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Objectives: In our center, an unusual rate of patients had abnormalities of hemostasis in immediate postoperative period of cardiac surgery. Our objectives were to identify the cause of these sudden hemostasis abnormalities and to evaluate the performances of point of care coagulation testing., Methods: In this prospective and descriptive study, we included 33 consecutive patients undergoing elective cardiac surgery for 1 month. Heparin-induced anticoagulation and calculation of the protamine dose were tested by the Hemostasis Management System Plus device (Medtronic, Minneapolis, MN, USA). Fifteen minutes after the end of the protamine infusion, activated clotting time (ACT), activated partial thromboplastin time and anti Xa activity were measured. In case of unusual clinical bleeding, a Quantra analysis (Stago, HemoSonics LLC, Charlottesville, VA) was added., Results: Residual antiXa activity >0.2 IU/mL after neutralization was present in 44% of patients. Our investigation concluded incomplete heparin reversal. There was no association between cellular reinfusate and the presence of heparin. The unusual rate of hemostasis abnormalities was explained by a less efficient protamine reversal of heparin. ACT and Clot Time Ratio (CTR, Quantra system) correlated with AntiXa with Spearman's coefficients of 0.85 ( p < .0001) and 0.95 ( p = .0012), respectively. About ACT, a threshold of 150 seconds had a sensitivity of 85% [58-97] and a specificity of 85% [58-97%] for detection of AntiXa>0.2. For CTR, a threshold of 1.4 had a sensitivity of 67% [30-94] and a specificity of 100% [18-100]., Conclusion: The use of point of care coagulation testing is effective in detecting incomplete reversal of heparin., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Inflammation is pivotal in the pathogenesis and development of cerebral venous thrombosis (CVT). Herein, we aimed to assess the anti-inflammatory effects of batroxobin combined with anticoagulation in CVT. Participants were categorized into the batroxobin group (batroxobin combined with anticoagulation) and the control group (anticoagulation only). Regression analysis was employed to explore the association between the number of episodes of batroxobin administration and the fluctuation of inflammatory indicators, as well as the proportion of patients with inflammatory indicators that were reduced after batroxobin use. Twenty-three cases (age: 39.9 ± 13.8 years, female: 39.1%) in the batroxobin group and 36 cases (40.3 ± 9.6 years, 52.8%) in the control group were analyzed. Compared to the control group, batroxobin combined with anticoagulation significantly decreased fibrinogen ( P  < .001), platelet-lymphocyte ratio (PLR) ( P  = .016) and systemic immune-inflammation index (SII) ( P  = .008), and increased the proportion of the patients with lower fibrinogen ( P  < .001), neutrophil-lymphocyte ratio (NLR) ( P  = .005), PLR ( P  = .026), and SII ( P  = .006). Linear analysis showed that as the number of episodes of batroxobin administration increased, the fibrinogen ( P  < .001), the PLR ( P  = .001), and the SII ( P  = .020) significantly decreased. Logistic regression analysis showed as the number of episodes of batroxobin administration increased, the ratio of the patients with decreased NLR ( P  = .008) and PLR ( P  = .015), as well as SII ( P  = .013), significantly increased. Batroxobin could decrease NLR, PLR, and SII in CVT. The effect was related to the number of episodes of batroxobin administration. Besides reducing fibrinogen and indirect thrombolysis effects, this may be another critical benefit of batroxobin for CVT., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Andexanet alfa (AA) - zhzo, recombinant coagulation factor Xa, is an approved antidote for oral Xa inhibitors (apixaban and rivaroxaban). Unfractionated heparin (UFH) is commonly used for therapeutic, interventional, and surgical indications. Protamine sulfate (PrSO 4 ) is frequently used to neutralize UFH. This study aimed to investigate the comparative neutralization profiles of AA and PrSO 4 for heparins of bovine, ovine, and porcine origin., Materials and Methods: The neutralization effect of PrSO 4 at 25 µg/ml and AA at 100 µg/ml was studied on an approximate surgical/interventional concentration of heparin by supplementing whole blood with each of the heparins at 25 µg/ml. For the clotting profile (activated partial thromboplastin time: aPTT), amidolytic (anti-Xa and anti-IIa), and thrombin generation assay each of the heparin were supplemented from -10-0.62 µg/ml., Results: In the whole blood ACT studies, all three heparins produced strong anti-coagulant effects (400-450 seconds) compared to saline (130-150 seconds). Both AA and PrSO 4 almost fully neutralized the anti-coagulant effects of heparins (140-160 seconds). Both antidotes completely reversed the anticoagulant effects of all three heparins in the aPTT and thrombin generation assay. However, PrSO 4 was more effective in neutralizing the anti-Xa, and anti-IIa effects than AA, which only partially neutralized these effects., Conclusion: Andexanet alfa at 100 µg/ml effectively neutralizes the therapeutic and surgical/interventional concentrations of heparins in in-vitro settings. While differences in the anti-Xa, and anti-IIa effects between heparins were noted, anti-coagulant effect of these agents in the aPTT assay were comparable. A similar neutralization profile was observed in the ACT and thrombin generation assays by both agents., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Direct oral anticoagulants (DOACs) exert anticoagulation effect by directly inhibiting Factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran). Though DOACs are characterized by fixed-dose prescribing and generally do not require routine laboratory drug-level monitoring (DLM), circumstances may arise where the DLM may aid in clinical decision-making, including DOAC dose adjustment, anticoagulant class change, or decisions to withhold or administer reversal agents. We review the current literature that describes high-risk patient groups in which DLM may be beneficial for improved patient anticoagulation management and stewardship. The review also summarizes the limitations of conventional coagulation testing and discuss the emerging utility of quantitative methods for routine and rapid emergent evaluation of DOAC drug levels-in particular, the Anti-Xa activity to detect Factor Xa Inhibitors (rivaroxaban, apixaban, and edoxaban). Both technical and regulatory barriers to widespread DLM implementation are limiting factors to further clinical research that must be overcome, in order to propose universal DOAC DLM strategies and provide clinical-laboratory correlation to formally classify high-risk patient groups., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In unfractionated heparin (UFH) monitoring during extracorporeal circulation, the traditional measures of activated clotting time (ACT) or activated partial thromboplastin time (APTT) may diverge, confounding anticoagulant adjustments. We aimed to explore the factors explaining this discrepancy in children and young adults. This retrospective observational study, conducted at an urban regional tertiary hospital, included consecutive pediatric patients who received UFH during extracorporeal circulation (continuous kidney replacement therapy or extracorporeal membrane oxygenation) between April 2017 and March 2021. After patients whose ACT and APTT were not measured simultaneously or who were also taking other anticoagulants were excluded, we analyzed 94 samples from 23 patients. To explain the discrepancy between ACT and APTT, regression equations were created using a generalized linear model (family  =  gamma, link  =  logarithmic) with ACT as the response variable. Other explanatory variables included age, platelet count, and antithrombin. Compared to APTT alone as an explanatory variable, the Akaike information criterion and pseudo-coefficient of determination improved from 855 to 625 and from 0.01 to 0.42, respectively, when these explanatory variables were used. In conclusion, we identified several factors that may explain some of the discrepancy between ACT and APTT in the routinely measured tests. Evaluation of these factors may aid in appropriate adjustments in anticoagulation therapy., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: The optimal method for monitoring of anticoagulation in patients on extracorporeal life support (ECLS) is unknown. The objective of this study was to assess the relationship between anti-factor Xa level (anti-Xa; IU/mL) and activated partial thromboplastin time (aPTT; seconds) for monitoring intravenous unfractionated heparin anticoagulation in adult ECLS patients., Methods: Charts of all adult patients cannulated for ECLS from 2015 through 2017 were reviewed and laboratory and heparin infusion data were extracted for analysis. Time matched pairs of anti-Xa and aPTT were considered concordant if both laboratory values were within the same clinically utilized range. A hierarchical logistic regression model was used to determine factors associated with discordance while accounting for patient level effects., Results: A total of 1016 paired anti-Xa and aPTT values from 65 patients were evaluated. 500 (49.2%) paired samples were discordant with a degree of variability on linear regression ( r 2 = 0.315). The aPTT fell into a higher therapeutic range compared to the anti-Xa in 31.6% and lower in 17.3%. Logistic regression demonstrated that discordance was independently associated with time from initiation of ECLS (OR 1.17 per day, p < 0.001), average heparin infusion rate (OR 1.25 per U/kg/hr, p < 0.001), and INR (OR 3.22, p < 0.001)., Conclusions: Nearly half of all aPTT and anti-Xa values were in discordant ranges and discordance is more likely as the time on ECLS and the INR level increase. The use of either assay in isolation to guide heparin anticoagulation may lead to misestimation of the degree of anticoagulation in complex ECLS patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: We performed in vitro experiments using whole human blood without anticoagulants to clarify the activity of anticoagulant proteins on membranes coated with acrylate-copolymer (ACP) with a hydrophilic blood-contacting layer compared to those coated by immobilizing heparin (IHP) in extracorporeal circulation., Methods: Whole human blood from healthy volunteers was recirculated in two types of experimental circuits with an ACP-coated reservoir and tubes and an ACP-coated or IHP-coated membrane. To compare the fluctuation of anticoagulant proteins, the circuit pressure at the inlet and outlet of the membrane was measured every 5 min; antithrombin antigen (ATQ), antithrombin activity, protein-C quantitation (PCQ), protein-C activity, protein-S free antigen (PSQ), and protein-S activity were measured at 0, 30, 60, 120, and 180 min in each experiment ( n = 5)., Results: The time taken to achieve high circuit pressure (> 300 mmHg) at the inlet of the membrane was significantly shorter in the ACP-coated membrane circuit (28 ± 2.7 min) than in the IHP-coated membrane circuit (54 ± 24 min); however, the ATQ, PCQ, and PSQ at 180 min of recirculation were significantly higher in the former than in the latter (all p < .05)., Conclusions: ACP-coated membranes can prevent the consumption of anticoagulant proteins but cannot delay circuit thrombogenicity compared to IHP-coated membranes. Considering patient care during the post-extracorporeal circulation period, the use of ACP coating, which can preserve anticoagulant protein, is better in extracorporeal circulation circuits.

