scholarly journals Mortality and Causes of Death in Families With the Factor V Leiden Mutation (Resistance to Activated Protein C)

Blood ◽  
1997 ◽  
Vol 89 (6) ◽  
pp. 1963-1967 ◽  
Author(s):  
Elysée T.M. Hille ◽  
Rudi G.J. Westendorp ◽  
Jan P. Vandenbroucke ◽  
Frits R. Rosendaal
Keyword(s):  
Life Expectancy ◽  
Cause Of Death ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Ischemic Heart ◽  
Malignant Neoplasms ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Apc Resistance

AbstractTo investigate whether resistance to activated protein C (APC resistance) because of a mutation in the factor V gene (factor V Leiden) leads to a decrease in life expectancy, we analyzed overall and cause-specific mortality in 171 parents whose offspring carried this mutation. Compared with the Dutch general population, and after adjustment for age, sex, and calendar period, we found no excess deaths in the parents (standardized mortality ratio [SMR], 1.0; 95% confidence interval [CI], 0.8 to 1.2). The cause-specific SMR for malignant neoplasms (1.0; 95% CI, 0.6 to 1.4), diseases of the circulatory system (1.0; 95% CI, 0.7 to 1.4), and cerebrovascular disease (1.0; 95% CI, 0.4 to 1.9) also did not differ from unity. The SMRs for diseases of the respiratory system (1.4; 95% CI, 0.6 to 2.6) and for ischemic heart diseases (1.1; 95% CI, 0.7 to 1.7) were slightly increased. Under the age of 45 years, there was a ninefold increase of dying from ischemic heart disease. Thromboembolic complications were mentioned only once (venous embolism or thrombosis) as an underlying (“primary”) cause of death (SMR, 2.3; 95% CI, 0.1 to 13.0) and three times (pulmonary embolisms) as a contributing (“secondary”) cause of death (SMR, 1.5; 95% CI, 0.3 to 4.4). We conclude that there is no major effect of APC resistance on life expectancy. Therefore, long-term anticoagulation in carriers of factor V Leiden, on the basis of the carrier state alone, is not indicated.

“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.

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.

Oral Contraceptive-Associated Thromboembolism. A Retrospective Analysis of Thrombophilic Work-out and Long Term Follow up in 57 Cases

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5348-5348
Author(s):  
Emmanouil Papadakis ◽  
Smaragda Efremidou ◽  
Haris Kartsios ◽  
Margarita Mpraimi ◽  
Kiriaki Kokoviadou ◽  
...  
Keyword(s):  
Family History ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Apc Resistance ◽  
Increased Risk ◽  
Fv Leiden

Abstract Introduction: The increased risk of venous thrombosis in women taking oral contraceptives (OCs) has been recognized since the early 1960s. Coexistence of hereditary risk factors appears to have an additive effect. Women under OCs that carry the factor V Leiden mutation have a 35-fold increased risk of thromboembolic events compared to women without the mutation who are not on OCs. Evaluation of family and personal history is the mainstay of prophylaxis prior to OC administration, but often family thrombophilia or thromboembolic (TE) events are not reported prior to OCs prescription. Patients-Methods: Fifty-seven women with a median age of 28 (21–48) years, which suffered OC-associated TE, were studied. The median period of OC therapy prior to TE event was 2 months (0.5–60). Fifty-five of them experienced VTE while 2 suffered stroke. Leg thrombosis was the most common clinical finding [37/55 (67,2%) patients] Apart from personal and family history, Thrombophilia investigation included measurement of : serum Homocysteine, Antithrombin, Protein C and S, Lipoprotein (a), Activated Protein C (APC) resistance, antiphospholipid antibodies and lupus anticoagulant. In addition the presence of FV Leiden, FII 20210 GA mutations and MTHFR 677 CT polymorphism were determined. Results: A high prevalence of the factor V Leiden mutation was detected in the study group; 50% had APC-resistance test positive, 26 (45%) patients were found to be heterozygous and 3 (5,2%) homozygous for the FV Leiden mutation. Lp(a) elevation was observed in 19,3% and Homocysteine elevation in 15,8% of patients. In 9 women (15,8%) both family history and thrombophilic profile were negative. Serious VTE events (2 abdominal and 6 CNS thromboses) were observed only in the Leiden subgroup. During the follow up period ranging from months to 18 years, 3 women (6,25%) experienced a miscarriage and 14 suffered additional VTE events (25%) and they are currently on permanent anticoagulation. Conclusions : Universal thrombophilia screening of women prior to prescription of OCs is not advisable as it does not appear to be cost effective. However, screening certain subgroups, such as women with a known personal or family history, may be of great value. If a full thrombophilic profile can’t be performed, a mere activated protein C resistance test, that reflects the presence of the factor V Leiden mutation, may provide an easy and cheap way of identifying and consulting properly women at higher risk for VTE prior to OC use. Women with OC-associated VTE and thrombophilia carry a substantial recurrence risk that persists for years.

