There has been accumulating data and indications that the factors which influence the formation of blood clots or venous thromboembolism (VTE) are not limited to the coagulation system alone. The immune system is also directly involved with the formation of thrombosis. The link between inflammation and thrombosis is supported by clinical data and can have critical consequences if one or both become unbalanced.

The immune system is the body’s defensive method which protects against foreign pathogens such as viruses and bacteria. One of the first indicators during an infection is inflammation.

What is the connection between coagulation and inflammation?

It is likely that inflammation of the vessel wall initiates thrombus formation, and that coagulation and inflammation systems are connected by a common activation pathway. Firstly, thrombus formation is probably activated by endothelial cells (tissue cells which form the lining of blood vessels), platelets and leukocytes (white blood cells); with initiation of inflammation and the creation of microparticles.

Microparticles are small vesicles which flow throughout the blood and are developed from a range of cell types including platelets and endothelial cells. Microparticles have an active role in thrombosis, inflammation and vascular reactivity. They are procoagulant because they offer a membrane surface for the construction of components of the coagulation cascade. Microparticles influence inflammation through their contribution to cell-cell interactions, and it has been determined that microparticles released by platelets and endothelial cells increase during inflammatory conditions.

The coagulation process is then triggered through the stimulation and increase of the procoagulant protein, tissue factor. Tissue factor is a vital membrane protein that is central to life and plays a major role in haemostasis (normal blood clotting in response to an injury) and is a major cellular activator of the clotting cascade and thrombosis. Consequently, the main event in the initiation of VTE formation is most likely vein wall inflammation, however the contribution of specific immune modulators is yet to be explained.

What the research is saying?

Research has demonstrated that there is a likely association between VTE and several inflammatory markers, called cytokines. These are small proteins which carry messages between cells and have a significant role in the body’s response to inflammation and immune attack. The inflammation markers referenced include:

• C-reactive protein (CRP) – the level increases when there is inflammation in the body.
• Interleukins – are pro-inflammatory and anti-inflammatory. Interleukin-6 (IL-6) are produced in reply to infections and tissue injuries and contributes to host defence through immune reactions. Interleukin-8 (IL-8) is an important protein which plays a major role in the recruitment of neutrophils and other immune cells to the site of infection.
• Tumour necrosis factor-alpha – produced during inflammation and is responsible for a range of signally events within cells leading to necrosis or apoptosis (the normal death of cells as a controlled part of an organism’s growth or development).

These pro-inflammatory cytokines have a significant role in VTE by promoting a pro-coagulant state, mainly by inducing the expression of tissue factor.

Image - New Links Between Inflammation and Thrombosis (Weibel-Palade bodies are small storage granules located in endothelial cells; P-selectin is a protein produced by activated platelets and endothelial cells that functions as a cell adhesion molecule; vWf (von Willebrand factor) is a protein crucial to primary hemostasis through platelet and subendothelial collagen adhesion, and the intrinsic coagulation cascade.

---

Immunothrombosis and thromboinflammation

Platelets are small blood cells which are involved in would healing to help stop bleeding by forming blood clots, and therefore have a major role in haemostasis and thrombosis. It has become established that platelets also have a relationship with processes such as inflammation, infections and preserving vascular integrity.

In 2004, researchers used the term thromboinflammation to describe platelet-leukocyte reactions; and in 2009 to illustrate the stimulation of an immune system receptor. Researchers in 2019 presented the notion that stroke was a thromboinflammatory disease. In 2013, the term immunothrombosis was used to describe a distinctive immune response provoked by intravascular thrombus formation which leads to recognition, containment and destruction of pathogens. Therefore, platelets have shown to not only participate in thrombus formation and inflammation, but they actively connect the two processes. Immunothrombosis and thromboinflammation are the terms created to reflect the dual role of these mechanisms.

