Clinical Thromboembolic Events Research Articles

Anticoagulation for Atrial Fibrillation after Resolution of Dengue Haemorrhagic Fever.

Dear Sir, In a recent publication, Pahadiya et al., presented a young patient with atrial fibrillation (AF) during dengue haemorrhagic fever, suggesting the role of acute viral myocarditis [1]. In this interesting case report, the patient was admitted after five days of dengue symptoms. The cardiac arrhythmia was observed in the 3rd day of hospital admission and persisted until the 8th day, two days after the initiation of steroid therapy with dexamethasone. No specific antiarrhythmic therapy was prescribed. The patient was discharged on 12th day, clinically stable, afebrile and with normal haematological laboratory parameters. Unfortunately, despite of the excellent hospital upshot of this patient, the authors did not present his long-term follow-up neither they contemplated the anticoagulation therapy after hospital discharge, late after resolution of the acute phase. AF is associated with the occurrence of thromboembolic complications, mainly stroke, that are preventable with anticoagulation therapy. The risk of thromboembolism for patients undergoing cardioversion of AF may reach 5% [2]. Pooled data from 32 studies of cardioversion of AF or atrial flutter suggest that 98% of clinical thromboembolic events occur within 10 days after restoration of sinus rhythm [3]. Thus, current guidelines for the management of patients with AF [4] are emphatic in recommending oral anticoagulation for at least 4 weeks after conversion of an episode of 48 hours’ duration or longer, regardless of the CHA2DS2-VASc score for thromboembolism. During the acute phase of haemorragic dengue fever, there is no statement regarding the management of anticoagulation in patients with indication for this therapy, but it seems reasonable the avoidance of any antithrombotic drugs in these days. However, after a good resolution of the acute phase of the infection, those patients must be considered for anticoagulation if their arrhythmia had lasted for more than 48 hours. In our first report of the association of AF with haemorrhagic dengue fever, the patient had the sinus rhythm restored in 24 hours with amiodarone infusion [5]. He did not receive oral anticoagulation due to the short duration of AF. In the case of Pahadiya et al., the episode of atrial fibrillation lasted for 5 days [1]. The decision for anticoagulation in this patient is difficult. However, I do believe that this therapy should have been initiated. Finally, I would like to state that, in our first report of atrial fibrillation due to dengue haemorrhagic fever [5], we had not mentioned some role for steroid therapy, as it was referred in the discussion of Pahadiya et al., [1].

A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-AT3) Targeting Antithrombin for Treatment of Hemophilia: Interim Weekly and Monthly Dosing Results in Patients with Hemophilia A or B

Background: Hemophilia A and B are bleeding disorders characterized by a profound defect in thrombin generation (TG). Furthermore, in the presence of normal levels of endogenous anticoagulants a deficiency in factor VIII and IX results in major hemostatic imbalance and a bleeding phenotype. ALN-AT3 is a subcutaneously administered investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin (AT) that aims to restore the hemostatic balance by increasing TG.Methods: We are conducting a phase 1 multi-center study (NCT02035605) in healthy volunteers and patients with moderate to severe hemophilia A or B. Part A of this study has been completed and assessed a single ascending dose study in healthy volunteers. Parts B and C are multiple ascending dose studies in patients with hemophilia who are receiving weekly or monthly dosing, respectively. Primary endpoints are safety and tolerability. Secondary endpoints include PK, AT knockdown; change in thrombin generation and whole blood clot formation as measured by Calibrated Automated Thrombin generation and ROTEM thromboelastometry. Exploratory endpoints include evaluations of bleed pattern and control.Results: Part A enrolled 4 healthy volunteers, randomized (3:1) to 30 mcg/kg ALN-AT3 or placebo; no serious adverse events (SAE) or injection site reactions were observed. A total of 12 patients with severe hemophilia (10 hemohilia A; 2 hemophilia B) were enrolled in Part B and received 3 weekly subcutaneous doses of ALN-AT3 at 15 (n=3), 45 (n=6), and 75 (n=3) mcg/kg. Similar to part A, weekly administration of ALT-AT3 was generally safe and well tolerated in patients with hemophilia; no SAEs, discontinuations, clinical thromboembolic events or clinically significant D-dimer increases were reported. In the 75 mcg/kg dosing cohort, the mean maximum AT knockdown was 59% (p<0.05, relative to baseline), with nadir levels achieved between days 28 and 42. Maximum plasma AT knockdown of 86% was achieved, resulting in thrombin generation increases that correlated with AT knockdown and a bleed-free period of 114 days in the patient achieving the highest level of AT knockdown. The association between AT KD and TG was assessed in a post hoc exploratory analysis in which AT KD was categorized into tertiles. Part C aims to enroll several cohorts (n=3 per cohort) and will assess a monthly dosing schedule (x3 doses) of ALN-AT3. Patients in cohort 1 and 2 were dosed at 225 and 450 mcg/kg, respectively. Up to 4 additional cohorts may be enrolled within Part C. Updated safety, PK, AT knockdown, TG results as well as bleed patterns from Parts B and C will be presented.Conclusions: Emerging clinical data suggest that targeting AT could be a promising approach for restoring hemostatic balance in hemophilia. The potential for low volume subcutaneous administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make ALN-AT3 a potentially encouraging investigational therapy. DisclosuresPasi:Octapharma: Research Funding; Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria. Off Label Use: ALN-AT3 is an investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin.. Mant:Quintiles: Employment, Equity Ownership. Creagh:Bayer Healthcare UK: Honoraria. Austin:SOBI: Other: member of advisory board and received educational support; Pfizer: Other: member of advisory board and received educational support; Novo Nordisk: Other: member of advisory board and received educational support; CSL Behring: Other: member of advisory board and received educational support; Bio Products Laboratory: Other: member of advisory board and received educational support; Bayer: Other: member of advisory board and received educational support; Baxter: Other: member of advisory board and received educational support. Brand:Alnylam: Honoraria. Chowdary:Bayer: Consultancy; Biogen Idec: Consultancy; Baxter: Consultancy; CSL Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; SOBI: Consultancy. Ragni:Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Bristol Myers Squibb: Research Funding; Biogen: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dimension: Research Funding; Bayer: Research Funding; SPARK: Research Funding; Genentech Roche: Research Funding; Pfizer: Research Funding; Vascular Medicine Institute: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; CSL Behring: Research Funding. Chen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Rangarajan:Octapharma: Other: Investigator.

