Coagulation Factors, Postmenopausal Hormone Replacement Therapy and the Risk of Venous Thrombosis: The WHI Clinical Trials of Postmenopausal Hormone Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 127-127 ◽  
Author(s):  
Mary Cushman ◽  
Joseph Larson ◽  
Frits R. Rosendaal ◽  
Lawrence S. Phillips ◽  
Barbara V. Howard ◽  
...  
Keyword(s):  
Risk Factors ◽  
Relative Risk ◽  
Venous Thrombosis ◽  
Protein C ◽  
Coagulation Factor ◽  
Protein S ◽  
Postmenopausal Hormone ◽  
Free Protein ◽  
Coagulation Marker ◽  
D Dimer

Abstract Background. Postmenopausal estrogen (E) therapy, especially in combination with progestin (P) doubles the relative risk of venous thrombosis (VTE). Risk with hormones is higher with increasing age, obesity and with factor V Leiden. We studied coagulation markers as susceptibility factors for postmenopausal hormone-related VTE. Methods. The Women’s Health Initiative program included two placebo-controlled double-blind randomized trials of two E regimens, E (conjugated equine estrogens) or E+P (E + medroxyprogesterone acetate), in 16,608 postmenopausal women aged 50–79. We performed a nested case control study that measured baseline levels of coagulation markers in 215 women who developed VTE during follow up and 867 age-matched controls. The joint effects of treatment assignment to either E regimen vs placebo and prespecified abnormal levels of each coagulation factor on relative risk of VTE were estimated by logistic regression adjusting for age, race, body-mass index and type of E regimen. Results. Low levels of protein C and free protein S (<5th percentile), high D-dimer (top quartile), and high plasmin antiplasmin complex (PAP) and prothrombin fragment 1–2 (top decile) were all associated with risk of VTE with adjusted odds ratios (95% CI) of 2.0 (1.0–4.1), 2.9 (1.5–5.6), 2.8 (2.0–4.0), 2.5 (1.6–4.0) and 1.9 (1.2–3.1), respectively. Elevated factors II, VIII, IX and fibrinogen were not VTE risk factors. Compared to women with normal coagulation marker levels assigned to placebo, the joint odds of VTE with either E regimen plus an abnormal coagulation marker were more than additive compared to the separate effects of hormones and coagulation abnormalities for low protein C, low free protein S, and elevated D-dimer, PAP and F1–2. The odds ratios of VTE with the combination of an abnormal coagulation factor and assignment to hormones were (in order listed in prior sentence), 4.5 (95% CI 2.0–10.2), 6.7 (3.0–14.5), 6.1 (3.7–10), 5.8 (3.2–10.5) and 4.4 (2.4–7.7). Conclusions. We report new findings of elevated F1-2 and PAP as VTE risk factors in women in this prospective study nested in trials of E or E+P versus placebo. Protein C or S values below the 5th percentile were also clinically relevant even though they do not represent inherited deficiency. Lower protein C and free protein S, and higher D-dimer, F1-2 and PAP all identified women at increased risk of VTE with hormones. If our findings are confirmed in management studies, measurement of these factors might assist women with decision-making on safety of E or E+P.

Free Protein S Deficiency Is a Risk Factor for Venous Thrombosis

1997 ◽  
Vol 78 (05) ◽  
pp. 1343-1346 ◽  
Author(s):  
Elena M Faioni ◽  
Carla Valsecchi ◽  
Alessandra Palla ◽  
Emanuela Taioli ◽  
Cristina Razzari ◽  
...  
Keyword(s):  
Risk Factor ◽  
Relative Risk ◽  
Venous Thrombosis ◽  
Protein S ◽  
Unexpected Finding ◽  
Reference Ranges ◽  
Protein S Deficiency ◽  
Men And Women ◽  
Free Protein ◽  
S Deficiency

SummaryA recent study suggests that protein S deficiency is not a risk factor for venous thrombosis. Since this unexpected finding would have important clinical implications if confirmed, we performed a case-control study with the aim to determine the prevalence of protein S deficiency in patients with thrombosis and in healthy individuals taken from the general population and the relative risk of thrombosis in protein S-deficient patients. Free protein S concentration was measured in 327 consecutive patients with at least one venous thrombotic episode and in 317 age- and sex-matched control individuals. Different normal reference ranges were obtained and adopted for men and women. Protein S deficiency was found in 3.1% (95% Cl: 1.5-5.2) of patients and in 1.3% of controls (95% Cl: 0.3-2.8). Ten patients and 4 control subjects had protein S deficiency, which determined a relative risk of thrombosis (sex- and age-adjusted odds ratio) of 2.4 (95% Cl: 0.8-7.9). When men and women were analyzed separately, the risk was 5.0 (95% CI: 0.6-43.6) and 1.6 (95% Cl: 0.4-6.7) respectively. PS-deficient men had more thrombotic episodes than women and later in life. Multivariate analysis established that sex was an independent determinant of the number of episodes, as was age, while PS deficiency was not. However sex and PS deficiency status were both determinants of age at first thrombotic episode.

