Establishment of a swine model of delayed bleeding after endoscopic procedure.

Objectives: Although delayed bleeding after endoscopic procedures has become a problem, currently, there are no appropriate animal models to validate methods for preventing it. This study aimed to establish an animal model of delayed bleeding after endoscopic procedures of the gastrointestinal tract. Methods: Activated coagulation time (ACT) was measured using blood samples drawn from a catheter inserted into the external jugular vein of swine (n = 7; age, 6 months; mean weight, 13.8 kg) under general anesthesia using the cut-down method. An upper gastrointestinal endoscope was inserted orally, and 12 mucosal defects were created in the stomach by endoscopic mucosal resection using a ligating device. Hemostasis was confirmed at this time point. The heparin group (n = 4) received 50 units/kg of unfractionated heparin via a catheter; after confirming that the ACT was ≥200 s 10 min later, continuous heparin administration (50 units/kg/h) was started. After 24 h, an endoscope was inserted under general anesthesia to evaluate the blood volume in the stomach and the degree of blood adherence at the site of the mucosal defect. Results: Delayed bleeding was observed in three swine (75%) in the heparin-treated group, who had a maximum ACT of >220 s before the start of continuous heparin administration. In the non-treated group (n = 3), no prolonged ACT or delayed bleeding was observed at 24 h. Conclusion: An animal model of delayed bleeding after an endoscopic procedure in the gastrointestinal tract was established using a single dose of heparin and continuous heparin administration after confirming an ACT of 220 s.

Heparin-Induced Thrombocytopenia in Patients Suffering Cardiogenic Shock.

OBJECTIVES: Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine. Primary purpose of this study was to: 1) determine HIT prevalence in CS, 2) assess the performance of common diagnostic tests for the workup of HIT, and 3) compare outcomes in CS patients with excluded and confirmed HIT. DESIGN: Retrospective dual-center study including adult patients 18 years old or older with diagnosed CS and suspected HIT from January 2010 to November 2022. SETTING: Cardiac ICU at the Ludwig-Maximilians University hospital in Munich and the university hospital of Bonn. PATIENTS AND INTERVENTIONS: In this retrospective analysis, adult patients with diagnosed CS and suspected HIT were included. Differences in baseline characteristics, mortality, neurologic and safety outcomes between patients with excluded and confirmed HIT were evaluated. MEASUREMENTS AND MAIN RESULTS: In cases of suspected HIT, positive screening antibodies were detected in 159 of 2808 patients (5.7%). HIT was confirmed via positive functional assay in 57 of 2808 patients, corresponding to a prevalence rate of 2.0%. The positive predictive value for anti-platelet factor 4/heparin screening antibodies was 35.8%. Total in-hospital mortality (58.8% vs. 57.9%; p > 0.999), 1-month mortality (47.1% vs. 43.9%; p = 0.781), and 12-month mortality (58.8% vs. 59.6%; p > 0.999) were similar between patients with excluded and confirmed HIT, respectively. Furthermore, no significant difference in neurologic outcome among survivors was found between groups (Cerebral Performance Category [CPC] score 1: 8.8% vs. 8.8%; p > 0.999 and CPC 2: 7.8% vs. 12.3%; p = 0.485). CONCLUSIONS: HIT was a rare complication in CS patients treated with unfractionated heparin and was not associated with increased mortality. Also, HIT confirmation was not associated with worse neurologic outcome in survivors. Future studies should aim at developing more precise, standardized, and cost-effective strategies to diagnose HIT and prevent complications.

Heparin-Binding Protein Stratifies Mortality Risk Among Ugandan Children Hospitalized With Respiratory Distress.

