The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI

2013 ◽  
Vol 109 (04) ◽  
pp. 606-613 ◽  
Author(s):  
Frans M. Helmerhorst ◽  
Kathrin Fleischer ◽  
Anders E. A. Dahm ◽  
Frits R. Rosendaal ◽  
Jan Rosing ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Oral Contraceptives ◽  
Acquired Resistance ◽  
Activated Protein C ◽  
Protein S ◽  
Hormonal Contraceptives ◽  
Free Protein ◽  
Routes Of Administration ◽  
Apc Resistance ◽  
Increased Risk

SummaryUse of combined oral contraceptives is associated with a three- to sixfold increased risk of venous thrombosis. Hormonal contraceptives induce acquired resistance to activated protein C (APC), which predicts the risk of venous thrombosis. The biological basis of the acquired APC resistance is unknown. Free protein S (PS) and free tissue factor pathway inhibitor (TFPI) are the two main determinants of APC. Our objective was to assess the effect of both hormonal and non-hormonal contraceptives with different routes of administration on free TFPI and free PS levels. We conducted an observational study in 243 users of different contraceptives and measured APC sensitivity ratios (nAPCsr), free TFPI and free PS levels. Users of contraceptives with the highest risk of venous thrombosis as reported in recent literature, had the lowest free TFPI and free PS levels, and vice versa, women who used contraceptives with the lowest risk of venous thrombosis had the highest free TFPI and free PS levels. An association was observed between levels of free TFPI and nAPCsr, and between free PS and nAPCsr. The effect of oral contraceptives on TFPI and PS is a possible explanation for the increased risk of venous thrombosis associated with oral contraceptives.

A Randomized Cross-over Study on the Effects of Levonorgestrel- and Desogestrel-containing Oral Contraceptives on the Anticoagulant Pathways

2000 ◽  
Vol 84 (07) ◽  
pp. 15-21 ◽  
Author(s):  
Guido Tans ◽  
Joyce Curvers ◽  
Saskia Middeldorp ◽  
M. Christella Thomassen ◽  
Martin Prins ◽  
...  
Keyword(s):  
Oral Contraceptives ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Third Generation ◽  
Free Protein ◽  
Apc Resistance ◽  
Α2 Macroglobulin ◽  
Increased Risk ◽  
Resistance Tests

SummaryThe use of oral contraceptives (OC) causes disturbances of the procoagulant, anticoagulant and fibrinolytic pathways of blood coagulation which may contribute to the increased risk of venous thrombosis associated with OC therapy. Here we report the results of a cyclecontrolled randomized cross-over study, in which we determined the effects of so-called second and third generation OC’s on a number of anticoagulant parameters. In this study, 28 non-OC using women were randomly prescribed either a second generation (150 µg levonorgestrel/30 µg ethinylestradiol) or a third generation OC (150 µg desogestrel/30 µg ethinylestradiol) and who switched to the other OC after a two month wash out period. The anticoagulant parameters determined were: antithrombin (AT), α2-macroglobulin (α2-M), α1-antitrypsin, protein C inhibitor (PCI), protein C, total and free protein S and activated protein C sensitivity ratios (APC-sr) measured with two functional APC resistance tests which quantify the effect of APC on either the activated partial thromboplastin time (aPTT) or on the endogenous thrombin potential (ETP). During the use of desogestrel-containing OC the plasma levels of αc2-M, α1-antitrypsin, PCI and protein C significantly increased, whereas AT and protein S significantly decreased. Similar trends were observed with levonorgestrel-containing OC, although on this kind of OC the changes in AT, PCI and protein S (which was even slightly increased) did not reach significance. Compared with levonorgestrel, desogestrel-containing OC caused a significant decrease of total (p <0.005) as well as free protein S (p <0.0001) and more pronounced APC resistance in both the aPTT (p = 0.02) and ETPbased (p <0.0001) APC resistance tests. These observations indicate that the activity of the anticoagulant pathways in plasma from users of desogestrel-containing OC is more extensively impaired than in plasma from users of levonorgestrel-containing OC.

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.

Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1935-1941 ◽  
Author(s):  
Michael Makris ◽  
Michael Leach ◽  
Nick J. Beauchamp ◽  
Martina E. Daly ◽  
Peter C. Cooper ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Protein S ◽  
Structural Defects ◽  
Protein S Deficiency ◽  
Gene Defect ◽  
Thrombotic Risk ◽  
Free Protein ◽  
First Degree Relatives ◽  
S Deficiency ◽  
Increased Risk

Abstract Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients' relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1.5-16.8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons withPROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency.

A Reduced Sensitivity for Activated Protein C in the Absence of Factor V Leiden Increases the Risk of Venous Thrombosis

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1271-1276 ◽  
Author(s):  
Marieke C.H. de Visser ◽  
Frits R. Rosendaal ◽  
Rogier M. Bertina
Keyword(s):  
Risk Factor ◽  
Confidence Interval ◽  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Apc Resistance ◽  
Increased Risk

Abstract Activated protein C (APC) resistance caused by the factor V Leiden mutation is associated with an increased risk of venous thrombosis. We investigated whether a reduced response to APC, not due to the factor V point mutation, is also a risk factor for venous thrombosis. For this analysis, we used the Leiden Thrombophilia Study (LETS), a case-control study for venous thrombosis including 474 patients with a first deep-vein thrombosis and 474 age- and sex-matched controls. All carriers of the factor V Leiden mutation were excluded. A dose-response relationship was observed between the sensitivity for APC and the risk of thrombosis: the lower the normalized APC sensitivity ratio, the higher the associated risk. The risk for the lowest quartile of normalized APC-SR (&lt;0.92), which included 16.5% of the healthy controls, compared with the highest quartile (normalized APC-SR &gt; 1.05) was greater than fourfold increased (OR = 4.4; 95% confidence interval, 2.9 to 6.6). We adjusted for VIII:C levels, which appeared to affect our APC resistance test. The adjusted (age, sex, FVIII:C) odds ratio for the lowest quartile was 2.5 (95% confidence interval, 1.5 to 4.2). So, after adjustment for factor VIII levels, a reduced response to APC remained a risk factor. Our results show that a reduced sensitivity for APC, not caused by the factor V Leiden mutation, is a risk factor for venous thrombosis.

Phenotypic APC Resistance in Carriers of the A20210 Prothrombin Mutation Is Associated with an Increased Risk of Venous Thrombosis

2001 ◽  
Vol 86 (09) ◽  
pp. 804-808 ◽  
Author(s):  
Alberto Tosetto ◽  
Monica Simioni ◽  
Marco Ruggeri ◽  
Domenico Madeo ◽  
Francesco Rodeghiero ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Normal Population ◽  
Activated Protein C ◽  
Strong Relationship ◽  
Normal Subjects ◽  
Apc Resistance ◽  
G20210a Mutation ◽  
Increased Risk ◽  
Prothrombin Gene Mutation ◽  
Prothrombin Gene

SummaryWe hypothesized that increased prothrombin levels associated with G20210A prothrombin gene mutation could affect the results of activated protein C (APC) resistance phenotype and increase the risk of venous thrombosis (VT). The increasing addition of purified prothrombin in plasma of 90 normal subjects resulted in a parallel significant increase of APC resistance. Significantly different mean n-APC-SR in 879 GG20210 subjects compared to 27 heterozygous carriers of isolated G20210A mutation was observed (1.0 ± 0.12 vs. 0.95 ± 0.11; P = 0.02) in a random sample of 906 normal population subjects. Twenty-seven families with VT and isolated G20210A mutation consecutively diagnosed during 1998-1999 were evaluated. Mean n-APC-SR was significantly lower in the 80 G20210A carriers compared to 58 GG 20210 relatives investigated, even after sex and age adjustment (0.92 ± 0.08 vs. 1.05 ± 0.13; P < 0.0001). A strong relationship between plasma prothrombin level and n-APC-SR was observed in the families. When n-APC-SR values were grouped in tertiles, the odds ratio for VTE, after exclusion of the index cases and adjustment for 20210 status, for subjects in the lowest tertile (n-APC-SR 0.73-0.90) was 4.58 (95% CI 0.78-26.88) compared to upper tertile (n-APC-SR 1.01-1.30). In conclusion, in subjects with G20210A mutation APC resistance is significantly increased, correlates with plasma prothrombin level and the carriers with the lowest APC resistance values have an increased risk of VTE.

Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 927-933 ◽  
Author(s):  
Jeanet M. Kemmeren ◽  
Ale Algra ◽  
Joost C. M. Meijers ◽  
Guido Tans ◽  
Bonno N. Bouma ◽  
...  
Keyword(s):  
Oral Contraceptives ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Third Generation ◽  
Double Blind Trial ◽  
Double Blind ◽  
Thrombotic Risk ◽  
Apc Resistance ◽  
Plausible Mechanism

AbstractA plausible mechanism to explain thrombotic risk differences associated with the use of second- and third-generation oral contraceptives (OCs), particularly in carriers of factor VLeiden, is still lacking. In a double-blind trial, 51 women without and 35 women with factor VLeiden were randomized to either a second- (30 μg ethinylestradiol/150 μg levonorgestrel) or third- (30 μg ethinylestradiol/150 μg desogestrel) generation OC. After 2 cycles of use and a wash-out of 2 cycles, the participants continued with the corresponding progestagen-only preparation. Hemostatic variables that probe the activity of the anticoagulant protein C system were determined. Compared with levonorgestrel, desogestrel-containing OCs significantly decreased protein S and increased activated protein C (APC) resistance in both groups. OCs with desogestrel had the most pronounced effects in carriers of factor VLeiden. Progestagen-only preparations caused changes of anticoagulant parameters opposite to those of combined OCs, which in a number of cases were more pronounced with levonorgestrel. Our data show that progestagens in combined OCs counteract the thrombotic effect of the estrogen component. The higher thrombotic risk associated with third-generation OCs compared with second-generation OCs may be explained by the fact that desogestrel appeared less antithrombotic than levonorgestrel, especially in women with factor VLeiden. (Blood. 2004;103:927-933)

Female Gender and Resistance to Activated Protein C (FV:Q506) as Potential Risk Factors for Thrombosis after Elective Hip Arthroplasty

1997 ◽  
Vol 78 (03) ◽  
pp. 0993-0996 ◽  
Author(s):  
P J Svensson ◽  
G Benoni ◽  
H Fredin ◽  
O Bjӧrgell ◽  
P Nilsson ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Female Gender ◽  
Prolonged Treatment ◽  
Factor V ◽  
Apc Resistance ◽  
Increased Risk ◽  
Postoperative Thrombosis

SummaryResistance to activated protein C (APC) caused by the R506Q mutation in factor V is the most common inherited risk factor for venous thrombosis. To elucidate whether APC-resistance is a risk factor for venous thrombosis after elective total hip replacement, the association between APC-resistance (presence of FV:Q506 allele) and postoperative thrombosis was investigated in patients (n = 198) randomised to received short (during hospitalisation, n = 100) or prolonged prophylaxis (three weeks after hospitalisation, n = 98) with low molecular weight heparin (LMWH). Among APC-resistant individuals receiving short prophylaxis, 7/10 developed thrombosis as compared to 2/12 receiving long prophylaxis (p <0.0179). Odds ratio for association between APC-resistance and thrombosis in the short prophylaxis group was 4.2 (CI 95% 1.02-17.5) (p <0.0465). Among those receiving prolonged, prophylaxis, there was no increased incidence of thrombosis associated with APC-resistance. Two unexpected observations were made. One was that APC-resistance was much more common in women (19/109) than in men (3/89) (p <0.001). The other was that even women without APC-resistance were much more thrombosis-prone than men. Thus, 24/48 of women with normal FV genotype and short prophylaxis developed thrombosis vs 8/42 among men, p = 0.002. The increased risk of thrombosis associated with female gender and APC-resistance was neutralised by the prolonged treatment. In conclusion, among patients receiving short prophylaxis, female gender was found to be a strong risk factor for venous thrombosis. Even though APC-resistance appeared to be a risk factor for postoperative thrombosis, the uneven distribution of APC-resistance between men and women, taken together with the increased risk of thrombosis among women, precluded valid conclusions to be drawn about the association between APC-resistance and an increased risk of thrombosis. Our results suggest that prolonged prophylaxis with LMWH after hip surgery is more important for women than for men.