scholarly journals Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study) [see comments]

Blood ◽  
1995 ◽  
Vol 85 (10) ◽  
pp. 2756-2761 ◽  
Author(s):  
T Koster ◽  
FR Rosendaal ◽  
E Briet ◽  
FJ van der Meer ◽  
LP Colly ◽  
...  
Keyword(s):  
Relative Risk ◽  
Venous Thrombosis ◽  
Protein C ◽  
Protein S ◽  
Population Based ◽  
Repeated Measurements ◽  
Protein C Deficiency ◽  
Antithrombin Deficiency ◽  
Vein Thrombosis ◽  
Thrombosis Risk

A deficiency of protein C (PC), antithrombin, or protein S is strongly associated with deep-vein thrombosis in selected patients and their families. However, the strength of the association with venous thrombosis in the general population is unknown. This study was a population-based, patient-control study of 474 consecutive outpatients, aged less than 70 years, with a first, objectively diagnosed, episode of venous thrombosis and without an underlying malignant disease, and 474 healthy controls who matched for age and sex. Relative risks were estimated as matched odds ratios. Based on a single measurement, there were 22 (4.6%) patients with a PC deficiency (PC activity, less than 0.67 U/mL or PC antigen, less than 0.33 U/mL when using coumarins). Among the controls, the frequency was 1.5% (seven subjects). Thus, there is a threefold increase in risk of thrombosis in subjects with PC levels below 0.67 or 0.33 U/mL [matched odds ratio, 3.1; 95% confidence interval (CI), 1.4 to 7.0]. When a PC deficiency was based on two repeated measurements, the relative risk for thrombosis increased to 3.8 (95% CI, 1.3 to 10); when it was based on DNA-confirmation, the relative risk increased further to 6.5 (95% CI, 1.8 to 24). In addition, there was a gradient in thrombosis risk, according to PC levels. The results for antithrombin are similar to those for PC, although less pronounced (relative risk, 2.2; 95% CI, 1.0 to 4.7). We could not find an association between reduced total protein S (relative risk, 0.7; 95% CI, 0.3 to 1.8) or free protein S levels (relative risk, 1.6; 95% CI, 0.6 to 4.0) and thrombosis risk. Although not very frequent, PC and antithrombin deficiency are clearly associated with an increase in thrombosis risk.

Effects of Hereditary and Acquired Risk Factors of Venous Thrombosis on a Thrombin Generation-Based APC Resistance Test

2002 ◽  
Vol 88 (07) ◽  
pp. 5-11 ◽  
Author(s):  
Joyce Curvers ◽  
M. Christella Thomassen ◽  
Janet Rimmer ◽  
Karly Hamulyak ◽  
Jan van der Meer ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Protein C ◽  
Thrombin Generation ◽  
Contraceptive Use ◽  
Hormone Replacement ◽  
Protein S ◽  
Resistance Test ◽  
Prothrombin G20210a ◽  
Apc Resistance

SummarySeveral hereditary and acquired risk factors for venous thromboembolism (VTE) are associated with impaired down-regulation of thrombin formation via the protein C pathway. To identify individuals at risk, functional tests are needed that estimate the risk to develop venous thrombosis.We determined the effects of hereditary and acquired risk factors of venous thrombosis on an APC resistance test that quantifies the influence of APC on the time integral of thrombin formation (the endogenous thrombin potential, ETP) initiated in plasma via the extrinsic coagulation pathway. APC sensitivity ratios (APCsr) were determined in plasma from carriers of factor VLeiden (n = 56) or prothrombin G20210A (n = 18), of individuals deficient in antithrombin (n = 9), protein C (n = 7) or protein S (n = 14) and of women exposed to acquired risk factors such as hormone replacement therapy (n = 49), oral contraceptive use (n = 126) or pregnancy (n = 35). We also analysed combinations of risk factors (n = 60).The thrombin generation-based APC resistance test was sensitive for the factor VLeiden and prothrombin G20210A mutation, to protein S deficiency, hormone replacement therapy, oral contraceptive use and pregnancy. The assay was not influenced by antithrombin-or protein C deficiency. The presence of more than one risk factor of venous thrombosis resulted in more pronounced APC resistance. The APCsr of individuals with a single or combined risk factors of VTE correlated well with reported risk increases.The thrombin generation-based APC resistance test identifies individuals at risk for venous thrombosis due to acquired risk factors and/or hereditary thrombophilic disorders that affect the protein C pathway.

