Thrombophilia and venous thromboembolism: implications for testing

In the last decades, the knowledge on the etiology of venous thromboembolism (VTE) has increased tremendously. In approximately half of patients presenting with VTE, one or more thrombophilic defects can be identified. This has led to widespread testing for thrombophilia, despite the fact that, at present, it is unclear whether this should have therapeutic consequences. Here we review the currently established hereditary and acquired thrombophilic defects, and focus on the pros and cons of testing in the setting of VTE. Thrombophilia is defined as a disorder associated with an increased tendency to venous thromboembolism (VTE). Thrombophilia can be acquired, such as in patients with cancer, or congenital, in which case a defect in the coagulation system is hereditary. Egeberg was the first to use the term thrombophilia in 1965, when he described a Norwegian family that had a remarkable tendency to VTE, based on a deficiency of antithrombin. Since then, various laboratory abnormalities, both hereditary and acquired, have been discovered that increase the risk of VTE. This article reviews the currently established thrombophilic abnormalities and discusses the potential usefulness and implications of testing for thrombophilia.     

Prevalence of thrombophilia according to age at the first manifestation of venous thromboembolism: results from the MAISTHRO registry

Thrombophilia is a well‐established risk factor for a venous thromboembolic event (VTE), and it has been proposed that hereditary thrombophilia may substantially contribute to the development of VTE in young patients. We aimed to analyse the prevalence of thrombophilia with special regard to the age of VTE manifestation. The study cohort consisted of 1490 patients (58% females) with a median age 43 years at the time of their first VTE. At least one thrombophilic disorder was identified in 50·1% of patients. The probability of detecting a hereditary thrombophilia declined significantly with advancing age (from 49·3% in patients aged 20 years and younger to 21·9% in patients over the age of 70 years; P < 0·001). This may be primarily attributed to the decreasing frequencies of the F5 R506Q (factor V Leiden) mutation and deficiencies of protein C or protein S with older age at the time of the initial VTE event. Moreover, thrombophilia was more prevalent in unprovoked compared with risk‐associated VTE (57·7% vs. 47·7%; P = 0·001). The decline in the prevalence of hereditary thrombophilia with older ages supports the use of a selected thrombophilia screening strategy dependent on age and the presence or absence of additional VTE risk factors.     

Sex,thrombosis and inherited thrombophilia

The incidence of venous thromboembolism (VTE) is two-fold higher in women than in men during reproductive age, which is likely explained by the use of hormonal contraceptives and by pregnancy in this phase of life. After adjustment for these factors, men have a two-fold higher risk of developing a first VTE compared with women, which is in line with earlier observations that men have a two-fold higher risk of recurrent VTE. These findings indicate that the intrinsic risk of VTE is higher in men than in women. Hormonal contraceptives increase the risk of VTE and the risk varies per type, dose, and administration route. In women with a high baseline risk of VTE, avoidance of some hormonal contraceptives should be considered, as well as thrombosis prophylaxis during pregnancy. Presence of hereditary thrombophilia increases the risk of a first VTE episode. This review focuses on the differences in risk of VTE between men and women, hormonal risk factors for women, and how these interact with common types of hereditary thrombophilia.     

Evidence-based approach to thrombophilia testing

Thrombophilia can be identified in about half of all patients presenting with VTE. Testing has increased tremendously for various indications, but whether the results of such tests help in the clinical management of patients has not been settled. I use evidence from observational studies to conclude that testing for hereditary thrombophilia generally does not alter the clinical management of patients with VTE, with occasional exceptions for women at fertile age. Because testing for thrombophilia only serves limited purpose this should not be performed on a routine basis.     

Venous thromboembolism in women

AbstractThe risk of venous thromboembolism (VTE) varies throughout a woman's life and is associated primarily with underlying hormonal exposure. Alteration in hemostatic mechanisms, including resistance to activated protein C, may explain this altered risk. Initially, development of VTE with the use of contraception in young adulthood may reveal inherited thrombophilia. Pregnancy, and particularly the post-partum period, likely confer the greatest risk of VTE, but the absolute risk is small. Guidelines for prevention of VTE during pregnancy are based on personal or family history of VTE, and known inherited thrombophilia. Use of hormone replacement therapy later in life is associated with increased risk of VTE, and may be safest if given as an estrogen-only preparation to young postmenopausal women for less than 5 years. Universal screening for thrombophilia prior to pregnancy or initiating hormonal therapy is not recommended; however, selected testing in high-risk groups may be warranted. The lack of firm recommendations for the prevention of VTE in women highlights the need for future investigation aimed at identifying high-risk groups and evaluating the efficacy of prophylactic measures.     

