Enoxaparin Dose Requirements to Achieve Therapeutic Low-molecular-weight Heparin Anti-factor Xa Levels in Infants and Young Children.

INTRODUCTION: Enoxaparin is commonly used to treat pediatric thrombosis. Several small retrospective studies have suggested that infants and young children require higher enoxaparin doses to achieve therapeutic anti-factor Xa levels compared with adults. MATERIALS AND METHODS: This is a retrospective study of hospitalized children who received enoxaparin for the treatment of thrombosis at a free-standing children's hospital. The primary objective was to ascertain the enoxaparin dose required to achieve an anti-factor Xa level of 0.5 to 1.0 U/mL among 4 age groups in a large cohort of infants and young children between 60 days and 5 years of age. RESULTS: A total of 176 infants and children were evaluated. The majority of patients were less than 1 year of age (n=104). An inverse relationship between enoxaparin dose needed to achieve therapeutic anti-factor Xa levels and patient age was noted, particularly in the first year of life. Patients who were 60 days to less than 7 months at the time of enoxaparin initiation (n=73) required the highest mean dose among the age groups at 1.73 mg/kg subcutaneously every 12 hours (P<0.0001). CONCLUSION: Infants and young children require higher doses of enoxaparin to achieve therapeutic anti-factor Xa levels compared with adults.

Association of Neutrophil Activation, More Than Platelet Activation, With Thrombotic Complications in Coronavirus Disease 2019.

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

Impact of exogenous antithrombin on low molecular weight heparin anti-Xa activity assays in a pediatric and young adult leukemia and lymphoma cohort with variable antithrombin levels.

BACKGROUND: Low molecular weight heparin (LMWH) remains the most commonly prescribed pediatric anticoagulant. There is debate whether LMWH anti-Xa assays with or without exogenous antithrombin (AT) best reflect anticoagulation effect, and how much discrepancy exists between assay types. OBJECTIVES: We assessed the effect of variable AT activity on LMWH anti-Xa levels in plasma samples from anticoagulated pediatric and young adult acute lymphoblastic leukemia and lymphoma (ALL/L) patients, using two instruments and their commercial kits with and without exogenous AT (ie, four platforms). METHODS: We analyzed LMWH anti-Xa levels on 60 plasma samples with known AT activity from 12 enoxaparin-treated ALL/L patients, using four commercial kits from Siemens and Stago containing AT or not, on Siemens BCS and Stago STA R Max, respectively. RESULTS: Of 236/240 samples with interpretable results, mean AT activity was 80% (46-138%). Correlation was acceptable for published kit ranges of LMWH anti-Xa levels when comparing kits containing AT (r = 0.82, P < .0001), or not (r = 0.93, P < .0001), and within a manufacturer (Berichrom to Innovance, r = 0.92, P < .0001; Stachrom to STA-Liquid Anti-Xa r = 0.98, P < .0001). LMWH anti-Xa levels were lower in platforms without added AT (P < .0001). For Stago kits, this effect increased when AT < 70% (P = .001, n = 19, mean 56%). Assay variability, measured as mean percent difference, was less pronounced with Stago kits (14.7%, n = 49) than Siemens (41.9%, n = 50). CONCLUSIONS: Although LMWH levels from anti-Xa assays with added AT trend higher than in those without, correlation was fairly good between platforms in pediatric ALL/L plasmas, even when AT activity was <70%.

Quality performance for indirect Xa inhibitor monitoring in patients using international external quality data.

