Update on the Pharmacological Actions of Enoxaparin in Nonsurgical Patients.

Low-molecular-weight heparins are a class of drugs derived from the enzymatic depolymerization of unfractionated heparin that includes enoxaparin. Several studies have been performed on enoxaparin in recent years, in particular for the prevention and treatment of venous thromboembolism and for the treatment of acute coronary syndrome. Furthermore, the use of enoxaparin has been extended to other clinical situations that require antithrombotic pharmacological prevention, such as hemodialysis and recurrent abortion. In this review, we report the main clinical experiences of using enoxaparin in the prevention of VTE in nonsurgical patients.

Enoxaparin improves COVID-19 by reducing Neutrophils Extracellular Traps (NETs) production.

BACKGROUND: COVID-19 causes consequences such as imbalance of the immune system and thrombotic events. During the infection process, NETs in excess induce a pro-inflammatory response and disseminated intravascular coagulation. We evaluated the role of enoxaparin as a potential inhibitor of NETs. METHODS: K18-hACE2 animals infected with the SARS-CoV-2 virus and a group of 23 individuals admitted to the hospital with COVID-19 treated with enoxaparin or without treatment and controls without the disease were included. RESULTS: Enoxaparin decreased the levels of NETs, reduced the signs of the disease and mitigated lung damage in the animals infected with SARS-CoV-2. These effects were partially associated with prevention of SARS-CoV-2 entry and NETs synthesis. Clinical data revealed that treatment with enoxaparin decreased the levels of inflammatory markers, the levels of NETs in isolated neutrophils and the organ dysfunction. CONCLUSION: This study provides evidence for the beneficial effects of enoxaparin in COVID-19 in addition to its anticoagulant role.

Hemostatics in patients with inhibited coagulation-A viscoelastic in-vitro analysis.

BACKGROUND: The military has used topical hemostatic agents to successfully treat life-threatening external bleeding for years. In contrast to the military environment, the general population are increasingly prescribed anticoagulants. There are only few comparative evaluations of topical hemostatic agents with anticoagulated human blood. It is important to understand the impact of these agents on those who take anticoagulants. STUDY DESIGN AND METHODS: Citrated blood of patients treated with enoxaparin, heparin, and acetylsalicylic acid, apixaban or phenprocoumon was incubated with different hemostatic agents (QuikClot Gauze, Celox Granules, Celox Gauze, Chito SAM 100, WoundClot Trauma Gauze, QuikClot Gauze Moulage Trainer and Kerlix) and rotational thromboelastometry was performed with non-activated thromboelastometry (NATEM reagent). RESULTS: All tested agents improved the onset of coagulation in all anticoagulants, mostly to a significant degree. Most significant improvements were produced by QuikClot Gauze and QuikClot Gauze Moulage Trainer, followed by the tested chitosans (Celox Granules, Celox Gauze, Chito SAM 100). Of the anticoagulant groups, the most significant improvements were seen in enoxaparin. This was followed in order by apixaban, heparin, and acetylsalicylic acid, and phenprocoumon. DISCUSSION: All the hemostatic agents tested were able to activate the clotting cascade earlier and initiate faster clot formation in anticoagulated blood. A definitive head-to-head comparison is not feasible, because of the limitations of an in-vitro analysis. However, the sometimes-presented hypothesis that kaolin-based hemostatic agents are ineffective in anticoagulated blood is inaccurate according to our data. Hemostasis with hemostatic agents appears most challenging with phenprocoumon.

The Effectiveness of the Intermediate and Therapeutic Doses of Enoxaparin in COVID-19 Patients: A Comparative Study of Factor Xa Inhibition.