Introduction: The Activated Clotting Time (ACT) is commonly used to manage anticoagulation during cardiac surgery. The aim of this study was to compare the older manually operated Hemochron ® Response and the automated Hemochron ® Signature Elite., Methods: In this observational study the clinically relevant differences of both devices were investigated simultaneously, using duplicate measurements, in 29 patients who underwent a Coronary Artery Bypass Grafting (CABG) or Aortic Valve Replacement (AVR) in order to determine reliability, bias, and to detect which method has the lowest variation. Blood samples were obtained from the arterial line prior to surgery, after administration of 300 IU/kg heparin, 5 minutes after initiation of cardiopulmonary bypass and successively every 30 minutes, and after protamine administration., Results: A total of 202 measurements were performed. Of these 10 measurements were out of range in the Response and 9 in the Elite. About 27 single unstable magnet errors were seen in the Response versus no measurement errors in the Elite. No statistically significant differences between the Response (p = 0.22, Wilcoxon rank) and Elite (p = 0.064) duplicates were observed. The Response values were consistently higher during heparinization than the Elite measurements (p = 0.002, repeated measurements) with an average positive bias of around 56 seconds during heparinization (Bland-Altman). Overall, the coefficient of variation (CoV) increased during heparinization., Conclusion: The Elite was more reliable, but the variation was higher for the Elite than the Response. The observed positive bias in the Response compared to the Elite could affect heparin administration during surgery making the two systems not interchangeable.

The National Institute of Cardiology has previously used the CoaguChek ® XS Plus system (Roche Diagnostics International Ltd), comparing capillary blood prothrombin time/international normalized ratio (PT/INR) results with those obtained using BCS-XP/Thromborel (Siemens). We assessed the reliability of PT/INR results using the third-generation CoaguChek Pro II system, the CoaguChek XS Plus system, and cobas ® t 411 for citrated plasma analysis. Venous and capillary PT/INR were measured (N = 204). Spearman's correlation, Bland-Altman, and concordance analysis between methods were conducted. Spearman's correlation coefficients between venous/capillary INR were high for CoaguChek Pro II versus CoaguChek XS Plus ( r  = 0.994), CoaguChek Pro II versus cobas t 411 ( r  = 0.967), and CoaguChek XS Plus versus cobas t 411 ( r  = 0.968). Good concordance was observed among capillary methods (concordance coefficient [κ] = 0.888) and remaining relationships ( P  < .001 for all): cobas t 411 versus CoaguChek XS Plus (κ = 0.696) and cobas t 411 versus CoaguChek Pro II (κ = 0.684). In conclusion, good agreement was observed between CoaguChek Pro II, CoaguChek XS Plus, and cobas t 411., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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

Background: Treatments for catastrophic antiphospholipid syndrome (CAPS) rose from recommendations and consensus of international experts based on case series or case reports. We aimed to evaluate the treatment scheme with the best cost-effectiveness ratio associated with lower mortality as a high-impact clinical benefit., Methods: The CAPS Registry was used as our source of structured data on the different therapeutic strategies, their frequency, and their effectiveness (survival). Starting from around 50 different schemes, we identified those with a mortality of less than 33% within the 18 most frequently utilized. After applying the efficiency frontier method, we included two schemes to conduct a cost-effectiveness analysis from the Colombian healthcare sector perspective. Scheme 1 (Glucocorticoids + Anticoagulation + Anti-aggregation + Intravenous IgG immunoglobulin) and scheme 2 (Glucocorticoids + Anticoagulation + Anti-aggregation + Plasma exchange) were compared in terms of costs and survival. Deterministic and probabilistic sensitivity analyses (Monte Carlo simulation) were conducted to evaluate model robustness and uncertainty., Results: Our analysis uses the information corresponding to 427 cases from the CAPS registry, the majority being women (68.8%), with a mean age of 45.7 years and bearing general mortality of 38.17% (female: 38.4%, male: 37.5%). Scheme 2 was the cost-effective strategy over scheme 1. The results were robust on discrete sensitivity analysis and probability sensitivity analysis (Monte Carlo simulation)., Conclusion: To our knowledge, this is the first economic evaluation focused on the treatment of CAPS. For the Colombian health system, schemes 1 and 2 have similar behavior; nevertheless, scheme 2 represents the best cost-effectiveness ratio. This treatment approach is highly susceptible to the allocation of resources by the system and beneficial in terms of health outcomes.

Introduction: Andexanet alfa (andexanet) is an approved antidote used to reverse the bleeding effects of Direct Oral Anticoagulant (Direct-Xa agents) agents because it reverses anti-Xa activity. Unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) exhibit anti-Xa activity. The purpose is to investigate the neutralization of UFH and LMWH by andexanet in activated clotting time (ACT), thrombelastography (TEG), and anti-Xa due to the protamine sulfate shortage., Methods: UFH and LMWH were studied with andexanet, PS, or saline as potential reversal agents/controls at varying concentrations in ACT, TEG, and anti-Xa and compared to each other., Results: Andexanet partially neutralized both drugs several TEG parameters at high andexanet concentrations, but it was not as effective as protamine sulfate in any of the assays used. Most TEG parameters were correlated with andexanet concentration. In ACT, significant neutralization was demonstrated at many andexanet concentrations for UFH, but not LMWH. UFH was completely neutralized by PS in ACT, while LMWH was partially neutralized by PS in ACT. Andexanet alfa was a less effective neutralization agent than the protamine sulfate as it only partially neutralized UFH in ACT and was ineffective at neutralizing LMWH when tested at the same concentration as PS (10 ug/mL)., Conclusion: Andexanet partially neutralized UFH and LMWH with variability between assays, necessitating investigation into assay-dependent differences.

