Endogenous Thrombin Potential (ETP) for Assessing the Risk of Recurrent Venous Thromboembolism.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1622-1622 ◽  
Author(s):  
Sabine Eichinger ◽  
Gregor Hron ◽  
Ansgar Weltermann ◽  
Marietta Kollars ◽  
Paul A. Kyrle
Keyword(s):  
Venous Thromboembolism ◽  
Factor V Leiden ◽  
Factor Ix ◽  
Clotting Factor ◽  
Study Endpoint ◽  
Cumulative Probability ◽  
Computer Assisted ◽  
Risk Of Recurrence ◽  
Increased Risk ◽  
Factor Ii

Abstract Venous thromboembolism (VTE) is a multifactorial chronic disease. The number and severity of risk factors determine the risk of recurrence. A laboratory method that measures the overall thrombophilia is required. In a prospective cohort study, we measured ETP in 778 patients with a first unprovoked VTE. Patients were followed after discontinuation of anticoagulants for an average of 49 months. The study endpoint was recurrent symptomatic VTE. ETP was determined by a commercially available (research use only) assay (Dade Behring, Marburg, Germany) in platelet poor plasma by use of a chromogenic substrate and automatic registration as well as computer assisted calculation of thrombin generation over time. Patients with recurrence had higher ETP than those without recurrence (104.2% ± 15.4% vs. 101.4% ±14.2%. Patients with ETP ≥ 100% had an almost two-fold higher relative risk (RR) of recurrence than patients with lower levels (RR 1.6, 95% CI 1.0 – 2.5). At 4 years, the cumulative probability of recurrence was 14.4% in patients with ETP ≥ 100% and 6.1% in those with lower levels (p = 0.05). Patients with ETP ≥ 100% had higher clotting factor levels (Table). ETP was significantly increased in heterozygous carriers of factor II G20210A as compared with patients with wild type factor II (128% ± 18% vs. 100 ± 12%, p < 0.001). Patients with a first unprovoked VTE and an ETP ≥ 100% have an increased risk of recurrence. Table Characteristics of 778 Patients with VTE ETP < 100% ETP ≥ 100% p-value Men, no. (%) 160 (42%) 174 (44%) n.s. Age at first VTE (yrs) 46 ± 17 47 ± 14 n.s. Factor V Leiden, no. (%) 124 (32%) 108 (28%) n.s. Factor II G20210A, no. (%) 4 (1%) 49 (13%) < 0.001 Factor VIII (IU/dL) 162 ± 46 168 ± 45 0.09 Factor IX (IU/dL) 113 ± 24 123 ± 27 < 0.001 Factor XI (IU/dL) 102 ± 21 110 ± 24 < 0.001

Prediction of Recurrent Venous Thromboembolism by Endogenous Thrombin Potential and D-Dimer

2008 ◽  
Vol 54 (12) ◽  
pp. 2042-2048 ◽  
Author(s):  
Sabine Eichinger ◽  
Gregor Hron ◽  
Marietta Kollars ◽  
Paul A Kyrle
Keyword(s):  
Venous Thromboembolism ◽  
Thrombin Generation ◽  
Factor V Leiden ◽  
Study Endpoint ◽  
Factor V ◽  
Risk Of Recurrence ◽  
Endogenous Thrombin Potential ◽  
Increased Risk ◽  
Recurrent Venous Thromboembolism ◽  
D Dimer

Abstract Background: Increased thrombin generation is associated with an increased risk of recurrent venous thromboembolism. We investigated the relation between endogenous thrombin potential (ETP) and risk of recurrent venous thromboembolism and evaluated whether prediction of recurrence can be improved by a combined analysis of ETP and D-dimer. Methods: We followed 861 patients with first spontaneous venous thromboembolism and determined ETP and D-dimer after discontinuation of anticoagulation. Patients with natural inhibitor deficiency, lupus anticoagulant, or cancer were excluded. The study endpoint was symptomatic recurrent venous thromboembolism. Results: One hundred thirty patients (15.1%) had recurrence. High ETP (≥100%) conferred a 1.6-fold increased risk of recurrence (95% CI 1.1–2.3) after adjustment for age, sex, factor V Leiden, factor II G20210A, and duration of anticoagulation. After adjustment for D-dimer, risk of recurrence remained significantly higher among patients with high ETP [hazard ratio 1.6 (95% CI 1.01–2.4)]. After adjustment for ETP, high D-dimer (≥0.5 mg/L) conferred a 1.8-fold (95% CI 1.1–2.8) increased risk of recurrence. Compared with patients with low ETP and low D-dimer, risk of recurrence was 2.8-fold (95% CI 1.5–5.3) higher among patients with both high ETP and high D-dimer after adjustment for potential confounders. Conclusions: ETP and D-dimer are independent predictors of recurrent venous thromboembolism. Assessing risk of recurrence can be optimized by combining these indicators of thrombin generation.

