Effect Of Heparin Research Articles

Study of the Anti-inflammatory Activity of 2-hydroxy-4-oxo-4-R-2-butenoates of Heterylammonium, which Have an Effect on the Blood Clotting System

Introduction. The use of anticoagulants is relevant in therapeutic, cardiological, neurological practice, geriatrics, obstetrics and gynecology, as well as in complications associated with COVID-19 infection and vaccination. In-depth studies of additional pleiotropic effects of existing anticoagulants are being conducted. The anti-inflammatory effect of heparins and direct oral anticoagulants was found. Special emphasis is placed on the existing close relationship between coagulation and inflammatory processes. The interaction of anticoagulants with nonsteroidal anti-inflammatory drugs when taken together is actively discussed. The combination of anticoagulant and anti-inflammatory action in one chemical molecule can solve the problem of polypragmasia.Aim. To study the anti-inflammatory activity of promising 2-hydroxy-4-oxo-4-R-2-butenoates of heterylammonium, which have an effect on the blood clotting system.Materials and methods. For further study of anti-inflammatory activity, 2-hydroxy-4-oxo-4-R-2-butenoates of heterylammonium, which have an effect on the blood clotting system, were selected. The anti-inflammatory effect was studied on a model of acute inflammatory edema in mongrel rats of both sexes weighing 180–250 g. The studied compounds were administered intragastrically. Diclofenac sodium and nimesulide substances administered similarly were used as comparison drugs. Acute toxicity of substances that showed activity was studied on white nonlinear mice of both sexes weighing 18–22 g with the definition of LD50.Results and discussion. All the studied 2-hydroxy-4-oxo-4-R-2-butenoates of heterylammonium have anti-inflammatory effects of varying severity. Data on the study of acute toxicity during intragastric administration, allow us to attribute the studied compounds to the 4.5 class of the hazard classification of chemical products.Conclusion. The anti-inflammatory activity of 14 2-hydroxy-4-oxo-4-R2-butenoates of heterylammonium has been studied. Five butanoate have an effect lower than comparison drugs, eight compounds are comparable to the effect of reference drugs, one compound is superior to nimesulide. The studied compounds can be assigned to class 4,5 of the hazard classification of chemical products. Medicinal candidates have been selected for further pharmacological, toxicological and technological study.

Low molecular weight heparin decreases pro-coagulant activity in clinical MSC products

Background aimsMesenchymal stromal cells (MSCs) are multipotent adult cells that can be isolated from tissues including bone marrow [MSC(BM)], adipose [MSC(AT)] and umbilical cord [MSC(CT)]. Previous studies have linked expression of tissue factor (TF) on MSC surfaces to a procoagulant effect. Venous thromboembolism (VTE), immediate blood-mediated inflammatory reaction (IBMIR) and microvascular thrombosis remain a risk with intravascular MSC therapy. We examined the effect of low molecular weight heparin (LMWH) on clinical-grade MSCs using calibrated automated thrombography (CAT). MethodsClinical grade MSC(BM)s, MSC(AT)s and MSC(CT)s harvested at passage 4 were added to normal pooled plasma (NPP) to a final concentration of either 400 000 or 50 000 cells/mL. LMWH was added to plasma in increments of 0.1 U/mL. Thrombin generation (TG) was measured using CAT. Flow cytometry was conducted on the cells to measure MSC phenotype and TF load. ResultsPresence of MSCs decreased lag time and increased peak TG. All cell lines demonstrated a dose response to LMWH, with MSC(AT) demonstrating the least thrombogenicity and most sensitivity to LMWH. TG was significantly reduced in all cell lines at doses of 0.2 U/mL LMWH and higher. DiscussionAll MSC types and concentrations had a decrease in peak thrombin and TG with increasing amounts of LMWH. While this in vitro study cannot determine optimal dosing, it suggests that LMWH can be effectively used to lower the risk of VTE associated with intravascular administration of MSCs. Future in vivo work can be done to determine optimal dosing and effect on IBMIR and VTE.

Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy.

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.

