The Impact Of Screening For Factor V Leiden (FVL) First Degree Relatives Of Patients With Venous Thromboembolism (VTE) And FVL On Their Risk Of VTE

Abstract Introduction Testing for inherited and acquired thrombophilias adds to the cost of care of patients with venous thromboembolism (VTE), though results may not influence patient management. Methods This is a single-center, retrospective study conducted at Emory University Hospitals from January to December 2015 to (1) determine the pattern of thrombophilia testing in patients with VTE, (2) study the impact of results of thrombophilia testing on clinical decision-making, and (3) determine the direct costs of thrombophilia testing in patients with VTE. Results Of the 266 eligible patients, 189 (71%) underwent testing; 51 (26.9%) tested positive and the results impacted management in 32 (16.9%) of tested patients. Patient undergoing testing were more likely to be younger than 40 years (30.9 vs. 18.2%), have had prior pregnancy loss (9.0 vs. 0%), or known family history of hypercoagulability (24.9 vs. 10.4%), and were less likely to have had provoked VTE (37 vs. 79.2%). The most common thrombophilias tested were antiphospholipid syndrome (60.1%), factor V Leiden (59.7%), and prothrombin gene mutation (57.5%). Direct costs of thrombophilia testing were $2,364.32 per patient, $12,331.55 to diagnose 1 positive, and $19,653.41 per patient-management affected. Conclusion We noted significant variability in selection of patients and panel of tests, sparse utilization of test results in patient management, but high cost associated with thrombophilia testing in patients with VTE. With guidelines advocating selective use of thrombophilia testing and attention to potential impact of test results in patient management, we propose the need for measures at institutional levels to improve test-ordering practices.

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Factor V Leiden Mutation Increases the Risk of Venous Thromboembolism in Cancer Patients – Results From the Vienna Cancer and Thrombosis Study (CATS).

Blood ◽

10.1182/blood.v120.21.2253.2253 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2253-2253

Author(s):

Ingrid Pabinger ◽

Cihan Ay ◽

Daniela Dunkler ◽

Johannes Thaler ◽

Eva-Maria Reitter ◽

...

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Factor V Leiden ◽

Treatment Modalities ◽

Individual Risk ◽

Factor V ◽

Newly Diagnosed ◽

Factor V Leiden Mutation ◽

Increased Risk ◽

The Impact

Abstract Abstract 2253 Background: Patients with cancer are at an increased risk of venous thromboembolism (VTE). The risk varies markedly in different patient populations and improvement of the prediction of VTE would be of advantage for tailoring thrombosis prophylaxis. Factor V Leiden is the most common genetic risk factor for VTE and the impact of factor V Leiden on cancer-associated thrombosis is not yet fully elucidated. Objective: To study the impact of factor V Leiden on the risk of VTE in cancer patients. Patients and Methods: Nine-hundred-eighty-two patients with newly diagnosed cancer (n=745) or progression of disease after complete or partial remission (n=237) were included in the cancer and thrombosis study (CATS), a prospective observational single centre cohort study at the Medical University Vienna. Patients were followed for a maximum period of 2 years. Blood samples were collected at inclusion and factor V Leiden was determined by genotyping. The main outcome measure was symptomatic or lethal objectively confirmed VTE. All VTE events were adjudicated independently. Results: Of the 982 patients (median age 62 years, interquartile range (IQR) 52–68, 537 men, 445 women) factor V-Leiden was found in 72 (7.3%), 70 had a heterozygous and two a homozygous genotype. Ten of 72 (14%) patients with factor V-Leiden developed VTE, whereas this was the case in 69 of 910 (7.6%) patients without factor V-Leiden. Interestingly, both patients with homozygous factor V Leiden developed VTE. In multivariable analysis that included age, sex, different tumour types, newly diagnosed versus recurrence of disease and the treatment modalities (chemotherapy, radiotherapy and surgery) the hazard ratio (HR) for factor V Leiden was 2.04 (95% confidence interval (CI) 1.04–3.97)). In patients with newly diagnosed tumours the HR for factor V Leiden was 3.7 (95% CI 1.2–12.2) after 30 days. In Kaplan Meier analysis the probability for development of VTE after 6 months was 5.7% in those without and 13% in those with factor V Leiden, after one year the corresponding rates were 7.3% and 15%. Conclusions: Factor V Leiden is a genetically determined and thus disease-independent parameter, which is associated with VTE in cancer patients, especially shortly after cancer diagnosis, and could therefore be used for individual risk assignment. Disclosures: No relevant conflicts of interest to declare.