DOAC Dipstick determines specifically the presence and absence of direct oral anticoagulants (DOACs) from patients' urine samples and handmade test strips performed as well as the commercial version. To compare plasma activity (chromogenic substrate assays) from plasma samples with results from urine samples (DOAC test strips) of patients treated with heparin, low-molecular weight heparin (LMWH) and without anticoagulation. Plasma anti-factor Xa (aXa) activity was determined by Coamatic chromogenic substrate assay and compared to the presence of anticoagulants in urine by DOAC test strips. Patients were treated for least 5 days and samples were taken 4 hrs after administration in comparison to no treatment with an anticoagulant (n = 42). A total of 100 patients were included treated with heparin (n = 29), LMWH nadroparin (n = 29) or no anticoagulants (n = 42). Plasma aXa levels of patients treated with heparin (2 × 7.500 IU daily subcutaneously, 12 male, age 67.4 ± 11.5 years) were 0,18 IU/ml ± 0,15 IU/ml (mean, standard deviation), with LMWH (1 × 3000 IU daily subcutaneously, 15 male, age 64.2 ± 14.1 years) 0,17 IU/ml ± 0,16 IU/l, and with no anticoagulants (28 male, age 64.2 ± 15.6 years) 0,02 IU/ml ± 0.01 IU/ml. All factor Xa and thrombin inhibitor pad results of test strips were negative. We conclude that DOAC Dipstick has a high probability of not detecting heparin and LMWH in patients on treatment as well as in urine samples of patients not treated with an anticoagulant.

The Na + -taurocholate cotransporting polypeptide (NTCP) acts as the major hepatic basolateral uptake system, and plays a key role in balancing bile flow. The anti-tuberculosis drugs rifampin (RFP) can affect bile flow causing liver injury, while tanshinone IIA (TAN IIA) has the effect of protecting liver. This study aimed to investigate the effects of RFP and TAN IIA on the NTCP expression and activity, and explore the potential connections. Herein, we established sandwich-cultured primary rat hepatocytes, and quantified mRNA and protein levels of NRF2 and NTCP after treatment with RFP (10, 25, or 50 μM) or co-treatment with TAN IIA (5, 10, or 20 μM) for 12, 24, 48 h (n = 3). NTCP activity was assessed by measuring the initial uptake rates of known substrates taurocholate (TCA) (n = 3) after treatment with different concentrations of RFP, TAN ⅡA for 12, 24 and 48 h. We found that RFP had inhibition effects on NRF2, NTCP mRNA and protein expression, and co-administration of TAN IIA could reverse RFP inhibition. TCA cellular accumulation was significantly decreased by RFP (39.1%), and TAN IIA could significantly induce TCA uptake of NTCP (2.9-fold at 48 h). The TCA uptake activity was correlated with the NTCP mRNA expression, confirming the role of RFP or TAN IIA on NTCP expression and activity is synchronous, and we can predict NTCP activity by detecting its mRNA expression. In conclusion, our work will enrich the significance of NTCP in the liver protection, and provide theoretical basis for TAN IIA to prevent RFP induced cholestatic liver injury.

Aim: To compare the safety and efficacy of direct oral anticoagulants (DOAC) relative to vitamin K antagonists (VKA) for the treatment of left ventricular thrombus (LVT)., Methods: This retrospective study enrolled patients diagnosed with LVT from 2014-2017. Patient characteristics and outcomes within 12 months of LVT diagnosis were recorded and analyzed. A meta-analysis was also performed by pooling our results with existing data in literature., Results: 14 DOAC and 59 VKA patients were included. Baseline demographic and clinical characteristics were similar except for age. Although more strokes within 12 months occurred in VKA (15%) than in DOAC (0%) patients, this was not statistically significant ( P = 0.189). There were no significant differences in outcomes between patients on DOAC and VKA for acute coronary syndrome (ACS) (7%, vs 3.4%, P = .477), LVT resolution (86% vs 76%, P = .499) or bleeding (14% vs 14%, P = 1) within 12 months. The meta-analysis included 6 studies (n = 408 for DOACs; n = 1207 for VKA). There were no significant differences between DOACs versus VKAs with respect to odds for unresolved thrombus (OR 0.61, 95% CI 0.26,1.41), embolic events (OR 1.24, 95% CI 0.90,1.69), embolic events and death (OR 1.10, 95% CI 0.84,1.45) or bleeding events (OR 1.13, 95% CI 0.74,1.72)., Conclusions: Our study and meta-analysis suggest similar efficacy and safety of DOACs in the treatment of LVT compared to VKA. These findings underscore the need for a randomized controlled trial.

Peripheral artery disease (PAD) is a common disease affecting over 200 million people worldwide. PAD is associated with significant limb and cardiovascular morbidity and mortality which is reduced by antiplatelet and antithrombotic therapy. However, the optimal type, dose, and time of antithrombotic therapy is still uncertain.We searched 4 electronic databases from January 1, 1990, to June 1, 2020, for randomized controlled trials of patients who received oral anticoagulant and antiplatelet therapy for PAD. The primary outcome was a composite of acute limb ischemia, major amputation, myocardial infarction, ischemic stroke, death from cardiovascular events, or death from any cause. Secondary outcomes included major bleeding, fatal bleeding, and intracranial hemorrhage events.We identified 3 studies that satisfied inclusion and exclusion criteria. Compared with antiplatelet alone, oral anticoagulant plus antiplatelet therapy improved acute limb ischemia (p < 0.00001), stroke (p = 0.005), and major amputation events (p = 0.11). However, oral anticoagulant plus antiplatelet therapy was not effective for prevention of myocardial infarction (p = 0.23), death from cardiovascular events (p = 0.65), or death from any cause (p = 0.66). Additionally, a significant increase in major bleeding events was demonstrated (p < 0.00001). There was no significant difference in fatal bleeding (p = 0.16) or intracranial hemorrhage events (p = 0.43). This meta-analysis showed that oral anticoagulant plus antiplatelet therapy for PAD may improve acute limb ischemia and major amputation or stroke risk compared with antiplatelet therapy alone, but could increase the risk of major bleeding events. On the other hand, measuring myocardial infarction, death, fatal bleeding, or intracranial hemorrhage risk remains controversial.

The management of pregnant women at increased risk of thromboembolic/other vascular events is still a matter of debate. In a single-center, retrospective, observational trial, we analyzed the safety and efficacy of prophylactic anticoagulation with certoparin in pregnant women at intermediate- or high-risk by EThIG criteria of thromboembolic/other vascular events. Subcutaneous certoparin 8,000 IU once daily was administered immediately after pregnancy confirmation and continued for 6 weeks postpartum. We investigated 74 pregnancies (49 women; mean age 31.8 years; weight 77.3 kg). Most prevalent risk factors were factor V Leiden mutation (40.5%), thrombogenic factor II mutation (12.2%) and protein S deficiency (8.1%). In 76 control pregnancies prior to registry inclusion/without anticoagulation there were 14 cases [18.4%] of venous thromboembolism (between week 7 gestation and week 8 postpartum); 63.2% pregnancies resulted in abortion (median week 8.6 gestation). With certoparin anticoagulation, thromboembolism was 1.4%, exclusively non-major bleeding was 4.1% and abortion was 10.8%. One case of pre-eclampsia necessitating obstetric intervention occurred. Prophylactic anticoagulation with intermediate-dose certoparin throughout pregnancies at increased venous vascular risk was safe and effective.