P-selectin gene haplotypes modulate soluble P-selectin concentrations and contribute to the risk of venous thromboembolism

2008 ◽  
Vol 99 (11) ◽  
pp. 899-904 ◽  
Author(s):  
Alexandra Kaider ◽  
Silvia Koder ◽  
Simon Panzer ◽  
Ingrid Pabinger ◽  
Cihan Ay ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Plasma Concentrations ◽  
Factor V Leiden ◽  
Chromosome 1 ◽  
Computer Assisted ◽  
Factor V Leiden Mutation ◽  
Individual Snps ◽  
Increased Risk ◽  
Recurrent Vte ◽  
Soluble P

SummaryThe cell adhesion molecule P-selectin mediates the interaction of activated platelets or endothelial cells with leukocytes. In arterial and venous thromboembolism (VTE) increased soluble P-selectin (sP-selectin) concentrations have been found, and associations of P-selectin genotypes with thrombotic disease have been proposed. We assessed the effect of four single nucleotide polymorphisms (SNPs) [one in the promoter region (c.–2123C>G) and three (S290N, c.1087G>A; D562N, c.1902G>A; T715P, c.2363A>C) in the coding region] and the calculated haplotypes in the P-selectin gene (SELP) on sP-selectin concentrations and VTE risk. The analysis was carried out in 116 high-risk patients with a history of objectively confirmed recurrent VTE and 129 age- and sex-matched healthy individuals. Haplotypes were generated using computer-assisted haplotype reconstruction with Phase 2.1. sP-selectin (μg/l) was measured by ELISA. Frequencies of all four individual SNPs were not statistically significantly different between patients and controls. Tenhaplotypes were obtained for the control population, and nine for the patient group. The most frequent haplotype among controls was CGGA (major allele at all positions) (27.8%; frequency in patients 19.0%), which was used as reference for statistical analyses. Among patients GGAA was most frequent (23.3%; frequency in controls 17.5%). Haplotypes were significantly associated with sP-selectin concentrations in patients and in controls (p<0.001 and p=0.011). Compared to CGGA some but not all haplotypes conferred an increased risk for VTE with odds ratios (ORs) between 5.4 (95% CI: 2.5–12.2) for CAGA, 3.3 (1.2–9.2) for CGAC, and 2.4 (1.3–4.7) for GGAA. All ORs remained statistically significant after adjustment for the factor V Leiden mutation, located in close proximity to SELP on chromosome 1, as well as all other established risk factors for VTE. In conclusion, SELP haplotypes modulate plasma concentrations of sP-selectin and affect the risk of recurrent VTE.

Predicting the risk of recurrent venous thromboembolism

2013 ◽  
Vol 33 (03) ◽  
pp. 201-209 ◽  
Author(s):  
L. Eischer ◽  
P. A. Kyrle
Keyword(s):  
Venous Thromboembolism ◽  
Vena Cava ◽  
Factor V Leiden ◽  
Recurrence Risk ◽  
Clotting Factor ◽  
Factor V ◽  
Vein Thrombosis ◽  
Increased Risk ◽  
Thrombophilia Screening ◽  
Recurrent Vte

SummaryVenous thromboembolism (VTE) is a disease, which often recurs. The recurrence risk is highest in patients with unprovoked proximal deep-vein thrombosis (VT) or pulmonary embolism. Men have a higher risk than women. The risk is low in patients with VTE related to a temporary risk factor such as surgery or estrogen use. Other risk factors include overweight, post-thrombotic syndrome, history of VTE, residual VT or a vena cava filter.Both factor V Leiden and the prothrombin mutation confer a negligible increase in recurrence risk. High clotting factor levels, deficiency of a natural coagulation inhibitor, or hyperhomocysteinaemia are also associated with an increased risk. Reasons why routine laboratory thrombophilia screening however is no longer warranted are addressed in this article. Prediction rules combining clinical characteristics and coagulation assays have recently been developed. One such model, the Vienna Prediction Model, allows predicting recurrent VTE on the basis of VTE location, sex and D-dimer. This article describes strategies to distinguish between patients with high risk of recurrent VTE from those with a lower risk, who might not benefit from long-term antithrombotic therapy.

