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OBJECTIVES Enoxaparin for the prevention of venous thromboembolism (VTE) in pediatric patients is typically dosed twice a day. The use of once-daily dosing like that used in adult patients is limited because of a lack of safety and efficacy data. The aim of this study was to evaluate the safety and efficacy of once-daily versus twice-daily dosing of enoxaparin for pediatric VTE prophylaxis based on incidence of thrombotic and bleeding events. METHODS This was a 3-year retrospective chart review of enoxaparin received for VTE prophylaxis at Cohen Children's Medical Center, New Hyde Park, NY. Exclusion criteria were age 18 years or older, and renal dysfunction. RESULTS A total of 177 enoxaparin courses (81 in the once-daily and 96 in the twice-daily group) were included. The median dose in the once-daily group was 0.68 mg/kg/dose with dose capping at 40 mg/dose in 70% of patients. One patient in the once-daily group had a VTE, whereas no patients in the twice-daily group experienced a VTE. One major bleeding event occurred in the once-daily group (p = 0.46); however, minor bleeding events were comparable between the 2 groups (p = 0.69). CONCLUSIONS Once-daily enoxaparin prophylaxis appears to be safe and effective based on minimal differences in incidence of thrombotic and bleeding events when compared to twice-daily dosing. Based on this study, it may be reasonable to consider once-daily enoxaparin dosing for prophylaxis, especially in older children. A larger multicenter cohort study evaluating once-daily dosing for prophylaxis is warranted to validate the safety and efficacy specifically for risk-based dosing strategies. [ABSTRACT FROM AUTHOR]

Abstract Background This study compares the symptomatic 90-day venous thromboembolism (VTE) rates in patients receiving aspirin to patients receiving low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs), after total hip (THA) and total knee arthroplasty (TKA). Methods Data were collected from a multi-centre cohort study, including demographics, confounders and prophylaxis type (aspirin alone, LMWH alone, aspirin and LMWH, and DOACs). The primary outcome was symptomatic 90-day VTE. Secondary outcomes were major bleeding, joint related reoperation and mortality within 90 days. Data were analysed using logistic regression, the Student’s t and Fisher’s exact tests (unadjusted) and multivariable regression (adjusted). Results There were 1867 eligible patients; 365 (20%) received aspirin alone, 762 (41%) LMWH alone, 482 (26%) LMWH and aspirin and 170 (9%) DOAC. The 90-day VTE rate was 2.7%; lowest in the aspirin group (1.6%), compared to 3.6% for LMWH, 2.3% for LMWH and aspirin and 2.4% for DOACs. After adjusted analysis, predictors of VTE were prophylaxis duration

Splanchnic vein thrombosis (SVT) is an uncommon manifestation of venous thromboembolism in the splanchnic venous system, with scarce evidence surrounding its management. We assessed the efficacy and safety of direct oral anticoagulant (DOAC) to low-molecular-weight heparins (LMWH), vitamin-k antagonists (VKAs), or no anticoagulation. We conducted a systematic review and meta-analysis with the primary efficacy outcome being complete recanalization of affected vessels and primary safety outcome being major bleeding. Meta-analysis was done using a random-effects model, with dichotomous outcomes being synthesized with odds ratios (ORs) and corresponding 95 % CIs. Seven non-randomized and one randomized study involving 883 participants were included for analysis. DOACs were more effective than VKAs (OR = 4.33; 95 % CI: 2.4, 7.83; n = 1 study) in non-cirrhotic patients and no anticoagulation in cirrhotic patients (OR = 3.86; 95 % CI: 1.49, 10.03; n = 3 studies). DOACs had a statistically significant reduction in major bleeding compared to observation [OR = 0.09; 95 % CI: 0.03, 0.29; n = 3 studies], LMWHs [OR = 0.13; 95 % CI: 0.03, 0.29; n = 1 study] and VKAs [OR = 0.12; 95 % CI: 0.02, 0.69; n = 2 studies] in non-cirrhotic patients. No difference in major bleeding was found between DOACs and observation, LMWH, or VKAs in cirrhotic patients. DOACs appear to be a favorable alternative to VKAs and LMWHs in non-cirrhotic patients. This avenue of research would benefit from larger studies that adjust for SVT etiologies, patient risk factors, and overall bleeding risk. [Display omitted] • DOACs appeared more effective than VKAs or observation in non-cirrhotic patients. • DOACs appeared safer than VKAs, LMWH, or observation in non-cirrhotic patients. • Similar safety between DOACs and observation, LMWH, or VKAs in cirrhotic patients [ABSTRACT FROM AUTHOR]

Background: This study compares the symptomatic 90-day venous thromboembolism (VTE) rates in patients receiving aspirin to patients receiving low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs), after total hip (THA) and total knee arthroplasty (TKA). Methods: Data were collected from a multi-centre cohort study, including demographics, confounders and prophylaxis type (aspirin alone, LMWH alone, aspirin and LMWH, and DOACs). The primary outcome was symptomatic 90-day VTE. Secondary outcomes were major bleeding, joint related reoperation and mortality within 90 days. Data were analysed using logistic regression, the Student's t and Fisher's exact tests (unadjusted) and multivariable regression (adjusted). Results: There were 1867 eligible patients; 365 (20%) received aspirin alone, 762 (41%) LMWH alone, 482 (26%) LMWH and aspirin and 170 (9%) DOAC. The 90-day VTE rate was 2.7%; lowest in the aspirin group (1.6%), compared to 3.6% for LMWH, 2.3% for LMWH and aspirin and 2.4% for DOACs. After adjusted analysis, predictors of VTE were prophylaxis duration < 14 days (OR = 6.7, 95% CI 3.5–13.1, p < 0.001) and history of previous VTE (OR = 2.4, 95% CI 1.1–5.8, p = 0.05). There were no significant differences in the primary or secondary outcomes between prophylaxis groups. Conclusions: Aspirin may be suitable for VTE prophylaxis following THA and TKA. The comparatively low unadjusted 90-day VTE rate in the aspirin group may have been due to selective use in lower-risk patients. Trial Registration: This study was registered at ClinicalTrials.gov, trial number NCT01899443 (15/07/2013). [ABSTRACT FROM AUTHOR]

Abstract Objective The present study describes the preferences and current practices of a sample of knee surgeons in Brazil regarding thromboprophylaxis in total knee arthroplasty (TKA). Method In the present internet survey, surgeons from the Brazilian Knee Surgery Society (SBCJ, in the Portuguese acronym) voluntarily answered an anonymous questionnaire including time of personal surgical experience, perceptions about the best thromboprophylaxis options, and actual practices in their work environment. Results From December 2020 to January 2021, 243 participants answered the questionnaire. All, except for 3 (1.2%), reported using thromboprophylaxis, and most (76%) combined pharmacological and mechanical techniques. The most prescribed drug was enoxaparin (87%), which changed to rivaroxaban (65%) after discharge. The time of thromboprophylaxis initiation varied according to the length of training of the knee surgeon (p ≤ 0.03), and their preferences and practices differed according to the Brazilian region (p< 0.05) and the health system in which the surgeons work (public or private sector; p= 0.024). The option for mechanical thromboprophylaxis also depended on the training time of the surgeon. Conclusion Thromboprophylaxis preferences and practices in TKA are diverse across Brazilian regions and health systems (public or private sectors). Given the lack of a national clinical guideline, most orthopedists follow either their hospital guidelines or none. The mechanical prophylaxis method and the little use of aspirin are the points that most diverge from international guidelines and practices.

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. [ABSTRACT FROM AUTHOR]

Heparin and heparan sulfate are important glycosaminoglycans that can regulate the activities of many vital proteins, especially the fibroblast growth factor (FGF) family. Because FGF7 (KGF) has an important role in tissue repair and maintaining the integrity of the mucosal barrier, recombinant human keratinocyte growth factor (rhKGF, palifermin) has been approved for the treatment of wound healing and oral cavity. Due to heparin plays an important role in the KGF signaling pathway, a more detailed study of the drug–drug interactions (DDIs) between rhKGF and heparin at the atomic level and investigating their synergistic effect on each other in terms of biology, especially in silico, is necessary for a better understanding of DDIs. In this study, DDIs between rhKGF and low‐molecular weight heparin types (LMWH) were investigated. In this regard, scrutiny of the influence of the synergistic heparin types on the structure and biostability of rhKGF is accomplished using computational methods such as molecular docking and molecular dynamic simulations (MDs). Subsequently, the motion behavior of rhKGF in interaction with LMWHs was evaluated based on eigenvectors by using principal component analysis (PCA). Also, the binding free energies of rhKGF‐LMWH complexes were calculated by the molecular mechanics/Poisson–Boltzmann surface area (MM‐BPSA) method. The result showed that rhKGF‐idraparinux (−6.9 kcal/mol) and rhKGF‐heparin (−6.0 kcal/mol) complexes had significant binding affinity as well as they had a more stable binding to rhKGF than to other LMWH during 100 ns simulation. However, in order to confirm the curative effect of these drugs, clinical trials must be done. [ABSTRACT FROM AUTHOR]

Accumulated evidence suggest that the adverse outcome of severe coronavirus disease 2019 (COVID-19) is closely related to prothrombotic microvascular pathology with a high risk of venous thromboembolism. Furthermore, the first observational studies indicated that adjunct therapy with low-molecular weight heparin (LMWH) was associated with lower mortality in this cohort of patients. However, the timing of starting LMWH and the dose remain controversial in COVID-19 patients. Considering the above, the aim of this study was to reveal the rationale for using LMWH in the therapy of symptomatic COVID-19 patients based on experimental and clinical studies on LMWH in inflammatory settings with special consideration given to randomized trials.