The Risk of Abortion and Stillbirth in Antithrombin-, Protein C-, and Protein S-deficient Women

1996 ◽  
Vol 75 (03) ◽  
pp. 387-388 ◽  
Author(s):  
Bernd Jan Sanson ◽  
Philip W Friedrich ◽  
Paolo Simioni ◽  
Sandra Zanardi ◽  
Menno V Huisman ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Relative Risk ◽  
Venous Thrombosis ◽  
Family Member ◽  
Protein C ◽  
Protein S ◽  
Fetal Demise ◽  
Naturally Occurring ◽  
Obstetric History ◽  
Recurrent Venous Thromboembolism

SummaryHereditary deficiencies of the naturally occurring anticoagulants are well recognized conditions predisposing to recurrent venous thromboembolism. Since thrombotic phenomena have been implied as a cause of abortion and stillbirth, we hypothesized that these deficiencies increase the risk of fetal demise.A group of 129 female subjects who had been pregnant at least once and who had a family member with documented venous thrombosis associated with a deficiency of AT, PC or PS were studied. We first assessed the obstetric history and subsequently determined the deficiency status. In the 60 deficient subjects 42 (22.3%) of the 188 pregnancies resulted in miscarriage or stillbirth as compared to 23 (11.4%) of the 202 pregnancies in the 69 non-deficient subjects. The relative risk of abortion and stillbirth per pregnancy for deficient women as compared to non-deficient women was 2.0 (95% C.I. 1.2-3.3).

Low levels of plasma protein S, protein C and coagulation factor XII during early pregnancy and adverse pregnancy outcome

2015 ◽  
Vol 114 (07) ◽  
pp. 65-69 ◽  
Author(s):  
Yasuhiko Ebina ◽  
Masahiro Ieko ◽  
Sumiyoshi Naito ◽  
Gen Kobashi ◽  
Masashi Deguchi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Plasma Protein ◽  
Early Pregnancy ◽  
Protein C ◽  
Coagulation Factor ◽  
Protein S ◽  
Factor Xii ◽  
Independent Risk Factors ◽  
Low Levels ◽  
Adverse Pregnancy

SummaryIt was the study objective to evaluate whether low levels of plasma protein S (PS) activity, free PS, protein C (PC) activity and coagulation factor XII (FXII) during early pregnancy are related to adverse pregnancy outcomes. Peripheral blood samples were obtained at 8–14 gestational weeks (GW) from a consecutive series of 1,220 women. The levels of plasma PS activity, free PS, PC activity, and FXII were measured. Cut-off values were defined as < 1st, < 5th, and < 10th percentiles of values obtained from 933 women whose pregnancies ended in normal deliveries without complications. PS activity of < 10th percentile yielded risks of pregnancy-induced hypertension (PIH) and severe PIH, while free PS level of < 5th percentile yielded a risk of preeclampsia. FXII level of < 1st percentile yielded a risk of premature delivery (PD) at < 34 GW. None was associated with PD at < 37 GW, fetal growth restriction or fetal loss. A multivariate analysis demonstrated that PS activity of < 10th percentile (odds ratio 5.9, 95 % confidence interval 1.7–18.1) and body mass index (BMI) ≥ 25 kg/m2 (4.3, 1.1–13.3) were independent risk factors for severe PIH. Similarly, free PS level of < 5th percentile (4.4, 1.0–14.3) and BMI ≥ 25 kg/m2 (4.0, 1.3–10.9) were independent risk factors for pre-eclampsia. In conclusion, women with low levels of plasma PS activity and free PS during early pregnancy might have increased risks of PIH, severe PIH or pre-eclampsia. Women with low FXII level might have an increased risk of PD at < 34 GW.

