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CORRESPONDENCE Although the association between the plasma levels of total
homocysteine (tHcy) and the risk of atherosclerosis and thrombosis is
well documented, the mechanism(s) by which hyperhomocysteinemia might
contribute to atherogenesis and thrombogenesis are scarcely understood.1 In vitro studies showed that homocysteine,
among other effects, inhibits both protein C activation and the
activity of activated protein C (APC).1,2 The inhibition
of APC activity in vitro apparently depends on the interaction of
homocysteine with cysteine residues of factor V, which interferes with
the proteolytic action of APC on factor Va, resulting in APC
resistance, a very common and well-established risk factor for venous
thromboembolism.2 However, several in vitro findings have
not been confirmed in in vivo studies. For instance, in a study of
healthy individuals and patients with previous thrombotic events,
Cattaneo et al3 showed that neither the fasting plasma
levels of tHcy nor their acute increase after an oral methionine load
affects the plasma concentration of APC. These data, which suggest that
hyperhomocysteinemia does not interfere with protein C activation in
vivo, have recently been supported by the results of the study by Lentz
et al,4 which showed that hyperhomocysteinemia did not
interfere with protein C activation in vivo in cynomolgus monkeys to
which an intravenous injection of thrombin had been administered. In
the same study, Lentz et al4 showed that
hyperhomocysteinemia did not interfere with the in vitro inactivation
of factor V by APC in mice deficient in cystathionine- The results were expressed as normalized ratios.6
Hyperhomocysteinemia was diagnosed when the plasma tHcy exceeded the 90th percentile of distribution of values obtained in a population of
553 healthy subjects (14.8 µM). We enrolled 1254 subjects (median age
43 years, range 9-83 years) who had normal APTT and absence of factor V
Leiden (the most common congenital cause of APC
resistance7). Of these subjects, 730 were women, of whom
108 (15%) used oral contraceptives; 434 (34.6%) had previous episodes
of venous or arterial thrombosis; and 820 had a negative personal
history for thrombosis. The plasma levels of tHcy ranged from 3.9 µM
to 223 µM in the subjects studied. The mean APC normalized ratio of
subjects with normal tHcy plasma levels (0.97 ± 0.13) was not
different from that of subjects with hyperhomocysteinemia
(0.96 ± 0.16, P = .73). There was no statistically
significant correlation between the plasma levels of fasting tHcy and
APC ratio
(Table 1) whether considering the total number of subjects, those with
hyperhomocysteinemia, or those with previous thrombotic events. In
conclusion, in agreement with Lentz et al,4 our findings
do not support the hypothesis that hyperhomocysteinemia negatively
affects the in vitro anticoagulant response to APC.
GianMarco Podda, Elena M. Faioni, Maddalena L. Zighetti, and Marco Cattaneo
References 1. Cattaneo M. Hyperhomocysteinemia and thrombosis. Lipids. 2001;36(suppl):S13-S26.
2.
Undas A, Williams EB, Butenas S, Orfeo T, Mann KG.
Homocysteine inhibits inactivation of factor Va by activated protein C.
J Biol Chem.
2001;276:4389-4397
3.
Cattaneo M, Franchi F, Zighetti ML, Martinelli I, Asti D, Mannucci PM.
Plasma levels of activated protein C in healthy subjects and patients with previous venous thromboembolism: relationships with plasma homocysteine levels.
Arterioscler Thromb Vasc Biol.
1998;18:1371-1375
4.
Lentz SR, Piegors DJ, Fernandez JA, et al.
Effect of hyperhomocysteinemia on protein C activation and activity.
Blood.
2002;100:2108-2112 5. Zighetti ML, Cattaneo M, Falcon CR, et al. Absence of hyperhomocysteinemia in ten patients with primary pulmonary hypertension. Thromb Res. 1997;85:279-282[CrossRef][Medline] [Order article via Infotrieve]. 6. Faioni EM, Franchi F, Asti D, Sacchi E, Bernardi F, Mannucci PM. Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay. Thromb Haemost. 1993;70:1067-1071[Medline] [Order article via Infotrieve].
7.
Tripodi A, Mannucci PM.
Laboratory investigation of thrombophilia.
Clin Chem.
2001;47:1597-1606   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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-synthase nor
in 10 human volunteers in whom hyperhomocysteinemia was acutely induced
by an oral methionine load. Like Lentz and collaborators, we recently addressed the problem of whether or not hyperhomocysteinemia influences the anticoagulant response to APC. We studied subjects referred to our
center between June 1991 and December 2001 to undergo screening for
thrombophilic states, which included the measurement of fasting tHcy
and the in vitro anticoagulant response to APC. The plasma levels of
tHcy were measured by high-performance liquid chromatography (HPLC) and fluorometric detection