Objectives Chromogenic anti-activated factor X (FXa) assays are currently the "gold standard" for monitoring indirect anticoagulants. However, anti-FXa has been shown to vary according to the choice of reagents. In the present study, the performance of anti-FXa measurement was evaluated in order to gain more insight into the clinical applications. Furthermore, the longitudinal coefficient of variation (CV) was studied to investigate whether there is improvement over time. Methods Laboratory tests results were evaluated for samples spiked with unfractionated heparin (UFH), low-molecular-weight-heparin (LMWH), fondaparinux and danaparoid sodium. External quality assessment (EQA) data from multiple years were used from more than 100 laboratories. Results Comparison of the results for all methods showed significant differences in measured values between the frequently used methods (ANOVA: p < 0.001). The largest differences were observed for LMWH and UFH measurements. These differences may be caused by differences in method composition, such as the addition of dextran sulphate. Substantial interlaboratory variation in anti-FXa monitoring was observed for all parameters, particularly at low concentrations. Our results showed that below 0.35 IU/mL, the CVs for UFH and LMWH increase dramatically and results below this limit should be used with caution. Conclusions Our study demonstrates that the choice of the anti-FXa method is particularly important for UFH and LMWH measurement. The variation in measurements may have an effect on clinical implications, such as therapeutic ranges. Furthermore, the longitudinal EQA data demonstrated a constant performance and, in at least 50% of the cases, improvement in the CV% of the anti-Xa results over time.

Venous thromboembolism chemoprophylaxis regimens in trauma and surgery patients with obesity: A systematic review.

BACKGROUND: Venous thromboembolism (VTE) continues to be a devastating source of morbidity and mortality in obese patients who suffer traumatic injuries or obese surgery patients. High incidence rates in VTE despite adherence to prevention protocols have stirred interest in new dosing regimens. The purpose of this study was to systematically review the literature and present the existing VTE chemoprophylaxis regimens for obese trauma and surgical patients in terms of efficacy and safety as measured by the incidence of VTE, anti-factor Xa levels, and the occurrence of bleeding events. METHODS: An online search of seven literature databases including PubMed, Excerpta Medica Database, GoogleScholar, JAMA Network, CINAHL, Cochrane, and SAGE Journals was performed for original studies evaluating the safety and efficacy of VTE chemoprophylaxis dosing regimens according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The risk of bias was assessed using the Cochrane Risk of Bias Tool and the quality of evidence was determined using the GRADE Working Group criteria. RESULTS: Of the 5,083 citations identified, 45 studies with 27,717 patients met inclusion criteria. In this group, six studies evaluated weight-based dosing regimens, four used a weight-stratified or weight-tiered strategy, five used a body mass index-stratified approach, 29 assessed fixed-dose regimens, and two used continuous infusions. The majority of the studies evaluated anti-factor Xa levels as their primary outcome rather than reduction in VTE. CONCLUSION: Weight-based and high fixed-dose chemoprophylaxis regimens achieved target anti-Xa concentrations more frequently than standard fixed-dose regimens but were not associated with a reduction in VTE. Additionally, high fixed-dose approaches are associated with increased bleeding complications. Further evaluation with large randomized trials is warranted in trauma and surgery patients with obesity. LEVEL OF EVIDENCE: Systematic review, level III.

Monitoring of heparins in antithrombin-deficient patients.

INTRODUCTION: Heparins exert their anticoagulant effect through activation of antithrombin. Whether antithrombin deficiency leads to clinically relevantly reduced anti-Xa activity of heparins is unknown. We investigated the relation between antithrombin deficiency and anti-Xa activity measurements of plasma samples spiked with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). MATERIALS AND METHODS: Plasma samples from 34 antithrombin-deficient subjects and 17 family controls were spiked with UFH and LMWH (nadroparin) aimed to correspond with an anti-Xa activity of 0.8 IU/mL. Antithrombin, ß-antithrombin and anti-Xa activities were measured. RESULTS: Mean anti-Xa activity with LWMH was 0.55 IU/mL (0.30-0.74) (recovery 69%, 38-93%) in antithrombin-deficient subjects and 0.82 (0.71-0.89) IU/mL in controls (recovery 103%, 89-111%). Expected anti-Xa measurements after LMWH spiking were found in 17/17 non-deficient subjects and in 8/34 antithrombin-deficient subjects. Anti-Xa measurements in the expected range (0.6-1.0 IU/mL) after UFH spiking were found in 17/17 non-deficient subjects and in 1/22 antithrombin-deficient subjects. Antithrombin activity correlated with anti-Xa activity of UFH (R = 0.77) and LMWH (R = 0.66). Mixing studies of pooled normal plasma and antithrombin-deficient plasma showed that anti-Xa recovery was linearly reduced with antithrombin activity decreasing below 100%. CONCLUSIONS: Reduced antithrombin activity causes significantly reduced anti-Xa levels. Standard LWMH- or UFH-doses are likely to lead to under treatment in antithrombin-deficient individuals.

