scholarly journals The Role of APC-Resistance for Predicting Venous Thrombosis and Pregnancy Complications in Carriers of Factor V Leiden (1691) G/A Mutation

2018 ◽  
Author(s):  
Andrey Pavlovich Momot ◽  
Maria Gennadevna Nikolaeva ◽  
Valeriy Anatolevich Elykomov ◽  
Ksenia Andreevna Momot
Keyword(s):  
Venous Thrombosis ◽  
Pregnancy Complications ◽  
Factor V Leiden ◽  
Factor V ◽  
Apc Resistance

scholarly journals Factor V Cambridge: A New Mutation (Arg306→Thr) Associated With Resistance to Activated Protein C

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1140-1144 ◽  
Author(s):  
David Williamson ◽  
Karen Brown ◽  
Roger Luddington ◽  
Caroline Baglin ◽  
Trevor Baglin
Keyword(s):  
Venous Thrombosis ◽  
Cleavage Site ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Degree Relative ◽  
Prothrombinase Complex ◽  
Apc Resistance ◽  
The Common

AbstractA new factor V mutation associated with resistance to activated protein C and thrombosis (factor V Cambridge, Arg306→Thr) was found in one patient from a carefully selected group of 17 patients with venous thrombosis and confirmed APC resistance in the absence of the common Gln506 mutation. The Arg306 mutation was also present in a first degree relative who also had APC resistance. Other potential causes of APC resistance, such as a mutation at the Arg679 site and the factor V HR2 haplotype, were excluded. Subsequent screening of 585 patients with venous thromboembolism and 226 blood donors did not show any other individual with this mutation. Factor VThr306 is the first description of a mutation affecting the Arg306 APC cleavage site and is the only mutation, other than factor V Leiden (Arg506→Gln), that has been found in association with APC resistance. This finding confirms the physiologic importance of the Arg306 APC-cleavage site in the regulation of the prothrombinase complex. It also supports the concept that APC resistance and venous thrombosis can result from a variety of genetic mutations affecting critical sites in the factor V cofactor.

scholarly journals Fibrinogen γ′ increases the sensitivity to activated protein C in normal and factor V Leiden plasma

Blood ◽  
2014 ◽  
Vol 124 (9) ◽  
pp. 1531-1538 ◽  
Author(s):  
Farida Omarova ◽  
Shirley Uitte de Willige ◽  
Paolo Simioni ◽  
Robert A. S. Ariëns ◽  
Rogier M. Bertina ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Common Risk Factor ◽  
Apc Resistance ◽  
Key Points

Key Points Fibrinogen, and particularly fibrinogen γ′, counteracts plasma APC resistance, the most common risk factor for venous thrombosis. The C-terminal peptide of the fibrinogen γ′ chain inhibits protein C activation, but still improves the response of plasma to APC.

scholarly journals Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection of patients

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4205-4208 ◽  
Author(s):  
RP Lensen ◽  
FR Rosendaal ◽  
T Koster ◽  
CF Allaart ◽  
H de Ronde ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Age Of Onset ◽  
Factor V Leiden ◽  
Factor V ◽  
Protein C Deficiency ◽  
Apc Resistance ◽  
Selection Of Patients ◽  
Control Study ◽  
Selection Of

Both activated protein C (APC) resistance and protein C deficiency are associated with an increased risk for venous thrombosis. To assess their tendencies to venous thrombosis, we compared the median age of first venous thromboembolism in patients with factor V Leiden or protein C deficiency, who were identified either within unselected consecutive cases with a first deep venous thrombosis derived from a population-based case-control study, or identified by selection of patients with a deep venous thrombosis, who were referred for thrombophilIa work-up. The median age of onset for 92 unselected APC resistant cases was 43 years and for 13 unselected protein C-deficient cases 47 years. The median age at the first thrombotic event for 28 APC- resistant members of thrombophilia families was 29 years and for 50 protein C-deficient members of thrombophilia families 31.5 years. The median age of onset for all unselected patients (n=105) was 45 years of age (range, 16 to 69 years) and the median age of onset for all selected patients from the thrombophilia families (n=78) was 30.5 years (range, 16 to 67 years). These results show that within the case-control study and the family studies, the median age of onset is very similar in patients with APC resistance and patients with protein C deficiency. This suggests that APC resistance is not less severe with respect to risk of thrombosis than (heterozygous) protein C deficiency. In conclusion, the median age at which the first thrombosis occurs mainly depends on the way the patients are identified and not on the type of thrombophilia.

Simple and Reliable Factor V Genotyping by PNA-Mediated PCR Clamping

1998 ◽  
Vol 79 (04) ◽  
pp. 773-777 ◽  
Author(s):  
Moira Behn ◽  
Marcus Schuermann
Keyword(s):  
Venous Thrombosis ◽  
Large Scale ◽  
Single Point ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Single Point Mutation ◽  
Factor V ◽  
Apc Resistance ◽  
Novel Approach ◽  
Pcr Rflp

SummaryResistance to activated protein C (APC resistance) is the most common cause of thrombophilia and linked to a single point mutation in the factor V gene (G>A transition at nucleotide 1691). In the past, several PCR based methods have been proposed to determine the allelostatus of individual patients from small amounts of blood DNA including PCR followed by restriction fragment length polymorphism detection (PCR-RFLP), PCR using sequence-specific primers (PCR-SSP) and oligonucleotide ligation assay (OLA). Here, we present a novel approach based on the method of peptide nucleic acid(PNA)-mediated PCR clamping which is extremely sensitive to base pair mismatches. If PNAs specific for the two allelic variants are applied separately in each case a clear discrimination between a heterozygous or homozygous normal or homozygous Factor V Leiden status is possible and no further confirmation step is required. In a prospective study, 60 patients with suspected venous thrombosis events were tested and compared to the conventional PCR-RFLP technique. The concordance between both methods was 100%. PNA-based factor V genotyping, therefore, should be considered for large scale screening of those patients considered to be at risk for deep venous thrombosis.

