Melandri et al Table 1 Reasons for preferring thrombolysis (TBL) to primary angioplasty (P-PCI) TBL is immediately available everywhere The time-delay to perform P-PCI exceeds 90 minutes in a large fraction of patients P-PCI does not reduce mortality consistently, particularly vs pre- hospital TBL TBL can be improved by new adjunctive treatments (clopidogrel and enoxaparin) Currently, only 25% of American hospitals provide primary angioplasty and the majority of patients must be transferred to receive the mechanical intervention.5 As a consequence, only approximately 4% of transferred patients receive P-PCI within 90 minutes from ﬁrst medical contact.6 Attempts to improve this situation so far have required “huge” efforts, with a negligible mortality yield.7 An increase in the number of catheterization laboratories has been pro- posed to cope with these shortcomings. However, such a proliferation dilutes the number of patients treated in each catheteriztion laboratory, endangering quality,8 not to say the costs of increasing population-based coronary angiograms in patients without myocardial infarction. Further difﬁcul- ties arise during weekends and at night,5 again jeopardizing quality. Pre-hospital thrombolytic therapy On the other hand, TBL can be delivered everywhere and particularly when used in the pre-hospital setting is extremely competitive with P-PCI, as demonstrated by the CAPTIM study.9 In the recent, important MINAP registry the pre- hospital use of TBL (nearly always TNKase) ranked among the strongest independent predictors of in-hospital survival in the United Kingdom.10 The American College of Cardiology/American Heart Association guidelines encourage the recording of the 12-lead electrocardiogram “on-scene” and performing pre-hospital TBL within 30 minutes.1 Indeed, the STEMI picture is dominated by time, with the small incremental beneﬁt of P-PCI rapidly vanishing after 90 minutes after ﬁrst medical contact, particularly among young patients with large myocardial infarction, for whom the equivalence of TBL and P-PCI may already be achieved by a delay of only 45 minutes.11 Since time is so important, it is believed that most beneﬁt may be achieved by treating as many patients as possible in the ﬁrst 3 hours from the onset of symptoms, regardless of whether TBL or P-PCI is used.12 It is now estimated that an efﬁcient network can offer pre-hospital 250 TBL in the ﬁrst 3 hours in approximately 50% to 60% of STEMI patients.13 TBL can be further improved by reducing the re-infarction rate by adjunctive use of clopidogrel14 and enoxaparin15 as soon as possible, ideally pre-hospital. Pharmacologic properties of TNKase in acute myocardial infarction TNKase consists of the alteplase molecule (with the excep- tion of three point mutations) and has a molecular weight of 65,000 kD. Thr103 substitution by Asn and the mutation of the sequence Lys296 – His-Arg-Arg to Ala-Ala-Ala-Ala prolong the half-life and increase the resistance to plasminogen activator inhibitor-1 (PAI-1). Additional substitution of Asn117 by Gln results in an 8-fold decrease in clearance and in a 200-fold increase in resistance to PAI-1. Compared with other molecules used in clinical prac- tice, TNKase has the highest degree of ﬁbrin speciﬁcity and binding. Fibrin speciﬁcity, in turn, implies a reduced propensity for causing major non-cerebral bleeds, because lytic activity is restricted to plasmin on the ﬁbrin surface, thus avoiding the breakdown of ﬁbrinogen, factor V, factor VIII and α2-antiplasmin.16 The TNKase conformational change reduces its elimination and prolongs its plasma half- life (α-half-life 11–20 minutes, β-half-life 41–138 minutes). Nitrates do not appear to affect TNKase levels, as opposed to what happens with alteplase levels.17 Moreover, the inhibition by PAI-1 is reduced 80 times compared with alteplase. The above properties are interesting in the treatment of patients with STEMI, allowing single bolus infusion and pre- venting drug inactivation at the site of platelet-rich coronary thrombosis. In addition, TNKase has more intense anti- platelet properties both in vitro and in vivo compared with those of alteplase.18 In experimental models the thrombolytic potency of TNKase is 3-fold higher than that of alteplase.19 Clinical use of TNKase in acute myocardial infarction The ﬁrst experience of dose-testing TNKase in STEMI began in the TIMI-10A trial, showing a dose-dependent increase in TIMI-3 ﬂow rates in the 5 to 50 mg dose range (p = 0.032).20 In the dose-escalating pilot TIMI 10B patency trial, involving 886 patients 18 to 80 years old, bolus TNKase injection achieved coronary TIMI grade-3 ﬂow rates of 55%, 63% and 66% at 90 minutes after 30, 40 and 50 mg bolus Vascular Health and Risk Management 2009:5