Periodontitis impacts on thrombotic diseases: from clinical aspect to future therapeutic approaches

Abstract

Periodontitis is a chronic inflammatory disease initiated by biofilm microorganisms and mediated by host immune imbalance. Uncontrolled periodontal infections are the leading cause of tooth loss in adults. Thrombotic diseases can lead to partial or complete obstruction of blood flow in the circulatory system, manifesting as organ or tissue ischemia and necrosis in patients with arterial thrombosis, and local edema, pain and circulatory instability in patients with venous thrombosis, which may lead to mortality or fatality in severe case. Recent studies found that periodontitis might enhance thrombosis through bacterial transmission or systemic inflammation by affecting platelet-immune cell interactions, as well as the coagulation, and periodontal therapy could have a prophylactic effect on patients with thrombotic diseases. In this review, we summarized clinical findings on the association between periodontitis and thrombotic diseases and discussed several novel prothrombotic periodontitis-related agents, and presented a perspective to emphasize the necessity of oral health management for people at high risk of thrombosis.

Fig. 1

Representative periodontitis-related thrombotic diseases encountered in clinical practice. Arterial thrombotic diseases can be categorized as AS-related and nonAS-related, characterized by organ or tissue ischemia and necrosis. Stroke, acute coronary syndrome (ACS) and peripheral artery disease (PAD) are most common AS-related arterial thrombotic diseases, while thromboangiitis obliterans (TAO), atrial fibrillation (AF) and arterial dissection-related thrombosis are the most prevalent nonAS-related thrombotic diseases. Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), manifesting as edema, pain and circulatory instability. Autoimmune-related thrombotic disorders are relatively rare and can affect small vessels in both arterial and venous systems. Examples of such conditions include Behçet’s syndrome, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and antiphospholipid syndrome (APS). The illustration was created by C.W

Fig. 2

Endothelial injury, hypercoagulability and hemodynamic changes constitute Virchow’s triad. Specifically, endothelial injury and hypercoagulability are the predominant mechanisms underlying periodontitis-related thrombotic diseases, which may indirectly contribute to hemodynamic changes and ultimately culminate in the formation of thrombosis. The illustration was created by C.W

Fig. 3

Periodontitis induces systemic inflammation and promotes thrombosis through bacterial dissemination and the release of pro-inflammatory factors into the circulation. Platelet activation and expression of neutrophil extracellular traps are important features in thrombosis with periodontitis. Gut dysbiosis and diabetes mellitus are also potential mechanisms by which periodontitis accelerates thrombosis. The illustration was created by X.Z. using BioRender.com

Fig. 4

Periodontal infections can lead to bacteremia. Bacteria (eg., P. gingivalis) and their metabolites (e.g., LPS) can activate platelets via TLR2/4. Pro-inflammatory cytokines triggered by periodontitis (e.g., TNF-α and IL-6) promote high endothelial cell expression of P-selectin, which is responsible for neutrophil and monocyte recruitment and activation. Neutrophil extracellular traps (NETs) produced by neutrophil activation bind to platelets and accelerate blood cell aggregation. The mtDNA released from periodontal tissue destruction and the CpG DNA released from periodontal bacterial death can activate immune cells through the intracellular nucleic acid receptor TLR9 and accelerate the formation of platelet monocyte complexes. Meanwhile, Poly P produced by periodontal pathogen activates collagen fiber synthesis and participates in thrombus formation by triggering the factor XII-XI-IX cascade signaling mechanism. The illustration was created by X.Z. using BioRender.com

Fig. 5

Future perspective regarding the potential role of oral health management in the treatment of thrombotic diseases. Numerous studies have consistently demonstrated the impact of periodontitis on thrombotic diseases across various stages, ranging from pre-clinical to post-operative. Moreover, it has been observed that periodontal treatment positively influences the prognosis of patients with thrombotic diseases. However, current therapeutic approaches for thrombotic conditions primarily revolve around lifestyle modifications, medications, and surgical interventions. The significance of oral health management in preventing and treating thrombotic diseases is currently underappreciated, while the underlying key molecules and pathways through which periodontitis exacerbates these conditions remain elusive. It is essential to integrate oral health surveillance and management into the overall treatment plan for individuals with thrombotic diseases. Additionally, further exploration of the intricate mechanisms by which periodontitis impacts thrombosis can pave the way for potential targeted therapeutic strategies aimed at improving patient outcomes. The illustration was created by C.W