Abstract 12465: Dabigatran in Real World of Atrial Fibrillation: Systematic Review and Meta-analysis of Comparison Studies With Vitamin K Antagonists

Background: In the clinical trial RE-LY, dabigatran showed a better efficacy/safety profile in comparison with warfarin, but clinical trials are few representative of the real world. We aim to access if dabigatran in real-world patients with atrial fibrillation (AF) showed a better profile in comparison with warfarin, through a systematic review and meta-analysis of observational studies comparing with vitamin K antagonists. Methods: PubMed, Embase and Scopus databases were searched through December 2014. We include observational studies comparing dabigatran to warfarin for non-valvular AF that reported clinical events during a follow-up for dabigatran 75mg, 110 mg or 150 mg, and warfarin. We proceeded to the extraction and analysis of data for clinical thromboembolic events, bleeding and mortality. Data were pooled by meta-analysis using a random-effects model. Results: We selected 9 studies involving a total of 291,703 patients, 85,399 treated with dabigatran and the remaining 206,304 with warfarin. The incidence of stroke was 1.71 / 100 patient-years for dabigatran and 2.44 / 100 patient years for warfarin (relative risk [RR] 0.91, 95% CI 0.66 to 1.27, p=0.58). The major bleeding rate was 3.90 / 100 patient-years for dabigatran and 3.92 / 100 patient years for warfarin (RR 0.90; 0.78 to 1.03, p=0.11). The all-cause mortality (RR 0.81, 0.75-0.88, p&lt;0.001) and intracranial hemorrhage (RR 0.45, from 0.27 to 0.76, p=0.002) were significantly lower in patients treated with dabigatran in comparison to those treated with warfarin. There were no significant differences in risk of myocardial infarction (RR 0.55; 0.29 to 1.07, p=0.08), total hemorrhage (RR 1.00; 0.57 to 1.77, p=0.99), and gastro-intestinal bleeding (RR 1.14; 0.78 to 1.69, p=0.50). Conclusions: In this combined analysis of observational studies of real world, dabigatran compared to warfarin was associated with a similar risk of stroke, myocardial infarction, major bleeding, total bleeding and gastrointestinal bleeding, and a lower risk of intracranial hemorrhage and mortality.

