Are anticoagulant drugs ecotoxic for meiobenthic nematodes from Saudi Arabia? First data on taxon/functional diversity and computational evidences.

Community-level effects of anticoagulants have little been studied in the laboratory. In the current study, the different effects of Warfarin and Tinzaparin, individually or in combination, on meiofauna were investigated for the first time using two concentrations (5 and 25 mg·l-1) of Warfarin (W1 and W2) and Tinzaparin (T1 and T2) for 30 days. The results obtained highlighted the highest tolerance of nematodes and amphipods toward the two anticoagulants tested. Moreover, nematode abundance and taxonomic diversity decreased directly after exposure to T2 and T2W1 because of the high mortality of diatom feeders and their replacement by non-selective deposit feeders (case of Tinzaparin) or omnivores-carnivores (case of Warfarin). The relative taxon/functional similarity between controls and mixtures T1W1 and T2W2 recommends that the toxicity of Tinzaparin can be attenuated by Warfarin. Finally, the computational study of Warfarin supports its potential ecotoxicity since it satisfactorily bound and interacted with GLD-3 and SDP macromolecules.

Effect of factor XI inhibition on tumor cell-induced coagulation activation.

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.

TILE pilot trial study protocol: Tinzaparin Lead-in to Prevent the Post-Thrombotic syndrome study protocol.

INTRODUCTION: The post-thrombotic syndrome (PTS) is a form of chronic venous insufficiency due to a prior ipsilateral deep venous thrombosis (DVT). This is a frequent complication that develops in 20%-50% of patients after a proximal DVT and is associated with significant healthcare, economic and societal consequences. In the absence of effective and well-tolerated treatment options for established PTS, effective preventative measures are needed. Anticoagulation itself reduces the risk of PTS, and low-molecular-weight heparin may reduce this further through anti-inflammatory properties targeting the initial acute inflammatory phase of DVT. METHODS AND ANALYSIS: The Tinzaparin Lead-In to Prevent the Post-Thrombotic syndrome pilot trial is an investigator-initiated, multicentre, open-label assessor-blinded trial that will randomise patients with first acute symptomatic common femoral or iliac DVT to receive either a 3-week lead-in course of tinzaparin, followed by rivaroxaban (experimental arm) or rivaroxaban alone (control arm). Its primary objectives are to assess: (1) proportion of PTS at 6 months using the Villalta scale and (2) study feasibility, which consists of (a) the proportion of screened patients eligible for the study, (2) the proportion of eligible patients recruited and (c) the proportion of recruited patients adherent to treatment (defined as at least 80% of drug taken). This study will determine the feasibility of a subsequent larger definitive trial. Secondary outcomes include change of quality of life scores, PTS severity, global improvement, patient satisfaction, bleeding, recurrent venous thromboembolism, leg pain, death and lost to follow-up. Target recruitment will be a total of 60 participants, recruited at 5-6 centres. ETHICS AND DISSEMINATION: Primary ethics approval was received from the Sunnybrook Health Sciences Center Research Ethics Board (approval ID 3315). Results of the study will be disseminated via peer-reviewed presentation at scientific conferences and open access publication. TRIAL REGISTRATION NUMBER: NCT04794569.

Tinzaparin for venous thromboembolism in patients with renal impairment: a single-centre, prospective pilot study.

