Direct Thrombin Inhibitor Research Articles

Direct Thrombin Inhibition in Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a widely used technique to provide circulatory and/or respiratory support in critically ill patients. ECMO treatment usually necessitates systemic anticoagulation. Unfractionated Heparin (UFH) is a commonly used anticoagulant in patients on ECMO support. In situations where UFH is contraindicated, alternative anticoagulation strategies can be applied, such as the use of direct thrombin inhibitors (DTI). Bivalirudin and argatroban are the most widely used DTIs. In this report we give account of the current evidence regarding dosing, monitoring and complications associated with the use of these agents in ECMO dependent patients.

How to dose and monitor argatroban for treatment of HIT.

Dosing and monitoring of argatroban for treatment of heparin-induced thrombocytopenia (HIT) remain uncertain. Marchetti and colleagues critically and systematically reviewed their institutional experience using this direct thrombin inhibitor to treat patients with laboratory-confirmed HIT, and have formulated several practical recommendations for managing this challenging clinical situation. Commentary on: Marchetti et al. Managing argatroban in heparin-induced thrombocytopenia: A retrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia. Br J Haematol. 2022;197:766-790.

Global Research Status and Trends in Venous Thromboembolism After Hip or Knee Arthroplasty From 1990 to 2021: A Bibliometric Analysis.

BackgroundVenous thromboembolism (VTE) after hip or knee arthroplasty has attracted increasing attention over the past few decades. However, there is no bibliometric report on the publications in this field. The purpose of this study was to analyze the global research status, hotspots, and trends in VTE after arthroplasty.MethodsAll articles about VTE research after hip or knee arthroplasty from 1990 to 2021 were retrieved from the Web of Science Core Collection database. The information of each article including citation, title, author, journal, country, institution, keywords, and level of evidence was extracted for bibliometric analysis.ResultsA total of 1,245 original articles from 53 countries and 603 institutions were retrieved. The USA contributed most with 457 articles, followed by England and Canada. McMaster University in Canada was the leading institution for publications. The journals with the highest output and citation were the Journal of Arthroplasty and the Thrombosis and Haemostasis, respectively. The median number of citations was significantly different among the levels of evidence (F = 128.957, P < 0.001). The research hotspots switched from VTE diagnosis and heparin to factor Xa inhibitors (fondaparinux, rivaroxaban, apixaban) and direct thrombin inhibitors (dabigatran etexilate, ximelagatran), and finally to aspirin, risk factor studies, which can be observed from the keyword analysis and co-cited reference cluster analysis.ConclusionsThis study observed an increasing trend of research articles on VTE after arthroplasty. Publications with higher levels of evidence gained further popularity among researchers and orthopedic surgeons. Additionally, individualized VTE prevention and the development of new, safe, effective, and inexpensive oral agents would be emerging trends in the future.

Rivaroxaban Reduces the Dabigatran Dose Required for Anticoagulation During Simulated Cardiopulmonary Bypass.

