Genetic evaluation of fetal loss and risk of cardiovascular
disease by arterial or venous thrombosis
For women planning to be pregnant
Women with recurrent miscarriages
Women planning to take contraceptive pill
Did you know that…
Miscarriages may have a genetic cause
Genetic studies show an association between hereditary thrombophilia and complications during pregnancy.
Contraceptive pill may lead to serious issues of venous thrombosis
The use of oral contraceptives represents per si a 4-5 fold increase in the risk of thromboembolic events
Thrombophilia represents the major cause of fetal loss during pregnancy and child labor
A pregnant woman has a 5-10 times higher chance of having an thromboembolic event
FamilyCare may prevent life traumatic events.
Small changes in lifestyle or preventive therapies may avoid serious health issues.
FamilyCare Genetic Test
FamilyCare with just a sample of blood evaluates the genetic risk of Hereditary Thrombophilia (TRB) in women.
Genetic studies have demonstrated an association between TRB and several complications during pregnancy, child labor or hormonal therapies, such as oral contraceptives intake.
FamilyCare prevents women to go through health complications in important moments of their life.
FamilyCare is indicated for women that:
- Are planning to have children
- Present recurrent pregnancy problems
- Have suffered more than two miscarriages
- Have a familial history of cardiovascular diseases
- Intend to start oral contraceptive therapy
Relatives of patients with this kind of pathology also benefit from the evaluation of carrier status of these genetic variants
Why is TRB evaluation important in obstetrics practice?
TRB consists in genetic changes that predispose to an increased risk of blood clots formation. These blood clots may obstruct blood vessels and cause pulmonary and cerebral embolisms and acute myocardial infarction.
Pulmonary embolism is the third cause of death, right after acute myocardial infarction and stoke.
Why does it
manner matter for pregnant women ?
During pregnancy TRB may contribute to placental insufficiency, placental abruption, pre-eclampsia and inhibition of intrauterine growth.
Why does it matter for women taking oral contraceptives?
During administration of Oral contraceptives, thrombophilia may contribute to XXXXXX
substituir por: Therapy with oral contraceptives is by itself a predisposing factor to thromboembolic events.
This pathology manifests itself in:
Young women (before 50 years of age). In individuals between 20 and 44 years of age, the incidence of a first VTE is higher in woman than in men, which is likely explained by the use of hormonal therapies, pregnancy and postpartum period. [Bleker 2014]
10% of world population. onde está a ref? este bloco é sobre a importância na pratica obstetrica, não vejo relevancia desta info neste bloco em particular 1 to 2 in every 1000 pregnant women, considering only cases of venous thromboembolism (VTE), just one of the consequences of TRB.
substituir por: During pregnancy and puerperium. There is an increased risk of developing venous thromboembolism (VTE): the estimated risk is 1-2 in every 1000 births. [bleker 2014; clin adv hematol oncol 2005]
Patients with early stroke events (before 50 years of age), including children and teenagers, have an increased prevalence of TRB related genetic variants.
Thrombophilia in pregnancy
The combination of lifestyle options with genetic factors may predispose your body to form blood clots inside your veins and arteries. When a blood clot gets loose inside a vein, it migrates along your vessels following the natural blood flow. When it is too large, it can get stuck in your vessels blocking the blood flow, leading to a thromboembolism.
Thrombophilia is the main cause of maternal thromboembolism and is associated to an increased risk of recurrent fetal loss.
There are several hemostatic alterations during pregnancy and postpartum that lead to a hypercoagulable state and therefore for an increased risk of VTE, as all the elements of the Virchow’s triad are present during this stage of a woman’s life:
1. Hypercoagulability, due to higher levels of fibrinogen and coagulation factors, coupled with decreased levels of natural anticoagulant activity;
2. Venous stasis, promoted by hormone-mediated venous distention, increased vascular volume, and the pregnant uterus compressing blood vessels;
3. Vascular damage, which is induced by delivery.
TRB has been suggested to be a cause for microembolism in the placenta resulting in miscarriage or adverse outcome of pregnancy. [Jayasree 2012]
Pregnancy complications are due to hemostatic changes and inflamatory mechanisms, which can be worsened by TRB, leading to vascular damage, ischaemia and placental insufficiency. [acta med port 2012]
FALTA DESENVOLVER UM POUCO MAIS AQUI. Como se explica a perda do feto exactamente? Quais sao as implicações para a mae? Saude e psicologicas.
