Markers of Procoagulant Imbalance in Patients with Inherited Thrombophilic Syndromes

Mannucci, Pier Mannuccio; Tripodi, Armando; Bottasso, B.; Baudo, F.; Finazzi, Guido; Stefano, V. De; Palareti, G; Manotti, Cesare; Mazzucconi, Maria Gabriella; Castaman, Giancarlo

doi:10.1055/s-0038-1648412

Cited by 82 publications

(53 citation statements)

References 9 publications

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“…The patients studied had none of the known congenital or acquired thrombophilic states, in which the circulating levels of markers of activation of the coagulation system may be increased. [21][22][23][24] Even though the recently described G20210A mutation of the prothrombin gene 17 could be looked for retrospectively in only approximately one third of the patients, also those patients in whom the prothrombin mutation was ruled out had high APC levels, excluding that they were mainly due to the presence of the mutation. APC is generated from its plasma precursor, protein C, on activation by thrombin-thrombomodulin complex on the endothelial cell surface, probably acting in concert with the endothelial cell protein C receptor.…”

Section: Discussionmentioning

confidence: 99%

Plasma Levels of Activated Protein C in Healthy Subjects and Patients With Previous Venous Thromboembolism

Cattaneo

Franchi

Zighetti

et al. 1998

ATVB

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Abstract-The proteolytic enzyme activated protein C (APC) is a normal plasma component, indicating that protein C (PC) is continuously activated in vivo. High concentrations of homocysteine (Hcy) inhibit the activation of PC in vitro; this effect may account for the high risk for thrombosis in patients with hyperhomocysteinemia (HyperHcy). We measured the plasma levels of APC in 128 patients with previous venous thromboembolism (VTE) and in 98 age-and sex-matched healthy controls and correlated them with the plasma levels of total Hcy (tHcy) measured before and after an oral methionine loading (PML). Forty-eight patients had HyperHcy and 80 had normal levels of tHcy. No subject was known to have any of the congenital or acquired thrombophilic states at the time of the study. Because the plasma levels of APC and PC were correlated in healthy controls, the APC/PC ratios were also analyzed. Plasma APC levels and APC/PC ratios were significantly higher in VTE patients than in controls (Pϭ0.03 and 0.0004, respectively). Most of the increase in APC levels and APC/PC ratios were attributable to patients with HyperHcy. Patients with normal tHcy had intermediate values, which did not differ significantly from those of healthy controls. There was no correlation between the plasma levels of tHcy or its PML increments and APC or APC/PC ratios in controls. The fasting plasma levels of APC and APC/PC ratios of 10 controls did not increase 4 hours PML, despite a 2-fold increase in tHcy. This study indicates that APC plasma levels are sensitive markers of activation of the hemostatic system in vivo and that Hcy does not interfere with the activation of PC in vivo. (Arterioscler Thromb Vasc Biol. 1998;18:1371-1375.)

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Section: Discussionmentioning

confidence: 99%

Plasma Levels of Activated Protein C in Healthy Subjects and Patients With Previous Venous Thromboembolism

Cattaneo

Franchi

Zighetti

et al. 1998

ATVB

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“…Enhanced generation of thrombin measured as increased levels of prothrombin fragment 1+2 (F1+2) or thrombin-antithrombin complexes in basal conditions has been observed in subjects with deficiencies of protein C [14,15] and protein S [14,16] as well as in subjects heterozygous for Gln506-FV [16][17][18][19]. The enhanced thrombin formation has been interpreted to indicate a clinical hypercoagulable state.…”

Section: Introductionmentioning

confidence: 99%

Circulating Activated Protein C inSubjects with Heterozygous Gln506-Factor V

Petäjä

Hakala²,

Rasi³

et al. 1998

Pathophysiol Haemos Thromb

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Congenital resistance to activated protein C due to a point mutation in the factor V gene (Gln506-FV) is the most common genetic risk factor for familial venous thrombosis. Considering the central role of activated protein C as a physiological anticoagulant, the question of why the thrombotic risk associated with Gln506-FV was not more pronounced was asked. We hypothesized that in Gln506-FV heterozygotes, enhanced thrombin formation might preferentially activate protein C and thereby constitute a compensatory antithrombotic effect. We compared the circulatory level of activated protein C in twelve heterozygous carriers of Gln506-FV mutation with that in eighteen noncarriers in same families, and used prothrombin fragment 1+2 as a measure of thrombin generation. The circulating level of activated protein C was higher but not significantly different in heterozygotes compared with normal relatives. Activated protein C levels correlated strongly and positively with protein C antigen levels in both carriers (Spearman R 0.684, p < 0.05) and controls (Spearman R 0.642, p < 0.01). Correlation between activated protein C and prothrombin fragment 1+2 levels was of borderline significance (Spearman R 0.354, p = 0.055). In the current study, thrombin formation assessed by prothrombin fragment 1+2 levels was not significantly enhanced in subjects with heterozygous Gln506-FV compared with family members without the mutation. In conclusion, enhanced thrombin formation is not present in all healthy Gln506-FV heterozygotes in basal conditions. It seems that enhanced protein C activation by thrombin does not constitute a compensatory anticoagulant feedback loop in heterozygous carriers of Gln506-FV. However, the positive correlation between prothrombin fragment 1+2 and activated protein C suggests that, in healthy subjects and in basal conditions, thrombin upregulates the anticoagulant protein C pathway. Thus, it is questionable whether prothrombin fragment 1+2 can directly be used as an indicator of a hypercoagulable state.

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“…However, around twenty years ago they were tested in various small studies that gave contradictory results. Increased F1+2 was found in individuals with antithrombin, protein C and S deficiencies (Demers et al, 1992;Mannucci et al, 1992), as well as in those with activated protein C (APC) www.intechopen.com resistance (Simioni et al, 1996;Bauer et al, 2000), prothrombin G20210A mutation (Bauer et al, 2000) antiphospholipid syndrome (Ames et al, 1996), hyperhomocysteinemia (Kyrle et al, 1997a) and increased levels of factor VIII (O'Donnell et al, 2001). Not all studies, however, confirmed the association of increased F1+2 levels with TF (Kyrle et al, 1998;Eichinger et al, 1999;Lowe et al, 1999).…”

Section: Specific Markers Of Haemostasis Activationmentioning

confidence: 99%

Association of Haemostasis Activation Markers with Thrombophilia and Venous Thromboembolism

Vizintin-Cuderman¹,

Mijovski²,

Antovič³

et al. 2011

Thrombophilia

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Markers of Procoagulant Imbalance in Patients with Inherited Thrombophilic Syndromes

Cited by 82 publications

References 9 publications

Plasma Levels of Activated Protein C in Healthy Subjects and Patients With Previous Venous Thromboembolism

Plasma Levels of Activated Protein C in Healthy Subjects and Patients With Previous Venous Thromboembolism

Circulating Activated Protein C inSubjects with Heterozygous Gln506-Factor V

Association of Haemostasis Activation Markers with Thrombophilia and Venous Thromboembolism

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