Comparative evaluation of effect of phlebotropic agents on vascular wall permeability in preclinical studies

Introduction. As there is insufficient evidence to date to determine phlebotropic drug preferences, further research in this area is warranted. Aim. To evaluate the effect of topical and oral phlebotropic agents on vascular wall permeability in preclinical studies. Materials and methods. The objects of the study were 6 phlebotropic agents for external and oral use, which were administered according to the recommendations specified in the instructions for use, 2 hours before the trypan blue. The model for preclinical studies: the xylene petechiae test with trypan blue staining. The evaluation criterion was the intensity of staining, which was expressed semiquantitatively (points). The test system was 100 white male outbred conventional mice. Results and discussion. Heparin + EPL + escin (Detragel) significantly reduces the intensity of staining in the xylene petechiae test. It was found that with a single external application reduces the intensity of staining by 25.0% compared to the control, which significantly by 60.0% exceeded the effectiveness of the drug heparin 1000 IU; with a course application of 15 days in 2 times, which significantly, least by 50%, exceeded the effect of the drug heparin 1000 IU and cosmetic product containing troxerutin. MPFF 1000 mg (Detralex) at a single oral administration significantly reduced the intensity of staining by 35.0% compared to the control group, which significantly by 69.2% exceeded the effectiveness of the reproduced preparations of MPFF and diosmin 600 mg. The indicated results are explained by differences in production technology, composition of components and are consistent with the known data on clinical efficacy of different groups of venotonics. Conclusion. In preclinical studies on the model of xylene petechiae with trypan blue staining, high efficacy of the original drug MPFF 1 (Detralex) at a single oral application and the drug heparin + EPL + escin (Detragel) at external single and course application for 15 days was established, which showed a significant difference with the control group, not less than 50% exceeded the efficacy of analogues and may indicate the effect on the permeability of the vascular wall.

Clot-Based Assay for Factor XI (FXI) Activity Is Highly Sensitive to Lupus Anticoagulant (LA) and Heparin with Potential Misdiagnosis of FXI Deficiency: The Importance of Recognizing Non-Parallelism

Introduction: Clot-based assays are employed to estimate coagulation factor activity in clinical pathology laboratories. These assays are PT- or aPTT-based and utilize dilutions of the patient's plasma in factor-deficient plasma. The curves of activity for each dilution follow a parallelism or non-parallelism pattern and the latter is typically seen in the presence of Lupus Anticoagulant (LA). Identification of this pattern is critical to avoid misdiagnosis of factor deficiency in patients who actually have an inhibitor. Materials and Methods: We observed low Factor XI (FXI) levels in patients with LA, while other factors were not affected. In order to determine the reason(s) why FXI levels are sensitive to LA, we collected 34 plasma samples from patients with dRVVT confirm ratio > 1.2, and estimated FVIII and FXI levels. FXI activity was also estimated with Dade ® Actin ® FS, a reagent that is not sensitive to the LA. The coefficient of variance (CV) for both FXI and FVIII levels were compared. To estimate the effects of heparin, plasma was spiked (0.1-1.0 IU/ML) and tested in the PTT, FXI, and FVIII assays. We tested with Dade ® Actin ® FS 4 known normal patients, 3 known FXI deficient patients, 20 known plasma positive for LA, and 10 with heparin. All assays were performed on a Siemens CS-5100 analyzer. Results: The results show that FXI is highly sensitive to LA, with non-parallelism and high CV, not observed with FVIII activity. As expected, FXI levels were not affected when LA-insensitive Dade ® Actin ® FS was used. Heparin (0.3-0.7 IU/ML) also showed non-parallelism in FXI activity, but not for FVIII. Only the highest dose of heparin (1.0 IU/ML) affected FVIII levels. Notably, the sensitivity of FXI activity to LA and heparin was explained by a few dilutions of the patient's plasma (5X) in the FXI assay, compared to other coagulation factors (20X). Of note, less diluted plasma is required for FXI activity because relatively higher levels of FXI is required to sustain and produce clot in the FXI-deficient plasma. Conclusion: This simple, yet not recognized explanation based on a literature search, is helpful to increase awareness of this analytical variable. It is also important to avoid misdiagnosis of FXI deficiency in patients with LA.

The Additional Value of Activated Clotting Time-Guided Heparinization During Interventions for Peripheral Arterial Disease.

