Administration Of Low Molecular Weight Heparin Research Articles

Indication-based use of low molecular weight heparin during pregnancy: A retrospective study in Northern Greece

Introduction: Venous thromboembolism (VTE) is a condition with high morbidity and mortality rates and presents as the third leading cause of cardiovascular deaths, globally. During the antenatal period, the risk of VTE occurrence increases, therefore, in pregnant women at high-risk for VTE, the use of low molecular weight heparin (LMWH) is recommended. This study aimed to investigate the indication-based administration of LMWH in pregnancy. Material and methods: This was a retrospective cohort study (2019-2022) conducted at the Third Department of Obstetrics and Gynecology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Greece. All pregnant women at the first trimester of pregnancy were eligible. Their physical characteristics were recorded and information about their personal, familial, gynecological and obstetrical medical history was collected. By utilizing the above characteristics, a score of the risk of developing VTE during pregnancy was calculated for each woman, using the algorithm recommended by the Royal College of Obstetricians & Gynecologists. Results: In total, 2,716 pregnant women were included in the study. Of these, 149 (5.5%) received LMWH throughout their pregnancy with only 2 of them (0.1%) having appropriate indications. Of the women not prescribed LMWH, 2,567 (94.5%), none had an indication for LMWH administration. Notably, 495 (19.3%) women had a history of at least one miscarriage and 89 (59.7%) of them used LMWH, regardless of whether they had an indication or not. Conclusion: There was a high percentage of women with no indication for LMWH who, in fact, received this medication. Physicians should refrain their use following evaluation based on appropriate risk factors.

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

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

Low-molecular-weight heparin in the prevention of unexplained recurrent miscarriage: a systematic review and meta-analysis

The etiology of recurrent pregnancy loss (RPL) is complex and multifactorial and in half of patients it remains unexplained (U-RPL). Recently, low-molecular-weight heparin (LMWH) has gained increasing relevance for its therapeutic potential. On this regard, the aim of this systematic review and meta-analysis is to analyze the efficacy of low molecular weight heparin (LMWH) from the beginning of pregnancy in terms of live birth rates (LBR) in U-RPL. Registered randomized controlled trials (RCTs) were included. We stratified findings based on relevant clinical factors including number of previous miscarriages, treatment type and control type. Intervention or exposure was defined as the administration of LMWH alone or in combination with low-dose aspirin (LDA). A total of 6 studies involving 1016 patients were included. The meta-analysis results showed that LMWH used in the treatment of U-RPL was not associated with an increase in LBR with a pooled OR of 1.01, a medium heterogeneity (26.42%) and no publication bias. Results of other sub-analyses according to country, treatment type, and control type showed no significant effect of LMWH on LBR in all subgroups, with a high heterogeneity. The results highlight a non-significant effect of LMWH in U-RPL on LBR based on moderate quality evidence.Registration number: PROSPERO: (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022326433).

Ressenti des femmes après traitement prophylactique par héparine de bas poids moléculaire après une césarienne

ObjectiveTo assess women's experiences with skin-related side effects following subcutaneous low molecular weight heparin (LMWH) injections after a cesarean section, and to analyze their impact on treatment adherence. MethodA questionnaire was developed in collaboration with Cesarine, a patients’ association, to explore various aspects of LMWH administration, including prevention methods, cutaneous side effects, treatment compliance, perceived constraints, apprehension, and understanding of treatment benefits. Additionally, women's opinions on an alternative oral administration approach were solicited, taking into consideration breastfeeding contraindication. The questionnaire was on the Facebook® page and blog of the association. ResultsOne hundred and sixty-four women participated in the survey. Among them, 139 women (84.8%) reported bruising, while 117 (71.3%) reported pruritus, erythema, or nodules at the injection site. Treatment discontinuation was observed in 36 cases (22%), decided mostly by the women themselves (77.8%). The main reasons cited for discontinuation were discomfort during injection (71.4%), skin reactions (31.4%), and a perceived lack of effectiveness (54.3%). Furthermore, 88 women (53.7%) wanted to quit the treatment prematurely, citing similar reasons. Thirty-three women (20.1%) reported oversights. For most women, the treatment was perceived as burdensome and caused apprehension. An alternative oral administration method was of interest to 131 women (79.9%). However, only 28 (17.8%) would have accepted if the medication was incompatible with breastfeeding. ConclusionCutaneous side effects of LMWH injections, as well as injection process itself, have a negative impact on adherence in the postpartum period following a c-section. These findings highlight the need to explore alternative to improve women's compliance and comfort.

Safety and comparative efficacy of initiating low-molecular-weight heparin within 24 hours of injury or surgery for venous thromboembolism prophylaxis in patients with spinal cord injury: a prospective TRACK-SCI registry study.