Heparin is one of the most widely used drugs in the world. It has been described as a lifesaving drug due to its roles in treating many serious diseases and illnesses including kidney dialysis, surgery, cardiac-invasive, heart attack, cardiac arrhythmia, acute coronary syndrome, pulmonary embolism, stroke, deep vein thrombosis, blood clot prevention, and many other related uses. Heparin drug products currently approved in the United States are obtained from porcine intestinal mucosa sourced from pigs, the majority of which is imported from China. However, due to the heparin contamination crisis (2008) and potential shortage and to safeguard the quality of current and future heparin supply chains including raw material, Food and Drug administration (FDA) posted a notification on its website titled "FDA Encourages Reintroduction of Bovine-Sourced Heparin". This perspective is intended to address the history of regulatory and scientific background of heparin drug products obtained from bovine and porcine sources and general recommendations for improving the quality of current heparin manufacturing process including Critical Quality Attributes (CQA), control management, process control, related tests, limits, etc. Additionally, a general plan with systematic steps is proposed for diversifying heparin supply chains by reintroduction of bovine sourced heparin to the US market.

Antiphospholipid syndrome (APS) with cerebral venous sinus thrombosis (CVST) is a relatively rare phenomenon, and this observational study aimed to investigate the clinical characteristics of APS patients complicated with CVST. We retrospectively investigated the clinical characteristics of CVST events in APS and compared differential characteristics and associated factors between APS patients with and without CVST. Twenty-one CVST patients with APS were enrolled including 14 females (9.4%) and 7 males (5.8%). The median age and disease duration at onset of CVST was 33 years (IQR 28-48) old and 1.3 months (IQR 0.7-4), respectively. Among APS patients with CVST, 12 (57.1%) cases presented with neurologic symptoms of CVST as the initial manifestation. Onset of CVST was mainly chronic (52.4%). Headache (90.5%) was the most common neurological symptom. The common locations of CVST were transverse sinus (76.2%) and superior sagittal sinus (57.1%), with more frequently (76.2%) dual or multiple sinuses involved. All patients with CVST were treated with anticoagulant, and 5 (23.8%) patients received endovascular therapy. Sixteen (84.2%) patients had good outcomes and 3 (15.8%) patients died at last follow-up. There were no significant differences ( P > 0.05) between two groups in the analysis of related APS indicators. There were no significant differences ( P > 0.05) between two groups in the analysis of related APS indicators. Although APS complicated with CVST is rare and predominately chronic developed. The evaluation of CVST should be performed for APS patients with intracranial hypertension syndrome. The routine screening of antiphospholipid antibodies (aPLs) is highly recommended in unexplained CVST patients. Most CVST patients with APS will have a good prognosis after treatment, and endovascular therapy is an alternative treatment.

The treatment process of patients using warfarin is expected to be hindered during the COVID-19 pandemic. Therefore we investigated whether the time in therapeutic range (TTR) and bleeding complications were affected during the COVID-19 pandemic. 355 patients using warfarin were included between March 2019 to March 2021. Demographic parameters, INR (international normalized ratio), and bleeding rates were recorded retrospectively. The TTR value was calculated using Rosendaal's method. The mean age of the patients was 61 ± 12 years and 55% of them were female. The mean TTR value during the COVID-19 pandemic was lower than the pre-COVID-19 period (56 ± 21 vs 68 ± 21, P < 0.001). Among the patients, 41% had a lack of outpatient INR control. During the COVID-19 pandemic, 71 (20%) patients using VKA suffered bleeding. Among patients with bleeding, approximately 60% did not seek medical help and 6% of patients performed self-reduction of the VKA dose. During the COVID-19 pandemic, TTR values have decreased with the lack of monitoring. Furthermore, the majority of patients did not seek medical help even in case of bleeding.

Introduction: Pulmonary endarterectomy requires cardiopulmonary bypass and deep hypothermic circulatory arrest, which may prolong the activated clotting time. We investigated whether activated clotting time-guided anticoagulation under these circumstances suppresses hemostatic activation., Methods: Individual heparin sensitivity was determined by the heparin dose-response test, and anticoagulation was monitored by the activated clotting time and heparin concentration. Perioperative hemostasis was evaluated by thromboelastometry, platelet aggregation, and several plasma coagulation markers., Results: Eighteen patients were included in this study. During cooling, tube-based activated clotting time increased from 719 (95% confidence interval = 566-872 seconds) to 1,273 (95% confidence interval = 1,136-1,410 seconds; p < 0.01) and the cartridge-based activated clotting time increased from 693 (95% confidence interval = 590-796 seconds) to 883 (95% confidence interval = 806-960 seconds; p < 0.01), while thrombin-antithrombin showed an eightfold increase. The heparin concentration showed a slightly declining trend during cardiopulmonary bypass. After protamine administration (protamine-to-heparin bolus ratio of 0.82 (0.71-0.90)), more than half of the patients showed an intrinsically activated coagulation test and intrinsically activated coagulation test without heparin effect clotting time >240 seconds. Platelet aggregation through activation of the P2Y12 (adenosine diphosphate test) and thrombin receptor (thrombin receptor activating peptide-6 test) decreased (both -33%) and PF4 levels almost doubled (from 48 (95% confidence interval = 42-53 ng/mL) to 77 (95% confidence interval = 71-82 ng/mL); p < 0.01) between weaning from cardiopulmonary bypass and 3 minutes after protamine administration., Conclusion: This study shows a wide variation in individual heparin sensitivity in patients undergoing pulmonary endarterectomy with deep hypothermic circulatory arrest. Although activated clotting time-guided anticoagulation management may underestimate the level of anticoagulation and consequently result in a less profound inhibition of hemostatic activation, this study lacked power to detect adverse outcomes.

Objective: Deep venous thrombosis (DVT) is a common complication in patients with traumatic injury. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant protein in the extrinsic coagulation pathway. However, the relationship between DVT after trauma and the anticoagulant activity of TFPI remains unclear. In this prospective study, we investigated the role of TFPI in trauma patients with DVT to evaluate whether the anticoagulant activity of TFPI measured by a new functional assay can be used to help predict the risk of DVT. Patients and methods: This prospective nested case-control study enrolled trauma patients and healthy volunteers. Forty-eight trauma patients diagnosed with DVT and forty-eight matched trauma patients without DVT were included in the study. 120 healthy volunteers were also included as controls. Blood samples and case information were collected at admission. Patients accepted angiography before surgery to diagnose DVT. The parameters examined included TFPI anticoagulant activity, free-TFPI antigen, blood cell counts, and routine clinical coagulation tests. Results: For the parameters of TFPI anticoagulant activity, three were markedly increased in the DVT group compared to the non-DVT group (TFPI initial anticoagulant time ratio, P  =  .022; TFPI whole anticoagulant time ratio, P  =  .048; and TFPI anticoagulant rate, P  =  .034). The free-TFPI antigen concentration also showed a significant increasing trend in trauma patients with DVT compared with trauma patients without DVT (P  =  .035). Multivariate logistic regression analysis identified four independent factors for the development of DVT (TFPI initial anticoagulant time ratio, free-TFPI antigen, prothrombin time, and red blood cell count). We calculated the TFPI correlation coefficient and found that the area under the receiver operating characteristic curve was .821. Conclusions: A novel functional assay was developed to measure the anticoagulant activity of TFPI. The anticoagulant activity of TFPI can be used as a potential biomarker for diagnosing DVT in trauma patients.