Should patients with venous thromboembolism be screened for thrombophilia?

In the mid-19th century, Virchow identified hypercoagulability as part of the triad leading to venous thrombosis, but the specific causes of hypercoagulability remained a mystery for another century. The first specific cause to be identified was antithrombin III deficiency. Many other causes of thrombophilia, both genetic and acquired, have been discovered since then. The 2 most common genetic causes of thrombophilia are the Leiden mutation of factor V and the G20210A mutation of prothrombin. The most common acquired cause is antiphospholipid syndrome. These factors increase the relative risk of an initial episode of venous thromboembolism (VTE) by a factor of 2 to 10, but the actual risk remains relatively modest. Therefore, thrombophilia screening to prevent initial episodes of VTE is not indicated, except possibly in women with a family history of idiopathic VTE who are considering oral contraceptive therapy. Some physicians screen for thrombophilia to aid decision making concerning the duration of anticoagulant therapy. However, several studies have demonstrated that, with the exception of antiphospholipid syndrome, thrombophilia does not significantly increase the risk of recurrent VTE. On the other hand, idiopathic VTE significantly increases the risk of recurrence in patients with or without thrombophilia.     

Inherited thrombophilia, pregnancy, and oral contraceptive use: clinical implications

Inherited thrombophilia has been reported to be associated with an increased risk for complications of pregnancy, including venous thromboembolism (VTE) as well as preeclampsia (PEC), fetal loss (FL), fetal growth retardation (FGR), and abruptio placentae (AP), the latter probably due to inadequate placental perfusion. The estimate of risk largely depends on the kind of thrombophilia and on the criteria applied for the selection of the patients, producing in some cases contradictory results. Convincing evidence is available that deficiency of antithrombin III (AT), protein C (PC), and protein S (PS) is a risk factor for VTE and late FL. Factor V (Leiden) is associated with an increased risk for VTE, unexplained recurrent FL, late FL, and perhaps PEC; prothrombin G20210A is a weak risk factor for VTE. So far, the data available for FGR and AP are scarce. However, the absolute risk for VTE during pregnancy and puerperium is between 1 and 3%, in comparison with the baseline risk of 0.08%. Antithrombotic prophylaxis with subcutaneous heparin is warranted during puerperium in all women with thrombophilia and throughout all pregnancy in women at higher risk (AT deficiency, homozygosity for factor VLeiden, and perhaps PC and PS deficiencies); treatment with subcutaneous heparin for prevention of FL among women with thombophilia is under investigation. Presence of inherited thrombophilia increases the risk for VTE due to oral contraceptives up to an absolute risk of 3 per 1000 person-years, in comparison with the baseline risk of 3 to 6 per 10000 person-years; the risk is further increased by first usage, the use of preparations containing third-generation progestins, and thrombophilia due to AT, PC, and PS deficiency as well as homozygous factor V (Leiden) and combined defects.     