Venous thromboembolism (VTE) following traumatic spinal cord injury (SCI) is a significant clinical concern. This study sought to determine the incidence of VTE and hemorrhagic complications among patients with SCI who received low-molecular-weight heparin (LMWH) within 24 hours of injury or surgery and identify variables that predict VTE using the prospective Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) database. The TRACK-SCI database was queried for individuals with traumatic SCI from 2015 to 2022. Primary outcomes of interest included rates of VTE (including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and in-hospital hemorrhagic complications that occurred after LWMH administration. Secondary outcomes included intensive care unit and hospital length of stay, discharge location type, and in-hospital mortality. The study cohort consisted of 162 patients with SCI. Fifteen of the 162 patients withdrew from the study, leading to loss of data for certain variables for these patients. One hundred thirty patients (87.8%) underwent decompression and/or fusion surgery for SCI. DVT occurred in 11 (7.4%) of 148 patients, PE in 9 (6.1%) of 148, and any VTE in 18 (12.2%) of 148 patients. The analysis showed that admission lower-extremity motor score (p = 0.0408), injury at the thoracic level (p = 0.0086), admission American Spinal Injury Association grade (p = 0.0070), and younger age (p = 0.0372) were significantly associated with VTE. There were 3 instances of postoperative spine surgery-related bleeding (2.4%) in the 127 patients who had spine surgery with bleeding complication data available, with one requiring return to surgery (0.8%). Thirteen (8.8%) of 147 patients had a bleeding complication not related to spine surgery. There were 2 gastrointestinal bleeds associated with nasogastric tube placement, 3 cases of postoperative non-spine-related surgery bleeding, and 8 cases of other bleeding complications (5.4%) not related to any surgery. Initiation of LMWH within 24 hours was associated with a low rate of spine surgery-related bleeding. Bleeding complications unrelated to SCI surgery still occur with LMWH administration. Because neurosurgical intervention is typically the limiting factor in initializing chemical DVT prophylaxis, many of these bleeding complications would have likely occurred regardless of the protocol.

Potential of anticoagulant therapy in cardiology practice for thrombocytopenia. Literature review

The review article discusses the issues of anticoagulant therapy in cardiovascular patients with thrombocytopenia (TP), gives the concept of ethylenediaminetetraacetic acidand heparin-induced TP. The management of patients with heparin-induced TP is analyzed in detail, which consists in the discontinuation of unfractionated and low molecular weight heparin administration with replacement to direct thrombin inhibitors (lepirudin or argatroban), fondaparinux or direct oral anticoagulants.The authors emphasize that the anticoagulant administration to most patients with platelet count >50×109/l is possible in full prophylactic and therapeutic doses. Reducing the level of platelets to 25-50×109/l in most cases requires a reduction in the anticoagulant dose by 50%. At a platelet level of 20-25×109/l or less, anticoagulant therapy should be avoided in most patients.In addition to the scope of anticoagulant therapy, TP also determines the choice of anticoagulant as follows: in patients with acute coronary syndrome, bivalirudin or fondaparinux are recommended, while in patients with cancer and stable TP, warfarin or direct oral anticoagulants can be prescribed. In progressive TP (if heparin-induced TP is ruled out), low molecular weight heparins should be used.

Achieving durable compliance with venous thromboembolism prophylaxis in bariatric surgery: 3-year data from a major academic medical center

BackgroundMetabolic and bariatric surgery (MBS) venous thromboembolism (VTE) prescribing practices vary widely. Our institutional VTE prophylaxis protocol has historically been unstandardized. ObjectivesTo create a standardized MBS VTE prophylaxis protocol, track protocol compliance, and identify barriers to protocol compliance and address them with Plan-Do-Study-Act (PDSA) cycles. SettingSingle Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program-accredited academic hospital. MethodsWe conducted a retrospective study for all patients undergoing MBS (January 2019 to September 2022). A multidisciplinary group of bariatric clinicians reviewed literature and developed the following standardized VTE prophylaxis protocol: 5000 units preoperative subcutaneous (SC) heparin within 60 minutes of anesthesia induction and postoperative 40 mg SC low molecular weight heparin (LMWH) within 24 hours of surgery. This protocol was distributed to relevant clinical stakeholders. We assessed monthly compliance rates through chart review. Goal compliance was ≥90%. We identified sources of noncompliance and addressed them with PDSA methodology. ResultsA total of 796 patients were included. Preoperative heparin administration increased from a mean of 47% (107/228) preintervention to 96% (545/568) postintervention (P < .0001), and postoperative LMWH administration increased from 71% (47/66) to 96% (573/597, P = .0002). These compliance rates were sustained for 3 years. Barriers to protocol noncompliance included order set timing errors (n = 45), surgeon error (n = 44), surgeon discretion (n = 40), and nursing error (n = 20). No change in bleeding or VTE rates was observed. ConclusionsDeveloping a standardized VTE prophylaxis protocol, monitoring process measures, and engaging relevant stakeholders in PDSA cycles resulted in drastic and durable improvement in VTE prophylaxis compliance rates.

