Standard Heparin Research Articles

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Deep vein thrombosis and our treatment applications: 12-year results

Introduction: Deep vein thrombosis is an important health problem that is frequently encountered in the general population and especially in surgical clinics and has a negative impact on quality of life. In this study, treatment options and results of patients with deep vein thrombosis who have been hospitalized for 12 years in Atatürk University and Erzurum Regional Hospital were examined and discussed. Methods: In our clinic, 412 cases of deep vein thrombosis (211 female, 201 male) were hospitalized between 2009 and 2021. The mean age of the patients was 49 ± 19 years. While medical treatment with heparin was given to all 412 patients; thrombolytic therapy, surgical embolectomy (vascular and pulmoner), and pharmaco-mechanical thrombectomy were applied to some of these patients. Results: Deep vein thrombosis was more common in the lower extremity (n=322, 78.2%). All patients had at least one of the complaints of pain, swelling and redness. All cases were diagnosed by color Doppler ultrasonography. Medically, standard and low molecular weight heparin therapy was given to all patients after hospitalization. Thrombolytic therapy was applied to 66 (16,1%) of the cases, pulmonary embolectomy to 8 (1,9%), surgical thrombectomy to 10 (2,4%) and pharmacomechanical thrombectomy to 44 (10,7%) patients. In addition to these 120 patients (29.1%), a vena cava filter was placed for prophylactic purposes. Conclusions: In patients diagnosed with deep vein thrombosis and hospitalized, the diagnosis should be supported by Doppler ultrasound in addition to clinical diagnosis after an etiology investigation. Early diagnosis, rapid and effective treatment methods are important for the subsequent quality of life of patients. In addition to low molecular weight heparins being the first choice agents, standard heparin administration still needs to be applied in some clinical pictures. In addition, we believe that pharmacomechanical thrombectomy can be applied in appropriate acute cases. Keywords: Deep vein thrombosis; anticoagulant treatment; heparin therapy; low-molecular-weight heparin; mechanical thrombectomy.

Pharmacokinetics and Pharmacodynamics of Ionis-FXIRx, an Antisense Inhibitor of Factor XI, in Patients with End-Stage Renal Disease on Hemodialysis

BACKGROUNDPatients with end-stage renal disease (ESRD) on hemodialysis are at high risk of both thrombotic and bleeding events. Experimental and clinical data indicate that reducing factor XI (FXI), a key component of the intrinsic pathway, prevents thrombosis without causing bleeding. FXI activity can be lowered with IONIS-FXIRx, a 2nd generation antisense oligonucleotide that specifically reduces human FXI mRNA expression in the liver. This study sought to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-FXIRx in participants with ESRD. METHODSIn this Phase 2 multicenter study, we enrolled a total of 49 ESRD patients: (A) 6 participants receiving chronic in-center hemodialysis (HD) to receive an open-label single-dose of 300 mg IONIS-FXIRx either 5 minutes before or 10 minutes after HD and assessed the effects of HD on peak (Cmax) and the extent of exposure (AUC0-24hr) parameters of IONIS-FXIRx and (B) another 43 participants in a double-blind design to one of two multiple-dose regimens (200 mg or 300 mg) IONIS-FXIRx or placebo for 12 weeks with 12 weeks of additional follow up. In the double-blind portion, IONIS-FXIRx was administered subcutaneously ~10 minutes after HD. For PK, plasma trough concentration and apparent elimination half-life (t1/2λz) were evaluated. The PD parameters including FXI activity and antigen, aPTT, prothrombin time (PT), and INR were evaluated in the per-protocol population (N= 34) that was defined as all participants who received the complete protocol-specified administration of IONIS-FXIRx or placebo through week 8 and who did not have any major protocol violations. The rate and frequency of clotting on the HD filters and circuit were qualitatively measured with a clotting scale as an exploratory PD analysis. RESULTSThe PK cohort included 6 males (5 white) with a mean age of 61 years. The plasma PK profile of IONIS-FXIRx was not significantly altered whether injected before or after HD. After multiple dosing, plasma Cmax values were dose-dependent and similar between Day 1 (first dose) and Day 78 (last dose), suggesting no accumulation of IONIS-FXIRx in ESRD participants after 12-weeks of dosing. After treatment cessation, IONIS-FXIRx had an apparent elimination half-life of approximately 2 weeks. In the double-blind portion of the study, 22 (51.2%) of the participants were male, 24 (55.8%) were white and the mean age was 59 years. Attenuation of FXI activity was associated with a reduction in the incidence of severe clotting events on both the air filter and dialyzer (Table). The reduction in severe clotting events was observed when FXI activity was < 0.4 U/mL. Consistent with prior observations in healthy subjects, IONIS-FXIRx prolonged aPTT in a time and dose-dependent manner with maximum mean percent changes from baseline of 53.3% (p < 0.05) for the 200 mg dose group and 75.6% (p < 0.05) for the 300 mg dose group at Week 14, but had no effect on PT. Treatment emergent adverse events (TEAEs) were mostly mild; participants reporting serious TEAEs were 1 (16.7%) for the PK cohort, 4 (30.8%) for placebo and 3 (20.0%) each for the 200 mg and 300 mg IONIS-FXIRx dose groups. There were no drug-related SAEs and no drug-related major or clinically-relevant non-major bleeding events. Minor bleeds were primarily observed in the 300 mg multiple-dose group at AV fistula/graft sites but did not correlate with reduction of FXI activity. No clinically significant reductions in platelet counts were reported during the study. CONCLUSIONSThis study demonstrated that (i) HD had no effect on IONIS-FXIRx PK, (ii) IONIS-FXIRx was well tolerated and produced sustained, and dose-dependent reductions in FXI antigen and activity, and (iii) IONIS-FXIRx reduced severe dialysis circuit clotting events beyond standard heparin use. Collectively, these data support further evaluation of IONIS-FXIRx as a potentially safe, effective antithrombotic therapy in ESRD patients on HD. [Display omitted] DisclosuresBethune:Ionis Pharmaceuticals: Employment. Walsh:Population Health Research Institute: Employment; Ionis Pharmaceuticals: Consultancy. Jung:Ionis Pharmaceuticals: Employment. Yu:Ionis Pharmaceuticals: Employment. Geary:Ionis Pharmaceuticals: Employment. Bhanot:Ionis Pharmaceuticals: Employment.

