Short-term Thromboprophylaxis Research Articles

Postpartum thromboprophylaxis with enoxaparin: a prospective cohort study on patients' adherence, injection experience, and information retention after counselling by pharmacists.

This research aimed to determine postpartum females' self-reported adherence to and experience with short-term thromboprophylaxis using enoxaparin injection, after counselling by pharmacists. It also sought to assess their knowledge of thromboprophylaxis, injection techniques, and confidence in self-injecting. This prospective cohort study was conducted at a public tertiary hospital in Malaysia from March to June 2023. Self-injection-naïve postpartum females who were initiated on thromboprophylaxis and counselled by a pharmacist were conveniently sampled. Knowledge regarding thromboprophylaxis, injection readiness, and technique were assessed one day after the counselling session. A telephonic interview was conducted at the end of the 10-day therapy to determine adherence and adverse effects experienced. A total of 259 subjects were successfully followed up, with 87.6% (n = 227) adherent to the therapy. Nonadherence was predominantly due to forgetfulness; four had their treatment withheld due to bleeding. One-third of subjects experienced localised pain and bruising. Subjects answered a median of 5/7 knowledge questions and recalled a median of 8/10 injection steps correctly, with those who read the information leaflet provided after counselling scoring significantly higher (P = .02). The majority declared moderate confidence in their ability to self-inject. Subjects who intended to self-inject (P < .01) and were more confident (P = .02) demonstrated better injection technique. Postpartum females counselled by pharmacists largely adhered to short-term enoxaparin for thromboprophylaxis. The impact of the counselling session may be enhanced by addressing their psychological readiness to self-inject, awareness of adverse effects identification, mitigation, and management, as well as setting reminders to prevent forgetfulness to inject.

Pulmonary Embolism in Adipsic DI: Can Desmopressin Be a Contributing Factor?

Background: Adipsic DI (ADI) is a rare disease associated with various morbidities. One of them is venous thromboembolism (VTE). In literature there are less than 10 reported cases and scarce management orientations. Classically, in ADI, VTE risk is due to dehydration and acute hypernatremia. Desmopressin should also be considered as it has a known role in blood coagulation such as increasing platelet cohesion and promoting von Willebrand factor release. Clinical Case: A 51-year woman with past medical history of obesity class 3 and a craniopharyngioma surgically intervened 8 months before, underwent a second craniotomy due to recurrent lesion. Postoperatively the patient developed an ADI, hypopituitarism and impairement of higher brain functions namely short-term memory and sleep-wake cycles impairment. She was discharged on desmopressin 0.35mg/day, levetiracetam 1500mg/day, hidrocortisone 15mg/day, levothyroxine 75mcg/day and quetiapine 25mg/day. Two weeks after discharge, the patient was admitted to the emergency room with anorexia and malaise. Tests were consistent with PE: elevated D-dimmer levels and CT angiography revealing bilateral PE. Treatment with enoxaparin was initiated. There was no hemoconcentration or polycythemia; kidney and liver function were normal, and sodium of 148 mEq/L (135-145 mEq/L). Three days before she had normal sodium levels. Respiratory insufficiency, deep vein thrombosis and infection were excluded. The patient did not present signs of dehydration. Brain CT did not show acute alterations. There was no personal history of smoking or family history of thrombosis and the patient was not on bed rest in the previous couple of weeks. During hospital stay abdominal and pelvic CT did not reveal malignancies. The patient was discharged on enoxaparin and posteriorly underwent a mammogram and colonoscopy; both exams without relevant alterations. At the last follow-up visit, she remained hypocoagulated and with desmopressin, with no further episodes of thrombosis. Conclusion: We report for the first time a case of PE in an obese patient with ADI treated with desmopressin and without overt hypernatremia or dehydration. All previously published cases of VTE in ADI have occurred in patients presenting with moderate to severe hypernatremia (sodium 157-181 mEq/L) and some degree of dehydration at the time of the event. Obesity and a recent hospitalization may have contributed to the development of VTE but desmopressin should also be taken into consideration due to its known effects on coagulation. Thromboprophylactic treatment after pituitary surgery and during acute episodes of hypernatremia and dehydration is already warranted in ADI but we additionally suggest considering at least short-term thromboprophylaxis in obese patients with recent ADI diagnosis treated with desmopressin as they might have this additional increased thrombotic risk.

Trial protocol: preoperative administration of tranexamic acid in sleeve gastrectomy (PATAS) to reduce haemorrhage rates. A randomised controlled trial

IntroductionFast-track protocols often include short-term thromboprophylaxis and short length of hospital stay. These treatment strategies may negatively affect the occurrence and diagnosis of postoperative haemorrhage. Over the years, the rates...