Low-molecular-weight heparin in thrombophilic women receiving in vitro fertilization/intracytoplasmic sperm injection: A meta-analysis.

This meta-analysis aimed to evaluate the efficacy and safety of low-molecular-weight heparin (LMWH) on pregnancy outcomes in thrombophilic women receiving in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). A systematic literature search of PubMed, EMBASE, the Cochrane Library, and China National Knowledge Infrastructure was performed to identify randomized controlled trials (RCTs) comparing LMWH with no treatment or placebo published from database inception until February 19, 2023. Primary outcomes were the clinical pregnancy rate and implantation rate, and secondary outcomes were the live birth rate, miscarriage rate, and the risk of bleeding events. The certainty of the evidence was rated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system. Meta-analysis was conducted using STATA 14.0. Five RCTs involving 1094 thrombophilic women receiving IVF/ICSI were finally included. Administration of LMWH was associated with statistically higher clinical pregnancy rate (4 RCTs, risk ratio [RR] 1.50, 95% confidence interval [CI] 1.23-1.82, p < 0.001, low certainty evidence), implantation rate (5 RCTs, RR 1.49, 95% CI 1.25-1.78, p < 0.001, very low certainty evidence), and live birth rate (2 RCTs, RR 2.15, 95% CI 1.60-2.89, p < 0.001, very low certainty evidence), but with statistically lower miscarriage rate (2 RCTs, RR 0.36, 95% CI 0.15-0.86, p = 0.021, very low certainty evidence). However, using LMWH was linked to a higher risk of bleeding events (2 RCTs, RR 2.36, 95% CI 1.49-3.74, p < 0.001, very low certainty evidence). Very low certainty evidence suggests that administration of LMWH may benefit pregnancy outcomes in thrombophilic women receiving IVF/ICSI treatment, although it may also increase the risk of bleeding events. However, before putting our findings into practice, healthcare professionals should conduct an in-depth evaluation of the available evidence and specific patient situations. Furthermore, due to the low methodological quality of the included studies, more high-quality studies are needed to validate our findings in the future.

P-506 Administration of low molecular weight heparin alleviate immune physiology in recurrent implantation failure modulating CCL2-CCR2 axis during frozen embryo transfer: effort from clinic to bench

Abstract Study question Does low molecular-weight heparin (LMWH) administration modulate CCL2-CCR2 axis in recurrent implantation failure (RIF) patients undergoing frozen embryo transfer (FET) to improve pregnancy salvage? Summary answer LMWH treatment attests beneficial immunological tolerance in vivo and in vitro through modulation of CCL2-CCR2 axis suggesting possible restoration of weak pro-inflammatory response in RIF. What is known already Immune imbalance in proportion of activated macrophages (M1) and alternatively activated macrophages (M2) impede endometrial receptivity and contribute to RIF. CCL2 (M2-asscociated) - CCR2 (t-helper-2 associated) axis orders macrophage polarization by influencing expression of functionally relevant and polarization associated genes and down-modulate pro-inflammatory cytokine production. Immunological effects of LMWH regulate pregnancy-promoting processes at foetal-maternal interface to provide an appropriate implantation process; outcomes being controversial. We aim to investigate the potential immunoregulatory properties of LMWH in patients with RIF undergoing FET, with particular regard to effects on macrophages and T-helper (Th) cells; two key players in promoting immune tolerance during pregnancy. Study design, size, duration This prospective cohort study constituted 121 women with RIF (≥3 failed embryo transfer) undergoing FET at Institute of Reproductive Medicine between January to October 2022. An incremental dose (4-12mg/day) of estradiol with (Group A; n = 62) or without (Group B; n = 59) LMWH (40 mg/day) from d2 to d12 with sequential ultrasound following intra-muscular progesterone (100mg/day) for 4 days was administered in all participants. Blood samples were collected to isolate plasma and peripheral-blood-mononuclear-cells (PBMCs). Participants/materials, setting, methods Monocytes were purified from PBMCs and cultured with GM-CSF or M-CSF to analyze factor/s which control CCL2-CCR2 expression along macrophage polarization by flow cytometry. Influence of CCL2 on GM-CSF-cultured macrophages (GM-MØ) and M-CSF-cultured macrophages (M-MØ) specific gene markers was analysed using quantitative RT-PCR (qRT-PCR). To assess immunological effects of LMWH in-vivo, Th-specific cytokine profile/s and respective chemokines were measured from plasma by Luminex xMAP technology. Statistical significance was set at p &amp;lt; 0.05. Main results and the role of chance The clinical pregnancy rate was higher in group A. (A vs B: 37.09% vs. 27.11%, p = 0.24). LMWH exposure significantly decreased the secretion of CCL2 (p &amp;lt; 0.01) and CCL22 (p &amp;lt; 0.001) in GM-CSF-cultured macrophages, while it increased CCL2, CCL20 production (p &amp;lt; 0.001) in both GM-MØ and M-MØ. However, expression of CCL7 was significantly lower (p &amp;lt; 0.01) in M-MØ and GM-MØ generated from CD14+ CD16+ monocytes and CD14 ++ CD16- monocytes respectively under LMWH exposure. qPCR analysis revealed a significant increase (p &amp;lt; 0.01) in the expression of various GM-MØ–specific genes including EGLN3, and SERPINE1 in macrophage supernatant post LMWH treatment. Expression of various M-MØ-specific marker/s such as IGF1, FOLR2, and HTR2B, is significantly up-regulated (p &amp;lt; 0.01) in Group B. Group A, although documented a decreased concentration/s (pg/ml) of Th17-type cytokine/s (IL-6 (1.88 ± 0.65 vs. 0.91 ± 0.43; p &amp;lt; 0.04 and IL-23 (17.94 ± 9.76 vs. 7.78 ± 3.43; p &amp;lt; 0.01)), at end of treatment, concentration of TGF-β was significantly higher (3909.05 ± 1248.35 vs. 2469.83 ± 1058.71; p &amp;lt; 0.01) which cue to probable maintenance in balance of inflammatory response at the time of implantation. No differences were observed in Th1-type cytokine level/s (IFN-γ and TNF-α). CXCL10, CXCL11, CXCL1, CXCL8, CCL17, CCL22 do not differ in vivo. Limitations, reasons for caution Beneficial effects of LMWH administration with a good sample size are clearly needed to confirm this hypothesis; hence result/s should be dealt with caution. Further to this, inclusion of other arm/s (corticosteroids, intralipid and/or intravenous immunoglobulin) will make the study much robust and conclusive. Wider implications of the findings The identification of atypical Th1-associated pro-inflammatory effects of LMWH drives to evaluate modulation of CCL2 expression to limit or potentiate macrophage activation in RIF; especially where anticoagulant effect is not the primary goal. Further, modification of cytokine expression/s might potentiate novel strategy derived from deregulated macrophage polarization. Trial registration number Not Applicable