Unfractionated heparin is widely used to lower the risk of arterial thromboembolic complications (ATECs) during interventions for peripheral arterial disease (PAD), but it is still unknown which heparin dose is the safest in terms of preventing ATECs and bleeding complications. This study aims to evaluate the incidence of complications during interventions for PAD and the relation between this incidence and different heparinization protocols. A retrospective analysis of a prospective multicenter cohort study was performed. Between June 2015 and September 2022, 355 patients who underwent peripheral interventions for PAD were included. All patients who were included before July 2018 received 5000 international units (IU) of heparin (group 1). Starting from July 2018, all included patients received an initial dose of 100 IU/kg, with potential additional heparin doses based on activated clotting time (ACT) values (group 2). Data on ACT values and complications within 30 days post-procedurally were collected. In total, 24 ATECs and 48 bleeding complications occurred. In group 1, 8.7% (n=11) of patients suffered from ATEC, compared with 5.7% (n=13) in group 2. Thirteen percent of patients (n=17) in group 1 had a bleeding complication, compared with 14% (n=31) in group 2. Arterial thromboembolic complications were more often found in patients with peak ACT values of <200 seconds, compared with ACT values between 200 and 250 seconds, 15% (n=6) versus 5.9% (n=9), respectively, p=0.048. Patients with peak ACT values >250 seconds had a higher incidence of bleeding complications compared with an ACT between 200 and 250 seconds, 24% (n=21) versus 9.8% (n=15), respectively, p=0.003. Forty-four percent of patients (n=23) in group 1 reached a peak ACT of >200 seconds, compared with 95% (n=218) of patients in group 2 (p=0.001). ATEC was found in 6.8% (n=24) and bleeding complications in 14% (n=48) of patients who underwent a procedure for PAD. There was a significantly higher incidence of ATECs in patients with a peak ACT value <200 seconds, and a higher incidence of bleeding complications in patients with a peak ACT value >250 seconds. The findings obtained from this study may serve as a basis for conducting future research on heparinization during procedures for PAD, with a larger sample size. Heparin is administered during arterial interventions for peripheral arterial disease (PAD) to decrease the risk of arterial (thrombo)embolic complications (ATEC) during or shortly following surgery. The effect of heparin is unpredictable in the individual patient, and the optimal dosage of this anticoagulant has not yet been established. Using the activated clotting time (ACT), the anticoagulatory effect of heparin can be monitored periprocedurally. Previous research on the incidence of both ATEC and bleeding complications, or on the optimal dosage of heparin administration, is scarce. This study aims to investigate the incidence of ATEC and bleeding complications between 2 different dosage protocols of heparin-a standard bolus of 5000 IU or ACT-guided heparinization-and thereby provide clarity on the optimal dose of heparin during peripheral arterial interventions for PAD.

Anti-factor Xa as the preferred assay to monitor heparin for the treatment of pulmonary embolism.

The mainstay of acute pulmonary embolism (PE) treatment is anticoagulation. Timely anticoagulation correlates with decreased PE-associated mortality, but the ability to achieve a therapeutic activated partial thromboplastin time (aPTT) with unfractionated heparin (UFH) remains limited. Although some institutions have switched to a more accurate and reproducible test to assess for heparin's effectiveness, the anti-factor Xa (antiXa) assay, data correlating a timely therapeutic antiXa to PE-associated clinical outcomes remains scarce. We evaluated time to a therapeutic antiXa using intravenous heparin after PE response team (PERT) activation and assessed clinical outcomes including bleeding and recurrent thromboembolic events. This was a retrospective cohort study at NYU Langone Health. All adult patients ≥18 years with a confirmed PE started on IV UFH with >2 antiXa levels were included. Patients were excluded if they received thrombolysis or alternative anticoagulation. The primary endpoint was the time to a therapeutic antiXa level of 0.3-0.7 units/mL. Secondary outcomes included recurrent thromboembolism, bleeding and PE-associated mortality within 3 months. A total of 330 patients with a PERT consult were identified with 192 patients included. The majority of PEs were classified as sub massive (64.6%) with 87% of patients receiving a bolus of 80 units/kg of UFH prior to starting an infusion at 18 units/kg/hour. The median time to the first therapeutic antiXa was 9.13 hours with 93% of the cohort sustaining therapeutic anticoagulation at 48 hours. Recurrent thromboembolism, bleeding and mortality occurred in 1%, 5% and 6.2%, respectively. Upon univariate analysis, a first antiXa <0.3 units/ml was associated with an increased risk of mortality [27.78% (5/18) vs 8.05% (14/174), p = 0.021]. We observed a low incidence of recurrent thromboembolism or PE-associated mortality utilizing an antiXa titrated UFH protocol. The use of an antiXa based heparin assay to guide heparin dosing and monitoring allows for timely and sustained therapeutic anticoagulation for treatment of PE.

