Asunto(s)
Adenina/análogos & derivados , Glomeruloesclerosis Focal y Segmentaria , Péptidos y Proteínas de Señalización Intracelular , Leucemia Linfocítica Crónica de Células B , Proteínas de la Membrana , Síndrome Nefrótico , Piperidinas , Humanos , Glomeruloesclerosis Focal y Segmentaria/inducido químicamente , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Glomeruloesclerosis Focal y Segmentaria/genética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Síndrome Nefrótico/genéticaRESUMEN
BACKGROUND: Cancer-associated thrombosis is a frequent complication in patients with malignancies. While factor XI (FXI)/FXIa inhibition is efficacious in preventing postoperative venous thromboembolism, its role in tumor cell-induced coagulation is less defined. OBJECTIVES: We thus aimed to provide mechanistic insights into FXI/FXIa inhibition in tumor cell-induced coagulation activation. METHODS: Procoagulant activity (PCA) of 4 different tissue factor (TF) expressing tumor cell lines was analyzed by single-stage clotting and thrombin generation assay in the presence of a FXIa inhibitor, BMS-262084 (BMS), an inhibitory FXI antibody (anti-FXI), or peak and trough concentrations of rivaroxaban or tinzaparin. Further, tumor cell-induced platelet aggregation was recorded. Recombinant human TF served as positive control. RESULTS: Although BMS and anti-FXI potently inhibited FXIa amidolytic activity, both inhibitors efficiently mitigated recombinant human TF- and tumor cell-induced fibrin clot formation and platelet aggregation only in the presence of low TF PCA. The anticoagulant effects showed an inverse correlation with the magnitude of cellular TF PCA expression. Similarly, BMS markedly interfered with tumor cell-induced thrombin generation, with the most prominent effects on peak and total thrombin. In addition, anticoagulant effects of FXIa inhibition by 10 µM BMS were in a similar range to those obtained by 600 nM rivaroxaban and 1.6 µM tinzaparin at low TF PCA levels. However, rivaroxaban and tinzaparin also exerted marked anticoagulant activity at high TF PCA levels. CONCLUSION: Our findings indicate that FXI/FXIa inhibition interferes with tumor cell-induced coagulation activation only at low TF PCA expression levels, a finding with potential implications for future in vivo studies.
Asunto(s)
Factor XI , Neoplasias , Humanos , Factor XI/metabolismo , Rivaroxabán , Tinzaparina , Trombina/metabolismo , Tromboplastina/metabolismo , Anticoagulantes/farmacología , Neoplasias/tratamiento farmacológico , Factor XIa/metabolismoRESUMEN
This review article describes insights into the prevention and treatment of cancer-associated venous thromboembolism (VTE) with direct factor Xa inhibitors (FXaI) and refers in particular to the CALLISTO study program with rivaroxaban. CALLISTO includes randomized clinical trials on different topics as well as real-world evidence.Prevention and treatment of cancer-associated VTE have so far relied on low molecular weight heparins (LMWH). Meanwhile, randomized controlled trials have found comparable to superior efficacy of FXaI vs. LMWH, and the findings are now being incorporated into recommendations and guidelines. A possibly increased risk of bleeding, especially in patients with unresected gastrointestinal or urogenital tumors, should be considered. This was first observed during therapy with FXaI but can also affect LMWH. The selection of suitable patients and the optimization of treatment pathways are therefore of great importance.
Asunto(s)
Neoplasias , Tromboembolia Venosa , Humanos , Rivaroxabán/efectos adversos , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & control , Heparina de Bajo-Peso-Molecular/efectos adversos , Anticoagulantes/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológicoRESUMEN
Diagnosis and treatment of paraneoplastic coagulation disorders are a challenge in daily practice. While prophylactic anticoagulation to prevent venous thromboembolism (VTE) is standard of care in all surgical and acutely ill medical cancer patients, particularly careful evaluation of risks and benefits using validated risk assessment models is required during outpatient chemotherapy. Low-molecular-weight heparin and direct oral factor Xa inhibitors are available to treat established cancer-associated VTE, adhering to algorithms for bleeding risk stratification. In patients with overt disseminated intravascular coagulation, therapeutic measures should strictly follow clinical symptoms. An acquired von Willebrand syndrome may evoke a severe bleeding tendency in patients with myeloproliferative neoplasms or plasma cell dyscrasias. In 15% of cases, acquired hemophilia A, due to the formation of inhibitory autoantibodies against coagulation factor VIII, is associated with malignancy.