Background: Current prognostic tools do not reliably and objectively identify children with pneumonia at risk of a severe or life-threatening episode. Heparin-binding protein (HBP) is a host immune protein that is released in response to infection. We hypothesized that measuring HBP concentrations at hospital admission could help risk-stratify children with pneumonia and identify those at higher risk of an adverse prognosis. Methods: We evaluated the prognostic accuracy of HBP for predicting in-hospital mortality among children with respiratory distress, and whether HBP could improve the accuracy of validated composite clinical severity scores. Results: Of 778 Ugandan children under 5 years of age and presenting with clinically defined pneumonia, 60 (7.7%) died during hospital admission. HBP concentrations at presentation were significantly higher in children with fatal outcomes (median, 76 ng/mL [interquartile range {IQR}, 41-150]) compared to children who survived (median, 31 ng/mL [IQR, 18-57]) (P < .001). Children with HBP >41 ng/mL on admission had an elevated risk of death (hazard ratio, 5.3 [95% confidence interval {CI}, 2.9-9.5]; P < .0001). In receiver operating characteristic (ROC) curve analysis, HBP concentrations distinguished between fatal and nonfatal outcomes (area under the ROC curve, 0.75 [95% CI, .66-.84]) and significantly improved the prediction provided by the Respiratory Index of Severity in Children, a composite clinical severity score (P = .0026). Conclusions: Measuring HBP at presentation could help identify children at risk of severe and fatal pneumonia. Adding HBP to clinical scores could improve the recognition and triage of children with pneumonia at risk of death.

Flow cytometry vs conventional methods for the evaluation of anti-PF4/heparin antibodies: a single center study.

Aim: Heparin-induced thrombocytopenia (HIT) is a rare, life-threatening, immune-mediated adverse effect of heparin administration. This study compares frequently used laboratory assays in terms of their effectiveness in HIT diagnosis. Materials & methods: Fifty patients with suspected HIT were tested by gel immunoassay and solid phase PF4/heparin antibody ELISA. On positive results, platelet activation markers P-selectin and Annexin V were assayed using flow cytometry. Results: Thirty/50 patients were negative for both immunoassays. Flow cytometry was performed in the 20 immunoassay positive patients. Platelet activation was observed in 7/20 in the presence of low heparin concentration (0.2 IU/ml). Conclusion: The results are in accordance with the currently available literature and flow cytometry seems a promising alternative in HIT laboratory investigation.

[Box: see text].

Identification of heparin interaction sites on thrombin-activatable fibrinolysis inhibitor that modulate plasmin-mediated activation, thermal stability, and antifibrinolytic potential.

Background: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen that provides a molecular link between coagulation and fibrinolysis. Studies have shown that the presence of glycosaminoglycans accelerates TAFI activation by plasmin and stabilizes activated TAFI (TAFIa). Objectives: We aimed to define the elements of TAFI structure that allow these effects. Methods: Based on crystallographic studies and homology to heparin-binding proteins, we performed mutagenesis of surface-exposed charged residues on TAFI that putatively constitute heparin-binding sites. We determined heparin binding, kinetics of activation by plasmin in the presence or absence of heparin, thermal stability, and antifibrinolytic potential of each variant. Results: Mutagenesis of Lys211 and Lys212 did not impair heparin binding but affected the ability of TAFI to be activated by plasmin. Mutagenesis of Lys306 and His308 did not impair heparin binding, but mutation of His308 had a severe negative effect on TAFI/TAFIa function. Mutation of Arg320 and Lys324 in combination markedly decreased heparin binding but had no effect on heparin-mediated acceleration of TAFI activation by plasmin while somewhat decreasing TAFIa stabilization by heparin. Mutagenesis of Lys327 and Arg330 decreased (but did not eliminate) heparin binding while decreasing the ability of heparin to accelerate plasmin-mediated TAFI activation, stabilize TAFIa, and increase the antifibrinolytic ability of TAFIa. A quadruple mutant of Arg320, Lys324, Lys327, and Arg330 completely lost heparin-binding ability and stabilization of the enzyme by heparin. Conclusion: Basic residues in the dynamic flap of TAFIa define a functionally relevant heparin-binding site, but additional heparin-binding sites may be present on TAFI.

Efficacy of unfractionated heparin in patients with moderate sepsis-induced coagulopathy: An observational study.