Objective: The aim of this study was to assess the utilization of surgical interventions in patients diagnosed with superficial vein thrombosis (SVT) and its potential association with the occurrence of venous thromboembolism (VTE) and bleeding events., Methods: INSIGHTS-SVT, a prospective, non-interventional, multicenter study in Germany, investigated the management and outcomes of patients with acute SVT who received conservative and/or invasive treatments at the discretion of the treating physician., Results: Among the 872 patients with 12-month data, 657 had medical therapy only, and 215 patients underwent vascular surgery (70 within 3 months of SVT diagnosis, 136 between months 4 and 12, and nine had an intervention in both periods). The most commonly performed procedures included endovenous thermal ablation, ligation of the saphenofemoral or saphenopopliteal junction, and vein stripping. The primary outcome of symptomatic VTE was observed in 5.8% of conservatively treated patients and 6.3% of those who underwent surgical intervention. Additionally, the secondary outcome of recurrent or extended SVT was documented in 4.7% of conservatively treated patients and 5.3% of invasively treated patients. Bleeding events occurred in 1.4% of conservatively treated patients and 2.1% of surgically treated patients. These differences were statistically not significant. Furthermore, our analysis indicated a potential protective effect associated with surgical treatments, such as ligation of the saphenofemoral or saphenopopliteal junction, stripping and endovenous thermal ablation, concerning the endpoint of VTE for patients when applied after 3 months from the index SVT event., Conclusions: In line with previous research, our study suggests that surgical interventions are not frequently employed in the management of SVT, although they may be warranted in select cases. Nevertheless, additional research is essential to gain a deeper understanding of the indications, criteria, and benefit of surgical interventions in the treatment of SVT., Competing Interests: Disclosures E.R. has received honoraria for lectures and advisory boards from Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Leo Pharma, and Pfizer. R.B. has received research support from AFNET, CPC, and FADOI; and honoraria from Bayer, BMS, Leo, Pfizer, and Viatris. H.G. has received honoraria for lectures and advisory boards from Aspen, Mylan, Bayer, and Boehringer-Ingelheim. D.P. has received honoraria for consultancy, advisory boards, or lectures by Actelion, Bayer, Biogen, Aspen, Amgen, MSD, Boehringer Ingelheim, Novartis, Daiichi Sankyo, Genzyme, and Zambon. F.L. has received honoraria for lectures or consultancy from Aspen, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, LEO Pharma, Pfizer, Sanofi, and Viatris. U.H. has received research support and honoraria for lectures and advisory boards from Bayer HealthCare Pharmaceuticals, Bristol-Myers-Squibb, Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Leo Pharma, and Aspen. T.N. has received honoraria for consultancy from Medi Bayreuth; and honoraria for presentations from Aspen, Bayer, Bristol-Myers Squibb, and Mylan. A.H. was, at the time of the study, a full-time employee of Aspen Pharma GmbH, Munich, and is now an employee of Amgen GmbH, Germany. A.S. is a full-time employee of Mylan Germany GmbH, Germany., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Studies available in the literature have shown alterations in blood coagulation tests in severe cases of COVID-19 pneumonia, with a significant risk of venous thromboembolism (VTE). Since microvascular thrombosis is a well-known fact in COVID-19 disease, requiring therapeutic anticoagulation, low-molecular weight heparin (LMWH) in prophylactic dose is a part of the clinical management of hospitalized COVID-19 patients. In this scenario, we describe three cases of abdominal spontaneous retroperitoneal hematoma (SRH) in hospitalized reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed COVID-19 patients.

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. [ABSTRACT FROM AUTHOR]

Low‐molecular weight heparins (LMWH) are widely used for preventing clotting during hemodialysis (HD). Although injection in the venous blood line is recommended to avoid initial loss of LMWH through the dialyzer, LMWH is still frequently administered in the arterial blood line at the start of dialysis. This study aimed to compare the safety and efficacy of the same enoxaparin dose administered through the venous blood line or arterial blood line. We also evaluated antifactor Xa (aXa) activity according to the injection route and dialysis modalities: high‐flux (HF) HD, medium cut‐off (MCO) HD, and online hemodiafiltration (OL‐HDF). Forty‐three patients were studied over 18 consecutive dialysis sessions using a fixed enoxaparin dose (20 or 40 mg), first administered through the arterial blood line bolus and then through the venous blood line for another 18 sessions. Compared to arterial blood line administration, venous blood line bolus resulted in a significant increase in median post‐dialysis aXa activity: 0.16 (0.1–0.6) IU/ml versus 0.31 (0.1–1.3) IU/ml, respectively, p = 0.006. After arterial blood line bolus of 40 mg enoxaparin, median post‐dialysis aXa activity was significantly lower with OL‐HDF compared to HF‐HD: 0.14 (0.1–0.35) versus 0.32 (0.15–0.49), p = 0.02. A trend for lower clotting within lines and bubble trap using venous blood line bolus was observed. In conclusion, venous blood line enoxaparin injection is safe in OL‐HDF patients. However, in HF‐HD and MCO‐HD, venous blood line injection of 40 mg enoxaparin may increase overdosing risk. Thus, aXa activity should be monitored in HF‐HD and MCO‐HD patients at risk of bleeding and/or on vitamin K antagonists and careful surveillance is required when administering a 40 mg enoxaparin dose through the venous blood line route. [ABSTRACT FROM AUTHOR]

Plasminogen activator inhibitor type 1 (PAI-1) is a main inhibitor of fibrinolysis. The PAI-1 gene ( SERPINE1 ) harbors genetic variants with the potential of modifying plasma levels of PAI-1. A delicate balance exists between the coagulation and fibrinolytic system, and changes in PAI-1 have been suggested to compromise establishment of a successful pregnancy. Therefore, this systematic review investigated the association between genetic variants and/or plasma levels of PAI-1 and placenta-mediated pregnancy complications. An extensive literature search was conducted in PubMed, Embase, and Web of Science on the 29 th of April 2021. All studies underwent quality rating according to The Study Quality Assessment Tools checklist provided by National Heart, Lung and Blood Institute. A total of 71 studies were included, among which 60 studies investigated PAI-1 genotypes and 11 studies measured PAI-1 plasma levels. In 32 out of 59 studies, no association was found between the PAI-1 4G/5G polymorphism (rs1799768) and placenta-mediated pregnancy complications, which was stated as no significant difference in the genotype distribution comparing women with and without placenta-mediated pregnancy complications or no significantly increased odds of placenta-mediated pregnancy complications carrying the 4G/4G or 4G/5G genotype. Eight out of 11 studies reported significantly higher PAI-1 plasma levels in preeclamptic women than in women without preeclampsia. In conclusion, no clear evidence indicates that PAI-1 polymorphisms are associated with placenta-mediated pregnancy complications, and the possible association between high PAI-1 plasma levels and preeclampsia needs further investigations. Thus, investigation of PAI-1 genotypes and PAI-1 plasma levels does not currently seem to have a place in daily clinical practice managing placenta-mediated pregnancy complications. [ABSTRACT FROM AUTHOR]

Critically ill COVID‐19 patients are at high risk of thromboembolic events despite routine‐dosed low‐molecular‐weight heparin thromboprophylaxis. However, in recent randomized trials increased‐intensity thromboprophylaxis seemed futile and possibly even harmful. In this explorative pharmacokinetic (PK) study we measured anti‐Xa activities on frequent timepoints in 15 critically ill COVID‐19 patients receiving dalteparin and performed PK analysis by nonlinear mixed‐effect modelling. A linear one‐compartment model with first‐order kinetics provided a good fit. However, wide interindividual variation in dalteparin absorption (variance 78%) and clearance (variance 34%) was observed, unexplained by routine clinical covariates. Using the final PK model for Monte Carlo simulations, we predicted increased‐intensity dalteparin to result in anti‐Xa activities well over prophylactic targets (0.2‐0.4 IU/mL) in the majority of patients. Therapeutic‐intensity dalteparin results in supratherapeutic anti‐Xa levels (target 0.6‐1.0 IU/mL) in 19% of patients and subtherapeutic levels in 22%. Therefore, anti‐Xa measurements should guide high‐intensity dalteparin in critically ill COVID‐19 patients. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a common complication in patients with cancer. Warfarin has largely been replaced by low-molecular-weight heparin (LMWHs) and direct oral anticoagulants (DOACs) as the standard of care in cancer-associated VTE. The survival benefit of these anticoagulants over warfarin in the cancer population has not been demonstrated in clinical trials. There are emerging population-based studies suggesting that warfarin may be associated with improved overall survival in cancers. Warfarin has anti-neoplastic activity mediated through both coagulation pathway -dependent and -independent mechanisms, the latter of which includes inhibition of the Gas6-AXL signaling pathway. Further research is warranted to understand the clinical and laboratory predictors of survival benefit with warfarin. In this review article, we summarize and update the current evidence regarding the potential impact of warfarin on the overall survival of cancer patients and incidence of cancer, as well as review the potential mechanism of such effect and future perspectives. • Emerging population-based evidence suggests an association of warfarin with improved overall survival in cancer patients. • Anti-neoplastic mechanisms of warfarin include inhibition of thrombin and Gas6 signaling. • Implications for future research include identifying subgroups with improved outcomes. [ABSTRACT FROM AUTHOR]