Effect of Heparin on Antigen-Antibody Interaction in a Model System of the Bevacizumab Therapeutic Antibody And its Target VEGF-А165

In this work, we studied the effect of heparin on the binding process of VEGF-A165, the most common and important growth factor, and the monoclonal antibody bevacizumab by bio-layer interferometry. A complex of the full-length bevacizumab antibody with VEGF-A165 was modeled. The data obtained can be used in therapy with this antibody, as well as in the development of other therapeutic antibodies with maximum target specificity under various conditions.

The Antineoplastic Effect of Heparin on Colorectal Cancer: A Review of the Literature.

Heparin and derivatives are commonly used for thrombophylaxis in surgical colorectal cancer (CRC) patients. Recent studies have suggested that, besides its protective effect on the incidence of venous thromboembolism, heparin has an anti-cancer effect. The aim of this review was to explore the literature and report the antineoplastic effect of heparin and derivatives on CRC. MEDLINE and EMBASE databases were searched for relevant articles. Nineteen studies were included (n = 19). Fifteen were lab studies conducted in vivo or in vitro on CRC cell lines and/or mice (n = 15). Four were in vivo clinical studies (n = 4). CRC tumor growth was reduced by 78% in one study, (p < 0.01), while tumorigenesis was suppressed in heparin-treated mice in seven studies. A high dose of low molecular weight heparin for extended duration significantly reduced post-operative VEGF, suggesting that such a regime may inhibit tumor angiogenesis and distant metastasis. A randomized trial demonstrated the antineoplastic effect of nadroparin as the 6 month survival in palliative patients increased. Another study has reported that disease-free survival of CRC patients was not affected by a similar tinzaparin regime. The anti-cancer properties of heparin and derivatives are promising, especially in lab studies. Further clinical trials are needed to investigate the anti-cancer benefit of heparin on CRC.

Changes of osteodifferentiation potential of MSC-AT during in vitro co-cultivation with heparin

The aim of this study was to investigate the effect of heparin at a concentration of 1 IU/mL on changes in the osteodifferentiation potential of MSC from human adipose tissue under in vitro cocultivation.Materials and methods. Assessment of the phenotypic profile of MSC from human adipose tissue during cultivation in the presence/absence of heparin was performed by the flow cytometry method using the appropriate dyes according to the manufacturer’s protocol on a MACS Quant flow cytometer after 14 days of cultivation. To evaluate the migration and proliferation potential of MSCs in the presence of heparin, we were using a continuous monitoring electrode system, xCELLigence ® RTCA DP. After cultivation MSCs with heparin for 14 days, the intracellular expression of osteodifferentiation genes was evaluated by real-time PCR. In addition, the differentiation profile of MSCs from human adipose tissue cultured with heparin was evaluated by cytological staining with alizarin red to detect islands of mineralization after 21 days of cultivation. In addition, the amount of growth factors, chemokines, molecules with pro- and anti-inflammatory activity was estimated in the supernatants of the 14-day cultures.Results. There was a significant decrease ( compared with the control group of the study) in the number of cells with stem markers (CD73, CD90, CD105) on the cell surface of the culture in the MSC + heparin model; increase in proliferative and decrease in migratory activity of MSCs during co-cultivation with heparin; increased levels of relative mRNA expression of genes for osteodifferentiation (ALPL, RUNX2, BMP2, BMP6) and cell adhesion (CD49d); increase in mineralization area in the study model in the presence of heparin after 21 days of cultivation. There was a tendency to increase secretion of growth factor VEGF and pro-inflammatory factor IL -6 in the MSC + heparin model.Conclusion. The obtained results may serve as a basis for the development of new therapeutic tactics for the treatment of surgical patients undergoing osteosynthesis operations with a high risk of thrombosis.

Symptoms and Impaired Quality of Life After COVID-19 Hospitalization: Effect of Therapeutic Heparin in Non-ICU Patients in the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute Trial: Effect on 3-Month Symptoms and Quality of Life

BackgroundTherapeutic-dose heparin decreased days requiring organ support in non-critically ill patients hospitalized for COVID-19 but its impact on persistent symptoms or quality of life (QoL) is unclear. Research QuestionIn the ACTIV-4a trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs. prophylactic heparin associated with less symptoms and better QoL at 90-days? Study Design and MethodsThis was an open-label randomized controlled trial at 34 hospitals in the US and Spain. 727 non-critically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs. prophylactic heparin. Only patients with 90-day data on symptoms and QoL were analyzed. We ascertained symptoms and QoL by EQ-5D-5L at 90-day follow-up in a pre-planned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L were mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analysis were performed. ResultsAmong 571 patients, 288 (50.4%) reported at least one symptom. In 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of EQ-5D-5L. Presence of 90-day symptoms were associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted odds ratio (aOR) 2.37, 95% CI 1.22-4.59), usual activity (aOR 3.66, 95% CI 1.75-7.65), pain (aOR 2.43, 95% CI 1.43-4.12), and anxiety (aOR 4.32, 95% CI 2.06-9.02), compared to patients reporting no symptoms There were no differences in symptoms or the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR 0.32, CI 0.11-0.96). InterpretationIn a randomized controlled trial of hospitalized non-critically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals. Clinical Trial RegistrationNCT04505774

