Genetic Evaluation of Hereditary Thrombophilia
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Understanding genetics of hereditary thrombophilia: risk factors and testing
Did you know that…
10% of the world population can have hereditary thrombophilia
Obesity and diabetes are risk factors contributing for thromboembolism.
Smoking is a modifiable risk factor for thromboembolism.
One of the risk factors for fetal loss and recurrent miscarriage is hereditary thrombophilia.
The use of oral contraceptives is a well established risk factor for venous thrombosis.
Pulmonary embolism is the third cause of death, right after acute myocardial infarction and stroke.
The most common presentations of venous thrombosis are deep vein thrombosis (DVT) of the lower extremity and pulmonary embolism.
What is Hereditary Thrombophilia?
Thrombophilia is defined as a disorder of hemostasis with an increased risk for blood clots. The development of a blood clot is called thrombosis. In this disease it is verified a tendency for thrombosis in veins or arteries due to abnormalities in blood composition, blood flow, or the vascular wall.
Blood clots may obstruct blood vessels causing stroke, myocardial infarction or venous thromboembolism (VTE).
VTE is the most common vascular disease after acute myocardial infarction and stroke. It is represented by two main clinical events: deep venous thrombosis (DVT) and pulmonary embolism (PE), which often constitute an unique clinical picture in which PE follows DVT.
Previous thrombotic episodes are a major risk factor for recurrent VTE.
When detected early, there are lifestyle changes and therapeutic measures that can be adopted.
Thrombophilia is a multifactorial disease
that may have hereditary, lifestyle or acquired causes.
1. Risk Factors
1.1. Genetic risk factors
Several scientific and clinical studies established that hereditary thrombophilia can be caused by genetic alterations that cause abnormal clotting by:
– deregulation of coagulation factors;
– deregulation of anti- coagulation factors.
1.2. Lifestyle related risk factors
The additive effect of lifestyle and genetic risk factors predispose to an increased risk for thrombosis.
Major lifestyle risk factors are:
– Muscular or vessel trauma (that could be related to intense sports practice)
Thrombophilia and Long-term Immobilization
Long periods of body immobilization (travelling or illness) can alter blood flow and raise the likelihood of blood clotting.
When resting, people may be predisposed to stasis in lower body limbs. Usually, this is not a health issue as when a person moves again, the blood flow increases and distributes evenly throughout the body. However, a prolonged immobilization, due to hospitalization (major and orthopedic surgeries) or long journeys in an individual that carries a genetic alteration related to hereditary may predispose to an increased thromboembolic risk.
Thrombophilia and lifestyle
Smoking and obesity are established risk factors for cardio and cerebrovascular diseases.
Some people exhibit at least one cardiovascular related risk factor, such as smoking, physical inactivity, diabetes, obesity, hypertension making them more prone to developing a serious cardio-cerebrovascular disease.
As acquired and genetic risk factors interact, it is important to be aware of the influence of genetic factors on the increased risk for these diseases.
1.3. Non modifiable risk factors
– Age. There is an increase in the risk of both arterial and venous thrombotic events with age.
– Gender. The risk of recurrent thromboembolism is higher among men than women.
– Chronic diseases. Such as congestive heart failure.
Thrombophilia and pregnancy
Pregnancy is an acquired and independent risk factor for VTE. Acquired risk determinants can increase the thrombotic risk further during pregnancy and the puerperium. These include maternal age (over 35 years), caesarean section, obesity, infection, and a personal or family history of VTE.
As acquired and genetic risk factors interact, it is important to be aware of the the influence of heritable thrombophilias on risk of thrombosis.
2. How can hereditary thrombophilia affect family planning?
Pregnancy induces a number of physiologic changes that affect the hypercoagulability state and venous stasis being an independent risk factor for the development of VTE.
Pregnancy is associated with a 5 to 10-fold increase in the risk for VTE, and the absolute risk of VTE in pregnancy has been estimated to be 1 to 2 per 1,000 deliveries. In women with a previous history of pregnancy-related VTE, the risk of recurrent VTE with subsequent pregnancies is increased.
Hereditary thrombophilia may contribute to placental insufficiency, placental abruption, pre-eclampsia, intrauterine growth restriction and fetal losses.
Estrogen use, meaning hormonal contraception or hormone replacement therapy associated with genetic risk factors, smoking, dyslipidemia, adiposity, smoking, hypertension or migraine, can contribute to thromboembolic risk.