BACKGROUND: Low molecular weight heparins (LMWH) are used extensively for prophylaxis and treatment of venous thromboembolism (VTE), bridging therapy for warfarin and standard of care in cancer-associated VTE (CA-VTE). Tinzaparin has the highest molecular weight of all LMWH and relies least on renal clearance to Cockcroft-Gault creatinine clearance (CrCl) of 20 mL/min. Previous pharmacological studies have demonstrated safety and effectiveness in elderly patients. Prospective clinical trials have confirmed these findings to CrCl 20 mL/min and in CA-VTE. We describe the pilot program developed at Concord Repatriation General Hospital for tinzaparin. AIMS: We aim to confirm the deliverability of tinzaparin in patients with renal insufficiency. METHODS: Twenty patients were established on tinzaparin as therapeutic anticoagulation with CrCl or CKD-EPI estimated glomerular filtration rate (eGFR) 20-50 mL/min with an indication for anticoagulation. Tinzaparin was given as a subcutaneous injection at 175 units/kg as a single daily dose, rounded to the nearest vial size. Tinzaparin anti-Xa levels were tested at Days 2, 7 and 14 (±1 day) and transition to oral anticoagulants were allowed at clinician discretion. RESULTS: No accumulation of tinzaparin was seen into Day 14. Two patients required dose-adjustment, five patients had bleeding complications (two major, three minor) and four patients died during follow-up, all attributable to patients' comorbidities. CrCl and body surface area-standardised CrCl were significantly correlated with tinzaparin anti-Xa level only on Day 2, and this effect was lost when patients with CrCl >50 mL/min were excluded. Data from our cohort confirm the deliverability of therapeutic tinzaparin in patients with CrCl or CKD-EPI eGFR 20-50 mL/min. Bleeding and death outcomes were also comparable to other trials using tinzaparin in CA-VTE. CONCLUSION: For patients with renal insufficiency, tinzaparin represents an attractive alternative anticoagulant with once-daily administration in a range of potential indications.

Risk of recurrent thromboembolic events according to treatment duration in patients with superficial vein thrombosis treated with intermediate dose of tinzaparin.

OBJECTIVES: To evaluate the risk of symptomatic venous thromboembolism (VTE) recurrence at 3 months in relation to treatment duration, according to baseline risk factor profiles, in patients with superficial vein thrombosis (SVT) treated with intermediate dose of tinzaparin. METHODS: We performed a pooled analysis on individual data from two prospective studies designed to assess the efficacy and safety of tinzaparin in intermediate dose (131 IU/kg) in patients with SVT. Treatment duration was at the treating physician's discretion. All patients were followed up for at least 3 months. RESULTS: A total of 956 patients (65% female, mean age 58.7 ± 13.7 years) were included. The median treatment duration was 30 days (range, 3-200 days). History of deep vein thrombosis (DVT), location of SVT above the knee, and palpable induration were the only independent factors associated with prolonged treatment duration. During follow-up, 95.9% of patients were event free. Outcomes-related adverse events occurred in 39 (4.1%) patients and their median duration of treatment was 33 days (range, 7-200 days). Recurrent VTE events occurred in 33 patients, including 22 cases of SVT recurrence, 8 cases of DVT, and 1 case of pulmonary embolism. The median time to the event was 29 (6-113) days. Recurrent thromboembolic events were not related to treatment duration as occurred in 17 patients (51.5%) treated up to 30 days and in 16 patients (48.8%) received prolong treatment (p = .46). Length of thrombus at the index event was significantly associated with higher risk for VTE recurrence. CONCLUSIONS: Intermediate dose of tinzaparin for 30 days is an effective and safe treatment for SVT. The risk of recurrent VTE events may be higher in patients with greater amount of thrombus at index event.

A prophylactic subcutaneous dose of the anticoagulant tinzaparin does not influence qPCR-based assessment of circulating levels of miRNA in humans.

Circulating microRNAs (miRNAs) have become increasingly popular biomarker candidates in various diseases. However, heparin-based anticoagulants might affect the detection of target miRNAs in blood samples during quantitative polymerase chain reaction (qPCR)-based analysis of miRNAs involving RNA extraction, cDNA synthesis and the polymerase catalyzed reaction. Because low-molecular-weight heparins (LMWH) are widely used in routine healthcare, we aimed to investigate whether a prophylactic dose of the LMWH tinzaparin influences qPCR-based quantification of circulating miRNAs. A total of 30 subjects were included: 16 fracture patients with tinzaparin treatment and 14 non-fracture controls without anticoagulation therapy. To control for the effect of tinzaparin on miRNA analysis an identical concentration of synthetic miRNAs was added to plasma, isolated RNA and prepared complementary DNA (cDNA) from all samples in both groups. No significant difference was observed for cDNA synthesis or qPCR when comparing tinzaparin-treated patients with untreated controls. Among the tinzaparin-treated patients, plasma levels of six endogenous miRNAs (hsa-let-7i-5p, hsa-miR-30e-5p, hsa-miR-222-3p, hsa-miR-1-3p, hsa-miR-133a-3p, hsa-miR-133b) were measured before and one to six hours after a subcutaneous injection of tinzaparin 4500IU. No significant effect was observed for any of the investigated miRNAs. A prophylactic dose of 4500IU tinzaparin does not seem to affect cDNA synthesis or qRT-PCR-based quantification of circulating miRNAs.

