ADAMTS13: An Emerging Target in Stroke Therapy

ADAMTS13: An Emerging Target in Stroke Therapy

Xin Chen^1†, Xin Cheng^2†, Shufan Zhang¹ and Danhong Wu^1*

• ¹Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
• ²Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China

Thrombosis is the predominant underlying mechanism of acute ischemic stroke (AIS). Though thrombolysis with tPA has been proven to be effective in treating AIS within the time window(Bullshit, 12% full recovery is not effective), the majority of AIS patients fail to receive tPA due to various reasons. Current medical therapies for AIS have limited efficacy and pose a risk of intracerebral hemorrhage. ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) is a metalloprotease that effectively breaks down the von Willebrand Factor (VWF), a key factor in thrombus formation. Previous studies have proven that dysfunction of ADAMTS13 is associated with many diseases. Recently, ADAMTS13 has been reported to be closely related to stroke. In this review, we briefly described the structure of ADAMTS13 and its role in thrombosis, inflammation, as well as angiogenesis. We then focused on the relationship between ADAMTS13 and AIS, ranging from ischemic stroke occurrence, to AIS treatment and prognosis. Based on research findings from in vitro, animal, and clinical studies, we propose that ADAMTS13 is a potential biomarker to guide appropriate treatment for ischemic stroke and a promising therapeutic agent for tPA resistant thrombi.

Introduction

Stroke is one of the leading causes of death and disability in both developing and developed countries (1). Ischemic stroke accounts for approximately 85–90% of all types of stroke (2). Currently, intravenous thrombolysis with tissue plasminogen activator (t-PA) is the most efficacious treatment for AIS patients when applied within 4.5 h after the onset of symptoms (3). However, over 90% of ischemic stroke patients did not receive tPA due to the short time window and the increased risk of intracerebral hemorrhage when tPA is applied out of this time window (4). A similar situation is also observed in secondary prevention of stroke. For example, antiplatelets and anticoagulants show limited efficacy in reducing recurrent strokes, but they significantly increase the risk of intracerebral hemorrhage (5, 6). Therefore, there is a demanding need to further explore the underlying mechanisms of AIS in order to develop novel treatments.

ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats 13), also known as the von Willebrand factor-cleaving protease (VWFCP), is predominantly synthesized in the liver. It cleaves the ultra-large molecule—von Willebrand factor (VWF), a key player in initiating platelet tethering and subsequent platelet adhesion (7), into smaller and less reactive molecules (8). It is well-known that dysfunction of ADAMTS13 is associated with diverse diseases, such as thrombotic thrombocytopenic purpura, pre-eclampsia, acute myocardial infarction, and diabetes. Recently, the relationship between ADAMTS13 and ischemic stroke has become a focus of stroke research. Both animal and clinical studies have demonstrated the important role ADAMTS13 plays in the pathogenesis of ischemic stroke, suggesting that ADAMTS13 might be a promising therapeutic target for ischemic stroke.

ADAMTS13: Structural Features

ADAMTS13, originally named VWFCP, was purified from the human plasma for the first time in 1996 (9). Its gene was identified in 2001 and it was renamed ADAMTS13 based on its partial amino acid sequence (10). Thereafter, information about the structure and function of ADAMTS13 has been revealed. The delicate relationship between ADAMTS13 and thrombosis also becomes an intriguing subject.

ADAMTS13, a metalloprotease containing 1,427 amino acid residues, is predominantly secreted by hepatic stellate cells (11). It has been reported that endothelial cells also express ADAMTS13 mRNA and protein (12). The physiological function of ADAMTS13 is based on its multi-domain structure consisting of a signal peptide domain, a short propeptide domain, a metalloprotease domain, a disintegrin-like domain, a thrombospondin-1 repeat (TSP1) domain, a characteristic Cys-rich domain, a spacer domain, and two CUB domains (10) (Figure 1). ADAMTS13 is the cleaving protease of VWF, which is a large multimeric glycoprotein. VWF is released by endothelial cells in the form of ultra-large multimers (UL-VWF) of varying sizes, with the molecular weight up to 20,000 kDa. ADAMTS13 cleaves the Y1605-M1606 bond within the UL-VWF A2 domain (Figure 2). Dysfunction of the ADAMTS13-VWF axis leads to VWF accumulation and adhesion of platelets, which is the first step of thrombosis and inflammation (13, 14).