BACKGROUND: Management of anticoagulant therapy in COVID-19 patients is critical. Low-molecular-weight heparin (LMWH) thromboprophylaxis is already recommended, and anti-Factor Xa (anti-FXa) monitoring has been used to titrate LMWH doses. METHODS: Through a cross-sectional study, we evaluated anti-FXa activity in patients admitted to the ICU, receiving intermediate dose (30, 40, 50 mg, subcutaneously [SC], twice daily) or therapeutic dose (1 mg/kg, SC, Q12h) of enoxaparin to find whether the patients in these two groups achieved anti-FXa levels in the accepted thromboprophylaxis range. RESULTS: The occurrence of deep vein thrombosis was 26% in the therapeutic-dose group and 17% in the intermediate-dose group. D-dimer values were nearly 3.5-fold higher in those who received a therapeutic dose of anticoagulants than in those who received intermediate-dose thromboprophylaxis. Patients in the therapeutic-dose group had significantly higher IL-6 levels (p ≤ 0.001). More than one-third of the patients in the therapeutic-dose group (n = 8; 42.18%) and approximately half of the patients in the intermediate-dose group (n = 12; 52.2%) achieved the target range level of anti-FXa. Patients who received therapeutic doses were more likely to have anti-FXa levels above the expected range (47.4 vs 13% in the intermediate-dose group; p < 0.05). CONCLUSION: Therapeutic dose of enoxaparin in critically ill COVID-19-infected patients did not reduce the incidence of thromboembolic events and, on the other hand, may predispose these patients to increased risk of bleeding by increasing anti-FXa activity above the desired level. Administration of intermediate-dose thromboprophylaxis is suggested to achieve anti-FXa levels in the accepted thromboprophylaxis range.

Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives.

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has caused a pandemic of historic proportions and continues to spread globally, with enormous consequences to human health. Currently there is no vaccine, effective therapeutic, or prophylactic. As with other betacoronaviruses, attachment and entry of SARS-CoV-2 are mediated by the spike glycoprotein (SGP). In addition to its well-documented interaction with its receptor, human angiotensin-converting enzyme 2 (hACE2), SGP has been found to bind to glycosaminoglycans like heparan sulfate, which is found on the surface of virtually all mammalian cells. Here, we pseudotyped SARS-CoV-2 SGP on a third-generation lentiviral (pLV) vector and tested the impact of various sulfated polysaccharides on transduction efficiency in mammalian cells. The pLV vector pseudotyped SGP efficiently and produced high titers on HEK293T cells. Various sulfated polysaccharides potently neutralized pLV-S pseudotyped virus with clear structure-based differences in antiviral activity and affinity to SGP. Concentration-response curves showed that pLV-S particles were efficiently neutralized by a range of concentrations of unfractionated heparin (UFH), enoxaparin, 6-O-desulfated UFH, and 6-O-desulfated enoxaparin with 50% inhibitory concentrations (IC50s) of 5.99 µg/liter, 1.08 mg/liter, 1.77 µg/liter, and 5.86 mg/liter, respectively. In summary, several sulfated polysaccharides show potent anti-SARS-CoV-2 activity and can be developed for prophylactic as well as therapeutic purposes.IMPORTANCE The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in Wuhan, China, in late 2019 and its subsequent spread to the rest of the world has created a pandemic situation unprecedented in modern history. While ACE2 has been identified as the viral receptor, cellular polysaccharides have also been implicated in virus entry. The SARS-CoV-2 spike glycoprotein (SGP) binds to glycosaminoglycans like heparan sulfate, which is found on the surface of virtually all mammalian cells. Here, we report structure-based differences in antiviral activity and affinity to SGP for several sulfated polysaccharides, including both well-characterized FDA-approved drugs and novel marine sulfated polysaccharides, which can be developed for prophylactic as well as therapeutic purposes.

Impaired bone healing by enoxaparin via inhibiting the differentiation of bone marrow mesenchymal stem cells towards osteoblasts.

