Hereditary resistance to activated protein C: An uncommon risk factor for thromboembolic disease in lupus patients with antiphospholipid antibodies

Sasso, Eric H.; Suzuki, Lucy A.; Thompson, Arthur R.; Petri, Michelle

doi:10.1002/art.1780400925

Cited by 7 publications

(5 citation statements)

References 6 publications

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“…These results suggest that acquired APCR may represent a mechanism of thrombosis in patients with SLE. The prevalence of factor V Leiden in SLE patients (4%) was similar to the prevalence seen in the whole population 24,25 (4% in the present control series). Additionally, factor V Leiden has not been found the unique cause of APCR in patients with primary antiphospholipid syndrome.…”

Section: Discussionsupporting

confidence: 88%

Clinical significance of acquired activated protein C resistance in patients with systemic lupus erythematosus

Muñoz-Rodríguez

Reverter

Font

et al. 2002

Lupus

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Antiphospholipid antibodies (aPL) may induce acquired activated protein C resistance (acquired APCR). The role of acquired APCR in patients with systemic lupus erythematosus (SLE) is not well known. To evaluate the prevalence of acquired APCR and its association with clinical manifestations we studied 103 consecutive SLE patients and 103 matched controls. APCR in the undiluted test and after dilution in factor V deficient plasma, factor V Leiden, protein C and S, lupus anticoagulant, and anti-cardiolipin, anti-beta2-glycoprotein I and anti-prothrombin antibodies were determined. Factor V Leiden was found in 4% in both patients and controls. The prevalence of acquired APCR was 22% for the undiluted assay and 17% in the diluted test. In SLE patients, acquired APCR was associated with aPL (39 vs 13% in undiluted assay, P = 0.007; and 33 vs 7% in the diluted test, P = 0.001). Arterial thromboses were found in 24% of patients with acquired APCR and in 6% of patients without (P = 0.04). However, no relationship was found with venous thrombosis. Acquired APCR was also associated with pregnancy losses: miscarriages in 70% of women with acquired APCR vs 32% in those without (P=0.03). Thus, in SLE patients acquired APCR seems to be associated with increased prevalence of arterial thrombosis and pregnancy losses.

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Section: Discussionsupporting

confidence: 88%

Clinical significance of acquired activated protein C resistance in patients with systemic lupus erythematosus

Muñoz-Rodríguez

Reverter

Font

et al. 2002

Lupus

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“…163 In a Dutch study, the FV : Q506 allele was found to be an independent risk factor for venous (odds ratio 4.9; CI 1.2-19.6), but not for arterial thrombosis, among SLE patients. 164 Other studies have not found a significant link between the FV : Q506 allele and venous thrombosis in patients with antiphospholipid antibodies secondary to SLE [165][166][167] or patients with primary antiphospholipid syndrome. 161,165,168…”

Section: Interaction Between Fv : Q506 and Acquired Prothrombotic Statesmentioning

confidence: 97%

Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

Dahlbäck¹

1999

Semin Thromb Hemost

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Inherited resistance to activated protein C (APC) is the most common genetic risk factor of venous thrombosis. It is caused by a single point mutation in the factor (F)V gene which predicts replacement of Arg506 with a Gln (FVR506Q, FV: Q506 or FV Leiden). This mutation affects the function of the protein C system, a physiologically important natural anticoagulant pathway. APC inhibits coagulation by cleaving a limited number of peptide bonds in both intact and activated forms of factor V (FV/FVa) and factor VIII (FVIII/FVIIIa). Degradation of FVa by APC is stimulated by protein S, whereas inactivation of FVIIIa requires the synergistic cofactor function of protein S and FV proteolytically modified by APC. Thus, FV has the potential to express opposing functions, as a procoagulant after cleavage by thrombin or FXa and as an anticoagulant after cleavage by APC. The FVR506Q mutation not only confers partial resistance of FVa to APC but also impairs the degradation of FVIIIa because APC-mediated cleavage of FV at Arg506 is required for expression of the anticoagulant activity of FV. The impaired degradation of both FVIIIa and FVa yield a hypercoagulable state conferring a lifelong increased risk of thrombosis. The FV mutation is common in Caucasians, whereas it is rarely found among other groups worldwide. In patients with severe thrombophilia having other inherited defects such as deficiencies of protein S, protein C, or antithrombin, APC resistance is often found as a contributing genetic risk factor. Individuals with combined genetic defects have a high risk of thrombosis, and it is now generally accepted that thrombophilia is a multigenetic disease.