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

VASA ◽  
2015 ◽  
Vol 44 (4) ◽  
pp. 313-323 ◽  
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.

Combined Effect of Factor V Leiden and Prothrombin 20210A on the Risk of Venous Thromboembolism

2001 ◽  
Vol 86 (09) ◽  
pp. 809-816 ◽  
Author(s):  
Frits Rosendaal ◽  
Marco Cattaneo ◽  
Maurizio Margaglione ◽  
Valerio De Stefano ◽  
Tony Cumming ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Odds Ratio ◽  
Large Population ◽  
Factor V Leiden ◽  
Pooled Analysis ◽  
Factor V ◽  
Case Control Studies ◽  
Vein Thrombosis ◽  
G20210a Mutation ◽  
Factor Ii

SummaryFactor V Leiden and factor II G20210A mutations are two frequent genetic risk factors involved in venous thromboembolism (VTE). The goal of this pooled analysis of 8 case-control studies, comprising a total of 2310 cases and 3204 controls, was to precisely estimate the risk of VTE in patients bearing both mutations (double heterozygotes). Odds ratios for VTE were 4.9 (95% CI; 4.1-5.9) for the factor V Leiden and 3.8 (3.0-4.9) for the factor II G20210A mutation. Fifty-one cases (2.2%) and none of the controls were double heterozygotes. The odds ratio for venous thrombosis in double heterozygotes was 20.0 (11.1-36.1). Twelve percent of patients heterozygous for factor V Leiden were also heterozygous for factor II G20210A and conversely 23% of patients heterozygous for factor II G20210A were also heterozygous for factor V Leiden. Furthermore, in this large population we analyzed the effect of oral contraceptive (OC) in women carrying one of these mutations. Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-18.45). The odds ratio of the association of factor II mutation and OC use was 7.14 (3.39-15.04). Finally, we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69). Conversely, factor II G20210A mutation was equally balanced in both patient groups.

Is APC Resistance a Risk Factor for Venous Thromboembolism in Patients over 70 Years?

2002 ◽  
Vol 88 (10) ◽  
pp. 587-591 ◽  
Author(s):  
Karine Lacut ◽  
Grégoire Le Gal ◽  
Patrick Van Dreden ◽  
Luc Bressollette ◽  
Pierre-Yves Scarabin ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thromboembolism ◽  
Odds Ratio ◽  
Dna Analysis ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Apc Resistance ◽  
Increased Risk ◽  
History Of

SummaryActivated protein C (APC) resistance is the most common risk factor for venous thromboembolism (VTE). Previous studies mostly analysed patients under 70 years and reported a four-to sevenfold increased risk. This case-control study included consecutive patients referred for a clinical suspicion VTE to our medical unit: 621 patients with a well-documented diagnosis (cases) and 406 patients for which the diagnosis was ruled out and who had no personal history of VTE (controls). APC resistance related to factor V Leiden was defined by either a positive DNA analysis or a positive STA® Staclot APC-R assay. Under 70 years, APC resistance was associated with a threefold increased risk of VTE (odds ratio 3.2, 95% CI, 1.7 to 6.0), whereas in patients over 70 years, it appeared to be no longer a strong risk factor (odds ratio 0.8, 95% CI, 0.4 to 1.7). Age appeared as an effectmeasure modifier with a significant interaction (p = 0.005). Our data suggest that APC resistance is not a risk factor for VTE in elderly.

