Risk Factors for Bleeding in Cancer Patients Treated with Conventional Dose Followed by Low-Dose Apixaban for Venous Thromboembolism.

BACKGROUND: Incidence of and risk factors for bleeding in cancer patients with venous thromboembolism (VTE) treated with apixaban are poorly described. METHODS: We analyzed data from the prospective CAP study where 298 cancer patients with any type of VTE received 5 mg apixaban twice daily for 6 months, and then 2.5 mg apixaban twice daily for 30 months. For most analyses, major bleedings and clinically relevant nonmajor bleedings were merged to "clinically relevant bleedings." Risk factors were estimated by odds ratios (OR) and 95% confidence intervals (CIs). RESULTS: The incidence of clinically relevant bleedings was 38% per person-year during the first 6 months of treatment, 21% per person-year from 7 to 12 months, and between 4 and 8% per person-year from 13 to 36 months. Clinically relevant bleedings were associated with age above 74 years (OR: 2.0, 95% CI: 1.0-4.1), body mass index (BMI) below 21.7 (OR: 2.3, 95% CI: 1.1-4.8), and hemoglobin at baseline below 10.5 for females (OR: 2.8, 95% CI: 1.1-7.3) and 11.1 for males (OR: 3.3, 95% CI: 1.3-8.4) during the first 6 months. Gastrointestinal (GI) or urogenital cancer was not associated with clinically relevant bleedings compared with other cancers. Among patients with luminal GI cancer, nonresected cancer had increased risk of bleeding (OR: 3.4, 95% CI: 1.0-11.6) compared with resected GI cancer. CONCLUSION: There were very few bleedings while patients were on low-dose apixaban. Factors associated with bleeding in patients treated with full-dose apixaban were high age, low BMI, and low hemoglobin, and probably nonresected luminal GI cancer.

Behandling av eldre med akutt myelogen leukemi uten allogen stamcelletransplantasjon ved Akershus universitetssykehus.

BACKGROUND: It is uncertain what the best treatment is for older patients with acute myeloid leukaemia who are not candidates for allogeneic stem cell transplantation. The purpose of the study was to examine the treatment practices for this patient group at Akershus University Hospital, as well as survival according to treatment choices and the genetic risk of a tumour. MATERIAL AND METHOD: The study is based on a review of the medical records of patients aged 65 and older with recently diagnosed acute myeloid leukaemia treated without allogeneic stem cell transplantation at Akershus University Hospital from 1 January 2006 to 1 January 2021. RESULTS: We included 151 out of 156 identified patients. The median age was 76 years, 42 patients (28 %) received intensive chemotherapy, 38 (25 %) received low-intensity chemotherapy and 71 (47 %) received supportive care only. Supportive care was mainly given in the early part of the period. From 2014 onwards, low-intensity chemotherapy made up a significant part of the treatment. Tumour genetic analyses were available for 88 patients, of which 17, 47 and 24 had a favourable, intermediate and unfavourable genetic risk of a tumour respectively. None of the patients with an unfavourable genetic risk of a tumour survived for 2 years. There were no statistically significant differences in survival between low-intensity and intensive chemotherapy. In the group with a favourable genetic risk of a tumour, the median survival was 573 days with intensive chemotherapy (n=12) and 101 days with low-intensity chemotherapy (n=4) (p=0.09). Patients treated with intensive chemotherapy were in hospital the longest. INTERPRETATION: The results suggest that knowledge of the genetic risk of a tumour is useful when choosing treatment for older patients with acute myeloid leukaemia.

Arterial events in cancer patients treated with apixaban for venous thrombosis.

