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Background Thromboprophylaxis is recommended for patients undergoing total hip or total knee replacement (THR, TKR). An international, open-label, prospective, observational, single-arm study in a routine clinical setting was performed to assess the safety and efficacy of dabigatran etexilate 220 mg once daily in patients undergoing THR or TKR, and in subgroups of patients with potentially increased risk of bleeding or venous thromboembolism (VTE). Materials and methods Patients were ≥18 years and required to be eligible to receive dabigatran 220 mg once daily (first dose 110 mg 1–4 h after THR/TKR surgery) according to the European Summary of Product Characteristics. The primary safety and efficacy outcomes were incidence of major bleeding events (MBEs), and the composite incidence of symptomatic VTE events and all-cause mortality, respectively. Results In total, 5292 patients (median age 64 years) were enrolled and received dabigatran (2734 THR and 2558 TKR). Median drug exposure was 31 days (THR 34 days; TKR 27 days). Overall incidence of MBEs was 0.72 % (95 % confidence interval [CI] 0.51, 0.98), and this rate was comparable between types of surgery and was not significantly affected by protocol-defined risk factors. The overall incidence of symptomatic VTE and all-cause mortality was 1.04 % (95 % CI 0.78, 1.35); the only significant risk factor was history of VTE events (odds ratio 5.59; 95 % CI 2.53, 11.08). A post-hoc analysis showed that the incidence of MBEs in this observational study was similar to or lower than those reported in previous phase 3 trials. Conclusions Results from this observational study of dabigatran etexilate administered to patients undergoing THR or TKR surgery are reassuring and supportive of those obtained in dabigatran phase 3 trials. Trial registration ClinicalTrials.gov identifier: NCT00846807. Electronic supplementary material The online version of this article (doi:10.1186/s12959-016-0082-4) contains supplementary material, which is available to authorized users.

Background Cancer patients are at increased risk for venous thromboembolism (VTE). Objective This monocenter cross-sectional study prospectively assessed the association between a history of ≥1 VTE episode and the presence of pulmonary hypertension (PH) among cancer patients presenting with pulmonary or cardiac symptoms. Methods A consecutive series of 583 patients underwent a diagnostic work-up for heart and lung disease. PH was diagnosed if a patient’s peak systolic pressure gradient across the tricuspid valve was ≥35 mmHg, as measured by echocardiography. Using multiple logistic regression analysis, the association between VTE and PH was assessed, following adjustments for age, the presence of severe airway obstruction, atrial fibrillation and left heart diseases. Results The prevalence values for PH (n = 90) and a history of VTE (n = 72) were 15.4 and 12.3 %, respectively. The median time interval between the first VTE episode and referral was 43 months. The odds of PH was higher in the subgroup with VTE (19/72; 26.4 %) than that without VTE (71/511; 13.9 %) in the unadjusted analysis [odds ratio (OR) 2.2, 95 % confidence interval (CI) 1.2, 4.0] and the adjusted model [OR 2.4, 95 % CI 1.2, 4.5]. The risk of PH did not depend on the time interval between VTE and referral. Older age and the presence of severe airway obstruction, atrial fibrillation, and left heart diseases were also associated with an increased odds of PH. Conclusion In cancer patients presenting with cardiac or pulmonary symptoms, previous VTE is associated with an increased risk of persistent PH.

Deep vein thrombosis (DVT) and pulmonary emboli (PE), known together as venous thromboembolic (VTE) disease remain major complications following elective hip and knee surgery. This study compares three chemoprophylactic regimens for VTE following elective primary unilateral hip or knee replacement, one of which was designed to minimize risk of post-operative bleeding. Patients were randomized and stratified for hip vs. knee to receive A: variable dose warfarin (first dose on the night preceding surgery with subsequent target INR 2.0–2.5), B: 2.5 mg fondaparinux daily starting 6–18 h postoperatively, or C: fixed 1.0 mg dose warfarin daily starting 7 days preoperatively. All treatments continued until bilateral leg venous ultrasound day 28 ± 2 or earlier upon a VTE event. The study examined primary endpoints including leg DVT, PE or death due to VTE and secondary endpoints including effects on D-dimer, estimated blood loss (EBL) at surgery and hemorrhagic complications. Three hundred fifty-five patients were randomized. None was lost to follow-up. Taking 1.0 mg warfarin for seven days preoperatively did not prolong the prothrombin time (PT). Two patients in Arm C had asymptomatic distal DVT. One major bleed occurred in Arm B and one in Arm C (ischemic colitis). Elevated d-dimer did not predict delayed VTE for one year. Fixed low dose warfarin started preoperatively is equivalent to two other standards of care under study (95 % CI: -0.0428, 0.0067 for both) as VTE prophylaxis for the patients having elective major joint replacement surgery. ClinicalTrials.gov identifier # NCT00767559 FDA IND: 103,716