Heparin is the standard anticoagulant for cardiopulmonary bypass (CPB); however, there are problems with its use that make the development of suitable alternatives desirable. Currently, no ideal alternative exists. We have previously reported that the direct thrombin inhibitor dabigatran can prevent coagulation in simulated CPB at high concentrations. These high concentrations may cause difficulties in achieving the reversal of dabigatran with idarucizumab, given the markedly different pharmacokinetics of the 2 drugs. Herein, we test the hypothesis that the addition of the anti-Xa drug rivaroxaban would provide suitable anticoagulation at a lower concentration of dabigatran given likely synergy between the 2 classes of drugs. The primary goal of the study was to investigate whether the addition of rivaroxaban reduces the concentration of dabigatran necessary to allow 2 hours of simulated CPB. The study was performed in sequential steps. Blood collected from consenting healthy donors was used throughout. First, we added graded concentrations of dabigatran and rivaroxaban alone and in combination and assessed inhibition of anticoagulation using thromboelastometry. Using results from this step, combinations of dabigatran and rivaroxaban were tested in both Chandler loop and simulated CPB circuits. Dabigatran and rivaroxaban were added before recalcification, and the circuits were run for 120 minutes. In both models of CPB, 120 minutes of circulation without visible thrombus was considered successful. In the Chandler loop system, idarucizumab was added to reverse anticoagulant effects. In the CPB circuits, the arterial line filters were examined using scanning electron microscope (SEM) to qualitatively assess for fibrin deposition. In vitro analysis of blood samples treated with dabigatran and rivaroxaban showed that dabigatran and rivaroxaban individually prolonged clotting time (CT) in a dose-dependent manner. However, when combined, the drugs behaved synergistically. In the Chandler loop system, dabigatran 2400 and 4800 ng/mL plus rivaroxaban (150 ng/mL) effectively prevented clot formation and reduced the dynamics of clot propagation for 120 minutes. Idarucizumab (250-1000 µg/mL) effectively reversed anticoagulation. In the CPB circuits, dabigatran (2500 ng/mL) and rivaroxaban (200 ng/mL) were successful in allowing 120 minutes of simulated CPB and prevented fibrin deposition. Biomarkers of coagulation activation did not increase during simulated CPB. Heparin controls performed similarly to dabigatran and rivaroxaban. The dual administration of oral anticoagulant drugs (dabigatran and Rivaroxaban) with different pharmacologic mechanisms of action produced synergistic inhibition of coagulation in vitro and successfully prevented clotting during simulated CPB.

Direct thrombin inhibitor-bivalirudin improved the hemocompatibility of electrospun polycaprolactone vascular grafts

Synthetic artificial vascular grafts are hampered by their low patency rate in substituting small-caliber arteries (inner diameter <6 mm) because of their poor hemocompatibility . As compared to the heparin, bivalirudin (BV), a direct thrombin inhibitor, is a more reliable anticoagulant. In this study, BV-loaded polycaprolactone (PCL) grafts (PCL-BV) were fabricated by electrospinning. The loading rate of BV was approximately 87%. The PCL-BV grafts achieved the sustained release of BV for up to 30 days in vitro , but mainly released in the first 15 days. Scanning electron microscopy (SEM) and mechanical testing revealed that the BV loading did not affect the structure and mechanical properties of PCL grafts. In vitro coagulation analysis showed that the loading of the BV reduced thrombin activity, prolonged hemocompatibility parameters (activated partial thromboplastin time (APTT), prothrombin time (PT) and thromboplastin time (TT)), reduced blood coagulation, and inhibited the adhesion and activation of fibrinogen (FIB) and platelets. The assessment of vascular grafts in a rabbit arteriovenous (AV)-shunt ex vitro and carotid artery implantation in vivo indicated that BV significantly improved the antithrombogenicity and patency of PCL grafts. Overall, these results suggested that the incorporation of BV into electrospun grafts would be an effective approach to improve the hemocompatibility and patency rate of synthetic vascular grafts.

Characteristics and Outcomes of Patients Supported with Impella Percutaneous VAD Device at Pediatric Institutions: Action Collaborative Experience