Optimal duration of anticoagulant thromboprophylaxis in total hip arthroplasty: new evidence in 55,540 patients with osteoarthritis from the Nordic Arthroplasty Register Association (NARA) group

Background and purpose — The recommended optimal duration of the thromboprophylaxis treatment in total hip arthroplasty (THA) patients has been a matter of debate for years. We examined the association between short (1–5 days), standard (6–14 days), and extended (≥ 15 days) duration of thromboprophylaxis, with regards to the risk of venous thromboembolism (VTE), major bleeding, and death in unselected THA patients.Patients and methods — We performed a cohort study using prospectively collected data from the population-based hip arthroplasty registries, prescription databases, and patient administrative registries in Denmark and Norway. We included 55,540 primary THA patients with osteoarthritisResults — The 90-day cumulative incidence of VTE was 1.0% for patients with standard treatment (reference), 1.1% for those with short-term treatment (adjusted hazard ratio [aHR] of 1.1, 95% confidence interval (CI) 0.8–1.5) and 1.0% for those with extended treatment (aHR of 0.9, CI 0.8–1.2). The aHRs for major bleeding were 1.1 (CI 0.8–1.6) for short and 0.8 (CI 0.6–1.1) for extended vs. standard treatment. In addition, patients with short and extended treatment had aHRs for death of 1.2 (CI 0.8–1.8) and 0.8 (CI 0.5–1.1) vs. standard treatment, respectively. Patients who started short treatment postoperatively had an aHR for death of 1.8 (CI 1.1–3.1) and absolute risk difference of 0.2%, whereas patients who started short treatment preoperatively had an aHR for death of 0.5 (CI 0.2–1.2) and absolute risk difference of 0.3% compared with patients who had standard treatment with post- and preoperative start, respectively.Interpretation — In routine clinical practice, we observed no overall clinically relevant difference in the risks of VTE and major bleeding within 90 days of THA with respect to thromboprophylaxis duration. However, our data indicate that short-term thromboprophylaxis started postoperatively is associated with increased 90-day mortality. The significance of these data should be explored further.

Length of Thromboprophylaxis in Patients Operated on for a High-Grade Glioma: A Retrospective Study.

High-grade gliomas are associated with venous thromboembolism (VTE). This retrospective study with a parallel cohort design investigated influence of continuing prophylactic anticoagulation after discharge on rate of VTE and intracranial hemorrhage (ICH) in patients operated on for high-grade glioma. Consecutive adult patients who underwent subtotal or gross total resection for high-grade glioma at a single institution were included. Multivariable logistic regression analysis was used to investigate the association between duration of thromboprophylaxis (dalteparin administered 21 days vs. 0-7 days) and occurrence of VTE and ICH within 21 or 90 days after surgery, corrected for known risk factors. Of 301 included patients, 166 received short-term thromboprophylaxis, and 135 received prolonged thromboprophylaxis. In multivariable analysis, prolonged thromboprophylaxis was not significantly associated with occurrence of VTE within 21 days (3.0% vs. 1.2%; P= 0.24) or 90 days (8.9% vs. 4.8%; P= 0.09) after surgery; however, prolonged prophylaxis was associated with occurrence of ICH (5.9% vs. 0.6%; P= 0.03). Additionally, immobility (P=0.03) and high body mass index (P= 0.02) were associated with occurrence of VTE. Prophylactic anticoagulation for 21 days postoperatively was not associated with a decreased rate of VTE compared with thromboprophylaxis until discharge. ICH was more common with prolonged thromboprophylaxis. These results provide insufficient evidence to extend duration of prophylaxis beyond hospitalization. Large-scale randomized prospective studies are needed to clarify safety, efficacy, and optimal timing of postoperative thromboprophylaxis in patients with high-grade glioma.

Abstract 16074: Risk of Blood Transfusion(s) With New Oral Anticoagulants for Short-Term Thromboprophylaxis in Hip and Knee Surgery: Insights From a Meta-Analysis of Fifteen Randomized Trials Including 36,176 Patients

