Treatment of cancer-associated thrombosis.

Therapeutic options for the management of venous thromboembolism (VTE) in patients with cancer remain very limited. Although low-molecular-weight heparin monotherapy has been identified as a simple and efficacious regimen compared with an initial parenteral anticoagulant followed by long-term therapy with a vitamin K antagonist, many clinical questions remain unanswered. These include optimal duration of anticoagulant therapy, treatment of recurrent VTE, and the treatment of patients with concurrent bleeding or those with a high risk of bleeding. Treatment recommendations from consensus clinical guidelines are largely based on retrospective reports or extrapolated data from the noncancer population with VTE, as randomized controlled trials focused on cancer-associated thrombosis are sorely lacking. Furthermore, with improvements in imaging technology and extended survival duration of patients with cancer, we are encountering more unique challenges, such as the management of incidental VTE. Clinicians should be aware of the limitations of the novel oral anticoagulants and avoid the use of these agents because of the paucity of evidence in the treatment of cancer-associated thrombosis.

Dual direct oral anticoagulant therapy in challenging thrombosis: a case series.

Background: While anticoagulation therapy is highly effective at treating venous thromboembolism, some patients can develop rapidly progressive thrombosis in multiple organs or sites despite therapeutic anticoagulation. Effective strategies to manage life-threatening thrombosis in these patients are elusive. Objectives: We describe our experience using dual direct oral anticoagulant (DOAC) therapy with a factor (F)Xa inhibitor (such as rivaroxaban or apixaban) and a FIIa inhibitor (dabigatran) for refractory cases of thrombosis. Methods: A retrospective chart review of all patients treated with simultaneous dabigatran and an oral FXa inhibitor at our institution was conducted. We included all patients over the age of 18. The study was approved by the University of British Columbia Research Ethics Board (REB number: H23-02575). Results: Eight patients were included. All patients initiated standard therapeutic anticoagulation upon diagnosis of acute venous thromboembolism with a median of 3 breakthrough thrombotic events prior to dual DOAC use. Five patients had a positive heparin-induced thrombocytopenia screen, but only 2 had heparin-induced thrombocytopenia confirmed on serotonin release assay testing. There were no recurrent deep vein thrombosis, pulmonary embolism, or bleeding events during dual DOAC use. Most patients ultimately transitioned to a single oral FXa inhibitor. Conclusion: Dual DOAC therapy may be a useful strategy for managing challenging thrombosis cases resistant to conventional anticoagulation. Further research is warranted to validate these findings and explore the broader applicability of dual DOAC therapy in challenging thrombotic scenarios.

Clinical care pathway for the evaluation of patients with suspected VITT after ChAdOx1 nCoV-19 vaccination.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) adenoviral vector vaccination. In British Columbia (BC), Canada, a provincial clinical care pathway was developed to guide clinicians in evaluating for VITT among patients who present with thrombocytopenia or thrombosis symptoms within 4 to 28 days after adenoviral vector vaccine exposure. All patients had enzyme-linked immunosorbent assay (ELISA) testing for platelet factor 4 (PF4) antibodies, and all cases with positive PF4-ELISA or d-dimer levels ≥2.0 mg/L fibrinogen equivalent units (FEU) had further testing for platelet-activating PF4 antibodies using a modified serotonin release assay (SRA). Between 1 May and 30 June 2021, 37% of 68 patients investigated for VITT had thrombosis, but only 3 had VITT confirmed by PF4-ELISA and SRA. Platelet counts, d-dimer levels, and ELISA optical density values were significantly different between those with and without VITT. Three patients had thrombocytopenia and thrombosis with d-dimer levels >4.0 mg/L FEU but had negative PF4-ELISA and SRA results. Patients with VITT were treated successfully with IV immunoglobulin, nonheparin anticoagulants, and corticosteroids. Our pathway demonstrated that thrombosis is common among patients investigated for VITT and that PF4-ELISA testing is necessary to confirm VITT in those presenting with thrombosis and thrombocytopenia.

Update from the clinic: what's new in the diagnosis of cancer-associated thrombosis?

