ADAMTS13: An Emerging Target in Stroke Therapy

Abstract

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, 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.

Biomechanical thrombosis: the dark side of force and dawn of mechano-medicine

“… 88 It was found that under pathologically high-shear flow, shear force becomes sufficiently large to trigger cleavage of normal-sized VWF by ADAMTS13 in a growing thrombus, thereby inhibiting thrombosis. 88 89 This makes recombinant ADAMTS13 (BAX 930) a promising antithrombotic agent 90 ( table 1 ; figure 1 ): in preclinical tests, infusing recombinant ADAMTS13 before reperfusion significantly reduced the infarct volume and other stroke effects. 91 Moreover, the mechanoredox regulation of VWF reactivity suggests that using antioxidative agents or more specific disulfide isomerases to reverse plasma VWF from oxidized to its reduced form can reduce platelet binding and thereby suppress thrombosis.…”

The Value of ADAMTS13 in Predicting Clinical Outcomes in Patients With Acute Ischemic Stroke Receiving Thrombolysis

“…The dysregulated VWF-ADAMTS13 axis has great effects on ischemic stroke ( 10 ). Bustamante et al ( 15 ) revealed that reduced ADAMTS13 activity level was related to poor response to recanalization therapies (both in patients treated with rt-PA and mechanical thrombectomy) and Putzer et al ( 16 ) found that the lowest quartile of ADAMTS13 activity was independently associated with less early improvement in NIHSS score (OR 1.298, p = 0.050).…”

“…Interestingly, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a protease that can cleave ultra-large VWF into smaller, less reactive multimers, and the deficiency of ADAMTS13 can cause thrombotic occlusion of micro-vessels from multiple organs, including the brain (9). The VWF-ADAMTS13 axis has been proven to play a significant role in the pathophysiological microcirculatory disturbance of ischemic stroke (10). In animal studies, absence of ADAMTS13 exacerbates outcomes of ischemia or reperfusion injury (11,12), while injecting recombinant ADAMTS13 reduces rt-PA-associated hemorrhage (13).…”

Stroke Classification: Critical Role of Unusually Large von Willebrand Factor Multimers and Tissue Factor on Clinical Phenotypes Based on Novel “Two-Path Unifying Theory” of Hemostasis

“…Current interpretation is increased VWF/ULVWF is a prothrombotic marker for stroke. 103 But, as discussed earlier in the text, “two-path unifying theory” of hemostasis supports transiently increased VWF and ULVWF is not the cause of ischemic stroke, but is the result of increased exocytosis from endothelial damage causing TIA and AIS in vascular injury. It is likely that decreased ADAMTS13 activity could have been related to imbalance due to excessive exocytosis of ULVWF or might have preexisted due to heterozygous mutation of ADAMTS13 gene in some patients, which potentiated TIA and AIS once intravascular injury had occurred.…”