Screening for inherited thrombophilia: indications and therapeutic implications

BACKGROUND AND OBJECTIVES: In recent years knowledge concerning inherited and acquired causes of thrombophilia has increased greatly. The most common inherited traits (deficiency in antithrombin, protein C, or protein S, factor V Leiden, prothrombin G20210A) and mild hyperhomocysteinemia are diagnosed in at least 40% of patients with venous thromboembolism (VTE). INFORMATION SOURCES: The authors work in this field, contributing to multicenter clinical and laboratory investigations and to peer-reviewed journals with original papers. The material examined in this review includes articles published in journals covered by MedLine. STATE OF THE ART: The associated risk for VTE is different according to genotype, being higher among the carriers of natural anticoagulant deficiencies and homozygotes for factor V Leiden. The overall prevalence of thrombophilic traits in the general population being near to 10% renders the probability of carrying multiple defects not excessively rare, with a further increase in thrombotic risk of up to 20-fold. Thus, clinical penetrance is heterogeneous, producing either mild or severe venous thrombotic manifestations, which can be unprovoked or associated with circumstantial risk factors and occur in either young or advanced age. More recently, inherited thrombophilia has been focused on as an important determinant of complications of pregnancy and puerperium. As expected, inherited thrombophilia produces an increased risk of VTE, particularly during puerperium. Moreover it is well established that thrombophilic women have an increased risk of late and/or recurrent fetal loss; whether they are at higher risk of pre-eclampsia, fetal growth restriction, and abruptio placentae is debated. Overall, 40% of women with obstetric complications other than VTE carry a thrombophilic trait. Yet, as a rule VTE and obstetric complications seem to occur in different individuals, probably because of the presence of unknown factors favoring one or other of these clinical manifestations. CONCLUSIONS AND PERSPECTIVES: Inherited thrombophilia is now viewed as a multicausal model, the clinical event being the result of gene-gene and gene-environment age-dependent interactions; the associated clinical manifestations can be heterogenous as regards severity as well as type of event (VTE or obstetric complication). Therefore the criteria for screening affected individuals who have suffered from the above complications or their relatives should not be very stringent. The patient's genotype could be a main determinant of the features of primary or secondary prophylaxis used in the affected individual.     

Inherited thrombophilia and venous thromboembolism

The term thrombophilia includes any inherited and acquired disorders associated with an increased tendency to venous thromboembolism (VTE). Inherited thrombophilia is one of the main determinants of VTE, and the presence of inherited thrombophilic defects exposed carriers to increased risks for VTE compared with noncarriers. There is no clear relationship between clinical manifestations and the type of underlying thrombophilic defect. Thus, the diagnosis of inherited thrombophilia has to be established on a laboratory basis. Carriers of thrombophilic defects may experience thrombosis at a younger age than noncarriers. However, a first thrombotic manifestation that occurs late in life may also be an expression of thrombophilia and this remains in many cases the only etiopathogenetic explanation for the event. Screening of family members of symptomatic probands has the potential to identify still asymptomatic carriers who may benefit from more appropriate thromboprophylaxis during high-risk situations for VTE. Women of fertile age who belong to these thrombophilic families might receive the greatest advantage from screening. Many inherited thrombophilic disorders can be considered risk factors for recurrent VTE, especially if more than one defect is present in the same patient. More intensive or prolonged duration of VTE treatment might be requested for the prevention of recurrent VTE in the most severe thrombophilic conditions. The availability of new methods for the assessment of thrombin generation in terms of endogenous thrombin potential are very promising tools for the identification of those carriers of inherited thrombophilia who will develop thrombosis or who will encounter recurrence of VTE.     

Thrombophilia: 2009 update

As venous thrombosis is mostly caused by disturbances in the plasma coagulation system, abnormalities of coagulation factors are mostly risk factors for venous thromboembolism (VTE). Relatively little is known about thrombophilias that predispose to arterial thromboembolism. Although some abnormalities in the fibrinolytic pathway appear to predispose to arterial thrombosis, the associations are weak and often inconsistent between studies. At present, there is not enough consistent and clinically meaningful information to include fibrinolytic parameters in a clinical thrombophilia workup. Controversy exists as to which patients and family members to test for thrombophilia. Several testing guidelines exist. Routine screening for inherited thrombophilias is not indicated in patients with VTE provoked by immobility, surgery, and malignancy, or in those with arterial thrombosis with arteriosclerosis risk factors. Heterozygous factor V Leiden (FVL) and prothrombin 20210 mutations increase the risk for recurrent VTE only slightly once anticoagulation is stopped. Therefore, decisions regarding the length of anticoagulant therapy typically are not influenced by finding one of these heterozygous mutations. The main reason to perform thrombophilia testing in a patient is to detect a strong thrombophilia (ie, antithrombin deficiency, antiphospholipid antibody syndrome, homozygous FVL, double-heterozygous FVL plus prothrombin 20210 mutation, protein C deficiency, and maybe protein S deficiency). The finding of a strong thrombophilia has several clinical consequences: it decreases the threshold to recommend long-term anticoagulation in a patient with unprovoked VTE; facilitates discussion regarding whether anticoagulant or antiplatelet therapy is the preferred empiric treatment for a patient who had an unexplained arterial, nonarteriosclerotic thromboembolic event; and leads to the consideration of testing asymptomatic female family members for the identified thrombophilia(s) so they can be counseled on their risk of thromboembolism, the use of hormonal therapies, and the potential benefit of pre- and postpartum anticoagulant therapy.     