Influence of Peptide Bioregulators on Indicators of Hemostasis in Blood of Irradiated Experimental Animals at Low Altitude Conditions

In modern biology and medicine, much attention is paid to the study of the hemostasis regulation of some cell populations by substances of a peptide nature. They have the ability to regulate the functional and proliferative activity of cells and ensure communication in normal and pathological conditions. Research data showed that significant violations of the hemostatic system also occur with radiation damage to the body. One of the first radiation responses involves the coagulation cascade's activation, which leads to the breakdown of fibrinogen and the formation of fibrin clots. The potential threat of this is quite evident due to the existence of uranium mining tailings in several regions of the Kyrgyz Republic. Considering that significant disturbances of the hemostatic system occur during radiation damage to the body, and effective means are clearly not enough, the study of the effect of bioregulatory peptides in these conditions is of great importance. In the study, we carried out the total X-ray irradiation of laboratory animals on the X-ray therapeutic apparatus RUM-17. Peptide bioregulators peptide-1 and peptide-2 were administered intramuscularly to irradiated animals. Throughout the research, we used methods characterizing all links of hemostasis: vascular-platelet hemostasis, coagulation hemostasis, and fibrinolysis. The study has shown that the use of the peptide bioregulators in the background of acute radiation pathology leads to a decrease in the intensity of the chronic course of post-radiation thrombo hemorrhagic syndrome, contributing to an increase in the content of antithrombin III in the blood and modulating the versatile effects of endogenous heparin, which undoubtedly have a beneficial effect on the pathogenesis of radiation sickness.

Comparative effectiveness and safety of apixaban and low-molecular weight heparin among patients with venous thromboembolism and active cancer in an extended treatment setting

Abstract Background The 2020 European Society of Cardiology guidelines recommend extended anticoagulant (AC) treatment among patients with VTE and with progressive or persistent risk factors (such as cancer) as they are at a high risk of a recurrent VTE episode. Purpose The study evaluated the risk of recurrent VTE and major bleeding (MB) among patients with VTE and active cancer prescribed apixaban or LMWH (reference) for ≥3 months. Methods This retrospective study included patients ≥18 years with VTE who initiated apixaban or LMWH within 30 days following the first VTE event using a large administrative claims database, representing ≥140 million patients enrolled in US health plans. Data from July 1, 2016, through April 30, 2022, was used. Patients were required to have ≥3 months of continuous enrollment (CE) and ≥3 months of continuous primary AC treatment following the date of apixaban/LMWH initiation. The end of 3 months of primary treatment was designated as index date. The follow-up period was from the day after the index date until the earliest of disenrollment, discontinuation of index anticoagulant, switch to another anticoagulant, or the end of the study period. The MB and recurrent VTE outcomes were evaluated and compared in the follow-up period. Inverse-probability treatment weighting (IPTW) was used to balance the treatment cohorts on relevant demographic and clinical characteristics including VTE and cancer-related variables. Incidence rate for the outcomes were calculated per 100 person-years. Cox proportional hazard models were used to evaluate the adjusted risk of recurrent VTE and MB reported as hazard ratios (HR) along with 95% confidence interval (CI). Results After the eligibility criteria was met, the study included 13,527 apixaban and 2,914 LMWH treated patients with VTE and active cancer. Post IPTW, the treatment cohorts were balanced on baseline patient characteristics (Figure 1). In the follow-up period, the incidence rates (IR) per 100 person-years for recurrent VTE and MB were lower for apixaban than LMWH among patients with VTE and active cancer (Figure 2). Apixaban patients had a lower risk of recurrent VTE (HR: 0.42; 95% CI: 0.34–0.53) and MB (HR: 0.50; 95% CI: 0.41–0.61) when compared to LMWH (Figure 2). Conclusion In this observational cohort analysis of patients with VTE and active cancer, extended anticoagulation treatment of ≥3 months with apixaban was associated with a lower risk of recurrent VTE and MB compared with LMWH. Additional research is required to confirm these findings.Figure 1Figure 2