Anti-Xa Oral Anticoagulant Plasma Concentration Assay in Real Life: Rivaroxaban and Apixaban Quantification in Emergency With LMWH Calibrator.

BACKGROUND: Oral anti-Xa inhibitors have demonstrated noninferiority to vitamin K antagonists (VKAs) for the prevention of stroke in patients with atrial fibrillation and recurrent venous thromboembolism. They are associated with a decrease in major bleeding. In contrast with VKA, no coagulation monitoring is required. However, in clinical practice, determination of drug concentration is sometimes necessary. OBJECTIVE: The objective of this study was to evaluate a low-molecular-weight heparin (LMWH) calibrated anti-Xa assay for the quantification of rivaroxaban and apixaban plasma concentration in emergency. METHODS: The anti-Xa plasma concentration of rivaroxaban and apixaban were measured in emergency in 210 patients using STA anti-Xa liquid assay. For each plasma concentration <150 ng/mL of rivaroxaban or apixaban, an anti-Xa assay calibrated with LMWH was performed. RESULTS: We demonstrated a significant correlation between LMWH anti-Xa activity and rivaroxaban ( R2 = 0.947) or apixaban ( R2 = 0.959) concentration and a significant correlation between rivaroxaban and apixaban plasma concentration ( R2 = 0.972). A LMWH anti-Xa activity <0.50 IU/mL could exclude a plasma concentration of rivaroxaban and apixaban >30 ng/mL and indicate the feasibility of invasive procedure. Conclusion and Relevance: In the absence of a specific test, LMWH-calibrated anti-Xa assay could be used to determine the presence and evaluate the plasma concentration of oral anti-Xa inhibitors. However, these initial findings require confirmation using other chromogenic calibrated oral anti-Xa assays.

Direct oral anticoagulants and heparins: laboratory values and pitfalls in 'bridging therapy'.

Objectives: The three direct oral anticoagulants (DOACs) dabigatran, apixaban and rivaroxaban are now widely used in clinical practice. For patients requiring perioperative interruption of DOACs, heparin bridging is still under discussion. Here we show, for the first time, the influence of concomitantly used DOACs and heparins on laboratory assays. Methods: For spiking experiments, 10 healthy donors and nine patients treated with DOACs were investigated. The measurement of DOACs and heparins was performed with routine methods on the ACL TOP [HEMOCLOT ® direct thrombin inhibitor (CoaChrom Diagnostica, Austria), COAMATIC ® Heparin (Chromogenix, USA) calibrated with rivaroxaban, apixaban, unfractionated heparin (UFH) and low molecular weight heparin (LMWH), additionally PT reagent RecombiPlasTin 2G and aPTT reagent SynthASil (Instrumentation Laboratory, Germany)] and the DOACs were additionally quantified with liquid chromatography-mass spectrometry. A linear regression model has been used to estimate the effect of DOAC prestimulation. Results: No influence of dabigatran could be demonstrated in the anti-Xa testing methods for LMWH, UFH, rivaroxaban or apixaban. All FXa-inhibiting drugs affected all the anti-Xa testing methods in their own specific ways. Compared with heparin alone, measurement of heparins in samples with a basic concentration of DOACs (200 ng/ml) displays a more dramatic increase. Samples of patients with therapeutic intake of DOACs spiked with UFH and LMWH showed the expected pharmacokinetic profiles, but increased pharmacodynamic effects. Conclusions: Direct thrombin and FXa inhibitors exhibit distinct effects on assay results when used concomitantly with heparins. These interactions must be considered in the interpretation of assay results during bridging therapy.

Repeated Oral or Subcutaneous LMWH Has similar Antithrombotic Activity in a Rat Venous Thrombosis Model: Antithrombotic Activity Correlates With Heparin on Endothelium When Orally Administered.