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“…This mechanism seems to be one of the possible causes of thrombosis in SLE with aPL antibody (19,22). Thus, we studied the prevalence of factor V Leiden and the additional role of Leiden mutation on the development of haemostatic imbalance in SLE patients (26)(27)(28). aPL, antiphospholipid antibody (LA and/or aCL); CNS, central nervous sytem; F, female; FV, factor V; M, male; P, the number of pregnancies; SAB, spontaneous abortions; SLE, systemic lupus erythematosus.…”

Section: Discussionmentioning

confidence: 99%

“…This mechanism seems to be one of the possible causes of thrombosis in SLE with aPL antibody (19,22). Thus, we studied the prevalence of factor V Leiden and the additional role of Leiden mutation on the development of haemostatic imbalance in SLE patients (26)(27)(28). The epidemiological studies have determined the prevalence of FV mutated gene in the various populations and it is hypothesized that the Leiden mutation has originated and accumulated in European Caucasians (3%--9%) (8,9,10,33,34).…”

Section: Discussionmentioning

confidence: 99%

“…In these cases, the molecular diagnosis is relevant to detect FVL mutation, but combined thrombophilic risk factors could be present (21,(23)(24)(25). The acquired coagulation defect resulting in APC resistance phenotype could play a major role in the pathogenesis of thrombosis in antiphospholipid syndrome that is closely related with SLE (17)(18)(19)(20)(21)(22)24,(26)(27)(28)(29).…”

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confidence: 99%

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State-of-the-Art-Review : The Leiden Mutation of Coagulation Factor V in Hungarian SLE Patients

Regéczy

Lakos

Balogh

et al. 2000

Clin Appl Thromb Hemost

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We studied the prevalence and the effect of coagulation factor V Leiden mutation on the occurrence of thrombotic episodes in 120 Hungarian patients having systemic lupus erythematosus (SLE) with or without antiphospholipid antibody. The frequency of the factor V Leiden mutation in Hungarian SLE patients was 13%, which is comparable with those found previously in a healthy Caucasian population. The incidence of venous thrombosis among factor V Leiden carriers has been found to be higher (odds ratio [OR] 1.7) than it is in patients without Leiden mutation (38% vs 29%). In addition, the frequency of venous thrombosis in the heterozygous SLE patients (OR 8.4 [confidence interval (CI) 0.8-83.9] P = 0.06) is dependent on the coexistence of other risk factors, such as antiphospholipid antibody. Moreover, among heterozygous factor V SLE patients, the Leiden mutation could explain the tendency to have significantly higher prevalence of fetal losses (OR 3.9 [CI 1.2-12.0] P = 0.02) and higher prevalence of cerebrovascular lesions, cardiac valvular abnormalities, and Raynaud's syndrome than that found in individuals without factor V Leiden mutation of those having antiphospholipid antibody. Systemic lupus erythematosus patients with combined defects suffer more severely from thrombosis than those with a single risk factor do, suggesting that thrombophilia is a multifactorial disorder in SLE, also. Although, the factor V Leiden mutation does not seem to be a significant risk factor for venous thrombosis in SLE, these data demonstrate that Leiden mutation can be regarded as an additive thrombogenic factor providing higher predisposition to several vasoocclusive disorders in SLE.

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Hereditary resistance to activated protein C: An uncommon risk factor for thromboembolic disease in lupus patients with antiphospholipid antibodies

Cited by 7 publications

References 6 publications

Clinical significance of acquired activated protein C resistance in patients with systemic lupus erythematosus

Clinical significance of acquired activated protein C resistance in patients with systemic lupus erythematosus

Activated Protein C Resistance and Thrombosis: Molecular Mechanisms of Hypercoagulable State Due to FVR506Q Mutation

State-of-the-Art-Review : The Leiden Mutation of Coagulation Factor V in Hungarian SLE Patients

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