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial

BackgroundCOVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population.MethodsWe did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3–0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed.FindingsFrom June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59–1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61–8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group.InterpretationIn patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.FundingCoalition COVID-19 Brazil, Bayer SA.

MO786HEPARIN VERSUS SODIUM BICARBONATE CATHETER LOCK SOLUTION: AN ALTERNATIVE LOCK HEMODIALYSIS CATHETER?

Abstract Background and Aims Infections and thrombosis of central venous catheter (CVC) in hemodialysis patients are the major causes of catheter loss resulting in hospitalization and increased costs. Interdyalitic catheter lock solutions, usually heparin, avoid these complications. Among the many, sodium bicarbonate has been proved as effective and safe catheter lock solution due to its antimicrobial and antithrombotic properties. The aim of this study was to compare the efficacy of two different CVC lock solution: sodium heparin versus sodium bicarbonate, to prevent catheter–related thrombosis and infection in hemodialysis patients Method They were enrolled, in a 12 months case-control study, 17 hemodialysis patients with tunneled hig-flux CVC (femoral or internal jugular). Each patient was evaluated in its common treatment for CVC dysfunction (Qb, CVC that works in reverse branches during the hemodialysis session, use of urokinase or extra lock with sodium heparin or 4% citrate) and infection (WBC count, C reactive protein -CRP, bloodstream culture, exit-site infection -ESI) during standard sodium heparin CVC lock solution (hep-lock), for the first 6 months, and then, during sodium bicarbonate lock solution (10 mEq/10 ml, bic-lock) for following 6 months. aPTT, PLT, Hct and albumin are also montly evaluated. Type and anticoagulant dose during hemodialysis sessions were unchanged over the study as well as any antiplatelet/anticogulant home therapy. Results Fifteen patients on 17 completed the study and the main results are reported in table 1. There were no significant differences between patients on demographics and number of catheter days treatments for both study periods. The blood flow was similar in either study phases and stable during the hemodialysis sessions (Qb 225±13 ml/m’ at 2-hours vs 225±15 ml/min at start of dialysis), even the use of reverse branches was similar. Hep-lock showed a lower usage of extra lock drug in comparison with Bic-lock (0,4% vs 3,1%, p&amp;lt;0,05), data confirmed also for Urokinase (1,9% vs 3,4%, p=0,274). None bloodstream are registred while ESI and WBC count show no significant differences between two study periods. No HD catheter was loss during the study due to thrombosis or infection. Finally, Hct, CRP and Albumin was found slightly lower on Bic-lock phase. Conclusion There is no CVC ideal lock solution and although sodium bicarbonate is inexpensive and readily avalaible our data shows better CVC performances with sodium heparin.

Development of Selective FXIa Inhibitors Based on Cyclic Peptides and Their Application for Safe Anticoagulation.