3. Complete risk assessment
The use of genetic testing for hereditary thrombophilia can be considered in several clinical situations, including the following:
• Assessment of the risk for thrombosis in asymptomatic patients, meaning screening for inherited thrombophilia
• Evaluation of a patient with established thrombosis, to take in consideration anticoagulant management
• Evaluation of close relatives of patients with documented inherited thrombophilia, or with a clinical and family history that is consistent with an inherited thrombophilia
• Evaluation of patients that are considered of high risk for thrombosis, e.g. planned major surgery, or estrogen use.
• Evaluation of pregnancy with or without history of complications, including recurrent pregnancy loss and recurrent early pregnancy loss
4. Signs and Symptoms
Of venous thromboembolism:
- Swelling of the leg
- Pain or tenderness in the leg
- Increased warmth in the area of the leg that is swollen or painful
- Red or discolored skin
Of pulmonary embolism:
- Shortness of breath (dyspnea)
- Abrupt onset of pleuritic chest pain
- Cardiac arrhythmia
5. Thromboembolism treatment
The specific course of treatment depends on several factors:
- location and severity of blood clot
- personal history of previous clots
- family history of clots
- Specific conditions: pregnancy, obesity, age, gender, chronic disease
An evidence-based genetic test for hereditary thrombophilia
TromboGene evaluates the genetic risk for cardio and cerebrovascular diseases, venous thromboembolism, including deep venous thrombosis and pulmonary embolism.
It is recommended for:
For individuals with personal or family history of:
Deep vein thrombosis
Stroke or myocardium infarction at young ages
Exposed to environmental risk factors
In a context of obstetrics or family planning, for women:
Planning to be pregnant
With recurrent miscarriages
Planning to take contraceptive pill/estrogen use
Benefits of genetic testing for thrombophilia
FOR ASYMPTOMATIC INDIVIDUALS BUT WITH FAMILY HISTORY
1. Carrier testing.
Identifies individuals who are relatives of patients with documented inherited thrombophilia being possible to provide clinical vigilance and take preventive measures.
2. Women at fertile age.
Provide guidance about the use of oral contraceptives.
There are lifestyle changes and therapeutic measures that prevent a thromboembolic event.
FOR SYMPTOMATIC INDIVIDUALS
The genetic test supports clinical diagnosis, establishing the cause of hereditary thrombophilia.
There are lifestyle changes and preventive therapeutics that prevent recurrent thromboembolic events.
3. Family planning.
Couples with recurrent miscarriages and/or fetal loss and with a genetic alteration can be advised by a medical doctor or a geneticist to undergo anticoagulant therapy in a future pregnancy.
Start improving the diagnosis of hereditary thrombophilia today
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TromboGene is a diagnostic tool that identifies the genetic cause of thrombophilia.
The Scientific Background
1. Genetics of Hereditary Thrombophilia
Hereditary thrombophilia predisposes for venous or arterial thrombosis.
Results from various clinical and genetic studies [1, 2] established that hereditary thrombophilia may be caused by insufficient coagulation inhibition from:
a) genetic alterations that result in natural coagulation inhibitors deficiency;
b) genetic alterations that lead to an increased level / function of coagulation factors.
Hereditary thrombophilia include the following abnormalities: Activated protein C resistance (factor V Leiden mutation), prothrombin gene mutation and hyperhomocysteinemia (MTHFR mutations).
Meta-analysis and other studies show that:
Factor V Leiden (F5) and Prothrombin (F2) mutations are associated with coronary artery disease, stroke, pulmonary embolism, fetal loss and increased risk for thromboembolism in women under hormonal therapy [11-18].
MTHFR genetic polymorphisms may be a susceptibility factor that increase the predisposition for vascular thrombosis, stroke, coronary heart disease, and peripheral arterial disease [20-24].
PAI-1 genetic polymorphisms may be associated with an increased risk for deep venous thromboembolism, myocardial infarction, portal vein thrombosis, fetal loss, implantation failure and preeclampsia in the presence of other genetic variants and acquired or modifiable risk factors associated with thrombophilia [25-28].
Protein C receptor mutations are associated with venous and arterial thromboembolism [14,29-32].
Protein S mutations are associated with venous and arterial thromboembolism and fetal loss [14,17,32].
Antithrombin mutations (SERPINC1) are associated with venous thromboembolism and cardiovascular disease [14,32-34].
Fibrinogen beta chain (FGB) mutation may be a susceptibility factor for stroke, venous thrombosis and coronary artery disease if combined with other risk factors .
