Anticoagulation for cancer-associated venous thromboembolism (VTE) can be challenging due to complications—including bleeding and potential drug–drug interactions with chemotherapy—associated with ...vitamin K antagonists and inconvenience of low-molecular-weight heparin (LMWH). Direct oral anticoagulants (DOACs) could partially overcome these issues, but until recently there were no large clinical trials assessing their efficacy and safety in cancer patients. This review summarizes clinical treatment guidelines, prior clinical and real-world evidence for anticoagulant choice, recent clinical trials assessing DOACs for cancer-associated VTE (i.e. Hokusai-VTE Cancer, SELECT-D, CARAVAGGIO, and ADAM VTE), and special considerations for DOAC use. Based on established data, clinical guidelines recommend patients with cancer-associated VTE receive LMWH treatment of at least 3–6months. Nevertheless, LMWH is underused and associated with poor compliance and persistence in these patients relative to oral anticoagulants. Clinical data supporting DOAC use in cancer patients are becoming available. In Hokusai-VTE Cancer, edoxaban was noninferior to dalteparin for the composite of recurrent VTE and major bleeding (12.8% versus 13.5%), with numerically lower recurrent VTE (7.9% versus 11.3%) and significantly higher major bleeding (6.9% versus 4.0%); only patients with gastrointestinal cancer had significantly higher risk of bleeding with edoxaban. In SELECT-D, rivaroxaban had numerically lower VTE recurrence (4% versus 11%), comparable major bleeding (6% versus 4%), and numerically higher clinically relevant nonmajor bleeding (13% versus 4%) versus dalteparin. Most bleeding events were gastrointestinal or urologic; patients with esophageal/gastroesophageal cancer had higher rates of major bleeding with rivaroxaban (36% versus 11%). For comparison of apixaban versus dalteparin, CARAVAGGIO is ongoing, and preliminary results from ADAM VTE are favorable. This review concludes that DOACs appear to be reasonable alternatives to LMWH for treatment of cancer-associated VTE. In patients with gastrointestinal cancer, DOAC use should be considered on a case-by-case basis with consideration of the relative risks and benefits.
•Cancer-associated thrombosis is a major health problem that affects morbidity and mortality of people with cancer.•Surgical and systemic pharmacological anticancer treatments have a significant ...impact on the thrombotic risk of patients.•Primary thromboprophylaxis may be considered in high-risk ambulatory cancer patients using validated risk models.•Anticoagulant treatment of VTE in cancer patients is effective but may be associated with increased bleeding.•LMWH or DOACs are effective treatments and generally safe options for cancer-associated thrombosis.
Essentials
Neutrophil extracellular traps (NETs) might play a role in cancer‐related coagulopathy.
We determined NET biomarkers and followed cancer patients for venous thromboembolism (VTE).
We found ...a constant association with VTE for citrullinated histone H3.
Biomarkers of NET formation could reflect a novel pathomechanism of cancer‐related VTE.
Summary
Background
Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients.
Objectives
To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell‐free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients.
Patients/Methods
Nine‐hundred and forty‐six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3‐month, 6‐month, 12‐month and 24‐month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively.
Results
Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2‐year risk of 14.5%) than patients with levels below this cut‐off (2‐year risk of 8.5%, n = 710). In a competing‐risk regression analysis, a 100 ng mL−1 increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio SHR 1.13, 95% confidence interval CI 1.04–1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D‐dimer level, and soluble P‐selectin level (SHR 1.13, 95% CI 1.04–1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time‐dependent, with associations with a higher risk of VTE only during the first 3–6 months.
Conclusion
These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer‐associated thrombosis.
Background: Tissue factor (TF) expression by tumors contributes to tumor growth. Release of TF‐positive microparticles (MPs) may contribute to venous thromboembolism (VTE).
Objectives: To conduct a ...prospective cohort study to determine whether elevated MP‐associated TF (MP‐TF) activity is predictive of VTE and mortality in four cancer types.
Patients/Methods: We determined MP‐TF activity in pancreatic, gastric, colorectal and brain cancer patients. We used a chromogenic endpoint assay for all patients and also a chromogenic kinetic assay for patients with pancreatic and brain cancer.