INTRODUCTION: Enoxaparin is widely used to prevent venous thromboembolism after orthopedic surgery and has some adverse effects, such as osteoporosis and delay in fracture healing. However, the exact mechanism delaying bone healing by enoxaparin is still unclear. MATERIALS AND METHODS: X-ray and Micro-CT scanning were performed to detect the effects of enoxaparin on bone healing at rat model of bone defeat. CCK-8 assay and flow cytometry were conducted to measure the effects of enoxaparin on bone marrow mesenchymal stem cells (BMSCs). The mRNA/protein levels of osteocalcin (OCN), runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 2 (BMP2) were analyzed by real-time PCR and western blotting, respectively. Alizarin red staining was used to observe the mineralized nodules. RESULTS: Enoxaparin (2000 AXaIU/kg) not only profoundly increased the trabecular separation, but also notably decreased the trabecular bone volume/tissue volume, trabecular thickness, trabecular number and OCN level, in vivo. Additionally, significantly inhibiting proliferation of BMSCs by enoxaparin (1.0 and 10 AXaIU/ml) was detected. The apoptosis and the ratio of G phase cells in enoxaparin (0.1, 1.0 and 10 AXaIU/ml) group were obviously higher than that in control group. While the ratio of S phase cells was downregulated markedly by enoxaparin (0.1,1.0 and 10 AXaIU/ml) compared with the control group. Most importantly, inducing significant decreases of OCN/Runx2 mRNA/protein expression and formation of mineralized nodules by enoxaparin (0.1, 1.0 and 10 AXaIU/ml) were observed compared with the control group. While the notable decreases of BMP2 mRNA/protein level were only detected in enoxaparin (10 AXaIU/ml) group. CONCLUSION: It was suggested that enoxaparin impaired bone healing through suppressing the differentiation of BMSCs towards osteoblasts.

Anti-factor X activity levels with continuous intravenous infusion and subcutaneous administration of enoxaparin after coronary artery bypass grafting: A randomized clinical trial.

BACKGROUND: Low-molecular-weight heparin enoxaparin is widely used in pharmacological thromboprophylaxis after coronary artery bypass grafting (CABG). The aim of this study was to compare anti-factor X activity (anti-Xa) levels when the thromboprophylactic dose of enoxaparin was provided after CABG, with two different administration routes: continuous intravenous infusion (CIV) and subcutaneous bolus (SCB) injection. We hypothesized that the current standard method of SCB administration might lead to lower anti-Xa levels than recommended in other patient groups, due to reduced bioavailability. METHODS: In this prospective, randomized, controlled clinical trial, 40 patients scheduled for elective CABG were randomized to receive 40 mg of enoxaparin per day either as CIV or SCB for 72 h. Enoxaparin was initiated 6-10 h after CABG. Anti-Xa levels were measured 12-14 times during the study period. The primary outcome, that is, the maximum anti-Xa concentration over 0-24 h (Cmax0-24h ), was calculated from these measured values. Secondary outcomes were Cmax25-72h and the trough concentration of anti-Xa after 72 h of enoxaparin initiation (C72h ). RESULTS: Twenty patients were randomized to the CIV-group and 19 to the SCB-group. The median anti-Xa Cmax0-24h was significantly lower in the CIV-group than in the SCB-group: 0.15 [interquartile range (IQR) 0.13-0.19] IU/ml versus 0.25 (IQR 0.18-0.32) IU/ml, p < .005. The median anti-Xa Cmax25-72h was 0.12 (IQR, 0.1-0.17) IU/ml versus 0.23 (IQR 0.19-0.31) IU/ml, respectively, p < .005. At 72 h, there was no difference between the groups in their anti-Xa levels. CONCLUSIONS: In this low-risk CABG patient population, SCB administration of a thromboprophylactic dose of enoxaparin provided anti-Xa levels that are considered sufficient for thromboprophylaxis in other patient groups. CIV administration resulted in lower anti-Xa levels compared to the SCB route.

Anticoagulant profile of subcutaneous enoxaparin in healthy dogs.