Low-molecular-weight heparins (LMWHs) endure as important drugs for thromboprophylaxis. Although clinical use relies on the subcutaneous (SC) route, our previous studies show that single-dose orally administered LMWHs have antithrombotic activity. Since thromboprophylaxis requires long-term treatment, we examined antithrombotic effects of subacute oral LMWHs in a rat venous thrombosis model and compared results to SC or single-dose oral administration. We measured LMWH in endothelium and plasma, weight change and complete blood counts (CBC). Oral LMWH tinzaparin (3 × 0.1 mg/kg/12 or 24 hours) or reviparin (3 × 0.025 mg/kg/24 hours) significantly decreased thrombosis compared to saline. In the subacute study (60 × 0.1 mg/kg/12 hours), oral or SC tinzaparin significantly reduced thrombosis compared to saline but not to single or 3 × 0.1 mg/kg/12 hours oral tinzaparin. Antithrombotic effects were similar between oral and SC administration. LMWH was found on endothelium following oral but not SC administration. Endothelial concentrations were significantly correlated with incidence of stable thrombi ( P = 0.021 and 0.04 for aortic and vena cava endothelium respectively, χ2 test) and total thrombi ( P = 0.003 for vena cava endothelium). Anti-Xa activity was significantly greater for oral or SC LMWH than saline and significantly greater for SC versus oral LMWH. Values for CBCs were within normal ranges (mean ± 2 SD). There was no evidence of bleeding. Weight gain was similar between groups. In conclusion, subacute oral and SC LMWH have similar antithrombotic effects. Antithrombotic activity with oral administration is correlated with endothelial LMWH concentrations but not with plasma anticoagulant activity.

Plasma anti-FXa level as a surrogate marker of the adequacy of thromboprophylaxis in critically ill patients: A systematic review.

BACKGROUND: Critical care patients are prone to venous thromboembolism (VTE) and, thus, pharmacological thromboprophylaxis is generally advised. Low-molecular weight heparins (LMWHs) have become the drug of choice in ICU patients, since their predictable and reproducible dose response. Monitoring their pharmacological effect is not usually necessary except in special occasions (i.e. with obese or renal failure patients), where anti-FXa level measuring is recommended. However, there is neither recommendation of adequate anti-FXa levels in critically ill patients nor is it known whether peak or trough level should be measured. The aim of this systematic review was to evaluate the recommended LMWH doses, and the reasons to monitor anti-FXa levels. METHODS: We searched MEDLINE, Scopus, Cochrane Central Register of Controlled Trials and ClinicalTrials.com to identify all potentially relevant studies. Prospective studies done in critically ill patients were included if at least one anti-FXa level (i.e. peak or trough) after any specified LMWH thromboprophylaxis dose was measured. RESULTS: Total 18 eligible studies including 1644 patients were included. There was a wide variation in the median peak anti-FXa levels (<0.1-0.35IU/ml). Trough levels were generally low. Of note, none of the studies detected any correlation with bleeding events and anti-FXa levels. Low trough level increased incidence of DVT in one study only. CONCLUSION: Based on the current literature, no definite conclusions can be drawn on targeted anti-FXa level in critically ill patients when using LMWH thromboprophylaxis.

Higher Tinzaparin Dosing Is Needed to Achieve Target Anti-Xa Levels in Pediatric Cardiac Intensive Care Patients.

OBJECTIVES: This study was conducted to evaluate tinzaparin dosing and therapeutic drug monitoring. DESIGN: Retrospective study. SETTING: Single tertiary-level PICU. PATIENTS: Tinzaparin doses and anti-Xa levels from all children admitted to a PICU (from October 1, 2010, to December 31, 2013) were retrospectively analyzed. Thirty-nine children, median age of 13 months (interquartile range, 73 mo), with 46 episodes of newly started therapeutic tinzaparin were identified. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Local hospital policy is to determine the first anti-Xa level after 3-4 doses, 4 hours post dose, targeting 0.5-1.0 IU/mL for therapeutic dosing. First anti-Xa levels were determined after 3.8 (± 2.4; range, 1-14) doses and were below the target range in 37 of 46 episodes (76%) of tinzaparin use: mean, 0.30 (± 0.11) IU/mL. Tinzaparin was then increased by 23% (± 19) in 23 of 37 episodes (62%), and further anti-Xa levels were determined. In 14 episodes, further levels were not available because of cessation of tinzaparin therapy. Target anti-Xa levels, 0.69 (± 0.24) IU/mL, were eventually reached in the PICU in 22 patients after a mean of 8.8 (± 7.3) doses. In the entire cohort, the dose required to achieve target anti-Xa levels was significantly higher (+51 [± 62] U/kg; p = 0.003) than the recommended starting dose. CONCLUSIONS: Target anti-Xa levels were reached with tinzaparin dosing in PICU patients after more than 8 doses, warranting further dose-effect research. Especially in the younger age group, substantially higher dose requirements than proposed in the internationally used guidelines are required. With the results of our study, we suggest a different therapeutic drug monitoring approach than that currently used.