Testing the father.
When evaluating the risk of intrauterine fetal loss, studies also highlight the importance of analyzing both parents’ DNA in order to detect genetic variants associated to TRB
Studies evaluating carrier status of the fetus, defend that placental complications may occur on either side of the maternal-fetal interface. The homozygosity of genetic changes in placental tissue necessarily includes a role of the father’s genetic contribution in the outcome of the pregnancy. [fertil steril 2010]
FALTA EXPLICAR PORQUE? GENETIC CONTRIBUTION?
Thrombophilia when taking oral contraceptives
The use of oral contraceptives is, by itself, associated to a 4 to 5 times increase in thromboembolic events. Coupled with genetic variants associated to TRB
HT, the risk of venous thromboembolism in women increases greatly [4,5,6].
The use of hormonal contraceptives leads to a procoagulant risk profile through various mechanisms: increased levels of coagulation factors coupled with decreased levels of natural anticoagulant proteins and fibrinolytic activity. [bleker 2014]
Causes of TRB
HT is a multifactorial disease that may have genetic, lifestyle or acquired causes.
- Genetic risk factors: genetic changes in genes encoding clotting factors or anticoagulant proteins
- Ethnicity: the incidence of thromboembolic events is higher in Afro-american individuals followed by European populations
- Lifestyle related risk factors:
- Taking oral contraceptives or other hormonal therapies
- Pregnancy and puerperium
- Fatty liver disorder
- Chronic diseases: arterial hypertension, dyslipidaemia, diabetes mellitus, chronic renal disease, cardiac fibrillation, diseases of cardiac rhythm, congenital cardiac diseases, auto-immune diseases, congestive heart failure, …
- Prolonged immobilization due to inpatient hospitalization or long journeys
- Surgeries: major or orthopedic
- Trauma: muscular or in vessels
The association between molecular risk factors and clinical profile allows following up each patient in a personalized way, advocating a preventive medicine associated to TRB
In cases of familial history of trombophilia, FamilyCare is indicated to prevent life-traumatic events.
FamilyCare in the path of personalized medicine!
It is important to notice that a negative result the genetic test does not exclude the existence of pathology as there are other causative factors that are not included in this evaluation.
References – dps de definido o texto revejo a referenciação (VM)
 Maedica (Buchar). 2012 Sep;7(3):222-6. “Association of Prothrombin (A20210G) and Factor V Leiden (A506G) with Recurrent Pregnancy Loss.”
 Eur J Obstet Gynecol Reprod Biol. 2004 Mar 15;113(1):31-5. “Fetal inherited thrombophilias influence the severity of preeclampsia, IUGR and placental abruption.”
 A. L. Tranquilli, F. Saccucci, S. R. Giannubilo, M. Cecati, L. Nocchi, S. Lorenzi, and M. Emanuelli, Fertility and
sterility 94, 378 (2010).
 Haematologica 2000, 85(12):1271-1276
 J Thromb Haemost 2007, 5 Suppl 1:264-269
 Eur J Epidemiol. 2013 Aug;28(8):621-47. “Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls.”
Benefits of FamilyCare Genetic Test
Evaluates the predisposition to the occurrence of thrombosis allowing the recognition of signs and symptoms.
Evaluates the impact that TRB can have in the different stages of life as a woman.
There are simple therapeutic measures and lifestyle changes that can avoid a thrombotic event.
Supports the evaluation and determination of TRB according to a specific genetic profile.
2. Follow up.
Follow more closely targeted-diseased organs, preventing its worsening condition.
3. Familial Planning.
Allows familial planning choices that are tailored for each person.
Avoid uncertainty in the clinical diagnosis of TRB.
FamilyCare is an actionable, non-invasive and safe molecular diagnostic tool
FamilyCare is a novel diagnostic tool that evaluates the genetic risk of Hereditary Thrombophilia development.
