Differential impact of conventional and low-dose oral hormone therapy (HT), tibolone and raloxifene on functionality of the activated protein C system

2007 ◽  
Vol 97 (06) ◽  
pp. 938-943 ◽  
Author(s):  
Sigurd Liestøl ◽  
Marie-Christine Mowinckel ◽  
H. Coen Hemker ◽  
Per-Morten Sandset ◽  
Anette Eilertsen
Keyword(s):  
Hormone Therapy ◽  
Protein C ◽  
Low Dose ◽  
Acquired Resistance ◽  
Activated Protein C ◽  
System Sensitivity ◽  
Conventional Dose ◽  
Apc Resistance ◽  
The Difference ◽  
Progestin Therapy

SummaryRecent studies have shown that hormone therapy (HT) is associated with an acquired resistance to activated protein C (APC). The aims of the present study were to evaluate a possible dose-response relationship and differential effects of different HT regimens on functionality of the APC system. Two hundred two healthy women were randomly assigned to receive treatment for 12 weeks with tablets containing either low-dose HT containing 1 mg 17β-oestradiol + 0.5 mg norethisterone acetate (NETA) (n=50), conventional-dose HT containing 2 mg 17β-oestradiol and 1 mg NETA (n=50), 2.5 mg tibolone (n=51), or 60 mg raloxifene (n=51). Normalized APC system sensitivity ratios (nAPCsr) were determined in plasma collected at baseline and after 12 weeks using a thrombin generation-based APC resistance test probed with either recombinant APC (rAPC) or thrombomodulin (rTM). NAPCsr increased in both the conventional- and low-dose HT groups, consistent with reduced sensitivity to APC. The increase was slightly more pronounced in the conventional-dose group, but the difference between the two HT groups was not statistically significant. The sensitivity to APC was only marginally altered in those allocated to tibolone. Consequently, tibolone showed a different phenotype as compared with the low-dose HT group. A small increase in nAPCsr with both rAPC and rTM was seen in the raloxifene-group, but the increase was less than in the low-dose HT group. Our findings indicate that oestrogen-progestin therapy induces an APC resistant phenotype, which may be related to dose, whereas tibolone and raloxifene only marginally alter the sensitivity to APC.

scholarly journals Thrombinography shows acquired resistance to activated protein C in patients with lupus anticoagulants

2003 ◽  
Vol 89 (02) ◽  
pp. 208-212 ◽  
Author(s):  
Véronique Regnault ◽  
Suzette Béguin ◽  
Denis Wahl ◽  
Emmanuel de Maistre ◽  
H. Coenraad Hemker ◽  
...  
Keyword(s):  
Protein C ◽  
Platelet Rich Plasma ◽  
Acquired Resistance ◽  
Activated Protein C ◽  
Lag Phase ◽  
Thrombotic Risk ◽  
Lupus Anticoagulants ◽  
Apc Resistance ◽  
Thrombin Activity ◽  
Lag Times

SummaryIn patients with lupus anticoagulants (LA), acquired resistance to activated protein C (APC) is difficult to demonstrate with clot-based assays due to the presence of the anticoagulant. Via the conversion of a fluorogenic substrate (thrombinography), we monitored the complete process of thrombin formation and decay and its delimitation by the protein C system in eight consecutive LA-patients without anticoagulant therapy and non-carriers of the V Leiden polymorphism. Thrombin generation was triggered in platelet-poor and platelet-rich plasma by recalcification in the presence of a low concentration of tissue factor.In 7 out of 8 patients we observed a long lag-time before the thrombin burst (LA effect) together with a marked inability of APC to diminish the thrombin activity. The lag-phase was however prolonged to some degree by APC. The effects were more outspoken in the presence of phospholipids from patients' platelets than with added phospholipids.Thrombinography thus demonstrates APC resistance in LA-patients despite the occurrence of long lag-times (clotting times). The amount of thrombin activity generated in the presence of APC could be a better indicator of the thrombotic risk than the moment at which the thrombin burst starts.

Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study

The Lancet ◽  
1999 ◽  
Vol 354 (9195) ◽  
pp. 2036-2040 ◽  
Author(s):  
Jan Rosing ◽  
Saskia Middeldorp ◽  
Joyce Curvers ◽  
M Christella L GDlig; Thomassen ◽  
Gerry AF Nicolaes ◽  
...  
Keyword(s):  
Oral Contraceptives ◽  
Protein C ◽  
Low Dose ◽  
Acquired Resistance ◽  
Activated Protein C ◽  
Dose Oral

Hypercoagulable State in Patients with Advanced Gastrointestinal Cancer: Evidence for an Acquired Resistance to Activated Protein C

1997 ◽  
Vol 83 (6) ◽  
pp. 948-952 ◽  
Author(s):  
Domenico De Lucia ◽  
Ferdinando DeVita ◽  
Michele Orditura ◽  
Valter Renis ◽  
Antonello Belli ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Gastrointestinal Cancer ◽  
Protein C ◽  
Acquired Resistance ◽  
Activated Protein C ◽  
Poor Response ◽  
Coagulation Cascade ◽  
Control Group ◽  
Factor V ◽  
Apc Resistance

Aims and background Thromboembolic complications are common in patients with cancer and represent the second cause of death in patients with overt malignant disease. The aim of this study was to investigate the activated protein C pathway in cancer. Methods We studied the coagulation cascade, natural clotting inhibitors, fibrinolytic proteins and resistance to activated protein C in 20 patients with advanced gastrointestinal cancer and 84 volunteers by measuring PT, APTT, fibrinogen, AT III, PC, PS, APC resistance, fibrinolytic system (PLG, ANPL, PAI-1 and t-PA) and activation peptides (D-Dimers, prothrombin 0 fragment 1+2/F1+2). Results Laboratory tests confirmed coagulation abnormalities in cancer patients. Fibrinogen, D-Dimers and F1+2 were increased, while t-PA activity was significantly lower than that of controls. APC resistance was higher in cancer patients compared to the control group (55% vs 2%; P < 0.0001). Excess thrombin generation was manifested by increased F1+2 plasma levels in APC-resistant cancer patients. Genetic analyses showed that only one patient with a poor response to APC carried a factor V R506Q mutation in exon 10. Conclusions Our findings show a high prevalence of APC resistance in cancer, compatible with an acquired defect in the APC pathway.

“Pseudo Homozygous” Activated Protein C Resistance due to Double Heterozygous Factor V Defects (Factor V Leiden Mutation and Type I Quantitative Factor V Defect) Associated with Thrombosis: Report of Two Cases Belonging to Two Unrelated Kindreds

1996 ◽  
Vol 75 (03) ◽  
pp. 422-426 ◽  
Author(s):  
Paolo Simioni ◽  
Alberta Scudeller ◽  
Paolo Radossi ◽  
Sabrina Gavasso ◽  
Bruno Girolami ◽  
...  
Keyword(s):  
Protein C ◽  
Dna Analysis ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Type I ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
Apc Resistance ◽  
Quantitative Factor

SummaryTwo unrelated patients belonging to two Italian kindreds with a history of thrombotic manifestations were found to have a double heterozygous defect of factor V (F. V), namely type I quantitative F. V defect and F. V Leiden mutation. Although DNA analysis confirmed the presence of a heterozygous F. V Leiden mutation, the measurement of the responsiveness of patients plasma to addition of activated protein C (APC) gave results similar to those found in homozygous defects. It has been recently reported in a preliminary form that the coinheritance of heterozygous F. V Leiden mutation and type I quantitative F. V deficiency in three individuals belonging to the same family resulted in the so-called pseudo homozygous APC resistance with APC sensitivity ratio (APC-SR) typical of homozygous F. V Leiden mutation. In this study we report two new cases of pseudo homozygous APC resistance. Both patients experienced thrombotic manifestations. It is likely that the absence of normal F. V, instead of protecting from thrombotic risk due to heterozygous F. V Leiden mutation, increased the predisposition to thrombosis since the patients became, in fact, pseudo-homozygotes for APC resistance. DNA-analysis is the only way to genotype a patient and is strongly recommended to confirm a diagnosis of homozygous F. V Leiden mutation also in patients with the lowest values of APC-SR. It is to be hoped that no patient gets a diagnosis of homozygous F. V Leiden mutation based on the APC-resi-stance test, especially when the basal clotting tests, i.e., PT and aPTT; are borderline or slightly prolonged.