Interactions of variants of human apolipoprotein A-I with biopolymeric model matrices. Effect of collagen and heparin

BackgroundThe extracellular matrix (ECM) is a complex tridimensional scaffold that actively participates in physiological and pathological events. The objective of this study was to test whether structural proteins of the ECM and glycosaminoglycans (GAGs) may favor the retention of human apolipoprotein A-I (apoA-I) variants associated with amyloidosis and atherosclerosis. MethodsBiopolymeric matrices containing collagen type I (Col, a main macromolecular component of the ECM) with or without heparin (Hep, a model of GAGs) were constructed and characterized, and used to compare the binding of apoA-I having the native sequence (Wt) or Arg173Pro, a natural variant inducing cardiac amyloidosis. Protein binding was observed by fluorescence microscopy and unbound proteins quantified by a colorimetric assay. ResultsBoth, Wt and Arg173Pro bound to the scaffolds containing Col, but the presence of Hep diminished the binding efficiency. Col-Hep matrices retained Arg173Pro more than the Wt. The retained protein was only partially removed from the matrices with saline solutions, indicating that electrostatic interactions may occur but are not the main driving force. Using in addition thermodynamic molecular simulations and size exclusion chromatography approaches, we suggest that the binding of apoA-I variants to the biopolymeric matrices is driven by many low affinity interactions. ConclusionsUnder this scenario Col-Hep scaffolds contribute to the binding of Arg173Pro, as a cooperative platform which could modify the native protein conformation affecting protein folding. General significanceWe show that the composition of the ECM is key to the protein retention, and well characterized biosynthetic matrices offer an invaluable in vitro model to mimic the hallmark of pathologies with interstitial infiltration such as cardiac amyloidosis.

The Effect of Smoking on the Activated Clotting Time and the Incidence of Complications in Noncardiac Arterial Procedures.

Smoking is a well-known risk factor for developing arterial diseases and for an increase of complications during and after vascular procedures. Although smoking has a proven effect on hemostasis, no literature is available on the effect of smoking on the activated clotting time (ACT), which is used to monitor the effect of heparin during noncardiac arterial procedures (NCAP). The aim of this study was to examine the effect of smoking on ACT values and the incidence of complications during the same admission or 30 day follow-up of NCAP. A post hoc analysis of a prospective multicenter cohort study was performed. Patients older than 18 years, who underwent NCAP between December 2016 and April 2021, were enrolled. Patients were divided into 2 groups based on smoking status: never/former smokers and current smokers. Two heparin dosing protocols were used: an initial bolus of 5000 IU or 100 IU/kg bodyweight. In total, 773 patients met the inclusion criteria. Five minutes after administration of 5000 IU of heparin, mean ACT values were 190 and 196 seconds for nonsmokers and smokers, respectively (p=0.078). After 100 IU/kg of heparin, mean ACT values were 229 and 226 seconds for nonsmokers and smokers, respectively (p=0.37). Incidence of complications in the whole study cohort was not significantly different for nonsmokers compared with smokers (arterial thrombo-embolic complication [ATEC] 4.7% vs 5.7% p=0.55; hemorrhagic complications 15% vs 18% p=0.29). In subgroup-analysis, a significant difference between smoking groups was found for hemorrhagic complications after open aneurysm repair (p=0.024). However, after adjusting for confounders, the difference between the smoking groups annulled. The results of this study suggest that smoking does not have a significant effect on ACT values or on the incidence of complications in NCAP. Large-scale studies are required to further analyze potential factors having an effect on the ACT and perioperative and postoperative complications, which could help individualize heparinization strategy. There is high variance between patients in their response on administration of heparin, this is not yet fully understood. This study investigated the effect of smoking in a large prospective multicentre cohort. The results suggests that active smoking does not have an effect on the activated clotting time after administration of heparin. Also no significant effect of smoking could be found on the incidence of all registered complications. Monitoring of the effect of heparin remains important to provide patients with safe anticoagulation during vascular procedures.

