Rare Defects: Looking at the Dark Face of the Thrombosis

Abstract

Venous thromboembolism (VTE) constitutes a serious and potentially fatal disease, often complicated by pulmonary embolism and is associated with inherited or acquired factors risk. A series of risk factors are known to predispose to venous thrombosis, and these include mutations in the genes that encode anticoagulant proteins as antithrombin, protein C and protein S, and variants in genes that encode instead pro-coagulant factors as factor V (FV Leiden) and factor II (FII G20210A). However, the molecular causes responsible for thrombotic events in some individuals with evident inherited thrombosis remain unknown. An improved knowledge of risk factors, as well as a clear understanding of their role in the pathophysiology of VTE, are crucial to achieve a better identification of patients at higher risk. Moreover, the identification of genes with rare variants but a large effect size may pave the way for studies addressing new antithrombotic agents in order to improve the management of VTE patients. Over the past 20 years, qualitative or quantitative genetic risk factors such as inhibitor proteins of the hemostasis and of the fibrinolytic system, including fibrinogen, thrombomodulin, plasminogen activator inhibitor-1, and elevated concentrations of factors II, FV, VIII, IX, XI, have been associated with thrombotic events, often with conflicting results. The aim of this review is to evaluate available data in literature on these genetic variations to give a contribution to our understanding of the complex molecular mechanisms involved in physiologic and pathophysiologic clot formation and their role in clinical practice.

Role of Genetic Thrombophilia Markers in Thrombosis Events in Elderly Patients with COVID-19

“…It would be logical to assume that patients with COVID-19 having genetic predisposition factors for thrombophilia are more likely to have thrombosis than those who do not have such mutations. However, few studies on the thrombosis events and anticoagulant therapy in patients with thrombophilia markers have been reported so far [ 14 , 15 , 16 ]. Do genetic thrombophilia factors in patients with COVID-19 continue to play a triggering role in the occurrence of thrombosis with prophylactic or therapeutic anticoagulants?…”

Whole-Exome Sequencing in a Family with an Unexplained Tendency for Venous Thromboembolism: Multicomponent Prediction of Low-Frequency Variant Deleteriousness and of Individual Protein Interaction

“…More recently, through genomic-transcriptomic-wide analysis [ 26 ], single and multimarker genetic testing [ 27 ] and large meta-analyzed GWAS [ 28 ], novel genetic risk modifiers for VTE have been suggested to contribute, even with small effects, to VTE susceptibility. Many of the recently identified loci, being outside of known or currently hypothesized pathways for thrombosis, suggest new molecular components belonging to platelet and blood biology, inflammation and immuno-mediated processes, potentially contributing to VTE susceptibility [ 29 , 30 ].…”

The burden and predictors of venous thromboembolic diseases in patients with multiple primary malignancies

“…6,7 Thrombosis susceptibility is largely attributed to endothelial damage, flow stasis, and hypercoagulation, collectively known as the Virchow's triad. 8,9 In addition to the genetic variants that predispose VTE such as factor V Leiden, complete plasminogen activator inhibitor 1, antithrombin, and protein C and S deficiencies, prothrombin gene mutation, and fibrinogen gamma, [10][11][12] provoking and non-provoking environmental factors, including cancer, trauma, immobility, surgery, pregnancy, age, gender, ethnicity, obesity, oral contraceptive, and corticosteroid are also implicated. 13,14 The risk of VTE in cancer patients can be sixfold higher than in patients without cancer, especially in the first year of diagnosis, and metastasis increases the risk by 20-fold.…”