Critical appraisal of evidence for anti-Xa monitoring and dosing of low-molecular-weight heparin in renal insufficiency.

INTRODUCTION: Several guidelines advise to monitor therapeutic LMWH therapy with peak anti-Xa concentrations in renal insufficiency with subsequent dose adjustments. A better understanding of the clinical association between peak anti-Xa concentrations and clinical outcomes is mandatory, because misunderstanding this association could lead to erroneous, and potentially even harmful, LMWH dose adjustments. AREAS COVERED: We reviewed the evidence of the widely applied therapeutic window for anti-Xa peak concentrations and report on the evidence for pharmacokinetic dose reduction in renal insufficiency, limitations of peak and trough anti-Xa concentration monitoring. EXPERT OPINION: The added value of peak anti-Xa monitoring in patients with renal insufficiency, receiving a dose reduced for pharmacokinetic changes, is not supported by data. Enoxaparin and nadroparin should be adjusted to 50-65% and 75-85% of the original dose for patients with a creatinine clearance (CrCL) of <30 ml/min and 30-60 ml/min, respectively. Tinzaparin should be adjusted to around 50% of the original dose for patients with a CrCL of <30 ml/min. In case anti-Xa monitoring is applied, trough concentration anti-Xa monitoring is preferred over peak monitoring, aiming at a maximum concentration of 0.4 IU/mL for once-daily dosed tinzaparin and 0.5 IU/mL for twice-daily dosed enoxaparin and nadroparin.

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial.

OBJECTIVE: To determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer. DESIGN: Multicentre, open label, randomised controlled trial. SETTINGS: 12 hospitals in Quebec and Ontario, Canada, between 25 October 2011 and 31 December 2020. PARTICIPANTS: 614 adults (age ≥18 years) were eligible with pathologically confirmed invasive adenocarcinoma of the colon or rectum, no evidence of metastatic disease, a haemoglobin concentration of ≥8 g/dL, and were scheduled to undergo surgical resection. INTERVENTIONS: Random assignment to extended duration thromboprophylaxis using daily subcutaneous tinzaparin at 4500 IU, beginning at decision to operate and continuing for 56 days postoperatively, compared with in-patient postoperative thromboprophylaxis only. MAIN OUTCOME MEASURES: Primary outcome was disease-free survival at three years, defined as survival without locoregional recurrence, distant metastases, second primary (same cancer), second primary (other cancer), or death. Secondary outcomes included venous thromboembolism, postoperative major bleeding complications, and five year overall survival. Analyses were done in the intention-to-treat population. RESULTS: The trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 (77%) of 307 patients in the extended duration group and in 243 (79%) of 307 patients in the in-hospital thromboprophylaxis group (hazard ratio 1.1, 95% confidence interval 0.90 to 1.33; P=0.4). Postoperative venous thromboembolism occurred in five patients (2%) in the extended duration group and in four patients (1%) in the in-hospital thromboprophylaxis group (P=0.8). Major surgery related bleeding in the first postoperative week was reported in one person (<1%) in the extended duration and in six people (2%) in the in-hospital thromboprophylaxis group (P=0.1). No difference was noted for overall survival at five years in 272 (89%) patients in the extended duration group and 280 (91%) patients in the in-hospital thromboprophylaxis group (hazard ratio 1.12; 95% confidence interval 0.72 to 1.76; P=0.1). CONCLUSIONS: Extended duration to perioperative anticoagulation with tinzaparin did not improve disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection compared with in-patient postoperative thromboprophylaxis alone. The incidences of venous thromboembolism and postoperative major bleeding were low and similar between groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT01455831.

Cancer-Associated Thrombosis: Not All Low-Molecular-Weight Heparins Are the Same, Focus on Tinzaparin, A Narrative Review.

Cancer-associated thrombosis (CAT) is the second main cause of cancer death with high related mortality and morbidity, leading to anticancer agent delays and interruptions. The recommended therapy, low-molecular-weight heparin (LMWH), however, is burdensome for patients and costly for society, as treatment should last until cancer is no longer active, even indefinitely. Tinzaparin is a manageable, efficient, safe, and cost-effective option. Compared to the other LMWHs, advantages are single-daily dose and safety in the elderly and those with renal impairment (RI). The purpose of this review is to critically discuss recent data on its efficacy and safety in CAT.

