Dissolving porcine and human microthrombi by short exposure to microdoses of alteplase in an in vitro model of microvascular obstruction

Coronary microvascular obstruction (MVO) occurs in up to 57% of patients suffering from ST-segment elevation myocardial infarction (STEMI). One cause for MVO is distal embolization by microthrombi after percutaneous coronary intervention (PCI) of the infarct-related coronary artery. MVO is associated with an adverse cardiac prognosis post-STEMI. However, there are no evidence-based therapies for MVO, presenting an unmet therapeutic need. We investigated a novel pharmacotherapeutic approach to resolve embolizing MVO using an in vitro microfluidic model with porcine or human microthrombi to investigate thrombolysis with alteplase, a fibrinolytic drug. We show that a brief (90 s) exposure to concentrated microdoses of alteplase significantly reduces microthrombus size by up to 75%. 50% lysis occurred within six to twelve minutes after alteplase exposure depending on the initial microdose. Our results suggest that delivering a therapeutic drug directly to the microvasculature to briefly achieve high local drug concentrations has the potential to address embolizing MVO. The combination of short drug exposure and high local concentration is possible with a recently developed infusion system based on intracoronary controlled flow infusion (CoFI). CoFI uses microdoses of alteplase that are up to 1300 times lower than intravenous doses and could thereby minimize bleeding risk.