A systematic review on the accumulation of prophylactic dosages of low-molecular-weight heparins (LMWHs) in patients with renal insufficiency.

PURPOSE: Although therapeutic dosages of most low-molecular-weight heparins (LMWHs) are known to accumulate in patients with renal insufficiency, for the lower prophylactic dosages this has not been clearly proven. Nevertheless, dose reduction is often recommended. We conducted a systematic review to investigate whether prophylactic dosages of LMWH accumulate in renal insufficient patients. METHODS: A comprehensive search was conducted on 17 February 2015 using Embase, Medline, Web of Science, Scopus, Cochrane, PubMed publisher, and Google scholar. The syntax emphasized for LMWHs, impaired renal function, and pharmacokinetics. The search yielded 674 publications. After exclusion by reading the titles, abstracts, and if necessary the full paper, 11 publications remained. RESULTS: For dalteparin and tinzaparin, no accumulation was observed. Enoxaparin, on the other hand, did lead to accumulation in patients with renal insufficiency, although not in patients undergoing renal replacement therapy. Bemiparin and certoparin also did show accumulation. No data were available for nadroparin. CONCLUSIONS: In this systematic review, we show that prophylactic dosages of tinzaparin and dalteparin are likely to be safe in patients with renal insufficiency and do not need dose reduction based on the absence of accumulation. However, prophylactic dosages of enoxaparin, bemiparin, and certoparin did show accumulation in patients with a creatinine clearance (CrCl) below 30 ml/min, and therefore, dose reduction is required. The differences in occurrence of accumulation seem to depend on the mean molecular weight of LMWHs.

Plasma free fatty acid levels influence Zn(2+) -dependent histidine-rich glycoprotein-heparin interactions via an allosteric switch on serum albumin.

BACKGROUND: Histidine-rich glycoprotein (HRG) regulates coagulation through its ability to bind and neutralize heparins. HRG associates with Zn(2+) to stimulate HRG-heparin complex formation. Under normal conditions, the majority of plasma Zn(2+) associates with human serum albumin (HSA). However, free fatty acids (FFAs) allosterically disrupt Zn(2+) binding to HSA. Thus, high levels of circulating FFAs, as are associated with diabetes, obesity, and cancer, may increase the proportion of plasma Zn(2+) associated with HRG, contributing to an increased risk of thrombotic disease. OBJECTIVES: To characterize Zn(2+) binding by HRG, examine the influence that FFAs have on Zn(2+) binding by HSA, and establish whether FFA-mediated displacement of Zn(2+) from HSA may influence HRG-heparin complex formation. METHODS: Zn(2+) binding to HRG and to HSA in the presence of different FFA (myristate) concentrations were examined by isothermal titration calorimetry (ITC) and the formation of HRG-heparin complexes in the presence of different Zn(2+) concentrations by both ITC and ELISA. RESULTS AND CONCLUSIONS: We found that HRG possesses 10 Zn(2+) sites (K' = 1.63 × 10(5) ) and that cumulative binding of FFA to HSA perturbed its ability to bind Zn(2+) . Also Zn(2+) binding was shown to increase the affinity with which HRG interacts with unfractionated heparins, but had no effect on its interaction with low molecular weight heparin (~ 6850 Da). [Correction added on 1 December 2014, after first online publication: In the preceding sentence, "6850 kDa" was corrected to "6850 Da".] Speciation modeling of plasma Zn(2+) based on the data obtained suggests that FFA-mediated displacement of Zn(2+) from serum albumin would be likely to contribute to the development of thrombotic complications in individuals with high plasma FFA levels.