INTRODUCTION: In a recent interventional study of cancer patients with newly diagnosed venous thrombosis (VT), we found a high risk of arterial thrombotic events (AT) during treatment with therapeutic doses of apixaban. METHODS: Total 298 cancer patients with VT received apixaban as treatment and secondary prophylaxis for up to 36 months. AT was registered as a serious adverse event, and this is a post hoc analysis of risk factors for AT. Clinical risk factors and concomitant medication were assessed through odds ratios (OR) with 95 % confidence interval using multivariate logistic regression. Biomarkers were assessed by non-parametric testing. RESULTS: AT occurred in 16/298 patients (5.4 %, 95 % confidence interval (CI) 3.1-8.6 %). Median leucocyte count at baseline was higher in patients with AT compared with patients without AT (11 vs. 6.8·109/L, p < 0.01). Clinical factors associated with AT were pancreatic cancer (OR 13.7, 95 % CI 4.3-43.1), ovarian cancer (OR 19.3, 95 % CI 2.3-164.4), BMI <25 percentile (OR 3.1, 95 % CI 1.1-8.8) and previous VT (OR 4.4, 95 % CI 1.4-13.7). Pancreatic cancer had a cumulative incidence of AT of 36 % compared with 0.8 % for all other cancers at 6 months (p < 0.01). Non-steroidal anti-inflammatory drugs (OR 4.9, 95 % CI 1.0-26) and antiplatelet treatment (OR 3.8, 95 % CI 1.2-12.2) were associated with AT. CONCLUSION: In cancer patients with apixaban treated VT, pancreatic cancer was strongly associated with AT. In addition, ovarian cancer, BMI < 25 percentile, previous VT, antiplatelet treatment, non-steroidal anti-inflammatory drug use and high leucocyte count at baseline were associated with AT. The CAP study is registered with the unique identifier NCT02581176 in ClinicalTrials.gov.

The Effects of Exercise Training in Patients With Persistent Dyspnea Following Pulmonary Embolism: A Randomized Controlled Trial.

BACKGROUND: Persistent dyspnea, functional limitations, and reduced quality of life (QoL) are common following pulmonary embolism (PE). Rehabilitation is a potential treatment option, but the scientific evidence is limited. RESEARCH QUESTION: Does an exercise-based rehabilitation program improve exercise capacity in PE survivors with persistent dyspnea? STUDY DESIGN AND METHODS: This randomized controlled trial was conducted at two hospitals. Patients with persistent dyspnea following PE diagnosed 6 to 72 months earlier, without cardiopulmonary comorbidities, were randomized 1:1 to either the rehabilitation or the control group. The rehabilitation program consisted of two weekly sessions of physical exercise for 8 weeks and one educational session. The control group received usual care. The primary end point was the difference in Incremental Shuttle Walk Test between groups at follow-up. Secondary end points included differences in the Endurance Shuttle Walk Test (ESWT), QoL (EQ-5D and Pulmonary Embolism-QoL questionnaires) and dyspnea (Shortness of Breath questionnaire). RESULTS: A total of 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 m; 95% CI, 17.7-88.3; P = .0035). The rehabilitation group reported better scores on the Pulmonary Embolism-QoL questionnaire (mean difference, -4%; 95% CI, -0.09 to 0.00; P = .041) at follow-up, but there were no differences in generic QoL, dyspnea scores, or the ESWT. No adverse events occurred during the intervention. INTERPRETATION: In patients with persistent dyspnea 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 dyspnea following PE. Further research is needed, however, to assess the optimal patient selection, timing, mode, and duration of rehabilitation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03405480; URL: www. CLINICALTRIALS: gov.

[Factor Xa inhibitors in the prevention and treatment of venous thromboembolism in cancer patients]. / Faktor Xa-hemmere til forebygging og behandling av venøs tromboembolisme ved kreft.

Venous thromboembolism is a common complication of cancer. The prevalence varies according to cancer type and increases proportionally with the stage of cancer. In the past 15-20 years, low molecular weight heparin has been recommended as the first-line treatment. New international guidelines now allow for use of direct factor Xa inhibitors both as prophylaxis and treatment for venous thromboembolism. Prophylaxis should as a general rule only be initiated in patients with moderate to high risk. Bleeding risk assessment is important before starting anticoagulation. Both thrombosis and bleeding risk can change and should therefore be assessed on an ongoing basis. In this clinical review, use of anticoagulation therapy in cancer patients is discussed with particular emphasis on the use of direct factor Xa inhibitors.

Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients - 30 months follow-up.

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 6 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 6 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 6 months of full-dose treatment. After 12 months the incidence rate of recurrent VTE and major bleeding remained low.

Cancer and Thrombosis: New Treatments, New Challenges.

The direct-acting oral anticoagulant (DOAC) has become an alternative to low-molecular-weight heparin (LMWH) for treatment and prophylaxis of venous thromboembolism (VTE) in cancer patients. The clinicians are, however, faced with difficult decisions regarding DOAC treatment: Which patients cannot use DOACs? Should incidental VTE be treated similar to symptomatic VTE? Is it safe to give DOACs to patients with gastrointestinal or urogenital cancers? How about drug-drug interactions? Should all cancer patients receive thromboprophylaxis? Is arterial thrombosis a problem? The current article reviews the available literature regarding these questions and aims to provide practical solutions based on data from the clinical trials and new guidelines.