INTRODUCTION: The 2021 Surviving Sepsis Campaign guidelines recommend low-molecular-weight heparin for the prevention of venous thromboembolism in sepsis. However, observational studies suggest that anticoagulants as a whole may benefit severely ill sepsis patients with coagulopathy, but the optimal targets of unfractionated heparin remain unclear. This study investigated which sepsis patients could most benefit from unfractionated heparin. MATERIALS AND METHODS: In this retrospective observational study, we identified adult sepsis patients requiring urgent hospitalization from 2006 to 2019 using a large-scale Japanese medical database. Patients were divided into two groups: those receiving unfractionated heparin within 72 h of admission and those who did not. We compared in-hospital mortality, major bleeding complications, and thromboembolic events between these groups using a multivariate logistic regression model adjusted for patient and treatment variables. Additionally, we assessed the association between heparin administration and in-hospital mortality across various subgroups. RESULTS: Among 30,342 sepsis patients, 2520 received early heparin administration, and 27,822 did not. Multivariate logistic regression revealed a significant association between heparin and reduced in-hospital mortality (adjusted OR: 0.735, 95 % CI: 0.596-0.903) but no significant association with major bleeding and thromboembolic risk (adjusted OR: 1.137, 1.243; 95 % CI: 0.926-1.391, 0.853-1.788, respectively). Subgroup analyses suggested significant survival benefits associated with heparin only in the sepsis patients with moderate coagulopathy and sepsis-induced coagulopathy scores of 3 or 4 (adjusted OR: 0.452, 0.625; 95 % CI: 0.265-0.751, 0.410-0.940, respectively). CONCLUSIONS: Early heparin administration upon admission is associated with lower in-hospital mortality, especially in moderate sepsis-induced coagulopathy, and no significant increase in complications.

Systematic literature review comparing clinical utility of heparin-bonded expanded polytetrafluoroethylene graft to autologous saphenous vein graft for management of below-knee peripheral arterial disease.

INTRODUCTION: This systematic literature review compares the clinical outcomes of heparin-bonded expanded polytetrafluoroethylene with autologous saphenous vein in the management of patients undergoing below-the-knee bypass to treat peripheral arterial disease. METHODS: An electronic literature search was conducted in MEDLINE and EMBASE to identify comparative studies in patients undergoing below-the-knee surgical bypass. Studies were screened at abstract and full text review using pre-defined inclusion criteria by two independent reviewers and critically appraised for risk of bias. Meta-analyses were conducted using Review Manager 5 software (Nordic Cochrane Centre, Copenhagen, Denmark). RESULTS: Eight retrospective cohort studies were identified. Meta-analysis of primary patency demonstrated no significant difference between heparin-bonded expanded polytetrafluoroethylene and autologous saphenous vein grafts after one year (0.91 [0.52-1.59], P=0.74), two years (1.12 [0.60-2.10], P=0.77), three years (0.62 [0.26-1.48], P=0.28) and 4 years [0.36 -1.39], P=0.31). Similarly, for secondary patency, no significant difference was detected at one (0.62 [0.33-1.15], P=0.13), two (0.83 [0.32-2.13], P=0.69), three (0.60 [0.27-1.32], P=0.20) and 4 years (0.66 [0.32-1.36], P=0.26) respectively. There was no significant difference between autologous veins and heparin-bonded expanded polytetrafluoroethylene for limb salvage and mortality at all timepoints. A sensitivity analysis to compare outflow vessel was conducted in only tibial bypass identified no differences. All analyses were considered at high-risk bias due to heterogeneity in study populations and attrition in follow-up. CONCLUSION: This meta-analysis demonstrates similar outcomes between autologous saphenous vein and heparin-bonded expanded polytetrafluoroethylene for patency, limb salvage, and mortality through 4 years. Primary and secondary patency are superior at four years with autologous veins, but limb salvage and overall survival remained similar. The use of heparin-bonded expanded polytetrafluoroethylene synthetic grafts is a satisfactory option to prevent amputation, particularly when autologous saphenous vein grafts are not available. Controlled clinical studies are needed to further inform future decision making and economic modeling related to the choice of conduit for below-the-knee graft construction.

Direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer-associated venous thrombosis: a cost-effectiveness analysis.