Tinzaparin-a review of its molecular profile, pharmacology, special properties, and clinical uses.

PURPOSE: Low molecular weight heparins (LMWHs) are a group of heterogenous moieties, long used in the prevention and treatment of thrombosis. They derive from heparin and since they are prepared by different methods of depolymerization, they differ in pharmacokinetic properties and anticoagulant profiles, and thus are not clinically interchangeable. METHODS: In this review we provide an overview of tinzaparin's main characteristics and uses. RESULTS: Tinzaparin which is produced by the enzymatic depolymerization of unfractionated heparin (UFH) can be used for the treatment and prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE); it has been also used in special populations such as elders, obese, pregnant women, and patients with renal impairment and/or cancer with favorable outcomes in both safety and efficacy, with a once daily dose regimen. Furthermore, LMWHs are extensively used in clinical practice for both thromboprophylaxis and thrombosis treatment of COVID-19 patients. CONCLUSION: Tinzaparin features support the hypothesis for having a role in immunothrombosis treatment (i.e. in the context of cancer ,COVID-19), interfering not only with coagulation cascade but also exhibiting anti-inflammatory potency.

Long-term use of tinzaparin for the treatment of cancer-associated thrombosis in clinical practice: Insights from the prospective TROPIQUE study.

BACKGROUND: Real word data on the efficacy and safety of long-term use of tinzaparin for the treatment of cancer-associated thrombosis (CAT) are scarce. METHODS: We performed a post-hoc analysis of all cancer patients included in the prospective multicenter observational TROPIQUE study who received long-term treatment with tinzaparin for a first venous thromboembolism (VTE) event. We evaluated the patterns of anticoagulant prescription, the adherence to clinical practice guidelines (CPGs) for the treatment of CAT, and the clinical outcomes within a 6-month follow-up. RESULTS: In total, 301 patients were included in this post-hoc analysis. At study entry, their mean age was 64.6±11.9years and 143 (47.5%) patients were men. The most frequent cancer type was gastrointestinal (23.9%), followed by breast (17.9%) and lung (15.3%) cancer. At time of VTE diagnosis, 164 (57.8%) patients had metastatic disease and 245 (81.42%) were receiving chemotherapy. Based on the aggregation of all study pre-defined criteria, tinzaparin prescription was fully compliant with CPGs in 219 (72.8%) patients. The mean effective treatment duration with tinzaparin was 6.07±0.17months. At 6-month follow-up, the cumulative incidence of recurrent VTE was 5.4% (95% CI: 3.2-9.2%) and the cumulative incidence of major bleeding was 5.8% (95% CI: 3.6-9.6%). Clinical outcomes tended to differ across different types of cancer. Death from any cause occurred in 102 (33.9%) patients, mainly related to cancer progression. CONCLUSIONS: This post-hoc analysis of TROPIQUE confirms the favorable benefit-risk ratio of tinzaparin for the long-term treatment of CAT.

Can thromboprophylaxis build a link for cancer patients undergoing surgical and/or chemotherapy treatment? The MeTHOS cohort study.

BACKGROUND: Patients with active cancer have a 4-sevenfold increased risk for venous thromboembolism (VTE) especially during systematic anticancer treatment. Simultaneously, surgery is an additional risk factor. METHODS: The Metaxas's Hospital THromboprophylaxis program in Oncological & Surgical Patients (MeTHOS) is a prospective, phase IV, observational, non-interventional cohort study, aiming to record the thromboprophylaxis practice patterns in high-risk active cancer patients undergoing surgical and/or chemotherapy treatment. RESULTS: We are reporting results from 291 ambulatory patients (median age: 67 years, Q1-Q3: 59-73 years, 54.6% males) who received anti-neoplastic treatment and administered thromboprophylaxis. 59.8% had cardiovascular disease (mostly hypertension), 76.6% were reported as having at least one comorbidity, while 27.5% and 15.8% accumulated two and three comorbidities, respectively. 94.9% of the patients were receiving highly thrombogenic agents such as platinum-based agents, 5-FU, immunotherapy, antiangiogenics/anti-VEGF, or erythropoietin. 26.5% of the patients were initially surgically treated. In terms of anticoagulation, all patients were treated with tinzaparin (fixed dose, 10,000 Anti-Xa IU, OD). The median anticoagulation duration was 6.2 months. Six thrombotic events were observed (2.06%, 95% CI: 0.76-4.43%): 5 were DVT, and one PE. With respect to safety, 7 bleeding events occurred (2.6%, 95% CI: 1.0-5.3%); 6 of them were minor. CONCLUSIONS: Thromboprophylaxis with LMWH in patients with active cancer and high thrombotic burden was safe and effective. Intermediate dose of tinzaparin seems to be an appropriate agent for cancer-associated thromboprophylaxis management. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04248348.