FamilyCare is suitable to:
- Women with recurrent gestational problems
- Couples with familial history of thrombotic events
- Women with more than two miscarriages
- Women intending to start oral contraceptive therapy
- Family planning
Clinical benefits of FamilyCare:
- Evaluates. Evaluates genetic causes of thrombophilia.
- Classifies. Allows the individual and familial risk stratification
- Effective. Makes possible to modulate therapies and intervention strategies specific for HT
- Approaches. Improves proximity doctor-patient and increases adhesion to therapy.
- Alerts. Alerts for asymptomatic subjects carrier the risk of disease.
Improve your clinical diagnosis and prognosis.
Genetics of Hereditary Thrombophilia (TRB
Thrombophilia consists of an increased risk of blood clots formation. Blood clots may obstruct blood vessels, and may cause thrombophlebitis, stroke, myocardial infarction or pulmonary embolism. The risk of thromboembolic disease is increased by having a condition that causes the blood to clot more easily than normal. Several genetic studies established that TRB can be caused by insufficient inhibition of the coagulation cascade due to genetic changes that:
- result in deficiency in natural anticoagulant proteins
- lead to an increased activity of coagulation factors.
Pregnancy is a state characterized by physiological hypercoagulability, venous stasis and homeostasis alterations changes, and can contribute for an increased risk of thromboembolism. TRB may contribute to placental insufficiency, placental abruption, pre-eclampsia, intrauterine growth restriction and fetal losses. Hormonal contraception or hormone replacement therapy associated with thrombotic genetic factors, smoking, dyslipidemia, adiposity, hypertension or migraine, can contribute to thromboembolic risk. [3-5]
Key genes and proteins in TRB
Factor V Leiden (F5 gene)
Leiden factor V mutation (FVL) results in a genetic change on factor V that makes it partially resistant to protein C, an anticoagulant protein. FVL is therefore associated to hypercoagulable states and increased susceptibility to venous and arterial thromboembolism. The incidence of Leiden Factor V (FVL) is 2% to 5% in the general population and is responsible for 25% of recurrent venous thrombosis and/or pulmonary embolism cases. FVL is the most prevalent risk factor of thrombosis in the Caucasian population (3-7%). However, is rare in populations native to Africa or Asia. The FVL mutation in heterozygosity increases 3-8 times the risk of thromboembolic events, which is cumulative with age, pregnancy and use of oral contraceptives. [6-8]
Evidences show that pregnant women that carry this mutation have higher risk of late fetal loss. It also increases the susceptibility of venous thromboembolism in women using oral contraceptives. [9,10]
Methylenetetrahydrofolate reductase (MTHFR gene)
This enzyme converts homocysteine into methionine. Genetic variants in this gene decrease homocysteine conversion rate leading to hyper homocysteinemia which may cause thromboembolic events. Genetic variants in MTHFR gene are quite prevalent in the general population, but when combined with mutations in other associated genes such F5 or PAI-1, it may increase the risk of intra uterine fetal death. There is also an increased risk of VTE in women under oral contraceptive therapy. [10,12]
Plasminogen activator inhibitor type 1 (PAI-1 gene).
This protein is an inhibitor of fibrinolysis, that when in high concentrations may contribute to a pro-thrombotic status. A well known deletion in this gene is associated to an increased risk of recurrent fetal loss. [13,14]
Mutations in these genes may cause functional and/or structural changes in the proteins responsible for TRB
The identification of specific mutations has a huge value in your prognosis.
FamilyCare Testimonials: applications of Genetic test
No cases to present……
FamilyCare Gene Panel
FamilyCare genetic test evaluates 14 genetic variants in 10 genes associated to the hereditary predisposition for thrombotic events.
F2, F5, GP1BA, PROCR, PAI-1, MTHFR, PROS1, SERPINC1, F13A1 and FGB.
Clinical Guidelines (REFORMULADO DIRIGINDO SÓ AO ALVO FAMILY CARE)
Several international study groups recognize the impact of gene mutations in hereditary thrombophilia.
