Potency Adjusted Blended Heparin of Bovine, Ovine, and Porcine Heparin Exhibit Comparable Biologic Effects to Referenced Single-Sourced Porcine Heparin.

Introduction: Bovine and ovine mucosa represent alternate anticoagulants to porcine mucosa for production of unfractionated heparin (UFH). Standardized heparins from various sources can be blended and potency adjusted, blended heparins exhibit comparable effects as single-sourced porcine UFH. This study evaluated the pharmacologic profile of blended heparin and compared their activities to that of single sourced porcine, ovine, and bovine heparins. Methods: The anticoagulant effects of gravimetric and potency-adjusted heparins were evaluated with aPTT, TT, anti-Xa, anti-IIa, ACT, and TGA studies. Protamine sulfate studies were used for neutralization potential of each of the individual heparins. Results: The potency-adjusted heparins demonstrated comparable aPTT, TT, anti-Xa, anti-IIa, and ACT values at all concentrations (U/mL). However, in gravimetric studies, bovine heparin consistently showed lower values with the exception of thrombin generation inhibition studies. The protamine sulfate neutralization studies demonstrated complete neutralization at all concentrations for the potency-adjusted heparins. However, at gravimetric concentrations, minor differences were noted in the neutralization profile in each of these heparins. Conclusion: These studies support the hypothesis that blended heparin from bovine, ovine, and porcine tissue, when standardized in unit-equivalent proportions, exhibits a comparable anticoagulant profile to the single species derived heparins.

Eficacia de la tromboprofilaxis con heparina de bajo peso molecular en pacientes críticos con COVID-19: estudio observacional, prospectivo y multicéntrico / Effectiveness of thromboprophylaxis with low molecular weight heparin in critically ill patients with COVID-19. An observational prospective, multicenter study

Introducción: Los pacientes COVID-19 presentan una coagulopatía caracterizada por una elevada incidencia de complicaciones tromboembólicas. Ante la controversia existente sobre el manejo de la tromboprofilaxis, se llevó a cabo un estudio con el objetivo de analizar el efecto de las diferentes dosis de heparina de bajo peso molecular (HBPM) utilizadas en los pacientes críticos con COVID-19. Material y métodos: Se evaluaron datos del Reg-COVID-19. Se compararon 2 grupos de pacientes según la dosis de HBPM administrada: profilaxis y tratamiento. El objetivo primario fue determinar si había relación de la dosis de HBPM con la mortalidad. Los objetivos secundarios incluyeron la incidencia de eventos trombóticos y hemorrágicos, la duración de la estancia en la UCI, la ventilación mecánica invasiva y los parámetros trombóticos e inflamatorios. Resultados: Se analizaron datos de 720 pacientes, 258 en el grupo de profilaxis y 462 en el de tratamiento. La proteína C reactiva, la ventilación mecánica invasiva y el tratamiento con tocilizumab o corticosteroides se relacionaron con la elección de la dosis de HBPM. La incidencia de complicaciones hemorrágicas (66/720, 9,2%) y trombóticas (69/720, 9,6%) fue similar en ambos grupos, al igual que el curso temporal de los eventos trombóticos, que ocurrieron antes que los hemorrágicos (9 [3-18] y 12 [6-19] días, respectivamente). La mortalidad fue menor en el grupo de profilaxis (25,2 frente al 35,1%), pero al aplicar un modelo de ponderación de probabilidad inversa, no se encontraron diferencias entre los grupos. Conclusión: No se encontraron efectos beneficiosos ni perjudiciales relacionados con la administración de dosis profilácticas o terapéuticas de HBPM en pacientes críticos COVID-19, con una tasa similar de complicaciones hemorrágicas o trombóticas. A partir de estos resultados, consideramos que son necesarios más estudios para determinar el protocolo óptimo de tromboprofilaxis en estos pacientes.(AU)

