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J-C. Gris et al.
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Placenta-mediated complications ICU admission, patient
ICU admission, neonate
Venous thrombosis
All deep events
Deep vein thrombosis, all
Deep vein thrombosis, distal Deep vein thrombosis, proximal Pulmonary embolism Superficial vein thrombosis
Arterial thrombosis
All events
Transient ischemic attack / stroke Myocardial infarction
Antithrombotic treatments, last evaluation Low-dose aspirin
Thienopyridine
Vitamin K antagonists
Direct oral anticoagulants
Low-molecular weight heparin
Control grou
139 (17.5%) 48 (6.0%) 67 (8.4%)
59 (7.4%) 59 (7.4%) 23 (2.9%) 36 (4.5%) 17 (2.1%) 20 (2.5%)
21 (2.6%) 14 (1.8%) 5 (0.6%)
9 (1.1%) 21 (2.6%) 0
35 (4.4%) 1 (0.1%)
Thrombophilia group
62 (22.2%) 23 (8.2%) 37 (13.3%)
27 (9.7%) 27 (9.7%) 6 (2.2%) 21 (7.5%) 6 (2.2%) 18 (6.5%)
15 (5.4%) 10 (3.6%) 3 (1.1%)
6 (2.2%) 15 (5.4%) 0
20 (7.2%) 1 (0.4%)
APS group
149 (28.8%) 67 (12.9%) 89 (17.2%)
129 (24.9%) 129 (24.9%) 47 (9.1%) 82 (15.9%) 38 (7.4%) 40 (7.7%)
49 (9.5%) 30 (5.8%) 11 (2.1%)
362 (70%)
84 (16.2%) 120 (23.2%) 0
5 (1%)
Quantitative data are given as median (interquartile range) [range] and qualitative data as number (percentage) values. APS: antiphospholipid syndrome; PL: pregnancy loss; WG: weeks of gestation; LA: lupus anticoagulant; aCL: anticardiolipin; ICU: intensive care unit
was the only aPL antibody found to be significantly associ- ated with incident cancers (Table 3).
As the aPL antibodies did not always remain positive dur- ing follow-up, we studied the association with individual exposures to positive aPL antibodies during the follow-up, that is, the “E” parameter, which, for each of the five aPL antibodies, is the sum of all the annual positivities through- out the duration of the follow-up (Table 4). Only exposure to LA was associated with incident cancers.
We also explored the association between the strength of the antibody titers and the risk of cancer, studying intensi- ties of exposure to aPL antibodies during the follow-up, that is, the “IE” parameter, which, for each of the five aPL anti- bodies, is the sum of the corresponding positive antibody titers throughout the duration of the follow-up (Table 5). Only intensity of exposure to LA was associated with inci- dent cancers.
A total of 14 women developed symptomatic VTE before a diagnosis of cancer: nine in the APS group, two in the Thrombophilia group and three in the Control group. These cases accounted for a minority of all cases of VTE (n=215) observed during the follow-up of the cohort [14/215: 6.5% (3.9%-10.6%)]. In six cases, VTE occurred in the 100 days preceding the diagnosis of cancer, and was thus considered to be related to the malignancy (4 pancre- atic cancers and the 2 primary brain tumors). In our popu- lation, incident VTE was a limited global indicator of an underlying cancer [6/52: 11.5% (5.4%-22.9%)], but was associated with types of cancer known to activate the hemostatic system strongly.
Discussion
In this exploratory analysis of long-term follow-up data from a cohort of women with a personal history of preg- nancy loss categorized according to the results of throm- bophilia screening, a diagnosis of obstetric APS was asso-
ciated with a higher rate of incident cancers than the rate in women with negative thrombophilia screening. The risk of a diagnosis of cancer was influenced by age, body mass index, development of diabetes mellitus during fol- low-up and evidence of atherothrombosis in a first- degree relative. The risk of cancer was associated with positivity for LA, not with anti-β2GP1 antibodies, both in terms of initial positivity at inclusion and in terms of cumulative exposure to this aPL antibody during follow- up. The risk was not associated with positivity for anti- β2GP1 antibodies.
We did not observe a significantly increased cancer risk in the APS group compared to that in the Thrombophilia group. However, this latter group was the smallest, thus limiting the capacity to detect significant differences, since there was a clear lack of statistical power for detect- ing moderate differences. For the same reason, we cannot definitely exclude that the risk of incident cancer in women positive for the F5 rs6025 or F2 rs1799963 poly- morphism is slightly higher than that in women with negative thrombophilia screening, intermediate between the risk in the Control group and the risk in the APS group. Finally, the mean standardized incidence ratio of cancer was close to 1.5 in the Control group, but was not significant. Here also, we paid the price of a lack of statis- tical power. A huge retrospective population-based study in the southern district of Israel, which included 106,265 patients with a history of two or more consecutive preg- nancy losses and a mean follow-up of 12 years, evidenced an aHR of 1.4 for the future risk of female malignancies.12 Part of the association between aPL antibodies and the increased risk of incident cancers may thus be related to the unfavorable obstetric outcomes. However, in women sharing the same initial clinical history, aPL antibodies were associated with an increased risk.
A recent systematic review and meta-analysis of data from individual patients showed that occult cancer is detected in around one in 20 patients within a year of
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haematologica | 2020; 105(2)