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Thrombin generation in first-degree relatives of patients with venous thromboembolism who have factor V Leiden

Thrombosis and Haemostasis ◽

10.1160/th07-08-0515 ◽

2008 ◽

Vol 99 (01) ◽

pp. 223-228 ◽

Cited By ~ 21

Author(s):

Jèrôme Duchemin ◽

Christophe Leroyer ◽

Bènèdicte Delahousse ◽

Jean François Abgrall ◽

Dominique Mottier ◽

...

Keyword(s):

Venous Thromboembolism ◽

Odds Ratio ◽

Thrombin Generation ◽

Adjusted Odds Ratio ◽

Factor V Leiden ◽

Factor V ◽

Oestrogen Therapy ◽

Prothrombotic State ◽

First Degree Relatives ◽

Generation Test

SummaryThe thrombin generation test appears to be a highly sensitive and specific test in the detection of thrombophilia in patients with venous thromboembolism. We aimed to determine the accuracy of the thrombin generation test to detect factorV Leiden and/or other prothrombotic states in first-degree relatives of patients with venous thromboembolism and factor V Leiden. Sixty-two first-degree relatives of 21 index cases were tested for factor V Leiden, the G20210A prothrombin gene mutation and thrombin generation. Information about oestrogen therapy and previousVTE was also collected. The normalized Thrombomodulin sensitivity ratio (n-TMsr) was defined as the ratio of endogenous thrombin potential determined in the presence and absence of thrombomodulin which was normalized against the same ratio determined in normal control plasma. The mean n-TMsr was 1.37 (± 0.33) in the 45 relatives with one or more prothrombotic state (factor V Leiden, G20210A prothrombin mutation, oestrogen therapy or hormonal therapy) and 1.02 (± 0.34) in the 17 relatives without prothrombotic state (p = 0.001). The positive predictive value was 90.3 (95%CI, 73.1 – 97.4). In relatives with an abnormal n-TMsr, the adjusted odds ratio for having a prothrombotic state was 8.3 (95%CI, 1.9 – 36.9) and the adjusted odds ratio for having the factor V Leiden was 14.3 (95%CI, 2.9 – 71.2).An abnormal thrombin generation test appears highly predictive for having factor V Leiden and/or other prothrombotic states in first-degree relatives of patients with venous thromboembolism and factor V Leiden.

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The Impact of Multiple Risk Factors for Venous Thromboembolism and Its Implications for Management

Global Pediatric Health ◽

10.1177/2333794x19859161 ◽

2019 ◽

Vol 6 ◽

pp. 2333794X1985916

Author(s):

Anil P. George ◽

Paul Kent

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Pediatric Patients ◽

Assessment Tool ◽

Factor V Leiden ◽

Prothrombin G20210a ◽

Factor V ◽

Multiple Risk Factors ◽

Multiple Risk ◽

The Impact

Venous thromboembolism (VTE) is a rare multifactorial disorder in childhood with an annual incidence of about 0.07 to 0.14 per 10 000 children. A 15-year-old female with a body mass index of 48 kg/m2 who endorsed oral contraceptive use presented with clinical findings consistent with deep venous thrombosis along with the presence of a pulmonary embolism. Further workup revealed that the patient was heterozygous for factor V Leiden and homozygous for prothrombin G20210A mutations. There are no current pediatric guidelines for the antithrombotic management of patients with multiple risk factors for VTE. Two such risk factors, obesity and the use of estrogen-containing hormone contraceptives, have been implicated in adult VTE cases but have not been clearly delineated in pediatric patients. The need for guidance regarding the VTE management of these patients has become more apparent given the increasing incidence of childhood obesity and the number of adolescents using oral contraceptives. Additionally, thrombophilia testing remains controversial though testing may be indicated in asymptomatic first-degree relatives and in families with antithrombin, protein C, or protein S deficiencies. Given the increased incidence of multiple risk factors for VTE, there is also a need to develop a comprehensive risk assessment tool for pediatric patients at high risk of VTE.