Aims Although quantitative anti-FXa assays can be used to measure rivaroxaban plasma levels, they are not widely performed or available. We aimed to tentatively determine the cut-off for thromboembolism and bleeding prevention based on the clotting effect of non-rivaroxaban conjugate-activated FX plasma levels in patients with rivaroxaban using a coagulometric method. Methods and results Rivaroxaban was added in vitro to normal plasma at a range of 0 to 241 μg/L to cover expected peak and trough levels. Rivaroxaban chromogenic (μg/L) and RVV-confirm as a ratio were determined. Patient plasma samples were assayed with the RVV-confirm reagent. The appropriate rivaroxaban plasma concentration to inhibit clotting mechanisms was based on the remaining FXa in plasma, which was expressed as the ratio of patients/normal, R-C. There is a high correlation between R-C in vitro and spiked normal plasma rivaroxaban concentration (R-Square 0.910, linear equation; 0.971 quadratic equation, p

Background The introduction of central venous catheters has advanced medical care, particularly in hemato-oncology. However these can be associated with an increased thrombotic risk. Previous studies have compared the rate of thrombotic events between peripherally- inserted (PICCs) and long term skin tunneled catheters (LTSTCs) noting fewer complications associated with the latter, though this has rarely translated into clinical practice. The objectives of our study was to compare the cumulative incidence of thrombotic events between peripherally-inserted and long term skin tunneled venous catheters. Patients/methods We performed a retrospective, single center cohort analysis of patients with hematological malignancies who had either a PICC or LTSTC line inserted between January 2010 through January 2013. Cumulative incidences of thrombotic events were compared between the two groups, and post-thrombotic complications were also examined. Results 346 patients had a PICC inserted with cumulative incidence of symptomatic thrombosis of 5.8%, while 237 patients had a LTSTC inserted with a cumulative incidence of 1.7% (p = 0.003). Post-thrombotic complication rates, particularly infection, were higher in the PICC group compared to the LTSTC group (p = 0.597). Conclusions Our study showed that the incidence of thrombotic events in hemato-oncology patients was significantly lower in those who had a LTSTC compared to PICC line. As the use of central venous lines increases in hemato-oncology patient care, a randomized trial comparing PICCs and LTSTCs is necessary to address which venous access is most appropriate in this cohort of patients, with minimal risk of morbidity and mortality.

BACKGROUND: Dabigatran is an alternative to warfarin (WF) for the thromboprophylaxis of stroke in patients with non-valvular atrial fibrillation (NVAF). The advantage of dabigatran over WF is that monitoring is not required; however, a method to monitor the effect and the safety of dabigatran is not currently available. The Global Thrombosis Test (GTT) is a novel method to assess both clot formation and lysis activities under physiological conditions. OBJECTIVE: The aim of this study was to evaluate whether treatment with dabigatran might affect shear-induced thrombi (occlusion time [OT], sec) by the GTT, and to investigate the possibility that the GTT could be useful as a monitoring system for dabigatran. PATIENTS/METHODS: The study population consisted of 50 volunteers and 43 NVAF patients on WF therapy, who were subsequently switched to dabigatran. Using the GTT, the thrombotic status was assessed one day before and 1 month after switching anticoagulation from WF to dabigatran. RESULTS: The OT was 524.9 ± 17.0 sec in volunteers whereas that of NVAF patients on WF therapy was 581.7 ± 26.3 sec. The switch from WF to dabigatran significantly prolonged OT (784.5 ± 19.3 sec). One patient on WF therapy and 12 patients on dabigatran therapy were shown to have OT > 900 sec. CONCLUSION: The GTT could be used to assess the risk of dabigatran-related bleeding complications.

Introduction Platelet activation, thrombin generation and fibrin formation play important roles in intracoronary thrombus formation, which may lead to acute myocardial infarction. We investigated whether the prothrombotic markers D-dimer, pro-thrombin fragment 1 + 2 (F1 + 2) and endogenous thrombin potential (ETP) are associated with myocardial necrosis assessed by Troponin T (TnT), and left ventricular impairment assessed by left ventricular ejection fraction (LVEF) and N-terminal pro b-type natriuretic peptide (NT-proBNP). Materials/Methods Patients (n = 987) with ST-elevation mycardial infarction (STEMI) were included. Blood samples were drawn at a median time of 24 h after onset of symptoms. Results Statistically significant correlations were found between both peak TnT and D-dimer (p

Background: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. Methods/design: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. Results: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. Conclusion: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. Trial registration: Registered in DRKS register, ID number: DRKS00004795