ProC® Global Assay in the Evaluation of Women with History of Severe Preeclampsia or HELLP Syndrome

2002 ◽  
Vol 8 (4) ◽  
pp. 319-324 ◽  
Author(s):  
Lothar Heilmann ◽  
Georg-Friedrich v. Tempelhoff ◽  
Kuhnhart Pollow
Keyword(s):  
Hellp Syndrome ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Protein S ◽  
Anticardiolipin Antibodies ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Lupus Anticoagulants ◽  
Apc Resistance

Preeclampsia/HELLP syndrome has been associated with a high incidence of defects in the protein C pathway and increased anticardiolipin-antibodies/lupus anticoagulants. It is also apparent that thrombophilia is responsible for other pregnancy complications, such as recurrent spontaneous abortion, fetal growth restriction, intrauterine fetal death, and abruptio placentae. ProC® Global is a new global clotting assay designed to evaluate the abnormalities in the protein C anticoagulant pathway. It is based on the ability of endogenous activated protein C, generated by activation of protein C by Protac®, to prolong an activated partial thromboplastin time. A total of 61 patients with a history of severe preeclampsia or HELLP syndrome and 61 normal pregnant women (controls) were evaluated, 15 of whom had factor V Leiden mutation, 12 had protein C/S deficiency, 30 had a repeated lupus anticoagulants, and 27 increased anticardiolipin antibodies (ACA). All carriers of factor V Leiden mutation (N= 15) as well as all the patients with low activated protein C (APC) resistance ratio (N= 15) had a ProC® Global normalized ratio (NR) less than 0.80 (sensitivity 100%). Twenty-four patients positive for the lupus anticoagulants (LA) and 19 patients positive for ACA (> 5.0 IgG U/mL) had a ProC® Global NR less than 0.8, while six and eight, respectively, had a ProC® Global NR greater than 0.8 (sensitivity, 70%-80%). The detection of a reduced protein C/protein S activity (<70%) was low (sensitivity, 33%-44%). In 25 cases with pathologic ProC® Global results, a thrombophilic defect (protein S/LA/ACA without APC resistance) was diagnosed in 18 women; but in 7 cases, no known thrombophilic defect was present. ProC® Global is a new screening test to identify patients with defects of the protein C system and an activated clotting system in preeclampsia but cannot correctly cover each thrombophilic component.

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.

Oral contraceptive use in women with poor anticoagulant response to activated protein C but not carrying the factor V Leiden mutation increases the risk of venous thrombosis

2004 ◽  
Vol 91 (04) ◽  
pp. 712-718 ◽  
Author(s):  
Michela Cini ◽  
Benilde Cosmi ◽  
Silvia Mattarozzi ◽  
Giuseppa Manto ◽  
Gualtiero Palareti ◽  
...  
Keyword(s):  
Protein C ◽  
Contraceptive Use ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Reproductive Age ◽  
Factor V ◽  
Lower Quartile ◽  
Factor V Leiden Mutation ◽  
Healthy Women ◽  
Apc Resistance

SummaryThe factor V Leiden mutation (FVL), associated with reduced sensitivity to activated Protein C (APC), is a risk factor for venous thromboembolism (VTE) and displays a strong interaction with oral contraceptives (OC). The aim of this study was to evaluate the risk of VTE in OC users with reduced APC sensitivity unrelated to the FVL. APC sensitivity was measured by an original aPTT-based test (without sample pre-dilution in factor V-deficient plasma) in 195 women who suffered from VTE in reproductive age and in 487 healthy women with results being expressed as normalized ratio. Subjects with currently known clinically relevant thrombophilic alterations were excluded. APC normalized ratios were stratified into quartiles. The adjusted ORs of subjects in the lower quartile (≤0.90) was 2.46 (95%CI: 1.02–5.95). Of the 195 patients, 89 had suffered VTE during OC. The 181 healthy women who had used OC for at least 6 months in the two year period before presentation but who had stopped OC at least 3 months before blood sampling were considered OC users. The risk of VTE in subjects using OC with APC normalized ratio in the lower quartile was increased 4.9-fold (95% CI: 1.92–12.6). In conclusion, our results showed that altered APC resistance in women not carrying the FVL significantly increased the VTE risk, albeit to a lesser extent than in women also carrying the FVL. Our data also showed that OC use in women with altered APC resistance further increased the risk of VTE in a way that exceeded the additive expectation.

