The Role of Inflammation in Venous Thromboembolism

Abstract

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT), and pulmonary embolism (PE), is becoming increasingly recognized as a cause of morbidity and mortality in pediatrics, particularly among hospitalized children. Furthermore, evidence is accumulating that suggests the inflammatory response may be a cause, as well as consequence, of VTE, but current anticoagulation treatment regimens are not designed to inhibit inflammation. In fact, many established clinical VTE risk factors such as surgery, obesity, cystic fibrosis, sepsis, systemic infection, cancer, inflammatory bowel disease, and lupus likely modulate thrombosis through inflammatory mediators. Unlike other traumatic mechanisms of thrombosis involving vascular transection and subsequent exposure of subendothelial collagen and other procoagulant extracellular matrix materials, inflammation of the vessel wall may initiate thrombosis on an intact vein. Activation of endothelial cells, platelets, and leukocytes with subsequent formation of microparticles can trigger the coagulation system through the induction of tissue factor (TF). Identification of biomarkers to evaluate VTE risk could be of great use to the clinician caring for a patient with inflammatory disease to guide decisions regarding the risk:benefit ratio of various types of potential thromboprophylaxis strategies, or suggest a role for anti-inflammatory therapy. Unfortunately, no such validated inflammatory scoring system yet exists, though research in this area is ongoing. Elevation of C-reactive protein, IL-6, IL-8, and TNF-alpha during a response to systemic inflammation have been associated with increased VTE risk. Consequent platelet activation enhances the prothrombotic state, leading to VTE development, particularly in patients with other risk factors, most notably central venous catheters.

Behçet’s syndrome as a tool to dissect the mechanisms of thrombo-inflammation: clinical and pathogenetic aspects

“…In this context, inflammation-dependent platelet activation plays a fundamental role by enhancing tissue factor expression, thrombin production and activation of coagulation factors leading to a hypercoagulable state [34]. This concept is supported by accumulating evidence highlighting the role of inflammation in venous thromboembolism (VTE), a condition where endothelial damage is not mandatory and can occur without the traditional risk factors for atherothrombosis [32,33,35].…”

Cancer‐associated thrombosis: The search for the holy grail continues

“…45 Interestingly, increased IL-6 and IL-8 levels in plasma are associated with increased risk of VTE in non-cancer patients. 47 It should, however, be noted that no correlations were found between interleukins and VTE in the Vienna Cancer and Thrombosis Study cohort, 48 except for patients with pancreatic cancer. This might be attributed to the relatively low incidence of VTE in the cohort (7.2%) and that plasma was collected prior to cancer-related therapy, ruling out contributions of surgery and/or chemotherapy.…”

“…Moreover, elevated levels of inflammatory mediators, eg, IL‐6 and IL‐8, may be found in tumor cells harboring a K‐ras mutation 45. Interestingly, increased IL‐6 and IL‐8 levels in plasma are associated with increased risk of VTE in non‐cancer patients 47. It should, however, be noted that no correlations were found between interleukins and VTE in the Vienna Cancer and Thrombosis Study cohort,48 except for patients with pancreatic cancer.…”

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

“…Only once the immune system establishes that a thrombus is sterile does the resolution progress, and this requires additional detection of the thrombus microenvironment to take the appropriate next step. Both policing and repairing phases are mediated by various cytokines and chemokines [56]. Biochemically or genetically shifting the immune response in ways that simulate sepsis or hypersensitize it toward infection slow thrombus resolution because immune cells cannot remodel the tissue until they recognize that their primary job of sterilization has been achieved.…”