Background Current clinical practice guidelines recommend the use of prophylactic doses of low molecular weight heparins for cancer patients requiring hospitalization for acute medical illness. However, a recently published meta-analysis suggested that the risk-benefit ratio of current thromboprophylaxis regimens administered to all cancer patients admitted for medical illness is unclear. We sought to assess the clinical equipoise in using thromboprophylaxis for hospitalized medically ill cancer patients. Methods An electronic survey was conducted. The target sample included Thrombosis experts and members of Thrombosis Canada or the VECTOR research group. Results The survey was distributed 54 participants. The final response rate was 67% (36/54). The majority (75%; 95% CI: 60.3 to 85%) of responders indicated that the benefits of pharmacological parenteral thromboprophylaxis outweigh the risks. However, 63.9% (95% CI: 50.6 to 77.3%) believe that there is still clinical equipoise around the use of thromboprophylaxis in this patient population, and 88.9% (95% CI: 77.3 to 95.8%) would consider participating in a randomized trial—30.6% and 58.3% in a placebo-controlled or comparison of different agents/dosing-controlled randomized trial, respectively. For participants who would consider a randomized-controlled trial comparing different doses of thromboprophylaxis agents, the MCID was 2% between the two arms. The most common drug to be compared was enoxaparin (26%), and the two suggested doses were 30 mg and 40 mg SC twice daily. Conclusions Our clinical survey of thrombosis experts confirms that there is equipoise regarding the use of current regimens of parenteral pharmacological thromboprophylaxis in medically ill cancer patients. A majority of physicians would participate in a randomized-controlled trial comparing different dose of LMWH. The MCID in the risk of VTE identified was 2%.

Introduction: Venous thromboembolism (VTE) requires urgent diagnosis and treatment to avoid related complications. Clinical presentations of VTE are nonspecific and require definitive confirmation by imaging techniques. A clinical pretest probability (PTP) score system helps predict VTE and reduces the need for costly imaging studies. D-dimer (DD) assay has been used to screen patients for VTE and has shown to be specific for VTE. The combined use of PTP and DD assay may improve exclusion of VTE and safely avoid imaging studies. Materials and methods: We prospectively used the Wells PTP score and a DD test to evaluate 230 consecutive patients who presented with VTE symptoms. The receiver operating characteristic curve was used to identify a new DD cutoff value, which was applied to VTE diagnosis and compared with the upper limit of locally established reference range for prediction of thrombosis alone and in combination with the clinical PTP score. Results: We evaluated 118 patients with VTE symptoms fulfilling the inclusion criteria, 64 (54.2%) with clinically suspected deep vein thrombosis (DVT) and 54 (45.8%) with symptoms of pulmonary embolism (PE). The PTP was low in 28 (43.8%) and moderate/high in 36 (56.25%) of the suspected DVT patients, and low in 29 (53.7%) and moderate/high in 25 (46.3%) of the suspected PE patients. Eighteen cases were confirmed by imaging studies: 9 DVT and 9 PE. The agreement between confirmed cases and PTP was significant with PE but not DVT. The negative predictive value for both DVT and PE with current DD cutoff value of

Background Erythropoietin (Epo) has been shown to improve myocardial function in models of experimental myocardial infarction, but has also been associated with a rise in thromboembolic events. Thus, the aim of this study was to investigate the influence of Epo on platelet activation and coagulation in patients with acute myocardial infarction (AMI). Methods The study was designed as a substudy of the randomised, double-blind, placebo controlled REVIVAL-3 (REgeneration of VItal Myocardium in ST-Segment EleVation MyocardiAL Infarction by Erythropoietin) study that investigated the effects of recombinant human Epo in AMI. Serial venous blood samples were collected before and after study medication. Circulating prothrombin fragment F1 + 2, FVII, active FVII, beta thromboglobulin (TG) and P-Selectin were measured before and 60 hours after randomization by immunoassay (n = 94). In a randomly selected subgroup platelet aggregation was measured using whole blood aggregometry (Multiplate Analyzer, n = 45). Results After 5 days an increase in FVII was observed after Epo as compared to placebo (P = 0.02), yet active FVII and prothrombin fragment F1 + 2 remained unchanged. Moreover, no statistically significant differences in circulating TG or P-selectin were observed between the groups. As an expected response to peri-interventional therapy with clopidogrel and aspirin, platelet aggregation after stimulation with ADP, TRAP, ASPI or collagen decreased 12 hours and 2 days after PCI. However, no difference between the Epo and the placebo group was observed. Conclusion After treatment with Epo in patients with AMI a slight increase in circulating FVII after Epo was not associated with an increase in active FVII, prothrombin fragment F1 + 2, TG or P-selectin. Moreover, platelet aggregation was not altered after treatment with Epo as compared to placebo. Trial registration ClinicalTrials.gov Identifier: NCT01761435