Factor V Leiden (G1691A) and Prothrombin Gene G20210A Mutations as Potential Risk Factors for Venous Thromboembolism after Total Hip or Total Knee Replacement Surgery

2002 ◽  
Vol 87 (04) ◽  
pp. 580-585 ◽  
Author(s):  
G. Larson ◽  
T. L. Lindahl ◽  
C. Andersson ◽  
L. Frison ◽  
D. Gustafsson ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Factor V Leiden ◽  
Composite Endpoint ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
G20210a Mutation ◽  
Symptomatic Pulmonary Embolism ◽  
Increased Risk ◽  
Prothrombin Gene

SummaryPatients (n = 1600) from 12 European countries, scheduled for elective orthopaedic hip or knee surgery, were screened for Factor V Leiden and prothrombin gene G20210A mutations, found in 5.5% and 2.9% of the populations, respectively. All patients underwent prophylactic treatment with one of four doses of melagatran and ximelagatran or dalteparin, starting pre-operatively. Bilateral ascending venography was performed on study day 8-11. The patients were subsequently treated according to local routines and followed for 4-6 weeks postoperatively. The composite endpoint of screened deep vein thrombosis (DVT) and symptomatic pulmonary embolism (PE) during prophylaxis did not differ significantly between patients with or without these mutations. Symptomatic venous thromboembolism (VTE) during prophylaxis and follow-up (1.9%) was significantly over-represented among patients with the prothrombin gene G20210A mutation (p = 0.0002). A tendency towards increased risk of VTE was found with the Factor V Leiden mutation (p = 0.09). PE were few, but significantly over-represented in both the Factor V Leiden and prothrombin gene G20210A mutated patients (p = 0.03 and p = 0.05, respectively). However, since 90% of the patients with these genetic risk factors will not suffer a VTE event, a general pre-operative genotyping is, in our opinion, of questionable value.

"ProC Global": A functional screening test that predicts recurrent venous thromboembolism

2005 ◽  
Vol 93 (03) ◽  
pp. 600-604 ◽  
Author(s):  
Shannon Bates ◽  
Marilyn Johnston ◽  
Simon McRae ◽  
Jeffrey Ginsberg ◽  
Anne Grand’Maison
Keyword(s):  
Venous Thromboembolism ◽  
Protein C ◽  
Specific Inhibitor ◽  
Factor V Leiden ◽  
First Episode ◽  
Functional Screening ◽  
Factor V ◽  
Increased Risk ◽  
Global Result ◽  
Recurrent Vte

SummaryAbnormalities of the Protein C (PC) pathway are found in the majority of patients with thrombophilia. ProC Global is a coagulation assay that reflects the net effect of the PC pathway by measuring the activated partial thromboplastin time (APTT) of patient and control plasma, before and after activation of endogenous PC by Protac, a snake venom. Previous studies have suggested that abnormalities in this test are associated with an increased risk of venous thromboembolism (VTE). A retrospective analysis was performed using frozen plasma samples from 140 patients with confirmed VTE to determine whether an abnormal ProC Global result (in the presence and in the absence of known abnormalities in the PC pathway) is a predictor of initial and recurrent VTE. Patients were tested for the presence of activated protein C resistance, Factor V Leiden, PC and protein S (PS) deficiency, and non-specific inhibitor positivity. Mean ProC Global results were significantly lower in patients with recurrent VTE than in patients without recurrent VTE. The association between abnormal ProC Global result and recurrent VTE showed a strong trend, before (odds ratio, OR 3.6) and after (OR 3.1) exclusion of known thrombophilic abnormalities. Patients with a first episode of idiopathic VTE also expressed significant lower ProC Global results than those with secondary VTE. After exclusion of known PC pathway abnormalities, there was a statistically significant association between abnormal ProC Global and initial idiopathic VTE (p=0.04). These results suggest that ProC Global may serve as a predictor of recurrent VTE and potentially for first episode of idiopathic VTE. ProC Global may help identify patients at increased risk of initial and recurrent VTE.

scholarly journals Geographic Distribution of the 20210 G to A Prothrombin Variant

1998 ◽  
Vol 79 (04) ◽  
pp. 706-708 ◽  
Author(s):  
C. J. M. Doggen ◽  
A. Zivelin ◽  
V. R. Arruda ◽  
M. Aiach ◽  
D. S. Siscovick ◽  
...  
Keyword(s):  
Geographical Location ◽  
Factor V Leiden ◽  
Prevalence Estimate ◽  
Clotting Factor ◽  
Northern Europe ◽  
Nucleotide Position ◽  
Factor V ◽  
Summary Estimate ◽  
Factor Ii ◽  
Prevalence Estimates