Introduction: COVID-19 induces coagulopathy associated with an increase of thromboembolic events. Due to the lack of agreement on recommendations for thromboprophylactic management, the aim of this study was to study the dosages of LMWH used in critically ill COVID-19 patients assessing the effect on their outcome. Metohds: We evaluated data of the Reg-COVID19. According to LMWH dose two groups were analyzed: prophylaxis and treatment. Primary outcome was the relationship of LMWH dosage with mortality. Secondary outcomes included the incidence of thrombotic and bleeding events, length of ICU stay, invasive mechanical ventilation, and thrombotic and inflammatory parameters. Results: Data of 720 patients were analyzed, 258 in the prophylaxis group and 462 in the treatment group. C Reactive Protein, invasive mechanical ventilation, tocilizumab and corticosteroid treatments were related with the choice of LMWH dose. Hemorrhagic events (66/720, 9.2%) and thrombotic complications (69/720, 9.6%) were similar in both groups (P=.819 and P=.265), as was the time course of the thrombotic events, earlier than hemorrhagic ones (9 [3-18] and 12 [6-19] days respectively). Mortality was lower in prophylaxis group (25.2% versus 35.1%), but once an inverse probability weighting model was applied, we found no effect of LMWH dose. Conclusion: We found no benefit or harm with the administration of therapeutic or prophylactic LMWH dose in COVID19 critically ill patients. With a similar rate of hemorrhagic or thrombotic events, the LMWH dose had no influence on mortality. More studies are needed to determine the optimal thromboprophylaxis protocol for critically ill patients.(AU)

Efficacy and safety of direct oral anticoagulants for the treatment of cancer-associated venous thromboembolism: A systematic review and Bayesian network meta-analysis / Eficacia y seguridad de los anticoagulantes orales directos para el tratamiento de la tromboembolia venosa asociada al cáncer: una revisión sistemática y un metaanálisis en red bayesiana

Introduction: Direct oral anticoagulants (DOACs) could effectively prevent the occurrence of cancer-associated venous thromboembolism (CAVTE), which incidence rate was estimated to be 4–20%. But the efficacy and safety remain controversial between DOACs and low molecular weight heparin (LMWH).Materials and methodsPubMed, Cochrane Library, Embase, ClinicalTrials.gov databases for randomized controlled trials (RCTs) were systematically searched from inception to March 15, 2022. A random-effects model was used to report the odds ratio (OR) and 95% confidence interval (CI) for both direct and network meta-analyses.ResultsSeven studies were included totaling 3242 patients. A lower rate of recurrence VTE was noted in the DOACs compared with LMWH (OR 0.62, 95% CI 0.47–0.82, I2=0.0%). The aspect of major bleeding (MB) was similar (OR 1.30, 95% CI 0.77–2.18, I2=34.9%). When assessing clinically relevant nonmajor bleeding (CRNMB) (OR 1.61, 95% CI 1.17–2.22, I2=20.7%) and clinically relevant bleeding (CRB) (OR 1.39, 95% CI 1.11–1.74, I2=0.0%), a higher risk of events was observed in DOACs. In subgroup analyses, the MB of gastrointestinal and genitourinary malignancies had a higher rate in the DOACs. For ranking, apixaban ranked the first in prevention of VTE and reducing MB events. Edoxaban had the highest risk drug in MB. In terms of CRNMB and CRB, LMWH showed the lowest risk.ConclusionsCompared with LMWH, DOACs seemed to have a decreased risk of recurrence VTE while increasing CRNMB and CRB. DOACs and LMWH were equivalent to the aspect of MB, but DOACs had a higher MB risk in patients with gastrointestinal and genitourinary malignancies. Apixaban may be the lowest risk compared to the other DOACs in precaution of VTE and reducing bleeding events. (AU)