Low-molecular-weight heparin therapy reduces 28-day mortality in patients with sepsis-3 by improving inflammation and coagulopathy.

Sepsis is a syndromic response to infection and is associated with high mortality, thus imposing a significant global burden of disease. Although low-molecular-weight heparin (LMWH) has been recommended to prevent venous thromboembolism, its anticoagulant and anti-inflammatory effects in sepsis remain controversial. Owing to the modification of the Sepsis-3 definition and diagnostic criteria, further evaluation of the efficacy and benefit population of LMWH is required. We performed a retrospective cohort study to assess whether LMWH improved the inflammation, coagulopathy, and clinical outcomes against Sepsis-3 and to identify the target patients. All patients diagnosed with sepsis at the First Affiliated Hospital of Xi'an Jiaotong University (the largest general hospital in northwest China) from January 2016 to December 2020 were recruited and re-evaluated using Sepsis-3 criteria. After 1:1 propensity score matching, 88 pairs of patients were categorized into the treatment and control groups based on subcutaneous LMWH administration. Compared with the control group, a significantly lower 28-day mortality was observed in the LMWH group (26.1 vs. 42.0%, p = 0.026) with a comparable incidence of major bleeding events (6.8 vs. 8.0%, p = 0.773). Cox regression analysis showed that LMWH administration was the independent protective factor for septic patients (aHR, 0.48; 95% CI, 0.29-0.81; p = 0.006). Correspondingly, the LMWH treatment group showed a significant improvement in inflammation and coagulopathy. Further subgroup analysis showed that LMWH therapy was associated with favorable outcomes in patients younger than 60 years and diagnosed with sepsis-induced coagulopathy (SIC), ISTH overt DIC, non-septic shock, or non-diabetics and in patients included in the moderate-risk group (APACHE II score 20-35 or SOFA score 8-12). Our study results showed that LMWH improves 28-day mortality by improving inflammatory response and coagulopathy in patients meeting Sepsis-3 criteria. The SIC and ISTH overt DIC scoring systems can better identify septic patients who are likely to benefit more from LMWH administration.

The optimized anticoagulation strategy in prolonged hemodialysis.

