In two large prospective cohorts, we observed a nearly two times increased risk of idiopathic PE among participants with non-O blood type, when compared to those with blood type O. For inheritance of non-O blood type, the population attributable fraction was 33% for idiopathic PE. In addition, non-O blood type conferred a statistically significantly increased risk of non-idiopathic PE and any PE in our study population. The risk of PE with non-O blood type was more pronounced among current or past smokers in comparison to never smokers, suggesting a possibly important interaction between an inherited predisposition and environmental exposure.
A number of case-control studies over the past several decades have demonstrated an association of ABO blood type with the risk of VTE, primarily suggesting an increased frequency of blood types A or B and a decreased frequency of blood type O among cases compared with selected groups of controls (16
). A meta-analysis of studies including idiopathic and non-idiopathic VTE demonstrated a pooled odds ratio (OR) of 1.79 (95% CI, 1.56–2.05) for VTE among participants with non-O versus O blood type (7
). However, significant heterogeneity was observed among studies and the findings of the individual studies were inconsistent, with ORs of 1.1 (non-significant) to 3.9.
In the current prospective study, with a uniform base population and rigorous ascertainment of case status and important co-variates, we noted HRs of 1.86 for idiopathic PE and 1.29 for non-idiopathic PE. These findings suggest blood type is associated with additional risk in patients already at high risk for PE due to recent surgery, trauma or cancer; however, blood type may play a larger role in the development of idiopathic PE. A study of ABO blood type and VTE risk in the Longitudinal Investigation of Thromboembolism Etiology (LITE) cohort (20
) similarly noted a greater point estimate of risk for idiopathic VTE (OR, 1.83; 95% CI, 1.33–2.52) than secondary VTE (OR, 1.46; 95% CI, 1.11–1.92). Nevertheless, cross study comparisons should be made cautiously given the use by prospective cohort studies of differing definitions of “non-idiopathic” PE (21
), which depend on availability of data for provoking events, such as active malignancy or recent surgery, trauma, air travel, or immobilisation.
Although some studies have suggested an increased risk for VTE predominantly with blood type A (7
), we noted similar hazard ratios for blood types A, AB, and B, when compared to blood type O. This finding would appear to support a protective role for blood type O, as opposed to a specific detrimental effect of either blood type A or B. The protective role for blood type O may in part be explained by the differential survival of circulating von Willebrand factor (vWF) and clotting factor VIII in subjects with blood type O compared to those with non-O blood type (24
). Specifically, subjects with blood type O have approximately 25% lower levels of circulating vWF than those with blood types A or B (27
), and correspondingly lower levels of circulating factor VIII, as vWF acts as a carrier molecule for factor VIII in blood. More recently, these lower levels of vWF and factor VIII have been related to a shorter half-life of vWF in the circulation, due to increased clearance (24
). Given the previously demonstrated associations of vWF and factor VIII with risk of VTE (28
), alterations in circulating vWF and factor VIII levels due to differences in ABO glycosylation may be partly responsible for the association of blood type with risk of VTE (29
Another mechanism is suggested by the results of several recently performed genome-wide association studies (GWAS), which attempt to characterise common genetic determinants of complex traits (30
). In five recent studies, single nucleotide polymorphisms (SNPs) at the ABO
gene locus were found to be genetic determinants of circulating levels of soluble E-selectin, soluble P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), and tumour necrosis factor-alpha (TNF-α) (31
). In each of these studies, the most statistically significant SNPs were proxies for defining the O vs. non-O allele.
