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Hereditary thrombophilia in elite athletes

HILBERG, THOMAS; JESCHKE, DIETER; W. GABRIEL, HOLGER H.

Medicine and Science in Sports and Exercise: February 2002 - Volume 34 - Issue 2 - p 218-221
CLINICAL SCIENCES: Clinically Relevant
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HILBERG, T., D. JESCHKE, and H. H. W. GABRIEL. Hereditary thrombophilia in elite athletes. Med. Sci. Sports Exerc., Vol. 34, No. 2, pp. 218–221, 2002.

Purpose Although under normal circumstances exercise prevents thrombosis, there are cases in the literature that indicate a connection between exercise and the onset of thrombosis. In the average population, hereditary thrombophilia is a major cause of thrombosis. However, nothing is known about the prevalence of hereditary thrombophilia in elite athletes. Because high-performance sports are known to carry an increased risk of thrombogenesis, measures to avoid thrombosis must be initiated in cases of known hereditary thrombophilia.

Methods Hereditary thrombophilia was checked for in 173 elite athletes, members of the German national team. Antithrombin III, protein C, protein S, and the APC ratio, followed by a molecular genetic analysis, were measured, and molecular analysis of factor II G20210A mutation was used to detect the presence of an antithrombin III-, protein C- and protein S-deficiency, as well as factor V Leiden (factor V 506Arg to Gln) and factor II G20210A mutation.

Results No definite antithrombin III-, protein C- or protein S-deficiency was found. In 12 cases, an APC resistance caused by a factor V Leiden mutation (11 heterozygous; 1 homozygous) was detected. In 10 cases, a heterozygous factor II G20210A was observed; a combination of both mutations was not found. For factor V Leiden, this corresponds to a prevalence of 6.9% (CI 95% 3.6–11.8%) in our group, similar to prevalence rates in the general population. Additionally, the observed prevalence of 5.8% (CI 95% 2.8–10.4%) of factor II G20210A is nearly within the range as reported by several authors.

Conclusion Based on the observed prevalence of APC resistance and factor II G20210A mutation in our group of athletes, along with consideration of additional circumstantial risks, screening tests for elite athletes should be considered to allow the undertaking of preventive measures.

Department of Sports Medicine, Friedrich-Schiller-University Jena, Jena, GERMANY; and Department of Preventive and Rehabilitative Sports Medicine, Munich Technical University, Munich, GERMANY

Submitted for publication January 2001.

Accepted for publication May 2001.

The yearly incidence of venous thrombosis in the general population is approximately 1 per 1000 (6). An existing thrombophilia is often the cause a developing thrombosis or of a thromboembolic complication. Along with acquired forms of thrombophilia, inheritable forms also exist. Inherited thrombophilia is a genetically caused tendency toward venous thrombosis. Important genetic defects previously known to be associated with thrombophilia are deficiencies of protein C (PC) and -S (PS) or antithrombin III. However, these deficiencies account for only 5–10% of all cases (8). The most prevalent cause of hereditary thrombophilia is the resistance to the activated protein C (APC). This was first described by Dahlbäck in 1993 (6,9,26), with a reported prevalence from 2-(9%) to 15% in the general population. Vandenbroucke et al. (30) found APC resistance in about 20% of patients with venous thrombosis in the Netherlands. In a Swedish study, APC resistance was present in 33% of patients with thrombotic events (27). In more than 90%, 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 (factor V 506Arg to Gln or factor V Leiden) (9). This mutation was named the factor V Leiden mutation after the Dutch city where it was first found. After mutation, the inactivation of factor Va by activated PC is delayed, resulting in an increased number of thrombotic events. Additionally, a genetic variation in the prothrombin gene, the G to A transition at nucleotide 20210, is associated with an increased plasma level of factor II activity, which results in a two- to five-fold increase in the risk for venous thrombosis and embolism (34). The prevalence of factor II G20210A heterozygotes is 1–6% among Caucasians, whereas it is very rare or absent in non-Caucasians (34). To prevent thrombosis, persons in categories at risk for thromboembolism are being tested for hereditary thrombophilia. Elite athletes are exposed to several thrombogenic risk factors. The literature contains a number of different case reports of thrombosis developing after strenuous exercise (1,11,20,33). 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 female subjects. Because of these existing risk factors, elite athletes should be informed if they have a hereditary thrombophilia, so that they may take appropriate preventive steps.

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METHODS

Subjects.

During their routine checkups for 1 yr, 173 elite athletes of the German National team (26 different sports) were tested for antithrombin-, PC-, PS-deficiency, APC resistance, and for the factor II G20210A mutation. Written informed consent was obtained from the subjects, and the study design received ethical clearance by the Faculty of Medicine of the Technical University of Munich. The group of athletes comprised 73 women and 100 men. The mean value of the age was 19.1 ± 4.8 yr (mean ± standard deviation) with a range of 11–37 yr. The mean value of the weight was 66.9 ± 12.9 kg (mean ± SD), and the mean value of the height was 172.9 ± 9.3 cm (mean ± SD). No athlete had a history of thrombosis or a thromboembolic event, but three athletes (2 female, 1 male) mentioned a thrombotic event in their family history. No athlete was taking antithrombotic medicine, but 22 female subjects were taking oral contraceptives.