Results: During follow‐up, 12/60 (20%) pancreatic, 6/43 (14%) gastric, 12/126 (10%) colorectal and 19/119 (16%) brain cancer patients developed VTE; 46/60 (77%), 30/43 (70%), 47/126 (37%) and 67/119 (56%), respectively, died. MP‐TF activity levels were highest in pancreatic cancer. We did not find a statistically significant association of MP‐TF activity with the risk of VTE in any of the four cancer types by using two statistical methods. An association of MP‐TF activity with the risk of mortality was detected in pancreatic cancer with the endpoint assay (hazard ratio HR 1.8 and 95% confidence interval CI 1.4–2.3 per doubling of activity, P < 0.001) and the kinetic assay (HR 1.2, 95% CI 1.1–1.4, P < 0.001); adjustment for type of treatment was not performed. In pancreatic cancer, MP‐TF activity correlated with D‐dimer level (endpoint assay, r = 0.51; chromogenic assay, r = 0.48), and a correlation between assays (r = 0.61) was found.
Conclusion: MP‐TF activity was not associated with future VTE in pancreatic, gastric, colorectal and brain cancer. However, we found a strong association of MP‐TF activity with mortality in pancreatic cancer. MP‐TF activity might be reflective of an aggressive pancreatic cancer phenotype.
Background: Prothrombin complex concentrate (PCC) can substantially shorten the time needed to reverse antivitamin K oral anticoagulant therapy (OAT). Objectives. To determine the effectiveness and ...safety of emergency OAT reversal by a balanced pasteurized nanofiltered PCC (Beriplex® P/N) containing coagulation factors II, VII, IX, and X, and anticoagulant proteins C and S. Patients and methods: Patients receiving OAT were eligible for this prospective multinational study if their International Normalized Ratio (INR) exceeded 2 and they required either an emergency surgical or urgent invasive diagnostic intervention or INR normalization due to acute bleeding. Stratified 25, 35, or 50 IU kg−1 PCC doses were infused based on initial INR. Study endpoints included INR normalization (≤1.3) by 30 min after PCC infusion and hemostatic efficacy. Results: Forty‐three patients, 26 requiring interventional procedures and 17 experiencing acute bleeding, received PCC infusions at a median rate of 7.5 mL min−1 (188 IU min−1). At 30 min thereafter, INR declined to ≤1.3 in 93% of patients. At all postinfusion time points through 48 h, median INR remained between 1.2 and 1.3. Clinical hemostatic efficacy was classified as very good or satisfactory in 42 patients (98%). Prompt and sustained increases in circulating coagulation factors and anticoagulant proteins were observed. One fatal suspected pulmonary embolism in a patient with metastatic cancer was judged to be possibly PCC‐related. Conclusions: PCC treatment serves as an effective rapid hemorrhage control resource in the emergency anticoagulant reversal setting. More widespread availability of PCC is warranted to ensure its benefits in appropriate patients.
Platelets are the smallest circulating blood cells and their major function is the maintenance of haemostasis. They do not have a nucleus, but instead a multitude of granules that contain molecules ...important for several physiological processes. These granules can be released after platelet activation and thereby platelets take part in haemostasis, wound repair or immunological processes. Furthermore, platelets are also involved in the pathophysiology of several diseases, including cancer. Platelets can support various steps of cancer development and progression by promoting tumour growth, angiogenesis and metastasis. Moreover, platelets contribute to the hypercoagulable state frequently observed in cancer patients, leading to an increased risk of venous thromboembolism (VTE). In previous studies a high platelet count was repeatedly found to be associated with an elevated risk of VTE and a worse prognosis in patients with cancer. The aim of this review is to give an overview of the most important alterations of platelet physiology in cancer patients and how these alterations may influence cancer disease and contribute to cancer-associated VTE.
Essentials
Risk stratification for venous thromboembolism (VTE) in patients with brain tumors is challenging.
Patients with IDH1 wildtype and high podoplanin expression have a 6‐month VTE risk of ...18.2%.
Patients with IDH1 mutation and no podoplanin expression have a 6‐month VTE risk of 0%.
IDH1 mutation and podoplanin overexpression in primary brain tumors appear to be exclusive.
Summary
Background
Venous thromboembolism (VTE) is a frequent complication in primary brain tumor patients. Independent studies revealed that podoplanin expression in brain tumors is associated with increased VTE risk, whereas the isocitrate dehydrogenase 1 (IDH1) mutation is associated with very low VTE risk.
Objectives
To investigate the interrelation between intratumoral podoplanin expression and IDH1 mutation, and their mutual impact on VTE development.
Patients/Methods
In a prospective cohort study, intratumoral IDH1 R132H mutation and podoplanin were determined in brain tumor specimens (mainly glioma) by immunohistochemistry. The primary endpoint of the study was symptomatic VTE during a 2‐year follow‐up.