Background: Direct oral anticoagulants (DOACs) have demonstrated clinical benefits and better patient adherence over low-molecular-weight heparin (LMWH) in treating patients with cancer-associated venous thrombosis (CAT). We aimed to compare the cost-effectiveness of DOACs against LMWH in patients with CAT from the perspective of the Hong Kong healthcare system. Methods: A Markov state-transition model was performed to estimate the incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) for DOACs and LMWH in a hypothetical cohort of 10,000 patients with CAT over a 5-year lifetime horizon. The model was primarily based on the health states of no event, recurrent venous thromboembolism, bleeding, and death. Transition probabilities, relative risks, and utilities were derived from the literature. Resource cost data were obtained from the Hong Kong Hospital Authority. Deterministic and probabilistic sensitivity analyses tested the robustness of the results. Results: Relative to LMWH, DOACs were associated with increased QALYs (1.52 versus 1.50) at a lower medical cost of USD 2,232 versus 8,224 in five years. The cost of LMWH was the main contributor to the outcome. Out of 10,000 simulated cases, DOACs were dominant in 15.8% and cost-effective in 42.1%, at the willingness-to-pay threshold of USD 148,392 per additional QALY. Conclusions: DOACs were associated with greater QALY improvements and lower overall costs compared to LMWH. Accounting for uncertainty, DOACs were between cost-effective and dominant in 57.9% of cases. DOACs are a cost-effective alternative to LMWH in the management of CAT in Hong Kong.

Long-term outcomes of below-the-knee bypass surgery using heparin-bonded expanded polytetrafluoroethylene grafts.

PURPOSE: To report the outcomes of below-the-knee (BK) bypass surgery using heparin-bonded expanded polytetrafluoroethylene (ePTFE) grafts, performed in two centers since its launch in Japan. METHODS: We conducted a retrospective analysis of databases from two medical centers, evaluating 51 limbs in 42 consecutive patients with peripheral arterial disease (PAD), who underwent BK bypass surgery using heparin-bonded ePTFE grafts between October, 2013 and April, 2023. RESULTS: Thirty-three limbs (64.7%) were classified as Rutherford category 4-6 and 33 limbs (64.7%) had a history of ipsilateral revascularization. Technical success was achieved in 98% of the patients. The 30 day mortality rate was 2.4% (n = 1) and the overall 30 day complication rate was 9.5% (n = 4). The median follow-up period was 38 (interquartile range 13-67) months. Three patients required major amputation and 14 died during follow-up. Primary patency rates at 1, 3, and 5 years were 67.8%, 57.5%, and 46.5%, respectively, while secondary patency rates for these periods were 84.6%, 70.0%, and 66.0%, respectively. Overall survival rates at 1, 3, and 5 years were 90.1%, 74.5%, and 70.9%, respectively. CONCLUSIONS: BK bypass surgery using heparin-bonded ePTFE graft is a viable and durable option for patients with PAD, who are deemed unsuitable for autologous vein bypass surgery.

Postpercutaneous Coronary Intervention Anticoagulation With Unfractionated Heparin in Acute Coronary Syndrome: Insight from the STOPDAPT-3 Trial.

The current guidelines for acute coronary syndrome (ACS) discourage the use of anticoagulation after percutaneous coronary intervention (PCI) without specific indications, although the recommendation is not well supported by evidence. In this post hoc analysis of the ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-3 (STOPDAPT-3) trial, 30-day outcomes were compared between the 2 groups with and without post-PCI heparin administration among patients with ACS who did not receive mechanical support devices. The co-primary end points were the bleeding end point, defined as the Bleeding Academic Research Consortium type 3 or 5 bleeding, and the cardiovascular end point, defined as a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke. Among 4,088 patients with ACS, 2,339 patients (57.2%) received post-PCI heparin. The proportion of patients receiving post-PCI heparin was higher among those with ST-elevation myocardial infarction compared with others (72.3% and 38.8%, p <0.001), and among patients with intraprocedural adverse angiographic findings compared with those without (67.6% and 47.5%, p <0.001). Post-PCI heparin compared with no post-PCI heparin was associated with a significantly increased risk of the bleeding end point (4.75% and 2.52%, adjusted hazard ratio 1.69, 95% confidence interval 1.15 to 2.46, p = 0.007) and a numerically increased risk of the cardiovascular end point (3.16% and 1.72%, adjusted hazard ratio 1.56, 95% confidence interval 0.98 to 2.46, p = 0.06). Higher hourly dose or total doses of heparin were also associated with higher incidence of both bleeding and cardiovascular events within 30 days. In conclusion, post-PCI anticoagulation with unfractionated heparin was frequently implemented in patients with ACS. Post-PCI heparin use was associated with harm in terms of increased bleeding without the benefit of reducing cardiovascular events. Trial identifier: STOPDAPT-3 ClinicalTrials.gov number, NCT04609111.