<h3>Purpose</h3> We describe Advanced Cardiac Therapies Improving Outcomes Network (ACTION) pediatric multicenter experience with Impella® percutaneous ventricular assist device (PVAD) support for management of cardiogenic shock. <h3>Methods</h3> Retrospective review of patients supported with a Impella PVAD 15 pediatric centers participating in ACTION Collaborative from 10/2014 to 09/2021. Only patients supported with Impella PVAD alone were included. Demographics, device, and outcomes data was reviewed and reported using descriptive statistics. <h3>Results</h3> Total of 47 patients met the inclusion criteria. Median age was 16.1 years (range 6.38,34.4), weight 65.0 kg (range 29.6,124), and BSA 1.75 m² (range 1.05,2.52). PVAD was used most often for transplant graft dysfunction (40.4%) followed by dilated cardiomyopathy/myocarditis (31.9%), end stage congenital heart disease (14.9%) and others (12.5%). INTERMACS Profile 1 was reported in 42.6%, Profile 2 in 42.6%, and Profile 3 in 10.6%. Strategies for support included bridge to recovery (55.3%), bridge to transplant (23.4%) and bridge to decision (19.1%). Ten patients (21.3%) were bridged to durable VAD support. Impella CP was used in 64% cases, 5.0 in 18% and 5.5 in 18%. Nine (19%) patients had >1 device implanted. Anticoagulation was achieved with unfractioned heparin in 91% and a direct thrombin inhibitors in 9%. Median duration of support was 5.5 days (range 1,116) on CP device, 27 days (range 6,64) on 5.5 device and 21.5 days (range 8,143) on 5.0 device. Most common device complications included hemolysis (39.0%), major bleeding (15.3%), device malfunction (13.6%), renal failure (8.5%), arterial non-CNS thrombus (5.1%), and cardiac arrhythmia (3.2%). There were no neurological events. A positive clinical outcome was achieved in 85% of patients (77% survived to explant; 8% alive on device). <h3>Conclusion</h3> This study reports the Impella PVAD pediatric multi center experience for support of cardiogenic shock, with overall low morbidity and satisfactory survival benefit for a high-risk population. This device should be considered as part of the mechanical support armamentarium used in management of cardiogenic shock. Further investigation into optimal patient selection and support environment is needed to optimize its use in pediatric institutions and minimize adverse events.

Jumping and Pumping: Balancing Physical Activity and Anticoagulation in Ventricular Assist Devices

<h3>Introduction</h3> Pre-transplant rehabilitation, which includes physical activity, is critical for optimal outcomes in heart transplantation. Patients supported on ventricular assist devices (VAD) are on anticoagulation to limit adverse vascular events and ensure VAD function. However, anticoagulation is not without risk. We present the case of traumatic arthropathy related to physical activity in an anticoagulated VAD patient. <h3>Case Report</h3> A 27-month-old with left ventricular noncompaction, restrictive cardiomyopathy, developmental delay, and sensory processing disorder presented in heart failure. Despite inotropic support, he continued to decline and underwent placement of a 15-mL Berlin Heart EXCOR VAD as a bridge to transplant. He recovered well from the procedure and was maintained on bivalirudin and aspirin for anticoagulation. Direct thrombin inhibition (DTI) measurements were within goal (80-100 secs). He was able to participate in structured physical and occupational rehabilitation and continue physical activity outside of scheduled sessions. On VAD day 161 he developed irritability with resistance to flexion and increased pain at the right hip, shortly after jumping on a trampoline provided by the family. Ultrasonography demonstrated an effusion without soft tissue abscess or inflammation. An initial C-reactive protein was normal (0.9 mg/dl), increased to 17.7 mg/dl, but then normalized within 24 hours. He had a normal white blood cell (WBC) count and remained afebrile and hemodynamically stable. A right hip aspiration demonstrated an elevated WBC (152 K/microliter) with a neutrophil predominance (72%) and a red blood cell count of 14 K/microliter. Due to concern for septic arthritis he was started on broad spectrum antibiotics and had a right hip arthrotomy. As the gram stain and hip cultures remained negative for 72 hours, antibiotics were stopped. Following rest and pain control he was able bear weight and successfully underwent heart transplant. <h3>Summary</h3> Musculoskeletal symptoms in VAD patients require careful evaluation as they may represent a variety of pathologies. It is important for clinicians to balance anticoagulation strategies with structured and unstructured rehabilitative endeavors for patients on VAD support, recognizing that local trauma related to physical activity may be magnified by anticoagulation.