Malignancy is associated with a high risk of venous thromboembolism (VTE), and treatment with anticoagulant therapy is associated with a high risk of bleeding. Thus, accurate and timely VTE diagnosis in cancer patients is essential for identifying individuals who would benefit from anticoagulant therapy and for avoiding unnecessary treatment that can cause anticoagulant-related bleeding. The approach to the diagnosis of VTE in non-cancer patients involves a stepwise process beginning with an assessment of the pretest probability (PTP) of VTE using a validated clinical prediction rule (CPR) followed by D-dimer testing and/or diagnostic imaging. In patients with a low PTP and a negative D-dimer result, VTE can be excluded without additional imaging. However, published data suggest that CPRs and D-dimer testing may not be as accurate or as useful in patients with cancer. Studies have shown that the combination of a low PTP and negative D-dimer result is not efficient for exclusion of deep vein thrombosis (DVT) or pulmonary embolism (PE) in the cancer patient population because the vast majority of patients still require radiologic imaging. We propose that cancer patients with suspected VTE should proceed directly to radiologic imaging to confirm or exclude a diagnosis of DVT or PE.

Cell-specific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism.

The serotonin-1A (5-HT1A) receptor is the primary somatodendritic autoreceptor that inhibits the activity of serotonergic raphe neurons and is also expressed in nonserotonergic cortical and limbic neurons. Alterations in 5-HT1A receptor levels are implicated in mood disorders, and a functional C(-1019)G 5-HT1A promoter polymorphism has been associated with depression, suicide, and panic disorder. We examined the cell-specific activity of identified transcription factors, human nuclear deformed epidermal autoregulatory factor-1 (DEAF-1)-related (NUDR)/Deaf-1 and Hes5, at the 5-HT1A C(-1019) site. In serotonergic raphe RN46A cells, Deaf-1 and Hes5 repressed the 5-HT1A receptor gene at the C(-1019)-allele but not the G(-1019)-allele. However, in nonserotonergic cells that express 5-HT1A receptors (septal SN48, neuroblastoma SKN-SH, and neuroblastoma/glioma NG108-15 cells), Deaf-1 enhanced 5-HT1A promoter activity at the C(-1019)-allele but not the G-allele, whereas Hes5 repressed in all cell types. The enhancer activity of Deaf-1 was orientation independent and competed out Hes5 repression. To test whether Deaf-1 activity is intrinsic, the activity of a Gal4DBD (DNA binding domain)-Deaf-1 fusion protein at a heterologous Gal4 DNA element was examined. Gal4DBD-Deaf-1 repressed transcription in RN46A cells but enhanced transcription in SN48 cells, indicating that these opposite activities are intrinsic to Deaf-1. Repressor or enhancer activities of Deaf-1 or Gal4DBD-Deaf-1 were blocked by histone deacetylase inhibitor trichostatin A. Thus, the intrinsic activity of Deaf-1 at the 5-HT1A promoter is opposite in presynaptic versus postsynaptic neuronal cells and requires deacetylation. Cell-specific regulation by Deaf-1 could underlie region-specific alterations in 5-HT1A receptor expression in different mood disorders.

Clinical practice guidelines on cancer-associated thrombosis: a review on scope and methodology.

Cancer-associated thrombosis is a well-recognized complication in patients with cancer. It imposes significant patient morbidity and anxiety, increases personal and societal financial burden, and is the second-leading cause of death in this population. There have been increasing research efforts to reduce the incidence of venous thromboembolism (VTE) and optimize its treatment but the quality of evidence is diverse. To assist clinicians in providing care based on best-available evidence, many international and national organizations have issued clinical practice guidelines. Among these, the most highly cited resources include those developed by the American College of Chest Physicians, the American Society of Clinical Oncology and the European Society of Medical Oncology. Nationally-based guidelines have also been published by various groups, including the Italian Association of Medical Oncology, the National Comprehensive Cancer Network, the French National Federation of the League of Centers Against Cancer, and the British Committee for Standards in Haematology. This review will cover fundamental aspects of clinical practice guideline development and evaluation, summarize the scope and methodology of published guidelines on the management of cancer-associated thrombosis and assess the quality of selected, international guidelines using the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. Areas of consensus and uncertainties will be briefly highlighted.