Introducción: Los anticoagulantes orales directos (ACOD) son eficaces en la prevención de la tromboembolia venosa (TEV) relacionada con el cáncer, cuya tasa de incidencia se estima en 4-20%. Sin embargo, la eficacia y seguridad de ACOD y heparina de bajo peso molecular (HBPM) siguen siendo controvertidas.Materiales y métodosDesde el inicio hasta el 15 de marzo de 2022 se realizaron búsquedas sistemáticas en las bases de datos de ensayos controlados aleatorios (ECA) en PubMed, The Cochrane Library, Embase, ClinicalTrials.gov. Se utilizó el modelo de efectos aleatorios para informar la razón de probabilidades (RP) y los intervalos de confianza (IC) de 95% para los metaanálisis directos y de red.ResultadosSe incluyeron siete estudios con un total de 3.242 pacientes. En comparación con HBPM, los ACOD tienen una tasa más baja de recurrencia de TEV (OR 0,62, IC 95%: 0,47 a 0,82, I2 = 0,0%). La frecuencia de hemorragias mayores fue similar (OR 1,30, IC 95% 0,77 a 2,18, I2 = 34,9%). Se observó un mayor riesgo de eventos en los ACOD. Cuando se evaluaron las hemorragias no mayores clínicamente relevantes (CRNMB) (OR 1,61, IC 95%: 1,17 a 2,22, I2 = 20,7%) y las hemorragias clínicamente relevantes (OR 1,39, IC 95%: 1,11 a 1,74, I2 = 0,0%), En los análisis de subgrupos, las hemorragias mayores en las neoplasias malignas gastrointestinales y genitourinarias fueron más frecuentes con los ACOD. Apixabán ocupó el primer lugar en la prevención de TEV y la reducción de eventos hemorrágicos mayores. Edoxabán tuvo el mayor riesgo de hemorragias mayores. Las HBPM demostraron tener menor riesgo de hemorragias mayores clínicamente relevantes y hemorragias clínicamente relevantes. (AU)

Data linkage of two national databases: Lessons learned from linking the Dutch Arthroplasty Register with the Dutch Foundation for Pharmaceutical Statistics.

BACKGROUND: To provide guidance on data linkage in case of non-unique identifiers, we present a case study linking the Dutch Foundation for Pharmaceutical Statistics and Dutch Arthroplasty Register to investigate opioid prescriptions before/after arthroplasty. METHODS: Deterministic data linkage was used. Records were linked on: sex, birthyear, postcode, surgery date, or thromboprophylaxis initiation as a proxy for the surgery date. Different postcodes were used, depending on availability: patient postcode (available from 2013 onwards), hospital postcode with codes for physicians/hospitals, and hospital postcode with catchment area. Linkage was assessed in several groups: linked arthroplasties, linked on patient postcode, linked on patient postcode, and low-molecular-weight heparin(LWMH). Linkage quality was assessed by checking prescriptions after death, antibiotics after revision for infection, and presence of multiple prostheses. Representativeness was assessed by comparing the patient-postcode-LMWH group with the remaining arthroplasties. External validation was performed by comparing our opioid prescription rates with those derived from datasets from Statistics Netherlands. RESULTS: We linked 317,899 arthroplasties on patient postcode/hospital postcode(48%). Linkage on the hospital postcode appeared insufficient. Linkage uncertainty ranged from roughly 30% in all arthroplasties to 10-21% in the patient-postcode-LMWH-group. This subset resulted in 166.357(42%) linked arthroplasties after 2013 with somewhat younger age, fewer females, and more often osteoarthritis than other indications compared to the other arthroplasties. External validation showed similar increases in opioid prescription rates. CONCLUSIONS: After identifier selection, checking data availability and internal validity, assessing representativeness, and externally validating our results we found sufficient linkage quality in the patient-postcode-LMWH-group, which consisted of around 42% of the arthroplasties performed after 2013.

Hereditary thrombophilia and low -molecular -weight heparin in women: useful determinants, including thyroid dysfunction, incorporating the management of treatment and outcomes of the entity.

OBJECTIVE: Our study purposed to examine the complex relationship between low-molecular-weight heparin therapy, multiple pregnancy determinants, and adverse pregnancy outcomes during the third trimester in women with inherited thrombophilia. METHODS: Patients were selected from a prospective cohort of 358 pregnant patients recruited between 2016 and 2018 at the Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, Belgrade. RESULTS: Gestational age at delivery (ß=-0.081, p=0.014), resistance index of the umbilical artery (ß=0.601, p=0.039), and D-dimer (ß=0.245, p<0.001) between 36th and 38th weeks of gestation presented the direct predictors for adverse pregnancy outcomes. The model fit was examined using the root mean square error of approximation 0.00 (95%CI 0.00-0.18), the goodness-of-fit index was 0.998, and the adjusted goodness-of-fit index was 0.966. CONCLUSION: There is a need for the introduction of more precise protocols for the assessment of hereditary thrombophilias and the need for the introduction of low-molecular-weight heparin.

Placenta-mediated pregnancy complications in women with a history of late fetal loss and placental infarction without thrombophilia: risk of recurrence and efficacy of pharmacological prophylactic interventions. A 10-year retrospective study.