To analyze the recurrence rate of placenta-mediated diseases (PMDs) such as preeclampsia (PE) and/or intrauterine growth restriction (IUGR), intrauterine fetal death (IUFD), and placental abruption (PA) in high-risk patients on antithrombotic therapy (AT) because of a previous obstetrical history for such complications. The study group (SG) included 150 patients to whom either 100 mg of aspirin or low-molecular weight heparin (LMWH) was administered due to a previous history of PMDs. The AT in the SG was started before 16 gestational weeks (g.w.). The patients in the first control group (CG-1) were 150 who also had a previous obstetrical history of PMDs, but did not receive antithrombotic therapy (AT) throughout their ongoing pregnancies. The second CG (CG-2) comprised 320 patients with a previous history of normally developing pregnancies and without AT throughout their ongoing pregnancies. The total percentage of PE in pregnant patients from the SG was 25.3% (38/150 patients), with 22.2% (10/45) in the SG on AT only with LDA (SG-LDA group), 25% (17/68) in the SG on AT only with LMWHs (SG-LMWH group) and 29.7% (11/37) in the SG on combined AT with LDA and LMWHs (SG-LDA + LMWH group), as opposed to 18.67% (28/150) in CG-1 and 0.62% (2/320) in CG-2. The recurrent severe PE/total PE ratio in the SG was 44.7% (17/38), with 30% (3/10) in the SG-LDA group, 47% (8/17) in the SG-LMWH group and 54% (6/11) in the SG-LDA + LMWH group, against 75% (21/28) in CG-1. There were no cases with severe PE in CG-2. All cases with recurrent IUGR from the SG were equal to 13.3% (20/150), with 13.3% (6/45) in the SG-LDA group, 11.76% (8/68) in the SG-LMWH group and 16.2% (6/37) in the SG-LDA + LMWH group, as compared to 30% (45/150) in CG-1 and 5% (16/320) in CG-2. As a whole, the overall recurrence rate of PMDs in the SG was 38.67% (58/150), with 35.56% (16/45) in the SG-LDA group, 36.76% (25/68) in the SG-LMWH group and 45.9% (17/37) in the SG-LDA + LMWH group, as compared to 50.67% (76/150) in CG-1 and 5.94% (19/320) in CG-2. AT had a partial beneficial effect on the prophylaxis of recurrent PMDs. On the one hand, AT led to a significant reduction in the recurrent severe PE/total PE ratio, as well as in the total PMDs' recurrence rate in the SG as compared to the one in CG-1. On the other hand, the percentage of recurrent PMDs still remained significantly higher in the SG as compared to CG-2. Pregnant patients with previous PMDs still need close surveillance in subsequent pregnancies as they remain at a high risk for complications. [ABSTRACT FROM AUTHOR]

Heparin is a centennial anticoagulant drug broadly employed for treatment and prophylaxis of thromboembolic conditions. Although unfractionated heparin (UFH) has already been shown to have remarkable pharmacological potential for treating a variety of diseases unrelated with thromboembolism, including cancer, atherosclerosis, inflammation, and virus infections, its high anticoagulant potency makes the doses necessary to exert non-hemostatic effects unsafe due to an elevated bleeding risk. Our group recently developed a new low-anticoagulant bovine heparin (LABH) bearing the same disaccharide building blocks of the UFH gold standard sourced from porcine mucosa (HPI) but with anticoagulant potency approximately 85% lower (approximately 25 and 180 Heparin International Units [IU]/mg). In the present work, we investigated the pharmacokinetics profile, bleeding potential, and anticancer properties of LABH administered subcutaneous into mice. LABH showed pharmacokinetics profile similar to HPI but different from the low-molecular weight heparin (LMWH) enoxaparin and diminished bleeding potential, even at high doses. Subcutaneous treatment with LABH delays the early progression of Lewis lung carcinoma, improves survival, and brings beneficial health outcomes to the mice, without the advent of adverse effects (hemorrhage/mortality) seen in the animals treated with HPI. These results demonstrate that LABH is a promising candidate for prospecting new therapeutic uses for UFH.

DOAC Dipstick determines specifically the presence and absence of direct oral anticoagulants (DOACs) from patients' urine samples and handmade test strips performed as well as the commercial version. To compare plasma activity (chromogenic substrate assays) from plasma samples with results from urine samples (DOAC test strips) of patients treated with heparin, low-molecular weight heparin (LMWH) and without anticoagulation. Plasma anti-factor Xa (aXa) activity was determined by Coamatic chromogenic substrate assay and compared to the presence of anticoagulants in urine by DOAC test strips. Patients were treated for least 5 days and samples were taken 4 hrs after administration in comparison to no treatment with an anticoagulant (n = 42). A total of 100 patients were included treated with heparin (n = 29), LMWH nadroparin (n = 29) or no anticoagulants (n = 42). Plasma aXa levels of patients treated with heparin (2 × 7.500 IU daily subcutaneously, 12 male, age 67.4 ± 11.5 years) were 0,18 IU/ml ± 0,15 IU/ml (mean, standard deviation), with LMWH (1 × 3000 IU daily subcutaneously, 15 male, age 64.2 ± 14.1 years) 0,17 IU/ml ± 0,16 IU/l, and with no anticoagulants (28 male, age 64.2 ± 15.6 years) 0,02 IU/ml ± 0.01 IU/ml. All factor Xa and thrombin inhibitor pad results of test strips were negative. We conclude that DOAC Dipstick has a high probability of not detecting heparin and LMWH in patients on treatment as well as in urine samples of patients not treated with an anticoagulant. [ABSTRACT FROM AUTHOR]

Abstract Objectives To assess the hypothesis that an adjunctive therapy with methylprednisolone and unfractionated heparin (UFH) or with methylprednisolone and low molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill ventilated patients with pneumonia from SARS-CoV-2 infection compared to LMWH alone. Trial design The study is designed as a multi-centre, interventional, parallel group, superiority, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the three treatment groups in a ratio 1:1:1. Participants Inpatients will be recruited from 8 Italian Academic and non-Academic Intensive Care Units Inclusion Criteria (all required) 1. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 2. Positive pressure ventilation (either non-invasive or invasive) from > 24 hours 3. Invasive mechanical ventilation from < 96 hours 4. PaO2/FiO2 ratio lower than 150 mmHg 5. D-dimer level > 6 times the upper limit of normal reference range 6. C-reactive Protein > 6-fold upper the limit of normal reference range Exclusion Criteria 1. Age < 18 years 2. On-going treatment with anticoagulant drugs 3. Platelet count < 100.000/mm3 4. History of heparin-induced thrombocytopenia 5. Allergy to sodium enoxaparin or other LMWH, UFH or methylprednisolone 6. Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment 7. Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery 8. Chronic assumption or oral corticosteroids 9. Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available 10. Clinical decision to withhold life-sustaining treatment or “too sick to benefit” 11. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 12. Lack or withdrawal of informed consent Intervention and comparator • LMWH group: patients in this group will be administered enoxaparin at standard prophylactic dosage. • LMWH + steroid group: patients in this group will receive enoxaparin at standard prophylactic dosage and methylprednisolone. • UFH + steroid group: patients in this group will receive UFH at therapeutic dosages and methylprednisolone. UFH will be administered intravenously in UFH + steroid group at therapeutic doses. The infusion will be started at an infusion rate of 18 UI/kg/hour and then modified to obtain aPTT Ratio in between the range of 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with UFH will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician. Enoxaparin will be administered in both LMWH group and LMWH + steroid group at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered subcutaneously once a day up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered in both LMWH + steroid group and UHF + steroid group intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14. Main Outcomes Primary Efficacy Endpoint: All-cause mortality at day 28 Secondary Efficacy Endpoints: - Ventilation free days (VFDs) at day 28, defined as the total number of days that patient is alive and free of ventilation (either invasive or non-invasive) between randomization and day 28 (censored at hospital discharge). - Need of rescue administration of high-dose steroids or immune-modulatory drugs; - Occurrence of switch from non-invasive to invasive mechanical ventilation during ICU stay; - Delay from start of non-invasive ventilation to switch to invasive ventilation; - All-cause mortality at ICU discharge and hospital discharge; - ICU free days (IFDs) at day 28, defined as the total number of days between ICU discharge and day 28. - Occurrence of new infections from randomization to day 28; including infections by Candida, Aspergillus, Adenovirus, Herpes Virus e Cytomegalovirus - Occurrence of new organ dysfunction and grade of dysfunction during ICU stay. - Objectively confirmed venous thromboembolism, stroke or myocardial infarction; Safety endpoints: - Occurrence of major bleeding, defined as transfusion of 2 or more units of packed red blood cells in a day, bleeding that occurs in at least one of the following critical sites [intracranial, intra-spinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal], bleeding that necessitates surgical intervention and bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death); - Occurrence of clinically relevant non-major bleeding, defined ad acute clinically overt bleeding that does not meet the criteria for major and consists of any bleeding compromising hemodynamic; spontaneous hematoma larger than 25 cm2, intramuscular hematoma documented by ultrasonography, haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures; haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention or any other bleeding requiring temporary cessation of a study drug. Randomization A block randomisation will be used with variable block sizes (block size 4-6-8), stratified by 3 factors: Centre, BMI (

