Correspondence

Coagulation Factor XI and Venous Thrombosis

N Engl J Med 2000; 343:220-221July 20, 2000

Article

To the Editor:

Meijers et al. (March 9 issue),1 who report that high levels of coagulation factor XI are a risk factor for deep venous thrombosis, did not take into account the possible role of antiphospholipid antibodies. During the past decade, the antiphospholipid-antibody syndrome has been recognized as one of the most common types of acquired thrombophilia. According to the international consensus statement on preliminary classification criteria for definite antiphospholipid syndrome, the syndrome is defined by the presence of antiphospholipid antibodies or lupus anticoagulant and a history of arterial, venous, or small-vessel thrombosis or pregnancy-related morbidity.2

The risk of recurrent thrombosis in patients with the antiphospholipid-antibody syndrome is very high, and this risk has been variously reported to be between 22 percent and 69 percent.3 Therefore, in an assessment of the effect on public health of a high level of factor XI as a risk factor for venous thrombosis, the possible presence of the antiphospholipid-antibody syndrome must be taken into account. In the study by Meijers et al., no data concerning the presence of antiphospholipid antibodies or lupus anticoagulant and no clinical data concerning pregnancy-related morbidity in women were reported, and the odds ratio for deep venous thrombosis in the subjects who had factor XI levels above the 90th percentile was not adjusted for these important risk factors.

Roberto Perricone, M.D.
Stella Modica, M.D.
Luigi Fontana, M.D.
University of Rome Tor Vergata, 00100 Rome, Italy

3 References

1. 1

   Meijers JCM, Tekelenburg WLH, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000;342:696-701
   Full Text | Web of Science | Medline

2. 2

   Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999;42:1309-1311
   CrossRef | Web of Science | Medline

3. 3

   Khamashta MA. Management of thrombosis and pregnancy loss in the antiphospholipid syndrome. Lupus 1998;7:Suppl 2:S162-S165
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Perricone and colleagues question the validity of the conclusions of our study of the effect of high levels of factor XI on the risk of venous thrombosis, because pregnancy or the presence of the antiphospholipid-antibody syndrome may have influenced our results. In our study (part of the Leiden Thrombophilia Study), we found that levels of factor XI exceeding the 90th percentile of the level in control subjects doubled the risk of deep-vein thrombosis (odds ratio, 2.2; 95 percent confidence interval, 1.5 to 3.2). There are many risk factors for thrombosis, of which pregnancy and the antiphospholipid-antibody syndrome are established examples.1,2 However, there is no compelling reason to adjust for all risk factors; in fact, doing so would lead to untenable paradoxes because of unknown risk factors. Only confounding risk factors need be taken into consideration. A factor is a confounder if it in itself is a risk factor for the disease (here, deep-vein thrombosis) and if it is associated with the factor under study (in this instance, high levels of factor XI).

Both pregnancy and the antiphospholipid-antibody syndrome are risk factors for thrombosis, thereby fulfilling the first criterion, but there is no known association between the levels of factor XI and pregnancy or the antiphospholipid-antibody syndrome. Adjustment for pregnancy or the antiphospholipid-antibody syndrome is therefore neither necessary nor justified.

However, for further reassurance, we reanalyzed our data. First, we confirmed that pregnancy (in eight patients and two controls) and the antiphospholipid-antibody syndrome, defined as the presence of lupus anticoagulant (in four patients and no controls), increased the risk of venous thrombosis. Second, we did not observe a relation between the levels of factor XI and pregnancy (since venipuncture took place at least six months after the thrombotic event) or lupus anticoagulant (the mean factor XI levels in patients with lupus anticoagulant and those without it were 107.7 percent and 104.1 percent, respectively [P=0.75]). Since these factors do not fulfill the criteria for confounding, adjustment had no effect; the odds ratio remained 2.2 after adjustment for pregnancy and after exclusion of the patients with lupus anticoagulant.

In conclusion, the association we observed between high levels of factor XI and the risk of deep-vein thrombosis cannot be explained by pregnancy or the presence of lupus anticoagulant (the antiphospholipid-antibody syndrome).

Joost C.M. Meijers, Ph.D.
Academic Medical Center, 1100 DD Amsterdam, the Netherlands

Frits R. Rosendaal, M.D.
Leiden University Medical Center, 2300 RC Leiden, the Netherlands

2 References

1. 1

   Carter CJ. The natural history and epidemiology of venous thrombosis. Prog Cardiovasc Dis 1994;36:423-438
   CrossRef | Web of Science | Medline

2. 2

   Rosendaal FR. Risk factors for venous thrombosis: prevalence, risk, and interaction. Semin Hematol 1997;34:171-187
   Web of Science | Medline