PURPOSE: To evaluate the risk of recurrence of severe placenta-mediated pregnancy complications and compare the efficacy of two different anti-thrombotic regimens in women with a history of late fetal loss without thrombophilia. PATIENTS AND METHODS: We performed a 10-year retrospective observational study (2008-2018) analyzing a cohort of 128 women who suffered from pregnancy fetal loss (>20 weeks of gestational age) with histological evidence of placental infarction. All the women tested negative for congenital and/or acquired thrombophilia. In their subsequent pregnancies, 55 received prophylaxis with acetylsalicylic acid (ASA) only and 73 received ASA plus low molecular weight heparin (LMWH). RESULTS: Overall, one-third of all pregnancies (31%) had adverse outcomes related to placental dysfunction: pre-term births (25% <37 weeks, 5.6% <34 weeks), newborns with birth weight <2500 g (17%), and newborns small for gestational age (5%). The prevalence of placental abruption, early and/or severe preeclampsia, and fetal loss >20 weeks were 6%, 5%, and 4% respectively. We found a risk reduction for combination therapy (ASA plus LMWH) compared with ASA alone for delivery <34 weeks (RR 0.11, 95% CI: 0.01-0.95 p = 0.045) and a trend for the prevention of early/severe preeclampsia (RR 0.14, 95% CI: 0.01-1.18, p = 0.0715), while no statistically significant difference was observed for composite outcomes (RR 0.51, 95%CI: 0.22-1.19, p = 0.1242). An absolute risk reduction of 5.31% was observed for the ASA plus LMWH group. Multivariate analysis confirmed a risk reduction for delivery <34 weeks (RR 0.32, 95% CI 0.16-0.96 p = 0.041). CONCLUSION: In our study population, the risk of recurrence of placenta-mediated pregnancy complications is substantial, even in the absence of maternal thrombophilic conditions. A reduction of the risk of delivery <34 weeks was detected in the ASA plus LMWH group.

Evaluation of Low-Molecular-Weight Heparin for Treatment of Portal Vein Thrombosis in Liver Cirrhosis Patients.

Background and Objectives: Even though low-molecular-weight heparin (LMWH), including dalteparin, has a critical role in portal vein thrombosis (PVT) treatment in liver cirrhosis (LC) patients, the predictive factors and the proper dose of dalteparin for PVT treatment and relapse have not yet been investigated. Materials and Methods: This retrospective study evaluated the records of LC patients receiving dalteparin from July 2013 to June 2019. The odds ratio (OR) and adjusted OR were calculated from univariate and multivariable analyses, respectively. Results: Among data from 121 patients, the overall recanalization rate of all patients was 66.1% (80 patients). No history of variceal bleeding (OR 4.6, 95% CI: 1.88-11.43) and the case of newly developed thrombus before dalteparin treatment (OR 3.2, 95% CI: 1.24-8.08) were predictive factors associated with increased treatment response. Relapse of PVT occurred in 32 out of 80 patients (40%) who showed a recanalization. The risk of relapse was 3.1-3.9 times higher in those who took more than three months or more than six months from the diagnosis of PVT to dalteparin treatment compared to those who took less than these durations, respectively. In the dosing regimen, patients with the kg-based dosing regimen showed 2.6 times better response than those with the fixed dosing regimen. However, no difference in bleeding complications was observed. Conclusion: In the dosing regimen, the kg-based regimen that was the same as the venous thromboembolism regimen was a better option for the efficacy and safety of dalteparin therapy. Additionally, when treating PVT in LC patients, careful monitoring is recommended for patients with predictive factors for treatment response and relapse of PVT.

Low-Dose Low-Molecular-Weight Heparin for Thromboprophylaxis During Pregnancy.

According to this study: In women who have a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and postpartum periods didn't reduce the risk of recurrence compared with fixed low-dose low-molecular-weight heparin.Further study is needed to determine whether intermediate-dose low-molecular-weight heparin may be more effective than low-dose low-molecular-weight heparin during the postpartum period.

Prolonged thromboprophylaxis with rivaroxaban after bariatric interventions: single centre experience.