Coagulation Factor V Leiden Mutation Was Detected in the Patients with Activated Protein C Resistance in Thailand

1998 ◽  
Vol 80 (08) ◽  
pp. 344-345 ◽  
Author(s):  
Pasra Arnutti ◽  
Motofumi Hiyoshi ◽  
Wichai Prayoonwiwat ◽  
Oytip Nathalang ◽  
Chamaiporn Suwanasophon ◽  
...  
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Factor V ◽  
Activated Protein C Resistance ◽  
Factor V Leiden Mutation ◽  
Coagulation Factor V

A Hemi-nested, Allele Specific, Whole Blood PCR Assay for the Detection of the Factor V Leiden Mutation

1997 ◽  
Vol 77 (06) ◽  
pp. 1154-1155 ◽  
Author(s):  
Gary D Sinclair ◽  
Sandra Low ◽  
Man-Chiu Poon
Keyword(s):  
Whole Blood ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Restriction Enzyme Digestion ◽  
Factor V ◽  
Pcr Assay ◽  
Specific Primers ◽  
Factor V Leiden Mutation ◽  
Allele Specific

SummaryWe describe a novel hemi-nested, allele specific whole blood PCR assay for detection of the factor V Leiden mutation associated with the plasma defect, activated protein C resistance. This assay utilizes 5 μl of whole blood without prior DNA extraction. The hemi-nested design, employing an outer primer pair in combination with nested, allele specific primers obviates the need for restriction enzyme digestion. PCR reactions are analysed directly on agarose or polyacrylamide minigels. The assay confirmed the genotypes of 50 individuals previously categorized by PCR and Mnll digestion, and has been subsequently utilized in the genotyping of 445 individuals referred for thrombosis studies.

APC-RESISTANCE ASSOCIATED WITH FACTOR V LEIDEN GENE MUTATION (GENOTYPE GA): CLINICAL OCCURRENCE IN PREGNANCY

2018 ◽  
Author(s):  
М.Г. Николаева ◽  
А.П. Момот ◽  
Г.В. Сердюк ◽  
В.А. Елыкомов ◽  
К.А. Момот ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Gene Mutation ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Control Group ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Apc Resistance ◽  
Factor Va ◽  
And Control

Цель исследования: изучить связь феномена резистентности фактора Vа к активированному протеину С (АПС-резистентность) при носительстве мутации гена FVL (1691) GA с клинической реализацией во время беременности тромботических событий и гестационных осложнений, таких как преэклампсия, задержка развития плода и невынашивание беременности. Материалы и методы. Проведено проспективное клиническое когортное исследование 1100 беременных. Выделено 2 когорты: основная группа – 500 пациенток с генотипом FVL (1691) GA и группа контроля – 600 женщин с генотипом FVL (1691) GG. Результаты. Медиана нормализованного отношения (НО) АПС-резистентности в контрольной группе у беременных с генотипом FVL (1691) GG колебалась в диапазоне 1,0→0,86. У беременных – носителей генотипа FVL (1691) GA этот показатель был достоверно ниже – 0,55→0,48 (р < 0,05). У пациенток при НО > 0,5 течение беременности было благоприятным. Более выраженная АПС-резистентность (НО ≤ 0,49) ассоциировалась с гестационными осложнениями. Заключение. Полученные данные по АПС-резистентности позволяют относить в группу высокого риска по тромботическим и акушерским осложнениям женщин – носительниц мутации фактора V Лейден (1691) не только с генотипом АА, но и с генотипом GA. AПС-резистентность ≤ 0,49 (по показателю НО) при носительстве мутации фактора V Лейден (1691) GA может рассматриваться как прогностический маркер развития гестационных осложнений с наибольшей точностью при сроке 7-8 недель беременности. Aim: to study during pregnancy the relationship between factor Va resistance to activated protein C (APC-resistance) in carriers of FVL gene mutation (1691) GA with clinical realization of thrombotic events and gestational complications such as preeclampsia, fetal growth retardation and miscarriage. Materials and methods. A prospective clinical cohort study of 1100 pregnant women was performed. Two cohorts were identified: main group – 500 patients with FVL genotype (1691) GA and control group – 600 women with FVL genotype (1691) GG. Results. The median of normalized ratio (NR) of APC resistance in the control group with FVL genotype (1691) GG ranged from 1.0→0.86. In pregnant women – the carriers of FVL genotype (1691) GA this parameter was significantly lower – 0.55→0.48 (р < 0.05). In patients with HO > 0.5 the course of pregnancy was favorable. More expressed APS-resistance (НО ≤ 0,49) was associated with gestational complications. Conclusion. The obtained data on APC-resistance allow to classify women – the carriers of Factor V Leiden (1691) mutation, not only with the AA genotype but also with GA genotype as the group of high risk for thrombotic and obstetric complications. APC resistance ≤ 0.49 (according NR) with the carriage of Factor V Leiden mutation (1691) GA can be considered as a prognostic marker for the development of gestational complications with the greatest accuracy at a period of 7-8 weeks of gestation.

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