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 (<0.92), which included 16.5% of the healthy controls, compared with the highest quartile (normalized APC-SR > 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.

Follow-up von Patienten mit persistierender APC-Resistenz ohne Faktor V Leiden

VASA ◽  
2001 ◽  
Vol 30 (1) ◽  
pp. 24-27 ◽  
Author(s):  
T. Schwarz ◽  
G. Siegert ◽  
U. Mikulin ◽  
S. Gehrisch ◽  
E. Runge ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Genetic Defect ◽  
Factor V Leiden ◽  
Arterial Disease ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
Apc Resistance

Background: Activated protein C (APC) resistance and factor V Leiden mutation are major risk factors for deep venous thrombosis. Previous work has led to the view that the coagulation phenotype and the genetic defect are associated in almost all patients. It has been reported about single APC-resistant patients without associated factor V Leiden, but significance and thrombotic risk of this constellation have not yet been established. Patients and methods: We tested 486 consecutive patients with deep venous thrombosis, arterial disease or other than vascular disease for APC-resistance with a factor VIII based assay. Results: 149 patients (31%) showed a pathological APC-ratio. Sensitivity and specificity for detection of factor V Leiden were 100% and 40%, respectively. At 6 months follow-up APC-ratio returned to normal in 55% of the patients with initial pathological APC-resistance. At 12 months follow-up 91% of the patients with persistent APC-resistance showed a pathological ratio as well. Conclusions: Patients with APC-resistance not due to factor V Leiden can be attributed to one subset with reversible APC-resistance – possibly due to a hypercoagulable state in an acute thrombotic situation, and to another with persistent APC-resistance.

Evolution of Factor V Leiden

2013 ◽  
Vol 110 (07) ◽  
pp. 23-30 ◽  
Author(s):  
Marcel Levi ◽  
Saskia Middeldorp ◽  
Thijs van Mens
Keyword(s):  
Blood Loss ◽  
Pregnancy Complications ◽  
Embryo Implantation ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Menstrual Blood Loss ◽  
Apc Resistance ◽  
Sperm Counts ◽  
High Prevalence

SummaryFactor V Leiden is a procoagulant mutation associated with venous and arterial thrombosis and pregnancy complications. Its high prevalence of 5% in Caucasians suggests that there are evolutionary benefits as well. Carriers are indeed reported to have various advantageous phenotypes related to haemostasis, inflammation and fertility: less acute blood loss; less menstrual blood loss; decreased risk of intracranial haemorrhage; milder phenotypes of haemophilia; higher survival in and lower susceptibility to severe sepsis; higher survival in acute respiratory distress syndrome; less severe diabetic nephropathy and higher fecundity in both men and women. Not all these associations come from high quality adequately powered studies and many have not been confirmed by further research. The evolutionary influence of the alleged associations varies and is difficult to establish, partly due to a shift over time in risk factors of the diseases concerned. For most of the phenotypes possible mechanistic explanations can be provided. The procoagulant phenotype and perhaps also certain pregnancy complications follow from activated protein C (APC) resistance. Elevated APC levels possibly mediate anti-inflammatory effects. Higher sperm counts and more successful embryo implantation seem to play a role in the increased fecundity.

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

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 (<0.92), which included 16.5% of the healthy controls, compared with the highest quartile (normalized APC-SR > 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.

scholarly journals Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection of patients

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4205-4208 ◽  
Author(s):  
RP Lensen ◽  
FR Rosendaal ◽  
T Koster ◽  
CF Allaart ◽  
H de Ronde ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Age Of Onset ◽  
Factor V Leiden ◽  
Factor V ◽  
Protein C Deficiency ◽  
Apc Resistance ◽  
Selection Of Patients ◽  
Control Study ◽  
Selection Of

Abstract Both activated protein C (APC) resistance and protein C deficiency are associated with an increased risk for venous thrombosis. To assess their tendencies to venous thrombosis, we compared the median age of first venous thromboembolism in patients with factor V Leiden or protein C deficiency, who were identified either within unselected consecutive cases with a first deep venous thrombosis derived from a population-based case-control study, or identified by selection of patients with a deep venous thrombosis, who were referred for thrombophilIa work-up. The median age of onset for 92 unselected APC resistant cases was 43 years and for 13 unselected protein C-deficient cases 47 years. The median age at the first thrombotic event for 28 APC- resistant members of thrombophilia families was 29 years and for 50 protein C-deficient members of thrombophilia families 31.5 years. The median age of onset for all unselected patients (n=105) was 45 years of age (range, 16 to 69 years) and the median age of onset for all selected patients from the thrombophilia families (n=78) was 30.5 years (range, 16 to 67 years). These results show that within the case-control study and the family studies, the median age of onset is very similar in patients with APC resistance and patients with protein C deficiency. This suggests that APC resistance is not less severe with respect to risk of thrombosis than (heterozygous) protein C deficiency. In conclusion, the median age at which the first thrombosis occurs mainly depends on the way the patients are identified and not on the type of thrombophilia.

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