© 1998 American Heart Association, Inc.
Original Contributions |
Clinical Studies and Thrombin Generation in Patients Homozygous or Heterozygous for the G20210A Mutation in the Prothrombin Gene
From the Departments of Internal Medicine I (Division of Hematology and Hemostaseology; P.A.K., A.W., M.S., B.B., I.P., K.L., S.E.) and II (Division of Angiology; A.S.) and the Clinical Institute of Medical and Chemical Laboratory Diagnostic (C.M., W.S.), University of Vienna, Vienna, Austria; the Cardiovascular Research Institute (CARIM; S.B.), Maastricht University, Maastricht, The Netherlands; and the Hanuschkrankenhaus (M.H.), Vienna, Austria.
Correspondence to Paul A. Kyrle, MD, Allgemeines Krankenhaus Wien, Department of Internal Medicine I, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Abstract—A genetic variation in the
prothrombin gene, the G
A transition at nucleotide 20210,
is a risk factor for venous thrombosis in heterozygotes and is
associated with increased prothrombin activity. The homozygous
phenotype and the extent of thrombin generation in heterozygous
and homozygous subjects are unknown. We investigated a family that
included 2 homozygous and 5 heterozygous carriers of the 20210 A
allele. The homozygous propositus and his presumably heterozygous
father suffered from deep-vein thrombosis. His presumably heterozygous
mother and his homozygous sister had recurrent phlebitis at a young
age. The remaining 5 affected family members are still
asymptomatic. We studied thrombin generation in the family
and in 22 unrelated carriers of the 20210 A allele by measuring (1)
prothrombin fragment F1+2 (F1+2) as an index of ongoing thrombin
generation and (2) the endogenous thrombin potential (ETP)
as an index of the possible thrombin-forming capacity. Their F1+2
levels were not different from those of age-matched controls, and thus,
ongoing hemostatic system activation was not detectable. A
significantly increased ETP was found in the heterozygous carriers of
the 20210A allele compared with the controls (527.8±114.9 versus
387±50.1 nmol/L · min, P<0.0001). In the 2
homozygotes, the ETP was almost twice (639 and 751 nmol/L · min,
respectively) as high as in the controls. We conclude that homozygosity
for the G20210A mutation in the prothrombin gene is associated with a
severe, albeit more benign, thrombotic diathesis compared with
homozygosity for deficiencies of antithrombin, protein C, or protein S.
In carriers of the 20210 A allele, the pathomechanisms leading to
thrombosis should be sought in the higher amounts of thrombin that may
be formed once thrombin generation is triggered, rather than in ongoing
thrombin generation in vivo.
Key Words: G20210A prothrombin mutation • deep-vein thrombosis • prothrombin fragment F1+2 • endogenous thrombin potential
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