Abstract Objectives To assess whether high doses of Low Molecular Weight Heparin (LMWH) (i.e. Enoxaparin 70 IU/kg twice daily) compared to standard prophylactic dose (i.e., Enoxaparin 4000 IU once day), in hospitalized patients with COVID19 not requiring Invasive Mechanical Ventilation [IMV], are: a) more effective in preventing clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1. Death 2. Acute Myocardial Infarction [AMI] 3. Objectively confirmed, symptomatic arterial or venous thromboembolism [TE] 4. Need of either: a. Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) or b. IMV in patients who at randomisation were receiving standard oxygen therapy 5. IMV in patients who at randomisation were receiving non-invasive mechanical ventilation b) Similar in terms of major bleeding risk Trial design Multicentre, randomised controlled, superiority, open label, parallel group, two arms (1:1 ratio), in-hospital study. Participants Inpatients will be recruited from 7 Italian Academic and non-Academic Internal Medicine Units, 2 Infectious Disease Units and 1 Respiratory Disease Unit. Inclusion Criteria (all required) 1. Age > 18 and < 80 years 2. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 3. Severe pneumonia defined by the presence of at least one of the following criteria: a. Respiratory Rate ≥25 breaths /min b. Arterial oxygen saturation≤93% at rest on ambient air c. PaO2/FiO2 ≤300 mmHg 4. Coagulopathy, defined by the presence of at least one of the following criteria: a. D-dimer >4 times the upper level of normal reference range b. Sepsis-Induced Coagulopathy (SIC) score >4 5. No need of IMV Exclusion Criteria 1. Age 80 years 2. IMV 3. Thrombocytopenia (platelet count < 80.000 mm3) 4. Coagulopathy: INR >1.5, aPTT ratio > 1.4 5. Impaired renal function (eGFR calculated by CKD-EPI Creatinine equation < 30 ml/min) 6. Known hypersensitivity to enoxaparin 7. History of heparin induced thrombocytopenia 8. Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (e.g. recent haemorrhagic stroke, peptic ulcer, malignant cancer at high risk of haemorrhage, recent neurosurgery or ophthalmic surgery, vascular aneurysms, arteriovenous malformations) 9. Concomitant anticoagulant treatment for other indications (e.g. atrial fibrillation, venous thromboembolism, prosthetic heart valves) 10. Concomitant double antiplatelet therapy 11. Administration of therapeutic doses of LMWH, fondaparinux, or unfractionated heparin (UFH) for more than 72 hours before randomization; prophylactic doses are allowed 12. Pregnancy or breastfeeding or positive pregnancy test 13. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 14. Lack or withdrawal of informed consent Intervention and comparator Control Group (Low-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at standard prophylactic dose (i.e., 4000 UI subcutaneously once day). Intervention Group (High-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at dose of 70 IU/kg every 12 hours, as reported in the following table. This dose is commonly used in Italy when a bridging strategy is required for the management of surgery or invasive procedures in patients taking anti-vitamin K oral anticoagulants Body Weight (kg) Enoxaparin dose every 12 hours (IU) 110 10000 The treatment with Enoxaparin will be initiated soon after randomization (maximum allowed starting time 12h after randomization). The treatment will be administered every 12 hours in the intervention group and every 24 hours in the control group. Treatments will be administered in the two arms until hospital discharge or the primary outcomes detailed below occur. Main outcomes Primary Efficacy Endpoint: Clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1. Death 2. Acute Myocardial Infarction [AMI] 3. Objectively confirmed, symptomatic arterial or venous thromboembolism [TE] 4. Need of either: a. Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) or b. IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces 5. Need for IMV, in patients who at randomisation were in Cpap or NIV Time to the occurrence of each of these events will be recorded. Clinical worsening will be analysed as a binary outcome as well as a time-to-event one. Secondary Efficacy Endpoints: Any of the following events occurring within the hospital stay 1. Death 2. Acute Myocardial Infarction [AMI] 3. Objectively confirmed, symptomatic arterial or venous thromboembolism [TE] 4. Need of either: a. Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) or b. IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces 5. Need for IMV in patients who at randomisation were in Cpap or NIV 6. Improvement of laboratory parameters of disease severity, including: o D-dimer level o Plasma fibrinogen levels o Mean Platelet Volume o Lymphocyte/Neutrophil ratio o IL-6 plasma levels Mortality at 30 days Information about patients’ status will be sought in those who are discharged before 30 days on Day 30 from randomisation. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Primary safety endpoint: Major bleeding, defined as an acute clinically overt bleeding associated with one or more of the following: Decrease in haemoglobin of 2 g/dl or more; Transfusion of 2 or more units of packed red blood cells; Bleeding that occurs in at least one of the following critical sites [intracranial, intraspinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal]; Bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death); Bleeding that necessitates surgical intervention Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Secondary safety endpoint: Clinically Relevant non-major bleeding, defined as an acute clinically overt bleeding that does not meet the criteria for major and consists of: 1. Any bleeding compromising hemodynamic 2. Spontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic cause 3. Intramuscular hematoma documented by ultrasonography 4. Epistaxis or gingival bleeding requiring tamponade or other medical intervention 5. Bleeding from venipuncture for >5 minutes 6. Haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures 7. Haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention 8. Any other bleeding requiring temporary cessation of a study drug. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Randomisation Randomisation (with a 1:1 randomisation ratio) will be centrally performed by using a secure, web-based system, which will be developed by the Methodological and Statistical Unit at the Azienda Ospedaliero-Universitaria of Modena. Randomisation stratified by 4 factors: 1) Gender (M/F); 2) Age (2) with random variable block sizes will be generated by STATA software. The web-based system will guarantee the allocation concealment. Blinding (masking) The study is conceived as open-label: patients and all health-care personnel involved in the study will be aware of the assigned group. Numbers to be randomised (sample size) The target sample size is based on the hypothesis that LMWH administered at high doses versus low doses will significantly reduce the risk of clinical worsening. The overall sample size in this study is expected to be 300 with 150 in the Low-Dose LMWH control group and 150 in the High-Dose LMWH intervention group, recruited over 10-11 months. Assuming an alpha of 5% (two tailed) and a percentage of patients who experience clinical worsening in the control group being between 25% and 30%, the study will have 80% power to detect at least 50% relative reduction in the risk of death between low and high doses of heparin. Trial Status Protocol version 1.2 of 11/05/2020. Recruitment start (expected): 08/06/2020 Recruitment finish (expected): 30/04/2021 Trial registration EudraCT 2020-001972-13, registered on April 17th, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Background: Although several studies suggest that heparins prevent arrhythmias caused by acute myocardial infarction (AMI), the molecular mechanisms involved remain unclear. To investigate the involvement of pharmacological modulation of adenosine (ADO) signaling in cardiac cells by a low-molecular weight heparin (enoxaparin; ENOX) used in AMI therapy, the effects of ENOX on the incidences of ventricular arrhythmias (VA), atrioventricular block (AVB), and lethality (LET) induced by cardiac ischemia and reperfusion (CIR) were evaluated, with or without ADO signaling blockers. Methods: To induce CIR, adult male Wistar rats were anesthetized and subjected to CIR. Electrocardiogram (ECG) analysis was used to evaluate CIR-induced VA, AVB, and LET incidence, after treatment with ENOX. ENOX effects were evaluated in the absence or presence of an ADO A1-receptor antagonist (DPCPX) and/or an inhibitor of ABC transporter-mediated cAMP efflux (probenecid, PROB). Results: VA incidence was similar between ENOX-treated (66%) and control rats (83%), but AVB (from 83% to 33%) and LET (from 75% to 25%) incidences were significantly lower in rats treated with ENOX. These cardioprotective effects were blocked by either PROB or DPCPX. Conclusion: These results indicate that ENOX was effective in preventing severe and lethal arrhythmias induced by CIR due to pharmacological modulation of ADO signaling in cardiac cells, suggesting that this cardioprotective strategy could be promising in AMI therapy.

Enoxaparin is an effective biological molecule for prevention and treatment of coagulation disorders. However, it is poorly absorbed in the gastrointestinal tract. In this study, we developed an Eudragit® L100 coated chitosan core shell nanoparticles for enoxaparin oral delivery (Eud/CS/Enox NPs) through a completely eco-friendly method without employing any high-energy homogenizer technique and any organic solvents. Spherical nanocarriers were successfully prepared with particle size lower than 300 nm, polydispersity index about 0.12 and zeta potential higher than +25 mV, entrapment efficiency greater than 95% and the in vitro release behavior confirms the good colloidal stability and the successful Eudragit® L100 coating process demonstrated by negligible cumulative enoxaparin release (<10%) when the particles are submitted to simulated gastric fluid conditions. Finally, we demonstrated that the core-shell structure of the particle influenced the drug release mechanism of the formulations, indicating the presence of the Eudragit® L100 on the surface of the particles. These results suggested that enteric-coating approach and drug delivery nanotechnology can be successfully explored as potential tools for oral delivery of enoxaparin. [ABSTRACT FROM AUTHOR]

