Deep Vein Thrombosis

Deep Vein Thrombosis

Observed genes

Polygenic score

Influential genes: F2, F5, F11

The F11 gene codes for a protein called Factor XI. This protein is important for the proper functioning of the clotting cascade.

A specific mutation in the F5 gene, known as Factor V Leiden, can increase the risk of developing DVT.

The F2 gene encodes prothrombin, a key factor in the blood clotting process, and certain variations in this gene can increase the risk of developing DVT.

Overview

Deep vein thrombosis is a condition when a blood clot is formed in one or more of the deep veins in your body, most commonly in the legs. You may experience symptoms like redness, swelling, warmth, pain, or skin discoloration in the affected limb. There are many risk factors that are associated with DVT. Around 40% of cases are attributable to some genetic mutation but usually some other risk factors are present too. These include immobility, trauma, surgery, some chronic illnesses, cancer, oral contraceptives, smoking, pregnancy, etc. The diagnosis is made using different blood tests (D-dimer and coagulation profile) and imaging methods like a duplex ultrasound or venography. There are various treatment options available, such as anticoagulation therapy or thrombolysis. The prognosis is generally good if treated properly, but there is a high chance of complications like post-thrombotic syndrome, pulmonary embolism (PE), and even recurrence of DVT. You can prevent its development by avoiding smoking and oral contraceptives, using compression stockings, and being physically active. 

Prevalence & Risk factors

The prevalence of DVT is often underestimated due to asymptomatic cases. Most commonly it affects the deep veins of lower limbs. The prevalence of lower limb DVT is around 0,1% in the general population.

There are many risk factors that promote the development of DVT. Some genetic mutations can increase coagulability (formation of blood clots) but usually the presence of other risk factors is needed before DVT develops.

There are multiple acquired factors that can put an individual at risk of getting DVT. These include:

  • Age (after the age of 40 the risk is higher but it can happen at any age)
  • Immobility (due to long flights, bed rest, stroke, etc.)
  • Compression of veins (caused by some tumor, stenosis, or congenital abnormalities)
  • Injury to the vein (due to trauma, surgery catheters, IV drug abuse, etc)
  • Increased blood viscosity (polycythemia vera, dehydration) 
  • Increased risk of coagulation (genetic/acquired - cancer, sepsis, MI, HF, SLE, nephrotic syndrome, oral contraception therapy, obesity, pregnancy, hypertension, diabetes, smoking, etc.)

The more risk factors a person has, the higher their chance of developing DVT.

Genetics

Deep vein thrombosis (DVT) is a multifactorial disorder. It can be triggered by several different causes, including surgeries, hormonal therapy, trauma, or inherited risk factors. According to the available data, it is estimated that genetic factors are responsible for about 60% of cases.[2] 

Many strategies, such as family studies, candidate gene analyses, genome-wide association studies (GWASs), and next-generation sequencing have been used for more detailed identification and description of one's chance to develop DVT.[3] However, Factor V (FV) Leiden is still considered to be one of the main risk factors contributing to DVT, followed by the second most frequent factor of DVT, Prothrombin 20210.[2] 

Risk factors can be divided into three categories, according to research:[4]

  • Strong genetic risk factors - deficiencies of coagulation inhibitors
  • Moderate genetic risk factors - Factor V Leiden, Prothrombin 20210A, blood group (non-O ABO blood groups are at higher risk)
  • Weak genetic risk factors - variants in MTHFR or FXIII gene

Genetic testing allows us to detect whether you have the predisposition to develop this disease and therefore directs us to take steps toward prevention, monitoring, and possible treatment options.
In Macromo, we use polygenic risk scores and causative evidence-based genetic variants for evaluation. The polygenic risk score (PRS) represents the total number of genetic variants that increase an individual's risk of developing a particular disease. All variants across their genome are summed and ranked according to their effect on disease development.

Signs & Symptoms

Deep vein thrombosis most commonly affects the veins of lower limbs. Rarely it can affect veins in arms, mesenteric, or cerebral veins. The person can experience localized symptoms on the affected leg, these include swelling of the affected leg, pain (can feel like cramping or soreness), red or discolored skin, feeling of warmness. The symptoms are usually unilateral, affecting only one leg. But if the thrombus is extending to pelvic veins, the symptoms may be affecting both limbs, although this is a rare case. 