Thrombin generation and low-molecular-weight heparin prophylaxis in pregnant women with thrombophilia.

Pregnancy is associated with increased risk of venous thromboembolism, especially in the presence of thrombophilia. However, there is no consensus on the optimal approach for thromboprophylaxis in this population. Recent evidence suggests that thrombin generation correlates with the overall procoagulant state of the plasma. Our aim was to evaluate thrombin generation in a prospective cohort of thrombophilic pregnant women, and investigate the effectiveness of low-molecular-weight heparin (LMWH) prophylaxis in pregnancy. Women with severe (n=8), mild (n=47) and no (n=15) thrombophilia were followed throughout their pregnancies. Thrombin generation was evaluated in each trimester as well as five days and eight weeks postpartum (as a reference category). In women undergoing LMWH prophylaxis, thrombin generation and anti-Factor-Xa activity were measured just before and 4 hours after administration (peak effect). Thrombin generation was determined using Technothrombin TGA assay system. For the analysis, median peak thrombin and endogenous thrombin potential were used. Peak thrombin and endogenous thrombin potential were increased during pregnancy compared to the non-pregnant state with the highest results in the severe thrombophilia group. In women receiving LMWH prophylaxis a decrease was observed in thrombin generation at peak effect but over the progression of pregnancy the extent of this decrease reduced in a stepwise fashion. Our results show that thrombin generation demonstrates the hypercoagulable state in thrombophilic pregnancies. In addition, we found the effect of LMWH prophylaxis to progressively decrease with advancing stages of pregnancy.

Clinical experience with prophylactic fondaparinux in critically ill patients with moderate to severe renal impairment or renal failure requiring renal replacement therapy.

BACKGROUND: Fondaparinux has an increased bleeding risk in patients with a CrCl ≤ 50 mL/min and is contraindicated if CrCl < 30 mL/min. Data regarding dosing and anti-Xa monitoring are lacking in this population. OBJECTIVE: To describe dosing, monitoring, and safety outcomes of prophylactic fondaparinux in critically ill patients with moderate to severe renal impairment, including renal replacement therapy (RRT). METHODS: Retrospective analysis from October 2006 to November 2012 of patients ≥ 18 years old who received fondaparinux for ≥ 72 hours with ≥ 1 dose in an intensive care unit and a CrCl ≤ 50 mL/min or RRT during therapy. Participants were divided into 4 cohorts: moderate impairment (CrCl = 30-50 mL/min), severe impairment (CrCl < 30 mL/min), hemodialysis (HD), or continuous venovenous hemofiltration (CVVH). Outcomes included the incidence of clinically significant bleeding and thromboembolic events. Fondaparinux dose, dosing frequency, and anti-Xa level monitoring are described. Pharmacokinetic modeling was performed to assess drug accumulation. RESULTS: In all, 95 patients met inclusion criteria: 64 (67.4%) with moderate impairment, 10 (10.5%) with severe impairment, 5 (5.3%) with HD, and 16 (16.8%) with CVVH. The median defined daily doses in the moderate, severe, HD, and CVVH cohorts were 2.5, 2.5, 0.9, and 1.9 mg. Anti-Xa monitoring occurred in 19 (20%) patients, although few concentrations were peaks. Clinically significant bleeding occurred in 4 (4.2%) patients. A pharmacokinetic model demonstrated drug accumulation. CONCLUSIONS: Empirical dose adjustments may be prudent in critically ill patients with renal dysfunction; however, the optimal fondaparinux dosage in this population remains unknown. Peak anti-Xa concentrations may help guide therapy.

Is extended pharmacologic venous thromboembolism prophylaxis uniformly safe after radical cystectomy?