Bivalirudin Anticoagulation in Extracorporeal Membrane Oxygenation (ECMO) for Severe Coronaviral Disease (COVID-19) Related Acute Respiratory Distress Syndrome (ARDS)

PurposeECMO as a bridge, is a potential option in patients with severe COVID-19 who develop respiratory failure despite maximal conventional therapy. Heparin has been the standard anticoagulant, but is associated with bleeding and thrombocytopenia. Bivalirudin has been successfully used as an alternative in cases of heparin induced thrombocytopenia (HIT). We evaluated Bivalirudin as an anticoagulant in COVID-19 patients on ECMO who develop HIT or had persistent thrombocytopenia despite multiple platelet transfusions.MethodsAfter institutional clearance, we performed retrospective analysis of all the COVID-19 related ECMO managed in our centre between January to August 2021. Femoral vein to internal jugular vein ECMO was instituted in all these patients and anticoagulation targets were monitored daily as per institutional protocols. We compared incidence of ECMO circuit and oxygenator changes, post procedural bleeding and the number of blood products transfused between the Heparin and Bivalirudin group. Descriptive analysis was carried out by mean and standard deviation. The mean values were compared using student t-test and categorical outcomes using Chi square test.ResultsTotal of 42 COVID-19 ARDS related ECMO were managed in our centre during the study period. 8 patients were switched to Bivalirudin, as 2 patients were diagnosed with HIT and 6 had persistent thrombocytopenia despite multiple platelet transfusions. In patients with HIT, the platelet count improved by 72 hours. The incidence of post tracheostomy and intercostal drain insertion bleed was statistically higher in Heparin group (p <0.05). Total number of packed cell transfusion was significantly less in Bivalirudin group but platelet transfusion was lower, though not statistically significant. The usage of fresh frozen plasma and cryoprecipitate were similar. The rates of ECMO oxygenator and circuit exchanges were comparable with mean duration of 13.5 days for change from the date of initiation.ConclusionBivalirudin is a feasible alternative anticoagulant in the COVID-19 ECMO with the benefit of lower rates of bleeding and consequent need for transfusion. Further large studies are needed to assess the efficacy and benefits of direct thrombin inhibitors as a practical and safe substitute to Heparin in these situations.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

Managing argatroban in heparin-induced thrombocytopenia: Aretrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia.

DOAC Dipstick Testing Can Reliably Exclude the Presence of Clinically Relevant DOAC Concentrations in Circulation.

In certain clinical situations, it is necessary to determine whether clinically relevant plasma levels of direct oral anticoagulants (DOACs) are present. We examined whether qualitative testing of DOACs in urine samples can exclude DOAC plasma concentrations of ≥30 ng/mL. This prospective single-center cohort study included consecutive patients treated with an oral direct factor Xa inhibitor (DXI) (apixaban, n = 31, rivaroxaban, n = 53) and direct thrombin inhibitor (DTI) (dabigatran, n = 44). We aimed to define the negative predictive value (NPV) and other statistical parameters of detecting DXIs and DTIs by DOAC Dipstick at plasma concentrations of ≥30 ng/mL. We also determined the best-fit threshold plasma levels using chromogenic substrate assays by logistic regression analysis. Between July 2020 and July 2021, 128 eligible patients (mean age 66 years, 55 females) were included into the study. The NPVs and sensitivities for DXI and DTI of DOAC Dipstick were 100% at ≥30 ng/mL plasma, for specificities 6 and 21% and for positive predictive values 62 and 72%, respectively. All diagnostic statistical tests improved to values between 86 and 100% at best-fitting plasma thresholds of ≥14 ng/mL for DXI and ≥19 ng/mL for DTI. Visual analysis using the DOAC Dipstick was 100% in agreement with that of the optoelectronic DOASENSE Reader for all the three DOACs. DOAC Dipstick testing can reliably exclude the presence of DOACs in urine samples at best-fitting thresholds of >14 and >19 ng/mL in plasma. The performance of the DOAC Dipstick at detecting lower DOAC concentrations in plasma requires confirmation.