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Analytical methods.

APTT, antithrombin III activity, PC activity, and PS activity were measured with standardized methods. Antithrombin III activity was determined using a DuPont Discrete Clinical Analyzer (Bad Homburg, Germany) via factor IIa in the presence of a saturating concentration of heparin (heparin cofactor method). The residual factor IIa after inhibition modified a chromogenic substrate, which was measured photometrically. The normal range for antithrombin III is about 84—123%. PC and PS activity was determined with test kits from Behring Diagnostics (Marburg, Germany). The functional PC assay (no. OUUX) was clotting based. Activation was initiated by use of a snake venom-based protein C activator (Agkistrodon contortrix). The activated PC led to an inactivation of factor Va and VIIIa and an increase of the clotting time. The prolongation of the clotting time was proportional to the PC activity. The normal range for PC is about 70–140%. The functional assay for PS (no. OQCE) assessed the cofactor function of this protein in the activated PC dependent inactivation of factor Va and VIIIa. A defined amount of activated PC was added to the sample in the presence of excess PS-deficient plasma. After incubation, the clotting was initiated by the snake venom, and the prolongation of the clotting time was proportional to the PS activity. The normal range for PS is about 70–123%. The determination of the APC ratio was also performed with a test kit from Behring Diagnostics. The APC ratio is defined as aPTT in the presence of APC divided by aPTT in the absence of APC. In addition to the APC ratio, a molecular genetic analysis of the factor V gene was instigated to either demonstrate or rule out a G1691A mutation. After isolation of genomed DNA from the leukocytes, the section of the factor V gene-containing nucleotide position 1691 in exon 10 was amplified by a 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 an agarose-gel electrophoresis and stained. The results showed the subject to be a heterozygous or homozygous carrier of the factor V Leiden mutation. For the identification of a genetic abnormality in the prothrombin gene (factor II G20210A mutation) in DNA, a PCR was used also, followed by direct sequencing. Genomic DNA was specifically amplified for the 14 exons with their flanking regions and for the 5′- and 3′-UT regions of the prothrombin gene using PCR. The fragments won by PCR were purified on an agarose gel. The results showed the subject to be either a heterozygous or homozygous carrier of the factor II G20210A mutation. The measurements were identical to those described in the previous study (21).

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Statistics.

The anthropometric data are mentioned as mean values with a standard deviation (mean ± SD). The prevalence rates are presented as means with a 95% confidence interval of binomial distribution (CI 95%), if the CI 95% was mentioned in the literature.

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RESULTS

For antithrombin III activity, a mean value of 106.2 ± 9.0% (mean ± SD) was investigated. The mean value of the PC activity was 94.7 ± 17.5% and 102.9 ± 16.9% for the PS activity in the group of elite athletes. In no case was a definite antithrombin III-, PC-, or a PS-deficiency found. In 10 of 173 subjects, a heterozygous factor II G20210A mutation was detectable; a homozygous mutation was not observed. This shows a prevalence of 5.8% (CI 95% 2.8–10.4%) for the heterozygous factor II G20210A mutation in our group of elite athletes. This prevalence is inside the range as published by Zivelin et al. (34) but a bit higher than that published by Junker and Nowak-Göttl (15) and Rosendaal et al. (25) (see Fig. 2). An APC resistance was detected in 12 cases (11 heterozygote and 1 homozygote), corresponding to a prevalence of APC resistance of 6.9% (CI 95% 3.6–11.8%) in this group. This prevalence observed in our athletes is in accordance with the prevalence in the general population as described by several authors (6,9,26) (Fig. 1). A combination of both mutations was not observed. The overview is shown in Table 1.

FIGURE 2

FIGURE 2

FIGURE 1

FIGURE 1

Table 1

Table 1

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DISCUSSION

There are several case reports of thrombosis in connection to exercise mentioned in the literature (11,31–33). In an average population, hereditary thrombophilia is a major cause of thrombosis or thromboembolic events, and therefore the prevalences have been shown in different studies.

The aim of this study was to first investigate the occurrence of hereditary thrombophilia in a group of elite athletes; subsequently, we compared our prevalence rate to that found in a normal population (as this is based on a testing of several thousand subjects) and to determine whether measurements to reduce the special thrombotic risk are necessary.

In this first study, we investigated not only the prevalence of the main causes of hereditary thrombophilia such as APC resistance and factor II G20210A mutation but also PC-, PS-, and antithrombin III-deficiencies in a group of elite athletes.