To evaluate the association between angiotensin I-converting enzyme insertion/deletion (ACE I/D) gene polymorphism and retinal vein occlusion (RVO). A total of 80 patients with retinal vein occlusion who was admitted to the Eye Department of Kartal Training and Research Hospital between 2008 and 2011, and 80 subjects were enrolled in this retrospective case–control study. Patients who experienced RVO within one week to six months of study enrolment were included, and those with coronary artery diseases, prior myocardial infarction history and coagulation disturbances were excluded from the study. The diagnosis was made by ophthalmoscopic fundus examination and fluorescein angiography. The ACE gene I/D polymorphism was determined by polymerase chain reaction, and the ACE gene was classified into three types: I/I, I/D and D/D. In multivariate logistic regression analysis, ACE D/D genotype (p = 0.035), diabetes-mellitus (p = 0.019) and hypertension (p = 0.001) were found to be independent predictive factors for RVO. The results of the present study reveal that ACE D/D polymorphism is an independent predictive factor for RVO. However, one cannot definitely conclude that ACE gene polymorphism is a risk factor for retinal vein occlusion.

Introduction In clinical trials new oral anticoagulants (NOAC) have proved to be as effective as warfarin for thromboprophylaxis in atrial fibrillation. The aim of this study was to evaluate the efficacy and safety of these drugs in clinical practise. Methods and results All patients treated with new oral anticoagulants at Skåne University hospital and Halland County Hospital Halmstad between 2009 and September 2013 was identified in the Swedish national quality registry for atrial fibrillation and anticoagulation (AuriculA). Medical records were reviewed to identify thromboembolism and major bleeding and compared to a warfarin cohort with a time in therapeutic range (TTR) of 76%. There were 826 patients, mean age 70.6, follow up 591 years, with atrial fibrillation treated with NOAC. Dabigatran was the initial drug in 79% of the cohort. The incidences of ischemic stroke/ TIA and major bleeding were 1.9 (95% CI; 1.0-3.2) and 2.0 (95% CI; 1.1-3.5) per 100 patient-years respectively. The corresponding incidences for warfarin were 1.5 (95% CI; 1.0-2.2) and 2.5 (95% CI; 1.8-3.3), with no statistical significance between the groups. Two subdural hematomas occurred 0.4 (95% CI; 0.06-1.1) per 100 patient-years. Mean age of patients with complications was 77.9 (±5.9) and 69.3 (±11.3) for those without (p

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism, poses a substantial clinical risk, and the incidence of these thrombotic-related diseases remains high. Anticoagulation aims to prevent thrombus extension and reduce the risk of recurrent events, particularly fatal pulmonary embolism. In EINSTEIN DVT, rivaroxaban was non-inferior to enoxaparin/vitamin K antagonists for the reduction of recurrent VTE, with a similar safety profile and a net clinical benefit. EINSTEIN EXT investigated patients receiving long-term treatment in whom there was no clear decision about continuing or stopping anticoagulation; rivaroxaban was superior to placebo in the reduction of recurrent VTE, showing an acceptable benefit-risk balance. Rivaroxaban has the potential to replace standard therapy, usually parenteral low molecular weight heparin overlapping with and followed by a vitamin K antagonist, for the treatment of acute symptomatic DVT and the secondary prevention of VTE. As the use of rivaroxaban for DVT treatment increases in clinical practice, a fundamental understanding of its clinical benefits in everyday patient care is essential. XALIA (XArelto for Long-term and Initial Anticoagulation in venous thromboembolism) is a multicentre, prospective, non-interventional, observational study investigating the effectiveness and safety of a single-drug approach with rivaroxaban compared with standard therapy in patients with DVT. The study cohort will include approximately 4800 patients (≥18 years old) with objectively confirmed acute DVT who will be treated for a period of ≥3 months. The primary outcomes will be the incidence of treatment-emergent adverse events (primarily major bleeding), symptomatic recurrent venous thromboembolic events and all-cause mortality. Secondary outcomes include: major cardiovascular events; patient-reported treatment satisfaction and adherence; healthcare resource utilization; reasons for drug switching or interruption of treatment; and adverse events. XALIA will follow an international cohort of patients in more than 20 European countries, and others including Israel and Canada. The first patient was enrolled in June 2012, with results expected in 2015. It is anticipated that XALIA will provide important information on the treatment of DVT in a heterogeneous, unselected patient population in a real-world setting and provide important supplementary information to that obtained from the EINSTEIN DVT phase III study.