Coagulation factor XI (FXI) has emerged as a promising target for the development of safer anticoagulation drugs that limit the risk of severe and life-threatening bleeding. Herein, we report the first cyclic peptide-based FXI inhibitor that selectively and potently inhibits activated FXI (FXIa) in human and animal blood. The cyclic peptide inhibitor (Ki = 2.8 ± 0.5 nM) achieved anticoagulation effects that are comparable to that of the gold standard heparin applied at a therapeutic dose (0.3-0.7 IU/mL in plasma) but with a substantially broader estimated therapeutic range. We extended the plasma half-life of the peptide via PEGylation and demonstrated effective FXIa inhibition over extended periods in vivo. We validated the anticoagulant effects of the PEGylated inhibitor in an ex vivo hemodialysis model with human blood. Our work shows that FXI can be selectively targeted with peptides and provides a promising candidate for the development of a safe anticoagulation therapy.

Coronary angioplasty and COVID-19: are heparin requirements and thrombotic complications increasing?

Funding AcknowledgementsType of funding sources: None.BackgroundCovid-19 infection is associated with coagulopathy and possible heparin resistance, raising concerns that routine heparin during percutaneous coronary intervention (PCI) is failing to achieve adequate anticoagulation. We examined heparin requirements and efficacy in patients treated by PCI before and after the first reported UK case of Covid-19 (January 31st 2020).MethodsWe retrospectively compared heparin dose, Activated Clotting Time (ACT) and coronary flow (TIMI grade) for PCI procedures at a London cardiac centre in the 3 months before the UK pandemic and the three months afterwards. Testing for COVID was not routinely performed. Pre-specified analyses in patients with STEMI, NSTEMI and Stable angina were undertaken.ResultsOf 1227 PCI procedures performed over the period of observation, 690 were pre-pandemic and 537 were afterwards. Overall median heparin dose per case was 11000units versus 11500units (p = 0.137) and maximum ACTs were 291s versus 305s, respectively (p = 0.135). Pre-PCI TIMI 3 flow was lower during the pandemic than before (60% v 65%, p = 0.005) but Post-PCI flow was similar (96% versus 96%, p = 0.839). There were no statistically significant differences in heparin dose or achieved ACT among patients with STEMI, NSTEMI or Stable presentations.ConclusionIn spite of the increasing evidence that COVID-19 infection causes thrombosis, it appears that standard heparin management during PCI is sufficient to achieve effective anticoagulation and avoid peri-procedural thrombotic complications. Group 1 Pre PandemicGroup 2 PandemicP valueNumber of doses given3 (3 to 4)3 (3 to 4)0.952Total Heparin dose (units)11000 (8000 to 14000)11500 (9000 to 14000)0.137Number of ACTs measured2 (1 to 2)2 (1 to 2)0.194First ACT (seconds)240 (199 to 318)248 (206 to 326)0.256Maximum ACT (seconds)291 (230 to 368)305 (239 to 369)0.135Heparin dose and Activated Clotting Times (ACT) in patients undergoing PCI before Covid-19 pandemic (Group 1) and during pandemic (Group 2); median and interquartile ranges Figure. Clinical Presentation

P136 Vegan orthopaedics

IntroductionBristol is the vegan capital of the UK. The UK vegan index reveals that Bristol has 360,000 Google searches each month for Vegan content. However, do we think about the possible animal source of the medications we prescribe. Although all medications in the UK need to be tested on animals prior to being licensed and therefore cannot be truly “vegan”, there are alternatives available for some commonly used medications that do not contain animal products. Several world religions prohibit their followers from consuming certain foods, ranging from those not prepared in a specific manner to those derived from certain animals.Kosher and halal diet adherents share concerns with those on vegan diets. Vegan options are a solution when only non-conforming or uncertain products are available.MethodsWe conducted a review of commonly used medications in Orthopaedics and reviewed their source. The BNF, local pharmacy and online Summary of Product Characteristics (SPCs) for the medications were reviewed.ResultsWhere possible we have compiled a list of those that contain animal derived components and suggest alternatives. Sometimes, pharmaceutical companies cannot guarantee or differentiate the specific sources of animal-derived ingredients, as various suppliers are used in the manufacturing process and the sources can change.All unfractionated or standard heparin is porcine in origin; Rivaroxaban and Fondaparinux are simple alternatives for example. Cholecalciferol (vitamin D3) – Manufacture also involves the use of lanolin from sheep’s wool. Vitamin D2 (ergocalciferol) is vegan.ConclusionDisclosure of animal content and excipients would help patients make an informed choice. With an increasingly informed population and ethnic diversity, we should all be aware of the drugs that may contain animal products so that we can offer alternatives. Patients are more likely to adhere to prescribed medicines if they have been actively involved in prescribing decisions.