A Case of Superior Mesenteric Artery Thrombosis Associated With Transient Elevation of Antiphospholipid Antibodies

Transient elevation of antiphospholipid antibody (APLA) is commonly observed in cases of viral infection; however, it is generally not associated with clinical thromboembolic events. In this report, we present a rare case of superior mesenteric artery (SMA) thrombosis associated with a transient elevation of APLA and discuss its relationship with fibromuscular dysplasia and adenomyosis of the uterus. Furthermore, we discuss the use of anticoagulant therapy in cases with transient elevation of APLA. In this case, a 46-year-old woman with no significant medical history was diagnosed with intestinal stenosis after SMA thrombosis that had been resolved with anticoagulant therapy. Laboratory examination showed elevated levels of anticardiolipin antibody. Resection of the stenosed ileum and hysterectomy for huge adenomyosis were performed. Anticardiolipin antibody level normalized 4 months after the operation. Anticoagulant therapy was withdrawn after anticardiolipin antibody normalized, and the patient has been free from thromboembolic events ever since. Transient elevation of APLA should be kept in mind in all patients with thromboembolic events, including those with no medical history of collagen diseases or infection. In the present case, association with fibromuscular dysplasia and adenomyosis of the uterus is suspected, but further investigation is required. Once the APLA level normalizes with the resolved thrombus, decision of withdrawing the anticoagulant therapy can be considered.

Effects of strontium ranelate on markers of cardiovascular risk in postmenopausal osteoporotic women.

Recent pooled analyses have shown that strontium ranelate increases the incidence of venous thromboembolism and non-fatal myocardial infarction, but no explanations were given. The aim of our study was to assess the effects a 12-month treatment with strontium ranelate on hemostasis factors and markers of cardiovascular risk in postmenopausal osteoporotic women. Forty osteoporotic postmenopausal women received orally strontium ranelate 2g daily, plus calcium and colecalcipherol for 12months. Forty postmenopausal osteopenic women matched for age, menopausal age, and body mass index served as controls and received orally calcium and colecalcipherol for 12months. Biochemical cardiovascular risk factors and hemostatic indices were assayed prior to treatment, and after 3, 6, and 12months of therapy. These indices included fibrinogen, fasting glucose, total serum cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, plasma levels of D-dimer, homocysteine, partial thromboplastin time, and prothrombin time. In addition, we evaluated possible changes in blood pressure and occurrence of venous thromboembolic events. At baseline, no statistically significance was observed between the two groups except for bone mineral density at lumbar spine, femoral neck, and total femur, which was lower in strontium ranelate group. After 12months of treatment, there was no statistically significant change in cardiovascular risk factors and hemostatic parameters. None of the 40 women developed any clinical venous thromboembolic event. A 12-month treatment with strontium ranelate did not alter hemostasis factors or markers of cardiovascular risk, suggesting that reported increased risk of venous thromboembolism and myocardial infarction with strontium is mediated by other factors.

Early detection of atrial high rate episodes predicts atrial fibrillation and thromboembolic events in patients with cardiac resynchronization therapy

In patients without any history of atrial fibrillation (AF), detection of subclinical atrial high rate episodes (AHRE) by implanted devices has been associated with an increased thromboembolic risk. The predictive value of AHREs in patients with cardiac resynchronization therapy (CRT) is uncertain. We aimed to investigate the prognostic value of early detected AHRE in patients with CRT. This observational study included patients who received CRT and no history of AF. Patients had standard indication for CRT treatment. They were screened for early detected AHREs longer than 6 minutes occurring before 6-month follow-up, and the longest duration of AHREs was recorded. Information on clinical AF and thromboembolic events was obtained from the Danish National Patient Registry. The Cox regression model was used to compute hazard ratios (HRs) with 95% confidence intervals (CIs). Of 394 eligible patients, 79 patients (20%) had early AHRE detected. During a median follow-up of 4.6 years, patients with early detected AHREs had an increased risk of clinical AF (HR 2.35; 95% CI 1.47-3.74; P < .001) and thromboembolic events (HR 2.30; 95% CI 1.09-4.83; P = .028). For patients with AHREs longer than 24 hours, these associations were stronger. The risk of mortality was not higher with early detected AHREs (HR 0.97; 95% CI 0.64-1.45; P = .87). Of the 27 patients with thromboembolic events, only 10 patients (37%) had AHREs detected within a 2-month period before the thromboembolic event. In patients without any history of AF, detection of early AHREs after CRT implantation is associated with a significantly increased risk of clinical AF and thromboembolic events, particularly AHRE longer than 24 hours.

Feasibility and safety of uninterrupted periprocedural apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: Results from a multicenter study.