Our study objective was to identify a subcutaneous enoxaparin dosage that provided a consistent anticoagulant intensity in dogs. Our hypotheses were that a dose of 0.8 mg/kg would provide inconsistent anticoagulation, a higher dose would provide consistent anticoagulation over a greater duration of time, and viscoelastometry would effectively monitor the anticoagulant status. Six healthy dogs received two subcutaneous enoxaparin doses (0.8 and 2 mg/kg) for anti-Xa activity determinations and pharmacokinetic modeling. Based on calculations derived from these results, 1.3 mg/kg, SC, q8 h was administered for seven doses. Target ranges for anticoagulant intensity were defined as anti-Xa activity of 0.5-1 U/ml, and change from baseline of two viscoelastometric parameters: activated clotting time (ΔACT; ≥40 s), and clot rate (CRpost; ≤20 U/min). Following an initial injection at 1.3 mg/kg, anti-Xa activity of 5/6 dogs reached or exceeded the target range. Following the final dose, anti-Xa activity reached or exceeded the target range in all dogs, and ΔACT and CRpost values exceeded target for 2-6 and 4-12 h, respectively. At an enoxaparin dosage of 1.3 mg/kg, SC, q8 h, anti-Xa activity was consistently above the minimum threshold of the target range; however, the safety of this dosage remains to be determined.

LPS-Induced Coagulation and Neuronal Damage in a Mice Model Is Attenuated by Enoxaparin.

Background. Due to the interactions between neuroinflammation and coagulation, the neural effects of lipopolysaccharide (LPS)-induced inflammation (1 mg/kg, intraperitoneal (IP), n = 20) and treatment with the anti-thrombotic enoxaparin (1 mg/kg, IP, 15 min, and 12 h following LPS, n = 20) were studied in C57BL/6J mice. Methods. One week after LPS injection, sensory, motor, and cognitive functions were assessed by a hot plate, rotarod, open field test (OFT), and Y-maze. Thrombin activity was measured with a fluorometric assay; hippocampal mRNA expression of coagulation and inflammation factors were measured by real-time-PCR; and serum neurofilament-light-chain (NfL), and tumor necrosis factor-α (TNF-α) were measured by a single-molecule array (Simoa) assay. Results. Reduced crossing center frequency was observed in both LPS groups in the OFT (p = 0.02), along with a minor motor deficit between controls and LPS indicated by the rotarod (p = 0.057). Increased hippocampal thrombin activity (p = 0.038) and protease-activated receptor 1 (PAR1) mRNA (p = 0.01) were measured in LPS compared to controls, but not in enoxaparin LPS-treated mice (p = 0.4, p = 0.9, respectively). Serum NfL and TNF-α levels were elevated in LPS mice (p < 0.05) and normalized by enoxaparin treatment. Conclusions. These results indicate that inflammation, coagulation, neuronal damage, and behavior are linked and may regulate each other, suggesting another pharmacological mechanism for intervention in neuroinflammation.

Anti-Inflammatory Effects and Decreased Formation of Neutrophil Extracellular Traps by Enoxaparin in COVID-19 Patients.

Neutrophil Extracellular Traps (NETs) are a contributing factor of vascular thrombosis and alveolar damage in COVID-19 patients. As enoxaparin is currently used to inhibit vascular thrombosis, this study aimed to investigate whether enoxaparin also reduced inflammation and NETs in COVID-19 patients. Patients with COVID-19 infection were classified into three groups: mild, moderate, and severe (n = 10 for all groups). Plasma was collected from patients and healthy donors (n = 10). Neutrophils isolated from healthy controls were incubated with COVID-19 or healthy plasma, and with or without enoxaparin pretreatment in vitro. Neutrophils and plasma isolated from patients treated with enoxaparin were also investigated. The levels of inflammatory cytokines and NET products such as dsDNA, NE, MPO−DNA and Histone−DNA complexes in plasma and supernatants were measured using immunofluorescence staining and ELISA kits. The expression of inflammatory signaling genes by neutrophils (RELA, SYK, ERK and PKC) was measured using real-time qPCR. The levels of NET products were elevated in the plasma of COVID-19 patients, particularly in the severe group (p < 0.01). Moreover, plasma from the severe group enhanced NET formation (p < 0.01) from neutrophils in vitro. Enoxaparin pretreatment in vitro decreased plasma-induced NETs in a dose-dependent manner and down-regulated the expression of inflammatory genes (p < 0.05). Patients treated with prophylactic enoxaparin showed lower inflammatory cytokine levels and expression of inflammatory genes (p < 0.05). Increased NETs were associated with the severity of COVID-19 infection, particularly in patients with severe pneumonia, and could be used as biomarkers to assess disease severity. Enoxaparin pretreatment inhibited NETs and reduced the expression of inflammatory cytokines, and these effects mostly persisted in patients treated with prophylactic enoxaparin.