Epidemiology, risk factors and sequelae of venous thromboembolism

The aim of this review was to discuss the epidemiology, risk factors and sequelae of venous thromboembolism (VTE). VTE has an incidence of 1-2 per 1000 people annually. The risk of VTE increases with age and is highest in Caucasians and African Americans. Combined oral contraceptives (COC), especially the third-generation COCs, have been strongly implicated in VTE. Hospitalized patients, especially patients with underlying malignancy and undergoing surgery, have a host of risk factors for VTE. Thrombophilia can predispose an individual to VTE but indiscriminate testing for thrombophilia in patients presenting with VTE is not indicated. VTE can have serious chronic sequelae in the form of post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTPH). The risk of PTS and CTPH is increased with recurrent deep vein thrombosis and pulmonary embolism, respectively. Mortality from VTE can be as high as 21.6% at one year. Patients who had an episode of VTE have a high risk of subsequent VTE and this risk is highest in patients who had a first VTE event associated with malignancy. A good understanding of the epidemiology and risk factors of VTE will enable the treating medical practitioners to identify patients at risk and administer appropriate VTE prophylaxis to prevent the long-term consequences of VTE.     

Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study

Screening for inherited thrombophilia (IT) is controversial; persons at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first- and second-degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (hazard ratio = 7.6; 95% confidence interval [CI], 4.0-14.5; P < .001) and highest among carriers of antithrombin, protein C, or protein S deficiency (hazard ratio = 25.7; 95% CI, 12.2-54.2; P < .001). Annual incidences of VTE were 2.82% (95% CI, 1.63%-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12%-0.53%) for factor II G202010A, 0.25% (0.12%-0.53%) for factor V G1691A, and 0.10% (0.06%-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S, and antithrombin deficiency, we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess whether thromboembolism can be prevented in this high-risk population.     

Prevention,management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency

Antithrombin (AT) deficiency is a rare hereditary thrombophilia with a mean prevalence of 0.02 % in the general population, associated with a more than ten-fold increased risk of venous thromboembolism (VTE). Within this multicenter retrospective clinical analysis, female patients with inherited AT deficiency were evaluated concerning the type of inheritance and extent of AT deficiency, medical treatment during pregnancy and postpartally, VTE risk as well as maternal and neonatal outcome. Statistical analysis was performed with SPPS for Windows (19.0). A total of 18 pregnancies in 7 patients were evaluated, including 11 healthy newborns ≥37th gestational weeks (gw), one small for gestational age premature infant (25th gw), two late-pregnancy losses (21st and 28th gw) and four early miscarriages. Despite low molecular weight heparin (LMWH) administration, three VTE occurred during pregnancy and one postpartally. Several adverse pregnancy outcomes occurred including fetal and neonatal death, as well as severe maternal neurologic disorders occurred. Patients with substitution of AT during pregnancy in addition to LMWH showed the best maternal and neonatal outcome. Close monitoring with appropriate anticoagulant treatment including surveillance of AT levels might help to optimize maternal and fetal outcome in patients with hereditary AT deficiency.     

