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Thrombosis is a major contributor to disability and mortality worldwide and is estimated to be the cause of one in four deaths [1]. It is the pathology responsible for triggering acute myocardial infarction (AMI) and ischemic stroke, and is the primary cause of venous thromboembolism. The pathogenesis has been well-studied starting with Virchow more than 150 years ago [2], and its prevention by anti-thrombotic drugs has made much progress, culminating most recently in the approval of new oral anticoagulants which are specific inhibitors of thrombin or factor Xa.  By contrast, treatment by thrombolysis, the only pharmacological means available, has remained at a near standstill since Genentech first applied for FDA approval of tissue plasminogen activator (tPA) in 1983. A replacement for streptokinase (SK) had been long-sought, but after early successes in AMI, tPA use has since been on the decline.  Instead, percutaneous coronary intervention (PCI) has become the treatment of choice in AMI, despite its technical, time-consuming, and costly demands. Pre-treatment with tPA to hasten coronary reperfusion, so-called facilitated PCI, was found to increase PCI complications including intracranial hemorrhage (ICH) making the two incompatible [3]. In ischemic stroke, tPA has been estimated to be used in only 2–5 % of patients over-all [4], and in pulmonary embolism, bleeding and stroke complications limited its use to the minority of patients with hemodynamic decompensation [5].  The recent trend in stroke has also begun to favor the use of endovascular devices with three major trials in ischemic stroke published in the first 2 months of 2015 in the NEJM [6–8]. In this same period, a clinical trial of catheter-directed ultrasound was also published which showed a significant acceleration of the thrombolysis rate by this method [9].  These device reperfusion techniques require bringing the patient to a qualified facility which inevitably consumes precious time for conditions in which “minutes are myocardium or neurons.” An optimal treatment for these time-sensitive conditions can only be one that can be brought to the patient and is easily and safely administered. The resort to alternative methods is a reflection on the inadequacy of current thrombolysis, a problem that was foretold by the results with tPA in major clinical trials.

Why so little progress in therapeutic thrombolysis? The current state of the art and prospects for improvement