Combination of polycarboxybetaine coating and factor XII inhibitor reduces clot formation while preserving normal tissue coagulation during extracorporeal life support

Blood contact with high surface area medical devices, such as dialysis and extracorporeal life support (ECLS), induces rapid surface coagulation. Systemic anticoagulation, such as heparin, is thus necessary to slow clot formation, but some patients suffer from bleeding complications. Both problems might be reduced by 1) replacing heparin anticoagulation with artificial surface inhibition of the protein adsorption that initiates coagulation and 2) selective inhibition of the intrinsic branch of the coagulation cascade. This approach was evaluated by comparing clot formation and bleeding times during short-term ECLS using zwitterionic polycarboxybetaine (PCB) surface coatings combined with either a potent, selective, bicyclic peptide inhibitor of activated Factor XII (FXII900) or standard heparin anticoagulation. Rabbits underwent venovenous ECLS with small sham oxygenators for 60 min using three means of anticoagulation (n = 4 ea): (1) PCB coating + FXII900 infusion, (2) PCB coating + heparin infusion with an activated clotting time of 220–300s, and (3) heparin infusion alone. Sham oxygenator blood clot weights in the PCB + FXII900 and PCB + heparin groups were 4% and 25% of that in the heparin group (p < 10−6 and p < 10−5), respectively. At the same time, the bleeding time remained normal in the PCB + FXII900 group (2.4 ± 0.2 min) but increased to 4.8 ± 0.5 and 5.1 ± 0.7 min in the PCB + heparin and heparin alone groups (p < 10−4 and 0.01). Sham oxygenator blood flow resistance was significantly lower in the PCB + FXII900 and PCB + heparin groups than in the heparin only group (p < 10−6 and 10−5). These results were confirmed by gross and scanning electron microscopy (SEM) images and fibrinopeptide A (FPA) concentrations. Thus, the combined use of PCB coating and FXII900 markedly reduced sham oxygenator coagulation and tissue bleeding times versus the clinical standard of heparin anticoagulation and is a promising anticoagulation method for clinical ECLS.

Low-Dose Intravenous Heparin Infusion After Aneurysmal Subarachnoid Hemorrhage is Associated With Decreased Risk of Delayed Neurological Deficit and Cerebral Infarction.

Patients who survive aneurysmal subarachnoid hemorrhage (aSAH) are at risk for delayed neurological deficits (DND) and cerebral infarction. In this exploratory cohort comparison analysis, we compared in-hospital outcomes of aSAH patients administered a low-dose intravenous heparin (LDIVH) infusion (12U/kg/h) vs those administered standard subcutaneous heparin (SQH) prophylaxis for deep vein thrombosis (DVT; 5000U, 3×daily). To assess the safety and efficacy of LDIVH in aSAH patients. We retrospectively analyzed 556 consecutive cases of aSAH patients whose aneurysm was secured by clipping or coiling at a single institution over a 10-yr period, including 233 administered the LDIVH protocol and 323 administered the SQH protocol. Radiological and outcome data were compared between the 2 cohorts using multivariable logistic regression and propensity score-based inverse probability of treatment weighting (IPTW). The unadjusted rate of cerebral infarction in the LDIVH cohort was half that in SQH cohort (9vs 18%; P=.004). Multivariable logistic regression showed that patients in the LDIVH cohort were significantly less likely than those in the SQH cohort to have DND (odds ratio (OR) 0.53 [95% CI: 0.33, 0.85]) or cerebral infarction (OR 0.40 [95% CI: 0.23, 0.71]). Analysis following IPTW showed similar results. Rates of hemorrhagic complications, heparin-induced thrombocytopenia and DVT were not different between cohorts. This cohort comparison analysis suggests that LDIVH infusion may favorably influence the outcome of patients after aSAH. Prospective studies are required to further assess the benefit of LDIVH infusion in patients with aSAH.

Comparative study of chemical pathology sample collection tubes at the largest hospital in South Africa.

BackgroundBarricorTM Lithium heparin plasma tubes are new blood tubes that have been introduced to overcome the effects of gel in serum separator tubes (SST) and the shortcomings of standard Lithium heparin plasma. We aimed to evaluate BarricorTM tubes as an alternative to serum separator tubes and compare the stability between the tubes.MethodsForty-four paired samples were collected using both BarricorTM and SST. We compared five analytes at baseline (<6 h) and after every 24 h using the PassingBablok and Bland-Altman plots. Aspartate aminotransferase (AST), potassium (K), phosphate (PO4) , lactate dehydrogenase (LDH), and creatinine were analysed in both tubes. We calculated the percentage difference for each analyte between the baseline and time intervals to assess analyte stability. The percentage difference was compared to the desirable specification for bias and reference change value (RCV).ResultsAll analytes were comparable at baseline. Statistical differences (p<0.001) became evident after 24 h. PO4, K, and creatinine had a mean difference that exceeded the desirable specification for bias (-9.59%, - 9.35%, and -4.59%, respectively). Potassium was stable up to 24 h in both tubes. LDH showed better stability in SST (144 h vs 96 h). PO4 concentrations were more stable in both tubes with the SST (96 h vs 72 h). Creatinine and AST had the longest stability in both tubes compared to other analytes (144 h).ConclusionsData demonstrated variability and similarities in analyte concentrations and stability, respectively, in both tubes.