Preferences of pregnant women for postpartum thromboprophylaxis: the bicentric PREFER-PP study.

BACKGROUND: Clinical guidelines for postpartum thromboprophylaxis differ due its uncertain effect and varying preferences of experts. Women's preferences for postpartum thromboprophylaxis are unknown, although they may inform practices and future research. Our aim was to elicit the pregnant women's preferences for postpartum thromboprophylaxis, according to different risks of venous thromboembolism (VTE) and bleeding. METHODS: In two Swiss and French maternity hospitals, we conducted structured interviews of pregnant or postpartum women. Participants were instructed on pulmonary embolism (PE), deep vein thrombosis (DVT), postpartum hemorrhage (PPH) and subcutaneous injections of low-molecular-weight heparin (LMWH). First, we randomized women to either standard gamble or time trade-off (two different validated methods) to estimate the utilities (quality-of-life, from 0-1) of these health states. Second, we elicited the preference for the use of short-term postpartum thromboprophylaxis with LMWH vs. none across different risks of postpartum VTE and bleeding, through direct-choice exercises. RESULTS: Among 122 participants, median (IQR) health states utilities were 0.725 (0.30-0.925) for PE, 0.75 (0.40-0.97) for PPH, 0.85 (0.60-0.97) for DVT and 0.96 (0.96-0.999) for LMWH injections. The median risk of postpartum VTE to prefer the use of postpartum thromboprophylaxis over no treatment was 0.1% (IQR 0.01-0.50%) without LMWH-associated bleeding risk and 0.2% (IQR 0.1-5%) with a 1% bleeding risk. CONCLUSIONS: European pregnant women appear to have a high willingness for 10-day postpartum thromboprophylaxis, preferred over no treatment even for low risks of postpartum VTE. This perspective from patients supports the urgent need for a randomized trial evaluating the efficacy and safety of postpartum thromboprophylaxis.

Heparin-induced thrombocytopenia with very high antibody titer is associated with slower platelet recovery and higher risk of thrombosis.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder mediated by platelet-activating antibodies targeting platelet factor 4 (PF4) and heparin complex. A higher antibody titer is reflected in a higher optical density (OD) by enzyme-linked immunosorbent assay for heparin-PF4 antibodies. This single-institution retrospective study of 116 HIT patients examined the effect of heparin-PF4 OD on time to platelet recovery, vascular thrombosis, and in-hospital mortality. Patients were divided into 3 cohorts based on heparin-PF4 OD: cohort 1 had an OD ≥ 2 and ≤ 2.4, cohort 2 had an OD > 2.4 and ≤ 2.8, and cohort 3 had an OD > 2.8. A higher OD titer was associated with significantly increased time to platelet recovery when compared between cohorts 1 versus 2 (HR = 0.599, p = 0.0221) and 1 versus 3 (HR = 0.515, p = 0.0014), as well as an increased risk of thrombosis (79.4%-cohort 3 vs 53.8%-cohort 2 vs 46.1%-cohort 1, p = 0.04), but had no impact on mortality (2.62-alive vs 2.65-deceased, p = 0.7432). A higher OD titer can inform risk assessment and support decision-making in HIT patients; however, prospective studies are needed to further clarify the impact of heparin-PF4 OD on outcomes.

Low-molecular-weight heparin ameliorates intestinal barrier dysfunction in aged male rats via protection of tight junction proteins.