Third-generation oral contraceptives and low free protein S as a risk for venous thrombosis

The Lancet ◽  
1996 ◽  
Vol 347 (8998) ◽  
pp. 397 ◽  
Author(s):  
Piedad Villa ◽  
Justo Aznar ◽  
Yolanda Mira ◽  
M. Angeles Fernández ◽  
Amparo Vayá
Keyword(s):  
Venous Thrombosis ◽  
Oral Contraceptives ◽  
Protein S ◽  
Third Generation ◽  
Free Protein

scholarly journals Oral contraceptives and gender affect protein S status

Blood ◽  
1987 ◽  
Vol 69 (2) ◽  
pp. 692-694 ◽  
Author(s):  
LM Boerger ◽  
PC Morris ◽  
GR Thurnau ◽  
CT Esmon ◽  
PC Comp
Keyword(s):  
Oral Contraceptives ◽  
Plasma Protein ◽  
Total Protein ◽  
Contraceptive Use ◽  
Binding Protein ◽  
Activated Protein C ◽  
Protein S ◽  
Free Protein ◽  
Protein Levels ◽  
And Gender

Protein S is a plasma protein that serves as a cofactor for the anticoagulant effects of activated protein C. Congenital protein S deficiency is often associated with thromboembolic disease. During pregnancy a decrease in the functional and antigenic levels of protein S occurs; this change in protein S status may contribute to the thromboembolic complications that sometimes occur during pregnancy. In certain patients, oral contraceptive use has also been associated with thrombotic complications. In this study, protein S status was determined in 21 women taking oral contraceptives and compared with that of 21 women not taking oral contraceptives and that of 21 men. The results show that women taking oral contraceptives have significantly lower total protein S (24.3 +/- 3.6 micrograms/mL; mean +/- SD) than women not taking oral contraceptives (28.6 +/- 3.9 micrograms/mL) (P less than .005). Men had significantly higher protein S levels (30.9 +/- 3.9 micrograms/mL, P less than .01) than age-matched women not taking oral contraceptives. In plasma, an equilibrium exists between free (functionally active) protein S and protein S complexed to C4b-binding protein, which is functionally inactive. The mean levels of C4b-binding protein were essentially the same among the three groups, but the levels of free protein S were significantly different and reflected different total protein S antigen levels. Additionally, we found that inflammation significantly elevated C4b-binding protein levels and could result in a further significant decrease in free protein S levels. These data indicate that plasma protein S levels are significantly affected by hormonal status and inflammation.

scholarly journals Oral contraceptives and gender affect protein S status

Blood ◽  
1987 ◽  
Vol 69 (2) ◽  
pp. 692-694 ◽  
Author(s):  
LM Boerger ◽  
PC Morris ◽  
GR Thurnau ◽  
CT Esmon ◽  
PC Comp
Keyword(s):  
Oral Contraceptives ◽  
Plasma Protein ◽  
Total Protein ◽  
Contraceptive Use ◽  
Binding Protein ◽  
Activated Protein C ◽  
Protein S ◽  
Free Protein ◽  
Protein Levels ◽  
And Gender

Abstract Protein S is a plasma protein that serves as a cofactor for the anticoagulant effects of activated protein C. Congenital protein S deficiency is often associated with thromboembolic disease. During pregnancy a decrease in the functional and antigenic levels of protein S occurs; this change in protein S status may contribute to the thromboembolic complications that sometimes occur during pregnancy. In certain patients, oral contraceptive use has also been associated with thrombotic complications. In this study, protein S status was determined in 21 women taking oral contraceptives and compared with that of 21 women not taking oral contraceptives and that of 21 men. The results show that women taking oral contraceptives have significantly lower total protein S (24.3 +/- 3.6 micrograms/mL; mean +/- SD) than women not taking oral contraceptives (28.6 +/- 3.9 micrograms/mL) (P less than .005). Men had significantly higher protein S levels (30.9 +/- 3.9 micrograms/mL, P less than .01) than age-matched women not taking oral contraceptives. In plasma, an equilibrium exists between free (functionally active) protein S and protein S complexed to C4b-binding protein, which is functionally inactive. The mean levels of C4b-binding protein were essentially the same among the three groups, but the levels of free protein S were significantly different and reflected different total protein S antigen levels. Additionally, we found that inflammation significantly elevated C4b-binding protein levels and could result in a further significant decrease in free protein S levels. These data indicate that plasma protein S levels are significantly affected by hormonal status and inflammation.

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