Identification of Kukoamine A, Zeaxanthin, and Clexane as New Furin Inhibitors.

The endogenous protease furin is a key protein in many different diseases, such as cancer and infections. For this reason, a wide range of studies has focused on targeting furin from a therapeutic point of view. Our main objective consisted of identifying new compounds that could enlarge the furin inhibitor arsenal; secondarily, we assayed their adjuvant effect in combination with a known furin inhibitor, CMK, which avoids the SARS-CoV-2 S protein cleavage by means of that inhibition. Virtual screening was carried out to identify potential furin inhibitors. The inhibition of physiological and purified recombinant furin by screening selected compounds, Clexane, and these drugs in combination with CMK was assayed in fluorogenic tests by using a specific furin substrate. The effects of the selected inhibitors from virtual screening on cell viability (293T HEK cell line) were assayed by means of flow cytometry. Through virtual screening, Zeaxanthin and Kukoamine A were selected as the main potential furin inhibitors. In fluorogenic assays, these two compounds and Clexane inhibited both physiological and recombinant furin in a dose-dependent way. In addition, these compounds increased physiological furin inhibition by CMK, showing an adjuvant effect. In conclusion, we identified Kukoamine A, Zeaxanthin, and Clexane as new furin inhibitors. In addition, these drugs were able to increase furin inhibition by CMK, so they could also increase its efficiency when avoiding S protein proteolysis, which is essential for SARS-CoV-2 cell infection.

Low-Molecular-Weight Heparins (LMWH) and Synthetic Factor X Inhibitors Can Impair the Osseointegration Process of a Titanium Implant in an Interventional Animal Study.

Background and objectives: Cementless total hip arthroplasty is a common surgical procedure and perioperative thromboprophylaxis is used to prevent deep vein thrombosis or pulmonary embolism. Osseointegration is important for long-term implant survival, and there is no research on the effect of different thromboprophylaxis agents on the process of osseointegration. Materials and Methods: Seventy rats were allocated as follows: Group I (control group), Group II (enoxaparin), Group III (nadroparin), and Group IV (fondaparinux). Ovariectomy was performed on all subjects, followed by the introduction of an intramedullary titanium implant into the femur. Thromboprophylaxis was administered accordingly to each treatment group for 35 days postoperatively. Results: Group I had statistically significantly lower anti-Xa levels compared to treatment groups. Micro-CT analysis showed that nadroparin had lower values compared to control in bone volume (0.12 vs. 0.21, p = 0.01) and percent bone volume (1.46 vs. 1.93, p = 0.047). The pull-out test showed statistically significant differences between the control group (8.81 N) compared to enoxaparin, nadroparin, and fondaparinux groups (4.53 N, 4 N and 4.07 N, respectively). Nadroparin had a lower histological cortical bone tissue and a higher width of fibrous tissue (27.49 µm and 86.9 µm) at the peri-implant area, compared to control (43.2 µm and 39.2 µm), enoxaparin (39.6 µm and 24 µm), and fondaparinux (36.2 µm and 32.7 µm). Conclusions: Short-term administration of enoxaparin, nadroparin, and fondaparinux can reduce the osseointegration of titanium implants, with nadroparin having the most negative effect. These results show that enoxaparin and fondaparinux are preferred to be administered due to a lesser negative impact on the initial implant fixation.

Prolonged enoxaparin therapy compared with standard-of-care antithrombotic therapy in opiate-treated patients undergoing primary percutaneous coronary intervention.