Background Venous thromboembolic disease (VTE) is associated with high morbi-mortality. Adherence rate to the recommendations of antithrombotic prophylaxis guidelines (ATPG) is suboptimal. The aim of this study was to describe the adequacy of antithrombotic prophylaxis (ATP) in hospitalized patients as the initial stage of a program designed to improve physician adherence to –ATP recommendations in Argentina. Methods This study was a multicenter, cross-sectional study that included 28 Institutions throughout 5 provinces in Argentina. Results 1315 patients were included, 729 (55.4%) were hospitalized for medical (clinical) reasons, and 586 (44.6%) for surgical reasons. Adequate ATP was provided to 66.9% of the patients and was more frequent in surgical (71%) compared to clinical (63.6%) subjects (p

Background Warfarin is known for its interaction with many drugs, resulting in undesired treatment outcomes such as bleeding. The study aimed to assess the prevalence of drug-drug interactions and determinants of bleeding among inpatients on warfarin therapy. Methods A cohort of inpatients on warfarin treatment was prospectively followed from date of admission until discharge. The study was carried out from January to October 2013 in Ayder Referral Hospital, Northern Ethiopia. Patients on warfarin therapy during the study period and willing to participate were included as study subjects. Each concurrent medication was collected and checked for drug-drug interactions using Micromedex® online drug reference. Data were analyzed using statistical software, SPSS for windows version 16. The relationship between bleeding complications and independent variables (age, sex, residence, type and number of co-medications, dose and duration of warfarin treatment, INR value) was assessed using binary logistic regression analysis (Odds ratio, 95% confidence interval). Results Of the total 133 patients enrolled in the study, 78 (58.9%) were females. The mean age of the study participants was 40.81 ± 17.6 years. The prevalence of drug-drug interactions was 99.2%. Among these, 65 (49.2%) patients had at least one major while the others had moderate level of drug-drug interaction. Twenty two (16.5%) patients have developed bleeding complications. Increase in international normalized ratio value was found to be strongly associated with risk of bleeding (P value = 0.00; OR = 0.03 (0.00-0.46)). Conclusion Drug-drug interactions with warfarin were prevalent in the study hospital. Bleeding complications due to warfarin were also high. Thus, clinicians should be aware of potential interactions and monitor patients’ international normalized ratio closely.

Background: Statins may reduce the risk of first and recurrent venous thromboembolism (VTE). No data are available on their potential benefit in patients treated with the oral anticoagulant rivaroxaban. Methods: The EINSTEIN DVT/PE and EINSTEIN Extension studies compared rivaroxaban with standard of care (n=8280) and placebo (n=1188), respectively. The incidences of recurrent VTE and major bleeding per 100 patient-years for exposure (or not) to statins were calculated. A Cox proportional hazards model was constructed, stratified by index event and intended treatment duration, with statin use as a time-dependent variable, for each treatment group (rivaroxaban vs enoxaparin/vitamin K antagonist or placebo) and adjusted for relevant variables. Results: In EINSTEIN DVT/PE, 1509 (18.3%) patients used statins during the at-risk period, and 6731 (81.7%) did not. Overall, 2.6 recurrent VTEs occurred per 100 patient-years with statin use compared with 3.8 per 100 patient-years without statins (adjusted hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.46–1.25). HRs for recurrent VTE were similar for concomitant use of rivaroxaban-statin and enoxaparin/VKA-sta tin. Major bleeding events occurred in 3.0 per 100 patient-years with statin use compared with 2.3 per 100 patient-years without statins (adjusted HR 0.77; 95% CI 0.46–1.29). Due to adjustments in the Cox regression model, the direction of this HR is in contrast to the crude comparison. In EINSTEIN Extension, no recurre nt VTEs occurred with statin use in the rivaroxaban group compared with 1.6 per 100 patient-years without statins. In the placebo group, 12.2 recurrent VTEs occurred per 100 patient-years with statin use compared with 13.2 per 100 patient-years without (adjusted HR 0.81; 95% CI 0.35–1.86). Conclusions: The effect of statins in this secondary analysis of the EINSTEIN VTE treatment program is consistent with other studies that suggest a reduced risk of recurrent VTE, but conclusive evidence of this benefit is lacking. Statins are simple to use, inexpensive, very safe and do not cause bleeding. Therefore, the potential effect on reducing recurrent VTE, which is in the range of that of acetylsalicylic acid, deserves evaluation in a large randomized trial. Trial registration number: ClinicalTrials.gov: EINSTEIN PE, NCT00439777; EINSTEIN DVT, NCT00440193; EINSTEIN Extension, NCT00439725.

Background Deep venous thrombosis (DVT), which is often associated with pulmonary embolism (PE), is a serious complication after total knee arthroplasty (TKA). In the present study, we examined the overall thrombotic and thrombolytic status using Global Thrombosis Test (GTT) in non-anticoagulated blood of patients undergoing TKA to develop the predictable marker for the incidence of DVT. Methods DVT was diagnosed using doppler ultrasonography a day after the surgery in 31 patients with osteoarthritis (n = 24), rheumatoid arthritis (n = 6) and ankylosing spondylitis (n = 1) by the well-trained operator. We measured overall thrombotic and thrombolytic status using GTT and other biomarkers, which is associated with blood coagulation and fibrinolysis, before and immediately after the surgery. Results Newly-generated DVT during the operation was detected in 11 of 31 patients (35.4%) 1 day after TKA. There were no differences in markers of coagulation (PT and APTT), platelet activity (platelet aggregation-induced by ADP and collagen) and fibrinolysis (FDP and D-dimer) between non-DVT and DVT group both before and after the surgery. Both Pre- and Post-operative GTT-occlusion times (OT), an index of platelet reactivity, were tended to be shorter, but not significant, in DVT group compared with non-DVT group. Pre-operative GTT-lysis time (LT), an index of thrombolytic activity, was significantly shorter in DVT group compared with non-DVT group, while there were no differences in post-operative value of this index between DVT group and non-DVT group, suggesting overall thrombolytic activity was enhanced in DVT group before surgery. Conclusions Our data suggest that enhancement of pre-operative thrombolytic activity assessed by GTT may be a predictable marker for the incidence of DVT after TKA.