Anticoagulation Strategies in Critically Ill Patients With SARS-CoV-2 Infection: The Role of Direct Thrombin Inhibitors

ObjectivesTo compare heparin-based anticoagulation and bivalirudin-based anticoagulation within the context of critically ill patients with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.DesignAn observational study.SettingAt the intensive care unit of a university hospital.Participants and InterventionsCritically ill patients with a SARS-CoV-2 infection receiving full anticoagulation with heparin or bivalirudin.Measurements and Main ResultsTwenty-three patients received full anticoagulation with bivalirudin and 60 with heparin. Despite patients in the bivalirudin group having higher mortality risk scores (SAPS II 60 ± 16 v 39 ±7, p < 0.001) and a higher need for extracorporeal support compared to the heparin group, hospital mortality was comparable (57% v 45, p = 0.3). No difference in thromboembolic complications was observed, and bleeding events were more frequent in patients treated with bivalirudin (65% v 40%, p = 0.01). Similar results were confirmed in the subgroup analysis of patients undergoing intravenous anticoagulation; in addition to comparable thrombotic complications occurrence and thrombocytopenia rate, however, no difference in the bleeding rate was observed (65% v 35%, p = 0.08).ConclusionsAlthough heparin is the most used anticoagulant in the intensive care setting, bivalirudin-based anticoagulation was safe and effective in a cohort of critically ill patients with SARS-CoV-2. Bivalirudin may be given full consideration as an anticoagulation strategy for critically ill patients with SARS-CoV-2, especially in those with thrombocytopenia and on extracorporeal support.

Design and fabrication of r-hirudin loaded dissolving microneedle patch for minimally invasive and long-term treatment of thromboembolic disease

Cardiovascular disease is the leading cause of global mortality, with anticoagulant therapy being the main prevention and treatment strategy. Recombinant hirudin (r-hirudin) is a direct thrombin inhibitor that can potentially prevent thrombosis via subcutaneous (SC) and intravenous (IV) administration, but there is a risk of haemorrhage via SC and IV. Thus, microneedle (MN) provides painless and sanitary alternatives to syringes and oral administration. However, the current technological process for the micro mould is complicated and expensive. The micro mould obtained via three-dimensional (3D) printing is expected to save time and cost, as well as provide a diverse range of MNs. Therefore, we explored a method for MNs array model production based on 3D printing and translate it to micro mould that can be used for fabrication of dissolving MNs patch. The results show that r-hirudin-loaded and hyaluronic acid (HA)-based MNs can achieve transdermal drug delivery and exhibit significant potential in the prevention of thromboembolic disease without bleeding in animal models. These results indicate that based on 3D printing technology, MNs combined with r-hirudin are expected to achieve diverse customizable MNs and thus realize personalized transdermal anticoagulant delivery for minimally invasive and long-term treatment of thrombotic disease.

Reversing direct factor Xa or thrombin inhibitors: Factor V addition to prothrombin complex concentrate is beneficial in vitro

BackgroundProthrombin complex concentrate (PCC) is a human plasma‐derived mixture of partially purified vitamin K‐dependent coagulation factors (VKCF). Current therapeutic indication is treatment and perioperative prophylaxis of bleeding in acquired VKCF deficiency. Off‐label uses include treatment of direct factor Xa‐ or thrombin inhibitor‐associated bleeds, treatment of trauma‐induced coagulopathy, and hemorrhagic complications in patients with liver disease. ObjectiveConsidering PCC as a general prohemostatic drug, we argued that its clinical efficacy can benefit from supplementation with coagulation factors that are absent in the current PCC formulation. In this study, we focused on factor V. MethodsWe mimicked a coagulopathy in vitro by spiking whole blood or derived plasma with the direct oral anticoagulants (DOAC) rivaroxaban or dabigatran. We studied DOAC reversal by PCC and factor V concentrate (FVC) using a thrombin generation assay, thromboelastography, fibrin generation clot lysis test, and microfluidic thrombus formation under flow. ResultsIn DOAC‐treated plasma, PCC increased the amount of thrombin generated. The addition of FVC alone or in combination with PCC caused a partial correction of the thrombin generation lag time and clotting time. In DOAC‐treated whole blood, the combination of PCC and FVC synergistically improved clotting time under static conditions, whereas complete correction of fibrin formation was observed under flow. Clot strength and clot resistance toward tissue plasminogen activator‐induced lysis were both increased with PCC and further enhanced by additional FVC. ConclusionOur in vitro study demonstrates a beneficial effect of the combined use of PCC and FVC in DOAC reversal.