Anticoagulation is the cornerstone in the prevention of stroke in atrial fibrillation. This study aimed at assessing the anticoagulation control and outcome and predictive factors in atrial fibrillation patients on warfarin therapy. A retrospective chart review was used to evaluate patients with atrial fibrillation who were on warfarin during two years follow up at the anticoagulation clinic of the hospital. The time in therapeutic range (TTR) was calculated using Rosendaal's method. Data were analyzed using SPSS software version 25. Univariable and multivariable analyses were computed to determine factors affecting TTR and bleeding events. We included 300 patients in this study. The mean percentage TTR was 42.03 ± 18.75. Only 38 (12.67%) patients achieved a TTR of above 65%. The average international normalized ratio (INR) testing frequency was 35 days (16.3-67.2 days). Taking 1 or 2 drugs along with warfarin was found to be better in achieving good TTR as compared to taking more than two drugs ( p  = .014). Having heart failure was associated with a 2.45 times odds of poor anticoagulation control (TTR< 65%) ( p  = .047). Male study participants were 2.53 times more likely of developing bleeding events than females ( p  = .009). Bleeding events were observed in 62 (20.67%) patients. Study participants, who didn't have Diabetic Mellitus and those not receiving aspirin were at lower odds developing bleeding events (AOR = .196; C.I. = .060-.638; p -.007 and AOR = .099; CI. = .024-.416; p -.02), respectively. In summary, the time spent in the therapeutic range was minimal in this population of patients with AF on warfarin managed at a hospital run anticoagulation clinic in Ethiopia. Moreover, the number of co-prescribed medications, and having heart failure were associated with poor TTR. Bleeding events were high and affected by male sex, having DM comorbidity, and using aspirin.

Background: Novel oral anticoagulants and warfarin are widely used for stroke prevention in patients with atrial fibrillation. The anticoagulation status of patients receiving warfarin or rivaroxaban has been studied. In this study, we aimed to evaluate the effect of dabigatran and warfarin on preventing thrombin generation (TG)., Methods: This retrospective study enrolled 237 nonvalvular atrial fibrillation (NVAF) subjects treated with 110 mg dabigatran etexilate twice daily and 224 NVAF patients received adjusted-dose warfarin (international normalized ratio [INR] of 2 to 3)). Coagulation assays, prothrombin fragment 1  +  2 (F 1+2 ), calibrated automated thrombogram, and thrombin-antithrombin complex (TAT) were detected at the steady state., Results: Activated partial thromboplastin time (APTT), antithrombin III activity, fibrinogen, and lag time showed no difference between the two groups. Compared to the dabigatran group, prothrombin time and INR values were higher in the warfarin group (all P  < .001). Thrombin time, endogenous thrombin potential, peak TG (C max ), F 1+2 , and TAT were lower in the warfarin group. The inhibition of TG was still stronger in the warfarin group when the patients were divided into subgroups., Conclusion: Conventional coagulation assays are suboptimal for assessing the coagulation status of dabigatran. TG could be used as supplementary assays to evaluate the anticoagulation effect of oral anticoagulants. Our results suggest that warfarin may inhibit TG more aggressively than dabigatran in patients regardless of age and kidney function.

Objective: To investigate the safety and efficacy of regional citrate anticoagulation (RCA) on elderly patients at high risk of bleeding after continuous renal replacement therapy (CRRT)., Methods: A total of 31 patients at high risk of bleeding who received CRRT in the intensive care unit were collected. The patients were divided into RCA group (n = 17) and no anticoagulation group (NA, n = 14) according to whether RCA was used or not. The levels of creatinine (Cr), blood urea nitrogen (BUN), prothrombin time (PT), activated partial thromboplastin time (APTT), total calcium (tCa), ionized calcium ion (iCa 2+ ), sodium ion (Na + ), bicarbonate ion (HCO 3 - ), tCa/iCa 2+ ratio, and pH were observed after treatment. The filter use time, number of filters used, filter obstruction events, clinical outcomes, and safety evaluation indexes were compared post-treatment., Results: After treatment, serum Cr and BUN levels, APTT and PT levels in the RCA group were significantly lower than the NA group. The tCa, iCa 2+ , HCO 3 - , tCa/iCa 2+ , and pH were within the normal range after RCA treatment while Na + levels saw a significant increase. In the RCA group, the filter using time was significantly longer, with significantly reduced numbers of filter use within 72 h and filter disorder events. Additionally, patients in the RCA group showed significant recovery of renal function and a significant reduction in bleeding events and in-hospital mortality., Conclusion: RCA treatment significantly improves clinical outcome of patients at high risk of bleeding after CRRT, safely and effectively prolongs the filter life and avoids coagulation incidences.

Measurement of a single marker of coagulation may not provide a complete picture of hemostasis activation and fibrinolysis in patients with chronic cardiovascular diseases. We assessed retrospective orders of a panel which included prothrombin fragment 1.2 (PF1.2), thrombin: antithrombin complexes, fibrin monomers, and D-dimers in patients with heart assist devices, cardiomyopathies, atrial fibrillation and intracardiac thrombosis (based on ordering ICD-10 codes). During 1 year there were 117 panels from 81 patients. Fifty-six (69%) patients had heart assist devices, cardiomyopathy was present in 17 patients (21%) and 29 patients (36%) had more than 1 condition. PF1.2 was most frequently elevated in patients with cardiomyopathy (61.1%) compared to those with cardiac assist devices (15.7%; P = 0.0002). D-dimer elevation was more frequent in patients with cardiac assist devices (98.8%) compared to those patients with cardiomyopathy (83.3%; P = 0.014). Patients with cardiomyopathy show increases of PF1.2 suggesting thrombin generation. In contrast, elevations of D-dimers without increase in other coagulation markers in patients with cardiac assist devices likely reflect the presence of the intravascular device and not necessarily evidence of hemostatic activation.

Background: During extracorporeal membrane oxygenation, the large contact surface between the blood and the extracorporeal circuit causes a continuous activation of coagulation and inflammation. Unfractionated heparin, a glycosaminoglycan that must bind to antithrombin as a cofactor, is currently the standard anticoagulant adopted during extracorporeal membrane oxygenation. Antithrombin, beyond being a potent natural anticoagulant, acts in the cross-talk between coagulation and inflammatory system through anticoagulation and coagulation-independent effects., Objectives: In this review, we describe, in the adult setting of veno-venous extracorporeal membrane oxygenation, the pathophysiological rationale for antithrombin use, the current practice of administration, and the effects of antithrombin on anticoagulation, bleeding, and outcomes., Data Sources: Studies on adults (18 years or older) on veno-venous extracorporeal membrane oxygenation published from 1995 to 2018 in order to evaluate the use of antithrombin., Results: In adults on veno-venous extracorporeal membrane oxygenation, antithrombin supplementation has a highly pathophysiological rationale since coagulation factor consumption, systemic inflammatory response syndrome, and endothelial activation are triggered by extracorporeal membrane oxygenation. Eleven articles are focused on the topic but among the authors there is no consensus on the threshold for supplementation (ranging from 70% to 80%) as well as on the dose (rarely standardized) and time of administration (bolus vs continuous infusion). Consistently, antithrombin is considered able to achieve better anticoagulation targets in or not in the presence of heparin resistance. The impact of antithrombin administration on bleeding still shows contrasting results., Conclusion: Antithrombin use in veno-venous extracorporeal membrane oxygenation should be investigated on the threshold for supplementation, dose, and time of administration.

Commercially available products used for antithrombin supplementation, for example, in extracorporeal life support, may contain latent antithrombin, a hyper-stable strongly procoagulative and anti-angiogenic residue. Latent antithrombin is associated with severe thrombosis in the critically ill. In the manufacturing process of fractionated antithrombin from plasma, heat treatment, citrate, and freeze drying speed up the transformation of native antithrombin to latent antithrombin. Manufacturers are not required to assess and report the latent antithrombin content of their products. When reported, the latent antithrombin fractions in their product range from <1% to 40% of total antithrombin compared with <3% in the healthy adult and less in children. The aims of this work were (1) to convey increased awareness to clinicians who may experience defaulted, expected effect after antithrombin supplementation in, for example, heparin anticoagulation during extracorporeal life support and (2) to urge manufacturers to assess and disclose latent antithrombin content in their products.

