Page 224 - 2020_07-Haematologica-web

B. Paulsen et al.
n=27,158
VTE-cases n=640 Sub-cohort n=3,734
Exclusions
Previous cancer n=232 Missing FGG rs2066865 n=9
interaction (RERI) was 9.61 (95% CI: -2.38-21.61) and the Rothmans synergy index (RSI) was 1.81 (95% CI: 1.02- 3.21). The proportion attributable to interaction (AP) was 0.43 (95% CI: 0.11-0.74). In sub-group analysis, the esti- mates of biological interaction were stronger for PE (RSI=2.37, 95% CI: 1.05-5.39) than for DVT (RSI=1.46, 95% CI: 0.65-3.27).
Discussion
In the present study, we aimed to investigate the joint effect of the rs2066865 SNP at FGG and active cancer on the risk of VTE in a case-cohort recruited from the general population. Homozygosity at rs2066865, occurring in 6.6% of the study population, was associated with an increased risk of VTE. The combination of an rs2066865 homozygous risk genotype and active cancer showed a synergistic effect on VTE risk (on an additive scale). The effect was particularly strong for PE. The cumulative inci- dence of VTE increased substantially during the first six months following a cancer diagnosis, especially among patients with two risk alleles at FGG rs2066865. Our find- ings suggest that homozygosity at FGG rs2066865 may aid to differentiate patients at high and low risk of cancer- related VTE.
Several observational studies have reported an associa- tion between homozygous genotype of rs2066865 and increased risk of VTE in Caucasians.14-16,21 In a recent meta- analysis including seven observational studies, the odds ratio of VTE was 1.61 for homozygosity at rs2066865.21 Accordingly, in cancer-free subjects, we found that those with two rs2066865 risk alleles had a 1.7-fold higher VTE risk than those with 0 risk alleles. The risk estimates for DVT and PE were essentially similar in cancer-free sub- jects.
Even though the role of prothrombotic genotypes in cancer-related VTE have been scarcely studied, previous studies have found that some prothrombotic genotypes (e.g. factor V Leiden and prothrombin G20210A) are asso- ciated with increased risk of cancer-related VTE.22,23,30,31 Further, the combined effect of cancer and factor V vari- ants (factor V Leiden and rs4524) exceeded the sum of the individual effects, implicating a biological interaction on VTE risk.22,24 Accordingly, we found that the combination of FGG and active cancer yielded a synergistic effect on VTE risk.
In cancer patients, the cumulative incidence curve of VTE was substantially steeper in individuals homozygous for FGG during the first six months following the cancer diagnosis. According to the thrombosis potential model,32 several risk factors need to be present concurrently to exceed the thrombosis potential and facilitate develop- ment of a VTE. In the period following a cancer diagnosis, treatment with surgery and/or chemotherapy is typically initiated, and treatment-related complications such as acute infection and immobilization frequently occur. Thus, the accumulation of several treatment-related risk factors, which adds to the background risk in patients with cancer and risk alleles at FGG, may partly explain the substantial increase in VTE incidence the first half year fol- lowing a cancer diagnosis.
In contrast to cancer-free subjects, we found that the effect of rs2066865 was stronger for PE than for DVT in cancer patients. This suggests that the FGG variant may
Figure 1. Flow chart for the case-cohort.
play a more essential role in the pathogenesis of PE than DVT in cancer patients. The underlying mechanism(s) for the latter observation is unknown, but may imply that rs2066865 is associated with fragile thrombi, which are prone to embolization and manifest clinically as PE rather than DVT in cancer patients.
The mechanism by which the rs2066865 affects suscep- tibility to VTE is not fully elucidated. However, the cur- rent hypothesis is that it acts through a phenotype with altered fibrinogen composition and formation. The rs2066865 SNP tags the FGG-H2 haplotype. Previous studies have shown that homozygous carriers of the FGG- H2 haplotype had lower levels of g’ fibrinogen and g’ fib- rinogen/total fibrinogen concentration14 without alter- ations in the total fibrinogen level.33 The suggested mech- anism is that the FGG variant favors formation of the abundant g-chain isoform (gA) above the minor g-chain (g’) through alternative splicing of the mRNA of the FGG- gene.14,33 Fibrinogen g’ exhibits an inhibitory activity towards thrombin, due to a high affinity binding site on the g’ chain for thrombin exosite II,34 which inhibits thrombin-mediated activation of factor VIII,35 factor V36 and platelets.37 Moreover, fibrinogen g’ has been shown to increase the activated protein C (APC) sensitivity.38 However, studies on the association between low plasma levels of fibrinogen g’ and VTE risk have shown some- what inconsistent results.14,20
Current anticoagulant prophylaxis regimens efficiently prevent first VTE in cancer patients, but at the expense of a substantial risk of major and life-threatening bleedings.39 Therefore, current international guidelines do not recom- mend prophylactic anticoagulation to all ambulatory can- cer patients.40,41 Thus, it is vital to recognize patients that are at high risk of cancer associated VTE, in order to iden- tify those who would benefit most from thromboprophy- laxis. Prothrombotic genotypes are attractive biomarker candidates, which could be used to distinguish between high and low risk of VTE in cancer patients, since they are fixed and not affected by the clinical status or treatment- related factors. In the present study, 6.4% of cancer
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haematologica | 2020; 105(7)