Background New oral anticoagulant (NOAC) drugs are known to influence the results of some routine hemostasis tests. Further data are needed to enable routine assessment of the effects of NOAC on clotting parameters in some special circumstances. Methods Following administration of rivaroxaban to patients, at the likely peak and trough activity times, we assessed the effects on prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and clotting time using Russell’s viper venom, and in the presence of phospholipids and calcium reagent available as DVVreagent® and DVVconfirm®. The data were used to determine an adequate NOAC plasma level based on anticoagulant activities expressed as a ratio (patients/normal, R-C). Results DVVconfirm as R-C could be rapidly performed, and the results were reasonably sensitive for rivaroxaban and probably for other FX inhibitors. This assay is not influenced by lupus anticoagulant and heparin, does not require purified NOAC as control, and will measure whole-plasma clotting activity. Conclusions We propose a cut-off R-C value of 4.52 ± 0.33 for safety, but clinical studies are needed to establish whether this cut-off is useful for identifying patients at increased risk of hemorrhage or exhibiting low anticoagulation effect. It also seems possible that normal R-C could indicate an absence of anticoagulant activity when rivaroxaban is discontinued due to episodes of uncontrolled bleeding during anticoagulation or for emergency surgery.

Background The incidence of venous thromboembolic disease (VTED) is estimated to be, on average, 1–2 cases per 1,000 individuals per year worldwide. There are few data concerning the incidence rate (IR) of VTED in the Argentinean population at large. Our aim was to estimate the IR of VTED at the Italian Hospital Medical Care Program (IHMCP) in Buenos Aires, the most populous city in Argentina. Methods This prospective cohort study evaluated all consecutive incident cases of pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) confirmed in patients over the age of 17 who were members of the IHMCP from June 2006 to May 2012. Any patient who had an initial confirmed VTED episode and was a member of the IHMCP at the time of diagnosis was considered an incident case. Results There were 1,138 cases of VTED for 687,871 person-years of follow-up. The crude IR of VTED was 1.65 (95% CI: 1.56 to 1.75) per 1,000 person-years. The highest IR was found in subjects >80 years old (5.92 per 1,000 person years; 95% CI: 5.41 to 6.49). The IRs adjusted to the population of the city of Buenos Aires were 0.90 (95% CI: 0.84 to 0.95) for VTED, 0.71 (95% CI: 0.66 to 0.76) for DVT, and 0.34 (95% CI: 0.31 to 0.37) for PTE. Conclusions VTED is a common health problem with a high IR in members of the IHMCP, especially the elderly. This is the first paper to report prospectively the cumulative incidence of VTED in Latin America.

Behcet’s disease is a chronic multi-system disorder of unknown etiology with protean manifestations. Venous thromboembolism is more common than arterial thrombosis, with deep vein thrombosis being the most frequent. Endothelial dysfunction resulting from vascular inflammation is considered to be an important factor of thrombosis, although the endothelial injury itself cannot completely explain the hypercoagulable state of the disease because other vasculitis syndromes do not increase the risk of thrombosis. The aim of this study is to evaluate the prevalence of activated protein C resistance (APC-R) in Egyptian patients with Behcet’s disease. Also, to detect hyperhomocysteinemia in selected cases (with vascular complications) to assess their relationship with thromboembolic complications. The APC resistance ratio mean in the group of patients with vascular involvement was 2.6 ± 0.8 which was less than the group with no vascular involvement 2.8 ± 0.6, with non- significant P-value (0.5). There was more incidence of ocular lesions in the group of patients with high homocysteine level than the group of patients with normal homocytsteine level with significant P-value (0.08).