A Method to Improve Continuous Renal Replacement Therapy Circuit Survival Time in Critically Ill Coronavirus Disease 2019 Patients With Acute Kidney Injury.

Optimizing continuous renal replacement therapy circuit survival in coronavirus disease 2019 patients admitted to the ICU. Single-center prospective observational cohort study. Tertiary academic teaching ICU. Between March 19, 2020, and May 18, 2020, 11 out of 101 coronavirus disease 2019 patients were treated with continuous renal replacement therapy comprising 127 continuous renal replacement therapy days. A nonrandomized observational comparison of circuit anticoagulation modalities using standard regional citrate anticoagulation, continuous IV heparin anticoagulation, or the combination of regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin. Circuit patency was shorter than 24 hours using standard regional citrate anticoagulation or continuous IV heparin anticoagulation. Median circuit survival increased with at least 165% when the combination of regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin was applied. Continuous renal replacement therapy circuit patency is diminished in coronavirus disease 2019 ICU patients. Combining regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin increases filter survival as compared with regional citrate anticoagulation alone in this nonrandomized observational study.

Venous thromboembolism and bleeding in critically ill COVID-19 patients treated with higher than standard low molecular weight heparin doses and aspirin: A call to action

BackgroundCritically ill COVID-19 patients have a clear pattern of inflammation and hypercoagulable state. The main aim of the study was to evaluate the outcome of severe COVID-19 patients basing on prothrombotic risk factors (i.e. D-dimer). We also evaluated the impact of different doses of low molecular weight heparin (LMWH) on the incidence of bleedings. MethodsThe data of forty-two patients admitted to the Intensive Care Unit (ICU) were retrospectively analyzed. On ICU admission, patients with D-dimer < 3000 ng/mL (Group 1) received enoxaparin 4000 UI (6000 UI, if body mass index >35) subcutaneously b.i.d. and patients with D-dimer ≥ 3000 ng/mL (Group 2) received enoxaparin 100 UI/kg every 12 h. Aspirin was administered to all patients once a day. ResultsBoth groups presented a high incidence of perivascular thrombosis (40.9% in Group 1 and 30% in Group 2). Patients of Group 2 suffered a higher incidence of venous thromboembolism (VTE) than Group 1 (65% vs 13.6%, p = 0.001). One patient (4.5%) of Group 1 and three patients (15%) of Group 2 suffered from minor bleeding; no patient had major bleeding. Group 2 had a longer ICU and hospital stay than Group 1 (11.5 ± 5.6 vs 9.0 ± 4.8 and 30 ± 4.9 vs 21 ± 2.3, p < 0.05, respectively) as well as increased ICU mortality (25% vs 9.1%). ConclusionsMore severe critically ill COVID-19 patients have a high incidence of VTE and worse outcome, despite the use of heparin at the therapeutic dose. However, the use of heparin did not increase the incidence of bleeding complications.

Toward Optimal Heparin Dosing by Comparing Multiple Machine Learning Methods: Retrospective Study.

BackgroundHeparin is one of the most commonly used medications in intensive care units. In clinical practice, the use of a weight-based heparin dosing nomogram is standard practice for the treatment of thrombosis. Recently, machine learning techniques have dramatically improved the ability of computers to provide clinical decision support and have allowed for the possibility of computer generated, algorithm-based heparin dosing recommendations.ObjectiveThe objective of this study was to predict the effects of heparin treatment using machine learning methods to optimize heparin dosing in intensive care units based on the predictions. Patient state predictions were based upon activated partial thromboplastin time in 3 different ranges: subtherapeutic, normal therapeutic, and supratherapeutic, respectively.MethodsRetrospective data from 2 intensive care unit research databases (Multiparameter Intelligent Monitoring in Intensive Care III, MIMIC-III; e–Intensive Care Unit Collaborative Research Database, eICU) were used for the analysis. Candidate machine learning models (random forest, support vector machine, adaptive boosting, extreme gradient boosting, and shallow neural network) were compared in 3 patient groups to evaluate the classification performance for predicting the subtherapeutic, normal therapeutic, and supratherapeutic patient states. The model results were evaluated using precision, recall, F1 score, and accuracy.ResultsData from the MIMIC-III database (n=2789 patients) and from the eICU database (n=575 patients) were used. In 3-class classification, the shallow neural network algorithm performed the best (F1 scores of 87.26%, 85.98%, and 87.55% for data set 1, 2, and 3, respectively). The shallow neural network algorithm achieved the highest F1 scores within the patient therapeutic state groups: subtherapeutic (data set 1: 79.35%; data set 2: 83.67%; data set 3: 83.33%), normal therapeutic (data set 1: 93.15%; data set 2: 87.76%; data set 3: 84.62%), and supratherapeutic (data set 1: 88.00%; data set 2: 86.54%; data set 3: 95.45%) therapeutic ranges, respectively.ConclusionsThe most appropriate model for predicting the effects of heparin treatment was found by comparing multiple machine learning models and can be used to further guide optimal heparin dosing. Using multicenter intensive care unit data, our study demonstrates the feasibility of predicting the outcomes of heparin treatment using data-driven methods, and thus, how machine learning–based models can be used to optimize and personalize heparin dosing to improve patient safety. Manual analysis and validation suggested that the model outperformed standard practice heparin treatment dosing.