BackgroundVenous thromboembolism (VTE) is common after bariatric surgery and extended prophylaxis is generally recommended. Low molecular weight heparin is the most commonly used agent but requires patients to be trained to self-inject and is expensive. Rivaroxaban is an oral daily formulation approved for VTE prophylaxis after orthopedic surgery. Efficacy and safety of rivaroxaban has been confirmed in major gastrointestinal resections by several observational studies. We report a single centre experience of using rivaroxaban as an agent for VTE prophylaxis in bariatric surgery. MethodsWe performed prospective cohort study assessing safety and efficacy of rivaroxaban as a medication for VTE prophylaxis in patients undergoing bariatric surgery in a single centre in Kyiv, Ukraine. Patients undergoing major bariatric procedure received perioperative prophylaxis of VTE with subcutaneous low molecular weight heparin and then were switched to rivaroxaban for total of 30 days starting on the 4th postoperative day. Thromboprophylaxis was performed in accordance with the VTE risks derived from the Caprini score. On the 3rd, 30th, 60th day after the operation, the patients underwent ultrasound examination of the portal vein, as well as the veins of the lower extremities. Telephone interviews were conducted 30 and 60 days after the surgery to evaluate the presence of complaints which may be characteristic for VTE as well as to assess compliance with the regimen and to assess patient satisfaction. Outcomes studies were incidence of VTE and adverse events related to rivaroxaban administration.Results110 patients were included in the study from July 2019 to May 2021. The average age of the patients was 43.6 years, the average preoperative BMI was 55 (35 to 75). One hundred and seven patients (97.3%) underwent laparoscopic intervention while three patients (2.7%) underwent laparotomy. Eighty-four patients underwent sleeve gastrectomy and twenty-six patients underwent other procedures, including bypass surgery. Average calculated risk of thromboembolic event was 5-6% based on Caprine index. All patients were treated with extended prophylaxis with rivaroxaban. The average follow-up period for patients was 6 months. There were no clinical or radiological evidence of thromboembolic complications in the study cohort. Overall complication rate was 7.2%, however, only one patient (0.9%) developed subcutaneous hematoma associated with rivaroxaban not requiring intervention. ConclusionExtended postoperative prophylaxis with rivaroxaban is safe and effective in preventing thromboembolic complications in patients undergoing bariatric surgery. It is preferred by patients and further studies should be considered to further evaluate its use in bariatric surgery.

Escherichia coli-related disseminated intravascular coagulation: Case report and literature review.

BACKGROUND: Escherichia coli can cause severe infections. The latter can lead to disseminated intravascular coagulation (DIC). The importance of an early diagnosis of DIC is illustrated through this case report. AIM: Review the utility and shortcomings of representative clinical indicators of E coli infection and DIC. CASE REPORT: A 48-year-old man presented with diarrhea, nausea, and vomiting with fever of 2-day duration, during which consciousness was lost for 12 hour. Hematology was undertaken. The coagulation profile, liver function, and kidney function were determined, and blood cultures undertaken. The final diagnosis was acute gastroenteritis complicated by DIC. Meropenem (1.0 g, q8h, i.v.) was started, along with active replacement of fluids. Anticoagulant therapy (low-molecular-weight heparin 0.4 mL, q.d.s.) was given. Plasma supplementation of coagulation factors and albumin was applied. On day-5 of therapy, hematology showed the platelet count, D-dimer level, and prothrombin time to be improved significantly. Low-molecular-weight heparin treatment was stopped and antibiotic treatment was continued for 1 week. The patient made a full recovery. CONCLUSIONS: In severe infection, timely assessment of the platelet count, procalcitonin level, coagulation function, as well as rational use of antibiotics, can improve the prognosis of patients.

Remodeling articular immune homeostasis with an efferocytosis-informed nanoimitator mitigates rheumatoid arthritis in mice.

Massive intra-articular infiltration of proinflammatory macrophages is a prominent feature of rheumatoid arthritis (RA) lesions, which are thought to underlie articular immune dysfunction, severe synovitis and ultimately joint erosion. Here we report an efferocytosis-informed nanoimitator (EINI) for in situ targeted reprogramming of synovial inflammatory macrophages (SIMs) that thwarts their autoimmune attack and reestablishes articular immune homeostasis, which mitigates RA. The EINI consists of a drug-based core with an oxidative stress-responsive phosphatidylserine (PtdSer) corona and a shell composed of a P-selectin-blocking motif, low molecular weight heparin (LMWH). When systemically administered, the LMWH on the EINI first binds to P-selectin overexpressed on the endothelium in subsynovial capillaries, which functions as an antagonist, disrupting neutrophil synovial trafficking. Due to the strong dysregulation of the synovial microvasculature, the EINI is subsequently enriched in the joint synovium where the shell is disassembled upon the reactive oxygen species stimulation, and PtdSer corona is then exposed. In an efferocytosis-like manner, the PtdSer-coroneted core is in turn phagocytosed by SIMs, which synergistically terminate SIM-initiated pathological cascades and serially reestablish intra-articular immune homeostasis, conferring a chondroprotective effect. These findings demonstrate that SIMs can be precisely remodeled via the efferocytosis-mimetic strategy, which holds potential for RA treatment.

