous Bolus Infusion of Heparin for Circulatory Insufficiency after Finger Replantation

Thrombolytic and Haemorrhagic Effects of Bolus Doses of Tissue-Type Plasminogen Activator and a Hybrid Plasminogen Activator with Prolonged Plasma Half-Life (K2tu-PA: CGP 42935)

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