Bias in animal studies of estrogen effects on cardiovascular disease: A systematic review and meta-analysis.

BACKGROUND: Randomized controlled trials on menopausal hormone therapy in humans have not confirmed the benefit of estrogens on cardiovascular disease found in animal studies. Flawed methodology or publication bias in animal studies may explain the dicrepancy. OBJECTIVES: The aim of this study was to investigate whether publication of the randomized controlled trials Heart and Estrogen/Progestin Replacement Study and Women's Health Initiative influenced study authors' assessment of research findings (confirmation bias) as well as to investigate publication bias and small-study effects in animal studies of estrogen effects on atherosclerosis. METHODS: The data source for this study was PubMed from inception to 2018. We selected animal studies with cardiovascular outcomes comparing 17-ß-estradiol, its natural metabolites, or conjugated equine estrogen with control. Qualitative data were extracted on authors' conclusions about estrogen effects on cardiovascular disease, as well as quantitative data for atherosclerosis outcomes. Fixed- and random-effects meta-analyses were used. Publication bias/small-study effects were assessed using funnel plots and Egger's regression. Trim-and-fill plots and extrapolation from Egger's regression were used to adjust for publication bias. The main outcomes and measures were the primary study authors' interpretation of their own results, and estrogen effects on cardiovascular disease in general before and after publication of the Women's health Initiative study (2003). The effects of estrogens on atherosclerosis were measured as standardized mean difference between intervention and control. RESULTS: Of 1925 studies retrieved, 360 were eligible for analyses. Study-specific statements concluded that estrogens were protective against cardiovascular disease in 75% of studies before 2003 and 78% after, but the percentage of general statements about estrogens being cardioprotective changed from 70% to 40%. Meta-analyses showed less atherosclerosis in estrogen-treated animals. Extremely skewed funnel plots and P < .01 in Egger's regression suggested publication bias and/or exaggerated effects in small studies, which was more pronounced after 2002. There was substantial heterogeneity of effects (I 2 = 68%-86%) overall and in all subgroups except cynomolgus monkeys (I 2 = 9%), the only animal subgroup without clear bias. Adjusting for publication bias, overall estimates of estrogen effects on atherosclerosis were close to null effect. CONCLUSIONS: We found substantial evidence of publication bias but not of confirmation bias. Publication bias and flawed small studies may partly explain why findings differ between animal studies and clinical trials on the effect of estrogens on cardiovascular disease.

Tissue factor pathway inhibitor upregulates CXCR7 expression and enhances CXCL12-mediated migration in chronic lymphocytic leukemia.

The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and ß-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated ß-catenin and the Wnt/ß-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients.

Venous thrombosis with oral postmenopausal hormone therapy: Roles of activated protein C resistance and tissue factor pathway inhibitor.

BACKGROUND: Oral postmenopausal hormone therapy (HT) increases the risk of venous thrombosis (VT). We postulated that activated protein C (APC) resistance induced by HT is one of the mechanisms causing VT, and also assessed the role of one of the main determinants of APC resistance (i.e., tissue factor pathway inhibitor [TFPI]). METHODS: We performed a nested case-control study embedded within two Women's Health Initiative hormone trials. Women were randomized to hormone therapy or placebo. Biomarkers were measured at baseline and after 1 year in 217 cases and 817 controls. RESULTS: Increased APC resistance and decreased TFPI at baseline were associated with VT (odds ratio 1.20-2.06). However, women with such prothrombotic profile at baseline did not have further increased risk of VT when randomized to HT compared with placebo. Although there was no change in APC resistance or TFPI in placebo group after 1 year, HT group showed prothrombotic changes in the biomarkers (i.e., an increase in APC resistance) (mean [standard deviation] 0.39 [0.54]) and decrease in TFPI (-0.21 [0.50]: free TFPI, -0.24 [0.22]: TFPI activity -0.22 [0.20]: total TFPI). However, HT induced prothrombotic change in biomarkers did not increase risk of VT. CONCLUSION: Women with prothrombotic levels of APC resistance and TFPI at baseline were not at increased risk of VT when randomized to HT compared with placebo. This suggests that testing for these biomarkers before starting HT is not required. HT led to prothrombotic change in these biomarkers after one year, but this did not relate to increased risk of VT.

Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism.