Background: Current guidelines have limited consensus on the approach to portal venous thrombosis (PVT) in cirrhotic patients. While there is rising interest in direct oral anticoagulants (DOACs) use for PVT, current evidence is limited by small sample size and lack of comparisons to traditional anticoagulants. Thus, a network meta-analysis was conducted to compare the use of DOACs with traditional anticoagulants. Methods: Medline and Embase were searched for articles about anticoagulation use in cirrhotic patients with nontumorous PVT for articles on DOACs, warfarin, low-molecular weight heparin (LMWH) or antithrombin III. A network analysis was conducted using risk ratios (RR) with surface under the cumulative ranking curve (SUCRA). A single-arm meta-analysis was used to summarize the outcomes of DOAC treatment. Results: A total of 10 articles were included in the study. 79.5% (CI 38.8–95.9) of DOACs patients achieved complete or partial recanalization and 9.80% (CI 4.50–20.0) experienced a bleeding event. DOACs were superior to LMWH (RR 2.299, CI 1.037–5.093, p = 0.040), warfarin (RR 1.762, CI 1.017–3.053, p = 0.043) and no treatment (RR 3.489, CI 1.394–8.733, p = 0.008) in complete recanalization. For partial recanalization, while DOACs were not superior to any treatment, they had the highest probability in achieving partial recanalization in SUCRA analysis. Bleeding risk and mortality were similar compared to other treatments. Conclusion: The network analysis supports the use of DOACs in cirrhotic patients, with significant rates of complete recanalization compared to other treatments without increasing bleeding risk. DOACs can potentially be considered for nontumorous PVT in cirrhosis. [ABSTRACT FROM AUTHOR]

Objectives Pharmacoeconomic dimensions linking clinical effectiveness of parenteral anticoagulants for management of acute venous thromboembolism (VTE) and cost of treatment are needed to support choices by healthcare providers. The objective of the study was to conduct a cost-effectiveness analysis for 5-day treatment with parenteral anticoagulants in Jordan. Methods Cost-effectiveness analysis was conducted based on decision analysis tree model. The perspective was the payer, considering direct medical costs. Probabilities of failure of treatment and major bleeding were derived from published clinical studies. Costs were estimated based on 2019 prices in Jordan. Key findings The average cost of VTE hospitalization and major bleeding management in Jordan were 2324.00 US$ and 3347.40 US$, respectively. Bemiparin was associated with the highest clinical efficacy and lowest probability of major bleeding. Nadroparin had the lowest clinical efficacy, while tinzaparin was found to have the highest risk of major bleeding. Bemiparin had the lowest average cost-effectiveness ratio (101.63 US$/success) and nadroparin had the highest cost-effectiveness ratio (295.56 US$/success). Throughout the sensitivity analysis calculations, bemiparin and nadroparin had the lowest and highest cost of treatment, respectively. Conclusions The cost of parenteral anticoagulant drugs, the same as many other drugs, does not always correlate with cost of VTE treatment. Other direct medical costs (e.g. treatment failure and management of bleeding) have a high contribution to the total cost calculation. Pharmacoeconomically, bemiparin is the dominant cost-effective parenteral anticoagulant in Jordan, while nadroparin is the dominated one. [ABSTRACT FROM AUTHOR]

Study Question: What evaluation and care is offered to women after unexplained recurrent pregnancy loss (RPL) or intra-uterine foetal death (IUFD) and what are the reproductive outcomes?Summary Answer: Women are assessed for thrombophilia and often treated with low-molecular weight heparin (LMWH) and/or low-dose aspirin (ASA).What Is Known Already: Randomized controlled trials (RCTs) on possible efficacy of heparins and/or aspirin have been inconclusive due to limited power to detect a difference and patient heterogeneity.Study Design, Size, Duration: Prospective multicentre cohort study performed in 12 hospitals in three countries between 2012 and 2019.Participants/materials, Setting, Methods: All consecutive pregnant women with recurrent PL (≥3 losses or 2 losses in the presence of at least one euploid foetal karyotype) or at least one IUFD. Eligible women may have undergone thrombophilia testing before conception, at the discretion of local providers. The possible assignment of women to treatments (such as LMWH) was not decided a priori but was determined based on the responsible provider's current practice. Aims of the study were: (i) to evaluate factors associated with pregnancy outcome; (ii) to compare clinical management strategies in women with and without a subsequent successful pregnancy; and (iii) to evaluate characteristics of women who may benefit from antithrombotic therapy. A propensity score matching method was used to balance the differences in baseline characteristics.Main Results and the Role Of Chance: A matched sample of 265 pregnant women was analysed, with all undergoing thrombophilia screening; 103 out of 119 (86.6%) with and 98/146 (67.1%) without thrombophilia were prescribed with LMWH and/or ASA. Overall, live-births were recorded in 204 cases (77%), PL or IUFD in 61 (23%) pregnancies. Logistic regression showed a significant interaction between thrombophilia and treatment with LMWH (P = 0.03). Findings from sensitivity analysis showed odds ratio (OR) for pregnancy loss in women with inherited or acquired thrombophilia in absence of any treatment was 2.9 (95% CI, 1.4-6.1); the administration of LMWH (with or without ASA) was associated with higher odds of live-birth (OR, 10.6; 95% CI, 5.0-22.3). Furthermore, in women without thrombophilia, the odds of live-birth was significantly and independently associated with LMWH prophylaxis (alone or in association with ASA) (OR, 3.6; 95% CI, 1.7-7.9).Limitations, Reasons For Caution: While the propensity score matching allows us to balance the differences in baseline characteristics, it does not eliminate all confounding.Wider Implications Of the Findings: Antithrombotic prophylaxis during pregnancy may be effective in women with otherwise unexplained PL or IUFD, and even more useful in those with thrombophilia.Study Funding/competing Interest(s): The study was funded by Italian Ministry of Health (Ricerca Corrente 2018-2020). Dr G.P. has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. Dr E.G. has received consultant fees from Italfarmaco and Sanofi. All other authors declare that they have no conflict of interest.Trial Registration Number: NCT02385461. [ABSTRACT FROM AUTHOR]

Asparaginase is essential in the initial management of acute lymphoblastic leukemia (ALL) but frequently leads to venous thromboembolism (VTE). Using anticoagulants for primary VTE prevention has been studied with no consensus. We conducted a systematic literature search in PubMed, Scopus, and Web of science and performed random-effect meta-analysis using Mantel-Haenszel method in RevMan 5.4 to analyze primary pharmacological thromboprophylaxis during asparaginase treatment in early-phase (induction, consolidation, or intensification phase) therapy in patients with ALL with all ages and followed with subgroup analysis by age. Meta-analysis of 13 articles describing the effect of antithrombin supplementation in 1375 patients showed that antithrombin prophylaxis decreases the risk of VTE by 43% (RR, 0.57; 95% CI, 0.38 ˗ 0.83; p =0.004), with mild heterogeneity (I2=35%, p =0.10) and moderate certainty by GRADE. 8 articles included for meta-analysis of low–molecular weight heparin (LMWH) treatment in 612 patients showed that it decreased the risk of VTE by nearly 40% (RR, 0.61; 95% CI, 0.45 ˗ 0.81; p =0.00081), with minimal heterogeneity (I2=14%, p =0.31) but low certainty. Subgroup analysis showed that only prophylaxis with antithrombin supplementation significantly decreased the VTE rate in adult patients with moderate certainty. In pediatric patients, one nonrandomized prospective study showed that LMWH combined with antithrombin has a better thromboprophylaxis effect than antithrombin alone. In the PREVAPIX-ALL trial, prophylaxis with direct factor Xa inhibitor Apixaban did not benefit children younger than 18 years except for cases of obesity. We concluded that thromboprophylaxis with antithrombin is effective in ALL patients older than 18 years during the early phase of therapy, and LMWH combined with antithrombin supplementation might be effective for pediatric patients with ALL. Apixaban is effective in pediatric ALL patients with obesity and needs further study in other high-risk patients. [Display omitted] • Antithrombin reduces VTE risk by 43% in acute lymphoblastic leukemia, notably in adults. • LMWH effective for adult ALL thromboprophylaxis, but uncertain. • LMWH + antithrombin is better for pediatric ALL thromboprophylaxis. • Apixaban helps prevent thrombosis in obese pediatric ALL patients. [ABSTRACT FROM AUTHOR]

Burn injured patients are at high risk of thromboembolic complications. Morbid obesity further increases this risk. Our objective was to evaluate the efficacy of enoxaparin dosed 40 mg twice daily in achieving prophylactic plasma anti-Xa levels in obese burn patients. A retrospective chart review from November 2018 until September 2019 identified patients who were either ≥100 kg or had a body mass index ≥30 kg/m2 and initiated on enoxaparin 40 mg twice daily for venous thromboembolism prophylaxis. Patients were ≥18 yr of age and received ≥3 sequential doses of enoxaparin with appropriately timed peak plasma anti-Xa levels to monitor efficacy. One hundred forty-eight patients were screened with 43 patients included for analysis. Forty-two percent of the patients did not reach target peak plasma anti-Xa levels (0.2-0.5 IU/ml) on enoxaparin 40 mg twice daily. Patients who did not meet prophylactic target levels were more likely to be male (P < 0.05) and have an increased mean body weight (129 ± 24 kg vs 110 ± 16 kg, P < 0.05). Thirteen out of 18 patients received dosage adjustments with subsequent anti-Xa levels available for follow-up assessment, of which an additional six patients required further dosage adjustment to meet prophylactic goals. Current utilization of a fixed 40 mg twice daily regimen of enoxaparin for venous thromboembolism (VTE) is inadequate to meet target prophylactic peak plasma anti-Xa levels in the obese burn patient population. Dose adjusting enoxaparin to target anti-Xa levels to reduce VTE rates in obese burn patients should be further evaluated. [ABSTRACT FROM AUTHOR]