Background While the assessment of analytical precision within medical laboratories has received much attention in scientific enquiry, the degree of as well as the sources causing variation between them remains incompletely understood. In this study, we quantified the variance components when performing coagulation tests with identical analytical platforms in different laboratories and computed intraclass correlations coefficients (ICC) for each coagulation test. Methods Data from eight laboratories measuring fibrinogen twice in twenty healthy subjects with one out of 3 different platforms and single measurements of prothrombin time (PT), and coagulation factors II, V, VII, VIII, IX, X, XI and XIII were analysed. By platform, the variance components of (i) the subjects, (ii) the laboratory and the technician and (iii) the total variance were obtained for fibrinogen as well as (i) and (iii) for the remaining factors using ANOVA. Results The variability for fibrinogen measurements within a laboratory ranged from 0.02 to 0.04, the variability between laboratories ranged from 0.006 to 0.097. The ICC for fibrinogen ranged from 0.37 to 0.66 and from 0.19 to 0.80 for PT between the platforms. For the remaining factors the ICC’s ranged from 0.04 (FII) to 0.93 (FVIII). Conclusions Variance components that could be attributed to technicians or laboratory procedures were substantial, led to disappointingly low intraclass correlation coefficients for several factors and were pronounced for some of the platforms. Our findings call for sustained efforts to raise the level of standardization of structures and procedures involved in the quantification of coagulation factors.

Background Bleeding remains a potentially lethal complication of cardio-pulmonary bypass (CPB) surgery. The purpose of this study was to obtain a better insight into in vitro thrombin generation in the context of CPB. Methods We used Calibrated Automated Thrombography to assess blood coagulation of 10 low-risk patients operated for valve replacement with CPB, under 2 experimental conditions, one implicating platelets as platelet dysfunction has been described to occur during CPB. Results Our main finding was that CPB-induced coagulopathy was differently appreciated depending on the presence or absence of platelets: the decrease in thrombin generation was much less pronounced in their presence (mean endogenous thrombin potential change values before and after CPB were -3.9% in the presence of platelets and -39.6% in their absence). Conclusion Our results show that experimental conditions have a profound effect in the study of in vitro thrombin generation in the context of CPB.

Background There has been a shift towards greater use of neuraxial over general anaesthesia for patients undergoing total hip or knee arthroplasty. Furthermore, suggestions that peripheral nerve block may reduce adverse effects have recently been put forward. Although older studies showed a reduction in venous thromboembolism (VTE) with neuraxial compared with general anaesthesia, this difference has not been confirmed in studies using effective current thromboprophylaxis. We used a large data set to investigate the pattern of anaesthesia usage, and whether anaesthesia type affects efficacy and bleeding outcomes of thromboprophylaxis overall, within each treatment group, or for the novel oral anticoagulant dabigatran etexilate versus enoxaparin. Methods Three previously reported trials compared 220 mg and 150 mg dabigatran etexilate once daily with enoxaparin after knee or hip arthroplasty. A pooled analysis was performed in patients receiving general or neuraxial anaesthesia, or the combination of either with peripheral nerve block (n = 8062). Outcome measures were major VTE plus VTE-related mortality, major bleeding and major plus clinically relevant bleeding events. Results General, neuraxial and combination anaesthesia were used in 29%, 52% and 19% of patients, respectively. Differences in efficacy and safety between anaesthesia subgroups were small and not significant, except for a slightly higher rate of major VTE and VTE-related mortality with general versus neuraxial anaesthesia (odds ratio: 1.40; 95% confidence interval: 1.03–1.90; p = 0.035) in the overall population. There were no significant effects of anaesthesia type on efficacy or safety of dabigatran etexilate versus enoxaparin. Conclusions Anaesthesia type did not greatly affect efficacy and safety outcomes in the pooled population of all three treatment groups. The efficacy and safety of dabigatran etexilate was comparable with enoxaparin, regardless of type of anaesthesia. Trial registration ClinicalTrials.gov identifiers: NCT00168805, NCT00168818, NCT00152971.

Background DVT is the main cause of death in hospitalized patients and thromboprophylaxis is the only way to prevent these deaths. International recommendations suggested that active monitoring of DVT/PE prophylaxis can improve the efficacy in Hospitals. Methods We performed a cohort study in three consecutives periods to evaluate DVT prophylaxis in 388 adults hospitalized in a General Hospital. Results 85% of the population had high risk factors for DVT. Thromboprophylaxis was in accordance with local and International guidelines (ACCP 2008) in 72.7% and 86% of the patients respectively. No significant difference could be founded between clinical and surgical patients. One every 10 patients received higher prophylaxis than suggested by guidelines and two out of ten received deficient or no prophylaxis. The worst 2 groups of patients were those with moderate/low risk of DVT and the group with a contraindication to pharmacologic prophylaxis. We observed a progressive improvement of the DVT prophylaxis in the 3 periods of evaluation. Conclusions Although the rate of recommended thromboprophylaxis is higher than many other reports in the region we still have some areas where we need to improve. Regular audits like these are very helpful to find out what specific areas of the hospital needs some careful attention in order to have a better quality of assistance.