Bleeding and Thrombotic Risk in Low Dose Heparin Infusion as Compared to Standard Dose Heparin Infusion.

Intravenous unfractionated heparin (UFH) remains one of the most commonly used anticoagulants in the hospital setting. The optimal protocol for initiation and maintenance of UFH has been difficult to determine. Over the past two decades, weight-based nomogram protocols have gained favor. Herein, we present a retrospective study of 377 patients at a single tertiary academic center treated with low intensity (LI) and standard intensity (SI) UFH protocols for therapeutic anticoagulation. UFH levels are measured by anti-Xa assay activity with therapeutic levels of 0.30 to 0.70 IU/mL for SI and 0.25 to 0.35 IU/mL for LI. Patients treated on the LI protocol were more likely to have had a previous history of bleeding and lower baseline hemoglobin. Incidence of new or worsening thrombus while on UFH was comparable between both protocols (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.29-2.98, p=0.899). Patients on LI protocol had higher incidence of bleeding while on UFH (OR 1.21, 95% CI 0.51-2.89, p=0.667). Our study thus suggests that the LI protocol may have comparable efficacy to the SI protocol in treating venous thromboembolism (VTE) and that target anti-Xa levels of 0.25 to 0.35 IU/mL may be more optimal in high-risk patients.

MON-182 Increased Risk of Bleeding and Excessive Anticoagulation Using Standard Dose Low Molecular Weight Heparin (LMWH) in Cushing’s Syndrome

Background: Cushing’s Syndrome (CS) is a hypercoagulable state with increased risk of venous thrombosis events (VTE) including pulmonary embolism (PE) and deep venous thrombosis (DVT). In the absence of clear recommendations (1), a standard dose of low molecular weight heparin (LMWH) is given: 1 mg/kg q12h (with dose reduction for CrCl < 30ml/min and low BMI). Here we report an excessive level of anticoagulation (based on standard LMWH anti-Xa levels) using standard dosing requirements in 8 of 11 patients with CS complicated by VTE who received treatment with Enoxaparin. Methods: We retrospectively studied 6 women and 5 men with active hypercortisolism and VTE (6 PE and 5 DVT) treated with Enoxaparin given at doses below every 12 hours. Self-declared race/ethnicity were 7 white (one Hispanic), 2 unknown, 1 Asian, and 1 African. Anticoagulation therapy was monitored 4 hours after administration with measurement of LMWH anti-Xa (therapeutic range: 0.5-1.2 IU/mL). Results: The (subsequent) etiology of CS was ectopic ACTH secretion in 6 patients (3 pulmonary NET, 3 occult) and Cushing’s disease in 5. Median age was 53 years (range 24 - 74); median BMI 34.7 kg/M2 (range 24.9 - 52.9). Median urine cortisol was 659 mcg/24h (range 122 - 32,444; nl reference range 3.5 - 45). All had CrCl > 60 ml/min. 6 patients were taking a CYP3A4 inhibitor (Ketoconazole: n=5 or Mifepristone: n=1). 6/7 patients who received an initial dose of 1 mg/kg had supratherapeutic anti-Xa levels, from 1.4 - 2 IU/ml; five were on a CYP3A4 inhibitor. One died from a massive retroperitoneal bleed leading to organ failure. The other five required dose reduction; the median dose at which anti-Xa levels were at goal was 0.56 mg/kg (range 0.36 - 0.87 mg/kg). The sixth patient had an initial anti-Xa level of 0.2 IU/ml, which normalized on a dose of 1.1 mg/kg.One patient started at 1.3 mg/kg exhibited an anti-Xa level of 1.7 IU/ml, with appropriate anti-Xa levels at a dose of 0.6 mg/kg. 3 patients started at reduced treatment doses (0.68, 0.78 and 0.87 mg/kg) exhibited therapeutic anti-Xa levels. In summary, therapeutic anti-Xa levels were achieved at a dose of approximately 1 mg/kg in only three patients (0.87, 0.96, 1.12 mg/kg); others required reduction of the usual recommended dose to between 0.36 and 0.78 mg/kg. CYP3A4 inhibitors were used in 5/8 patients with elevated anti-Xa levels. Conclusions: Patients with Cushing’s syndrome appear to require lower than standard dose of enoxaparin; which may be only partly explained by concomitant CYP3A4 inhibitors. We suggest that anti-Xa levels be more closely monitored in CS patients to avoid morbidity and mortality caused by PE or bleeding. Further studies are needed to determine if this risk is present in patients receiving supraphysiologic doses of exogenous glucocorticoids.1. Wagner J et al. Front Endocrinol (Lausanne). 9: 805, 2018