We describe our experience of bivalirudin use, a newer direct thrombin inhibitor, in an infant who was supported with Berlin Heart EXCOR VAD (Berlin VAD) as bridge to transplant for 122 days without complications and without need for pump exchange. An 11-month-old girl with dilated cardiomyopathy with acute heart failure was awaiting cardiac transplant. Lack of improvement despite maximizing medical therapy and anticipating a prolonged waitlist time, she was supported with Berlin LVAD as a bridge to transplant. Anticoagulation with bivalirudin was started and titrated with a goal partial thromboplastin time of 60-90 seconds. Therapeutic anticoagulation was achieved with bivalirudin for 50% of the days (61/122 days) on a dose of 2.1 mg/kg/hour and in a narrow dose range of 1.9 to 2.3 mg/kg/hour for 80% of the days (98/122 days). Antiplatelet regimen was started initially with aspirin and clopidogrel added later. She was supported for 122 days on a single pump without any evidence of thrombus or need for pump change. Berlin VAD explant and orthotopic heart transplant with biatrial anastomosis were performed uneventfully. Explanted Berlin VAD had no evidence of clot/fibrin or thrombus formation. The child was discharged to home uneventfully 15 days after cardiac transplant.

Data on drug-drug interactions (DDI) of antineoplastic drugs with anticoagulants is scarce. We aim to evaluate factors associated with DDI of antineoplastic and supportive care drugs with anticoagulants resulting in modification of pharmacokinetics of these last mentioned. A literature review on DDI databases and summaries of products characteristics (SmPC) was done. Drug-drug interactions of 257 antineoplastic and supportive care drugs with direct oral anticoagulants (DOACs), warfarin, enoxaparin, or fondaparinux were categorized as no clinically significant expected DDI, potentially weak DDI, potentially clinically significant DDI, and recommendation against coadministration. Logistic regression models were performed to analyze the association between the dependent variable potentially clinically significant interaction/recommendation against coadministration and the mechanisms of DDI. Of the 1799 associations, 84.4% were absence of DDI, 3.6% potentially weak DDI, 10.2% potentially clinically relevant DDI, and 2.0% recommendation against coadministration. Warfarin has higher DDI potential than other anticoagulants. Enoxaparin and fondaparinux have fewer DDI than others. There was no difference between DOACs. Drug-drug interactions with apixaban and rivaroxaban was independently associated with the absence of CYP3A4 competition, P-glycoprotein inhibition, CYP3A4 induction, and drug class of tyrosine kinase inhibitors. Drug-drug interactions with dabigatran and edoxaban was associated with inhibition of P-glycoprotein and tyrosine kinase inhibitors. Warfarin, induction of CYP3A4, and inhibition of CYP2C9. Enoxaparin and fondaparinux, only tyrosine kinase inhibitors. Direct oral anticoagulants did not differ regarding DDI with antineoplastic agents. Warfarin presented more DDI than other anticoagulants. P-glycoprotein inhibition and CYP3A4 induction were independently associated with DDI of antineoplastic agents with DOACs.

Dose adjustment of unfractionated heparin (UFH) anticoagulation is an important factor to reduce hemorrhagic events. High doses of heparin can be monitored by Activated Clotting Time (ACT). Because of limited information about the monitoring of low-dose heparin we assessed monitoring by ACT, aPTT and anti-Xa. Blood samples from healthy volunteers (n = 54) were treated ex vivo with increasing UFH doses (0-0.4 IU/ml). Samples from ICU-patients (n = 60), were drawn during continuous UFH infusion. Simultaneous ACT measurements were performed using iSTAT and Hemochron. In UFH treated blood, iSTAT and Hemochron showed a significant change of ACT at ≥0.075 IU/ml and ≥0.1 IU/ml UFH, respectively. In ICU-patients no relationship between ACT and either UFH dose, aPTT and anti-Xa was observed. Hemochron was affected by antithrombin and platelet count. iSTAT was sensitive to CRP and hematocrit. A moderate correlation was identified between UFH dose and aPTT (R 2 = 0.196) or anti-Xa (R 2 = 0.162). In heparin-spiked blood, ACT is sensitive to heparin at levels of ≥0.1 IU/ml heparin. In ICU-patients, ACT did not correlate with UFH dose or other established methods. Both systems were differently influenced by certain parameters.

Andexanet alfa is a recombinant factor Xa decoy protein, designed to reverse bleeding associated with oral anti-Xa agents. Andexanet alfa is also reported to neutralize the effects of heparin-related drugs. This study focused on the neutralization profiles of unfractionated heparin (UFH), enoxaparin, and, a chemically synthetic pentasaccharide, fondaparinux by andexanet alfa. Whole blood clotting studies were carried out using thromboelastography (TEG) and activated clotting time (ACT). The anticoagulant profile of UFH, enoxaparin, and fondaparinux was studied using the activated partial thromboplastin time (aPTT), thrombin time (TT), and amidolytic anti-Xa, and anti-IIa methods. Thrombin generation inhibition was studied using the calibrated automated thrombogram system. Reversal of each of these agents was studied by supplementing andexanet alfa at 100 µg/mL. In the TEG, andexanet alfa produced almost a complete reversal of the anticoagulant effects of UFH and enoxaparin; however, it augmented the effects of fondaparinux. In the ACT, aPTT, and TT, UFH produced strong anticoagulant effects that were almost completely neutralized by andexanet alfa. Enoxaparin produced milder anticoagulant responses that were partially neutralized, whereas fondaparinux did not produce any sizeable effects. In the anti-Xa and anti-IIa assays, UFH exhibited partial neutralization whereas enoxaparin and fondaparinux did not show any neutralization. All agents produced varying degrees of the inhibition of thrombin generation, which were differentially neutralized by andexanet alfa. These results indicate that andexanet alfa is capable of differentially neutralizing anticoagulant and antiprotease effects of UFH and enoxaparin in an assay-dependent manner. However, andexanet alfa is incapable of neutralizing the anti-Xa effects of fondaparinux.

Low SAMe-TT 2 R 2 score of <2 was validated as a predictor of optimum anticoagulation control, reflected by mean time in therapeutic range (TTR) above 65% to 70%, among warfarin-treated atrial fibrillation patients. This study aimed to validate the ability of SAMe-TT 2 R 2 score and its individual components in predicting anticoagulation control (mean TTR and clinical events) among a cohort of venous thromboembolism (VTE) patients in Qatar. A total of 295 patients were retrospectively evaluated. There was a trend toward statistical significance in mean TTR between low (<2) and high (≥ 2) SAMe-TT 2 R 2 score groups ( P = .05), a difference that was not sustained when a cutoff of 3 was used (ie, a score of 3 or more). Patients with poor INR control (TTR <70%) were numerically less likely to have SAMe-TT 2 R 2 score of <2 compared with those with good INR control, though the difference was not statistically significant (16.7% vs 83.3%, respectively, P = .4). No thromboembolic events were reported, and no association was found between the score and risk of bleeding. Non-Caucasian origin was the only significant predictor of good anticoagulation in the studied cohort. In conclusion, SAMe-TT 2 R 2 score could not predict quality of anticoagulation control in a cohort of VTE patients treated with warfarin in Qatar. Contribution of other clinical factors and whether a different scoring may yield better prediction of anticoagulation control remains to be tested.

Introduction: Sulodexide represents a mixture of fast-moving heparin (FMH) and dermatan sulfate (DS) and has been used for the management of venous diseases such as DVT and related disorders. The purpose of this study is to compare sulodexide and its components with unfractionated heparin (UFH) to determine its suitability for the indications in which UFH is used., Materials and Method: Active pharmaceutical ingredients (API) versions of sulodexide, FMH and DS were obtained from Alfasigma. API versions of UFH were obtained from Medefil Inc. Normal human citrated plasma was obtained from blood bank of the Loyola University Medical Center. Each of the individual agents were supplemented in plasma at a graded concentration of 0.0-10 µg/mL. Clotting assays (PiCT, aPTT, PT and TT), anti-Xa and anti-IIa and thrombin generation studies were carried out. Results were compiled as mean ± SD of 3 individual determination., Result: In the clot based (PiCT, aPTT and TT), anti-Xa and IIa assays, both the UFH and FMH produced stronger activities in these assays followed by sulodexide. DS did not show any anticoagulant activity. In the thrombin generation assay, FMH and UFH produced comparable inhibition of thrombin generation as measured by various parameters. Sulodexide was slightly weaker in this assay, whereas DS produced relatively weaker effects., Conclusion: In comparison to sulodexide, both UFH and FMH exhibit comparable anticoagulant activity despite differences in their molecular weight. These results suggest that sulodexide can be developed as a parenteral anticoagulant for indications in which UFH is used.

