Can adjunctive therapies augment the efficacy of endovascular thrombolysis? A potential role for activated protein C

Abstract

In the management of acute ischemic stroke, vessel recanalization correlates with functional status, mortality, cost, and other outcome measures. Thrombolysis with intravenous tissue plasminogen activator has many limitations that restrict its applicability, but recent advances in the development of mechanical thrombectomy devices as well as improved systems of stroke care have resulted in greater likelihood of vessel revascularization. Nonetheless, there remains substantial discrepancy between rates of recanalization and rates of favorable outcome. The poor neurological recovery among some stroke patients despite successful recanalization confirms the need for adjuvant pharmacological therapy for neuroprotection and/or neurorestoration. Prior clinical trials of such drugs may have failed due to the inability of the agent to access the ischemic tissue beyond the occluded artery. A protocol that couples revascularization with concurrent delivery of a neuroprotectant drug offers the potential to enhance the benefit of thrombolysis. Analogs of activated protein C (APC) exert pleiotropic anti-inflammatory, anti-apoptotic, antithrombotic, cytoprotective, and neuroregenerative effects in ischemic stroke and thus appear to be promising candidates for this novel approach. A multicenter, prospective, double-blinded, dose-escalation Phase 2 randomized clinical trial has enrolled 110 patients to assess the safety, pharmacokinetics, and efficacy of human recombinant 3K3A-APC following endovascular thrombolysis. This article is part of the Special Issue entitled 'Cerebral Ischemia'.

Activated Protein C in Cutaneous Wound Healing: From Bench to Bedside

“…APC may also have therapeutic benefits in a number of other diseases, including sepsis [ 13 ], central nervous system injury [ 78 ], ischaemic stroke [ 14 ], Alzheimer’s disease [ 79 ], acute kidney injury [ 80 ], lung disorders [ 81 ], acute pancreatitis [ 82 ], type I diabetes [ 83 ], rheumatoid arthritis [ 33 , 84 ], and cancer [ 85 ] ( Table 3 ). Besides its obvious use in homozygous PC deficiency, APC has only been approved for severe sepsis.…”

“…APC’s pleiotropic activities make it an attractive candidate for potential roles in the treatment of complex disorders, including sepsis [ 13 ], ischaemic stroke [ 14 ], and chronic wounds [ 15 ]. APC has two main classes of functions: anticoagulation and cytoprotection.…”

3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice

“…It directly protects neurons from divergent inducers of apoptosis via PAR1 and PAR3 (Guo et al, 2009a) similar to wild-type APC (Guo et al, 2004). Cell-signaling APC analogues, including 3K3A-APC, also protect brain endothelium and blood–brain barrier (BBB) integrity from different types of injury by inhibiting apoptosis of endothelial cells and promoting Rac1-dependent stabilization of the endothelial cytoskeleton, which requires PAR1 and endothelial protein C receptor (Guo et al, 2009a,b; Zlokovic and Griffin, 2011; Amar et al, 2018; Griffin et al, 2018). Additionally, APC and 3K3A-APC have potent anti-inflammatory activity (Griffin et al, 2015, 2018).…”

The Next Step in the Treatment of Stroke

“…For instance, endothelial cells have been reported to die acutely, sub-acutely, and chronically after infarct onset via activation of various pathways, e.g., lysosome-dependent, necroptosis, autophagy, and apoptosis, all of which may be potential targets for treatment (92). Along these lines, APC analogs, such as 3K3A-APC, have been reported to inhibit endothelial apoptosis through PAR1 and PAR3 receptors, stabilizing the endothelial cytoskeleton, and preserving the BBB (50, [93][94][95].…”