Periprocedural anticoagulation management with uninterrupted warfarin and a "therapeutic" international normalized ratio is the best approach for reducing both thromboembolic and bleeding complications in the setting of catheter ablation for atrial fibrillation (AF). The purpose of this study was to evaluate the safety and feasibility of uninterrupted apixaban in this setting. This was a prospective multicenter registry of AF patients undergoing radiofrequency catheter ablation at 4 institutions in United States and Europe with uninterrupted apixaban. These patients were compared with an equal number of patients, matched for age, gender, and type of AF, undergoing AF ablation on uninterrupted warfarin.The apixaban group was comprised of consecutive patients who had taken their last dose of apixaban the morning of the procedure. A subset of 29 patients in the apixaban group underwent diffusion magnetic resonance imaging (dMRI) to detect silent cerebral ischemia. A total of 400 patients (200 patients in each group) were included in the study. The average age was 65.9 ± 9.9 years, 286 (71.5%) were male, and 334 (83.5%) had nonparoxysmal AF. There were no statistical differences with regard to major complications (1% vs 0.5%, P = 1), minor complications (3.5% vs 2.5%, P = .56), or total bleeding complications (4.5% vs 3%, P = .43) between the apixaban and warfarin groups. There were no symptomatic thromboembolic complications. All dMRIs were negative for "new" silent cerebral ischemia in the apixaban group. Uninterrupted apixaban administration in patients undergoing AF ablation seems to be feasibleand effective in preventing clinical and silent thromboembolic events without increasing the risk of major bleeding.

The Clinical Significance and Risk Factors of Anti-Platelet Factor 4/heparin Antibody on Maintenance Hemodialysis Patients: A Two-Year Prospective Follow-up

BackgroundHeparin-induced thrombocytopenia is an immune response mediated by anti-PF4/heparin antibody, which is clinically characterized by thrombocytopenia and thromboembolic events. In this study, a prospective and multi-center clinical investigation determined the positive rate of anti-PF4/heparin antibody in maintenance hemodialysis patients in China, identified the related risk factors, and further explored the effect of the anti-PF4/heparin antibody on bleeding, thromboembolic events, and risk of death in the patients.MethodsThe serum anti-PF4/heparin antibody was measured in 661 patients from nine hemodialysis centers, detected by IgG-specific ELISA and followed by confirmation with excess heparin. Risk factors of these patients were analyzed. Based on a two-year follow-up, the association between the anti-PF4/heparin antibody and bleeding, thromboembolic events, and risk of death in the patients was investigated.Results The positivity rate of the anti-PF4/heparin antibody in maintenance hemodialysis patients was 5.6%. With diabetes as an independent risk factor, the positivity rate of the anti-PF4/heparin antibody decreased in the patients undergoing weekly dialyses ≥3 times. The positivity rate of the anti-PF4/heparin antibody was not related to the occurrence of clinical thromboembolic events and was not a risk factor for death within two years in maintenance hemodialysis patients. Negativity for the anti-PF4/heparin antibody combined with a reduction of the platelet count or combined with the administration of antiplatelet drugs yielded a significant increase in bleeding events. However, the composite determination of the anti-PF4/heparin antibody and thrombocytopenia, as well as the administration of antiplatelet drugs, was not predictive for the risk of thromboembolic events in the maintenance hemodialysis patients.ConclusionsA single detection of the anti-PF4/heparin antibody did not predict the occurrence of clinical bleeding, thromboembolic events, or risk of death in the maintenance hemodialysis patients.

Recombinant Activated Factor VII Use in Critically III Patients: Clinical Outcomes and Thromboembolic Events

Hemorrhage and coagulopathy are associated with morbidity and mortality in critically ill patients. Recombinant activated factor VII (rFVIIa) is frequently used in these situations to control bleeding; however, few controlled clinical trials have demonstrated clinical benefit and prolonged survival. To compare clinical outcomes and thromboembolic events in intensive care unit (ICU) patients who received rFVIIa versus ICU patients who did not between 2000 and 2005. A total of 2918 nonhemophiliac adult ICU patients, which included 1459 who received at least 1 dose of rFVIIa and 1459 matched controls who did not, were included in a retrospective database study. Data were extracted from the Solucient ACTracker database, which included 550 hospitals across the US. Measures included patient demographics, rFVIIa prescribing, death, thromboembolic events, discharge disposition, length of stay, and transfusion data. The most common primary diagnoses for patients receiving rFVIIa included traumatic brain injury, cirrhosis, and nontraumatic intracranial hemorrhage. Patients receiving rFVIIa were more likely to have comorbidities, including mechanical ventilation, acute kidney injury, sepsis, hemodialysis, and gastrointestinal bleeding (p < 0.0001). The average rFVIIa dose was 4.8 mg and 82% of patients received 1 dose. Compared to controls, patients receiving rFVIIa had greater odds of death (OR 2.1, 95% CI 1.8-2.6, p < 0.0001), transfusion (OR 2.1, 95% CI 1.8-2.5, p < 0.0001), and longer length of stay (p < 0.001). There was no significant difference in thromboembolic events between groups. While we cannot show direct causality between rFVIIa and the poor clinical outcomes documented in ICU patients, they provide important insight for critical care clinicians.