Low molecular weight heparins (LMWH) represent depolymerized heparin prepared by various methods that exhibit differential, biochemical and pharmacological profiles. Enoxaparin is prepared by benzylation followed by alkaline depolymerization of porcine heparin. Upon the expiration of its patent, several biosimilar versions of enoxaparin have become available. Heparinox (Sodic enoxaparine; Cristália Produtos Químicos Farmacêuticos LTDA, Sao Paulo, Brazil) is a new biosimilar form of enoxaparin. We assessed the molecular weight and the biochemical profile of Heparinox and compared its properties to the original branded enoxaparin (Lovenox; Sanofi, Paris, France). Clotting profiles compared included activated clotting time, activated partial thromboplastin time (aPTT), and thrombin time (TT). Anti-protease assays included anti-factor Xa and anti-factor IIa activities. Thrombin generation was measured using a calibrated automated thrombogram and thrombokinetic profile included peak thrombin, lag time and area under the curve. USP potency was determined using commercially available assay kits. Molecular weight profiling was determined using high performance liquid chromatography. We determined that Heparinox and Lovenox were comparable in their molecular weight profile. Th anticoagulant profile of the branded and biosimilar version were also similar in the clot based aPTT and TT. Similarly, the anti-Xa and anti-IIa activities were comparable in the products. No differences were noted in the thrombin generation inhibitory profile of the branded and biosimilar versions of enoxaparin. Our studies suggest that Heparinox is bioequivalent to the original branded enoxaparin based upon in vitro tests however will require further in vivo studies in animal models and humans to determine their clinical bioequivalence.

Pharmacists were found to play a key role in anticoagulation care. In order to make an appropriate selection and counselling regarding direct oral anticoagulants (DOACs), pharmacists should be knowledgeable and abiding by evidence-based practice. We aim in this study to assess the knowledge and practices of practicing hospital and community pharmacists in Qatar regarding DOACs and their reflection on the dispensing and patient education. A prospective cross-sectional survey was developed. It included questions on demographic and professional characteristics. Additionally, it evaluated the awareness regarding safety, efficacy, and dispensing of DOACs. Lastly, a separate question was used to address the participant's satisfaction with their knowledge. A total response were received from 211 pharmacists participating in the survey. Overall awareness score was moderate (41.6% ± 26%). These scores were in alignment with participants' self-satisfaction with knowledge on DOACs (72% of participants were not satisfied). Being a clinical pharmacist, of male gender, and with a board certification were factors associated with increased awareness on DOACs. Results from this survey point to the importance of having more educational activities in order to improve pharmacist's knowledge of DOACs.

Background: Cardiac surgery using cardiopulmonary bypass carries a high risk of bleeding and need for blood transfusion. Blood administration is associated with increased rates of morbidity and mortality. Perioperatively, strategies are often employed to reduce blood transfusions in high-risk patients or in situations where blood transfusion is contraindicated. Normovolemic hemodilution is a blood conservation technique used during cardiac surgery that involves replacement of blood with fluids. SANGUINATE ® (PEGylated carboxyhemoglobin bovine) is a novel hemoglobin-based oxygen carrier that can deliver oxygen effectively to tissues in the presence of severe hypoxia. The use of a hemoglobin-based oxygen carrier during hemodilution may augment tissue oxygen delivery and reduce blood transfusion., Methods: Six standardized cardiopulmonary bypass runs simulating normovolemic hemodilution using varying proportions of bovine whole blood and SANGUINATE were performed. Pump speed, flow rate, line pressures, hemoglobin concentration, oxygenation, and degree of anticoagulation were assessed at regular intervals. Membrane oxygenators and arterial line filters were inspected for evidence of clotting following each run., Results: Increases in the pressure drop across the membrane oxygenator were detected during runs 5 and 6. Median activated clotting time values were able to be maintained at goal during the runs, and SANGUINATE did not appear to be thrombogenic. Hemoglobin concentration decreased following the addition of SANGUINATE. Oxygenation was maintained during all runs that included SANGUINATE., Conclusion: SANGUINATE does not impact the performance of the cardiopulmonary bypass circuit in a bovine whole blood model. The results support further evaluation of SANGUINATE in the setting of normovolemic hemodilution and cardiopulmonary bypass.

Objective: To test the antifibrotic effect of dermatan sulphate in a bleomycin-induced mouse model of pulmonary fibrosis., Methods: C57 mice were randomly divided into four experimental groups: saline-treated control group, bleomycin-induced fibrosis group, prednisolone acetate group and dermatan sulphate group. Lungs were assessed using the lung index, and the extent of interstitial fibrosis was graded using histopathological observation of haematoxylin & eosin-stained lung tissue. Lung tissue hydroxyproline levels and blood fibrinogen levels were measured using a hydroxyproline colorimetric kit and the Clauss fibrinogen assay, respectively. Tissue-type plasminogen activator (tPA) was measured using a chromogenic tPA assay kit., Results: Lung index values were significantly lower in the dermatan sulphate group versus the fibrosis group. Histopathological analyses revealed that dermatan sulphate treatment ameliorated the increased inflammatory cell infiltration, and attenuated the reduction in interstitial thickening, associated with bleomycin-induced fibrosis. Hydroxyproline and fibrinogen levels were decreased in the dermatan sulphate group versus the fibrosis model group. Dermatan sulphate treatment was associated with increased tPA levels versus controls and the fibrosis group., Conclusions: Damage associated with bleomycin-induced pulmonary fibrosis was alleviated by dermatan sulphate.

Purpose:: We aim to determine whether hyperlactatemia, which suggests multi-organ dysfunction and impaired organic substrate metabolism, may predict intolerance to regional citrate anticoagulation (RCA) during continuous venovenous hemofiltration (CVVH)., Methods:: We performed a single-center, retrospective observational study in critically ill patients with acute kidney injury or end-stage renal disease and evaluated the association of peak serum lactate levels with citrate intolerance (CI) during the initial 72 hours of RCA-CVVH, defined by serum total-to-ionized calcium >2.5 plus systemic hypocalcemia., Results:: Eighty-eight patients were studied (aged 59 ± 14 years, 66% males, Acute Physiology and Chronic Health Evaluation II: 31 ± 8). Citrate was dosed at median 2.1 mmol/L of blood flow, with citrate load of 30 mmol/h, and CVVH effluent of 43 mL/kg/h. Twenty patients developed CI. Comparing patients with CI versus none, peak lactate levels were 8 (5-11) versus 3 (2-6) mmol/L, calcium replacement was 13 (10-17) versus 11 (8-12) mmol/h, and standard base excess was -4 (-12 to 1) versus 2(-4 to 7) mmol/L, respectively ( P < .05). Citrate intolerance developed in 38%, 44%, and 55%, in patients with peak lactate >4, >6, >7 mmol/L, respectively, versus 7% in those with peak lactate ≤4 mmol/L ( P ≤ .001), despite comparable citrate load and effluent rates across all categories. On multivariate analysis, hyperlactatemia and hyperbilirubinemia predicted CI ( P ≤ .01), which was associated with increasing calcium infusion requirement. Higher peak lactate from >4 to >7 mmol/L predicted CI with graded increase in odds ratio and specificity from 59% to 87%, but the corresponding negative predictive value from 93% to 87%. Area under nonparametric receiver operating characteristic curve for peak lactate and CI was 0.78., Conclusion:: Hyperlactatemia predicts CI during RCA-CVVH with reasonable discriminatory performance in critically ill patients. Serum lactate surveillance may help preempt issues with citrate toxicity.

