Blood, 1 November 2000, Vol. 96, No. 9, pp. 3295-3296
CORRESPONDENCE
To the editor:
Hyperprothrombinemia may result in acquired activated protein C
resistance
Activated protein C (APC) resistance1 due to the
factor V (FV) gene mutation G1691A (single-letter nucleotide
codes)2 and the prothrombin gene mutation
G20210A3 are the most common genetic disorders associated
with venous thrombosis. APC resistance not due to the FV gene mutation
G1691A,4,5 and the hyperprothrombinemia secondary to the
prothrombin gene mutation G20210A,3 are also independent
risk factors for venous thrombosis. Although it has been surmised that
high levels of prothrombin in plasma may result in an increased rate of
thrombin generation6 or increased thrombin potential,7 little is known on how hyperprothrombinemia
leads to venous thrombosis. Recently, Smirnov and colleagues reported on an additional mechanism that might contribute to the pathogenetic role of hyperprothrombinemia.8 They showed that
prothrombin may act as a modulator of the anticoagulant activity of APC
both in a purified system and in plasma by inhibiting the ability of APC to inactivate FVa.
On the basis of this observation, one would predict that
individuals with hyperprothrombinemia might also have acquired APC resistance as measured with the common aPTT-based test. To test this
hypothesis, we selected from our files data on 285 individuals who
served as controls in a previous study designed to assess the
prevalence of the prothrombin gene mutation G20210A in our patient
population.9 Individuals included in the analysis were those for whom APC resistance and prothrombin levels were available and
those who were not carriers of the FV gene mutation G1691A. APC
resistance was measured with the original aPTT-based test described by
Dahlback et al1 as modified by Faioni et
al10; results were expressed as normalized APC
ratios (n-APC-ratios) against a frozen pooled normal plasma.
Prothrombin was measured using S-2238 (Chromogenix, Mölndal,
Sweden) as substrate and Echis Carinatus (Sigma, St Louis, MO) as
activator11; results were expressed as U/dL against a
pooled normal plasma arbitrarily set at 100 U/dL.
As shown in the figure, there was an
inverse relationship between n-APC-ratios and prothrombin activity
(r = 
0.32, P < .001). In particular, 7 of
the 60 subjects (12%) with prothrombin levels higher than the 80th
percentile (ie, 110 U/dL) had n-APC-ratios lower than the lower limit
for APC resistance (ie, 0.76) established for this method at our
laboratory. In contrast, only 2 of the 225 subjects (1%) with
prothrombin levels lower than the 80th percentile had n-APC ratios
lower than the lower limit (P < .0001, Fisher exact
test). These results support the view that plasma prothrombin is a
determinant of APC resistance and may explain the mechanism through
which hyperprothrombinemia is associated with an increased risk for
venous thrombosis.
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| Figure 1.
Normalized activated protein C ratios as a
function of prothrombin levels in subjects without the FV gene mutation
G1691A.
n-APC-ratios are inversely correlated to prothrombin
levels (r = 0.32, P < .001).
|
|
Furthermore, these results indicate that hyperprothrombinemia is
another determinant of acquired APC resistance, like high factor VIII
(FVIII) plasma levels.12 We surmise, however, that high
levels of the 2 proteins act through different mechanisms. Perhaps high
FVIII levels act by increasing the procoagulant strength of plasma as
measured by the aPTT, a test that is very responsive to high FVIII
levels.12 In contrast, as shown by Smirnov and colleagues,
prothrombin is likely to act directly by inhibiting APC.8
Armando Tripodi, Veena Chantarangkul, and PierMannuccio Mannucci
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Department of Internal Medicine University and IRCCS Maggiore
Hospital Milano, Italy
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