Paciente com cardiopatia chagásica crônica, esquistossomose hepatoesplênica e síndrome da imunodeficiência adquirida: possível resolução espontânea de trombo no ventrículo direito

The presence of right-sided cardiac thrombi seems to increase the risk of death due to thromboembolic events. There is a discrepancy, however, between the prevalence of cardiac thrombus and clinical thromboembolic events. Besides, the individual characteristics associated with a high risk of mortality have not been established. We present here a case report of a patient with mansonic schistosomiasis and acquired immunodeficiency syndrome and chronic Chagas disease, who presents with a large thrombus in the right ventricle. The patient had uneventful evolution without any thromboembolic complications with resolution of right-ventricle thrombus.

Three-hour interval drain clamping reduces postoperative bleeding in total knee arthroplasty: a prospective randomized controlled trial

Total knee arthroplasty (TKA) is a common procedure that has a risk of significant blood loss and blood transfusion, and carries a substantial risk for immunologic reactions and disease transmission. Drain clamping is a popular method that is applied to reduce blood loss after TKA. However, the clamping protocol remains controversial. Therefore, we established a new protocol, 3-h interval clamping, and compared the bleeding control efficacy of this protocol following TKA with the non-clamping technique. Between March and July 2008, we enrolled 100 patients (100 knees) who underwent uncomplicated TKA using a minimally invasive surgical technique. The patients were randomly assigned into two groups based on the draining protocol: non-clamping (group A) and 3-h interval clamping (group B). For group A, a vacuum drain was connected to a container and was run continuously during the first postoperative day, whereas the vacuum was stopped twice (for ~3h each time) for group B. Demographic characteristics and clinical data were collected, including the levels of hemoglobin and hematocrit, the total blood loss volume, the number of patients who required a blood transfusion, and any complications that developed. The perioperative data were compared between the two groups. The drainage blood volume in the interval-clamping group (group B) was significantly lower than that in the non-clamping group (group A) during the first 48h following the procedure (p<0.001 and p=0.005 for first and second postoperative days, respectively). The mean fall in hemoglobin levels at 12h in the interval-clamping group (2.8±0.9g/dL) was also lower than in the non-clamping group (3.2±0.8g/dL). In the 3-h interval clamping protocol, the number of patients requiring a transfusion was 2.2 times less than the number in the non-clamping protocol, but was not significantly different (odds ratio=2.20, p=0.24), and the significant predictor of blood transfusion was the preoperative hemoglobin level (odds ratio=7.73, p<0.001). No wound infection or clinical venous thromboembolisms were detected in our study. The 3-h interval clamping is a newly developed protocol for reducing blood loss after TKA. The protocol lessens the decrease in postoperative hemoglobin levels. This protocol can be applied easily without increasing clinical thromboembolic events and wound complications.

Complications After Robotic Partial Nephrectomy at Centers of Excellence: Multi-Institutional Analysis of 450 Cases

We evaluated the incidence of perioperative complications after robotic partial nephrectomy. We retrospectively reviewed the records of patients treated with robotic assisted partial nephrectomy across the 4 participating institutions. Demographic, blood loss, warm ischemia time, and intraoperative and postoperative complication data were collected. All complications were graded according to the Clavien classification system. A total of 450 consecutive robotic assisted partial nephrectomies were done between June 2006 and May 2009. Overall 71 patients (15.8%) had a complication, including intraoperative and postoperative complications in 8 (1.8%) and 65 (14.4%), respectively. Hemorrhage developed in 2 patients (0.2%) intraoperatively and in 22 (4.9%) postoperatively. Seven patients (1.6%) had urine leakage. As classified by the Clavien system, complications were grade I-II in 76.1% of cases and grade III-IV in 23.9%. Robotic assisted partial nephrectomy was converted to open or conventional laparoscopic surgery in 3 patients (0.7%) and to radical nephrectomy in 7 (1.6%). There were no deaths. Current data indicate that robotic assisted partial nephrectomy is safe. Most postoperative complications are Clavien grade I or II, or can be managed conservatively.