SAT129 Clinical Conundrum Of Suspected Pancreatitis Masking Diabetic Ketoacidosis

Abstract Disclosure: A. Sood: None. O. Syed: None. A. Sood: None. P. Patel: None. M.M. Alosiyus: None. ​​Abstract: Patients with End-Stage-Renal-Disease (ESRD) have poor renal excretion which can cause false elevation in pancreatic enzymes. We present a case of a pregnant woman on hemodialysis (HD) with elevated lipase levels concerning for acute pancreatitis. Case Presentation: A 25-year-old African American female with history of type 1 diabetes mellitus, ESRD secondary to diabetic nephropathy, diabetic gastroparesis, hypertension presented to the hospital with diffuse severe abdominal pain following HD. Lab showed Anion gap 15, Glucose 304 mg/dL, Creatinine 4.6 mg/dL, Triglyceride 130 mg/dL, Lipase 390 mg/dL, with urine negative for ketones. The abdominal US was negative for gallstones, and revealed a normal size common bile duct. CT scan was deferred due to a positive urine pregnancy test. She was started on IV fluids for suspected pancreatitis. Patient had worsening blood glucose levels as well as anion gap despite being on Humalog and correctional scale insulin. Patient was started on an insulin drip with resolution of the anion gap. Discussion: Patient met 2 of 3 criteria for pancreatitis, with CT and MRI deferred in this case due to pregnancy and low suspicion secondary to negative US result.[5] Pancreatic enzymes can be falsely elevated in ESRD patients. Lipase can be elevated in HD[3] patients due to the lipolytic effect of heparin used during dialysis, while elevation of lipase in DKA remains unclear[2]. Acidosis is common in ESRD patients, thus masking the diagnosis of DKA which also presents with abdominal pain, nausea, vomiting, which can potentially cause a delay in the treatment. The mimicking and masking of these conditions by each other can thereby result in a diagnostic dilemma, which is why a prompt diagnosis of pancreatitis should be made in a patient presenting with DKA. Conclusion: Elevated levels of amylase and lipase are concerning for pancreatitis, however, metabolic processes could also be masked by underlying chronic diseases. While fluid resuscitation is the mainstay treatment for DKA and pancreatitis, it is extremely important to be cautious when a patient has an underlying ESRD. The diagnostic dilemma due to the overlapping diagnosis should be taken into consideration early during the hospitalization, and a high index of clinical suspicion can prevent the unnecessary delay in the treatment.

Effect of Heparin on the Formation and Healing of Gastric Ulcers Induced by Acetic Acid Application on the Gastric Mucosa in Rats

The key factor in maintaining the integrity of the gastric mucosa is its normal blood supply, respectively, the use of drugs that improve it, including through a positive effect on the rheological properties of blood, is in demand for the treatment of gastric ulcer. These drugs include the anticoagulant heparin. The aim of the work is to study the effect of heparin on the formation and healing of gastric ulcers induced by the application of 60% acetic acid to the gastric mucosa in rats, while assessing the possible risk of bleeding. After application of acetic acid (day 0), the area of gastric ulcers was assessed on the 4th day (formation of the ulcers) and the 7th day (healing of the ulcers). To assess the effect on ulcer formation, heparin (1000 IU/kg/day, subcutaneously) was administered from days 0 to 3, and on the healing from days 4 to 6 after acid application. To check for possible bleeding under the influence of heparin, the level of hemoglobin in the blood was tested before acid application (basal), on the 4th and 7th days after application. The degree of bleeding was assessed based on the relative decrease in hemoglobin levels. The administration of heparin led to a decrease in the average area of ulcers both on the 4th and on the 7th day compared with that in control rats (heparin vehicle). In control rats, both on the 4th and on the 7th day, the hemoglobin level was reduced compared to the corresponding basal level. Heparin had no effect on the hemoglobin level at day 4, but potentiated the decrease in mean hemoglobin level at day 7, increasing the number of animals having a greater relative decrease in hemoglobin level compared to the corresponding control group. Thus, heparin may have a gastroprotective effect, manifested both in the weakening of the formation of an ulcer and in the acceleration of its healing, however, there is a risk of bleeding when the ulcer heals.

OC 54.1 Effectiveness and Safety of Rivaroxaban and Low Molecular-Weight Heparin in Cancer-Associated Venous Thromboembolism: A Meta-Analysis of Oscar Programme Findings

OC 54.1 Effectiveness and Safety of Rivaroxaban and Low Molecular-Weight Heparin in Cancer-Associated Venous Thromboembolism: A Meta-Analysis of Oscar Programme Findings

Heparin for Women With Recurrent Miscarriage and Inherited Thrombophilia (ALIFE2): An International Open-Label, Randomized Controlled Trial

