We have evaluated a group of individuals who had been sent for aCL testing by their physician and who were recalled by us for further testing one to 4 years later. No information was available on why the test was ordered, and a selection bias towards oversampling of persons with higher thrombophilic risk factors may have occurred. Consequently, we cannot use this sample to estimate the magnitude of the thrombophilic risk of multiple factors with certainty, and the results of our study are not sufficient to recommend a change in current clinical practice. Our results can, however, generate important hypotheses to be tested in future studies, and act as proof of principle justifying more research on this topic.
Twenty individuals were negative and 67 were positive for aCL upon entry into the study. We found a high prevalence of concomitant immunologic and coagulation abnormalities in this group of individuals. Sixteen (16) of the 67 subjects (24%) who initially tested positive for aCL-IgG were found to have suffered thrombotic events previously. Multivariate regression analysis was performed to study the association between previous thrombosis and the number of prothrombotic risk factors. When controlling for age and gender, the odds of a previous thrombotic event were increased by 46% (OR = 1.46, 95% CI: 1.003–2.134, p = 0.048) with each additional prothrombotic risk factor.
The risk of thrombosis in persons with aPL increases with increasing titers of antibodies32–35
, particularly those of the IgG isotype36,37
. The coexistence of other thrombogenic conditions in the presence of aPL may be important in the development of thrombotic events. Reports have suggested an increased frequency of acquired protein S deficiency in patients with aPL38,39
. The significance of this observation remains unknown. Factor V506
Leiden mutation is the most common inherited condition in Caucasians leading to a hypercoagulable state6,8
. There is conflicting data concerning the role of factor V506
Leiden in patients with aPL. In one study of 30 women with APS, 10 of whom had a history of thrombosis, none of the women were found to be heterozygous or homozygous for factor V506
. Chopra reported an increase in the prevalence of Factor V506
Leiden in a population of persons with autoimmune aPL and thrombosis, but there was no significant association of this mutation with thrombosis, after adjustment for other clinical risk factors41
. In another study of 60 patients with aPL, 26 of whom had venous thrombosis, 4 patients were heterozygous and one was homozygous for the factor V506
. Furthermore, there are reports of an increased frequency of an acquired APCR phenotype in patients with aPL without a factor V506
. In contrast, there has been a lack of association between thrombosis in APS and the 20210A prothrombin gene mutation45,46
. Finally, the mutation Ala677 to Val in the MTHFR gene, which is associated with elevated homocysteinemia, has been shown to be a risk factor for thrombosis26
Our study has some limitations. The number of study participants (n = 87) was small, as was the number of individuals with confirmed thrombotic events (n = 20). Also, fluctuations in aCL-IgG titers were apparent, as has been previously described47,48
. Of the 67 patients with elevated aCL-IgG titers at study entry, only 40 (60%) had elevated titers on repeat testing. Given the tendency for aCL-IgG titers to fluctuate, isolated results are not conclusive and associations are more difficult to detect. A more recent definition of APS proposes to incorporate a certain level of positivity over a period of time1
. Finally, we found a high prevalence of immunologic and coagulation abnormalities in participants without aCL-IgG. We also found that 4 of these individuals (20%) had experienced thrombotic events. This could be explained by the fact that we chose these participants from a group of individuals who had undergone aCL testing on at least one occasion. Hence, there may have been a selection bias in favour of patients more likely to have a coagulation abnormality. Therefore, our results may not be applicable to the general population, but rather to individuals with a thrombophilic predisposition. In addition, although our study participants were randomly chosen from a cohort of individuals who had undergone aCL testing, women were over-represented in both the aCL positive (87%) and the aCL negative (80%) groups. This may reflect a selection bias for testing women for aCL, due to the higher risk of thrombosis generally reported in women49
, or it may reflect a true preponderance of aPL in women.
The increased risk of thrombosis associated with increasing numbers of potential prothrombotic risk factors seems modest (OR = 1.46, 95% CI: 1.003–2.134, p = 0.048). Nevertheless, it is consistent with our hypothesis that the concomitance of aCL-IgG and other immunologic and thrombophilic abnormalities may increase the risk of thrombosis. Larger, prospective studies are needed to confirm this observation and to assess the relative importance of each prothrombotic risk factor.