Background There are no data on the effect of low-dose anticoagulation as secondary prophylaxis for venous thromboembolism (VTE) in cancer patients. We assessed the efficacy and safety of low-dose apixaban for 30 months, after initial six months of full-dose treatment. Methods We included 298 patients with cancer and any type of VTE in a single arm interventional clinical trial. All patients were treated with full-dose apixaban (5 mg twice daily) for 6 months. Total 196 patients with active cancer after six months treatment continued with apixaban 2.5 mg twice daily for another 30 months. The main endpoints were recurrent VTE, major bleeding and clinically relevant non-major bleeding. Results During the 30 months of treatment with low-dose apixaban 14 (7.6%; 95% confidence interval (CI) 4.0-11.7%) patients experienced recurrent VTE, six (3.1%; 95% CI 1.1-6.5%) experienced major bleeding and 16 (8.1%, 95% CI: 4.7-12.8%) experienced clinically relevant non-major bleeding. The incidence rate per person month of recurrent VTE was 0.8% (95% CI 0.41-1.6) at 2-6 months with full-dose apixaban, and 1.0% (95% CI 0.5-1.9) at 7-12 months with low-dose apixaban. The incidence rate of major bleeding was 1.1% (95% CI 0.6-2.0) at 2-6 months, and 0.3% (95% CI 0.1-1.0) at 7-12 months. Between 12 and 36 months the incidence rate of recurrent VTE and major bleedings remained low. Conclusion Dose reduction of apixaban to 2.5 mg twice daily seems safe after six months of full-dose treatment. After 12 months the incidence rate of recurrent VTE and major bleeding remained low.

The procoagulant state in cancer increases the thrombotic risk, but also supports tumor progression. To investigate the molecular mechanisms controlling cancer and hemostasis, we conducted a case-control study of genotypic and phenotypic variables of the tissue factor (TF) pathway of coagulation in breast cancer. 366 breast cancer patients and 307 controls were genotyped for SNPs (n = 41) in the F2, F3 (TF), F5, F7, F10, TFPI and EPCR genes, and assayed for plasma coagulation markers (thrombin generation, activated protein C (APC) resistance, D-dimer, antithrombin, protein C, protein S, and TF pathway inhibitor (TFPI)). Associations with breast cancer were evaluated using logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs), or the chi-square test. Four SNPs in F5 (rs12120605, rs6427202, rs9332542 and rs6427199), one in F10 (rs3093261), and one in EPCR (rs2069948) were associated with breast cancer. EPCR rs2069948 was associated with estrogen receptor (ER) and progesterone receptor (PR) positivity, while the SNPs in F5 appeared to follow hormone receptor negative and triple negative patients. The prothrombotic polymorphisms factor V Leiden (rs6025) and prothrombin G20210A (rs1799963) were not associated with breast cancer. High APC resistance was associated with breast cancer in both factor V Leiden non-carriers (OR 6.5, 95% CI 4.1-10.4) and carriers (OR 38.3, 95% CI 6.2-236.6). The thrombin parameters short lag times (OR 5.8, 95% CI 3.7-9.2), short times to peak thrombin (OR 7.1, 95% CI 4.4-11.3), and high thrombin peak (OR 6.1, 95% CI 3.9-9.5) predicted presence of breast cancer, and high D-dimer also associated with breast cancer (OR 2.0, 95% CI 1.3-3.3). Among the coagulation inhibitors, low levels of antithrombin associated with breast cancer (OR 5.7, 95% CI 3.6-9.0). The increased coagulability was not explained by the breast cancer associated SNPs, and was unaffected by ER, PR and triple negative status. A procoagulant phenotype was found in the breast cancer patients. Novel associations with SNPs in F5, F10 and EPCR to breast cancer susceptibility were demonstrated, and the SNPs in F5 were confined to hormone receptor negative and triple negative patients. The study supports the importance of developing new therapeutic strategies targeting coagulation processes in cancer.