A novel enoxaparin regimen consisting of intra-arterial bolus (0.75 mg/kg) followed by intravenous infusion (0.75 mg/kg/6 hours) has been developed as a possible solution to the delayed absorption of oral P2Y12 inhibitors in opiate-treated ST-elevation myocardial infarction (STEMI) patients undergoing primary angioplasty. We aimed to study the feasibility of this regimen as an alternative to standard-of-care treatment (SOC) with unfractionated heparin ± glycoprotein IIb/IIIa antagonist (GPI). One hundred opiate-treated patients presenting with STEMI and accepted for primary angioplasty were randomized (1:1) to either enoxaparin or SOC. Fifty patients were allocated enoxaparin (median age 61, 40% females) and 49 allocated SOC (median age 62, 22% females). One developed stroke before angiography and was withdrawn. One SOC patient had a gastrointestinal bleed resulting in 1 g drop in hemoglobin and early cessation of GPI infusion. Two enoxaparin patients had transient minor bleeding: one transient gingival bleed and one episode of coffee ground vomit with no hemoglobin drop or hemodynamic instability. Two SOC and no enoxaparin group patients had acute stent thrombosis. These preliminary data support further study of this novel 6-hour enoxaparin regimen in opiate-treated PPCI patients.

Oral administration of dermatan sulphate reduces venous thrombus formation in vivo: potential use as a formulation for venous thromboembolism.

Dermatan sulphate (DS) is a sulphated polysaccharide that displays complexity in constituent sulphated disaccharides and interacts with proteins and signalling molecules to modulate numerous biological processes, including inhibition of the coagulation cascade and regulation of blood clotting and fibrinolysis. This study shows the antithrombotic and anticoagulant effects of DS prepared from bovine collagen waste liquor following oral and intravenous administrations in a deep vein thrombosis (DVT) rabbit model. In vitro, the prothrombin time, activated partial thromboplastin time, and thrombin citrated plasma clotting assays revealed that bovine DS had strong antithrombotic and anticoagulant effects comparable to low-molecular-weight heparin [Clexane® (enoxaparin sodium)]. In a DVT rabbit model, animals received intravenous and oral administrations of bovine DS and Clexane® providing further evidence that both agents had strong antithrombotic and anticoagulant effects by significantly reducing or preventing clot formation. Thromboelastography (TEG) assays revealed further that both bovine DS and Clexane® substantially prolonged the clotting time of recalcified citrated whole blood, but only bovine DS could retain clot strength suggesting that bovine DS had less effect on platelet-fibrin interactions. In conclusion, this is the first report that oral administration of DS from bovine collagen waste liquor reduces experimental venous thrombus formation warranting further research into bovine DS as an oral antithrombotic therapeutic.

Efficacy and safety of bemiparin compared with enoxaparin: Meta-analysis of randomized controlled trials.

BACKGROUND: Potential advantages of bemiparin compared to enoxaparin are a longer half-life, once-a-day dosage, and possibly a better safety profile due to the more selective antagonistic action toward Xa coagulation factor. We evaluated the efficacy and safety of bemiparin compared with enoxaparin as prophylaxis or treatment of venous thromboembolic disease. MATERIALS AND METHODS: We searched PubMed, Embase, Cochrane Library, Clinical Trials.gov, Google academics, and Conference Abstracts (2014 - 2019) of the American Society of Hematology and the Spanish Society of Hematology and Hemotherapy. Randomized trials that included bemiparin and enoxaparin were included as treatment arms. The outcomes evaluated were the incidence of venous thromboembolic disease and the proportion of adverse events in each group. Two independent researchers selected, evaluated, and extracted the data in duplicate. Four studies with a total of 5,473 patients were included. RESULTS: Most patients were included in prevention studies (N = 5,161). Bemiparin proved the non-inferiority in terms of efficacy with respect to enoxaparin (relative risk: 0.76; 95% confidence interval (95% CI): 0.56 - 1.01; p = 0.06) (heterogeneity I2 = 34%). We recorded 222 adverse events in 2,742 patients treated with bemiparin and 288 adverse events in 2,731 patients treated with enoxaparin (8.1 vs. 10.5 adverse events per 100 patients, respectively; p = 0.003). However, the meta-analysis for safety showed a significant heterogeneity making not possible to pool the result across the trials. CONCLUSION: Bemiparin proved a non-inferior efficacy compared to enoxaparin with a significant reduction in adverse events per 100 patients treated.

Effects of anticoagulant drugs on wound healing process in a rat model: a comparative study.