Asunto(s)
Hemofilia A , Neoplasias , Tromboembolia Venosa , Autoanticuerpos/uso terapéutico , Factor VIII/uso terapéutico , Inhibidores del Factor Xa/uso terapéutico , Hemofilia A/complicaciones , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Neoplasias/complicaciones , Tromboembolia Venosa/etiologíaRESUMEN
Aberrant expression of tissue factor (TF) by transformed myeloblasts and inflammatory monocytes drives coagulation activation in acute myeloid leukemia (AML). Although regulation of TF procoagulant activity (PCA) involves thiol-disulfide exchange reactions, the specific role of protein disulfide isomerase (PDI) and other thiol isomerases in AML-associated TF biology is unclear. THP1 cells and peripheral blood mononuclear cells (PBMCs) from healthy controls or AML patients were analyzed for thiol isomerase-dependent TF production under various experimental conditions. Total cellular and membrane TF antigen, TF PCA and TF mRNA were analyzed by ELISA, flow cytometry, clotting or Xa generation assay and qPCR, respectively. PBMCs and THP1 cells showed significant insulin reductase activity, which was inhibited by bacitracin or rutin. Co-incubation with these thiol isomerase inhibitors prevented LPS-induced TF production by CD14-positive monocytes and constitutive TF expression by THP1 cells and AML blasts. Downregulation of the TF antigen was mainly restricted to the cryptic pool of TF, efficiently preventing phosphatidylserine-dependent TF activation by daunorubicin, and at least partially regulated on the mRNA level in LPS-stimulated monocytes. Our study thus delineates a complex role of thiol isomerases in the regulation of myeloid TF PCA, with PDI being a promising therapeutic target in the management of AML-associated coagulopathies.
RESUMEN
Objectives: Dual platelet inhibition is commonly used for prevention of cardiovascular events in patients undergoing neuroendovascular procedures. Non-responsiveness to platelet inhibitors may be associated with adverse outcomes. The aim of this study was to evaluate the reliability of the platelet function analyzer PFA-100® in comparison to light transmittance aggregometry (LTA) for monitoring clopidogrel and acetylsalicylic acid (ASA) non-responsiveness in a cohort of patients treated for intracranial aneurysm or cranial artery stenosis. Methods: Non-responsiveness to clopidogrel and ASA was assessed by LTA using adenosine diphosphate (ADP) and arachidonic acid and by PFA-100® with the ADP/prostaglandin E1 (PGE1) and collagen/epinephrine cartridges, respectively. Results: A total of 203 patients (145 females; median age, 57 years) were analyzed. Agreement between the two tests was poor for clopidogrel non-responsiveness (Æ=0.19) and not better than chance for ASA non-responsiveness (Æ=0.01). Clopidogrel non-responsiveness by LTA and PFA-100® was associated with higher von Willebrand factor antigen and activity levels. ADP-induced platelet disaggregation was lower in patients with clopidogrel non-responsiveness as assessed by PFA-100®. Clopidogrel non-responsiveness by LTA was associated with a higher prevalence of diabetes and a higher body mass index (BMI). Adverse outcomes (death, thromboembolism, or in-stent thrombosis) occurred in 13% (n=26) of all patients independently of ASA and clopidogrel non-responsiveness as assessed by both devices. Conclusions: Our results show that LTA and PFA-100® are not interchangeable in the assessment of ASA and clopidogrel non-responsiveness in patients undergoing neuroendovascular interventions.