Studies available in the literature have shown alterations in blood coagulation tests in severe cases of COVID-19 pneumonia, with a significant risk of venous thromboembolism (VTE). Since microvascular thrombosis is a well-known fact in COVID-19 disease, requiring therapeutic anticoagulation, low-molecular weight heparin (LMWH) in prophylactic dose is a part of the clinical management of hospitalized COVID-19 patients. In this scenario, we describe three cases of abdominal spontaneous retroperitoneal hematoma (SRH) in hospitalized reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome coronavirus 2 infection is associated with hypercoagulability, which predisposes to venous thromboembolism (VTE). We analyzed platelet and neutrophil activation in patients with coronavirus disease 2019 (COVID-19) and their association with VTE.Methods: Hospitalized patients with COVID-19 and age- and sex-matched healthy controls were studied. Platelet and leukocyte activation, neutrophil extracellular traps (NETs), and matrix metalloproteinase 9, a neutrophil-released enzyme, were measured. Four patients were restudied after recovery. The activating effect of plasma from patients with COVID-19 on control platelets and leukocytes and the inhibiting activity of common antithrombotic agents on it were studied.Results: A total of 36 patients with COVID-19 and 31 healthy controls were studied; VTE developed in 8 of 36 patients with COVID-19 (22.2%). Platelets and neutrophils were activated in patients with COVID-19. NET, but not platelet activation, biomarkers correlated with disease severity and were associated with thrombosis. Plasmatic matrix metalloproteinase 9 was significantly increased in patients with COVID-19. Platelet and neutrophil activation markers, but less so NETs, normalized after recovery. In vitro, plasma from patients with COVID-19 triggered platelet and neutrophil activation and NET formation, the latter blocked by therapeutic-dose low-molecular-weight heparin, but not by aspirin or dypiridamole.Conclusions: Platelet and neutrophil activation are key features of patients with COVID-19. NET biomarkers may help to predict clinical worsening and VTE and may guide low-molecular-weight heparin treatment. [ABSTRACT FROM AUTHOR]

AIM: To investigate the ocular biodistribution and clearance of topically administered 7-taurocholic acid conjugated low-molecular weight heparin (LHT7) in a neovascularized mouse cornea using an in vivo optical imaging system. METHODS: A total of 10 eyes of 6 to 8-week-old BALB/c mice were analyzed. Corneal neovascularization (CoNV) was induced in the inferior cornea (IC) of each animal by penetrating the stroma with two interrupted sutures. The development of CoNV was verified after one week and the area of each neovascularized region was measured. A near-infrared fluorescent probe of 20 µmol/L Cy5.5 labeled LHT7 (LHT7-Cy5.5) in 0.02 mL solution was topically instilled onto the cornea in the experimental group (n=5). Free-Cy5.5 of 20 µmol/L in 0.02 mL was instilled in the control group (n=5). In vivo optical images were obtained before instillation and 5min, 2, 4, and 6h after instillation. The intensities were separately measured at the superior cornea (SC) and the IC. RESULTS: The mean CoNV areas were 1.97±0.17 mm2 and 1.92±0.96 mm2 in the experimental and control groups, respectively (P=0.832). The SC remained normal in all 10 subject animals. The IC intensity of the LHT7-Cy5.5 was greater than the SC intensity at 5min (P=0.038), 2h (P=0.041), and 4h (P=0.041) after application. The IC intensity fell to less than half of its initial value (42.9%±8.6%) at 6h in the experimental group. In the control mice, here were no significant differences in the free-Cy5.5 intensity between the IC and SC. CONCLUSION: Topically administered LHT7 shows a high biodistribution in CoNV areas for 4h and should be reapplied accordingly to maintain its effects. In vivo optical imaging can be a useful tool for evaluating the ocular biodistribution of a drug in an animal model.

Background: The aim of this study was to evaluate the safety and efficacy of low‐molecular weight heparin (LMWH) in the prevention of portal vein system thrombosis (PVST) after splenectomy. Methods: A systematic search was performed using PubMed, EMBASE, Springer and Cochrane Library databases to screen out studies comparing the prognoses between post‐splenectomy patients treated with and without LMWH. The incidences of PVST and bleeding complications were used as parameters to assess the effect of LMWH. Results: Six articles met the selection criteria and were included in this study. A total of 740 patients were involved in these six articles, including 336 patients treated with LMWH (LMWH group) and 385 patients not treated with LMWH (control group). The incidence of PVST in the LMWH group was significantly lower than that in the control group (relative risk 1.782 (1.449–2.192); P = 0.285; I2 = 19.7%), while the incidence of post‐operative bleeding in the LMWH group was significantly higher (relative risk 0.592 (0.195–1.799); P = 0.817; I2 = 0.0%). Conclusion: LMWH might decrease the incidence of PVST after splenectomy without a potential risk of bleeding. [ABSTRACT FROM AUTHOR]

Objectives: To examine the outcomes of planned induction of labour versus spontaneous onset of labour among women using prophylactic-dose low-molecular weight heparin (LMWH) therapy.Design: Retrospective cohort study.Setting: University hospital.Population: Women receiving antepartum prophylactic LMWH therapy undergoing a trial of vaginal delivery.Methods: Charts from 2018-2019 were reviewed.Main Outcome Measures: Duration of anticoagulation interruption and eligibility to receive neuraxial anaesthesia.Results: Data from 199 women were analysed; 78 (39.2%) were admitted following spontaneous onset of labour and 121 (60.8%) underwent planned induction of labour. Compared to women who underwent planned induction of labour, women who presented with spontaneous onset of labour had a shorter median admission-to-delivery interval (4.7 versus 29.3 hours, P < 0.001). Similarly, intervals from the last LMWH injection to delivery (25.8 versus 48.2 hours, P < 0.001) and to the first postpartum LMWH injection (41.2 versus 63.7 hours, P < 0.001) were shorter. Among those with spontaneous onset of labour, 69 (88.5%) were eligible to receive neuraxial anaesthesia. Rates of postpartum haemorrhage and blood transfusion were similar between the groups. No thrombotic events were encountered in those with spontaneous onset of labour, but four (3.3%) women who delivered following induction of labour developed a postpartum thrombotic event.Conclusion: Planned induction of labour was associated with a higher risk of postpartum thrombotic events than was spontaneous onset of labour (4 of 121 [3.3%] versus 0 of 78 [0%]), presumably due to prolonged duration of anticoagulation interruption, although the difference was not statistically significant. Allowing spontaneous onset of labour was associated with comparable rates of bleeding complications, and only a low proportion (9 of 78, 11.5%) were not eligible to receive neuraxial anaesthesia.Tweetable Abstract: Planned induction among women using prophylactic LMWH therapy might increase the risk of thromboembolic complications. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether high doses of Low Molecular Weight Heparin (LMWH) (i.e. Enoxaparin 70 IU/kg twice daily) compared to standard prophylactic dose (i.e., Enoxaparin 4000 IU once day), in hospitalized patients with COVID19 not requiring Invasive Mechanical Ventilation [IMV], are: a)more effective in preventing clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were receiving standard oxygen therapy5.IMV in patients who at randomisation were receiving non-invasive mechanical ventilationb)Similar in terms of major bleeding risk TRIAL DESIGN: Multicentre, randomised controlled, superiority, open label, parallel group, two arms (1:1 ratio), in-hospital study.Participants: Inpatients will be recruited from 7 Italian Academic and non-Academic Internal Medicine Units, 2 Infectious Disease Units and 1 Respiratory Disease Unit.Inclusion Criteria (all Required): 1. Age > 18 and < 80 years 2. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 3. Severe pneumonia defined by the presence of at least one of the following criteria: a.Respiratory Rate ≥25 breaths /minb.Arterial oxygen saturation≤93% at rest on ambient airc.PaO2/FiO2 ≤300 mmHg 4. Coagulopathy, defined by the presence of at least one of the following criteria: a.D-dimer >4 times the upper level of normal reference rangeb.Sepsis-Induced Coagulopathy (SIC) score >4 5. No need of IMV EXCLUSION CRITERIA: 1. Age <18 and >80 years 2. IMV 3. Thrombocytopenia (platelet count < 80.000 mm3) 4. Coagulopathy: INR >1.5, aPTT ratio > 1.4 5. Impaired renal function (eGFR calculated by CKD-EPI Creatinine equation < 30 ml/min) 6. Known hypersensitivity to enoxaparin 7. History of heparin induced thrombocytopenia 8. Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (e.g. recent haemorrhagic stroke, peptic ulcer, malignant cancer at high risk of haemorrhage, recent neurosurgery or ophthalmic surgery, vascular aneurysms, arteriovenous malformations) 9. Concomitant anticoagulant treatment for other indications (e.g. atrial fibrillation, venous thromboembolism, prosthetic heart valves) 10. Concomitant double antiplatelet therapy 11. Administration of therapeutic doses of LMWH, fondaparinux, or unfractionated heparin (UFH) for more than 72 hours before randomization; prophylactic doses are allowed 12. Pregnancy or breastfeeding or positive pregnancy test 13. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 14. Lack or withdrawal of informed consent INTERVENTION AND COMPARATOR: Control Group (Low-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at standard prophylactic dose (i.e., 4000 UI subcutaneously once day). Intervention Group (High-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at dose of 70 IU/kg every 12 hours, as reported in the following table. This dose is commonly used in Italy when a bridging strategy is required for the management of surgery or invasive procedures in patients taking anti-vitamin K oral anticoagulants Body Weight (kg)Enoxaparin dose every 12 hours (IU)<50200050-69400070-89600090-1108000>11010000 The treatment with Enoxaparin will be initiated soon after randomization (maximum allowed starting time 12h after randomization). The treatment will be administered every 12 hours in the intervention group and every 24 hours in the control group. Treatments will be administered in the two arms until hospital discharge or the primary outcomes detailed below occur.Main Outcomes: Primary Efficacy Endpoint: Clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces5.Need for IMV, in patients who at randomisation were in Cpap or NIV Time to the occurrence of each of these events will be recorded. Clinical worsening will be analysed as a binary outcome as well as a time-to-event one. Secondary Efficacy Endpoints: Any of the following events occurring within the hospital stay 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces5.Need for IMV in patients who at randomisation were in Cpap or NIV6.Improvement of laboratory parameters of disease severity, including: o D-dimer levelo Plasma fibrinogen levelso Mean Platelet Volumeo Lymphocyte/Neutrophil ratioo IL-6 plasma levels MORTALITY AT 30 DAYS: Information about patients' status will be sought in those who are discharged before 30 days on Day 30 from randomisation. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Primary safety endpoint: Major bleeding, defined as an acute clinically overt bleeding associated with one or more of the following: Decrease in haemoglobin of 2 g/dl or more;Transfusion of 2 or more units of packed red blood cells;Bleeding that occurs in at least one of the following critical sites [intracranial, intraspinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal];Bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death);Bleeding that necessitates surgical intervention Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Secondary safety endpoint: Clinically Relevant non-major bleeding, defined as an acute clinically overt bleeding that does not meet the criteria for major and consists of: 1.Any bleeding compromising hemodynamic2.Spontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic cause3.Intramuscular hematoma documented by ultrasonography4.Epistaxis or gingival bleeding requiring tamponade or other medical intervention5.Bleeding from venipuncture for >5 minutes6.Haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures7.Haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention8.Any other bleeding requiring temporary cessation of a study drug. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one.Randomisation: Randomisation (with a 1:1 randomisation ratio) will be centrally performed by using a secure, web-based system, which will be developed by the Methodological and Statistical Unit at the Azienda Ospedaliero-Universitaria of Modena. Randomisation stratified by 4 factors: 1) Gender (M/F); 2) Age (<75/≥75 years); 3) BMI (<30/≥30); 4) Comorbidities (0-1/>2) with random variable block sizes will be generated by STATA software. The web-based system will guarantee the allocation concealment. Blinding (masking) The study is conceived as open-label: patients and all health-care personnel involved in the study will be aware of the assigned group.Numbers To Be Randomised (sample Size): The target sample size is based on the hypothesis that LMWH administered at high doses versus low doses will significantly reduce the risk of clinical worsening. The overall sample size in this study is expected to be 300 with 150 in the Low-Dose LMWH control group and 150 in the High-Dose LMWH intervention group, recruited over 10-11 months. Assuming an alpha of 5% (two tailed) and a percentage of patients who experience clinical worsening in the control group being between 25% and 30%, the study will have 80% power to detect at least 50% relative reduction in the risk of death between low and high doses of heparin.Trial Status: Protocol version 1.2 of 11/05/2020. Recruitment start (expected): 08/06/2020 Recruitment finish (expected): 30/04/2021 Trial registration EudraCT 2020-001972-13, registered on April 17th, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. [ABSTRACT FROM AUTHOR]