Molecular Characterization of a Type I Quantitative Factor V Deficiency in a Thrombosis Patient that Is “Pseudo Homozygous” for Activated Protein C Resistance

1997 ◽  
Vol 77 (02) ◽  
pp. 252-257 ◽  
Author(s):  
Joan F Guasch ◽  
Ruud P M Lensen ◽  
Rogier M Bertina
Keyword(s):  
Protein C ◽  
Dna Analysis ◽  
Activated Protein C ◽  
Type I ◽  
Factor V ◽  
Sequencing Analysis ◽  
Apc Resistance ◽  
Quantitative Factor ◽  
Factor V Deficiency ◽  
Fv Leiden

SummaryResistance to activated protein C (APC), which is associated with the FV Leiden mutation in the large majority of the cases, is the most common genetic risk factor for thrombosis. Several laboratory tests have been developed to detect the APC-resistance phenotype. The result of the APC-resistance test (APC-sensitivity ratio, APC-SR) usually correlates well with the FV Leiden genotype, but recently some discrepancies have been reported. Some thrombosis patients that are heterozygous for FV Leiden show an APC-SR usually found only in homozygotes for the defect. Some of those patients proved to be compound heterozygotes for the FV Leiden mutation and for a type I quantitative factor V deficiency. We have investigated a thrombosis patient characterized by an APC-SR that would predict homozygosity for FV Leiden. DNA analysis showed that he was heterozygous for the mutation. Sequencing analysis of genomic DNA revealed that the patient also is heterozygous for a G5509→A substitution in exon 16 of the factor V gene. This mutation interferes with the correct splicing of intron 16 and leads to the presence of a null allele, which corresponds to the “non-FV Leiden” allele. The conjunction of these two defects in the patient apparently leads to the same phenotype as observed in homozygotes for the FV Leiden mutation.

scholarly journals A Factor V Genetic Component Differing From Factor V R506Q Contributes to the Activated Protein C Resistance Phenotype

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1552-1557 ◽  
Author(s):  
F. Bernardi ◽  
E.M. Faioni ◽  
E. Castoldi ◽  
B. Lunghi ◽  
G. Castaman ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Protein C ◽  
Activated Protein C ◽  
Functional Assay ◽  
Factor V ◽  
Resistance Phenotype ◽  
Apc Resistance ◽  
Genetic Components ◽  
Factor V Gene ◽  
V Gene

AbstractFactor V gene polymorphisms were investigated to detect components that may contribute to the activated protein C (APC) resistance phenotype in patients with venous thromboembolism. A specific factor V gene haplotype (HR2) was defined by six polymorphisms and its frequency was found to be similar in normal subjects coming from Italy (0.08), India (0.1), and Somalia (0.08), indicating that it was originated by ancestral mutational events. The relationship between the distribution of normalized APC ratios obtained with the functional assay and haplotype frequency was analyzed in patients heterozygous for factor V R506Q (factor V Leiden). The HR2 haplotype was significantly more frequent in patients with ratios below the 15th percentile than in those with higher ratios or in normal controls. Moreover, the study of 10 patients with APC resistance in the absence of the factor V R506Q mutation showed a 50-fold higher frequency of HR2 homozygotes. The HR2 haplotype was associated with significantly lower APC ratios both in patients with venous thromboembolism and in age- and sex-matched controls. However, the two groups showed similar HR2 haplotype frequencies. Plasma mixing experiments showed that an artificially created double heterozygote for the factor V R506Q mutation and the HR2 haplotype had an APC ratio lower than that expected for a simple R506Q heterozygote. Time-course experiments evaluating the decay of factor V in plasma showed the normal stability of the molecule encoded by the factor V gene marked by the HR2 haplotype, which ruled out the presence of a pseudo-homozygous APC resistance mechanism. Our results provide new insights into the presence of factor V genetic components other than the factor V R506Q that are able to contribute to the APC resistance phenotype in patients with venous thromboembolism.