Direct Thrombin Inhibitor Dabigatran Compromises Pulmonary Endothelial Integrity in a Murine Model of Breast Cancer Metastasis to the Lungs; the Role of Platelets and Inflammation-Associated Haemostasis.

Activation of the coagulation cascade favours metastatic spread, but antithrombotic therapy might also have detrimental effects on cancer progression. In this study, we characterized the effects of dabigatran, a direct reversible thrombin inhibitor, on the pulmonary endothelial barrier and metastatic spread in a murine model of breast cancer metastasis. Dabigatran etexilate (100 mg kg−1) was administered to mice twice daily by oral gavage. Pulmonary metastasis, pulmonary endothelium permeability in vivo, and platelet reactivity were evaluated after intravenous injection of 4T1 breast cancer cells into BALB/c mice. The effect of dabigatran on platelet-dependent protection of pulmonary endothelial barrier in the presence of an inflammatory stimulus was also verified in vitro using human lung microvascular endothelial cell (HLMVEC) cultures. Dabigatran-treated mice harbored more metastases in their lungs and displayed increased pulmonary endothelium permeability after cancer cell injection. It was not associated with altered lung fibrin deposition, changes in INFγ, or complement activation. In the in vitro model of the pulmonary endothelial barrier, dabigatran inhibited platelet-mediated protection of pulmonary endothelium. In a murine model of breast cancer metastasis, dabigatran treatment promoted pulmonary metastasis by the inhibition of platelet-dependent protection of pulmonary endothelial barrier integrity.

Long-term anticoagulation is associated with type II endoleaks and failure of sac regression after endovascular aneurysm repair

ObjectiveWithin the context of endovascular aneurysm repair (EVAR), the role of anticoagulation therapy on endoleak development and subsequent reintervention is unclear with conflicting data in the literature. The hypothesis of this study is that long-term anticoagulation is associated with persistent type II endoleaks and failure of sac regression in patients undergoing endoluminal repair of intact infrarenal aortic aneurysm. MethodsRetrospective cohort abstracted from the Vascular Quality Initiative index hospitalization and long-term follow-up datasets for EVAR (2003-2017) were included in the analysis. Patients not taking aspirin preoperatively and postoperatively were excluded. Patients taking anticoagulation and aspirin concomitantly (treatment) after the index procedure were compared against patients taking aspirin alone (control). Anticoagulation included warfarin and novel oral anticoagulants, including factor Xa inhibitors and direct thrombin inhibitors. One-to-one greedy matching using propensity scores was implemented to match patients. The primary end points were failure of aneurysm sac regression, sac expansion, risk of endoleak, and reintervention rate for endoleak at follow-up. Sac regression was defined as a decrease of at least 5 mm and sac expansion was defined as an increase of at least 5 mm. ResultsThere were 9004 patients who received ASA alone and 332 patients who received ASA and anticoagulation. Propensity scores were used to create 301 matching pairs to account for differences in baseline characteristics and comorbidities, including but not limited to age, sex, smoking, coronary artery disease, heart failure, and chronic kidney disease between the treatment and control groups. After adjusting for covariables anticoagulation use was independently associated with a significantly decreased abdominal aortic aneurysm sac regression (41.59% vs 58.41%; P = .001), but no statistically significant difference in sac expansion with long-term anticoagulation use (9.7% vs 4.9%; P = .056). There was increased risk of type II endoleaks (11.96% vs 6.31%; P = .023; relative risk, 1.89; 95% confidence interval, 1.11-3.23; P = .016), but no significant differences in type I, III, or indeterminate endoleaks. There was no statistical difference in 2-year reintervention rates (4.32% vs 2.66%; hazard ratio, 1.43; 95% confidence interval, 0.55-3.77; P = .461). There were no differences in any primary outcome between warfarin and novel oral anticoagulants. ConclusionsThese data demonstrate that long-term aspirin plus anticoagulation use is associated with a lack of aortic sac reduction and persistent type II endoleak, but not an increased risk for subsequent reintervention. Because prior studies have demonstrated that sac regression is a correlate of survival, these findings associating regression failure suggest a potential therapeutic failure for patients undergoing EVAR who also require long-term anticoagulation therapy. Although not a contraindication, long-term anticoagulation should be considered when counseling patients with a surgical indication aortic aneurysm.

