Hormonal Contraceptives and the Risk of Venous Thrombosis.

The risk of venous thrombosis (VT) varies according to the type of progestogen that is found in combined oral contraceptives (COCs). When combined with the estrogen component ethinylestradiol (EE), the androgenic progestogens are better able to counteract the EE-induced stimulation of liver proteins and hence are associated with a twofold decreased risk of VT compared with non- or antiandrogenic progestogens, which exert limited counteraction of EE. Because EE is responsible for the increased risk, novel estrogens such as estradiol were developed and seem to have a lower risk of VT than EE. Besides COCs, there are other methods of hormonal contraceptives, such as progestogen-only contraceptives, which do not increase VT risk, except for injectables. Other nonoral contraceptives are combined vaginal rings and patches. There is insufficient evidence regarding the risk of VT associated with these two methods compared with COCs. The increased risk associated with COCs is more pronounced in women with inherited thrombophilia. In these women, the progestogen levonorgestrel seems to be associated with the lowest risk of VT. Currently, there are no studies that have investigated the risk of VT in women who switch COCs. We hypothesize that switching COCs, even when switching from a high- to a low-risk COC, increases the risk of VT. Finally, risk prediction models in women who use COCs are lacking. Since there is a large number of VT cases associated with COC use, it is important to identify women at risk of VT and advise them on alternative contraception methods.

Role of Routine Laboratory Tests in Assessing Risk of Recurrent Venous Thrombosis: Results from the MEGA Follow-Up Study.

BACKGROUND: Kidney function, measured as estimated glomerular filtration rate (eGFR), glucose levels and haematologic variables (blood cell count) are easily obtainable tests, and have been associated with increased risk of first venous thrombosis (VT). Whether these routine tests can identify patients at risk of recurrence is unclear. AIM: Our aim was to investigate the predictive value of serum glucose levels, eGFR and haematologic variables in patients at risk of recurrent VT. METHODS: Patients with a first VT were followed from discontinuation of anticoagulant treatment. Percentile categories of eGFR, glucose levels and haematologic variables were established. Crude incidence rates with 95% confidence intervals (CIs) of recurrence were estimated in each percentile category. Cox regression models were used to compare groups, adjusted for age and sex. RESULTS: Of 2,106 patients followed for a median of 6.9 years, 326 developed recurrence (incidence rate, 2.7/100 patient-years; 95% CI, 2.5-3.1). The adjusted hazard ratio for recurrence was 1.5 (95% CI, 0.9-2.4) in the lowest eGFR percentile category (< 59 mL/min/1.73 m2) versus the reference (≥86 mL/min/1.73 m2). Stratification by unprovoked or provoked first events yielded similar results. The combination of a first unprovoked VT with renal dysfunction was associated with a threefold increased risk of recurrence compared with those with first provoked VT and normal kidney function (hazard ratio, 3.1, 95% CI, 1.6-5.9). Glucose levels and haematologic variables were not associated with increased recurrence risk. CONCLUSION: Testing glucose levels and haematologic variables did not identify patients at increased risk of recurrent VT. Renal dysfunction tests may have some predictive value, particularly in combination with other variables.

Whole exome sequencing in thrombophilic pedigrees to identify genetic risk factors for venous thromboembolism.

BACKGROUND: Family studies have shown a strong heritability component for venous thromboembolism (VTE), but established genetic risk factors are present in only half of VTE patients. AIM: To identify genetic risk factors in two large families with unexplained hereditary VTE. METHODS: We performed whole exome sequencing in 10 affected relatives of two unrelated families with an unexplained tendency for VTE. We prioritized variants shared by all affected relatives from both families, and evaluated these in the remaining affected and unaffected individuals. We prioritized variants based on 3 different filter strategies: variants within candidate genes, rare variants across the exome, and SNPs present in patients with familial VTE and with low frequency in the general population. We used whole exome sequencing data available from 96 unrelated VTE cases with a positive family history of VTE from an affected sib study (the GIFT study) to identify additional carriers and compared the risk-allele frequencies with the general population. Variants found in only one individual were also retained for further analysis. Finally, we assessed the association of these variants with VTE in a population-based case-control study (the MEGA study) with 4,291 cases and 4,866 controls. RESULTS: Six variants remained as putative disease-risk candidates. These variants are located in 6 genes spread among 3 different loci: 2p21 (PLEKHH2 NM_172069:c.3105T>C, LRPPRC rs372371276, SRBD1 rs34959371), 5q35.2 (UNC5A NM_133369.2:c.1869+23C>A), and 17q25.1 (GPRC5C rs142232982, RAB37 rs556450784). In GIFT, additional carriers were identified only for the variants located in the 2p21 locus. In MEGA, additional carriers for several of these variants were identified in both cases and controls, without a difference in prevalence; no carrier of the UNC5A variant was present. CONCLUSION: Despite sequencing of several individuals from two thrombophilic families resulting in 6 candidate variants, we were unable to confirm their relevance as novel thrombophilic defects.