OBJECTIVE: This study aims to compare the efficacy of enoxaparin, rivoraxaban and dabigatran on wound healing using a rat model. METHOD: Sprague-Dawley female rats (n=56), 10-12 weeks old, weight 245±30g, were used in this study. The rats were divided into four equally-sized groups. A type 1 (secondary wound healing) and type 2 (primary wound healing) wound was opened surgically on each rat in each group. Anticoagulent drugs enoxaparin, rivoraxaban and dabigatran and physiological saline solution were administered to Groups 1, 2, 3 and 4, respectively. After wound healing was scored tissue samples were taken from euthanised rats at days five and 10 and examined histologically. Since time was used as a classification (days five and 10), a time effect was included. RESULTS: There was no statistically significant difference in total score distribution in rats between type 1 secondary wounds for days five and 10 (p>0.05). There was no statistically significant difference in the overall score distribution in rats between type 2 primary wounds for days five and 10 (p>0.05). CONCLUSION: In addition to the use of low molecular weight heparin with well-known anticoagulation activity, the new generation oral medications are used efficiently in thromboembolic diseases. However, there was no evidence observed in this study that these drugs could be either beneficial or harmful to wound healing.

Low-Molecular-Weight Heparin Reduces Ventilation-Induced Lung Injury through Hypoxia Inducible Factor-1α in a Murine Endotoxemia Model.

Patients with sepsis frequently require mechanical ventilation (MV) to survive. However, MV has been shown to induce the production of proinflammatory cytokines, causing ventilator-induced lung injury (VILI). It has been demonstrated that hypoxia-inducible factor (HIF)-1α plays a crucial role in inducing both apoptotic and inflammatory processes. Low-molecular-weight heparin (LMWH) has been shown to have anti-inflammatory activities. However, the effects of HIF-1α and LMWH on sepsis-related acute lung injury (ALI) have not been fully delineated. We hypothesized that LMWH would reduce lung injury, production of free radicals and epithelial apoptosis through the HIF-1α pathway. Male C57BL/6 mice were exposed to 6-mL/kg or 30-mL/kg MV for 5 h. Enoxaparin, 4 mg/kg, was administered subcutaneously 30 min before MV. We observed that MV with endotoxemia induced microvascular permeability; interleukin-6, tumor necrosis factor-α, macrophage inflammatory protein-2 and vascular endothelial growth factor protein production; neutrophil infiltration; oxidative loads; HIF-1α mRNA activation; HIF-1α expression; bronchial epithelial apoptosis; and decreased respiratory function in mice (p < 0.05). Endotoxin-induced augmentation of VILI and epithelial apoptosis were reduced in the HIF-1α-deficient mice and in the wild-type mice following enoxaparin administration (p < 0.05). Our data suggest that enoxaparin reduces endotoxin-augmented MV-induced ALI, partially by inhibiting the HIF-1α pathway.

Weight-Based Enoxaparin for Venous Thromboembolism in Obesity Gives Similar Anti-Xa Levels to Patients <100 kg, with No Increase in Major Bleeding.

In trials assessing venous thromboembolism (VTE) treatment, obese patients are under-represented or excluded. The main objective of this article is to examine the safety of weight-based enoxaparin dosing in obesity, as assessed by anti-factor Xa (anti-Xa) activity, bleeding, and recurrence. A 5-year retrospective audit of patients with acute VTE, weighing > 100 kg, prescribed enoxaparin 1 mg/kg twice daily, with an anti-Xa level 2 to 6 hours post-dose. The primary outcome was anti-Xa levels, and the secondary outcomes were bleeding and recurrence. Results were compared with patients weighing < 100 kg (n = 64), and obese patients prescribed doses < 1 mg/kg (n = 28). One-hundred sixty-six patients weighing > 100 kg with VTE were identified, with 64 excluded for not fulfilling criteria. The remaining 102 patients had a median weight of 130 kg (range: 105-222 kg). The median peak anti-Xa level was 0.93 U/mL, with 56% of levels being in the proposed therapeutic range (0.5-1.0 U/mL), 40% > 1.0 U/mL, and 4% < 0.5 U/mL. The median anti-Xa levels and distribution were not significantly different between patients > 100 kg and patients < 100 kg, while obese patients prescribed < 1 mg/kg were more frequently subtherapeutic (21%). Regardless of weight, the majority of patients with moderate renal impairment (eGFR 30-59 mL/min) had an anti-Xa level > 1.0 U/mL (61%). In the obese patients, there was no major bleeding or recurrence within 30 days. In comparison, patients weighing < 100 kg, despite similar peak anti-Xa levels, had higher rates of bleeding and recurrence. This was likely due to their older age and comorbidities, particularly renal impairment and cancer. These data support weight-based dosing of enoxaparin in obesity with no maximum dose, ensuring therapeutic drug levels, with anti-Xa levels suggested in obese patients with clinical risk factors for bleeding.