INTRODUCTION: The direct oral anti-coagulants (DOAC) edoxaban and rivaroxaban are suggested treatment alternatives for cancer-associated venous thromboembolism (VTE) together with low molecular-weight heparins. New studies indicate that the DOAC apixaban also is an option for cancer-associated VTE. The current study assessed recurrent VTE, arterial thrombosis, bleedings and adverse events in a cohort of apixaban treated cancer patients with VTE. MATERIALS AND METHODS: Single-arm, interventional study of apixaban as treatment of cancer-associated VTE. Inclusion criteria were cancer with objectively verified VTE. Patients received apixaban 10 mg bid for seven days, then 5 mg bid for six months. Primary efficacy and safety outcomes were recurrent VTE and bleeding respectively. This trial is registered with ClinicalTrials.gov identifier NCT02581176. RESULTS: We recruited 298 cancer patients with VTE. During six months treatment, recurrent VTE or death related to VTE occurred in 12 patients (4.0%, 95% confidence interval (CI) 2.1-6.9%). Major bleeding occurred in 16 patients (5.4%, 95% CI 2.8-7.9), most frequently gastrointestinal bleeding. There were no overrepresentation of major bleedings among patients with gastrointestinal cancer (7/126, 5.5%, 95% CI 2.3-11%). Twenty-six patients experienced one or more clinically relevant non-major bleedings (8.9%, 95% CI 5.5-12%). Twelve patients had arterial thrombosis (4.0%, 95% CI 2.1-6.9%), of which the majority were strokes in patients with pancreatic cancer. Death occurred in 35 patients (12%, 95% CI 8.3-16%). CONCLUSION: The frequency of recurrent VTE and major bleedings are in line with other studies on apixaban in cancer-associated VTE. Arterial thrombosis was a frequent serious adverse event.

Neutropenia caused by hairy cell leukemia in a patient with myelofibrosis secondary to polycythemia vera: a case report.

BACKGROUND: Polycythemia vera is a myeloproliferative disease that sometimes evolves to myelofibrosis, causing splenomegaly and neutropenia. In this case report, we describe a patient with polycythemia vera and unexplained neutropenia who later turned out to also have hairy cell leukemia. CASE PRESENTATION: A middle-aged Caucasian man with polycythemia vera presented to our hospital with chronic mouth ulcers. Later he developed leukopenia and pancytopenia. Bone marrow biopsies showed fibrosis. Further morphological analyses of bone marrow and blood smears revealed probable transformation into acute myeloid leukemia. However, there were also cells indicating hairy cell leukemia. Morphological and immunohistochemical analyses later confirmed the presence of hairy cell leukemia in biopsies that had been present for 3 years. Treatment with cladribine temporarily reversed the patient's neutropenia. CONCLUSIONS: Hairy cell leukemia may mimic development to myelofibrosis in patients with polycythemia vera.

A novel hypoxia response element regulates oxygen-related repression of tissue factor pathway inhibitor in the breast cancer cell line MCF-7.

BACKGROUND: Hypoxia is one of the most pervasive physiological stresses in solid tumors. We have previously demonstrated that tissue factor (TF) pathway inhibitor (TFPI) expression was transcriptionally repressed by the activation of hypoxia inducible factor (HIF)-1α under hypoxic conditions. However, the role of HIF-2α, also known as endothelial PAS domain-containing protein 1 (EPAS1), on TFPI expression remains unclear. AIM: To explore the role of HIF-2α/EPAS1 in the regulation of TFPI expression under hypoxia in breast cancer cells. METHODS AND RESULTS: Quantitative RT-PCR showed that total TFPI mRNA and protein levels were decreased by the overexpression of HIF-2α/EPAS1 in MCF7 cells. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay indicated a HIF-2α/EPAS1 responsive region located in the TFPI promoter region at -170 to +21 relative to the transcriptional start site. Subsequent mutagenesis demonstrated a functional hypoxia response element (HRE) 5'-AAACAGGA-3' for HIF-2α/EPAS1 within the TFPI promoter located at -45 to -38. In breast cancer patients, a positive correlation between HIF-2α/EPAS1 and total TFPI mRNA expression was observed by using gene expression analysis. CONCLUSIONS: This study provides evidence that HIF-2α/EPAS1 is involved in the regulation of TFPI gene expression in breast cancer cells, suggesting that the activation of coagulation and the increased risk of thrombosis observed in breast cancer patients may correlate with local hypoxic regulation of coagulation factors and their inhibitors.

Increased coagulation activity and genetic polymorphisms in the F5, F10 and EPCR genes are associated with breast cancer: a case-control study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.