The intestinal barrier weakens and chronic gut inflammation occurs in old age, causing age-related illnesses. Recent research shows that low-molecular-weight heparin (LMWH), besides anticoagulation, also has anti-inflammatory and anti-apoptotic effects, protecting the intestinal barrier. This study aims to analyze the effect of LMWH on the intestinal barrier of old male rodents. This study assigned Sprague-Dawley male rats to four groups: young (3 months), young + LMWH, old (20 months), and old + LMWH. The LMWH groups received 1 mg/kg LMWH via subcutaneous injection for 7 days. Optical and transmission electron microscopy (TEM) were used to examine morphological changes in intestinal mucosa due to aging. Intestinal permeability was measured using fluorescein isothiocyanate (FITC)-dextran. ELISA kits were used to measure serum levels of IL-6 and IL-1ß, while Quantitative RT-PCR detected their mRNA levels in intestinal tissues. Western blotting and immunohistochemistry (IHC) evaluated the tight junction (TJ) protein levels such as occludin, zonula occludens-1 (ZO-1), and claudin-2. Western blotting assessed the expression of the apoptosis marker cleaved caspase 3, while IHC was used to detect LGR5+ intestinal stem cells. The intestinal permeability of aged rats was significantly higher than that of young rats, indicating significant differences. With age, the protein levels of occludin and ZO-1 decreased significantly, while the level of claudin-2 increased significantly. Meanwhile, our study found that the levels of IL-1ß and IL-6 increased significantly with age. LMWH intervention effectively alleviated age-related intestinal barrier dysfunction. In aged rats treated with LMWH, the expression of occludin and ZO-1 proteins in the intestine increased, while the expression of claudin-2 decreased. Furthermore, LMWH administration in aged rats resulted in a decrease in IL-1ß and IL-6 levels. LMWH also reduced age-related cleaved caspase3 expression, but IHC showed no difference in LGR5+ intestinal stem cells between groups. Research suggests that LMWH could potentially be a favorable therapeutic choice for age-related diseases associated with intestinal barrier dysfunction, by protecting TJ proteins, reducing inflammation, and apoptosis.

Association of Metal Cations with the Anti-PF4/Heparin Antibody Response in Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against complexes of heparin and platelet factor 4 (PF4). The electrostatic interaction between heparin and PF4 is critical for the anti-PF4/heparin antibody response seen in HIT. The binding of metal cations to heparin induces conformational changes and charge neutralization of the heparin molecule, and cation-heparin binding can modulate the specificity and affinity for heparin-binding partners. However, the effects of metal cation binding to heparin in the context of anti-PF4/heparin antibody response have not been determined. Here, we utilized inductively coupled plasma mass spectrometry (ICP-MS) to quantify 16 metal cations in patient plasma and tested for correlation with anti-PF4/heparin IgG levels and platelet count after clinical suspicion of HIT in a cohort of heparin-treated patients. The average age of the cohort (n = 32) was 60.53 (SD = 14.31) years old, had a mean anti-PF4/heparin antibody optical density [OD405] of 0.93 (SD = 1.21) units, and was primarily female (n = 23). Patients with positive anti-PF4/heparin antibody test results (OD405 ≥ 0.5 units) were younger, had increased weight and BMI, and were more likely to have a positive serotonin release assay (SRA) result compared to antibody-negative patients. We observed statistical differences between antibody-positive and -negative groups for sodium and aluminum and significant correlations of anti-PF4/heparin antibody levels with sodium and silver. While differences in sodium concentrations were associated with antibody-positive status and correlated with antibody levels, no replication was performed. Additional studies are warranted to confirm our observed association, including in vitro binding studies and larger observational cohorts.

Efficacy and safety of direct oral anticoagulants for preventing venous thromboembolism in hospitalized cancer patients: a national multicenter retrospective cohort study.

Introduction: Studies on the use of direct oral anticoagulants (DOACs) for preventing venous thromboembolism (VTE) in hospitalized cancer patients are lacking. Therefore, we conducted a multicenter retrospective cohort study to evaluate the efficacy and safety of DOACs versus low-molecular-weight heparin (LMWH) for the primary prevention of VTE in hospitalized cancer patients. Methods: Clinical outcomes included thrombosis, VTE, other thrombosis, all bleeding, major bleeding, nonmajor bleeding, and all-cause death. A 1:1 cohort of rivaroxaban and LMWH patients was created by propensity score matching. Results: A total of 2,385 cancer patients were included in this study. During the 3-month follow-up period, 129 (5.4%) thrombosis events occurred, 63 (2.7%) of which were VTEs and 66 (2.8%) of which were other thrombosis events. All bleeding occurred in 163 (6.8%) patients, 68 (2.9%) had major bleeding, and 95 (4.0%) had nonmajor bleeding. All-cause deaths occurred in 113 (4.7%) patients. After adjusting for various confounders, the incidence of thrombosis and other thromboses was significantly lower in the rivaroxaban group than in the LMWH group [OR 0.543, 95% CI (0.343-0.859), p = 0.009; OR 0.461, 95% CI (0.241-0.883), p = 0.020]. There were no significant differences in incidence of VTE, total bleeding, major bleeding, nonmajor bleeding, or all-cause death. Conclusion: In oncology patients receiving thromboprophylaxis, rivaroxaban has a lower incidence of thrombosis and other thrombosis and a similar incidence of VTE as LMWH and does not increase the risk of bleeding. Rivaroxaban may be an attractive alternative to LMWH for preventing VTE in hospitalized cancer patients.

