A Prothrombin-Gene Mutation Predisposes to Venous Thrombosis
ABSTRACTS & COMMENTARY
Sources: Margaglione M, et al. Increased risk for venous thrombosis in carriers of the prothrombin-G>A 20210 gene variant. Ann Intern Med 1998;129:89-93; Martinelli I, et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N Engl J Med 1998;338:1793-1797; Bertina RM, Rosendaal FR. Venous thrombosis-The interaction of genes and environment. N Engl J Med 1998;338:1841-1851.
A common mutation that involves a guanine (G) to adenine (A) transition at nucleotide 20210 of the gene encoding prothrombin recently has been identified. Persons with the A allele have higher plasma prothrombin levels and an almost three-fold increased risk of venous thrombosis compared with persons homozygous for the G allele.1
Margaglione and associates determined the presence of this mutation in patients with deep vein thrombosis (DVT). They studied 281 patients (128 men and 153 women; age range, 3-81 years). The median age at the time of the first thrombotic episode was 38 years for men and 35 years for women. The presenting thrombotic episode was DVT of a lower extremity in 234 patients, DVT of an upper extremity in 27, and mesenteric venothrombosis in 20. Forty-five patients also had an episode of PE. The control group included 850 age-matched, randomly selected apparently healthy persons. All patients and controls were white and from the same region of Italy.
The prothrombin G>A20210 mutation was present in 14% of patients but in less than 5% of controls. In addition, 18% of patients and 5% of controls carried the factor V Leiden mutation. (See Table 1.) Fourteen patients (5%) had both mutations. Carriers of the A20210 allele in both patient and control groups had significantly higher circulating prothrombin values.
The adjusted prevalence odds ratio of venous thrombosis was 3.13 with the prothrombin A20210 allele and 3.38 with the factor V Leiden mutation. A significant association also was noted between venous thrombosis and age (odds ratio per year, 1.02).
Table 1
Characteristics of Patients and Controls
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| Prothrombin A 20210 mutation, n (%) |
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| Factor V Leiden mutation, n (%) |
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| Coagulation abnormalities, n |
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| Protein C deficiency |
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| Protein S deficiency |
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| Antiphospholipid antibody |
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When the 27 patients who had upper extremity DVT were analyzed separately, none had inherited or other risk factors for thrombosis that differed from the control group. In contrast, the prevalence of inherited coagulation abnormalities was significantly higher in patients with lower extremity DVT.
These data confirm that the prothrombin A20210 allele predisposes patients to thrombosis-particularly DVT in the lower extremities.
In a complementary study, Martinelli and associates evaluated the prevalence of the prothrombin A20210 gene mutation and other risk factors, including the use of oral contraceptive agents in patients with cerebral-vein thrombosis (CVT). They studied 40 patients (9 men and 31 women, median age 31 years; range 15-64) with a first episode of CVT, 80 patients with DVT of the lower extremities, and 120 healthy controls. The prevalence of the prothrombin A gene mutation was higher in patients with CVT (20%) than in healthy controls (3%, odds ratio 10.2) and was similar to that in patients with lower extremity DVT (18%). The prevalence of the factor V Leiden mutation was similar. (See Table 2.)
Table 2
Characteristics of Patients and Controls
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| Prothrombin A 20210 mutation, n (%) |
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| Factor V Leiden mutation |
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| Coagulation abnormalities |
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| Pregnant or postpartum |
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| Oral contraceptive use |
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| Surgery or immobilization |
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The use of oral contraceptives was more frequent among women with CVT (96%) than among controls (32%; odds ratio, 22.1) and among those with DVT (61%; odds ratio, 4.1). For women who had both the prothrombin A20210 gene-mutation and who were taking oral contraceptives (7 CVT patients and 1 control), the odds ratio for CVT was 149.3. Smoking was not associated with an increased risk of CVT either alone or in combination with the prothrombin or factor V mutation.
Martinelli et al found that the prothrombin A20210 gene mutation and the factor V Leiden mutation are associated with CVT. The use of oral contraceptives is also independently associated with the disorder, and the presence of both the prothrombin A gene mutation and oral contraceptive use raises the risk of cerebral-vein thrombosis even further.
COMMENTARY
Both studies indicate the important role of prothrombotic mutations in the development of venous thrombotic disease. The frequency of the prothrombin A20210 and the Factor V Leiden mutations were similar in both studies-a not surprising finding since both populations were white and Italian. The prothrombotic mutations have a prevalence in whites of 2-15% for factor V Leiden and 0.5-4.0% for prothrombin A. Both mutations are rare in non-whites.
The report of Martinelli et al addressed the role of these mutations and the use of oral contraceptives in the development of idiopathic CVT, a rare condition. The similar prevalence of the prothrombin A and factor V Leiden mutations in patients with DVT or CVT indicates that genetic factors contribute to thrombus formation but does not explain the two different presentations of venous thrombosis.
The contribution of the use of the pill to the risk of CVT has been noted by many studies over the years. The present study points to an important interaction between the prothrombin A20210 mutation and oral contraceptives. An interaction between factor V Leiden and oral contraceptive use to cause DVT and CVT has been reported previously,2,3 and screening patients for the factor V mutation has become standard clinical practice. As yet, there is no clinically available test for the prothrombin A mutation.
Although the low incidence of CVT makes screening for the prothrombin A20210 mutation of questionable cost effectiveness, the catastrophic nature of CVT means that when testing is available, physicians will screen young, caucasian women for both prothrombin gene mutations before prescribing oral contraceptives.
As Bertina and Rosendaal point out in their editorial, we do not know why venous thrombosis develops in the brain of some patients and in the lower extremities in others. Therefore, the search for still unknown risk factors must continue. -JJC
References
1. Poort SR, et al. Blood 1996;88:3698-3703.
2. de Brijn SF, et al. BMJ 1998;316:589-592.
3. Vandenbrouche JP, et al. Lancet 1994;344:1453-1457.
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