E-selectin and P-selectin are transmembrane glycoproteins expressed on the surface of endothelial cells, which bind glycosylated ligands important for leukocyte and platelet adhesion to sites of vascular inflammation (36
). P-selectin is also expressed on the surface of activated platelets, where it helps mediate attachment to the vessel wall, other platelets and leukocytes (37
). Also important for leukocyte adhesion and migration, ICAM-1 is a member of the immunoglobulin gene superfamily that is expressed on the surface of endothelial cells and binds leukocyte integrins. Interestingly, expression of endothelial E-selectin and ICAM-1 are upregulated in response to inflammatory mediators, including TNF-α (38
). The extracellular domains of E-selectin, P-selectin and ICAM-1 are shed into the circulation (39
), where their levels have been linked to incident cardiovascular disease and diabetes mellitus (40
). Therefore, another possible mechanism linking ABO blood group antigens with the risk of VTE may involve the alteration of vascular inflammation and integrity, as mediated by levels of glycoproteins such as selectins and vascular adhesion molecules.
In the current study, we noted a greater increase in risk for VTE due to non-O blood type among smokers, with a hazard ratio of 2.6. Given its prospective design, our study avoids some of the difficulties associated with retrospective case-control studies, such as recall, selection, and survival biases, providing an ideal opportunity to evaluate effect modifiers of the relationship between ABO blood group and VTE risk. If this finding is validated in other studies, it points to a notable interaction between an inherited predisposition and an environmental exposure. Also of interest is the association of smoking with circulating inflammatory markers, such as ICAM-1, suggesting a possible overlapping pathophysiology of smoking with ABO blood group antigens on risk of VTE (42
Several genetic predispositions to VTE are known, including factor V Leiden (FVL) and a prothrombin gene polymorphism, with larger relative risks for VTE (5
). However, these abnormalities occur at much lower frequencies in the general population than the presence of non-O blood type and therefore are less influential at the population level (7
). This is of particular interest, since a recent GWAS of idiopathic VTE identified only polymorphisms at the factor V and ABO loci as associated with VTE at the level of genome-wide significance (43
). Although the sample size of this study was modest for a GWAS design, the study does indicate that other genetic factors are unlikely to be identified with as statistically strong an association with VTE risk as the ABO locus. Further work to incorporate blood type into clinical management algorithms for VTE may be warranted, with genotypically-defined blood group alleles likely to add further information beyond that provided by serology alone (44
A limitation of our study is the predominance of White participants, somewhat limiting the generalisability of our results. Although the distribution of blood type does vary between the world’s populations, data have not suggested that the underlying mechanism relating blood type to thrombosis is different by race/ethnicity. In addition, the distribution of blood type among our study participants was similar to that of the U.S. White population (9
We cannot rule out the presence of residual confounding. Nevertheless, age-adjusted hazard ratios for PE by blood type did not change substantially when other predisposing factors were included in multivariable models, and the risk of detecting a false association due to population stratification was low, given the prospective cohort design, primarily non-Hispanic European-American ancestry of the study population, and paucity of evidence for variation in PE risk in the ancestral population (47
). The use of self-reported ABO blood type likely introduced a modest degree of exposure misclassification. Nevertheless, two separate validation studies have demonstrated > 90% concordance between self-report and blood type determined serologically (9
) or genotypically (10
) in NHS and HPFS, indicating that misclassification is unlikely to have meaningfully altered our results. Furthermore, self-reported ABO blood type in NHS and HPFS similarly predicted risk of pancreatic cancer in comparison with genotypically defined ABO blood type in a consortium of 12 prospective cohort studies (9
). Moreover, any modest misclassification generated by the use of self-report was non-differential with respect to case status and highly unlikely to introduce bias, as blood type was reported by participants prior to pancreatic cancer diagnosis.
The prospective design of this study avoided recall or selection bias; further strengths included prospective covariate information ascertained at the time of initiation of follow-up; physician record review to establish PE diagnoses; high follow-up rates in both cohorts; and a large number of subjects with information on blood type.
In sum, prospective data from two large cohort studies with rigorous case definition and ascertainment of important covariates demonstrated a statistically significant association between ABO blood type and the risk of PE. Further investigation is needed to confirm a greater risk for non-O blood type among smokers compared with non-smokers.