Pharmacology of Heparin and Related Drugs: An Update.

Heparin has been used extensively as an antithrombotic and anticoagulant for close to 100 years. This anticoagulant activity is attributed mainly to the pentasaccharide sequence, which potentiates the inhibitory action of antithrombin, a major inhibitor of the coagulation cascade. More recently it has been elucidated that heparin exhibits anti-inflammatory effect via interference of the formation of neutrophil extracellular traps and this may also contribute to heparin's antithrombotic activity. This illustrates that heparin interacts with a broad range of biomolecules, exerting both anticoagulant and nonanticoagulant actions. Since our previous review, there has been an increased interest in these nonanticoagulant effects of heparin, with the beneficial role in patients infected with SARS2-coronavirus a highly topical example. This article provides an update on our previous review with more recent developments and observations made for these novel uses of heparin and an overview of the development status of heparin-based drugs. SIGNIFICANCE STATEMENT: This state-of-the-art review covers recent developments in the use of heparin and heparin-like materials as anticoagulant, now including immunothrombosis observations, and as nonanticoagulant including a role in the treatment of SARS-coronavirus and inflammatory conditions.

Anticoagulation Regimens in Pregnancy.

This article explores current recommendations for anticoagulation therapy in pregnancy, including antepartum, intrapartum, and postpartum guidelines. The authors review various screening strategies used to assess whether a patient is an appropriate candidate for anticoagulation during pregnancy and the postpartum period. The article includes dosing regimens, optimal surveillance, and medication reversal. The authors also address the challenges of transitioning between low-molecular-weight heparin and unfractionated heparin. Finally, there is a discussion of intrapartum anticoagulation management, especially as it relates to the administration of regional anesthesia, and the indications for and timing of thromboprophylaxis following delivery.

Approaches for optimizing venous thromboembolism prevention in injured patients: Findings from the consensus conference to implement optimal venous thromboembolism prophylaxis in trauma.

ABSTRACT: Venous thromboembolism (VTE) is a major issue in trauma patients. Without prophylaxis, the rate of deep venous thrombosis approaches 60% and even with chemoprophylaxis may be nearly 30%. Advances in VTE reduction are imperative to reduce the burden of this issue in the trauma population. Novel approaches in VTE prevention may include new medications, dosing regimens, and extending prophylaxis to the postdischarge phase of care. Standard dosing regimens of low-molecular-weight heparin are insufficient in trauma, shifting our focus toward alternative dosing strategies to improve prophylaxis. Mixed data suggest that anti-Xa-guided dosage, weight-based dosing, and thromboelastography are among these potential strategies. The concern for VTE in trauma does not end upon discharge, however. The risk for VTE in this population extends well beyond hospitalization. Variable extended thromboprophylaxis regimens using aspirin, low-molecular-weight heparin, and direct oral anticoagulants have been suggested to mitigate this prolonged VTE risk, but the ideal approach for outpatient VTE prevention is still unclear. As part of the 2022 Consensus Conference to Implement Optimal Venous Thromboembolism Prophylaxis in Trauma, a multidisciplinary array of participants, including physicians from multiple specialties, pharmacists, nurses, advanced practice providers, and patients met to attack these issues. This paper aims to review the current literature on novel approaches for optimizing VTE prevention in injured patients and identify research gaps that should be investigated to improve VTE rates in trauma.

Novel therapeutic medications for venous thromboembolism prevention in trauma patients: Findings from the Consensus Conference to Implement Optimal Venous Thromboembolism Prophylaxis in Trauma.

