Epidemiology and Genetics of Venous Thromboembolism and Chronic Venous Disease

Abstract

Venous disease is a term that broadly covers both venous thromboembolic disease and chronic venous disease. The basic pathophysiology of venous thromboembolism and chronic venous disease differ as venous thromboembolism results from an imbalance of hemostasis and thrombosis while chronic venous disease occurs in the setting of tissue damage because of prolonged venous hypertension. Both diseases are common and account for significant mortality and morbidity, respectively, and collectively make up a large health care burden. Despite both diseases having well-characterized environmental components, it has been known for decades that family history is an important risk factor, implicating a genetic element to a patient's risk. Our understanding of the pathogenesis of these diseases has greatly benefited from an expansion of population genetic studies from pioneering familial studies to large genome-wide association studies; we now have multiple risk loci for each venous disease. In this review, we will highlight the current state of knowledge on the epidemiology and genetics of venous thromboembolism and chronic venous disease and directions for future research.

Keywords: genetics; genome wide association study; varicose vein; venous insufficiency; venous thromboembolism; venous thrombosis.

Figure 1:. Chronic Venous Disease

(A) Normal venous return occurs through a system of superficial, perforating, and deep (intermuscular) veins propelled by the pressure gradient derived from muscle contraction and a network of bicuspid venous valves to prevent retrograde blood flow. During proper functioning, the pressure within the thin-walled veins remains relatively low (~20–30 mmHg) (B) Chronic venous disease occurs in the setting of prolonged venous hypertension arising from multiple factors including degenerate venous valves, weakened muscle contraction, and proximal obstruction. Rather than the standard flow of blood from the superficial to the deep veins, incompetent valves allow for blood to flow back into the superficial veins or pool in the deep vein increasing their local pressure. Overtime, the increased volume and pressures in the veins incites endothelial dysfunction including loss of the protective glycocalyx and venous wall inflammation resulting in adverse extracellular matrix remodeling. This is further exacerbated by RBC extravasation and leukocyte adhesion. Further support for these mechanistic changes within the venous wall have been derived from gene expression studies comparing healthy and diseased veins. (C) CEAP [Clinical-Eitology-Anatomy-Pathphysiology] classification system for patients with chronic venous disorders. (D) Summary table of genetic abnormalities (and when appropriate their associated genetic syndrome) that have been associated with varicose vein formation. These associations are nicely reviewed by Anwar et al.

Figure 2:. Placing the genetics of venous thromboembolism into context

Many of the early discoveries implicated genes coding for protein components of the coagulation/ anticoagulation pathways. Those factors that have been identified in previous studies to play a role in VTE risk have been bolded in the coagulation cascade or included at the bottom of the box if not neatly fitting into the cascade. As our understanding of the genetic influence on VTE has expanded, genes that appear to have a functional role outside of classical coagulation have been identified and appear to implicate multiple hematopoietic cell lineages including immune cells, platelets, and red blood cells. The functional role of many of the risk loci has yet to be determined. This figure was adapted from figure 2 of Zoller et al (2020) and was created using BioRender.com.