According to European Society of Cardiology Guidelines on the management of cardiovascular diseases during pregnancy:
“The presence of risk factors (Factor V Leiden mutation, prothrombin G20210 mutation, antithrombin deficiency, protein S and C deficiency) contributes to the increased risk of venous thromboembolism during pregnancy and the puerperium. Identification of risk factors in the individual patient is important for risk assessment and choice of preventive strategies. All women should undergo a documented assessment of risk factors before pregnancy.” 
According to the American College of Obstetricians and Gynecologists, testing for inherited thrombophilias should be considered for pregnant women in the following situations :
- Personal history of venous thromboembolism
- First-degree relative with a history of high-risk thrombophilia or venous thromboembolism before age 50 years
- Testing for inherited thrombophilias should include FVL, prothrombin gene mutation, antithrombin, protein S and protein C.
According to the International Consensus Guidelines, screening for thrombophilia should be performed in patients :
- with VTE whose only risk factor is oral contraceptive therapy, estrogen replacement therapy or pregnancy;
- with two consecutive or three non-consecutive abortions at any gestational age, or one fetal death after the 20th week;
- with severe pre-eclampsia.
How Genetic variants are selected:
- Research. Peer-reviewed scientific papers are selected using reference databases such as NCBI-Pubmed, HUGE Navigator, Scopus or ISI Web of Knowledge.
- Selection. Genetic mutations associated to HT and with clinical relevance to the disease are selected and compared against scientific databases, namely HGMDP, NCBI-OMIM, NCBI- ClinVar, NCBI-VariationReporter and Ensembl.
- Validation. HeartGenetics genetic panel is then validated by geneticists and cardiologists before being launched on the market.
How are FamilyCare reports?
- Comprehensive. FamilyCare panel includes all known* mutations and genetic variants associated to hereditary thrombophilia.
- Stratified. Our methodology directly targets the presence or absence of mutation, informing about the risk and severity for the development of:
– Fetal loss
– Venous thromboembolism
– Cardiovascular disease
- Rigorous. In technology. Our tests have 99% accuracy. In Knowledge: All evidences are supported by updated scientific knowledge and validated by medical doctors.
- Simple. All results include supporting information for each genetic variant including scientific references to guide the interpretation of test results.
Reports interpretation is supported through scientific papers published in PubMed and Human Gene Mutation Database (HGMD).
HeartGenetics results reports follow the recommendations from European Society of Human Genetics .
A parte abaixo riscada foi adaptada em conteudos acima sobre a genética da TRB.
Examples of supporting text. Factor V Leiden (F5 gene). Leiden factor V mutation (FVL) results in a genetic change on factor V that makes it partially resistant to protein C, an anticoagulant protein. FVL is therefore associated to hypercoagulable states and increased susceptibility to venous and arterial thromboembolism. Evidences show that pregnant women that carry this mutation have higher risk of late fetal loss . It also increases the susceptibility of venous thromboembolism in women using oral contraceptives . Prothrombin (F2 gene). During the coagulation process, prothrombin is converted into thrombin, a fundamental element to blood clot formation. The G20210A mutation in F2 gene is associated to high levels of prothrombin increasing thromboembolism risk. Meta-analysis studies refer that fetal loss may be associated to this mutation . Methylenetetrahydrofolate reductase (MTHFR gene). This enzyme converts homocysteine into methionine. Genetic variants in this gene decrease homocysteine conversion rate leading to hyper homocysteinemia which may cause thromboembolic events. Genetic variants in MTHFR gene are quite prevalent in the general population, but when combined with mutations in other associated genes such F5 or PAI-1, it may increase the risk of intra uterine fetal death [17,18]. Plasminogen activator inhibitor type 1 (PAI-1 gene). This protein is an inhibitor of fibrinolysis, that when in high concentrations may contribute to a pro-thrombotic status. A well known deletion in this gene is associated to an increased risk of recurrent fetal loss .
 J Genet Couns. 2007. 16(3):261-77. Inherited thrombophilia: key points for genetic counseling.
 Br J Haematol. 2008. 143(3):321-35. Does thrombophilia testing help in the clinical management of patients?
 N Engl J Med. 2001. 344(16):1222-31. Genetic susceptibility to venous thrombosis.
 Eur J Epidemiol. 2013. 28(8):621-47. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000controls.
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