Introduction: Blood transfusions have been associated with poor outcomes in cardiac patients. The objective of our study was to systematically examine the overall risk of blood transfusion with new oral anticoagulants (NOACs) and individually in thromboprophylaxis for hip and knee surgery. Hypothesis: Treatment with NOACs is safe for short-term thromboprophylaxis in patients undergoing hip and knee surgery compared with conventional therapy. Methods: PubMed, Cochrane CENTRAL, EMBASE, EBSCO, Web of Science and CINAHL databases were searched from January 01, 2001 through September 30, 2013. Systemic review of randomized controlled trials (RCTs) comparing the use of NOACs (apixaban, dabigatran and rivaroxaban) with conventional therapy was performed. Clinical and outcome data were extracted from individual studies by 2 independent authors. Primary endpoint of interest was transfusion events in the NOAC and comparator arms. Random effects model was used to pool event rates and results were expressed as risk ratios (RR) with 95% confidence intervals (CIs). Results: Fifteen randomized controlled trials (RCTs) including a total of 36,176 patients were included for analysis. Transfusion events were not higher with use of NOACs in comparison to all comparators in patients undergoing hip and knee surgery- RR 1.02 (95% CI 0.98-1.06), p=0.40. Statistical heterogeneity was negligible (I2=22%). Conclusions: Blood transfusion events with NOAC use were not significantly higher than that with conventional drugs in thromboprophylaxis for hip and knee surgery patients, as noted in evidence from contemporary RCTs.

Effects of thromboprophylaxis duration on coagulation indicators after total hip replacement

To compare the effects of short-term and long-term thromboprophylaxis after total hip replacement on coagulation indicators in plasma sampled before and 1, 7 and 35 days post-operation. A total of 40 patients scheduled for elective total hip replacement were randomly assigned into the short-term (n = 20) or long-term (n = 20) thromboprophylaxis groups on oral rivaroxaban 10 mg once daily for 7 or 35 days. The primary efficacy hemostatic variables included thrombin-antithrombin complexes (TAT), prothrombin fragment 1+2 (F1t2), D-dimer and fibrinogen (Fib) preoperatively and at Days 1, 7 and 35 postoperatively. And ultrasonography was performed on all patients preoperatively and at days 7 and 35 postoperatively to exclude deep vein thrombosis of lower extremities. None of them had deep vein thrombosis (DVT) of lower extremities. Among them, TAT, F1+2, D-dimer and Fib post-operation were higher than those preoperative baseline values. TAT and D-dimer peaked at day 1 postoperatively while the peaks of F1+2 and Fib appeared at day 7 postoperatively. At Day 35 post-operation, the levels of TAT and F1+2 in the long-term thromboprophylaxis group were significantly lower than those of the short-term thromboprophylaxis group (P < 0.05). The status of hypercoagulability may sustain at least 35 days after total hip replacement. Though not completely eliminated, it can still be reduced by prolonged thromboprophylaxis. However, according to ultrasonography, the effects of short-term and long-term thromboprophylaxis on the incidence rate of DVT remain to be further explored.

Comment on Ferroni et al.: "Impact of chemotherapy on venous thromboembolism.: Comment to: Regional lymph node metastases are a strong risk factor for venous thromboembolism: results from the Vienna Cancer and Thrombosis Study" HAEMATOL/2012/073338 and HAEMATOL/2013/092528

