By far the most common congenital cause of thrombophilia is the so-called“APC resistance.” Various studies show a prevalence of APC resistance in 2-6% of the general population (2,6) and 20-60% of thrombosis patients (3,4). In more than 90% of these patients, APC resistance was caused by a point mutation on the factor V gene, in which the amino acid arginine was replaced by glutamine at position 506 (4,6). This alteration is referred to as factor V Leiden (8). After mutation, inactivation of the factor Va by activated protein C is delayed, resulting in a susceptibility to thrombosis (8). Increasingly persons in categories at risk for thromboembolism are being tested for APC resistance. Among these are elite athletes since they are exposed to several thrombogenic factors. The literature contains a number of reports of thrombosis developing after strenuous sports activities (7,10,12). The risk factors include hypercoagulability and hemoconcentration after exertion, immobilization after sports injuries, frequent long-distance flights, exsiccosis after intentional weight loss before competition, and intake of oral contraceptives by females. Therefore, elite athletes must be informed about whether they have APC resistance so they can take appropriate preventive steps.
While undergoing a routine checkup, a healthy 26-yr-old elite athlete(mogul skiing) reported thrombotic incidents in several members of her family. Her sister had developed a thrombosis in her left calf after a knee injury, followed two years later by a thrombosis in her right calf without previous trauma. Her brother incurred a fracture of the left clavicle, which was followed by a thrombosis of his left subclavial vein. Another such incident involved her grandmother, who suffered retinal thrombosis; it could not be established whether a retinal artery or occlusion of the central retinal vein was involved. Further diagnosis was not done in any of these cases.
The subject herself had not had a thrombosis. Because of the family history, we initiated diagnostic procedures for thrombophilia, and informed consent was obtained. In particular, we strove to rule out a deficiency of antithrombin III, protein C, or protein S, or to verify a factor V Leiden disorder. Laboratory studies (Table 1) showed that the APC ratio defined as aPTT in the presence of APC divided by aPTT in the absence of APC was considerably below normal. Protein S was also diminished, at 51%; in functional assays, this finding may depend on APC resistance. Once resistance to activated protein C was confirmed by coagulometry, we instigated molecular genetic analysis of the factor V gene to demonstrate or rule out a G1691A mutation. After isolation of genomic DNA from leukocytes, the section of the factor V gene containing nucleotide position 1691 in exon 10 was amplified by polymerase chain reaction (PCR). The amplified DNA was then treated with the restriction enzyme Mnl I (endonuclease from Moraxella nonliquefaciens). The DNA fragments obtained in this manner were separated by size in agarose-gel electrophoresis and stained. The results showed that the subject was a heterozygous carrier of the factor V Leiden mutation. To our knowledge this is the first documented case of APC resistance in an female elite athlete.
APC resistance resulting from a factor V Leiden mutation is the most common hereditary risk factor for venous thrombosis (1). It has an autosomally dominant pattern of inheritance. The G1691A mutation leads to replacement of an amino acid in the factor V molecule at one of the sites acted upon by protein C. This results in considerable slowing of degradation of activated factor V by activated protein C and thus in increased coagulability (5). The risk of thrombosis varies in individuals and is determined to some extent by the presence of other predisposing factors. Statistically, the risk of venous thrombosis or pulmonary embolism in a person who is heterozygous for the mutation is estimated to be 3-7 times higher than normal (9,11); for homozygous individuals, the risk is 80 times as high. At least in heterozygous carriers, arterial thrombotic events apparently do not occur more often; the defect affects primarily the venous system(11).
For heterozygous carriers of a factor V Leiden mutation who have not yet experienced thrombosis, general preventive use of anticoagulants is not recommended. The following procedure is recommended:
- In bedridden or immobilized patients (e.g., those with trauma or influenza), early precautionary anticoagulation with low molecular weight heparin is recommended.
- For long distance flights, a single dose of low molecular weight heparin before departure and leg muscle exercises during flight are recommended.
- Oral contraceptives definitely cannot be considered safe, but evidence does not justify overall rejection of their use. Low estrogen oral contraceptives are preferable.
Whether hemoconcentration caused by exertion or erythrocytosis consequent to high altitude training represents a risk factor is still unresolved. Consistent oral fluid replacement during protracted exertion is necessary in any case and makes sense in this context as well. All data ought to be discussed in detail with the affected athletes to ensure that they observe the necessary precautions. In general, screening for APC resistance of athletes with a history or family history of thrombotic disease should be considered.
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