APC resistance during the normal menstrual cycle

2007 ◽  
Vol 98 (12) ◽  
pp. 1246-1251 ◽  
Author(s):  
Angela Silveira ◽  
Stella Thomassen ◽  
Jacob Odeberg ◽  
Anders Hamsten ◽  
Jan Rosing ◽  
...  
Keyword(s):  
Menstrual Cycle ◽  
Protein C ◽  
Activated Protein C ◽  
Serum Levels ◽  
Serum Estradiol ◽  
Menstrual Cycles ◽  
Apc Resistance ◽  
Exogenous Estrogen ◽  
Normal Menstrual Cycle ◽  
Estradiol Concentration

SummaryIncreased serum levels of endogenous as well as exogenous estrogen are regarded to be responsible for acquired activated protein C (APC) resistance. It was the objective of this study to evaluate whether the physiological increase in serum estradiol concentration during the normal menstrual cycle affects the individual’s sensitivity to APC. Seventy-two women with normal menstrual cycles were included in the study. Blood samples for analysis of estradiol (E2), progesterone (P4) and APC resistance were drawn at two time points of the menstrual cycle (day 3–5 and day 22–25). Two methods of measuring APC resistance were used: the activated partial thromboplastin time (aPTT)-based assay and the endogenous thrombin potential (ETP)-based APC resistance test. Independent of the method used, no changes in APC resistance were found, even though the E2 concentration increased significantly between the two menstrual phases. No correlations between E2 levels and APC resistance, P4 levels and APC resistance or changes in E2 concentrations and changes in APC resistance were detected. Ten women were carriers of the factor VLeiden mutation. Their baseline APC resistance was increased, but their response to elevated E2 during the menstrual cycle did not differ from that of non-carriers. In conclusion, our observations suggest that physiological differences in serum levels of estradiol and progesterone between the early follicular and the luteal phase in a normal menstrual cycle do not have any significant impact on the individual’s sensitivity to APC.

scholarly journals Turnover of *I-protein C inhibitor and *I-alpha 1-antitrypsin and their complexes with activated protein C

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2290-2295 ◽  
Author(s):  
M Laurell ◽  
J Stenflo ◽  
TH Carlson
Keyword(s):  
Complex Formation ◽  
Protein C ◽  
Activated Protein C ◽  
Human Protein ◽  
Relative Contribution ◽  
Protein C Inhibitor ◽  
The Difference ◽  
Alpha 1 Antitrypsin

Abstract The rates of clearance and catabolism of human protein C inhibitor (PCI) and human alpha 1-antitrypsin (alpha 1-AT) and their complexes with human activated protein C (APC) were studied in the rabbit. The radioiodinated-free inhibitors had biologic half-lives of 23.4 and 62.1 hours, respectively, while the corresponding *I-labeled activated- protein C complexes were cleared with half-lives of 19.6 +/- 3.1 and 72.2 +/- 6.1 minutes. Complex clearances were linked to their catabolism as shown by a correlation between clearance and the appearance of free radioiodine in the plasma. Thus, the difference in the rates of catabolism would result in a fivefold greater amount of alpha 1-AT-APC complex than PCI-APC complex 1 hour after the formation of equal amounts of these in vivo. These results lead to the conclusion that the relative contribution of PCI and alpha 1-AT to the physiologic inhibition of APC cannot be determined only from the rates of the formation of these complexes in vitro, or from measurement of their levels in plasma. The APC-PCI complex is unstable as compared with the APC-alpha 1-AT complex, compounding the problem of estimating rates of complex formation from their levels in plasma.

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