The notion of an increased venous thromboembolism (VTE) risk in patients with distant and regional stage cancer compared to those with local stage cancer can obviously be explained by the elevated tumor burden and an already systemic interaction of tumor cells via the lymph and blood system in regional and distant stage cancer.1 Ferroni et al.2 presented data of a cohort of ambulatory cancer patients who underwent chemotherapy and attempted to compare their results with our findings concerning VTE in regional stage cancer patients.1 Interestingly, there was a similar incidence of VTE between the cohorts: 7% in the cohort of Ferroni et al.2 and 6.9% in ours.1 Also similar to the results in our Vienna Cancer And Thrombosis Study (CATS), the authors found an association between tumor stage and the occurrence of VTE. The univariate hazard ratio (HR) of progressive tumor stage (from low to regional to distant stage) for VTE was 1.61 (95% confidence interval (95%CI) 1.02–2.54; P=0.042). However, in multivariate analyses, predictive value of progressive stage for VTE was completely lost in their study. Unfortunately, detailed results of multivariate analyses were not shown by Ferroni et al.2 Conversely, in CATS, patients with both regional stage and distant stage cancer had a significantly higher risk of VTE compared to local stage cancer patients in univariate and multivariate analyses. In detail, the association between progressive tumor stage and occurrence of VTE was strong and highly statistically significant (HR=1.81, 95%CI: 1.27–2.56; P=0.001; separate HRs for regional and distant stage versus local stage were 3.5 (95%CI: 1.4–8.9) and 4.0 (95%CI: 1.8–9.0), respectively. In a cross-tabulation analysis, Ferroni et al.2 found a higher administration of prothrombotic anti-cancer drugs in patients with regional and distant disease. They conclude that a more aggressive treatment with anti-cancer drugs may contribute to the high VTE incidence in patients with regional and distant disease. We completely agree with the authors that treatment with specific anti-cancer drugs is an important risk factor for the occurrence of VTE. However, we want to stress that treatment with anti-cancer drugs is only one of many risk factors for cancer-associated VTE.2–8 Naturally, there are interactions between the risk factors for cancer-associated VTE and thus not all risk factors are independent predictors of cancer-associated VTE. In our study we adjusted for multiple risk factors, including the administration of anti-cancer drugs. Moreover, the administration of anti-cancer drugs was considered as a time-dependent variable in the multivariable Cox regression analysis, to provide better weighting of the duration of treatment with anti-cancer drugs. Interestingly, in our study, chemotherapy was not independently associated with the occurrence of VTE. In contrast, regional stage and distant stage were independently associated with the occurrence of VTE. In our opinion, the conflicting results concerning the predictive value of tumor stage and administration of anti-cancer drugs on the occurrence of VTE can be largely attributed to the different cohorts of cancer patients in CATS and the study of Ferroni et al. Although, the distribution of tumor entities in both studies was almost similar, different patients’ inclusion criteria were applied. While the study of Ferroni et al. only included ambulatory cancer patients at start of a new chemotherapy,9 the CATS population was more heterogeneous, including patients who underwent cancer surgery, irradiation or even no treatment. During admission to the hospital due to intercurrent illness, patients received short-term thromboprophylaxis during follow up.10 Despite the concerns about an increased risk of VTE in advanced cancer patients by Ferroni et al., we believe the tumor stage (regional and metastatic disease) is an important and independent risk factor for cancer-associated VTE. This is substantiated by studies focusing on VTE as first manifestation of cancer. In these studies, VTE occurred before administration of chemotherapy. When VTE was concurrently diagnosed with cancer, VTE patients had a significantly higher risk of advanced tumor stage.11 However, to what extent the tumor stage contributes to the occurrence of VTE independently from chemotherapy in ambulatory cancer patients is still unclear. We are looking forward to seeing more detailed results regarding this issue in future publications by Ferroni et al. and other groups. Furthermore, large studies in single tumor entities considering the tumor stage and treatment with anti-cancer drugs could probably provide better answers to the question about the association between lymph node metastases, chemotherapy and occurrence of VTE.

Occult antithrombin deficiency manifesting as extensive superficial venous thrombosis after venous cannulation

Occult antithrombin deficiency manifesting as extensive superficial venous thrombosis after venous cannulation

Effectiveness of rivaroxaban for thromboprophylaxis of prosthetic heart valves in a porcine heterotopic valve model

Warfarin is used to reduce the risk of stroke and thromboembolic complications in patients with mechanical heart valves. Yet, despite frequent blood testing, its poor pharmacokinetic and pharmacodynamic profiles often result in variable therapeutic levels. Rivaroxaban is a direct competitive factor Xa inhibitor that is taken orally. It inhibits the active site of factor Xa without the need for the cofactor antithrombin, and thus, its mechanism of action is differentiated from that of the fractionated heparins and indirect factor Xa inhibitors. No in vivo data exist regarding the effectiveness of rivaroxaban in preventing thromboembolic complications of mechanical heart valves. We tested the hypothesis that rivaroxaban is as effective as enoxaparin for thromboprophylaxis of mechanical valves that use a previously described heterotopic aortic valve porcine model. A modified bileaflet mechanical valved conduit that bypassed the native, ligated descending thoracic aorta was implanted into 30 swine. Postoperatively, the animals were randomly assigned to groups receiving no anticoagulation (n = 10), enoxaparin at 2 mg/kg subcutaneously twice daily (n = 10) or rivaroxaban at 2 mg/kg orally twice daily (n = 10). The amount of valve thrombus was measured on post-implantation day 30 as the primary end point. Quantitative evaluation of radiolabelled platelet deposition on the valve prostheses was done and embolic and haemorrhagic events were measured as secondary end points. Animals with no anticoagulation had a thrombus mean of 759.9 mg compared with 716.8 mg with enoxaparin treatment and 209.6 mg with rivaroxaban treatment (P = 0.05 for enoxaparin vs rivaroxaban). Similarly, the mean number of platelets deposited on the valve prosthesis was lower in the rivaroxaban group (6.13 × 10(9)) than in the enoxaparin group (3.03 × 10(10)) (P = 0.03). In this study, rivaroxaban was more effective than enoxaparin for short-term thromboprophylaxis of mechanical valve prosthetics in the heterotopic aortic position. It reduced valve thrombus and platelet deposition on day 30 following implantation without increased adverse events. Future studies would provide additional support for clinical trials evaluating rivaroxaban as an alternative to warfarin for appropriately selected patients with prosthetic aortic valves.