Use of Ventricular Assist Devices in Patients with Mitral Valve Prostheses

Use of ventricular assist devices (VADs) in patients with prosthetic valves may carry an increased risk of thromboembolism; however, clinical information is lacking. The aim of this study was to report our experience of the use of VADs in patients with prosthetic mitral valves. A retrospective analysis of 747 VAD patients from January 1995 to May 2010 was performed. Thirteen patients with a prosthetic mitral valve (average age 56 ± 10 years of age, nine mechanical valve, four biological valve) were identified. Indications for VAD implantation were as a bridge to transplant in 11 patients and destination therapy in two patients. At the time of VAD implant, no intervention to the prosthetic mitral valve was performed. Eight patients received a HeartMate I (Thoratec Corporation, Pleasanton, CA, USA), three patients received a HeartMate II (Thoratec Corporation), and two patients received a Thoratec VAD (Thoratec Corporation). Among nine mechanical valve patients, six patients were anticoagulated with warfarin, and one patient with heparin, while two patients did not receive anticoagulation due to bleeding. Ten patients were successfully transplanted at an average of 123 days post-VAD implant, one died after 48 days from multiorgan failure, and two remained on VAD support. No clinical thromboembolic events were observed. No intracardiac thrombus was detected by echocardiogram or on the pathology of the explanted hearts. Five patients had experienced a bleeding event (postoperative mediastinal bleeds, gastrointestinal bleedings, retroperitoneal hematoma, and subconjuctival bleeding). In patients with mitral valve prostheses who require VAD support, leaving the prosthesis intact does not increase the incidence of adverse events.

Aortic Valve Procedures at the Time of Ventricular Assist Device Placement

Placement of a ventricular assist device (VAD) may lead to reduced or absent opening of the aortic valve and thus increase risk of thrombus formation in the aortic root as well as on the valve itself. The outcome of additional procedures to the aortic valve at the time of VAD placement is unclear. A retrospective analysis of 712 VAD patients from 1995 to 2009 was performed. Twenty-eight patients were identified who underwent aortic valve procedures in addition to VAD placement. Indication for VAD placement was bridge to transplant in 23 patients, destination therapy in 4, and postcardiotomy shock in 1. Aortic valve procedures were performed for preexisting mechanical aortic prosthesis in 8 (7 closure and 1 aortic valve replacement with biological prosthesis), and for moderate or severe aortic insufficiency in 20 patients (10 repair, 9 closure, and 1 aortic valve replacement with biological prosthesis). At the last follow-up, 16 patients had undergone heart transplant, 6 remained on VAD support, and 5 had died. While on VAD support, no adverse events related to the aortic valve procedures occurred. The 30-day operative mortality was 0.4%. No clinical thromboembolic events were observed. In 2 patients, there was evidence of thrombus formation in the explanted heart. Four patients had bleeding complications. Of the 9 patients who received aortic valve repair, 2 had recurrent aortic insufficiency on echocardiograms during an average follow-up of 118 days. Additional procedures to the aortic valve at the time of VAD placement are feasible. Overall outcomes are comparable to those seen in patients without the need for aortic valve manipulation at the time of VAD placement.

Hemorheological changes with strontium ranelate treatment do not seem to be related to its claimed prothrombotic effects

Strontium ranelate is claimed to be related with increased risk of thromboembolic events. No explanation of this increased incidence of thromboembolism has been identified. However, growing evidence has clearly demonstrated the involvement of blood rheology in any thrombotic process. The aim of this study was to assess hemorheological changes with strontium ranelate treatment in elderly women with osteoporosis. This study was designed in a prospective manner. Twenty-two elderly women diagnosed with osteoporosis were included. During a 2-month treatment period, participants received strontium ranelate 2 g/day. Hemorheological parameters including erythrocyte deformability, erythrocyte aggregation and plasma viscosity were measured before and after 2 months therapy with strontium ranelate. The median age of the patients was 70.0 (range = 65–80) years. After 60 days of treatment, there was no statistically significant change in hemorheological parameters. None of the subjects developed clinical venous thromboembolic event (VTE) during the 2-month period of strontium ranelate treatment. Our study demonstrated that in elderly women, treatment of osteoporosis with strontium ranelate did not change hemorheological parameters over 2 months of time. However, its long-term effects on hemorheologic parameters should be evaluated further with a larger sample.