Intensive-Dose Tinzaparin in Hospitalized COVID-19 Patients: The INTERACT Study.

(1) Background: It is well-established that coronavirus disease-2019 (COVID-19) is highly pro-inflammatory, leading to activation of the coagulation cascade. COVID-19-induced hypercoagulability is associated with adverse outcomes and mortality. Current guidelines recommend that hospitalized COVID-19 patients should receive pharmacological prophylaxis against venous thromboembolism (VTE). (2) INTERACT is a retrospective, phase IV, observational cohort study aiming to evaluate the overall clinical effectiveness and safety of a higher than conventionally used prophylactic dose of anticoagulation with tinzaparin administered for VTE prevention in non-critically ill COVID-19 patients with moderate disease severity. (3) Results: A total of 705 patients from 13 hospitals in Greece participated in the study (55% men, median age 62 years). Anticoagulation with tinzaparin was initiated immediately after admission. A full therapeutic dose was received by 36.3% of the participants (mean ± SD 166 ± 33 IU/Kgr/day) and the remaining patients (63.9%) received an intermediate dose (mean ± SD 114 ± 22 IU/Kgr/day). The median treatment duration was 13 days (Q1−Q3: 8−20 days). During the study (April 2020 to November 2021), 14 thrombotic events (2.0%) were diagnosed (i.e., three cases of pulmonary embolism (PE) and 11 cases of deep venous thrombosis, DVT). Four bleeding events were recorded (0.6%). In-hospital death occurred in 12 patients (1.7%). Thrombosis was associated with increasing age (median: 74.5 years, Q1−Q3: 62−79, for patients with thrombosis vs. 61.9 years, Q1−Q3: 49−72, p = 0.0149), increased D-dimer levels for all three evaluation time points (at admission: 2490, Q1−Q3: 1580−6480 vs. 700, Q1−Q3: 400−1475, p < 0.0001), one week ± two days after admission (3510, Q1−Q3: 1458−9500 vs. 619, Q1−Q3: 352−1054.5, p < 0.0001), as well as upon discharge (1618.5, Q1−Q3: 1010−2255 vs. 500, Q1−Q3: 294−918, p < 0.0001). Clinical and laboratory improvement was affirmed by decreasing D-dimer and CRP levels, increasing platelet numbers and oxygen saturation measurements, and a drop in the World Health Organization (WHO) progression scale. (4) Conclusions: The findings of our study are in favor of prophylactic anticoagulation with an intermediate to full therapeutic dose of tinzaparin among non-critically ill patients hospitalized with COVID-19.

Clinical use of low-dose parenteral anticoagulation, incidence of major bleeding and mortality: a multi-centre cohort study using the French national health data system.