ABSTRACT Thrombophilia has been implicated in the cause of recurrent miscarriage, which affects approximately 3% of couples trying to conceive. International professional guidelines recommend heparin anticoagulation for antiphospholipid syndrome, an acquired thrombophilia responsible for approximately 15% of recurrent miscarriage, but not for other inherited thrombophilias due to an absence of evidence. Many clinicians prescribe heparin to women with recurrent miscarriage and inherited thrombophilia despite the professional recommendations. This international, open-label, randomized controlled trial aimed to compare the effect of low-molecular weight heparin (LMWH) and standard pregnancy surveillance on livebirth rates in women with recurrent miscarriage and inherited thrombophilia. Women aged 18–42 years with recurrent miscarriages who were attempting to conceive or less than 7 weeks pregnant and had an inherited thrombophilia were recruited across 40 hospitals in 5 countries. Women were randomly assigned to LMWH or no LMWH in a 1:1 ratio. Women randomized to LMWH self-administered it once a day subcutaneously, beginning as soon as possible after a positive pregnancy test and before 7 weeks of gestation and continuing throughout pregnancy. The primary study outcome was livebirth after 24 weeks of gestation. Livebirth was compared across randomized treatment groups using an χ2 test with continuity correction, then a sensitivity analysis with logistic regression to adjust for stratification factors. A total of 326 women were randomized between August 2012 and January 2021. Of these, 164 were randomized to LMWH plus standard care and 162 to standard care alone. In the standard care group, 30 patients ultimately received LMWH for thromboprophylaxis per professional treatment guidelines. The mean age of participants was 33 years, and the median number of miscarriages before randomization was 3 (interquartile range, 2–4), with two thirds of patients having a history of 3 or more miscarriages. The most common thrombophilia diagnoses were heterozygosity for factor V Leiden, prothrombin G20210A mutation, and protein S deficiency. The livebirth rate was 72% (116/162) in the LMWH group, and 71% (112/158) in the standard care group, and no statistical significant was detected between the groups even after adjustment (odds ratio, 1.08; 95% confidence interval, 0.65–1.78; P = 0.77). No differences in adverse pregnancy outcomes or complications were observed between the groups. Easy bruising was reported by 45% (73) women in the LMWH group and 10% (16) in the standard care group. This randomized controlled trial demonstrates that although LMWH is safe in women with recurrent pregnancy loss and inherited thrombophilia, it does not result in an increased live birth rate compared with standard pregnancy surveillance.

Perprocedural Heparinization in Non-cardiac Arterial Procedures: The Current Practice in the Netherlands.

Heparin is the most widely-used anticoagulant to prevent thrombo-embolic complications during non-cardiac arterial procedures (NCAP). Unfortunately, there is a lack of evidence and consequently non-uniformity in guidelines on perprocedural heparin management. Detailed insight into the current practice of antithrombotic strategies during NCAP in the Netherlands is important, aiming to identify potential optimal protocols and local differences concerning perprocedural heparinization. A comprehensive online survey was distributed electronically to vascular surgeons of every hospital in the Netherlands in which NCAP were performed. Data were collected from September 2020 to October 2021. The response rate was 90% (53/59 hospitals). During NCAP, all surgeons generally administered heparin before arterial clamping. In 74% (39/54) of hospitals, a single heparin dosing protocol was used for all types of patients and vascular procedures. In 40%, there was no uniformity in heparin dosing between vascular surgeons. Depending on the procedure, a fixed bolus heparin, predominantly 5000 IU, was administered in 73% to 93%. In the remaining hospitals (7%-27%), a bodyweight-based heparin protocol was used, with an initial dose of 70 or 100 IU/kg. A minority (28%) monitored the effect of heparin in patients using the activated clotting time add (ACT) after activated clotting time. Target values varied between 180 and 250 seconds or 2 times the baseline ACT. This survey demonstrates considerable variability in perprocedural heparinization during NCAP in the Netherlands. Future research on heparin dosing is needed to harmonize and optimize heparin dosage protocols and contemporary guidelines during NCAP, and thereby improve vascular surgical care and patient safety. This survey demonstrated persisting intra- and inter-hospital variability in perprocedural heparinization during non-cardiac arterial procedures (NCAP) in the Netherlands. The observed variability in heparinization strategies highlights the need for high quality evidence on perprocedural anticoagulation strategies. This is needed in order to harmonize and optimize heparin dosage protocols and contemporary guidelines and thereby improve vascular surgical patient care. Based on the current results, an international survey will be conducted by the authors to gain additional insight into the antithrombotic strategies used during NCAP, aiming to harmonize anticoagulation protocols worldwide.