During extended (nocturnal) hemodialysis (ENHD), the dose of low-molecular-weight heparin (LMWH) can be administered as a single injection or as a divided dose over different time points. Our hypothesis was that a single injection might be sufficient to maintain dialyzer fiber patency. In addition, we investigated whether the biochemical clotting parameter anti-Xa accurately predicts fiber blocking. Our hypothesis was tested in 20 stable patients on ENHD in a random cross-over setting during two consecutive midweek sessions. The regular total dose of LMWH (i.e. enoxaparin, Clexane® 40-100 mg, Sanofi, Belgium) was either given (i) in a single injection at the dialysis start or (ii) divided over two injections, at the start and halfway the dialysis session. Blood samples were taken from the arterial blood line at different time points to determine plasma anti-Xa activity levels. Post-dialysis, the rinsed and dried hemodialyzers were scanned with a reference micro-computed tomography (µCT) scanning technique, and non-blocked fibers were counted in a central cross-section of the dialyzer outlet potting (ImageJ, NIH, USA). The percentage of open fibers in the dialyzers after a single injection of LMWH [91 (61-96)%] versus divided administration [94 (79-98)%] was not different. Time averaged anti-Xa activity levels were clinically not significantly different between both sessions. Anti-Xa activity levels correlated with the administered anticoagulation doses normalized for body weight, but not with the percentages open fibers in the dialyzers. Our results indicate that there is no need to administer enoxaparin over two injections for ENHD up to 8 h. The usefulness of monitoring anti-Xa levels to predict fiber patency, assessed by µCT, can be questioned, but further clinical trials are needed.

Obesity as a Risk Factor in the Appearance of Haematomas Caused by Low-Molecular-Weight Heparin: A Cross-Sectional Study.

Thromboembolic disease (TED) is an important health problem in Europe due to its high morbimortality. Pharmacological prevention is achieved with low-molecular-weight heparin (LMWH), among other strategies, which are supported by a high degree of evidence in the scientific literature. According to its safety data sheet, this injection produces local injuries at a rate of 0.1-1% after administration; however, these percentages are much lower than others reported in several studies focusing on LMWH (44-88%). This high incidence of injuries might be associated with procedural or individual variables. (1) Background: Among the most frequent side effects after the administration of LMWH are pain and haematomas (HMTs), which are influenced by obesity. We aimed to determine the relationship between abdominal skinfold (ASF) value and incidence of HMTs. In addition, I sought to determine how the risk of HMT changed with each mm increase in ASF. (2) Methods: A cross-sectional descriptive study developed in the hospital unit of orthopaedic and trauma surgery was conducted over one year. All participants in the sample were classified based on their ASF and the appearance and area of HMTs were assessed after the administration of enoxaparin. The STROBE checklist was used to evaluate the study. Descriptive statistical analysis and analysis of variance of non-parametric factors were carried out. (3) Results: In a sample of 202 participants (808 Clexane injections), more than 80% presented HMTs. More than 70% of the sample was overweight and more than 50% had an ASF > 36 millimetres (mm). (4) Conclusions: An ASF over 36 mm confers a higher risk of developing HMTs: with each mm increase in the ASF, the risk increases by 4%. Participants who are overweight or obese also present a higher risk of HMT, and these conditions correlate positively with the area of the HMTs. Providing education for the self-administration of the drug after discharge and information about the probability of suffering from local injuries in a more individualised way will lead to fewer primary care nursing consultations, more adherence to the antithrombotic treatment, and, as a consequence, a decrease in TED and health costs.

Practice Patterns of Antithrombotic Therapy during the Early Postoperative Course of Cardiac Surgery

The current practices regarding the management of antithrombotic therapy during the early postoperative course of cardiac surgery are not well described. An online survey with multiple-choice questions was sent to cardiac anesthesiologists and intensivists from France. The response rate was 27% (n = 149), with 2/3 of the respondents having less than 10 years of experience. A total of 83% of the respondents reported using an institutional protocol for antithrombotic management. A total of 85% (n = 123) of the respondents regularly used low-molecular-weight heparin (LMWH) during the immediate postoperative course. For 23%, 38%, 9%, and 22% of the physicians, LMWH administration was initiated between the 4th and 6th hour, between the 6th and 12th hour, between the 12th and 24th hour, and on postoperative day 1, respectively. The main reasons for not using LMWH (n = 23) were a perceived increased risk of perioperative bleeding (22%), poor reversal compared with unfractionated heparin (74%), local habits and the refusal of surgeons (57%), and its overly complex management (35%). The modalities of LMWH use were widely varied among the physicians. Chest drains were mostly removed within 3 days of surgery with an unchanged dose of antithrombotic therapy. Regarding temporary epicardial pacing wire removal anticoagulation, 54%, 30%, and 17% of the respondents left the dose unchanged, suspended the anticoagulation, or lowered the anticoagulation dose, respectively. LMWH was inconsistently used after cardiac surgery. Further research is warranted to provide high-quality evidence regarding the benefits and safety of LMWH use early after cardiac surgery.

Direct oral anticoagulants for venous thromboembolism prophylaxis in orthopaedic trauma: a clear first choice?