Heparin-induced thrombocytopenia after cardiac surgery. A single-center, retrospective cohort study.

Background: Cardiac surgery is a high-risk setting for heparin-induced thrombocytopenia (HIT). However, large differences in its incidence, rate of thrombotic complications, and mortality have been reported in this context. Few studies address the pharmacologic management of HIT specifically in this setting. Objectives: To describe the incidence, outcomes, and management of patients with HIT in our cohort and to compare them with patients presenting platelet factor 4/heparin antibodies but without platelet-activating capacity. Methods: A retrospective observational study was conducted over a period of 10 years and 6 months on 13,178 cardiac operations in a single high-volume cardiac surgery center. Results: HIT was diagnosed in 0.22% of patients. HIT with associated thromboembolic complications occurred in 0.04% of cases. Two deaths at 30 days were registered, both in patients with associated thrombosis. The 4T score showed a 99.9% negative predictive value. The immunoglobulin G-specific chemiluminescence test positivity rate was highly predictive of HIT. Warfarin was often started early after surgery, and although it was rarely stopped when the diagnosis of HIT was made, no new thromboembolic complications subsequently occurred. Thrombocytopenia appeared to be a poor prognostic sign, whatever the cause. Conclusion: Although rare, HIT is characterized by high mortality in this setting, especially if thrombotic complications occur. Large multicentric studies or an international registry should be created to enhance the scientific evidence on HIT diagnosis and management in this context.

Factor Xa inhibitors versus low-molecular-weight heparin for preventing coagulopathy following COVID-19: a systematic review and meta-analysis of randomized controlled trials.

Background: Hospitalized patients with COVID-19 have shown a significant occurrence of thromboembolism and a heightened risk of death. It remains unclear whether factor Xa inhibitors are superior to enoxaparin in this context. Hence, there is a need for a direct comparison to assess the preventive effects and safety of factor Xa inhibitors versus enoxaparin in hospitalized COVID-19 patients. Methods: MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials (RCTs) or retrospective studies that compared the effectiveness or safety of factor Xa inhibitors and enoxaparin in preventing thromboembolism in hospitalized patients with COVID-19. Embolic incidence, incidence of bleeding, and all-cause mortality were among the outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate relative risks (RRs) with 95 percent CIs. Results: The analysis included six RCTs and two retrospective studies containing 4048 patients. Meta-analysis showed a statistically significant reduction among patients on factor Xa inhibitors compared with low-molecular-weight heparin (LMWH) in the embolic incidence [risk ratio (RR) 0.64 (95%, CI 0.42, 0.98); P=0.04, I2=12%]. Upon subgroup analysis by type of study design, no significant reductions were noted in patients on factor Xa inhibitors in RCTs (RR: 0.62; 95% CI: 0.33-1.17; P=0.14) or observational studies (RR: 0.53; 95% CI: 0.23-1.26; P=0.15) when compared with enoxaparin Factor Xa inhibitors were not significantly associated with incidence of bleeding [RR 0.76 (95% CI 0.36, 1.61); P=0.47, I2=0%] or all-cause mortality (RR: 0.81; 95% CI: 0.48-1.36; P=0.43). Consistent results were obtained upon subgroup analysis by the type of study design. Conclusion: Factor Xa inhibitors are more effective than enoxaparin in preventing thromboembolism among patients with COVID-19 who are not acutely ill and are hospitalized. Additional rigorous RCTs comparing factor Xa inhibitors with enoxaparin are warranted.