Persistent dyspnoea, functional limitations and reduced quality of life (QoL) are common after pulmonary embolism (PE). Rehabilitation is a potential treatment option, but the scientific evidence is limited. Does an exercise-based rehabilitation programme improve exercise capacity in PE survivors with persistent dyspnoea? We conducted a randomized controlled trial at two hospitals. Patients with persistent dyspnoea after PE diagnosed 6-72 months earlier, without cardiopulmonary comorbidities, were randomized 1:1 to either rehabilitation or control group. The rehabilitation programme consisted of two weekly sessions of physical exercise for 8 weeks, and one educational session. The control group received usual care. The primary endpoint was the difference in Incremental Shuttle Walk Test (ISWT) between groups at follow-up. Secondary endpoints included differences in Endurance Shuttle Walk Test (ESWT), QoL (EQ-5D and Pulmonary Embolism-QoL questionnaires) and dyspnoea (Shortness of Breath questionnaire) RESULTS: In total 211 subjects were included: 108 (51%) were randomized to the rehabilitation group and 103 (49%) to the control group. At follow-up, participants allocated to the rehabilitation group performed better on the ISWT compared with the control group (mean difference 53.0 meters, 95% CI:17.7-88.3, P=0.0035). The rehabilitation group reported better score on the Pulmonary Embolism-QoL questionnaire (mean difference -4%, 95% CI:-9%-0%, P=0.041) at follow-up, but there were no differences in generic QoL, dyspnoea scores, or the ESWT. No adverse events occurred during the intervention. In patients with persistent dyspnoea following PE, those who underwent rehabilitation had better exercise capacity at follow-up than those who received usual care. Rehabilitation should be considered in patients with persistent dyspnoea following PE, though further research is needed to assess the optimal patient selection, timing, mode and duration of rehabilitation. ClinicalTrials.gov NCT03405480.

Summary. Tissue factor (TF) pathway inhibitor I (TFPI) is the physiological inhibitor of TF‐induced blood coagulation. Circulating blood contains full‐length TFPI and TFPI truncated at the C‐terminal end. Previous studies have shown that full‐length TFPI exerts a stronger anticoagulant effect on diluted prothrombin time (DPT) than truncated TFPI, and it has been suggested that full‐length TFPI is biologically more important in vivo. The objective of this study was to develop and validate an assay of TFPI anticoagulant activity. TFPI anticoagulant activity was assayed using a modified DPT assay. Plasmas were incubated in the absence and the presence of TFPI‐blocking antibodies. Results were expressed as a ratio with the clotting time in the presence of anti‐TFPI as the denominator. The ratio was normalized against a ratio obtained with a reference plasma. The assay was compared with assays of TFPI free antigen, total antigen, and bound TFPI, and TFPI chromogenic substrate activity. We performed all tests in 436 healthy individuals. The normalized TFPI anticoagulant ratio was strongly associated with TFPI free antigen (r = 0.73) but was weakly associated with TFPI chromogenic substrate activity (r = 0.46), TFPI total antigen (r = 0.48), and bound TFPI (r = 0.30). TFPI chromogenic substrate activity was strongly associated with TFPI total antigen (r = 0.73). We have developed a novel assay of TFPI anticoagulant activity in plasma, which may be considered a functional assay of full‐length TFPI. Further studies are needed to establish the role of TFPI anticoagulant activity for thrombotic disorders.

Hormone therapy, oral contraceptives, and tamoxifen increase the risk of thrombotic disease. These compounds also reduce plasma content of tissue factor pathway inhibitor-1 (TFPI), which is the physiological inhibitor of the tissue factor pathway of coagulation. The current aim was to study if estrogens and estrogen receptor (ER) modulators may inhibit TFPI production in cultured endothelial cells and, if so, identify possible mechanisms involved. Human endothelial cell cultures were treated with 17β-estradiol (E2), 17α-ethinylestradiol (EE2), tamoxifen, raloxifene, or fulvestrant. Protein levels of TFPI in cell media and cell lysates were measured by an enzyme-linked immunosorbent assay, and TFPI mRNA levels were assessed by quantitative PCR. Expression of ERα was analysed by immunostaining. All compounds (each in a concentration of 10 nM) reduced TFPI in cell medium, by 34% (E2), 21% (EE2), 16% (tamoxifen), and 28% (raloxifene), respectively, with identical inhibitory effects on cellular TFPI levels. Expression of TFPI mRNA was principally unchanged. Treatment with fulvestrant, which was also associated with down-regulation of secreted TFPI (9% with 10 nM and 26% with 1000 nM), abolished the TFPI-inhibiting effect of raloxifene, but not of the other compounds. Notably, the combination of 1000 nM fulvestrant and 10 nM raloxifene increased TFPI secretion, and, conversely, 10 nM of either tamoxifen or raloxifene seemed to partly (tamoxifen) or fully (raloxifene) counteract the inhibitory effect of 1000 nM fulvestrant. The cells did not express the regular nuclear 66 kDa ERα, but instead a 45 kDa ERα, which was not regulated by estrogens or ER modulators. E2, EE2, tamoxifen, raloxifene, and fulvestrant inhibited endothelial production of TFPI by a mechanism apparently independent of TFPI transcription.