Despite contemporary management, patients with coronary artery disease (CAD) remain at high risk for thrombotic events. Several randomized controlled trials have evaluated the use of direct oral anticoagulants (DOACs) in patients with CAD, including in the setting of acute coronary syndrome (ACS) and stable CAD, and in patients with concomitant atrial fibrillation. Trials of apixaban and dabigatran in patients with ACS demonstrate no benefit with an increased risk of bleeding. Conversely, rivaroxaban at a reduced dose of 2.5 mg twice daily reduced thrombotic events and all-cause mortality when added to dual antiplatelet therapy in patients with ACS. Similarly, the addition of low-dose rivaroxaban to acetylsalicylic acid reduced the risk of thrombotic events in patients with stable CAD. However, the addition of a DOAC to antiplatelet therapy increased the risk of major bleeding. In patients with atrial fibrillation undergoing percutaneous coronary intervention, dual-pathway or low-dose triple therapy regimens including dabigatran or rivaroxaban reduced bleeding risk compared to traditional warfarin-based triple therapy, although it remains unclear whether these regimens preserve antithrombotic efficacy. DOAC-based antithrombotic regimens prove useful in patients with CAD in various settings; however, careful selection of patients and regimens per trial protocols are critical to achieving net benefit.

Unfractionated heparin is the first anticoagulant drug and has been successfully used clinically for over 80 years. Heparin and its analogues are used during surgery and dialysis and are often used to coat indwelling catheters and other devices where the vascular system is exposed. Most of the heparins used clinically are derived from porcine intestinal mucosa. However, heparins have also been manufactured from tissues of other mammalian species such as cows and sheep. Recently there have been attempts to generate bioengineered heparin in order to overcome contamination and antigenicity problems. Currently there are some concerns about the shortage of the porcine heparins as they are widely used in the manufacturing of the low-molecular-weight heparins. Moreover, due to cultural and religious reasons in some countries, alternative sources of heparins are needed. The Food and Drug Administration and other regulatory agencies have considered alternative sourcing of heparin for potential substitution of porcine heparin and are currently reviewing this matter. Numerous studies are ongoing to understand the structure-activity relationships of these various heparins. In this article, heparins from different animal sources were studied to determine the extent of biosimilarity between them. For these investigations, 10 batches each of bovine mucosal heparin (BMH), ovine mucosal heparin (OMH), and porcine mucosal heparin (PMH) were studied. These studies have demonstrated that OMH and PMH have comparable anticoagulant and antiproteases activities. However, BMH exhibited somewhat a lower potency compared to OMH and PMH in functional assays.

Unfractionated heparin dosing is unpredictable and subject to numerous pharmacokinetic changes including distribution and metabolic changes associated with obesity and age. Weight-based dosing is commonly used to better predict the dose for a patient when targeting a therapeutic range. A dosing equation that adjusts weight-based doses for age and body mass index may improve therapeutic dose prediction. We conducted a 2-phase observational study with a derivation and validation period to develop an equation to adjust weight-based unfractionated heparin for age and body mass index to target a therapeutic activated partial thromboplastin time of 60 to 80 seconds. The first phase retrospectively identified patients who acheived therapeutic anticoagulation and utilized linear regression to determine a predictive equation for weight-based dosing that adjusts for age and body mass index. The second phase prospectively identified patients in an observational manner and compared the dose of unfractionated heparin on which they became therapeutic against both the weight-based dose and the predicted dose adjusted for age and body mass index. The correlation between predictive age and body mass index adjusted dose and actual therapeutic dose was 0.703 compared to the correlation between the empiric weight-based dose and actual therapeutic dose which was 0.532 ( P = .05). Age and body mass index adjusted weight-based dosing significantly improved therapeutic dose prediction for unfractionated heparin. Further study in a prospective, randomized trial is warranted for validation of this approach in a real world setting.

Recombinant coagulation factor Xa (FXa), inactivated Zh-zo, also known as andexanet alfa (AA), is a modified version of human FXa that has been developed to neutralize FXa inhibitors. We studied the reversal effect of AA for these inhibitors in various anticoagulant and thrombin generation (TG) assays. Individual aliquots of normal human plasma containing 1 µg/mL of apixaban, betrixaban, edoxaban, and rivaroxaban, were supplemented with saline or AA at a concentration of 100 µg/mL. Clotting profiles include prothrombinase-induced clotting time, activated partial thromboplastin time, and prothrombin time. Factor Xa activity was measured using an amidolytic method. Thrombin generation was measured using a calibrated automated thrombogram. Differential neutralization of all 4 anticoagulants was noted in the activated clotting time and other clotting tests. The FXa activity reversal profile varied with an observed decrease in apixaban (22%), betrixaban (56%), edoxaban (28%), and rivaroxaban (49%). Andexanet alfa also led to an increased TG in comparison to saline. The peak thrombin was higher (40%), area under the curve (AUC) increased (15%), whereas the lag time (LT) decreased (17%). Andexanet alfa added at 100 µg/mL to various FXa supplemented systems resulted in reversal of the inhibitory effects, restoring the TG profile; AUC, LT, and peak thrombin levels were comparable to those of unsupplemented samples. Andexanet alfa is capable of reversing anti-Xa activity of different oral FXa inhibitors but overshoots thrombogenesis in both the saline and FXa inhibitor supplemented systems. The degree of neutralization of Xa inhibitor is specific to each agent.

The risk of thromboembolic events after hip revision arthroplasty might be higher than in primary hip arthroplasty. However, evidence regarding the use of thromboprophylaxis in revisions is scarce. The purpose of this study is to determine whether thromboprophylaxis recommendations for primary arthroplasty produce similar results in hip revision arthroplasty. This comparative cohort study retrospectively analyzed consecutive patients undergoing primary hip arthroplasty and hip revision surgery between March 2004 and December 2015, who received thromboprophylaxis according to local clinical practice guidelines for primary hip arthroplasty. The prevalence of deep vein thrombosis and pulmonary embolism and the presence of major bleeding events were assessed during hospitalization and at 3 months after discharge and compared between groups. The overall prevalence of thromboembolic events in the hip revision surgery cohort and in the primary hip cohort was 1.62% and 1.35%, respectively ( P = .801). The 38.4% of hip revision patients and 20.3% of primary hip patients presented major bleeding events. Thromboembolic disease outcomes with the use of a standardized thromboprophylaxis regimen were similar in both cohorts, regardless of the high variability of hip revision surgery and the increased risk of complications. Implementation of this regimen is recommended in patients requiring joint replacement revision surgery.

There are few head-to-head trials directly comparing non-vitamin K antagonist oral anticoagulants (NOACs) against one other. A network meta-analysis (NMA) was performed to examine the indirect comparisons among NOACs in Asians with nonvalvular atrial fibrillation (NVAF). STATA 15.0 and ADDIS 1.16.8 softwares were used to perform the statistical analysis. Odds ratios with 95% credible intervals were applied to evaluate the end points. The probabilities of treatment rank were used to understand which interventions are more effective and safe, and the total rank probability was 1. In our NMA, the rank probabilities of apixaban in the case of stroke or systemic embolism, death from any cause, major bleeding, and intracranial hemorrhage (ICH) were 0.47, 0.49, 0.42, and 0.51, respectively. For cases of myocardial infarction, the rank probabilities of rivaroxaban were 0.40. This NMA indirectly compares the main efficacy and safety end points among NOACs in Asians with NVAF, and the rank probability analysis showed that apixaban likely performs best in cases of stroke or systemic embolism, death from any cause, and ICH; rivaroxaban may have the best performance for myocardial infarction.