Prevalence of Factor V Leiden Mutation in Yugoslav Thrombophilic Patients and Its Relationship to the Laboratory Diagnosis of APC Resistance

SummaryThe APC-resistance test consists of two APTT’s, one in the presence and one in the absence of a fixed amount of Activated Protein C (APC), and is a simple and reliable method to detect a reduced sensitivity to the anticoagulant action of APC (APC-resistance). At a fixed concentration of APC the prolongation of the APTT is dependent on the activator, the CaCl2 concentration, the citrate concentration in the sample, and on sample handling. The effect of sample handling can be reduced by calculating the APC-Sensitivity Ratio (APC-SR). The actual prolongation of the APTT is also influenced by low protein S levels (reduction of APC-SR) and by reduced levels of factors V, VIII and IX (increase of APC-SR). The APC-SR is most dramaticly effected by reduced levels of factors II and X, which result often in “unmeasurable” APC-SR’s in plasmas of patients on oral anticoagulant treatment. So at present no reliable APC-SR’s can be measured in these patients. Patients treated with heparin can be tested after treatment of their plasma with Hepzym®. The inter- and intra-assay variation in the APC-SR is 4% and 2%, respectively, when using the same batches of activator and APC. The variation which is introduced in the APC-SR by use of different batches of activator or APC, or by the use of different APC or CaCl2 concentrations, can effectively be avoided by expressing the result of the test in normalized-APC-SR (n-APC-SR).The diagnosis of APC-resistance is defined by a n-APC-SR < 0.84. Patients who are heterozygous for the Factor V Leiden mutation have a n-APC-SR of 0.45-0.70, while patients who are homozygous for the mutation have a n-APC-SR <0.45.

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The Incidence of Factor V Leiden in a Normal Irish Population and Its Relationship to the Laboratory Diagnosis of APC Resistance

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614545 ◽

1999 ◽

Vol 81 (04) ◽

pp. 661-663 ◽

Cited By ~ 2

Author(s):

Joseph Vaughan ◽

Cariosa Power ◽

Catherine Nolan ◽

Don McCarthy ◽

Ivan Shirley

Keyword(s):

Factor V Leiden ◽

Laboratory Diagnosis ◽

Factor V ◽

Irish Population ◽

Apc Resistance

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“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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650290 ◽

1996 ◽

Vol 75 (03) ◽

pp. 422-426 ◽

Cited By ~ 53

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.

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

Тромбоз, гемостаз и реология ◽

10.25555/thr.2018.1.0823 ◽

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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Expression of the normal factor V allele modulates the APC resistance phenotype in heterozygous carriers of the factor V Leiden mutation

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2005.01634.x ◽

2005 ◽

Vol 3 (12) ◽

pp. 2695-2702 ◽

Cited By ~ 26

Author(s):

J. M. BRUGGE ◽

P. SIMIONI ◽

F. BERNARDI ◽

D. TORMENE ◽

B. LUNGHI ◽

...

Keyword(s):

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Resistance Phenotype ◽

Apc Resistance ◽

Heterozygous Carriers

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APC-RESISTANCE ON THE BACKGROUND OF COMORBID STATES AS A POSSIBLE VTEC PREDICTOR IN THE CARRIERS OF FACTOR V LEIDEN MUTATION DURING PREGNANCY

Bulletin of Medical Science ◽

10.31684/2541-8475.2018.3(11).63-71 ◽

2018 ◽

pp. 63-71

Author(s):

M.G. NIKOLAEVA M.G. ◽

◽

A.P. MOMOT ◽

A.V. MOLCHANOV ◽

◽

...

Keyword(s):

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Apc Resistance

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

Blood ◽

10.1182/blood.v93.4.1271 ◽

1999 ◽

Vol 93 (4) ◽

pp. 1271-1276 ◽

Cited By ~ 202

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.

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

Blood ◽

10.1182/blood.v112.11.5348.5348 ◽

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.

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

VASA ◽

10.1024/0301-1526.30.1.24 ◽

2001 ◽

Vol 30 (1) ◽

pp. 24-27 ◽

Cited By ~ 3

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.

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