Journal of Hematology & Thromboembolic Diseases
Open Access

Genetic Basis of Thromboembolic Diseases and Their Contribution to Global Clinical Burden

Harrington Khan^{* *}Correspondence: Harrington Khan, Department of Hematology, Crestwood College of Biomedical Sciences, Dublin, Ireland, Email:

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Description

Thromboembolic diseases, encompassing deep vein thrombosis, pulmonary embolism and arterial thrombosis, continue to impose a substantial clinical and economic burden worldwide. While external factors such as surgery, immobility, cancer and hormonal therapy significantly contribute to the development of thrombosis, genetic predisposition plays an equally important role in shaping an individual’s baseline risk. In recent decades, advances in molecular diagnostics and genome-based research have considerably expanded our understanding of inherited influences on thrombotic disorders. These inherited susceptibilities, collectively referred to as thrombophilias, interfere with the delicate equilibrium between coagulation and anticoagulation, tipping the hemostatic balance toward a hypercoagulable state.

Among the most recognized genetic contributors is the Factor V Leiden mutation, a variant that causes resistance to activated protein C and subsequently prolongs procoagulant activity. Individuals who are heterozygous for this mutation face a severalfold increase in the risk of venous thromboembolism, while those who are homozygous have an even more profound susceptibility, often necessitating heightened vigilance during high-risk periods such as pregnancy, use of estrogen-containing contraceptives, or prolonged immobilization. Similarly, the prothrombin G20210A mutation, another well-established genetic factor, leads to elevated levels of prothrombin and enhances thrombin generation, thereby increasing the likelihood of clot formation. Although its prevalence varies between populations, this mutation remains one of the most clinically relevant contributors to inherited hypercoagulability.

In addition to these common variants, deficiencies in natural anticoagulants-including protein C, protein S and antithrombinplay an important role in predisposing individuals to thromboembolic events. These deficiencies, usually inherited in an autosomal dominant manner, impair the body’s internal mechanisms for controlling clot formation. Protein C and Protein S deficiencies hinder the inactivation of factors Va and VIIIa, elevating the risk of persistent thrombin generation. Antithrombin deficiency, often considered the most severe among the classical thrombophilias, disrupts the inhibition of thrombin and factor Xa, resulting in a markedly increased risk of both spontaneous and recurrent thrombosis. Individuals with these deficiencies may experience thrombotic episodes at a young age or in atypical anatomical sites, Emphasizing the importance of early detection and long-term management. Although these conditions are less prevalent than Factor V Leiden or prothrombin mutations, their clinical significance is substantial, especially in patients with recurrent or unprovoked thrombotic events.

Beyond the classical hereditary risk factors, research has highlighted a number of emerging genetic variants that may influence thromboembolic risk. Polymorphisms affecting fibrinogen production, plasminogen activator inhibitor-1 expression and elements of the fibrinolytic system have garnered attention in recent years. Among these, the Methylene Tetra Hydro Folate Reductase (MTHFR) C677T polymorphism has been widely studied due to its association with elevated homocysteine levels.

While the link between MTHFR variants and thrombosis remains controversial, evidence suggests that the mutation may contribute to thrombotic risk when combined with additional environmental or metabolic factors. Moreover, the increasing use of whole-genome sequencing and large-scale biobank data has facilitated the development of polygenic risk scores, offering a promising framework for assessing cumulative genetic risk. Such tools may help clinicians identify individuals at elevated risk even in the absence of high-impact single-gene mutations.

From a clinical standpoint, genetic testing plays a valuable role in evaluating patients with early-onset thrombosis, recurrent thromboembolic episodes, a strong family history, or thrombosis in unusual locations. Identifying a genetic predisposition allows healthcare providers to tailor preventive strategies, particularly during high-risk situations such as major surgical procedures, pregnancy, or initiation of hormone therapy. Knowledge of an individual’s genetic profile may also inform decisions regarding the duration and intensity of anticoagulation therapy, thereby reducing the risk of recurrence while minimizing bleeding complications.

Conclusion

However, it is important to note that the presence of a genetic mutation alone does not guarantee the development of thromboembolic disease; rather, clinical manifestation often results from the interplay between hereditary and environmental influences. As genetic research continues to evolve and as precision medicine becomes increasingly integrated into routine clinical practice, a comprehensive understanding of genetic contributions to thromboembolic disorders will play a pivotal role in improving prevention, risk assessment and long-term outcomes for affected individuals.