Clot Morphology in Acute Ischemic Stroke Decision Making

Abstract

Stroke is a leading cause of death and disability in the world, and the provision of reperfusion therapy and endovascular therapy, in particular, have revolutionized the treatment of patients with stroke and opened opportunities to look at brain clots retrieved after the procedure. The use of histopathology and molecular profiling of clots is of growing research and clinical interest. However, its clinical implications and incorporation within stroke workflows remain suboptimal. Recent studies have indicated that the study of brain clots may inform the mechanism of stroke and hence guide treatment decision-making in select groups of patients, especially patients without a defined cause or known mechanism. This article provides a comprehensive overview of various clot histopathological examinations in acute stroke-care settings, their clinical utility, and existing gaps and opportunities for further research. We also provide targeted recommendations to improve clot analysis workflow, hence standardizing its incorporation into clinical practice.

Keywords: biomarkers; cryptogenic; diagnosis; histopathology; stroke; thrombectomy; thrombosis.

Figure 1

Various techniques used in endovascular thrombectomy. A schematic displaying four techniques: (a) The stent-retriever technique in which an aspiration catheter (e.g., a catheter with an inner diameter (ID) of 0.060” or 0.070”) is inserted through the femoral or radial artery and guided up to the specific vessel (e.g., approximately 2.5–3.0 mm in the M1 segment of the middle cerebral artery (MCA)) blocked by the clot. The guidewire and microcatheter cross the clot, and the stent is unsheathed and integrated with the clot, providing immediate reperfusion in most cases. Then, the stent and microcatheter are retrieved, ideally along with the clot [26]. (b) Aspiration catheters, which are larger than a microcatheter but not a fully deployed stent retriever, aspirate the clot in order to remove it from circulation [27]. (c) The Solumbra technique utilizes both the above techniques, simultaneously aspirating and using a stent to retrieve the clot. (d) A balloon guide catheter can be inflated in place in the vessel, stopping antegrade blood flow and causing brief retrograde flow, diminishing the risk of distal embolization. Adapted from Munich et al. (2019) [26].

Figure 2

The pathogenesis of thromboembolism. Various pathways implicated in the pathogenesis of thromboembolism: (a) The accumulation of thrombotic mediators and cells, starting with primary hemostasis including platelet activation and immuno-thrombosis, followed by secondary hemostasis forming a thrombus. (b) The process of platelet activation: exposed connective tissue and collagen cause platelets to change shape and adhere to the vessel wall via pseudopods and platelet receptors. Activated platelets release factors from their granules such as adenosine diphosphate (ADP) (causing nearby platelets to adhere, creating a platelet plug), thromboxane A2 (TXA₂) (promoting platelet aggregation and release of more ADP), and thrombin (a strong platelet agonist converting fibrinogen to fibrin). The von Willebrand Factor (VWF) helps platelets adhere via platelet receptor Glycoprotein Ib (GP Ib) on the platelet membrane [28]. (c) Neutrophils release neutrophil extracellular traps (NETs), which further promote thrombus formation and help platelet activation. Monocytes express tissue factors on their surface, and aid red blood cell (RBC) recruitment and fibrin formation [29]. Adapted from Engelmann and Massberg (2013) and Bi et al. (2021) [29,31]. Abbreviations: TXA₂: thromboxane A2; ADP: adenosine diphosphate; PAR: protease-activated receptor; GP: glycoprotein; VWF: von Willebrand factor; NET: neutrophil extracellular trap; RBC: red blood cell; TLR: toll-like receptor; PSGL-1: P-selectin glycoprotein ligand-1.