Prophylactic protocol for dental care in ligneous gingivitis due to severe plasminogen deficiency: Case report and review of literature.

INTRODUCTION: Severe plasminogen (PLG) deficiency causes ligneous conjunctivitis, a rare disease characterized by the growth of fibrin-rich pseudomembranes on mucosal surfaces; gums involvement leads to ligneous gingivitis (LG). Specific therapy for LG is not available yet. We report a prophylactic treatment with enoxaparin and fresh frozen plasma (FFP) for invasive dental procedures in a patient with LG, and a review of literature on LG treatment. METHODS: A 43-year-old female with LG was studied. In order to prevent LG recurrence after dental care, FFP before and the day after the procedure, and enoxaparin were administered in addition to proper minimally invasive dentistry techniques and implant surgery. RESULTS: Plasminogen deficiency was confirmed by reduced PLG antigen (25 µg/mL) and activity (20%) levels, and genetic analysis. PLG levels rose to 46% after FFP transfusion and returned to baseline after 48 hours. Minimally invasive dental procedures and implants were performed. Small gingival pseudomembranes developed soon thereafter in some cases but disappeared within a few weeks; no bleeding complications were observed. CONCLUSIONS: In our patient with LG, the adoption of combined haematological and dentistry protocols appeared to be safe and effective in preventing abnormal gingival pseudomembranes growth after dental interventions, maintaining a healthy periodontal condition.

Evaluation of Treatment-Dose Enoxaparin in Acutely Ill Morbidly Obese Patients at an Academic Medical Center: A Randomized Clinical Trial.

BACKGROUND: Enoxaparin dosing recommendations for morbidly obese patients are lacking. Retrospective and observational studies reported goal anti-Xa levels with a median dose of 0.8 mg/kg using total body weight. Further studies are needed to determine if a more conservative dosing strategy is warranted. OBJECTIVE: To determine if reduced dose enoxaparin was more effective than standard dose at achieving goal anti-Xa levels in morbidly obese patients. METHODS: A prospective, randomized, controlled study was conducted in patients with a body mass index (BMI) ≥40 kg/m2. Patients were randomized to standard (1 mg/kg) or reduced dose (0.8 mg/kg) enoxaparin every 12 hours. The primary outcome was the proportion of patients with an initial anti-Xa at goal (0.5-1.1 IU/mL). RESULTS: A total of 62 patients were enrolled and randomized to 1 mg/kg (n = 32) or 0.8 mg/kg (n = 30), and 54 patients completed the study. The study did not meet accrual for 80% power. Goal anti-Xa levels were achieved in a similar proportion for the reduced-dose (n = 25/28) and standard dose arms (n = 20/26; 89.3% vs 76.9%; P = 0.29). Overall, 9 patients required dose adjustments, of which 6 were in the 1-mg/kg arm, and all were above goal. No documented bleeding or thrombotic events were reported. CONCLUSIONS AND RELEVANCE: This was the first randomized, controlled trial of enoxaparin dosing in patients with a BMI ≥40 kg/m2. Overall, 89% of patients had a goal anti-Xa when initiated on 0.8 mg/kg. Based on the results, reduced dose enoxaparin may be a reasonable dosing strategy in morbidly obese patients.