The 1691 G → A Mutation in the Factor V Gene: Relationship to Activated Protein C (APC) Resistance and Thrombosis in 65 Patients

Leroy-Matheron, Catherine; Levent, M; Pignon, Jean‐Michel; Mendonça, Caio; Gouault-Heilmann, M

doi:10.1055/s-0038-1650212

Cited by 31 publications

(22 citation statements)

References 25 publications

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“…In the AT group, VTE was mostly represented, SVT was rare, and arterial thrombosis absent, whereas in PC and PS groups the prevalence of SVT and arterial thrombosis was higher, as described in previous studies. 18,19,32 In patients with APCR, the prevalence of VTE and that of SVT were near those in PC-and PS-deficient patients (50% and 26%, respectively), in agreement with a recent study 35 that showed similar clinical manifestations in APCR, PC, and PS deficiency, despite a later occurrence of the first event in APCR.…”

Section: Discussionsupporting

confidence: 86%

Risk of Venous Thromboembolism and Clinical Manifestations in Carriers of Antithrombin, Protein C, Protein S Deficiency, or Activated Protein C Resistance

Bucciarelli

Rosendaal

Tripodi

et al. 1999

ATVB

155

105

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Abstract-Deficiencies of antithrombin (AT), protein C (PC) or protein S (PS), and activated protein C resistance (APCR) are very well-established coagulation defects predisposing to venous thromboembolism (VTE). We performed a retrospective cohort family study to assess the risk for VTE in individuals with AT, PC, or PS deficiency, or APCR. Five hundred thirteen relatives from 9 Italian centers were selected from 233 families in which the proband had had at least 1 episode of VTE. We calculated the incidence of VTE in the whole cohort and in the subgroups after stratification by age, sex, and defect. The overall incidence of VTE (per 100 patient-years) in the group of relatives was 0.52. It was 1.07 for AT, 0.54 for PC, 0.50 for PS, 0.30 for APCR, and 0.67 in the group with a double defect. The incidence was associated with age, but not with sex. The mean age at onset was between 30 and 40 years for all the coagulation defects. Women had the peak of incidence in the age range of 21 to 40 years, earlier than men. The lifetime risk for VTE was 4.4 for AT versus APCR, 2.6 for AT versus PS, 2.2 for AT versus PC, 1.9 for PC versus APCR, and 1.6 for PS versus APCR. AT deficiency seems to have a higher risk for VTE than the other genetic defects. There is a relation between age and occurrence of thrombosis for both men and women. The latter had the peak of incidence earlier than the former.

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Section: Discussionsupporting

confidence: 86%

Risk of Venous Thromboembolism and Clinical Manifestations in Carriers of Antithrombin, Protein C, Protein S Deficiency, or Activated Protein C Resistance

Bucciarelli

Rosendaal

Tripodi

et al. 1999

ATVB

155

105

View full text Add to dashboard Cite

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“…Several studies demonstrated that the APCR phenotype determined by the original clotting test was not in very good correlation with the presence of FV Leiden (detected by molecular biology assay) [115,116]. It was found that the original ratio may be affected by sodium citrate concentration, handling and storage conditions, standardization of the aPTT reagents and the instrument used [108,117].…”

Section: Measurement In Oral-anticoagulanttreated Patientsmentioning

confidence: 99%

Clinical Aspects and Laboratory Problems in Hereditary Thrombophilia

Samama

Gerotziafas²,

Conard³

et al. 1999

Pathophysiol Haemos Thromb

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Hereditary thrombophilia is a multifactorial disease which is mono- or plurigenic and its clinical expression is associated with a heterogeneous expression. Factor V (FV) Leiden and FII gene mutations are more frequent than antithrombin, and protein C and S deficiencies. All thrombophilias are not the same. Heterozygous carriers of FV Leiden or FII gene mutation have a weaker risk of venous thrombosis. The mean age at the first episode is older in the former and higher rate of recurrences is observed in the latter. The cosegregation of mutations significantly increases the risk of thrombosis. Both mutations have a geographic and ethnic distribution in relation with a gene founder effect. Clinical expression consists of deep or superficial venous thrombosis with or without pulmonary embolism, thromboses at unusual sites (e.g. cerebral, portal, mesenteric) or with an increased incidence of fetal loss and abortion. A precipitating cause is present in more than 50% of patients. The risk pf arterial thromboses seems to be restricted to some protein S and FII gene mutations. Laboratory diagnosis strategy should be oriented by careful selection of patients and preanalytical variables should be considered. It is highly probable that other unindentified gene mutations are, at least partly, other causes of the heterogeneous expression of hereditary thrombophilia.

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“…As a result, in the presence of both protein S and factor Xa. FVa:Q506 ¡s inhibited almost as rapidly as FVa:R506 which may explain why APC-resistance is such a mild risk factor for thrombosis and that even individuals with homozygous FV:Q506 have mild thrombotic symp toms as compared to individuals with homozygous protein C deficiency [15,35], The hyper coagulability in APC-resistance is reflected by increased levels of prothrombin fragment 1+2 [36][37][38].…”

Section: Apc Resistance Phenotype and Genotypementioning

confidence: 99%

“…thrombosis is highly variable in APC resistant indi viduals [15,37,38,53], Some never get thrombosis, whereas others suffer from recurrent, severe thrombotic events (Fig. 1).…”

Section: Epidemiology and Clinical Manifestations Of Apc Resistancementioning

confidence: 99%

Inherited Resistance To Activated Protein C Caused By Presence Of The FV:Q<sup>506</sup> Allele As A Basis Of Venous Thrombosis

Dahlbäck

Zöller²,

Hillarp³

1996

Pathophysiol Haemos Thromb

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Inherited resistance to activated protein C (APC) was recently discovered as a cause of familial throm-bophilia and is now known to be the most common genetic risk factor for venous thrombosis. In a majority of cases, APC resistance is associated with a single point mutation in the factor V gene, which results in substitution of arginine (R) at position 506 by glutamine (Q) (FV:Q⁵⁰⁶). The mutation renders factor Va partially resistant to degradation by activated protein C (APC), which leads to a hypercoagulable state and a life-long 5–10-fold increased risk of venous thrombosis. The previously known inherited deficiencies of antithrombin, protein S or protein C, are in western societies together found in less than 10–15% of thrombosis patients, whereas APC resistance is present in 20 to 60% of the patients. A functional APC resistance test, which includes predilution of the patient plasma with factor V deficient plasma, is 100% sensitive and specific for the presence of FV:Q⁵⁰⁶. The FV:Q⁵⁰⁶ allele is common in populations of Caucasian origin (prevalence ranging between 1 and 15%), whereas it is not found in certain other ethnic groups such as in Japanese and Chinese. The thrombotic risk in individuals with APC resistant may be further increased by other genetic defects such as protein C or protein S deficiency and by exposure to circumstantial risk factors such as oral contraceptives, pregnancy, immobilisation and surgery.

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The 1691 G → A Mutation in the Factor V Gene: Relationship to Activated Protein C (APC) Resistance and Thrombosis in 65 Patients

Cited by 31 publications

References 25 publications

Risk of Venous Thromboembolism and Clinical Manifestations in Carriers of Antithrombin, Protein C, Protein S Deficiency, or Activated Protein C Resistance

Risk of Venous Thromboembolism and Clinical Manifestations in Carriers of Antithrombin, Protein C, Protein S Deficiency, or Activated Protein C Resistance

Clinical Aspects and Laboratory Problems in Hereditary Thrombophilia

Inherited Resistance To Activated Protein C Caused By Presence Of The FV:Q<sup>506</sup> Allele As A Basis Of Venous Thrombosis

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