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Incidence of venous thromboembolism in first-degree relatives of patients with venous thromboembolism who have factor V Leiden

Thrombosis and Haemostasis ◽

10.1160/th06-06-0328 ◽

2006 ◽

Vol 96 (12) ◽

pp. 744-749 ◽

Cited By ~ 20

Author(s):

Clive Kearon ◽

Christophe Leroyer ◽

Bernard Mercier ◽

Jean Abgrall ◽

Grégoire Le Gal ◽

...

Keyword(s):

Venous Thromboembolism ◽

Factor V Leiden ◽

Annual Incidence ◽

Factor V ◽

Genetic Abnormality ◽

First Degree Relatives ◽

Threefold Increase ◽

Increased Risk ◽

Routine Prophylaxis ◽

The Difference

SummaryThe factor V Leiden (FVL) mutation, a genetic abnormality with an autosomal mode of inheritance, is associated with an increased risk of venous thromboembolism (VTE). We aimed to determine the annual incidence of VTE in first-degree relatives of patients with VTE and FVL and to identify factors in patients and the relatives that influence this incidence. In this retrospective and prospective cohort study, the incidence of objectively diagnosed first episodes of VTE was assessed in 553 first-degree relatives of 161 patients with acute VTE and FVL. The annual incidence of VTE was 0.43% (95% CI, 0.3 to 0.56) with FVL and 0.17 % (95% CI, 0.07 to 0.27) without FVL (relative risk of 2.5, 95% CI, 1.3 to 4.7). A majority (70%) of episodes of VTE were provoked, and this proportion was similar with and without FVL. A larger proportion of VTE was provoked in women (83%) that in men (33%), with the difference accounted for by pregnancy and use of oral contraceptives. The proportion of pregnancies complicated by VTE was 3.9% (95% CI, 2.0–5.8) with FVL and 1.4% (95% CI, 0.04–2.7) without FVL. FVL is associated with a two-to threefold increase in VTE in first-degree relatives of patients with VTE. No subgroup of relatives was identified who require more than routine prophylaxis because of a particularly high risk of VTE.

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Haemostaseome-associated SNPs: has the thrombotic phenotype a greater influence than ethnicity?

Thrombosis and Haemostasis ◽

10.1160/th14-02-0189 ◽

2015 ◽

Vol 113 (01) ◽

pp. 66-76 ◽

Cited By ~ 2

Author(s):

Sylvie Labrouche ◽

Christophe Hubert ◽

Frédéric Bauduer ◽

Geneviève Freyburger

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Genetic Markers ◽

Factor V Leiden ◽

Significant Snps ◽

Low Risk ◽

Coagulation System ◽

Factor V ◽

Wide Range ◽

The Impact

SummaryThe Genetic Markers for Thrombosis (GMT) study compared the relative influence of ethnicity and thrombotic phenotype regarding the distribution of SNPs implicated in haemostasis pathophysiology (“haemostaseome”). We assessed 384 SNPs in three groups, each of 480 subjects: 1) general population of Aquitaine region (Southwestern France) used as control; 2) patients with venous thromboembolism from the same area; and 3) autochthonous Basques, a genetic isolate, who demonstrate unusual characteristics regarding the coagulation system. This study sought to evaluate i) the value of looking for a large number of genes in order to identify new genetic markers of thrombosis, ii) the value of investigating low risk factors and potential preferential associations, iii) the impact of ethnicity on the characterisation of markers for thrombosis. We did not detect any previously unrecognised SNP significantly associated with thrombosis risk or any preferential associations of low-risk factors in patients with thrombosis. The sum of ϰ2 values for our 110 significant SNPs demonstrated a smaller genetic distance between patients and controls (321 cumulated ϰ2 value) than between Basques and controls (1,570 cumulated ϰ2 value). Hence, our study confirms the genetic particularity of Basques especially regarding a significantly lower expression of the non-O blood group (p< 0.0004). This is mitigated by a higher prevalence of factor II Leiden (p< 0.02) while factor V Leiden prevalence does not differ. Numerous other differences covering a wide range of proteins of the haemostaseome may result in an overall different genetic risk for venous thromboembolism.