Thrombophilia and its Treatment in Pregnancy

Pulmonary embolism is the most common cause of maternal death during pregnancy and the puerperium in the industrialized world. The risk of venous thromboembolism (VTE) in pregnancy is 0.05%–1.8%, 6 times greater than in the non-pregnant state. The risk is increased in women over 35 years and those with obesity, previous VTE, operative delivery, or underlying thrombophilia. Women presenting with recurrent miscarriages, preeclampsia, intrauterine growth restriction, abruptio placentae, or stillbirth (all associated with microvascular thrombosis in placental blood vessels) have high incidence (65%) of thrombophilia. About 70% of the women who present with VTE during pregnancy are carriers of hereditary or acquired thrombophilia. Treatment of women with VTE during pregnancy, and especially those with thrombophilia, requires individualized dosing and duration of antithrombotic therapy and the formulation of thromboprophylactic strategies for future pregnancies. Warfarin is contraindicated during the first trimester due to fetotoxicity; unfractionated heparin (UFH) is associated with practical disadvantages and the risk of heparin-induced thrombocytopenia (HIT) and osteoporosis with long-term use. Low molecular weight heparins (LMWHs) are convenient to use, do not cross the placenta, carry a lower risk of HIT and osteoporosis, and are safe and effective. LMWHs are replacing UFH as the anticoagulant of choice during pregnancy and improve pregnancy outcome in women with a history of obstetric complications and confirmed thrombophilia.     

Impact of high‐risk thrombophilia status on recurrence among children with a first non‐central‐venous‐catheter‐associated VTE: an observational multicentre cohort study

Deficiency of antithrombin (AT), protein C (PC) or protein S (PS) constitutes a major risk factor for venous thromboembolism (VTE). Individuals at high risk for recurrence who benefit from screening need to be identified. The primary study objective was to determine the individual recurrence risk among children with a first non‐central‐venous‐catheter‐associated VTE with respect to their thrombophilia status and to evaluate if the clinical presentation at first VTE onset differs between children with AT, PC or PS deficiency versus no thrombophilia. We calculated the absolute risk of VTE recurrence and event‐free‐survival adjusted for thrombophilia, age, sex and positive family VTE history in 161 consecutively enrolled paediatric VTE patients. The presence of a deficiency relative to no thrombophilia was evaluated as a potential predictor of recurrence. Predictors for recurrence were AT deficiency (hazard ratio/95% CI: 6·5/2·46–17·2) and female gender (2·6/1·1–6·35). The annual recurrence rates (95% CIs) were 5·4% (2·6–10) in AT‐deficient children, 1·3% (0·3–3·8) in patients with PC deficiency, 0·7% (0·08–2·4) in the PS‐deficient cohort and 0·9% (0·4–1·8) in patients with no thrombophilia. Positive family VTE history or combined thrombophilias did not predict recurrence. Given the overall annual incidence rate of recurrence of 1·5% we suggest screening for AT deficiency in children with VTE.     

D-dimer levels, constitutional thrombophilia, and venous thrombosis prediction: clinical aspects and implications

The negative predictive value of D-dimers in the diagnosis of a recent venous thromboembolism (VTE) episode is well established. The plasma level of D-dimer is usually increased in hypercoagulable states. The measurement of D-dimer could be of clinical interest in patients with constitutional thrombophilia as there is no close relationship between the clinical expression and the genotype indicating the existence of a hypercoagulable state. Moreover, the predictive value of D-dimer testing in patients with thrombophilia has been questioned. The review of the literature and results of a recent study of our group are presented. Decreased levels of D-dimer are observed in patients receiving an oral anticoagulant treatment versus untreated patients. In contrast, no significant difference was observed between those with and those without thrombophilia among treated or untreated patients. Patients with constitutional thrombophilia are supposed to have an increased risk of postoperative VTE. The review of the existing literature could not confirm this opinion but this could be due to the fact that most patients receive a prophylactic treatment. Thus, there is an indirect evidence of its efficacy in these patients.     