Comparative study of extended versus short term thromboprophylaxis in patients undergoing elective total hip and knee arthroplasty in Indian population

Background:Postoperative thromboprophylaxis with low molecular weight heparin (LMWH) for an extended period of 4 weeks is now preferred over short term thromboprophylaxis in patients undergoing total hip/knee arthroplasty (THA/TKA). However, most of the data demonstrating the efficacy and safety of extended thromboprophylaxis and short term thromboprophylaxis is from clinical trials done in the West. In India, the data of the incidence of venous thromboembolism (VTE) following THA/TKA has been conflicting and the duration has not been clearly defined. The aim of the study was to evaluate and compare the efficacy of extended thromboprophylaxis over short term thromboprophylaxis in Indian patients undergoing elective THA/TKA surgeries.Materials and Methods:A prospective arm of 197 consecutive patients undergoing elective THA/TKA surgeries who were administered extended thromboprophylaxis for 4 weeks was compared with a historical group of 795 patients who were administered short term thromboprophylaxis for only 7-11 days. In both groups, LMWH (enoxaparin) was used in a dose of 40 mg subcutaneously, in addition to mechanical thromboprophylaxis. Primary efficacy endpoint was objectively confirmed venous thromboembolism (VTE). The presence of DVT was confirmed by a combination of pretest scoring, D-dimer, and Color Doppler Flow Imaging (CDFI) of deep veins of the legs, and pulmonary thromboembolism (PTE) was confirmed by ventilation perfusion (V/Q) scan or pulmonary angiography. Fisher's exact test and t test were used for the statistical analysis. The baseline confounding factors were compared between the two groups using t test for comparing the means for continuous data and Fisher's exact test for categorical data.Results:In the prospective arm, only 1 patient developed symptomatic PTE compared to 26 (3.27%) cases of VTE (20 cases of PTE and 6 cases of DVT) in the retrospective group.Conclusion:Extended thromboprophylaxis (for 4 weeks) was found to be more effective than short term thromboprophylaxis in minimizing the risk of postoperative VTE in patients who underwent THA/TKA.

Prevention of Venous Thromboembolism with New Oral Anticoagulants versus Standard Pharmacological Treatment in Acute Medically Ill Patients

Venous thromboembolism (VTE) is a common and potentially avoidable cause of morbidity and mortality in patients hospitalized for acute medical illness. Our objective was to conduct a systematic review of studies that assessed the efficacy and safety of new oral anticoagulant (OAC) drugs versus standard pharmacological drugs and/or placebo in prevention of VTE in acute medically ill patients. PubMed.org and ClinicalTrials.gov databases were searched to identify studies that evaluated the efficacy and safety of a new OAC versus the standard pharmacological treatment and/or placebo in the prevention of VTE in medically ill patients. Relative risks (RR), weighted means and 95% CIs were calculated. Statistical heterogeneity was evaluated using Chi2 and I2 statistics. Two studies were included in the meta-analysis. The primary outcome in both studies was the composite of VTE-related death, symptomatic non-fatal pulmonary embolism (PE), symptomatic deep venous thrombosis (DVT) and asymptomatic proximal DVT. Both studies compared a factor (F)Xa inhibitor with enoxaparin in standard short-term thromboprophylaxis followed by a period where the FXa inhibitor was compared with placebo as prolonged thromboprophylaxis in medically ill patients. The primary major safety outcome in both studies was a composite of treatment-related major bleeding and clinically relevant non-major bleeding. A total of 14 629 patients were randomized. Compared with subjects treated with enoxaparin followed by placebo, the RR of the primary outcome during the prolonged treatment period was 0.79 (95% CI 0.66, 0.94), the RR for the primary outcome during the first short-term treatment period was 1.03 (95% CI 0.81, 1.31). For major bleeding during the prolonged treatment period, the RR was 2.69 (95% CI 1.65, 4.39) for patients treated with an FXa inhibitor compared with enoxaparin/placebo. For major bleeding during the shorter treatment period, the RR was 2.01 (95% CI 1.10, 3.65) in favour of enoxaparin. In acute medically ill patients, prolonged thromboprophylaxis with an oral FXa inhibitor is more protective than regular short-term treatment with enoxaparin. However, treatment with FXa inhibitors is significantly associated with major bleeding, both in long- and short-term treatment compared with enoxaparin.

