Under certain circumstances, abnormal clots can form in veins, called deep vein thrombosis (DVT). These can then break off and travel to the lungs as pulmonary emboli (PE), where they can clog the pulmonary arteries and stop blood flow.1 While the exact number of patients with PE are unknown, an estimated 900,000 people are affected every year in the United States. Between 10% and 30% of cases are fatal within a month of diagnosis.2 The severity of the condition makes it especially important to understand the etiology of the disease, as early diagnosis can enable prompt treatment and improve mortality.
There are many risk factors for PE, including cancer, surgery, inflammatory conditions, hormone therapies (e.g. birth control pills), and inherited disorders that affect clotting. All these conditions can increase the likelihood of pulmonary embolism.3 In this article, we focus on the inherited genetic mutations or abnormalities which affect the likelihood of PE.
Venous thromboembolism (VTE) which includes both DVT and PE, has a strong genetic basis, with genetic mutations contributing to approximately 50-60% of cases. Multiple genes contribute to VTE risk, with more than 30 genes currently known.4 Most of the genes have functions associated with coagulation of blood, and lead to hypercoagulability, or increased blood coagulation.4 Inherited abnormalities that increase the likelihood of PE can be divided into inherited defects of: coagulation; fibrinolysis (or the breakdown of clots); platelet function; and enzymatic pathways related to coagulation.5
There are several coagulation defects associated with PE. These include Factor V Leiden, protein C and protein S deficiency, prothrombin G20210A mutation, and antithrombin III deficiency.5 One of the most common inherited abnormalities associated with PE is Factor V Leiden mutation, which occurs in the F5 gene and is classified as a coagulation defect. The F5 gene encodes coagulation factor V which is involved in the coagulation cascade where it assists with clot formation.5 Factor V is typically inactivated by protein C to slow the clotting process and prevent clot growth; however, this inactivation step cannot occur in individuals with factor V Leiden disorder. Consequently, people with this mutation have an increased chance of developing large and abnormal clots, like PE.6 Individuals heterozygous for the mutation (i.e. one normal and one mutated copy of the gene) have a seven-fold higher risk of developing PE than the general population.7 In individuals homozygous for the mutation, PE risk is approximately 80 times that of individuals without the mutation.7
The second class of inherited abnormalities associated with PE are inherited defects in fibrinolysis, a process during which a stable fibrin blood clot is broken down to allow the restoration of normal blood flow.8 Defects or deficiencies in the proteins involved in this process – such as plasminogen and congenital tissue plasminogen activator deficiency – prevent clot clearance and allow clots to grow unchecked.5
The risk of PE also increases in the presence of inherited platelet defects such as sticky platelet syndrome and the Weinpenzing defect. Sticky platelet syndrome is an autosomal dominant platelet disorder wherein platelets hyper-aggregate in platelet-rich plasma in the presence of adenosine diphosphate and/or epinephrine.9 On the other hand, Weinpenzing defect is characterized by constituent hyper-activation of platelets due to changes in expression of platelet surface proteins. Both disorders result in increased platelet aggregation and thus increase the likelihood of PE.5
Lastly, inherited defects in certain enzymatic pathways also increase the likelihood of PE. For example, individuals with homocysteinuria are deficient in an enzyme that converts homocysteine to methionine, and thus have increased homocysteine levels. The effects of homocysteine accumulation are not completely understood; however, it has been shown to cause platelet abnormalities and vascular endothelial thickening, both of which may increase the likelihood of blood clot formation and the risk of PE.10
There are many genetic risk factors for VTE. Most of these inherited abnormalities are linked to mutations that increase the likelihood of clot formation. Currently, polymorphisms identified through genome-wide association studies have been able to explain approximately 35% of cases. To address this apparent gap, research is ongoing to identify low-frequency coding variants through meta-analyses of large data sets. However, it is important to note that genetics are not the only key factor in determining individual risk of developing PE. Some risk factors include age, sex, and raceOther factors such as cancer, surgery, trauma, and pregnancy can also increase the likelihood of clotting.4 Thus, while genetic abnormalities are some of the key drivers of PE, the interplay between genetic and environmental factors influence the likelihood of PE.
- Pulmonary embolism. Johns Hopkins Medicine. Available from: https://www.hopkinsmedicine.org/health/conditions-and-diseases/pulmonary-embolism [Accessed: 28thJanuary 2022]
- Data and Statistics on Pulmonary Embolism. Centers for Disease Control and Prevention. Available from: https://www.cdc.gov/ncbddd/dvt/data.html [Accessed: 28th January 2022]
- Pulmonary embolism. Mayo Clinic. Available from: https://www.mayoclinic.org/diseases-conditions/pulmonary-embolism/symptoms-causes/syc-20354647 [Accessed: 28th January 2022]
- Crous-Bou M, Harrington L, Kabrhel C. Environmental and genetic risk factors associated with venous thromboembolism. Seminars in Thrombosis and Hemostasis. 2016; 42(08): 808–820. doi:10.1055/s-0036-1592333
- Konecny, F. Inherited thrombophilic states and pulmonary embolism. J Res Med Sci. 2009; 14(1): 43–56. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129068/
- Factor V Leiden thrombophilia. https://medlineplus.gov/genetics/condition/factor-v-leiden-thrombophilia/ [Accessed 25th Jan 2022].
- Nizankowska-Mogilnicka, E. et al. Genetic polymorphisms associated with acute pulmonary embolism and deep venous thrombosis. European Respiratory Journal. 2003; 21: 25-30. doi: 10.1183/09031936.03.0003430
- McMillan, K. N. et al. Coagulation Disorders in Congenital Heart Disease. Critical Heart Disease in Infants and Children. 2019; 7: 282-302. https://doi.org/10.1016/B978-1-4557-0760-7.00024-3
- Mammen, E. F. Sticky Platelet Syndrome. Semin Thromb Hemost. 1999; 25(4):361-5. doi: 10.1055/s-2007-994939.
- Chapman, K. Homocystinuria due to Cystathionine Beta-Synthase Deficiency.https://rarediseases.org/rare-diseases/homocystinuria-due-to-cystathionine-beta-synthase-deficiency/[Accessed 25th Jan 2022].