Secondary prophylaxis of venous thromboembolism

Making decisions about any modality of secondary prophylaxis in patients with venous thromobembolism (VTE) has to balance the risk of bleeding induced by anticoagulants against the benefit of reducing the risk of recurrent disease. It has to be kept in mind that the magnitude of risk is not only defined by the number of events per time period but also by the impact of the event on the fate of the patient. With standard intensity Vitamin K antagonists, the risk of bleeding is more closely related to comorbidities than to other factors, e.g. age. The risk of VTE recurrence differs largely between patient groups. The criterion of presence, or absence of a permanent or transient clinical trigger factor for the actual VTE episode has a greater impact than an abnormal result in thrombophilia testing. The standard period ofsecondary prophylaxis for proximal deep vein thrombosis and for pulmonary embolism is three to six months. The concept of prolonging this period for several months according to the risk of recurrence is seriously challanged by the observation that the prolongation period seems to delay recurrencies rather than truly avoiding them. For this reason, patients who clearly are threatened by recurrent episodes should receive indefinitive secondary prophylaxis. This is the case for cancer patients, patients with the antiphospholipid syndrome, and those who belong to families with severe and symptomatic protein C, protein S, or antithrombin deficiencies. Patients with recurrent VTE, with idiopathic VTE, or with combined thrombophilic conditions may only benefit from indefinitive secondary prophylaxis if the bleeding risk of the anticoagulant regimen under consideration is very low.     

FV Leiden mutation and risk of recurrent venous thromboembolism in Serbian population

The absolute rate of recurrence of venous thromboembolism (VTE) is approximately 5% per year. There is a lower rate of recurrence in provoked VTE, and higher in idiopathic one. So far, there is no consensus whether hereditary thrombophilia should be considered as a persistent risk factor, and whether it requires long-term anticoagulant therapy. The aim of our study was to estimate the risk of recurrent VTE in patients carrying FV Leiden mutation in Serbian population.In retrospective study (1994-2006), we have evaluated the risk of recurrent VTE in 56 patients who are carriers of FV Leiden mutation, in comparison to group consisting of 56 patients non-carriers of FV Leiden mutation. Patients with FII G20210A and MTHFR C677T mutations, antiphospholipid antibodies, antithrombin III, protein C or protein S deficiency, malignancies and diabetes were excluded from the study.Recurrent VTE occurred in 44.6% of the patients, carriers of the FV Leiden mutations, vs. 26.7% in non-carriers group (P<0.05). The incidence rate was 3.7 and 2.2% per year, respectively. The estimated relative risk of recurrence for FV Leiden carriers was 1.67 (95% CI 0.99-2.81, P=0.049). The 60% of patients with mutation and only 13% without mutation develop rethrombosis during first year after discontinuance of therapy (P<0.01).In our study patients with symptomatic VTE who are carriers of the FV Leiden gene mutations have a higher risk of recurrent VTE than non-carriers. Our data suggest the importance of the FV Leiden mutation detection and the estimation of the clinical condition for successful secondary prophylaxis of VTE.     

Risk of thrombosis associated with oral contraceptives of women from 97 families with inherited thrombophilia: high risk of thrombosis in carriers of the G20210A mutation of the prothrombin gene

BACKGROUND AND OBJECTIVES: Oral contraceptives (OC) and inherited thrombophilia are well-known risk factors associated with venous thromboembolism (VTE). However, there are only few studies on the risk of VTE in women with inherited thrombophilia who use oral contraceptives. DESIGN AND METHODS: We performed a retrospective family cohort study of 325 women belonging to 97 families with inherited thrombophilia, including antithrombin, protein S and C deficiencies, the factor V Leiden mutation (FVL) and the G20210A mutation of the prothrombin gene (PT20210A) to determine the risk of VTE associated with OC intake. RESULTS: For carriers of the PT20210A mutation, the risk of VTE in OC users was 3-fold higher (95% CI 1.3-6.8) than that in non-carriers. Carriers of FVL mutation taking OC showed an OR of 1.4 (95% CI 0.6-3.3), indicating a tendency to increase the risk of VTE. INTERPRETATION AND CONCLUSIONS: Because of the high prevalence of the PT20210A (6.5%) and FVL (2%) mutations in the general Spanish population and the increased risk of VTE associated with OC intake, genetic screening for these mutations should be considered in potential OC users belonging to families with thrombophilia.     

Antithrombotic prophylaxis and treatment in thrombophilic disorders in gynaecology and obstetrics

Pregnancy and puerperium are physiological thrombophilic condition and risk of venous thromboembolism in pregnancy is 4 - 6 fold higher. This risk is further increased in the presence of the additional risk factors. Inherited thrombophilia is well-defined risk factor for VTE in pregnancy and also can be the risk for obstetrics complications. So that early diagnostic of inherited thrombophilia can result in the decrease of risk of VTE and the obstetrics complications.