Recombinant Factor XIII, Safe and Novel Treatment for Congenital Factor XIII Deficiency

AbstractAbstract 20Congenital Factor XIII (FXIII) deficiency is a rare autosomal recessive disorder affecting approximately 1 in 2–5 million individuals without gender or ethnic predilection. The plasma form of FXIII is a heterotetramer [A2B2] comprising two FXIII-A subunits and two FXIII-B subunits. A-subunit deficiency predominates (95%). FXIII deficient patients have a high risk of life-threatening bleeds, notably spontaneous intracranial haemorrhage. They experience impaired wound healing, and recurrent first trimester spontaneous abortions. Given the severity of the disorder there is a clinical need for providing effective haemostatic replacement therapy. Currently, only plasma derived products are approved for use in the United States. These may carry a risk of blood borne infection, sensitization and allergic reactions.A multi-center, multi-national, open-label, single-arm, multiple dosing phase 3 (prophylaxis) trial was undertaken to evaluate the efficacy and safety of a novel recombinant FXIII (rFXIII) in the prevention of bleeds in congenital FXIII-A subunit deficiency. This rFXIII-A2 dimer is expressed in Saccharomyces Cerevisiae and is an exact copy of the human A-subunit, which is the active cross-linking enzyme. When rFXIII is administered, it immediately binds to the B subunit that is present in the bloodstream. Forty-one patients aged ≥7 years [mean: 26.4 (range: 7–60); 23 males; 18 females] with a diagnosis of severe congenital FXIII-A subunit deficiency were enrolled. Patients entered a 4-week run-in period followed by monthly treatment with 35 IU/kg of rFXIII for 52 weeks. Informed consent was obtained prior to any trial-related activities. Bleeding episodes and adverse events were recorded. Testing was conducted monthly to measure pre- and post-dose FXIII activity and concentration, 5M urea clot solubility and anti-FXIII antibodies. Where antibodies were found, detailed testing for neutralizing potential was performed. Data were compared with bleeding rates based on historical data.During the treatment period with rFXIII (466 patient months) five bleeding episodes treated with FXIII-containing products were observed in four patients. All five were associated with trauma. No spontaneous bleeds that require treatment or intracranial haemorrhage occurred during rFXIII treatment period in any of the patients. The annual rate of bleeds requiring treatment was estimated via a Poisson model to be 0.048 bleeds/patient/year (95% CI: [0.0094; 0.2501] - significantly lower than the historic bleeding rate of 2.91 (p<0.0001). The crude mean rate of bleeding was 0.138 bleeds/patient/year. The occurrence of bleeds requiring treatment was not associated with low FXIII activity levels in study patients. The average FXIII activity at 1 hr post-dose was 77.0 ± 20.3% (mean±SD). The mean incremental increase in activity from pre-dose to 1 hr post-dose was 1.68 ± 0.51% /IU/ kg. Four patients developed transient, non-neutralizing, low-titer anti-rFXIII antibodies. None of these patients developed anaphylactic or allergic reactions, bleeding episodes or changes in FXIII pharmacokinetics at any time. Furthermore, the non-neutralizing antibodies declined below the limit of detection in all patients despite repeated exposure to rFXIII or other FXIII containing products. Consequently, these low titer, non-neutralizing antibodies appear to be clinically insignificant. No clinical safety issues, thromboembolic events, or fatal adverse events were recorded. In conclusion, rFXIII-A2 is safe and effective prophylaxis for preventing bleeding episodes in patients with congenital FXIII-A subunit deficiency. Disclosures:Inbal:NovoNordisk: Honoraria, Research Funding. Oldenburg:novonordisk: Research Funding. Carcao:NovoNordisk: Research Funding. Rosholm:NovoNordisk: Employment. Tehranchi:NovoNordisk: Employment. Nugent:NovoNordisk: Consultancy, Research Funding.

Increased levels of homocysteine in patients with ulcerative colitis

To investigate serum levels of homocysteine (Hcys) and the risk that altered levels carry for thrombosis development in ulcerative colitis (UC) patients. 55 UC patients and 45 healthy adults were included. Hcys, vitamin B12 and folic acid levels were measured in both groups. Clinical history and thromboembolic events were investigated. The average Hcys level in the UC patients was 13.3 +/- 1.93 micromol/L (range 4.60-87) and was higher than the average Hcys level of the control group which was 11.2 +/- 3.58 micromol/L (range 4.00-20.8) (P < 0.001). Vitamin B12 and folic acid average values were also lower in the UC group (P < 0.001). When multivariate regression analysis was performed, it was seen that folic acid deficiency was the only risk factor for hyperhomocysteinemia. Frequencies of thromboembolic complications were not statistically significantly different in UC and control groups. When those with and without a thrombosis history in the UC group were compared according to Hcys levels, it was seen that there were no statistically significant differences. A negative linear relationship was found between folic acid levels and Hcys. We could not find any correlations between Hcys levels and history of prior thromboembolic events.