SummaryA variant in prothrombin (clotting factor II), a G to A transition at nucleotide position 20210, has recently been shown to be associated with the prothrombin plasma levels and the risk of both venous and arterial thrombosis. The purpose of this study was to investigate the prevalence of carriership of this mutation in various populations.We combined data from 11 centres in nine countries, where tests for this mutation had been performed in groups representing the general population. We calculated an overall prevalence estimate, by a precision-weighted method, and, since the distribution of the prevalences did not appear homogeneous, by an unweighted average of the prevalences. We examined differences in the prevalences by geographical location and ethnic background as a possible explanation for the heterogeneity.Among a total of 5527 individuals who had been tested, 111 heterozygous carriers of the 20210A mutation were found. The prevalence estimates varied from 0.7 to 4.0 between the centres. The overall prevalence estimate was 2.0 percent (CI95 1.4-2.6%). The variation around the summary estimate appeared more than was expected by chance alone, and this heterogeneity could be explained by geographic differences. In southern Europe, the prevalence was 3.0 percent (CI95 2.3 to 3.7%), nearly twice as high as the prevalence in northern Europe (1.7%, CI95 1.3 to 2.2%). The prothrombin variant appeared very rare in individuals from Asian and African descent.The 20210A prothrombin variant is a common abnormality, with a prevalence of carriership between one and four percent. It is more common in southern than in northern Europe. Since this distribution within Europe is very different to that of another prothrombotic mutation (factor V Leiden or factor V R506Q), founder effects are the most likely explanation for the geographical distribution of both mutations.

Prospective Evaluation of Hemostatic System Activation and Thrombin Potential in Healthy Pregnant Women with and without Factor V Leiden

1999 ◽  
Vol 82 (10) ◽  
pp. 1232-1236 ◽  
Author(s):  
Ansgar Weltermann ◽  
Karl Philipp ◽  
Erich Hafner ◽  
Alexandra Kaider ◽  
Eva-Maria Kittl ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Pregnant Women ◽  
Factor V Leiden ◽  
Fibrinolytic System ◽  
Factor V ◽  
Uncomplicated Pregnancy ◽  
Hemostatic System ◽  
Increased Risk ◽  
System Activation ◽  
D Dimer

SummaryNormal pregnancy is associated with alterations of the hemostatic system towards a hypercoagulable state and an increased risk of venous thromboembolism. The risk of venous thrombosis is higher in pregnant women with factor V Leiden (FVL) than in those with wildtype factor V. Routine laboratory assays are not useful to detect hypercoagulable conditions. A prospective and systematic evaluation of hemostatic system activation in women with and without FVL during an uncomplicated pregnancy employing more sensitive markers of hypercoagulability, such as prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), D-Dimer, or the endogenous thrombin potential (ETP), an indicator of the plasma’s potential to generate thrombin, has not been performed. We prospectively followed 113 pregnant women with (n = 11) and without (n = 102) FVL and measured F1+2, TAT, D-Dimer and the ETP at the 12th, 22nd and 34th gestational week as well as 3 months after delivery (baseline) in each subject. None of the women developed clinical signs of venous thromboembolism during pregnancy or postpartum. Pregnant women with and without FVL exhibited substantial activation of the coagulation and fibrinolytic system as indicated by a gradual increase of F1+2, TAT and D-Dimer throughout uncomplicated pregnancy up to levels similar to those found in acute thromboembolic events (p < 0.0001 by analysis of variance for each parameters). Levels of F1+2 and TAT were comparable between women with and without FVL, but levels of D-Dimer were significantly higher in women with FVL than in those without the mutation (p = 0.0005). The ETP remained unchanged in both women with and without FVL at all timepoints. Our data demonstrate a substantial coagulation and fibrinolytic system activation in healthy women with and without FVL during uncomplicated pregnancy. An elevated F1+2, TAT or D-Dimer level during pregnancy is not necessarily indicative for an acute thromboembolic event. The normal ETP in both women with and without FVL suggests that the capacity of the plasma to generate thrombin after in vitro activation of the clotting system is not affected by pregnancy. Higher levels of D-Dimer in women with FVL than in women with wildtype factor V at baseline as well as during pregnancy indicate increased fibrinolytic system activation in carriers of the mutation.

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