J Stroke.  2024 May;26(2):164-178. 10.5853/jos.2023.03279.

Cancer-Associated Stroke: Thrombosis Mechanism, Diagnosis, Outcome, and Therapeutic Strategies

• Heo JH
• Yun J
• Kim KH
• Jung JW
• Yoo J
• Kim YD
• Nam HS

• KMID: 2556039
• DOI: http://doi.org/10.5853/jos.2023.03279

Abstract

Cancer can induce hypercoagulability, which may lead to stroke. This occurs when tumor cells activate platelets as part of their growth and metastasis. Tumor cells activate platelets by generating thrombin and expressing tissue factor, resulting in tumor cell-induced platelet aggregation. Histopathological studies of thrombi obtained during endovascular thrombectomy in patients with acute stroke and active cancer have shown a high proportion of platelets and thrombin. This underscores the crucial roles of platelets and thrombin in cancer-associated thrombosis. Cancer-associated stroke typically occurs in patients with active cancer and is characterized by distinctive features. These features include multiple infarctions across multiple vascular territories, markedly elevated blood D-dimer levels, and metastasis. The presence of cardiac vegetations on echocardiography is a robust indicator of cancer-associated stroke. Suspicion of cancer-associated stroke during endovascular thrombectomy arises when white thrombi are detected, particularly in patients with active cancer. Cancer-associated stroke is almost certain when histopathological examination of thrombi shows a very high platelet and a very low erythrocyte composition. Patients with cancer-associated stroke have high risks of mortality and recurrent stroke. However, limited data are available on the optimal treatment regimen for stroke prevention in these patients. Thrombosis mechanism in cancer is well understood, and distinct therapeutic targets involving thrombin and platelets have been identified. Therefore, direct thrombin inhibitors and/or antiplatelet agents may effectively prevent stroke recurrence. Additionally, this strategy has potential benefits in cancer treatment as accumulating evidence suggests that aspirin use reduces cancer progression, metastasis, and cancer-related mortality. However, clinical trials are necessary to assess the efficacy of this strategy involving the use of direct thrombin inhibitors and/or antiplatelet therapies.

Keyword

Cancer; Stroke; Thrombosis; Antithrombotic agents

Figure

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  Figure 1. Mechanism of thrombosis in cancer. Tumor cells activate platelets through thrombin generation and tissue factor expression. Growth factors, proteinases, and chemokines released from activated platelets promote tumor growth. Tumor cell-induced platelet aggregation facilitates metastasis by protecting tumor cells from natural killer (NK) cells and shear stress. This process is accompanied by thrombosis. VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; MMP, matrix metalloproteinase; u-PA, urokinase-type plasminogen activator; PAR-1, protease activated receptor-1.

• 

  Figure 2. Representative images of immunohistochemistry in (A) a patient with cancer-associated stroke and (B) a patient with atrial fibrillation without cancer. Thrombus retrieved from a patient with cancer-associated stroke shows stronger immunoreactivity to platelet and thrombin and weaker immunoreactivity to erythrocyte, compared with a patient without cancer. The primary antibodies for immunohistochemistry were anti-CD42b for platelet, anti-glycophorin A for erythrocyte, anti-fibrinogen for fibrin, and anti-thrombin for thrombin. Positive signals were developed using a 3,3’-diaminobenzidine and are shown in brown.

• 

  Figure 3. Representative thrombi and diffusion-weighted imaging in patients with cancer-associated stroke. (A) Thrombi retrieved during endovascular thrombectomy in a patient with metastatic gastric cancer exhibit multiple white appearances. The D-dimer level was 3,581 ng/mL. (B) Diffusion-weighted imaging of a patient with ovarian cancer and nonbacterial thrombotic endocarditis shows bilateral and multiple infarctions in the anterior and posterior circulations. The D-dimer level was 21,249 ng/mL.

Reference

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