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The Impact of Dalteparin (Fragmin®) on Thrombin Generation in Pregnant Women with Venous Thromboembolism: Significance of the Factor V Leiden Mutation

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615718 ◽

2001 ◽

Vol 85 (05) ◽

pp. 782-786 ◽

Cited By ~ 7

Author(s):

Edda Eberl ◽

Ulrich Geisen ◽

Ralf Grossmann ◽

Franz Keller ◽

Schambeck Christian

Keyword(s):

Venous Thromboembolism ◽

Pregnant Women ◽

Thrombin Generation ◽

Clinical Signs ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Asymptomatic Patients ◽

The Impact ◽

Fvl Mutation

SummaryHypercoagulability is observed in patients with inherited thrombophilia, e.g. factor V Leiden (FVL) mutation. Pregnancy represents a hypercoagulable state as well. This study addresses the effects of the FVL mutation on haemostatic activation during pregnancy as indicated by prothrombin fragments (F1+2). 233 pregnant women with no history of venous thromboembolism were studied. Additionally, two patient groups (25 pregnant FVL carriers and 36 pregnant women without thrombophilic diathesis) in whom low molecular weight heparin (dalteparin) was used prophylactically against rethrombosis were investigated.None of the women developed clinical signs of venous thromboembolism during pregnancy or after delivery. Untreated women exhibited substantial hypercoagulability. F1+2 levels were similar in FVL carriers and non-carriers (difference n. s.). After sufficient adjustment for anti-factor Xa activity (≥0.15; ≤0.4 U/mL), heparinized women without any thrombophilic diathesis had significantly lower levels of F1+2 than untreated pregnant women. This was evident only in the first and second trimenon (p <0.01). F1+2 levels in heparinized FVL carriers were quite similar to the levels observed in untreated pregnant women, however. In conclusion, our data support the thesis that in comparison to asymptomatic patients, thrombin generation is exaggerated in symptomatic FVL carriers. Coagulation activation during pregnancy can be reduced by dalteparin.

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Thrombophilia and risk of VTE recurrence according to the age at the time of first VTE manifestation

VASA ◽

10.1024/0301-1526/a000447 ◽

2015 ◽

Vol 44 (4) ◽

pp. 313-323 ◽

Cited By ~ 6

Author(s):

Lea Weingarz ◽

Marc Schindewolf ◽

Jan Schwonberg ◽

Carola Hecking ◽

Zsuzsanna Wolf ◽

...

Keyword(s):

Factor V Leiden ◽

Cox Proportional Hazards ◽

First Episode ◽

Factor V ◽

Factor V Leiden Mutation ◽

Younger Patients ◽

Risk Of Recurrence ◽

G20210a Mutation ◽

Increased Risk ◽

The Impact

Abstract. Background: Whether screening for thrombophilia is useful for patients after a first episode of venous thromboembolism (VTE) is a controversial issue. However, the impact of thrombophilia on the risk of recurrence may vary depending on the patient’s age at the time of the first VTE. Patients and methods: Of 1221 VTE patients (42 % males) registered in the MAISTHRO (MAin-ISar-THROmbosis) registry, 261 experienced VTE recurrence during a 5-year follow-up after the discontinuation of anticoagulant therapy. Results: Thrombophilia was more common among patients with VTE recurrence than those without (58.6 % vs. 50.3 %; p = 0.017). Stratifying patients by the age at the time of their initial VTE, Cox proportional hazards analyses adjusted for age, sex and the presence or absence of established risk factors revealed a heterozygous prothrombin (PT) G20210A mutation (hazard ratio (HR) 2.65; 95 %-confidence interval (CI) 1.71 - 4.12; p < 0.001), homozygosity/double heterozygosity for the factor V Leiden and/or PT mutation (HR 2.35; 95 %-CI 1.09 - 5.07, p = 0.030), and an antithrombin deficiency (HR 2.12; 95 %-CI 1.12 - 4.10; p = 0.021) to predict recurrent VTE in patients aged 40 years or older, whereas lupus anticoagulants (HR 3.05; 95%-CI 1.40 - 6.66; p = 0.005) increased the risk of recurrence in younger patients. Subgroup analyses revealed an increased risk of recurrence for a heterozygous factor V Leiden mutation only in young females without hormonal treatment whereas the predictive value of a heterozygous PT mutation was restricted to males over the age of 40 years. Conclusions: Our data do not support a preference of younger patients for thrombophilia testing after a first venous thromboembolic event.

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