Advances in understanding pathogenic mechanisms of thrombophilic disorders

Blood ◽  
2008 ◽  
Vol 112 (1) ◽  
pp. 19-27 ◽  
Author(s):  
Björn Dahlbäck
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Blood Coagulation ◽  
Coagulation Factor ◽  
Protein S ◽  
Medical Problem ◽  
Factor V ◽  
Genetic Traits ◽  
Increased Risk ◽  
American Society

AbstractVenous thromboembolism is a major medical problem, annually affecting 1 in 1000 individuals. It is a typical multifactorial disease, involving both genetic and circumstantial risk factors that affect a delicate balance between procoagulant and anticoagulant forces. In the last 50 years, the molecular basis of blood coagulation and the anticoagulant systems that control it have been elucidated. This has laid the foundation for discoveries of both common and rare genetic traits that tip the natural balance in favor of coagulation, with a resulting lifelong increased risk of venous thrombosis. Multiple mutations in the genes for anticoagulant proteins such as antithrombin, protein C, and protein S have been identified and constitute important risk factors. Two single mutations in the genes for coagulation factor V (FV Leiden) and prothrombin (20210G>A), resulting from approximately 20 000-year-old mutations with subsequent founder effects, are common in the general population and constitute major genetic risk factors for thrombosis. In celebration of the 50-year anniversary of the American Society of Hematology, this invited review highlights discoveries that have contributed to our present understanding of the systems that control blood coagulation and the genetic factors that are involved in the pathogenesis of venous thrombosis.

Ex vivo effects of low-dose rivaroxaban on specific coagulation assays and coagulation factor activities in patients under real life conditions

2013 ◽  
Vol 109 (01) ◽  
pp. 127-136 ◽  
Author(s):  
Christian Hesse ◽  
Gertrud Stratmann ◽  
Edelgard Lindhoff-Last ◽  
Helen Mani
Keyword(s):  
Protein C ◽  
Low Dose ◽  
Ex Vivo ◽  
Coagulation Factor ◽  
Protein S ◽  
Plasma Samples ◽  
Lupus Anticoagulants ◽  
Coagulation Assays ◽  
Administration Time ◽  
D Dimer

SummaryGlobal coagulation assays display variable effects at different concentrations of rivaroxaban. The aim of this study is to quantify the ex vivo effects of low-dose rivaroxaban on thrombophilia screening assays and coagulation factor activities based on the administration time, and to show how to mask possible interferences. Plasma samples from 40 patients receiving rivaroxaban 10 mg daily were investigated to measure activities of clotting factor II, V, VII, VIII, IX, XI, XII and XIII; protein C- and protein S-levels; lupus anticoagulants; anticardiolipin IgG and IgM; D-dimer, heparin-platelet factor 4 (HPF4) antibodies and screening tests for von Willebrand disease (VWD). Two hours after rivaroxaban administration, the activities of clotting factors were significantly decreased to different extents, except for factor XIII. Dilution of plasma samples resulted in neutralisation of these interferences. The chromogenic protein C activity assay was not affected by rivaroxaban. Depending on the timing of tablet intake in relation to blood sampling protein S activity was measured falsely high when a clotting assay was used. False-positive results for lupus anticoagulants were observed depending on the assay system used and the administration time of rivaroxaban. ELISA-based assays such as anticardiolipin IgG and IgM, D-dimer, HPF4-antibodies and the turbidimetric assays for VWD were not affected by rivaroxaban. Specific haemostasis clotting tests should be performed directly prior to rivaroxaban intake. Assay optimisation in the presence of rivaroxaban can be achieved by plasma dilution. Immunologic assays are not influenced by rivaroxaban, while chromogenic assays can be used, when they do not depend on factor Xa.

scholarly journals Increased D-Dimer Levels and Residual Venous Thrombosis Are Associated with Late Recurrence of Deep Venous Thrombosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3554-3554
Author(s):  
Bruna Moraes Mazetto ◽  
Fernanda Andrade Orsi ◽  
Mariane Flores-Nascimento ◽  
Sandra Silveira ◽  
Luis Fernando Bittar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Relative Risk ◽  
Venous Thrombosis ◽  
Conflicts Of Interest ◽  
Recurrence Risk ◽  
Late Recurrence ◽  
Long Time ◽  
Risk Patients ◽  
D Dimer