Effectiveness of dabigatran etexilate for thromboprophylaxis of mechanical heart valves

Warfarin reduces risk of stroke in patients with mechanical heart valves but increases risk of hemorrhage and is difficult to use. Dabigatran etexilate, a new oral direct thrombin inhibitor, is safe and effective in reducing risk of stroke among patients with atrial fibrillation. No data exist in the setting of mechanical heart valves. We tested the hypothesis that dabigatran etexilate is as effective as heparin for thromboprophylaxis of mechanical valves in a porcine heterotopic aortic valve model. Thirty swine underwent implantation of modified bileaflet mechanical valved conduit bypassing the ligated, native descending thoracic aorta. Animals randomly received no anticoagulation (n=10), enoxaparin 2mg/kg subcutaneously twice daily (n=10), or dabigatran etexilate 20 mg/kg orally twice daily. Primary end point was amount of valve thrombus at 30 days. Secondary end points included quantitative measurement of platelet deposition on valve prosthesis, thromboelastography, and hemorrhagic and embolic events. At 30 days, we observed 638 ± 895 mg thrombus in no anticoagulation group, 121 ± 128 mg in enoxaparin group, and 19 ± 31 mg in dabigatran etexilate group (P = .01 enoxaparin vs dabigatran etexilate). Fewer platelets were deposited on valves in dabigatran etexilate group (2.7×10(8)) than in enoxaparin group (1.8×10(9), P=.03). No major or occult hemorrhagic or embolic events were observed. By thromboelastographic analysis, dabigatran etexilate produced less prolongation of K value (P=.01) and less decreases in angle (P=.01) and maximum amplitude (P=.001) than enoxaparin. Dabigatran etexilate is as effective as enoxaparin for short-term thromboprophylaxis of mechanical valves. It prevents valve thrombus and platelet deposition at 30 days without increased adverse events. These promising results serve as a foundation for prospective clinical trials with dabigatran etexilate as an alternative to warfarin in patients with bileaflet mechanical aortic valves.

Fondaparinux in major orthopedic surgical patients

S.Capri and co-workers confirmed in an extensive number of patients undergoing major orthopaedic surgery (MOS) in Italy that prophylaxis with fondaparinux was more cost saving than enoxaparin [1]. This result is very important because other economic evaluations show an incremental cost-effectiveness ratio (ICER) in favour of fondaparinux only in short-term thromboprophylaxis, and none of them included Italian data. The authors assessed the overall cost of extended prophylaxis of venous thromboembolism (VTE), calculating the cost of management of each symptomatic VTE episode, taking into account early and late VTE events and other sequelae. This new evidence suggests more evaluations are needed. In addition to being more effective than enoxaparin in preventing VTE in patients undergoing MOS, in extended prophylaxis, fondaparinux is cost saving up to 5 years. In Capri and co-workers’ study, the occurrence of heparin-induced thrombocytopenia (HIT) was excluded from the cost-effectiveness analysis of fondaparinux versus enoxaparin. It has been observed that antiPF4 heparin antibodies occur less frequently in thromboprophylaxis with fondaparinux than with low molecular weight heparin (LMWH). Fondaparinux does not cross-react in vitro with HIT antibodies, particularly it does not react with PF4 in such a way as to cause sites for HIT antibody binding [2]. For these reasons the use of fondaparinux in thromboprophylaxis is associated with a lower risk of HIT, and specifically with a negligible risk in patients who may have recently undergone cardiac surgery or invasive cardiac procedures. In our opinion, this economic and clinical evaluation suggests that fondaparinux should be considered the standard therapy in patients undergoing MOS, in particular in Italian patients for whom this evaluation was done. Therefore, we think that new anticoagulant agents in MOS should be tested versus fondaparinux and not versus enoxaparin. This is very important in light of the recent introduction of dabigatran and rivaroxaban [3–5]. They are new effective drugs in patients undergoing MOS, but it is not clear if they are more effective than fondaparinux because at the moment there are no studies that compare these drugs.

The spatial dynamics of fibrin clot dissolution catalyzed by erythrocyte-bound vs. free fibrinolytics.