PURPOSE: Low-dose parenteral anticoagulation has demonstrated its efficacy for venous thromboembolism prophylaxis in randomized trials. However, current practice is not widely documented. In ambulatory settings, we aimed to provide an overview of the clinical use of low-dose parenteral anticoagulation in France and to assess the incidence of major bleeding and death rates. METHODS: A population-based prospective cohort study using the French national health data system (SNIIRAM) identified 142,815 adults living in five well-defined geographical areas who had a course of low-dose parenteral anticoagulants (a total of 150,389 courses) in the period 2013-2015. The main outcome measures were the types of low-dose parenteral anticoagulant, the duration and the clinical context. Adjusted incidence rate ratios (IRR) were derived from Poisson models. RESULTS: Enoxaparin was the most frequently prescribed anticoagulant (58.9%) followed by tinzaparin (27.3%) and fondaparinux (10.9%). Patients receiving unfractionated heparin (N = 766, 0.53%) were older, more frequently had renal disease (48.75%) and had a higher modified HAS-B(L)ED score (≥ 3 in 61.6%) than patients receiving low-molecular weight heparin (LMWH). Surgical thrombo-prophylaxis was the most frequent indication (47.6%), followed by medical prophylaxis (29.9%). Course durations were in line with regulatory agency specifications. Only 43 (0.028%) major bleeding events and 478 (0.32%) deaths were observed. Adjusted IRRs for major bleeding or death were not significantly different for dalteparin/nadroparin, tinzaparin or fondaparinux compared to enoxaparin. CONCLUSION: Very low incidence rates of major bleeding and all-cause mortality were observed. Our study confirms the safety of LMWHs and fondaparinux in thrombo-prophylaxis in ambulatory settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02886533.

Failure of the Ottawa Score to Predict the Risk of Recurrent Venous Thromboembolism in Cancer Patients: The Prospective PREDICARE Cohort Study.

INTRODUCTION: Recurrent venous thromboembolism (VTE) despite curative anticoagulation is frequent in patients with cancer. Identifying patients with a high risk of recurrence could have therapeutic implications. A prospective study was designed to validate the Ottawa risk score of recurrent VTE in cancer patients. METHODS: In a prospective multicenter observational cohort, adult cancer patients with a recent diagnosis of symptomatic or incidental lower limb deep vein thrombosis or pulmonary embolism (PE) were treated with tinzaparin for 6 months. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment. All clinical events were centrally reviewed and adjudicated. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. A C-statistic value of > 0.70 was needed to validate the Ottawa score. RESULTS: A total of 409 patients were included and analyzed on an intention-to-treat basis. Median age was 68 years, 60.4% of patients had PE, and VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), lower digestive tract (14.4%), and breast (13.9%) cancers. The Ottawa score was high (≥ 1) in 58% of patients. The 6-month cumulative incidence of recurrent VTE was 7.3% (95% confidence interval [CI]: 4.9-11.1) overall, and 5.0% (95% CI: 2.3-10.8) versus 9.1% (95%CI: 6.1-13.6) in the Ottawa low versus high risk groups, respectively. The C-statistic value was 0.60 (95% CI: 0.55-0.65). CONCLUSION: In this prospective cohort of patients with cancer receiving tinzaparin for VTE, the Ottawa score failed to accurately predict recurrent VTE.

Impact of Weight-Band Dosing of Tinzaparin for Venous Thromboembolism Prophylaxis on Persistent Wound Drainage in Adult Patients Undergoing Hip and Knee Arthroplasty.

BACKGROUND: Persistent wound drainage and venous thromboembolism (VTE) are potential complications of total joint arthroplasty, and these risks can be challenging to balance in clinical practice. Anecdotal observation has suggested that following joint arthroplasty, persistent wound drainage occurs more frequently with higher body weight and higher doses of tinzaparin when compared with lower body weight and lower doses of tinzaparin. OBJECTIVE: The overall purpose of this study was to describe the impact of a tinzaparin weight-band dosing table for VTE prophylaxis on wound healing, thrombosis, and bleeding outcomes in patients undergoing total joint arthroplasty. METHODS: This retrospective chart review included patients who underwent total hip or knee arthroplasty and received tinzaparin for thromboprophylaxis per their weight-banding category. The primary outcome was the incidence of persistent wound drainage. Secondary outcomes include the occurrence of VTE and clinically important bleeding during hospital admission. RESULTS: A total of 231 patients were included in the analysis. There was no significant difference in persistent wound drainage between the 3 weight categories, and there were no differences in rates of VTE or clinically important bleeding. Concurrent use of low-dose acetylsalicylic acid was associated with a 3-fold increased risk of persistent wound drainage (risk ratio = 3.35; 95% CI = 2.14-5.24; P = 0.00003). CONCLUSION AND RELEVANCE: In joint arthroplasty patients, we observed no significant difference in rates of persistent wound drainage between various weight categories receiving different weight-banded doses of tinzaparin. Our results do not suggest that the current weight-band dosing table for tinzaparin needs to be adjusted to optimize patient outcomes.