‘The brain may devise laws for the blood’ William Shakespeare, Merchant of Venice (1598)1 Prevention of venous thromboembolism (VTEp) is an integral part in the care of orthopaedic patients. VTE the leading cause of preventable mortality in hospital2 and orthopaedic surgery confers particularly high-risk.3 VTE currently complicates 2%–7% of all orthopaedic surgery.2 Symptomatic VTE results in reduced quality of life and causes mortality in 6%–12% of cases.4 VTE may increase length of stay (LOS) in hospital and confers large economic costs.5 Biological rationale supports the efficacy of direct oral anticoagulants (DOACs) for VTEp in orthopaedic surgery. Orthopaedic surgery accentuates all aspects of Virchow's Triad due to trauma-induced thromboplastin upregulation, intraoperative torniquet use, immobilization, bed rest and polymethylmethacrylate cement.6 DOACs prevent subsequent coagulation by inhibiting Factor Xa or II.6 Factor Xa inactivation is also the mechanism of action for low-molecular-weight heparins (LMWH) which are commonly used for VTEp after orthopaedic surgery.3 However, DOACs act directly on coagulation factors, unlike LMWH which is reliant on the presence of antithrombin III. DOACs do not require dose adjustment in obesity and avoid the gastrointestinal and renal side-effects of aspirin. The disadvantage of DOACs is that they are not all reversible and have a longer washout time than LMWH. DOACs have already demonstrated utility for VTEp in alternative domains. Most notably, DOACs are now suitable first-line options for VTEp after hip and knee arthroplasty. LMWHs such as enoxaparin, had historically been the gold-standard for VTEp after arthroplasty.7 However rivaroxaban and apixaban have demonstrated superior VTEp than LMWH in recent meta-analyses of randomized controlled trials (RCT).8, 9 Rivaroxaban was associated with a greater bleeding risk than LMWH.8, 9 This is important to note as, even minor bleeding is a concern to orthopaedic surgeons as it may increase risk of infection. However, apixaban has demonstrated a lesser bleeding risk than LMWH.8, 9 Meanwhile, aspirin has shown significantly increased VTE and mortality rates when compared to DOACs and LMWH.10, 11 Apixaban and rivaroxaban have also demonstrated reduced rates of symptomatic VTE than LMWH without increased incidences of major bleeding, when used for VTEp in oncology.12 Studies from the last decade have consistently demonstrated the benefits of DOACs over LMWH for VTEp in orthopaedic trauma surgery.13, 14 A recent systematic review and meta-analysis reported significantly reduced deep venous thrombosis rates when Factor Xa inhibiting DOACs were compared to LMWH for VTEp after lower limb fracture surgery.14 DOACs were also not inferior to LMWH for prevention of mortality, pulmonary embolism and bleeding, both major and minor. A RCT not included in the aforementioned study demonstrated reduced VTE risk with no increase bleeding risk, including minor bleeding, when rivaroxaban was compared to LMWH.13 Therefore the increased bleeding with rivaroxaban in some arthroplasty data is not reflected in orthopaedic trauma. Aspirin has not demonstrated effective VTEp after orthopaedic trauma surgery when compared to LMWH.15 The results of these studies have not yet effected an update to international guidelines for VTEp after orthopaedic trauma surgery (Table 1). DOACs also offer large economic savings, superior patient experience and improved adherence when compared to LMWH. In analyses for total hip replacement and total knee replacement, dabigatran, rivaroxaban and apixaban demonstrate saving of €152 and €116, €177 and €85, €223 and €135 per patient respectively.5 DOACs are administered orally compared to LMWH administration by subcutaneous injection. LMWH has subsequently been associated with high rates of non-adherence after hospital discharge.16 This is particularly concerning as the majority of VTE occurs following hospital discharge.17 Evidence suggests DOACs are the first choice over LMWH for VTEp after orthopaedic trauma surgery due to reduced rates of VTE, equivocal bleeding risk and mortality, reduced cost and improved patient experience. Where bleeding risk is high, apixaban may be used instead of rivaroxaban. Where risk of reoperation is high, DOACs should be avoided as they are not reversible. Open access publishing facilitated by The University of Adelaide, as part of the Wiley - The University of Adelaide agreement via the Council of Australian University Librarians. Bhuvanesh Ravichandran: Investigation; methodology; writing – review and editing. Brandon Stretton: Conceptualization; formal analysis; investigation; methodology; writing – review and editing. Joshua G. Kovoor: Conceptualization; formal analysis; investigation; methodology; writing – review and editing. Stephen Bacchi: Formal analysis; supervision; writing – review and editing. Joseph N. Hewitt: Investigation; resources; writing – review and editing. Christopher D. Ovenden: Formal analysis; investigation; supervision; writing – review and editing. Aashray K. Gupta: Conceptualization; investigation; resources; supervision; writing – review and editing. Ruurd L. Jaarsma: Conceptualization; supervision; validation; visualization; writing – review and editing. Guy J. Maddern: Conceptualization; supervision; validation; visualization; writing – review and editing. Ameya Bhanushali: Writing – review and editing.