B7-H3 enhances colorectal cancer progression by regulating HB-EGF via HIF-1α.

Background: B7-H3 (or CD276) represents an important costimulatory molecule expressed in many malignant solid tumors, including colorectal cancer (CRC). The receptor of B7-H3 is not known, and the intracellular function of B7-H3 remains obscure. Herein, we report that B7-H3 upregulated the epidermal growth factor heparin-binding epidermal growth factor (HB-EGF), likely by regulating hypoxia-inducible factor 1α (HIF-1α) and thereby promoting the progression of CRC. Methods: Lentiviral transfection was performed on CRC cells to establish stable low-B7-H3 expression cells. A mechanistic analysis with an Agilent human gene expression profiling chip was conducted on them. Clinical data and specimens were collected to detect the connection between B7-H3 and HB-EGF in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the messenger RNA (mRNA) level of B7-H3, HB-EGF, and HIF-1α. Chromatin immunoprecipitation (ChIP) quantitative real-time PCR was conducted. The protein level of HIF-1α and the phosphatidylinositide 3-kinases (PI3K)-protein kinase B (AKT) pathway were detected by western blot. HIF-1α was recovered by lentiviral transfection, and the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis ability were detected. Results: B7-H3 promoted tumor progression through HB-EGF and the PI3K-AKT pathway. As B7-H3 was downregulated, HB-EGF levels were significantly reduced simultaneously, a growth trend that was shown by both CRC cell lines and cancer tissues. In addition, B7-H3 and HB-EGF had significant associations with tumor-node-metastasis (TNM) stage and lymph node metastasis in 50 CRC patients. The binding ability of HIF-1α to the HB-EGF promoter region was significantly decreased in the shB7-H3 RKO group. Western blot revealed that PI3K, AKT, and mammalian target of rapamycin (mTOR) protein amounts and p-AKT and p-mTOR phosphorylation were also downregulated in shB7-H3 RKO cells, suggesting that B7-H3 may regulate HIF-1α via PI3K-AKT signaling. After recovery of the HIF-1α level by lentiviral transfection, the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis in CRC cells recovered as well. Conclusions: B7-H3 may transmit intracellular signals through PI3K-AKT-mTOR-HIF-1α signaling, upregulating HB-EGF. As the final transcription factor of the pathway, HIF-1α regulates the transcription of the HB-EGF gene, thereby promoting HB-EGF expression, which eventually mediates cell proliferation, invasion, and angiogenesis and promotes the progression of CRC.

Chemical Modification of Nanocrystalline Cellulose for Manufacturing of Osteoconductive Composite Materials.

Cellulose is one of the main renewable polymers whose properties are very attractive in many fields, including biomedical applications. The modification of nanocrystalline cellulose (NCC) opens up the possibility of creating nanomaterials with properties of interest as well as combining them with other biomedical polymers. In this work, we proposed the covalent modification of NCC with amphiphilic polyanions such as modified heparin (Hep) and poly(αL-glutamic acid) (PGlu). The modification of NCC should overcome two drawbacks in the production of composite materials based on poly(ε-caprolactone) (PCL), namely, (1) to improve the distribution of modified NCC in the PCL matrix, and (2) to provide the composite material with osteoconductive properties. The obtained specimens of modified NCC were characterized by Fourier-transform infrared spectroscopy and solid-state 13C nuclear magnetic resonance spectroscopy, dynamic and electrophoretic light scattering, as well as thermogravimetric analysis. The morphology of PCL-based composites containing neat or modified NCC as filler was studied by optical and scanning electron microscopy. The mechanical properties of the obtained composites were examined in tensile tests. The homogeneity of filler distribution as well as the mechanical properties of the composites depended on the method of NCC modification and the amount of attached polyanion. In vitro biological evaluation showed improved adhesion of human fetal mesenchymal stem cells (FetMSCs) and human osteoblast-like cells (MG-63 osteosarcoma cell line) to PCL-based composites filled with NCC bearing Hep or PGlu derivatives compared to pure PCL. Furthermore, these composites demonstrated the osteoconductive properties in the experiment on the osteogenic differentiation of FetMSCs.