Coupling fibrinolytic plasminogen activators to red blood cells (RBCs) has been proposed as an effective, yet safe method of thromboprophylaxis, because of increased circulation lifetime and reduced propensity to induce hemorrhage by selectivity for nascent thrombi rather than pre-formed hemostatic clots. We used confocal microscopy of fluorescently labeled fibrin and erythrocytes in plasma-derived clots to study the spatial dynamics of lysis catalyzed by RBC-coupled vs. free plasminogen activators (RBC-PA vs. PA). Clot lysis catalyzed by free PA progressed gradually and uniformly. In contrast, distinct holes formed surrounding RBC-PA while the rest of the clot remained intact until these holes enlarged sufficiently to merge, causing sudden clot dissolution. Compared with naïve RBCs within clots lysed by free PA, RBC-PA moved faster inside the fibrin network prior to clot dissolution, providing a potential mechanism for spatial propagation of RBC-PA induced lysis. We also showed the focal nature of fibrinolysis by RBC-PA as dense loading of PA onto RBCs initiates more efficient lysis than equal amounts of PA spread sparsely over more RBCs. In an in vitro model of clots exposed to buffer flow, incorporated RBC-PA increased permeability and formed channels eventually triggering clot dissolution, whereas clots containing free PA remained intact. Clot lysis by RBC-PA begins focally, has a longer lag phase when measured by residual mass than homogeneous lysis by PA, is propagated by RBC-PA motility and provides more effective clot reperfusion than free PA, making RBC-PA attractive for short-term thromboprophylaxis.

Soluble urokinase receptor conjugated to carrier red blood cells binds latent pro-urokinase and alters its functional profile

Coupling plasminogen activators to carrier red blood cells (RBC) prolongs their life-time in the circulation and restricts extravascular side effects, thereby allowing their utility for short-term thromboprophylaxis. Unlike constitutively active plasminogen activators, single chain urokinase plasminogen activator (scuPA) is activated by plasmin proteolysis or binding to its receptor, uPAR. In this study we conjugated recombinant soluble uPAR (suPAR) to rat RBC, forming RBC/suPAR complex. RBC carrying suPAR circulated in rats similarly to naïve RBC and markedly prolonged the circulation time of suPAR. RBC/suPAR carrying ~ 3 × 10 4 suPAR molecules per RBC specifically bound up to 2 × 10 4 molecules of scuPA, retained ~ 75% of scuPA-binding capacity after circulation in rats and markedly altered the functional profile of bound scuPA. RBC carrying directly conjugated scuPA adhered to endothelial cells, while showing no appreciable fibrinolytic activity. In contrast, RBC/suPAR loaded with scuPA did not exhibit increased adhesion to endothelium, while effectively dissolving fibrin clots. This molecular design, capitalizing on unique biological features of the interaction of scuPA with its receptor, provides a promising modality to deliver a pro-drug for prevention of thrombosis.

Role of antithrombin concentrate in treatment of hereditary antithrombin deficiency

Antithrombin (AT) functions as a potent natural anticoagulant and serine protease inhibitor that inactivates many enzymes in the coagulation cascade. Antithrombin also possesses antiinflammatory properties, many of which are mediated by its actions as an anticoagulant. Hereditary AT deficiency is a rare, underrecognised medical condition that is associated with inadequate endogenous anticoagulation thought to result from impaired inhibition of serine protease coagulation factors. Inherited as an autosomal dominant trait, congenital AT deficiency typically reduces functional AT levels to 40-60% of normal. As a result, individuals with hereditary AT deficiency have a > or = 50% lifetime risk of venous thromboembolism (VTE). Specifically, AT deficiency is associated with a three- to seven-fold higher risk of VTE compared with other thrombophilias. Thus, maintaining adequate levels of AT during high-risk periods is an important treatment goal. Long-term anticoagulant thromboprophylaxis is not recommended in asymptomatic patients with AT deficiency because of the increased risk of haemorrhage. However, treatment guidelines recommend short-term thromboprophylaxis in high-risk clinical settings, including surgery, trauma, and management of pregnancy, labour, and delivery. The goal of treatment for patients with hereditary AT deficiency is an initial increase in AT activity to > or = 120% of normal levels followed by maintenance of AT activity at > or = 80% of normal levels. Plasma-derived AT, heparin, fresh frozen plasma, and human recombinant AT are treatment options for individuals with hereditary AT deficiency. The objective of this review is to discuss hereditary AT deficiency and the role of AT replacement therapy in the treatment of patients with this congenital disorder.

Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial

The risk of venous thromboembolism is high after total hip arthroplasty and could persist after hospital discharge. Our aim was to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin. 2509 patients scheduled to undergo elective total hip arthroplasty were randomly assigned, stratified according to centre, with a computer-generated randomisation code, to receive oral rivaroxaban 10 mg once daily for 31-39 days (with placebo injection for 10-14 days; n=1252), or enoxaparin 40 mg once daily subcutaneously for 10-14 days (with placebo tablet for 31-39 days; n=1257). The primary efficacy outcome was the composite of deep-vein thrombosis (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism, and all-cause mortality up to day 30-42. Analyses were done in the modified intention-to-treat population, which consisted of all patients who had received at least one dose of study medication, had undergone planned surgery, and had adequate assessment of thromboembolism. This study is registered at ClinicalTrials.gov, number NCT00332020. The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group. The primary outcome occurred in 17 (2.0%) patients in the rivaroxaban group, compared with 81 (9.3%) in the enoxaparin group (absolute risk reduction 7.3%, 95% CI 5.2-9.4; p<0.0001). The incidence of any on-treatment bleeding was much the same in both groups (81 [6.6%] events in 1228 patients in the rivaroxaban safety population vs 68 [5.5%] of 1229 patients in the enoxaparin safety population; p=0.25). Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism, including symptomatic events, in patients undergoing total hip arthroplasty.