Antithrombin III deficiency is a heterogenous disorder. Tait et al. (28) described the prevalence of antithrombin III deficiency type I (reduction of both functional and immunological antithrombin) in healthy individuals as 0.02%. Focusing on the available data, it appears that antithrombin III leads to a higher risk of thrombosis than deficiencies of PC or PS (19). Protein C deficiency is similar to the antithrombin III deficiency in that it is also a heterogenous disorder (22) with a prevalence 0.2–0.4% in healthy individuals (29). Individuals carrying a PC deficiency have an approximately 8- to 10-fold increased risk of developing venous thrombosis (2,4). Protein S deficiency is an autosomal dominant trait, with a prevalence of up to 10% in families with inherited thrombophilia (10). PS is a nonenzymatic cofactor to activated protein C, a serine protease, in the proteolytic degradation of factors Va and VIIIa (10). The prevalence of PS deficiency in the general population varies between 0.005%(10) and 0.7–2.3%(5). Heijboer et al. (13) found a prevalence of 2% in consecutive patients with first deep venous thrombosis. In the present study, no cases of antithrombin III-, PC-, or PS-deficiency in the group of elite athletes were detected. Contrary to this, we determined the presence of 12 cases of APC resistance. APC resistance due to the fact that factor V Leiden mutation (factor V 506Arg to Gln) is the most common hereditary risk factor for venous thrombosis (7). It has an autosomally dominant heterozygous or homozygous pattern of inheritance. The mechanism by which the mutation leads to APC resistance is not known, but it is known that the replacement of Arg506 by Gln will prevent cleavage of factor Va at this site by APC, leading to the delayed inactivation of factor Va (12,17). The delayed inactivation of factor Va results in a susceptibility to thrombosis (16). The risk of venous thrombosis or pulmonary embolism increases 3–7 times in individuals who are heterozygous carriers (18,24). For homozygous carriers, the risk is 80 times higher. Even though the mutation affects primarily the venous system, a relationship to arterial thrombotic events also exists (3). The appearance of heterozygous as well as homozygous APC resistance in elite athletes was first described by Hilberg et al. (14). In this group of athletes, the prevalence of APC resistance was 6.9% with a 95% confidence interval (CI) of 3.6–11.8%, correlating with the observed prevalence in the general population (Fig. 1). Schwender et al. (26) mentioned a prevalence of 7.3% in the total German population based on 2676 test persons; Ridker et al. (23) found a prevalence of 5.3% in 2468 Caucasian Americans.

The genetic variation in the prothrombin gene, the G to A transition at nucleotide 20210, is associated with an increased plasma level of factor II activity. This results in a two- to five-fold increase of the risk for venous thrombosis and embolism. Additionally, this mutation is associated with myocardial infarction and cerebral ischemia (15). The prevalence of factor II G20210A heterozygotes is 1–6% among Caucasians, whereas it is very rare or absent in non-Caucasians (34). Heterozygous prothrombin G20210A mutation was detected in 10 cases, whereas homozygous mutation was not observed. The positive results of 10 cases correspond with a prevalence of 5.8% in this group (CI 95% 2.8–10.4%) and were in the range described by Zivelin et al. (34) among Caucasians but a bit higher in relation to data published by Junker and Nowak-Göttl (15) and Rosendaal et al. (25) (Fig. 2). A combination of both mutations was not detected.

In conclusion, hereditary thrombophilia exists, therefore, in elite athletes corresponding to the average population. Based on the detected prevalences among the elite athlete group and in the additional circumstantial risk profile, the following measurements are necessary and the following procedure is recommended:

General preventive use of anticoagulants without a history of thrombotic occurrence is not recommended.

The finding should be considered in all situations with a potentially higher risk of thrombosis:

1. By immobilization (trauma, injuries, operation) or bedridden patients (influenza), early precautionary anticoagulation with low-molecular-weight heparin together with physically antithrombotic measures is recommended.

2. For long-distance flights or travels, a single dose of low-molecular-weight heparin before departure and/or leg muscle exercises during the flight is recommended, especially for persons with severe or combined hereditary thrombophilia.

3. Avoid hemoconcentration as much as possible with sufficient oral fluid intake, before, during, and after exercise.

4. Oral contraceptives cannot be considered safe, but present evidence does not justify an overall rejection of their use. If necessary, low-estrogen oral contraceptives should be preferred.

5. Doping drugs like erythropoietin are strictly forbidden for any athlete.

The role of hemoconcentration due to exhaustive exercise or erythrocytosis consequent upon high-altitude training in relation to thrombotic events is still not clear, but constant oral fluid replacement during exercise is necessary in any case. One point is very clear: the data must be discussed in detail with the affected athletes so that they may take necessary precautions. A screening for hereditary thrombophilia of elite athletes, especially for those with a history or family history of thrombotic disease, should be considered.

Address for correspondence: Dr. Thomas Hilberg, Department of Sports Medicine, Friedrich-Schiller-University Jena, Wöllnitzerstr. 42, D-07749 Jena, Germany; E-mail: th.hilberg@ghz.de.

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Keywords:

FACTOR V LEIDEN; APC RESISTANCE; FACTOR II G20210A MUTATION; ANTITHROMBIN III DEFICIENCY; PROTEIN C DEFICIENCY; PROTEIN S DEFICIENCY; EXERCISE; SPORTS ACTIVITY

© 2002 Lippincott Williams & Wilkins, Inc.