Hirudin promotes proliferation and osteogenic differentiation of HBMSCs via activation of cyclic guanosine monophosphate (cGMP)/protein kinase-G (PKG) signaling pathway

ABSTRACT Osteoporosis is a public health problem resulting in higher susceptibility to bone fracture. Hirudin is known as a direct thrombin inhibitor, which is isolated from the salivary gland of the medicinal leech. The present study aimed to evaluate the effect of Hirudin on the proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (HBMSCs). In our study, the effect of Hirudin on the proliferation of HBMSCs was evaluated with the CCK-8 and MTT assays. The capacity of osteogenic differentiation and mineralization of HBMSCs was evaluated with ALP and alizarin red staining, respectively. cGMP content was determined by ELISA. Western blotting and qRT-PCR were used to investigate the effect of Hirudin on the expression of osteoblast-specific markers, including Runx2, osterix (OSX), osteocalcin (OCN), and collagen1 (Col1). In our study, Hirudin treatment promoted cell viability. Moreover, Hirudin treatment increased ALP activity of HBMSCs and red coloration of alizarin. Interestingly, cGMP inhibitor partly reversed the effect of Hirudin on the proliferation, differentiation and mineralization of HBMSCs. In conclusion, Hirudin promoted the proliferation, differentiation and mineralization of HBMSCs via activation of cGMP signaling pathway. Hence, Hirudin contributed to bone remodeling and might represent as an effective agent for the treatment of osteoporosis.

DEEP VEIN THROMBOSIS – A SYSTEMATIC REVIEW

Deep vein thrombosis (DVT) is the formation of blood clots in deep veins, commonly the leg veins and the pelvic veins. DVT is a potentially fatal condition leading to increased mortality and morbidity if not diagnosed and treated promptly.Incidence is more prevalent in 60- 65 years of age because of increased pro-coagulant factors like factor VIII, factor VII, homocysteine, brinogen. With the increase in age the risk of DVT development increases exponentially.All bed ridden patients should receive sequential compression device therapy as primary DVT prophylaxis in the form of intermittent pneumatic compression device (IPCDs), graduated compression stocking (GCS), and the venous foot pump.The pharmacological agents used in the prophylaxis of DVT include low-molecular-weight heparins (LMWH), fondaparinux, Unfractionated heparin (UFH), new oral direct selective thrombin inhibitors and factor Xa inhibitors.The complications of DVT include development of Pulmonary embolism (PE) , Paradoxical emboli, Recurrent DVT, Post thrombotic syndrome. Approximately 4% individuals treated for DVT develop PE. It accounts for 10-12% mortality rate in hospitalized patients.The prevention and treatment must be upgraded continuously with evidence base strategies. This article aims at reviewing the clinical presentation, diagnostic and treatment modalities of DVT

Cost-effectiveness analysis of alternative anticoagulation in suspected heparin-induced thrombocytopenia