Introduction: Low‐molecular weight heparin, such as dalteparin, is an alternative anticoagulation method in conventional hemodialysis (HD). However, there are limited studies on its use in quotidian and nocturnal HD. We assessed the optimal dose, treatment efficacy, and patient safety of dalteparin in quotidian and nocturnal HD populations. Methods: This study included 10 quotidian (7 in‐center and 3 home) and 8 nocturnal home HD patients. Dalteparin was initiated and titrated based on clotting score in these patients. Trough anti‐Xa levels were measured. The dalteparin dose, the dialyzer and HD circuit clotting scores, and bleeding episodes were recorded at 4 weeks. Patients who continued dalteparin were followed to 12 months. Findings: For the 10 quotidian HD patients, the median dalteparin dose was 1875 units [1250, 2500] after 4 weeks. For nocturnal HD patients, five of the eight patients switched back to heparin due to high clotting scores while on dalteparin within 4 weeks. However, three patients continued on dalteparin at 4 weeks. After 12 months, one maintained on 5000 units and the other two maintained on 7500 units of dalteparin. All the clotting scores at month 12 were ≤2. One patient died due to an unrelated cause. For all patients who continued on dalteparin, only 9% of the HD treatments had circuit clotting score >2 after reaching stable dose. All trough anti‐Xa levels were <0.1 IU/mL. There were no episodes of bleeding. Fistula compression times were not increased. Discussion: This small pilot study suggests that dalteparin can be used effectively and relatively safety in quotidian HD. However, its use in nocturnal HD was only successful in a small proportion of patients. Alternative methods, including second dalteparin bolus after 4 hours of HD treatment, should be assessed for efficacy and practicality. [ABSTRACT FROM AUTHOR]

Postpartum low-molecular-weight heparin (LMWH) thromboprophylaxis is indicated for a substantial proportion of women. We assessed women's adherence to postpartum thromboprophylaxis and the factors associated with adherence. This retrospective cohort study was conducted at a university hospital during 2018. Parturients for whom a recommendation for LMWH prophylaxis was given at discharge from the maternity ward were contacted at the end of the recommended post-discharge course of LMWH, and were invited to participate in a telephone survey. The main outcome measures were optimal (> 80%) and suboptimal adherence (< 80%) to LMWH administration, reasons for nonadherence, and views regarding LMWH, as assessed by an adapted Beliefs about Medication Questionnaire. Overall, 250 women completed the questionnaire. The median recommended duration of post-discharge LMWH was 7 [5–8] days. Suboptimal adherence was reported by 82 (32.8%); 45 (18.0%) women did not administer any LMWH dose following discharge and only 147 (58.8%) completed the full LMWH course. In multivariate analysis, patients' perceptions of the necessity of LMWH [odds ratio (95% CI): 3.50 (2.12, 9.53), P = 0.002] and of the adequacy of the explanation given prior to discharge regarding LMWH technical administration [odds ratio (95% CI): 5.0 (2.33, 11.11), P < 0.001] were positively associated with optimal adherence. Nearly one-third of women prescribed postpartum LMWH thromboprophylaxis reported suboptimal adherence. Patients' perceptions of the necessity of the treatment and their opinion of the adequacy of explanation regarding LMWH technical administration were identified as predictors of treatment compliance, and thus represent potential areas for improvement. [ABSTRACT FROM AUTHOR]

Objective: To quantify the pharmacodynamic (PD) activity of daily subcutaneous (SC) enoxaparin as venous thromboembolism (VTE) prophylaxis in high-risk trauma patients admitted to the intensive care unit (ICU).Methods: This was a prospective observational PD study conducted in the ICU of a state-wide major trauma referral centre. The study cohort included adult patients admitted to the ICU with a high risk of VTE, as defined by at least one of the following: age > 40 years, prior VTE, spinal cord injury (SCI), traumatic brain injury (TBI), major venous injury, pelvic fractures, spinal fractures requiring treatment, severe lower limb injuries, and major surgery >2 h in duration. Standard prophylactic enoxaparin dosing was 40 mg SC daily, unless amended by the treating clinician. Plasma anti-Xa activity was measured approximately 60 min before dosing (trough activity), and at 3-5 h after dosing (peak activity). Target peak and trough activity were defined as >0.2 IU/mL and >0.1 IU/mL respectively. Clinical data including the development of VTE and haemorrhagic complications were collected.Results: Twenty-five patients were enrolled. Median [IQR] age, weight, and plasma creatinine were 59 years [36,70], 85 kg [76.5,93.5] and 70μmol/L [60.5,109] respectively. Median APACHE III and Injury Severity Score were 54 [42.5,66.5] and 27 [17,34] respectively. Thirteen patients suffered a TBI, in 12 cases surgery extended beyond two hours, and five patients had spinal fractures requiring treatment. Twenty-two patients received enoxaparin 40 mg SC daily, two 60 mg, and one 20 mg. Median peak and trough anti-Xa activity was 0.21 IU/mL [0.125,0.25] and 0.01 IU/mL [0,0.05] respectively. Twelve (12/25; 48%) patients had low peak activity ≤0.2 IU/mL. Twenty-one (21/23; 91%) patients had low trough activity (≤0.1 IU/mL) and in six (6/23; 26%) cases, these were undetectable. Eight (8/25; 32%) patients had documented VTE of whom seven had low trough activity. There were no major haemorrhagic complications.Conclusions: In a cohort of high risk critically ill trauma patients receiving daily SC enoxaparin as VTE chemoprophylaxis, measured peak and trough plasma anti-Xa activity was inadequate in a significant proportion. On this basis, further systematic investigation concerning dose optimisation in this patient population appears warranted. [ABSTRACT FROM AUTHOR]

Heparin-induced thrombocytopenia syndrome (HITS) is a rare complication of low-molecular-weight heparin (LMWH). It is an autoimmune-mediated side effect of LMWH which is caused by platelet-activating antibodies that recognize platelet factor-4/heparin complexes. Although HITS often leads to thrombosis in large veins and arteries, it can be presented as microvascular thrombosis. In this article, we report a case of HITS complicated with multiple digital necrosis after administration of LMWH. [ABSTRACT FROM AUTHOR]