Abstract Background: Many patients present new thrombotic events even long-time after the first thrombotic episode and risk factors for recurrence in these cases are not fully elucidated. Aim: To evaluate the risk of late recurrence of thrombosis after a first DVT episode. Methods: This is a prospective observational study. We evaluated the association of D-dimer (DD) levels and persistent residual venous thrombosis (RVT), by Doppler ultrasound, with the occurrence of new thrombotic events long-time after the acute DVT episode. Results: Fifty-six patients were enrolled for the study. For all patients, DVT episode occurred more than 12 months apart from the enrollment day. Median follow-up was 28 months. During the follow-up time, 10 patients presented thrombosis recurrence. Patients who suffered DVT recurrence had higher DD levels than those who did not had recurrence (median= 0.99 vs 0.40, respectively). The best cut-off value to discriminate those at risk for recurrence was DD > 0.63mg/L (area= 0.7380 95%CI= 0.5800 to 0.8961, P=0.01). Recurrence occurred in 27.7% of patients with previous DD>0.63mg/L and in 5.9% of patients with previous DD< 0.63mg/L (relative risk = 6.46; 95%CI 1.36- 30.52, P=0.007). New thrombosis events occurred only in patients with previously documented RVT, mainly in patients with hypoechoic RVT. During follow-up, new thrombotic events were diagnosed in 75% of patients with hypoechoic RVT. The relative risk for recurrence according to the presence of RVT was 9.129 (95% CI= 2.60-32.02, P<0.001). The presence of RVT also modified the effect of DD on the recurrence risk. Patients with DD > 0,63mg/L but without RVT had similar risk of recurrence than those with DD< 0.63mg/L, whereas the risk for recurrence increased in 14-15 times in patients with RVT. Conclusion: These results suggests that the persistence of residual thrombosis combined with high levels of DD, long-time after the acute DVT, are risk factors associated with late thrombosis recurrence. Disclosures No relevant conflicts of interest to declare.

State-of-the-Art Review: Activated Protein C Resistance: Clinical Implications

1997 ◽  
Vol 3 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Bengt Zöller ◽  
Andreas Hillarp ◽  
Björn Dahlbäck
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Factor V ◽  
Thrombotic Risk ◽  
Western Countries ◽  
Apc Resistance ◽  
Increased Risk

The discovery of inherited resistance to activated protein C (APC) as a major risk factor for venous thrombosis has dramatically improved our understanding of the pathogenesis of venous thrombosis. In a majority of cases, APC resistance is associated with a single point mutation in the factor V gene (FV) that results in substitution of arginine, R, at position 506 by glutamine, Q. (FV:Q506). The mutation renders factor Va partially resistant to degradation by APC. A functional APC resistance test, which includes predilution of the patient plasma with factor V-deficient plasma, is found to be 100% sensitive and specific for the presence of FV:Q506 and is useful as a screening assay. Carriers of the FV:Q506 allele have increased thrombin generation, resulting in hypercoagulability and a lifelong increased risk of venous thrombosis. In Western countries, APC resistance due to the FV mutation is present in 20-60% of thrombosis patients and in 1-15% of healthy controls, whereas the mutation is virtually absent from ethnic groups other than Caucasians. This may explain the high incidence of venous thrombosis in Western countries. The thrombotic risk in APC-resistant individuals may be further increased by other genetic defects, e.g., protein C or protein S deficiency, and by exposure to circumstantial risk factors, e.g., oral contraceptives, pregnancy, immobilization, and surgery. The question is thus raised as to whether general screening for APC resistance before circumstantial risk factors occur is warranted in Western countries. Key Words: Factor V—APC resistance-Protein C-Protein S—Thrombosis—Mutation.

APC Resistance and other Haemostatic Variables during Pregnancy and Puerperium

1999 ◽  
Vol 81 (04) ◽  
pp. 527-531 ◽  
Author(s):  
U. Kjellberg ◽  
N.-E. Andersson ◽  
S. Rosén ◽  
L. Tengborn ◽  
M. Hellgren
Keyword(s):  
Factor Viii ◽  
Plasminogen Activator ◽  
Protein C ◽  
Activated Protein C ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Reference Level ◽  
Soluble Fibrin ◽  
Prothrombin Fragment ◽  
D Dimer

SummaryForty-eight healthy pregnant women were studied prospectively and longitudinally. Blood sampling was performed at 10-15, 23-25, 32-34 and 38-40 weeks of gestation, within one week and at eight weeks postpartum. Classic and modified activated protein C ratio decreased as pregnancy progressed. In the third trimester 92% of the ratios measured with the classic test were above the lower reference level whereas all modified test ratios were normal. Slight activation of blood coagulation was shown with increased levels of prothrombin fragment 1+2, soluble fibrin and D-dimer. Fibrinogen, factor VIII and plasminogen activator inhibitor type 1 and type 2 increased. Protein S and tissue plasminogen activator activity decreased. Protein C remained unchanged. No correlation was found between the decrease in classic APC ratio and changes in factor VIII, fibrinogen, protein S, prothrombin fragment 1+2 or soluble fibrin, nor between the increase in soluble fibrin and changes in prothrombin fragment 1+2, fibrinogen and D-dimer.

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