Immunothrombosis has received substantial consideration in the past few years due to COVID-19. Patients with severe COVID-19 which progresses to respiratory failure are distinguished by an exceedingly elevated risk of thrombosis. These processes are linked by extreme pulmonary immunothrombosis, where the initiation of immunothrombosis also results in thromboinflammation, which is described as a systemic prothrombotic trait.

VTE and an anti-inflammatory diet

Inflammation has been shown to facilitate clot formation and increase the risk of VTE. However, there is little data available demonstrating the positive effects of an anti-inflammatory diet. A study in 2021 did find a correlation between a diet high in anti-inflammatory foods and a reduced possibility of VTE.

The risk of VTE was reduced by 2% for one AIDI score increment. The AIDI is an empirically validated Anti-inflammatory Diet Index which is based on 12 foods with anti-inflammatory capacity and 5 foods which are pro-inflammatory. The major influence for an increased risk of VTE were French fries. The study also found a significant correlation between smokers and a high risk of VTE and that an anti-inflammatory diet may be beneficial.

A research review from 2021 investigated the characteristics of pro-inflammatory and anti-inflammatory diet from different regions around the world. They examined which components exert controlling or influencing factors in inflammation and found the regular consumption of foods abundant in anti-inflammatory compounds can have an effect on reducing inflammation.

---

Inflammatory conditions

There are several conditions which are linked to inflammation, with an increasing number of evidence linking them to thromboembolism. Please visit our website page Inflammatory conditions and thrombosis for additional information.

---

References

• Ardoin, S.P., Shanahan, J.C., & Pisetsky, D.S. (2007). The role of microparticles in inflammation and thrombosis. Scand J Immunol. 66(2-3): 159-165. doi:10.1111/j.1365-3083.2007.01984.x.
• Cognasse, F. et al. The role of microparticles in inflammation and transfusion: A concise review. Transfusion and apheresis science 53.2: 159–167.
• Hong, C. & Chih-Hung, L. (2023). A nationwide UK cohort study reveals an association between atopic dermatitis and venous thromboembolism.” British journal of dermatology (1951).
• Merola, J.F. et al. (2023). Comparative risk of venous thromboembolism (VTE) among patients with atopic dermatitis (AD) or other immune-mediated diseases: a cohort study using United States Claims Data.” British journal of dermatology (1951) 188.Supplement_2.
• Molander, V. et al. (2021). Risk of venous thromboembolism in rheumatoid arthritis, and its association with disease activity: a nationwide cohort study from Sweden.” Annals of the rheumatic diseases 80.2: 169–175.
• Owens, A.P., & Mackman, N. (2011). Microparticles in hemostasis and thrombosis. Circulation research 108.10: 1284–1297.
• Stark, K. & Steffen, M. (2021). Interplay between inflammation and thrombosis in cardiovascular pathology. Nature reviews cardiology 18.9: 666–682.
• Stromsnes, K., Correas, A.G., Lehmann, J., Gambini, J., & Olaso-Gonzalez, G. (2021). Anti-Inflammatory properties of diet: role in healthy aging. Biomedicines; 9(8): 922. doi:10.3390/biomedicines9080922.
• Xu, W., & Anis, L. (2018). Immunity and inflammation: From Jekyll to Hyde. Experimental gerontology, 107: 98–101.
• Yuan, S. et al. (2021). Anti-Inflammatory diet and venous thromboembolism: Two prospective cohort studies. Nutrition, metabolism, and cardiovascular diseases 31.10: 2831–2838.
• The Role of Inflammation in Venous Thromboembolism - PMC (nih.gov)
• Tissue factor structure and function - PubMed (nih.gov)
• Cytokines as Therapy | Center for Cancer Research
• C-reactive protein test - Mayo Clinic
• Interleukin - PubMed (nih.gov)
• Interleukin 8 - an overview | ScienceDirect Topics
• Thrombophlebitis - Symptoms & causes - Mayo Clinic
• Rheumatoid arthritis - Symptoms and causes - Mayo Clinic