OBJECTIVE: To quantitate the risk of clinically significant renal function deterioration after radical cystectomy (RC), which could result in supratherapeutic levels of low-molecular-weight heparin (LMWH) and increased risk of bleeding events with the use of extended pharmacologic venous thromboembolism prophylaxis (EPVTEP) after hospital discharge. METHODS: Patients undergoing RC between 2006 and 2011 were identified from the institutional registry. Estimated glomerular filtration rate (eGFR) was calculated and categorized as preoperative, discharge, and nadir. Perioperative eGFR trends in patients who would have been candidates for EPVTEP were evaluated. RESULTS: Three hundred four patients with eGFR >30 mL/min/1.73 m(2) at the time of hospital discharge were included in the analysis as potentially eligible for EPVTEP. Large portion of patients (43%) exhibited decline in eGFR after discharge. Importantly, 13.0% of patients (n = 40), who would have qualified for EPVTEP at discharge, experienced nadir GFR below the 30-mL/min/1.73 m(2) threshold value at which LMWH would have become supratherapeutic. The odds ratio for developing a GFR <30 mL/min/1.73 m(2) was 9.1 (95% confidence interval, 4.3-19.3; P <.001), comparing those with a discharge GFR ≥60 mL/min/1.73 m(2) with those with a discharge GFR <60 mL/min/1.73 m(2). CONCLUSION: More than 10% experienced an eGFR, which would have rendered LMWH supratherapeutic and potentially would have placed the patient at risk for clinically significant bleeding. Although postoperative venous thromboembolic event after RC is a recognized concern, a better understanding of the risks of EPVTEP is needed before this strategy is universally adopted in patients undergoing RC.

Prevention effect of orally active heparin conjugate on cancer-associated thrombosis.

Thrombogenesis is a major cause of morbidity and mortality in cancer patients. Prophylaxis with low-molecular-weight heparin (LMWH) is recommended for cancer patients, but requires non-parenteral delivery methods for long-term treatments. In this study, we sought to generate a new oligomeric-bile acid conjugate of LMWH that can be used for oral delivery. We first synthesized a tetramer of deoxycholic acid (tetraDOCA), which was site-specifically conjugated at the end saccharide of LMWH. When LMWH-tetraDOCA conjugate (LHe-tetraD) was orally administered at a dose of 5 mg/kg in ICR mice, the maximum anti-factor Xa level was increased up to 0.62±0.05 IU/mL without any evidence of liver toxicity, gastrointestinal damage, or thrombocytopenia. The cancer-associated thrombosis was induced in tumor-bearing mice by local heat application, and the fibrin deposition in tumors was evaluated. The oral administration of LHe-tetraD (either a single dose or multiple daily doses for up to 10 days) in mice substantially abolished the coagulation-dependent tropism of fibrinogen in the heated tumors and significantly decreased hemorrhage, compared to the mice treated with saline or subcutaneous injection of LMWH. Thus, the anticoagulation effect of oral LHe-tetraD invokes the benefits of oral delivery and promises to provide an effective and convenient treatment for cancer patients at risk of thrombosis.

Routine coagulation assays underestimate levels of antithrombin-dependent drugs but not of direct anticoagulant drugs in plasma from patients with cirrhosis.

There is increasing recognition that thrombotic complications may occur in patients with cirrhosis, and literature on antithrombotic treatment in these patients is rapidly emerging. Due to extensive haemostatic changes in patients with cirrhosis, careful monitoring of anticoagulant therapy may be required. Recent data suggest that plasma levels of low molecular weight heparin (LMWH) are substantially underestimated by the anti-activated factor X (anti-Xa) assay in patients with cirrhosis. We studied the in vitro recovery of antithrombin (AT)-dependent and -independent anticoagulant drugs in plasma from 26 patients with cirrhosis and 30 healthy controls and found substantially reduced anti-Xa levels when AT-dependent anticoagulant drugs were added to the plasma of patients with cirrhosis. LMWH (0·2 U/ml) had the poorest recovery in plasma from patients with cirrhosis (0·13 ± 0·06 U/ml, compared to 0·23 ± 0·03 U/ml in controls, P < 0·0001), followed by unfractionated heparin and fondaparinux. In contrast, the recovery of rivaroxaban and dabigatran was identical between patients and controls. These data suggest that the anti-Xa assay cannot be used to monitor AT-dependent anticoagulant drugs in patients with cirrhosis, as it substantially underestimates drug levels. The direct factor Xa and IIa inhibitors, however, may be monitored through the respective anti-Xa and anti-IIa assays in patients with cirrhosis.