ABSTRACT: Trauma patients are at high risk for venous thromboembolism (VTE). Despite evidence-based guidelines and concerted efforts in trauma centers to implement optimal chemoprophylaxis strategies, VTE remains a frequent diagnosis in trauma patients. Current chemoprophylaxis strategies largely focus on the subcutaneous injection of low-molecular-weight heparin, which is administered twice daily. Novel approaches to pharmacologic VTE prophylaxis have the potential to reduce VTE rates by improving patient compliance through oral administration or through their ability to target alternative pathways that mediate thrombosis. While novel pharmacologic VTE prophylaxis strategies have been studied in nontrauma patients, there is a paucity of literature in trauma patients where the risk of thrombosis versus hemorrhage must be carefully considered. As a component of the 2022 Consensus Conference to Implement Optimal VTE Prophylaxis in Trauma, this review provides an update of the novel chemoprophylaxis agents for potential use in trauma patients. Here, we will consider the relative risks and benefits related to the use of these drugs, evaluate the current literature in nontrauma patients, and consider future directions that could potentially improve posttrauma VTE prophylaxis.

[Advances in heparin structural analysis by chromatography technologies].

Heparin （Hp） is the most widely used anticoagulant drug in the clinics， with an annual global output of over 10 billion dollars. Hp， a member of the glycosaminoglycans （GAGs）， is prepared from porcine intestinal mucosa via extraction， separation， and purification. Hp is a linear polysaccharide with repeating disaccharide units. Low-molecular-weight heparins （LMWHs） are depolymerized from Hp via chemical or enzymatic degradation. Compared with Hp， LMWHs exhibit less bleeding side effect， milder immunogenicity， and higher bioavailability when injected subcutaneously. In general， Hps， including LMWHs， are high complex drugs with large molecular weights （MWs）， inhomogeneous MW distributions， and structural heterogeneity， including different degrees and locations of sulfonation， and unique residues generated from different production processes. Thus， developing efficient analytical methods to elucidate the structures of Hps and characterize or quantitate their properties is extremely challenging. Unfortunately， this problem limits their quality control， production optimization， clinical safety monitoring， and new applications. Research has constantly sought to elucidate the complicated structures of Hp drugs. Among the structural analysis and quality control methods of Hp currently available， chromatographic methods are the most widely studied and used. However， no literature thoroughly summarizes the specific applications of chromatographic methods in the structural analysis， manufacturing process， and quality control of Hp drugs. This paper systematically organizes and describes recent research progresses of the chromatographic methods used to analyze Hp drugs， including the identification and composition of monosaccharides， disaccharides， oligosaccharides， and polysaccharides. The applications， innovations， and limitations of these chromatographic methods are also summarized in this review. The insights obtained in this study will help production and quality control personnel， as well as drug researchers， obtain a deeper understanding of the complex structures of Hp drugs. This paper also provides a comprehensive reference for the structural analysis and quality control of Hps， proposes ideas for the development of new quality control methods， and lays a strong foundation for the in-depth structural elucidation of Hp drugs.

Inhibition of atherosclerosis progression by modular micelles.

Atherosclerosis is a chronic disease initiated by lipid-mediated vascular inflammation. From the perspective of conventional treatment, it is difficult to achieve good therapeutic effects via regulation of a single lipid or anti-inflammatory effects. Herein, we designed an amphiphilic low molecular weight heparin-unsaturated fatty acid conjugate (LMWH-uFA) that acted as both an antiatherosclerotic agent and a nanocarrier with self-delivery properties. Structurally, LMWH-uFA self-assembled to form micelles with LMWH as the shell and uFA as the core, without any additives, which guaranteed their biosafety. Functionally, the hydrophilic segment, LMWH, prevented monocyte adhesion to inhibit early vascular inflammation, and the hydrophobic segment, uFA, could participate in the regulation of blood lipids. The anti-inflammatory drug rapamycin (RAP) was encapsulated in the micellar core, which improved its water solubility, and cooperated with LMWH to achieve targeted blockade of the vascular inflammation cascade at P-selectin. The three treatment modules, LMWH, uFA and RAP, were integrated into one system for different therapeutic targets in anticipation of better efficacy. In an atherosclerosis mouse model, RAP-loaded NPs significantly reduced the plaque area and showed satisfactory curative effects, which were related to the targeting of lipid regulation and inflammation. Thus, these modular micellar nanoparticles offer a promising approach for the clinical treatment of atherosclerosis.