Preoperative Venous Thromboembolism Screening and Postoperative Selective Anticoagulant Therapy Effectively Prevents Postoperative Symptomatic Venous Thromboembolism in Gynecological Malignancies: A 15-Year, Single-Center Study.

The aim of this study was to determine which type of prophylaxis was effective for postoperative symptomatic venous thromboembolism (VTE) in patients with gynecological malignancies. A total of 1756 consecutive patients undergoing laparotomy as first-line treatment were included. In Period 1 (2004-2009), low-molecular weight heparin (LMWH) was not available for postoperative VTE prophylaxis, but available in after Period 2 (2009-2013). In Period 3 (2013-2020), patients with pretreatment VTE could switch from LMWH to direct oral anticoagulant (DOAC) as of 2015. Preoperative VTE was screened by measuring D-dimer, followed by venous ultrasound imaging, and computed tomography and/or perfusion lung scintigraphy. Postoperative symptomatic VTE occurred with an incidence of 2.8% by the measures without prophylactic LMWH administration in Period 1. The incidence of postoperative symptomatic VTE was 0.6% in Period 2 and 0.3% in Period 3, being significantly reduced compared with Period 1 (P < .01 and < .0001). The incidences were not significantly different between Periods 2 and 3, but no patient switching to DOAC in Period 3 (n = 79) developed symptomatic VTE. Our preoperative VTE screening and postoperative selective LMWH administration were significantly preventive against postoperative symptomatic VTE.

NEOnatal Central-venous Line Observational study on Thrombosis (NEOCLOT): evaluation of a national guideline on management of neonatal catheter-related venous thrombosis

BackgroundIn critically ill (preterm) neonates, catheter-related venous thromboembolism (CVTE) can be a life-threatening complication. Evidence on optimal management in the literature is lacking. In the Netherlands, a consensus-based national management guideline was developed to create uniform CVTE management. ObjectivesTo evaluate the efficacy and safety of the national guideline. MethodsThis prospective, multicenter, observational study included all infants aged ≤6 months with CVTE in the Netherlands between 2014 and 2019. CVTE was divided into thrombosis in veins and that in the right atrium, with their own treatment algorithms. The primary outcomes were recurrent venous thrombotic events (VTEs) and/or death due to CVTE as well as major bleeding. ResultsOverall, 115 neonates were included (62% male; 79% preterm). The estimated incidence of CVTE was 4.0 per 1000 neonatal intensive care unit admissions. Recurrent thrombosis occurred in 2 (1.7%) infants and death due to CVTE in 1 (0.9%) infant. Major bleeding developed in 9 (7.8%) infants: 2 of 7 (29%) on recombinant tissue plasminogen activator, which was given for high-risk right-atrium thrombosis, and 7 of 63 (11%) on low-molecular-weight heparin (LMWH). Five of the 7 bleedings because of LMWH were complications of subcutaneous catheter use for LMWH administration. ConclusionThe management of neonatal CVTE according to the Dutch CVTE management guideline led to a low incidence of recurrent VTEs and death due to VTEs. Major bleeding occurred in 7.8% of the infants. Specific guideline adjustments may improve efficacy and, especially, safety of CVTE management in neonates.

Uterine cytokine profiles after low-molecular-weight heparin administration are associated with pregnancy outcomes of patients with repeated implantation failure.

Low molecular-weight heparin (LMWH) plays a role in repeated implantation failure (RIF), but outcomes are controversial. LMWH can potentially modulate local immune responses associated with the establishment and maintenance of pregnancy. The study aimed to explore the effects of LWMH in uterine inflammatory cytokine profiles and pregnancy outcomes of patients with repeated implantation failure (RIF) but without thrombophilia. We compared clinical characteristics and reproductive outcomes among 326 patients with RIF, but not thrombophilia, undergoing frozen embryo transfer (FET) cycle with or without LMWH treatment. Endometrium secretions were aspirated from both groups after 3 days of progesterone administration before and after LMWH treatment. Cytokine mRNA expression was analyzed in primary endometrial cells in vitro. The clinical and ongoing pregnancy rates did not significantly differ between the groups (31.5% vs. 24.4%, p = 0.15; 29.6% vs. 20.7%, p = 0.06). Concentrations of IL-6 and granulocyte-colony stimulating factor (G-CSF) in uterine secretions were significantly increased in the LWMH group, regardless of pregnancy outcomes (P < 0.05). And, in all patients treated with LWMH, those of secreted IL-6, IL-15 and G-CSF were significantly increased in pregnant group (P < 0.05). The expression of mRNA for G-CSF and IL-6 was significantly increased in human endometrial stromal cells in vitro (P < 0.05) after stimulation with LWMH (10 IU/mL). Uterine cytokine profiles after LMWH administration are associated with pregnancy outcomes and LMWH may be beneficial for patients with three implantation failures who do not have coagulation disorders.

Systems Biology Approach for Personalized Hemostasis Correction.