Diagnosis

The diagnosis is made based on the D-dimer levels, coagulation profile, and ultrasound of the veins. D-dimer is a small piece of the protein that is formed when the blood clot is dissolved. A negative D-dimer test excludes DVT but a positive result doesn’t confirm it. Duplex ultrasound can visualize the blood flow through the veins. It is also possible to use venography (visualization of veins using contrast dye and x-ray) or MRI. 

Therapy

The treatment goals are to reduce morbidity and prevent complications of DVT like PE and post-thrombotic syndrome. Most commonly it is treated with blood thinners (anticoagulation therapy), these include heparin, vitamin K analogs, and some coagulation factors inhibitors (rivaroxaban). The other treatment possibility is to dissolve the clots (thrombolysis) injecting medications either by IV access or a catheter, directly into the clot. This method is usually reserved for more serious cases because of the chance of bleeding.

Prevention

There are various ways to prevent DVT and its complications. Physical activity is really important, regular exercising and staying mobile while traveling (walking at least every 2 hours) can be beneficial. Compression stockings can be used to improve the blood flow in your veins. They can be used during surgeries, long hospital stays, or just at home if you are at risk of DVT. Smoking, hormone replacement therapy, and oral contraceptives increase the risk of DVT so it is recommended to avoid all of it if possible. A diet high in vitamin K can also reduce the risk. You can find it in green vegetables like spinach, kale, Brussels sprouts, etc. For people that are at high risk of DVT, it can be beneficial to use anticoagulation prophylaxis.

Prognosis

There are several complications that may arise because of DVT. If the clot dislodges from the wall of the vein, it can travel through the veins and heart chambers and end up in the lung arteries. This condition is called pulmonary embolism (PE). Depending on the clot size, it can get stuck in bigger or smaller vessels. If the vessel affected is big enough it can lead to more severe symptoms like sudden shortness of breath, chest pain while inhaling or coughing, rapid breathing, rapid pulse, feeling faint or fainting, and coughing up blood. In cases of a massive pulmonary embolism cardiac arrest can occur. If it’s small, it will be less severe or even asymptomatic. Another complication is post-thrombotic syndrome. It can arise weeks or months after DVT causing chronic pain, swelling, skin pigmentation, and even venous ulcers. Most people will recover with treatment, but these complications are common. For example, post-thrombotic syndrome occurs in 43% of patients 2 years post-DVT. The risk of recurrence is also high, and is around 25%.

Recommendations

  • Move at least every 2 hours for a bit, especially when traveling
  • Avoid taking oral contraceptives if not needed or consider other contraceptive methods
  • Consider wearing compression stockings if you can’t move for a long time (e.g. Flights that take longer than 5 hours)
  • Stay hydrated

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Recommendations

  • Move at least every 2 hours for a bit, especially when traveling
  • Avoid taking oral contraceptives if not needed or consider other contraceptive methods
  • Consider wearing compression stockings if you can’t move for a long time (e.g. Flights that take longer than 5 hours)
  • Stay hydrated

Sources

  1. Waheed SM, Kudaravalli P, Hotwagner DT. Deep Vein Thrombosis. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507708/
  2. Hosseini S, Kalantar E, Hosseini MS, Tabibian S, Shamsizadeh M, Dorgalaleh A. Genetic risk factors in patients with deep venous thrombosis, a retrospective case control study on Iranian population. Thrombosis J. 2015;13(1). doi:10.1186/s12959-015-0064-y
  3. Baylis RA, Smith NL, Klarin D, Fukaya E. Epidemiology and Genetics of Venous Thromboembolism and Chronic Venous Disease. Circ Res. 2021;128(12):1988-2002. doi:10.1161/circresaha.121.318322
  4. OSENDAAL FR, REITSMA PH. Genetics of venous thrombosis. Journal of Thrombosis and Haemostasis. 2009;7:301-304. doi:10.1111/j.1538-7836.2009.03394.x
  5. Deep vein thrombosis - Symptoms and causes - Mayo Clinic, https://www.mayoclinic.org/diseases-conditions/deep-vein-thrombosis/symptoms-causes/syc-20352557
  6. Kahn S.F., (2022), Post-thrombotic syndrome, UptoDate, https://www-uptodate-com.ezproxy.is.cuni.cz/contents/post-thrombotic-postphlebitic-syndrome?search=post%20thrombotic%20syndrome&source=search_result&selectedTitle=1~48&usage_type=default&display_rank=1

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