AbstractHeparin-induced thrombocytopenia (HIT) is a life-threatening complication associated with high medical costs. Factor Xa inhibitors gradually replace approved treatment with intravenous direct thrombin inhibitors despite their off-label indication, because of easier management and favorable economic profile. Whether they are cost-effective remains unclear. We evaluated the cost-effectiveness of approved and off-label anticoagulants in patients with suspected HIT, based on census data from the largest Swiss hospital between 2015 and 2018. We constructed a decision tree model that reflects important clinical events associated with HIT. Relevant cost data were obtained from the finance department or estimated based on the Swiss-wide cost tariff. We estimated averted adverse events (AEs) and incremental cost-effectiveness ratio as primary outcome parameters. We performed deterministic and probabilistic sensitivity analyses with 2000 simulations to assess the robustness of our results. In the base-case analysis, the total cost of averting 1 AE was 49 565 Swiss francs (CHF) for argatroban, 30 380 CHF for fondaparinux, and 30 610 CHF for rivaroxaban; after adjusting for 4Ts score: 41 152 CHF (argatroban), 27 710 CHF (fondaparinux), and 37 699 CHF (rivaroxaban). Fondaparinux and rivaroxaban were more clinically effective than argatroban, with AEs averted of 0.820, 0.834, and 0.917 for argatroban, fondaparinux, and rivaroxaban, respectively. Treatment with fondaparinux resulted in less cost and more AEs averted, hence dominating argatroban. Results were most sensitive to AE rates and prolongation of stay. Monte Carlo simulations affirmed our base-case analysis. This is the first cost-effectiveness analysis comparing argatroban with fondaparinux and rivaroxaban using primary data. Fondaparinux and rivaroxaban resulted in more averted AEs, but fondaparinux had greater cost savings. Fondaparinux could be a viable alternative to argatroban.

Bivalirudin vs. heparin in paediatric and adult patients on extracorporeal membrane oxygenation: A meta-analysis.

Unfractionated heparin (UFH) has been the primary anticoagulant of choice on extracorporeal membrane oxygenation (ECMO). However, it is debatable whether bivalirudin (BIV), a direct thrombin inhibitor, may be considered a better alternative anticoagulant option. We searched Embase, Pubmed, Cochrane library, Clinicaltrials.gov, CNKI and Wanfang databases up to 15 June 2021. Randomized controlled trials and observational studies were considered eligible for inclusion. Random-effects meta-analyses, including subgroup analyses, were conducted. A total of 9 studies containing 994 patients were enrolled. All articles were retrospective cohort studies. Compared with UFH, BIV was associated with lower risks of major bleeding (risk ratio [RR]: 0.32, 95% confidence interval [CI] 0.22-0.49), ECMO in-circuit thrombosis (RR: 0.57, 95% CI 0.43-0.74), stroke (RR: 0.52, 95% CI 0.29-0.95) and in-hospital mortality (RR: 0.82, 95% CI 0.69-0.99), and higher rates of survival to ECMO decannulation (RR: 1.18, 95% CI 1.03-1.34). Pooled risk estimates did not show a significant association with clinical thrombotic events (RR: 0.69, 95% CI 0.45-1.07). Moreover, BIV was associated with a lower risk of ECMO in-circuit thrombosis and in-hospital mortality in the adult subgroup but not in the paediatric subgroup. However, leave-one-out sensitivity analyses indicated that the results of stroke, survival to ECMO decannulation and in-hospital mortality should be interpreted with caution. BIV appears to be a potential alternative to UFH in paediatric and adult patients requiring ECMO.

Antithrombotic Effect of Sorbus commixta in an Arterial Thrombosis Mouse Model

Sorbus commixta Hedlund ( S. commixta) is known to possess cardiovascular protective activity. However, its effect on thrombosis has not been reported, although thrombosis plays a primary role in diverse circulatory diseases. Thus, this study was performed to assess the antithrombotic activity of dried S. commixta fruit extract. Mice were fed with a diet containing 8.3% extract for 4 weeks, which corresponded to the consumption of approximately 1000 mg extract/kg/day. The antithrombotic effect was tested in a FeCl3-induced arterial thrombosis model. Additionally, the effects on platelet aggregation and plasma coagulation were examined in vitro using washed platelets (WP) and isolated blood plasma, respectively. Thrombotic vascular occlusion time was significantly prolonged by the 4-week administration of the extract. Treatment of WP with the extract resulted in a decrease in thrombin-induced aggregation, which was concentration-dependent over 10 to 100 μg/mL and was not attributed to the direct inhibition of thrombin. The extract did not affect blood plasma coagulation, which was assessed by measuring prothrombin time and activated partial thromboplastin time. S. commixta is capable of preventing arterial thrombosis and such an effect may be attributed to the inhibition of platelet aggregation.