Extended Thromboprophylaxis with Rivaroxaban Compared with Short-Term Thromboprophylaxis with Enoxaparin after Total Hip Arthroplasty: The RECORD2 Trial.

Venous thromboembolism (VTE) is a common, potentially fatal complication of major orthopaedic surgery. Pharmacologic thromboprophylaxis is recommended for patients undergoing total hip arthroplasty (THA) for a minimum of 10 days, and up to 35 days. However, extended thromboprophylaxis is not universally used. Therefore, this trial was conducted to evaluate the potential benefits of extended thromboprophylaxis after THA. RECORD2 is the largest, prospective, randomized clinical trial conducted to date, in this indication. This global, phase III, double-blind trial, was designed to compare short-term thromboprophylaxis with a low molecular weight heparin - enoxaparin - with extended thromboprophylaxis for up to 5 weeks with a novel, oral, direct Factor Xa inhibitor - rivaroxaban after THA. Patients received subcutaneous enoxaparin 40 mg once daily (od), beginning the evening before surgery, continuing for 10–14 days (short-term prophylaxis), and followed by placebo until day 35±4, or oral rivaroxaban 10 mg od beginning 6–8 hours after surgery and continuing for 35±4 days (extended prophylaxis). Mandatory, bilateral venography was conducted at the end of the extended treatment period. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The main secondary efficacy endpoint was major VTE; the composite of proximal DVT, non-fatal PE, and VTE-related death. Major and non-major bleeding during double-blind treatment were the primary and secondary safety endpoints, respectively. A total of 2509 patients were randomized; 2457 were included in the safety population and 1733 in the modified intention-to-treat (mITT) population. Extended thromboprophylaxis with rivaroxaban was associated with a significant reduction in the incidence of the primary efficacy endpoint and major VTE, compared with short-term thromboprophylaxis with enoxaparin (Table). The incidences of major and non-major bleeding were similar in both groups (Table). In conclusion, extended duration rivaroxaban was significantly more effective than short term enoxaparin for the prevention of VTE, including major VTE, in patients undergoing THA. Furthermore, this large trial demonstrated that extended thromboprophylaxis provides substantial benefits for patients undergoing THA, and that the oral, direct Factor Xa inhibitor rivaroxaban provides a safe and effective option for such a strategy.Short-term s.c. enoxaparin 40 mg od % (n/N)Extended oral rivaroxaban 10 mg od % (n/N)Relative risk reduction (%)P-value for differenceDVT, non-fatal PE, and all-cause mortalitya9.3% (81/869)2.0% (17/864)79%P<0.001Major VTEb5.1% (49/962)0.6% (6/961)88%P<0.001Major bleedingc0.1% (1/1229)0.1% (1/1228)-P=0.980Non-major bleedingc5.5% (67/1229)6.5% (80/1228)-P=0.246

Ximelagatran, the New Oral Anticoagulant: Would Warfarin Survive the Challenge?

The last decade witnessed major advances in the prevention and treatment of venous as well as of arterial thrombosis. Limitations of existing anticoagulants led to the development of novel therapeutic approaches. Ximelagatran is a new direct thrombin inhibitor (DTI) that is given orally, without the need for close monitoring. This compound was tried in the treatment of active venous thromboembolism, and the results were encouraging. Randomized trials suggest that ximelagatran is not inferior to warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Multiple controlled, prospective trials compared ximelagatran with low molecular weight heparin or warfarin in prevention of venous thromboembolism in patients undergoing major orthopedic procedures. The results of these clinical trials are reviewed in this article. Because of certain safety concerns (increased liver enzymes, potential hepatonecrosis, and increased coronary events) ximelagatran has not yet been approved by the FDA. Additional studies may be required to address these concerns. Ximelagatran has been approved, however, by the European regulatory authorities for short-term thromboprophylaxis. The success of ximelagatran or other oral antithrombin agents would provide significant proof of the concept for the long-term use of oral antithrombins in the prevention and treatment of both arterial and venous thrombosis.