Results
All brain tumors that expressed podoplanin to a medium‐high extent showed also an IDH1 wild‐type status. A score based on IDH1 status and podoplanin expression levels allowed prediction of the risk of VTE. Patients with wild‐type IDH1 brain tumors and high podoplanin expression had a significantly increased VTE risk compared with those with mutant IDH1 tumors and no podoplanin expression (6‐month risk 18.2% vs. 0%).
Conclusions
IDH1 mutation and podoplanin overexpression seem to be exclusive. Although brain tumor patients with IDH1 mutation are at very low risk of VTE, the risk of VTE in patients with IDH1 wild‐type tumors is strongly linked to podoplanin expression levels.
Summary
Background
Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low‐molecular‐weight heparin (LMWH) ...for at least 3–6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer‐associated VTE.
Methods
Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2–6 and 7–12.
Findings
Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient‐month during months 2–6 and 7–12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2–6, and 4.1% (8/194) during months 7–12. One hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding.
Conclusion
Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months.
Essentials
Hemostasis biomarkers impact thrombosis occurrence and survival in cancer patients.
We performed a longitudinal analysis of hemostatic parameters in 112 cancer patients.
Hemostatic ...parameters are associated with disease state, patients' prognosis, and the risk of VTE.
The procoagulant state exists not only at diagnosis, but also during the course of disease.
Summary
Background
Hemostasis biomarkers are known to have an impact on venous thromboembolism (VTE) occurrence and survival in cancer patients.
Objectives
As there are almost no data on longitudinal changes, we aimed to evaluate those in the present prospective observational study during chemotherapy and the course of disease.
Patients/Methods
Patients with cancer of the brain (n = 39), lung (n = 41), colon (n = 15) or pancreas (n = 17) were included before initiation of antitumor therapy. Blood samples for determination of factor VIII, thrombin peak height, D‐dimer, F1 + 2, fibrinogen and soluble P‐selectin (sP‐selectin) were drawn on a monthly basis. The study endpoints were death, VTE occurrence, or completion of the study period.
Results
Overall, 546 blood samples of 112 patients were analyzed. D‐dimer and sP‐selectin levels were significantly higher in patients with distant metastasis than in those without. Patients with complete remission had significantly lower levels of F1 + 2, D‐dimer and fibrinogen. Peak height thrombin levels showed a decrease over time in all tumor types. Levels of biomarkers behaved differently in the various tumor types. Patients who developed VTE (n = 14) showed increasing levels of FVIII, sP‐selectin, and D‐dimer. At the last blood sampling time‐point before VTE occurrence, in 13 patients the D‐dimer level was above the median, and in seven of these patients it was even above the 75th percentile; however, the individual course was highly variable. Regarding survival, steadily increased FVIII, sP‐selectin and D‐dimer levels were associated with higher mortality.
Conclusions
Hemostatic parameters show an association with disease state, prognosis, and the risk of VTE, not only at diagnosis, but also during the course of antineoplastic treatment.
Background: Diagnosis of the antiphospholipid syndrome (APS) is difficult as a result of limited specificity of existing assays for detecting clinically relevant antiphospholipid antibodies. ...Anti‐beta2‐glycoprotein I (beta2GPI) antibodies play a central role in the disease process of APS. Objectives: We have investigated the relation between antiphospholipid antibodies with specificity for domain I of beta2GPI and thrombosis/pregnancy morbidity in an international multicenter study. Patients/methods: Four hundred and seventy‐seven patients derived from nine different centres met the inclusion criterion of having anti‐beta2GPI antibodies in their plasma/serum. Clinical data and results of tests for lupus anticoagulant, anti‐cardiolipin antibodies and anti‐beta2GPI antibodies were established at the different centres of inclusion. After being re‐tested for the presence of IgG and/or IgM anti‐beta2GPI antibodies, the samples were tested for the presence of IgG‐directed against domain I of beta2GPI and results were correlated with the thrombotic and obstetric history. Results: Re‐testing for the presence of anti‐beta2GPI antibodies resulted in inclusion of 442/477 patients. IgG class anti‐domain I antibodies were present in plasma of 243/442 patients (55%). 201/243 (83%) had a history of thrombosis. This resulted in an odds ratio of 3.5 (2.3–5.4, 95% confidence interval) for thrombosis. Anti‐domain I IgG antibodies were also significantly correlated with obstetric complications odds ratio: 2.4 (1.4–4.3, 95% confidence interval). Conclusion: In this multicenter study, the detection of IgG antibodies that are directed against domain I of beta2GPI proved to be more strongly associated with thrombosis and obstetric complications than those detected using the standard anti‐beta2GPI antibody assay.
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