Thromboembolic and bleeding complications following primary total knee arthroplasty : a Danish nationwide cohort study.

AIMS: The aim of this study is to compare the effectiveness and safety of thromboprophylactic treatments in patients undergoing primary total knee arthroplasty (TKA). METHODS: Using nationwide medical registries, we identified patients with a primary TKA performed in Denmark between 1 January 2013 and 31 December 2018 who received thromboprophylactic treatment. We examined the 90-day risk of venous thromboembolism (VTE), major bleeding, and all-cause mortality following surgery. We used a Cox regression model to compute hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome, pairwise comparing treatment with dalteparin or dabigatran with rivaroxaban as the reference. The HRs were both computed using a multivariable and a propensity score matched analysis. RESULTS: We identified 27,736 primary TKA patients who received thromboprophylactic treatment (rivaroxaban (n = 18,846); dalteparin (n = 5,767); dabigatran (n = 1,443); tinzaparin (n = 1,372); and enoxaparin (n = 308)). In the adjusted multivariable analysis and compared with rivaroxaban, treatment with dalteparin (HR 0.68 (95% CI 0.49 to 0.92)) or dabigatran (HR 0.31 (95% CI 0.13 to 0.70)) was associated with a decreased risk of VTE. No statistically significant differences were observed for major bleeding or all-cause mortality. The propensity score matched analysis yielded similar results. CONCLUSION: Treatment with dalteparin or dabigatran was associated with a decreased 90-day risk of VTE following primary TKA surgery compared with treatment with rivaroxaban. Cite this article: Bone Joint J 2021;103-B(10):1571-1577.

Tinzaparin inhibits VL30 retrotransposition induced by oxidative stress and/or VEGF in HC11 mouse progenitor mammary cells: Association between inhibition of cancer stem cell proliferation and mammosphere disaggregation.

Tinzaparin is an anticoagulant and antiangiogenic drug with inhibitory properties against tumor growth. VEGF stimulates angiogenesis, while an association between reactive oxygen species (ROS) and angiogenesis is involved in tumor progression. The present study aimed to investigate the effect of tinzaparin on VL30 retrotransposition­positive mouse HC11 mammary stem­like epithelial cells, previously reported to be associated with induced mammosphere/cancer stem cell (CSC) generation and tumorigenesis. Under 24 h serum starvation, 15.2% nominal retrotransposition frequency was increased to 29%. Additionally, while treatment with 3­12 ng/ml VEGF further induced retrotransposition frequency in a dose­dependent manner (up to 40.3%), pre­incubation with tinzaparin (2 IU/ml) for 0.5­4 h reduced this frequency to 18.3% in a time­dependent manner, confirmed by analogous results in NIH3T3 fibroblasts. Treatment with 10­40 pg/ml glucose oxidase (GO) for 24 h induced HC11 cell retrotransposition in a dose­dependent manner (up to 82.5%), while a 3 h pre­incubation with tinzaparin (1 or 2 IU/ml) elicited a 13.5 or 25.5% reduction in retrotransposition, respectively. Regarding tumorigenic VL30 retrotransposition­positive HC11 cells, treatment with 2 IU/ml tinzaparin for 5 days reduced proliferation rate in a time­dependent manner (up to ~55%), and after 3 weeks, disaggregated soft agar­formed foci, as well as low­adherent mammospheres, producing single mesenchymal­like cells with a ~50% reduced retrotransposition. With respect to the VL30 retrotransposition mechanism: While 12 ng/ml VEGF increased the level of VL30 and endogenous reverse transcriptase (enRT) transcripts ~1.41­ and ~1.16­fold, respectively, subsequent tinzaparin treatment reduced both endogenous/ROS­ and VEGF­induced levels 1.15­ and 0.40­fold (VL30) and 0.60­ and 0.52­fold (enRT), respectively. To the best of our knowledge, these data demonstrate for the first time, the novel inhibition activity of tinzaparin against ROS­ and VEGF­induced VL30 retrotransposition, and the proliferation and/or aggregation of mouse HC11 mammosphere/tumor­initiating CSCs, thus contributing to the inhibition of VL30 retrotransposition­induced primary tumor growth.