A synthetic heparinoid blocks Tau aggregate cell uptake and amplification

Tau aggregation underlies neurodegeneration in Alzheimer's disease and related tauopathies. We and others have proposed that transcellular propagation of pathology is mediated by Tau prions, which are ordered protein assemblies that faithfully replicate in vivo and cause specific biological effects. The prion model predicts the release of aggregates from a first-order cell and subsequent uptake into a second-order cell. The assemblies then serve as templates for their own replication, a process termed "seeding." We have previously observed that heparan sulfate proteoglycans on the cell surface mediate the cellular uptake of Tau aggregates. This interaction is blocked by heparin, a sulfated glycosaminoglycan. Indeed, heparin-like molecules, or heparinoids, have previously been proposed as a treatment for PrP prion disorders. However, heparin is not ideal for managing chronic neurodegeneration, because it is difficult to synthesize in defined sizes, may have poor brain penetration because of its negative charge, and is a powerful anticoagulant. Therefore, we sought to generate an oligosaccharide that would bind Tau and block its cellular uptake and seeding, without exhibiting anticoagulation activity. We created a compound, SN7-13, from pentasaccharide units and tested it in a range of assays that measured direct binding of Tau to glycosaminoglycans and inhibition of Tau uptake and seeding in cells. SN7-13 does not inhibit coagulation, binds Tau with low nanomolar affinity, and inhibits cellular Tau aggregate propagation similarly to standard porcine heparin. This synthetic heparinoid could facilitate the development of agents to treat tauopathy.

Taurolidine citrate and unfractionated heparin combination versus unfractionated heparin alone in prevention of inflammation in hemodialysis catheters

Abstract Introduction and Aims Patients on hemodialysis (HD) using dialysis catheters have significantly higher rates of morbidity and mortality which has been associated with chronic inflammatory state. In Egypt 6.6% of HD patients use catheters, of which short term catheters represent 59.6% and 40.4% with long-term catheters. In this study we aim to assess the possible effect of using Taurolidine citrate and unfractionated heparin (Taurolock-hep500™) in comparison to unfractionated heparin, as a lock solution for temporary hemodialysis catheters, on inflammatory status in HD patients. Methods a randomized controlled clinical trial that included 60 stable HD patients recruited from Ain Shams University hospitals at the time of catheter insertion. They were divided into two groups, Group 1: 30 Patients received taurolidine and citrate (4%) and 500 i.u of heparin as a catheter lock solution after hemodialysis sessions, Group 2: 30 patients received unfractionated heparin (5000i.u) as a catheter lock solution after hemodialysis sessions. Standard aseptic techniques were used in handling catheters. High sensitive C-reactive protein (hsCRP) and interleukin 6 (IL-6) were measured in serum for both groups and samples were obtained at baseline and after 1 month of using the lock solutions. Results Group 1 (mean age 39.5 ± 14, 46.7% males), Group 2 (mean of age 39.3 ±14,60% males). At base line, there was no significant difference between both groups regarding hsCRP (P = 0.366) and IL-6 (p = 0.900). While after 1 month of using the lock solution there was significant difference as regard levels of hsCRP (p = 0.001) and IL-6 (p = 0.018),with the higher levels of inflammatory markers showed in group 2. Conclusions we may conclude that the use of Taurolidine citrate and unfractionated heparin combination as a lock solution for HD catheters reduces the inflammatory markers, and the inflammatory status in HD patients when compared to the standard unfractionated heparin lock as demonstrated by reducing the levels of inflammatory markers (hsCRP and IL-6). This may have good clinical consequences regarding the quality of life in HD patients.