Prospective, observational study of antiplatelet and coagulation biomarkers as predictors of thromboembolic events after implantation of ventricular assist devices

Long-term success in ventricular assist device (VAD) recipients is limited by thromboembolic events, the prediction of which remains elusive. We evaluated the predictive value of aspirin hyporesponsiveness and markers of coagulation and fibrinolysis. We prospectively enrolled patients scheduled to undergo VAD implantation between June 2004 and March 2006. Once before surgery, daily during hospitalization, and weekly after discharge we assessed platelet function, measured prothrombin activation fragment 1.2 (F1.2) and plasminogen activator inhibitor-1 (PAI-1) concentrations, and evaluated aspirin hyporesponsiveness by whole-blood aggregometry and thromboelastography. All patients received 325 mg oral aspirin daily from at least 7 days before VAD implantation. Follow-up continued until heart transplantation, death or closure of the database. We included 26 patients (median follow-up 315 days, range 9-833 days). In eight (31%) patients, 14 thromboembolic events occurred at a median of 42 (interquartile range 26-131) days. Only six (43%) events based on whole-blood aggregometry and one (7%) based on thromboelastography coincided with aspirin hyporesponsiveness. Within-patient variability was high for both tests (59% and 567%, respectively). Compared with levels before surgery, PAI-1 concentrations were raised for up to 45 days (P <0.0001) and those of F1.2 for up to 3 days (P = 0.0001) after VAD implantation. PAI-1 and F1.2 levels did not rise significantly further before thromboembolic events. Aspirin hyporesponsiveness was not associated with raised risk of future clinical thromboembolic events after VAD implantation. Impaired fibrinolysis, demonstrated by raised PAI-1 concentrations, might, however, indicate a predisposition to such events early after surgery.

Low thromboembolic risk for patients with the Heartmate II left ventricular assist device

Thromboembolic events can occur in up to 20% of patients with a left ventricular assist device. The aggressive use of anticoagulation with newer continuous-flow devices has potentially increased the risk of postoperative bleeding. The predecessor of the HeartMate II left ventricular assist device, the HeartMate XVE (Thoratec Corp, Pleasanton, Calif), was associated with an extremely low thromboembolic risk, even without anticoagulation, because of its unique textured surfaces. Even though several areas of the HeartMate II are textured, a protocol was adopted for this new axial flow pump requiring long-term anticoagulation with warfarin. In our study, we investigated whether the HeartMate II left ventricular assist device is associated with a similarly low thromboembolic risk as the HeartMate XVE. At our institution, 45 patients (mean age, 57.24 +/- 14.2 years) underwent implantation of the HeartMate II; 30 underwent bridge-to-transplantation therapy, 7 underwent destination therapy, and 8 underwent left ventricular assist device exchange for a failed XVE left ventricular assist device. Total duration of HeartMate II support was 352.13 patient-months (mean duration, 7.2 +/- 5.2 months). All 45 patients were treated postoperatively with warfarin and aspirin. We recorded use of these 2 medications and monthly international normalized ratios. Prospectively, we also monitored patients for any clinical thromboembolic events and for pump thrombus. Of our 45 study patients, 41 had a mean international normalized ratio of less than 2.0; of those 41 patients, 21 had a mean international normalized ratio of less than 1.6. Because of recurrent gastrointestinal bleeding episodes, 7 patients discontinued warfarin for a total duration of 39.1 patient-months. During the entire period of HeartMate II support, we noted 1 thromboembolic event. In addition, another patient had a suspected left ventricular assist device pump thrombus that resolved with a high-intensity heparin anticoagulation protocol (international normalized ratio, 1.3). Our preliminary single-center analysis suggests that the HeartMate II is associated with an extremely low thromboembolic risk and with less stringent requirements for anticoagulation. Selected patients at high risk for bleeding can be safely followed with either no or extremely low anticoagulation requirements for prolonged periods.

Prospective Study of Warfarin Dosage Requirements Based on CYP2C9 and VKORC1 Genotypes

Polymorphisms in CYP2C9 and VKORC1 have been shown to be associated with warfarin dose requirements and could be used to predict warfarin dose. We conducted a prospective study in which warfarin dose was prescribed based on CYP2C9 and VKORC1 polymorphisms in 108 Han-Chinese patients without prior warfarin treatments. Using the genotype-based dosing, 83% of patients reached stable, therapeutic international normalized ratio (INR) within 2 weeks of treatment initiation and none of the patients developed clinical bleeding or thromboembolic event. Ten percent (11) of patients with INR > 4 and no clinical bleeding were detected during this study. At 12 weeks, 69% of the patients' maintenance doses matched the prediction. Dosing algorithms incorporating genetic factors, age, and body surface area were developed, which could explain up to 62% of the total variation (R(2) of 0.62). This study demonstrated that pharmacogenetics-based dosing could improve time to stable, therapeutic INR, reduce adverse events, and achieve high sensitivity.