The patients with complicated surgical diseases are relating to the group of high risk of nascence of vein thrombosis and tromboembolism. Aim of the study: to measure of the anticoagulant abilities of bemiparin sodium among women were operated by laparoscopic access in gynecological practices. Materials and methods. 15 women who had been operated for multiple uterine fibroid were examined and enrolled in the basic group. The patients were administered bemiparin sodium 3500 IE (0.2 ml) injected subcutaneously in 6 hours after operative treatment, then once a day during 7 days for prevention of tromboembolic complications in the postoperative period. The control group included 10 healthy women. The following parameters were defined for the control of efficiency of using of bemiparin sodium, his influence on different components of the haemostatic system: D-dimer, thrombocytes quantity and level of fibrinogen. Results. The significant elevation of level of D-dimer and fibrinogen was discovered among patients of the basic group during the preoperative period (p

Certain patient populations (pregnancy, cancer, renal impairment, and obesity) may be at higher risk of adverse events during low molecular weight heparin (LMWH) therapy and may benefit from anti-Xa monitoring. Yet, evidence supporting a standardized approach to anti-Xa monitoring correlated to clinical outcomes is lacking. Patients with at least one documented anti-Xa level and receiving LMWH within a 6-month period were identified. In a 6-month period, 224 adult LMWH patients with 359 anti-Xa levels were identified. Anti-Xa monitoring was most commonly performed in patients with active cancer receiving venous thromboembolism (VTE) treatment doses (57.4%) or obese patients receiving VTE prophylaxis (48.1%). Anti-Xa monitoring during renal impairment and pregnancy were infrequent (0.9% and 1.8%, respectively). Most (71.9%) anti-Xa levels were therapeutic, but only 45% were drawn correctly in relation to LMWH administration time. Compared to those with therapeutic anti-Xa levels, patients with out-of-range levels were four times as likely to receive a LMWH therapy change (odds ratio, 4.16; 95% confidence interval, 2.53–6.84). However, when levels were supratherapeutic or subtherapeutic, the LMWH doses remained unchanged in one-third to one-half of patients, respectively. Anti-Xa monitoring was most commonly performed in patients with cancer or obesity and was more common with VTE prophylaxis dosing. The majority of levels were therapeutic, indicating that anti-Xa monitoring may be unnecessary even in high-risk patient populations. Many out-of-range anti-Xa levels did not prompt a change in LMWH therapy. Further research is still needed to determine if anti-Xa- guided LMWH dosing improves clinical outcomes. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality worldwide. For decades, low molecular weight heparins (LMWH) and vitamin K-antagonists have been the gold standard of anticoagulation for VTE. Recently, direct oral anticoagulants (DOACs) that can be administered in fixed doses, without laboratory monitoring and dose adjustment have revolutionized anticoagulation management in VTE. Here, we report on recent evidence regarding the safety of DOACs compared to traditional anticoagulants in surgical and medical prophylaxis as well as in acute and extended treatments of VTE. Additionally, we provide data on special situations such as elderly, cancer and renal impairment patients. Regarding antithrombotic prophylaxis, data are lacking on DOAC use in general surgical patients, while DOACs appear to be more effective than and as safe as LMWHs in VTE prophylaxis for major orthopedic surgical patients. Whether a medically ill patient may benefit from extended VTE prophylaxis remains unclear. In fact, in these patients, DOACs showed an increased risk of bleeding compared to conventional therapy. In the acute treatment of VTE, DOACs were non-inferior and probably safer than conventional anticoagulation therapy while in the extended VTE treatment DOACs were more effective than placebo or aspirin with a comparable risk of major bleeding. These favorable results were also confirmed in elderly, cancer and renal impairment patients. However, further investigations are needed in order to generalize the safe use of DOACs in these specific subgroups of patients. [ABSTRACT FROM AUTHOR]

Current treatment dose of enoxaparin is based on total body weight (TBW), however dosage in obesity remains unclear. "Dose capping" commonly occurs if TBW > 100 kg minimising bleeding risk. However, this may result in under-dosing and increasing embolisation risk. The primary objective evaluated efficacy of current dosing strategies in obese patients and determined if resultant anti-Xa concentrations (aXaC) were therapeutic. The secondary objective was to investigate if an uncapped 0.75–0.85 mg/kg (TBW) twice daily dose, advocated by previous authors, results in therapeutic aXaC (0.5–1.0 IU/ml). This retrospective study included 133 patients with a median TBW of 128 kg, producing 59% therapeutic, 15% sub-therapeutic and 26% supra-therapeutic aXaC. Approximately 60% of patients in each dose group (< 0.75, 0.75–0.85 and > 0.85 mg/kg) had a therapeutic aXaC, however the percentage of sub-therapeutic versus supra-therapeutic was higher in the < 0.75 (27% vs 9%) and > 0.85 mg/kg (10% vs 34%) groups respectively. Most patients who weighed 100–119 kg (TBW) received doses > 0.85 mg/kg, however 32% had toxic aXaC. Those between 120 and 139 kg (TBW) had a high percentage of therapeutic aXaC (87%) when dosed < 0.75 mg/kg and a high percentage of supra-therapeutic aXaC (71%) when dosed > 0.85 mg/kg; although numbers were low. Dose reduction occurred in patients > 140 kg (TBW), however < 0.75 mg/kg resulted in higher percentage of sub-therapeutic aXaC (42%). Dosing at 0.75–0.85 mg/kg results in 62% of therapeutic, 14% sub-therapeutic and 24% supra-therapeutic aXaC. This appears to be a "safe" starting dose-range, however all obese patients should have aXaC monitoring due to high inter-patient variability. [ABSTRACT FROM AUTHOR]

Stable cancer patients diagnosed with a pulmonary embolus or deep vein thrombosis are commonly referred to the emergency department for management. This practice strains an already overburdened emergency department and is associated with long wait times and poor disease/injection education for patients. This pilot study sought to determine if stable cancer patients with newly diagnosed cancer-associated thrombosis could be effectively managed by community-based pharmacists who followed an evidence-based protocol to prescribe and initiate low-molecular weight heparin therapy. We hypothesized that this novel care pathway could provide faster patient care with more comprehensive disease education, self-injection training, and follow-up. Fifty-five patients with various cancers, including gastroesophageal, urogenital, breast, brain, and lung were enrolled into this pilot study. We observed that this alternative first-dose treatment pathway provided safe and effective treatment of venous thromboembolism combined with excellent patient satisfaction. Following their interaction with the pharmacist, patients felt confident about their ability to self-inject and about their venous thromboembolism management overall. No occurrences of bleeding or other side-effects were observed. This pilot study demonstrates that community-based pharmacists are capable of delivering complex care services in the outpatient environment, particularly in the management of venous thromboembolism. [ABSTRACT FROM AUTHOR]

The article describes the main anticoagulant drugs used in cancer patients, taking into consideration pathogenetic aspects of hypercoagulation status in cancer patients: oral anticoagulants, heparin drugs, selective inhibitors of Xa factor. The basic advantages of low molecular weight heparin compared with unfractioned heparin. The comparison of low-molecular weight heparin drugs, their generics and biosimilar drugs is surveyed. Reviewed recommendations for the prevention of thrombotic complications in cancer patients. Overviewed the possible complications of heparin therapy and methods of prevention.

Abstract Objective To examine the laboratory anticoagulant effect of two thromboprophylactic low-molecular weight heparin (LMWH) regimens in post-cesarean obese patients. Methods A prospective cohort study, performed during 2017–2018 at a university hospital, of post-cesarean obese (>90 kg) patients receiving 40 mg/day (n = 30) or 60 mg/day (n = 30) enoxaparin, and a control group of non-obese (n = 30) post-cesarean patients receiving 40 mg/day enoxaparin. Thrombin generation and anti-Xa were measured twice on the third postoperative day: prior to and 3.5–4 h following the third LMWH dose. Results Age, parity, weight and body mass index were comparable between the obese study groups. Compared to the control non-obese group, the 40 mg obese and 60 mg obese groups showed increased baseline thrombin generation: medians 491, 581, 571 nM, respectively (P = 0.001 and P = 0.04, respectively). At peak LMWH activity, thrombin generation was higher in the 40 mg than in the 60 mg obese and control groups: medians 2599, 2391, 2229 nM, respectively (P = 0.01 and P < 0.0001, respectively); and thrombin generation was comparable between the 60 mg obese and the control groups (P = 0.58). Similarly, a significantly lower proportion of patients in the 40 mg obese group (10%) had anti-Xa levels within the recommended prophylactic range (0.2–0.5 IU/mL) than in the other groups (P < 0.0001 for both comparisons). Conclusion As determined by thrombin generation and anti-Xa testing, post-cesarean obese patients have an increased procoagulant potential, which was diminished only in those receiving higher dosages of LMWH. These findings support the need for clinical evaluation of LMWH dose adjustment in this setting. Highlights • A prospective study of 2 LMWH regimens in post-cesarean obese women. • Thrombin generation and anti-Xa levels were assessed. • Procoagulant potential was higher in post-cesarean obese women than in controls. • This was diminished only in those receiving higher LMWH dosage (60 vs. 40 mg/day). • Clinical evaluation of LMWH dose adjustment in postpartum obese patients is needed. [ABSTRACT FROM AUTHOR]

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