Bleeding complications after cardiac surgery, before anticoagulation start and then with argatroban or heparin in the early postoperative setting

ObjectivesAfter elective cardiac surgery a postoperative anticoagulation is obligatory. With critically ill patients the conventional anticoagulation standard heparin is sometimes impossible, e.g. based on HIT II. Then, argatroban is currently a possible alternative, however, due to its impaired metabolism in critically ill patients, anticoagulation effect is harder to anticipate, thus resulting in higher bleeding risk. Furthermore, to date no antidote is available. Hence, severe postoperative bleeding incidents under anticoagulation are commonly mono-causal attributed to the anticoagulation itself. This study concentrates on the number of well-defined postoperative bleeding incidents before any anticoagulation started, then actually under argatroban as well as compared to those under heparin (or switched from heparin to argatroban).Material and methodsRetrospective study including 215 patients undergoing elective cardiac surgery with a postoperative stay in ICU ≥48 h. Postoperative bleeding complications before and after start of anticoagulation were evaluated. Definition of bleeding complications were: decrease of hemoglobin by more than 2 g/dl without dilution (mean value of volume balance plus one standard deviation) and/or increased need of red blood cell transfusion/day (average transfusion rate + 2 standard deviations).ResultsWithin the study group of 215 patients, 143 were treated with heparin, 43 with argatroban, 29 switched from heparin to argatroban. Overall, 26.5% (57/215) postoperative bleeding complications occurred. In 54.4% (31/57) bleeding complications occurred before start of anticoagulation; in 43.6% (26/57) after. Of these, 14 bleeding incidents occurred under heparin 9.8% (14/143), 6 under argatroban 14% (6/43) and 6 switched 20.7% (6/29). Higher bleeding complications before start of anticoagulation was related to concomitant factors influencing the overall bleeding risk; e.g. score of severity of illness. These observations further correlate with postoperative, but not anticoagulation induced mortality rate of 2.8% of then given heparin, 20.9% then argatroban, 20.7% then switched.ConclusionsPostoperative bleeding complications cannot simply be attributed to anticoagulation since occurring often before anticoagulation was started. The risk for bleeding complications after start of anticoagulation was quite comparable for argatroban and heparin. Accordingly, the influence of argatroban on bleeding complications in the postoperative period may be less significant than previously thought.

P1498 Right atrial thrombus in a young septic patient with lymphoma

Abstract Background Catheter-related right atrial thrombosis is a rare, but potentially life threatening complication in patients with central venous catheters (CVCs). Echocardiography is an indispensable tool in the diagnosis of right atrial thrombosis. We present a case of a young man with lymphoma, Staphylococcus aureus sepsis and a peripherally inserted central catheter (PICC) who had a septic thrombus in the right atrium. Case summary A 23-year-old male patient with recently diagnosed Hodgkin’s lymphoma had an inserted PICC for the purpose of chemotherapy application. Three days after the first chemotherapy application a thrombosis of the cephalic and subclavian veins at the site of PICC was found. The PICC was removed and the patient was treated with therapeutic doses of dalteparin. A day after the discovery of thrombosis, the patient became clinically septic, with high inflammatory markers and Staphylococcus aureus was isolated from his blood cultures. He was promptly treated with flucloxacillin. Due to pain in his left knee, a knee puncture was performed, and Staphylococcus aureus was isolated also from the knee synovial fluid. A transthoracic echocardiography revealed a 2.8 x 2.8 cm sessile thrombus on the lateral wall of the right atrium. There were no vegetations on the tricuspid or other valves. Due to increasing pain in his left knee and an increase in inflammatory markers a synovectomy was performed. After the operation the clinical status improved and the inflammatory parameters decreased. A magnetic resonance imaging of the heart was performed, which confirmed the thrombus described by echocardiography and excluded the presence of abscesses. All the time the patient was treated in the intensive care unit with standard heparin, flucloxacillin, and piperacillin/tazobactam due to neutropenia. The inflammatory markers slowly decreased and all further blood cultures were negative. Follow-up echocardiography after 16 days of antibiotic and anticoagulant therapy revealed that the mass in the right atrium, attached on the lateral atrium wall, was slightly smaller than before. The mass was centrally un-echogenic with echogenic cover, appearing as a partial regression of the septic thrombus with a central colliquation. The heart valves remained free of vegetations. There was a minor pericardial effusion, with no signs of constriction. Due to improved clinical status the patient was able to start with chemotherapy again after a pause of three weeks. Conclusion The patient had three important risk factors for thrombosis: PICC, sepsis and malignancy. Echocardiography is an important tool for mass diagnosis and the exclusion of vegetations in a septic patient. Often there is a need for further specification of the mass etiology or for the exclusion of other pathology, like abscesses in our case. Magnetic resonance is an important tool that can complement the echocardiographic examination. Abstract P1498 Figure. Right atrial thrombus