The correction of blood coagulation impairments of a bleeding or thrombotic nature employs standard protocols where the type of drug, its dose and the administration regime are stated. However, for a group of patients, such an approach may be ineffective, and personalized therapy adjustment is needed. Laboratory hemostasis tests are used to control the efficacy of therapy, which is expensive and time-consuming. Computer simulations may become an inexpensive and fast alternative to real blood tests. In this work, we propose a procedure to numerically define the individual hemostasis profile of a patient and estimate the anticoagulant efficacy of low-molecular-weight heparin (LMWH) based on the computer simulation of global hemostasis assays. We enrolled a group of 12 patients receiving LMWH therapy and performed routine coagulation assays (activated partial thromboplastin time and prothrombin time) and global hemostasis assays (thrombodynamics and thrombodynamics-4d) and measured anti-Xa activity, fibrinogen, prothrombin and antithrombin levels, creatinine clearance, lipid profiles and clinical blood counts. Blood samples were acquired 3, 6 and 12 h after LMWH administration. We developed a personalized pharmacokinetic model of LMWH and coupled it with the mechanism-driven blood coagulation model, which described the spatial dynamics of fibrin and thrombin propagation. We found that LMWH clearance was significantly lower in the group with high total cholesterol levels. We generated an individual patient's hemostasis profile based on the results of routine coagulation assays. We propose a method to simulate the results of global hemostasis assays in the case of an individual response to LMWH therapy, which can potentially help with hemostasis corrections based on the output of global tests.

Novel pH-responsive and mucoadhesive chitosan-based nanoparticles for oral delivery of low molecular weight heparin with enhanced bioavailability and anticoagulant effect

Low molecular weight heparin (LMWH) shows great anticoagulant effect for prevention and treatment of deep venous thrombosis. However, its oral administration is seriously hindered by multiple obstacles. In this study, a pH-responsive delivery system was developed to protect LMWH from gastrointestinal tract degradation and facilitate its absorption across gastrointestinal mucosa. The LMWH-loaded nanoparticles (pH-TCS/O-CMCS@LMWH) were prepared by ionic-crosslinking reaction between positive-charged amino groups of thiolated chitosan (TCS) as well as o-carboxymethyl chitosan (O-CMCS) and oppositely charged HP55. As a result, the prepared nanoparticles proved to spherical shape with an average size of 332 nm, high encapsulation efficiency of 96.6% and drug-loading content of 12.04 IU/mg. The proposed pH-TCS/O-CMCS@LMWH also showed good colloidal stability, potential mucoadhesive effect and desirable pH-responsive drug release behavior, which decreased pre-mature LMWH release in acidic environment but increase its targeted release in intestine environment. After oral administration, the pH-TCS/O-CMCS@LMWH shown enhanced bioavailability and significant antithrombotic effect in a rat model of venous thrombosis. In conclusion, pH-TCS/O-CMCS nanoparticles can be successfully hold great promising for oral administration of LMWH and potential treatment for thrombosis.

Low-Molecular-Weight Heparin Resistance and Its Viscoelastic Assessment in Critically Ill COVID-19 Patients.

Critically ill COVID-19 patients present an inflammatory and procoagulant status with a high rate of relevant macro- and microvascular thrombosis. Furthermore, high rates of heparin resistance have been described; yet, individualized anticoagulation by drug monitoring has not been sufficiently researched. We analyzed data from critically ill COVID-19 patients treated at Innsbruck Medical University Hospital with routinely adapted low-molecular-weight heparin (LMWH) doses according to anti-Xa peak levels, and regularly performed ClotPro analyses (a viscoelastic hemostatic whole blood test). A total of 509 anti-Xa peak measurements in 91 patients were categorized as below (<0.008 IU/mL/mg), within (0.008-0-012 IU/mL/mg) or above (> 0.012 IU/mL/mg) expected ranges with respect to the administered LMWH doses. Besides intergroup comparisons, correlations between anti-Xa levels and ClotPro clotting times (CTs) were performed (226 time points in 84 patients). Anti-Xa peak levels remained below the expected range in the majority of performed measurements (63.7%). Corresponding patients presented with higher C-reactive protein and D-dimer but lower antithrombin levels when compared with patients achieving or exceeding the expected range. Consequently, higher enoxaparin doses were applied in the sub-expected anti-Xa range group. Importantly, 47 (51.6%) patients switched between groups during their intensive care unit (ICU) stay. Anti-Xa levels correlated weakly with IN test CT and moderately with Russell's viper venom (RVV) test CT. Critically ill COVID-19 patients present with a high rate of LMWH resistance but with a variable LMWH response during their ICU stay. Therefore, LMWH-anti-Xa monitoring seems inevitable to achieve adequate target ranges. Furthermore, we propose the use of ClotPro's RVV test to assess the coagulation status during LMWH administration, as it correlates well with anti-Xa levels but more holistically reflects the coagulation cascade than anti-Xa activity alone.