Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance

Abstract

Ischemic stroke is caused by a thromboembolic occlusion of cerebral arteries. Treatment is focused on fast and efficient removal of the occluding thrombus, either via intravenous thrombolysis or via endovascular thrombectomy. Recanalization, however, is not always successful and factors contributing to failure are not completely understood. Although the occluding thrombus is the primary target of acute treatment, little is known about its internal organization and composition. The aim of this study, therefore, was to better understand the internal organization of ischemic stroke thrombi on a molecular and cellular level. A total of 188 thrombi were collected from endovascularly treated ischemic stroke patients and analyzed histologically for fibrin, red blood cells, von Willebrand factor , platelets, leukocytes and DNA, using bright field and fluorescence microscopy. Our results show that stroke thrombi are composed of two main types of areas: red blood cell-rich areas and platelet-rich areas. Red blood cell-rich areas have limited complexity as they consist of red blood cells that are entangled in a meshwork of thin fibrin. In contrast, platelet-rich areas are characterized by dense fibrin structures aligned with von Willebrand factor and abundant amounts of leukocytes and DNA that accumulate around and in these platelet-rich areas. These findings are important to better understand why platelet-rich thrombi are resistant to thrombolysis and difficult to retrieve via thrombectomy and can guide further improvements of acute ischemic stroke therapy.

Platelet-rich emboli are associated with von Willebrand factor levels and have poorer revascularization outcomes

“…The results of our study also demonstrate that there was a significant inverse correlation between both platelets (CD42b), von Willebrand factor levels and red blood cell composition. These results are in agreement with a recent study on the structural analysis of acute ischemic stroke that found that red blood cell-rich clots are composed mainly of densely packed red blood cells supported by a thin fibrin network, whilst platelet-rich clots contain dense fibrin structures aligned with vWF and packed with platelets [22]. We demonstrate that platelet-rich clots correlated with a poor revascularization outcome and previous studies have also shown that fibrin/platelets rich clots are more difficult to retrieve that than red blood cell-rich clots [23].…”

A case report of thrombolysis resistance: thrombus ultrastructure in an ischemic stroke patient

“…Staessens et al [4] reported that, if the section was intact, each segment within a thrombus had the same elements, including fibrin, erythrocytes, platelets, and von Willebrand factor. This indicated that any segment of the thrombus could express the overall characteristics.…”

Characterization of the ‘White’ Appearing Clots that Cause Acute Ischemic Stroke

“…Recent studies have described important histological features that may explain the recombinant tissue plasminogen activator (rtPA)-resistance of AIS thrombi: the presence of a dense outer shell containing mainly platelets, vWF and extracellular DNA as well as the presence in the plateletrich thrombi of dense brin structures lined with vWF, extracellular DNA and lled with platelets. [15,16] Given these observations, we suggest that platelet and vWF-rich composition of 'white' clots may impair thrombolysis and therefore, antiplatelet treatment could be used in these cases to target non-brin components and improve rtPA e cacy.…”