Predictors of attempted inferior vena cava filters retrieval in a tertiary care centre.

BACKGROUND: Retrieval rates of optional recovery inferior vena cava (IVC) filters in US hospitals range from 11 - 70%. We conducted a retrospective study in a Canadian tertiary care centre to determine retrieval rates and predictors of filter removal. METHODS: Consecutive patients who had a retrievable IVC filter inserted or removed between January 2007 and December 2010 were identified. Data collected included baseline demographics, indications for filter insertion and removal, documentation of an IVC filter management plan, reasons for non-retrieval, complications, and death. RESULTS: 275 patients with a median age of 60years were followed in hospital for a median of 17 patient-days (range 1-876). Indications for filter placement were acute or prior VTE with contraindication to anticoagulation (72.4%), high risk of PE (11.3%) and primary prophylaxis (13.8%). Retrieval was attempted in 165 patients (60%) and was successful in 146 patients (53.1%). The most common reason for failed retrieval was filter thrombus. Predictors of attempted retrieval included documentation of filter plan (odds ratio [OR] 16.7; p<0.001), surgical indication for IVC filter insertion (OR 4.8; p=0.002), age ≤70years (OR 3.8; p=0.001), Hematology service involvement (OR 3.0; p=0.006), and presence of metastatic cancer (OR 0.2; p=0.001). Thrombotic complications occurred in 48 patients, including 3 patients who died of fatal PE. CONCLUSION: Our filter retrieval rate is suboptimal. Improvements in follow-up documentation or a dedicated clinical service may help increase retrieval rates.

Condensin is required for chromosome arm cohesion during mitosis.

We describe a novel requirement for the condensin complex in sister chromatid cohesion in Saccharomyces cerevisiae. Strikingly, condensin-dependent cohesion can be distinguished from cohesin-based pairing by a number of criteria. First, condensin is required to maintain cohesion at several chromosomal arm sites but, in contrast to cohesin, is not required at either centromere or telomere-proximal loci. Second, condensin-dependent interlinks are established during mitosis independently of DNA replication and are reversible within a single cell cycle. Third, the loss of condensin-dependent linkages occurs without affecting cohesin levels at the separated URA3 locus. We propose that, during mitosis, robust sister chromatid cohesion along chromosome arms requires both condensinand cohesin-dependent mechanisms, which function independently of each other. We discuss the implications of our results for current models of sister chromatid cohesion.

Thrombin induces endothelial cell-surface exposure of the plasminogen receptor annexin 2.

Cell-surface annexin 2 (A2) and its ligand p11 have been implicated in fibrinolysis because of their ability to accelerate tissue plasminogen activator (tPA)-mediated activation of plasminogen to plasmin. Because thrombin is a potent cell modulator obligately produced at the site of clot formation, we hypothesized that the amount of cell-surface A2 and p11 might be altered by thrombin with consequent effects on plasmin generation. In support of this hypothesis, immunofluorescence microscopy and hydrophilic biotinylation experiments showed that both A2 and p11 were significantly increased on the surface of human umbilical vein endothelial cells (HUVECs) treated with thrombin (0.8-8 nM) for 5 minutes followed by 1 hour at 37 degrees C. Intracellular immunofluorescence microscopy and immunoblot analyses of whole cell extracts revealed increased p11 but unchanged A2 in response to thrombin, suggesting that transbilayer trafficking of A2 might be controlled by p11. The thrombin receptor-activating peptide (TRAP) similarly affected cells, demonstrating that cell signaling at least involved the type-1 protease activated receptor (PAR-1). An effect on the fibrinolysis pathway after treatment of HUVECs with thrombin was shown by increased fluorescein-labeled plasminogen binding to cells, which was inhibited by an antibody specific for p11. This was confirmed by observing that thrombin pretreatment of HUVECs increased biotin-modified plasminogen binding. Utilizing a chromogenic assay, pretreatment of HUVECs by thrombin further enhanced activation of the Glu and Lys forms of plasminogen by tPA. These data suggest a novel mechanism that links the coagulation and fibrinolysis pathways by thrombin-mediated feedback.