Knowledge about inherited and acquired causes of thrombophilic disorders has increased significantly during the past decade, namely gene-gene and gene-environment interactions and their impact on clinical manifestations. Genetic testing in patients and their relatives can contribute to Predictive, Preventive and Personalised Medicine modifying morbidity and mortality.
2. Prevalence of genetic alterations
– The Factor V Leiden (FVL) mutation is the most prevalent thrombotic risk factor in Caucasian populations (3-7% are carriers) but is very rare in African and Asian populations [3,4].
– Prothrombin G20210A mutation has a prevalence of 0.7%-4% in Caucasian populations .
– Mutations that cause deficiencies in anti-coagulant proteins, such as protein S, protein C or SERPINC1 (antithrombin III) are found in less than 1% of the population [5,6].
– Another genetic factor related to thrombosis is the methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T, which is associated with elevated homocysteine levels and hence causing inflammation. This polymorphism presents a high prevalence in Mediterranean population (33- 46%).
During pregnancy, the thrombogenic potential is enhanced from the hypercoagulable state produced by normal pregnancy-associated changes in several coagulation factors, e.g.
– resistance to activated protein C increases in the second and third trimesters;
– protein S activity decreases due to reductions in total and free protein S antigen;
– increase of fibrinogen, factors II, VII, VIII, X and plasminogen activator inhibitor type 1 (PAI-1) and PAI-2 levels.
3. TromboGene Gene Panel
TromboGene genetic test evaluates 14 genetic variants in 10 genes associated to the hereditary predisposition for thromboembolic disorders.
10 Genes (14 Genetic variants)
F2, F5, GP1BA, PROCR, PAI-1, MTHFR, PROS1, SERPINC1, F13A1 and FGB.
4. How Genetic variants are selected
Our research is supported by highly cited papers that have been published in the reference journals in the field.
All genetic variants have been validated in reference databases (HGMDP, NCBI-OMIM, NCBI- ClinVar, NCBI-Variation Reporter and Ensembl).
The knowledge in our databases was approved by internationally recognised medical geneticists and cardiologists.
Validation of the clinical use of the genetic test is focused on three main principles:
1. Analytic validity of the test, which refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent;
2. Clinical validity of the test, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and
3. Clinical utility of the test, i.e., how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.
5. International Guidelines
Several international study groups recognize the value of TromboGene genetic testing to determine the aetiology of thromboembolic disease [3,4,7,8].
- The International Consensus Guidelines
- The French Consensus Guidelines
- The National Institute for Health and Clinical Excellence (NICE)
According to JAMA Internal Medicine :
“… all patients with a positive family history of thrombosis should undergo testing for the common genetic disorders.”
According to the Capital Blue Cross Blue Shield Blue Care Network joint medical policies 2014 :
“The analytic validity of genetic testing for inherited thrombophilia is high. Published literature reports that the analytic sensitivity and specificity for Factor V Leiden mutation testing is greater than 99% and for the prothrombin mutation is higher than 98%.”
6. How to read TromboGene reports?
1.1 Genetic Risk Analysis
3.0 Genetic Information
3.0 Scientific Evidences For Molecular Markers
HeartGenetics reports follow the recommendations from the European Society of Human Genetics .
Contact us here for complete genetic test model report
Start improving hereditary thrombophilia diagnosis today
(Only for registered medical doctors, register here)
 J Genet Couns. 2007. 16(3):261-77. Inherited thrombophilia: key points for genetic counseling.
 J Thromb Haemost. 2007. 5 Suppl 1:264-9. Past and future of genetic research in thrombosis.
 NICE. Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. Clinical guideline 144. London: National Institute for Health and Clinical Excellence, 2012.
 Thromb Haemost. 2013. 110(4):697-705. Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the Guidelines from Scientific Societies and Working Groups.
 Br J Haematol. 2008. 143(3):321-35. Does thrombophilia testing help in the clinical management of patients?
 Hematology Am Soc Hematol Educ Program. 2005. 1-12. Venous thrombosis: the role of genes, environment, and behavior.
 Int Angiol. 2005. 24(1):1-26. Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence.
 J Mal Vasc. 2009. 34(3):156-203. Recommendations on testing for thrombophilia in venous thromboembolic disease: a French consensus guideline.
 Arch Intern Med. 2001. 161(20):2433-9. Hypercoagulability syndromes.
 Capital Blue Cross Blue Shield Blue Care Network joint medical policies 2014. Genetic Testing for Inherited Thrombophilia (MP-2.253).