Background Venous thromboembolism (VTE) is a leading cause of hospital-related deaths worldwide. However, the proportion of patients at risk of VTE who receive appropriate prophylaxis in Egypt is unknown. The ENDORSE study in Egypt is part of a global initiative to uncover the incidence of high-risk surgical and medical patients and determine what proportion of these patients receive appropriate VTE prophylaxis. Methods Ten Egyptian hospitals participated in this observational study, enrolling all surgical and medical patients that met the study criteria. This resulted in a cohort of 1,008 patients in acute care facilities who underwent a retrospective chart review. Each patient’s VTE risk status and the presence or absence of appropriate prophylactic care was assessed according to the American College of Chest Physicians (ACCP) guidelines 2004. Results Of the 1,008 patients enrolled, 395 (39.2%) were found to be at high-risk for VTE. Overall, 227 surgical patients were at high-risk, although only 80 (35.2%) received ACCP-recommended prophylaxis. Similarly, 55/268 (32.75%) of high-risk medical patients received appropriate VTE prophylaxis. Low molecular weight heparin was the most commonly used anticoagulant, while mechanical prophylactic use was quite low (1.5%) in high-risk patients. Conclusions In Egypt, more than one-third of all patients hospitalized for surgery or acute medical conditions are at high risk for developing VTE. However, only a small fraction of these patients receive appropriate VTE prophylaxis. Corrective measures are necessary for preventing VTE morbidity and mortality in these high risk patients.

Background Effects of nitric oxide (NO) on hemostasis have been studied in various investigational settings, but data regarding inhaled NO on bleeding and platelet function are conflicting. It is not known if inhaled NO has an effect when administered with drugs that influence hemostasis. This trial evaluated effects of inhaled NO on hemostasis in the presence of heparin using aspirin as a positive control. Patients/Methods Twelve healthy adult males were enrolled in a single-center, randomized, single-blind, four-way crossover trial. Subjects received 80 ppm NO or medical air (placebo) inhalation for 30 min with simultaneous injection of placebo or heparin. Aspirin capsules were used as a positive control. Parameters of hemostasis were measured before treatment and at post-treatment intervals. Results Activated clotting time (ACT), prothrombin time (PT) and activated partial thromboplastin time (aPTT) increased only in groups that received heparin. Areas under the curve for ACT in heparin groups receiving inhaled NO were judged to be equivalent to those receiving medical air for both 0- to 4-h (ratio: 1.00; 90% CI, 0.90-1.11) and 0- to 24-h time intervals (ratio: 1.01; 90% CI, 0.92-1.12). Changes in bleeding time and platelet aggregation were observed only in aspirin groups. No clinically significant changes in hemoglobin, red blood cell counts or haematocrit were observed in any group. Conclusions Inhaled NO, when administered with heparin, exhibited no significant additive effects on ACT, PT, aPTT, bleeding time or platelet aggregation.

Background Patients who receive highly variable doses of warfarin may be at risk for poor anticoagulation control and adverse events. However, we lack a system to identify patients with the highest dose variability. Our objectives were to develop a scoring system to identify patients with high dose variability, and to validate this new measure by demonstrating that patients so identified have poor anticoagulation control and higher rates of adverse events (criterion validity). Methods We used a database of over 4, 000 patients who received oral anticoagulation in community practice between 2000-2002. We reviewed the charts of 168 patients with large warfarin dose variation and agreed on 18 risk factor definitions for high dose variability. We identified 109 patients with the highest dose variability (cases), as measured by coefficient of variation (CoV, SD/mean). We matched each case to two controls with low dose variability. Then, we examined all 327 charts, blinded to case/control status, to identify the presence or absence of the 18 risk factors for dose variability. We performed a multivariable analysis to identify independent predictors of high CoV. We also compared anticoagulation control, as measured by percent time in therapeutic range (TTR), and rates of adverse events between groups. Results CoV corresponded with other measures of anticoagulation control. TTR was 53% among cases and 79% among controls (p < 0.001). CoV also predicted adverse events. Six cases experienced a major hemorrhage versus 1 control (p < 0.001) and 3 cases had a thromboembolic event versus 0 control patients (p = 0.04). Independent predictors of high dose variability included hospitalization (OR = 21.3), decreased oral intake (OR = 12.2), use of systemic steroids (OR = 6.1), acetaminophen (OR = 4.0) and antibiotics (OR = 2.7; p < 0.05 for all). Conclusion CoV can be used to identify patients at risk for poor anticoagulation control and adverse events. This new measure has the potential to identify patients at high risk before they suffer adverse events.

Background To assess the incidence of venous thromboembolism (VTE) and bleeding events with or without thromboprophylaxis and the associated costs in a cohort of medically ill patients in both in-hospital and outpatient settings. Methods A large hospital drug database and linked outpatient files were used to identify patients eligible for this analysis, based on demographic and clinical characteristics. Results Among 11,135 patients identified, 1592 (14.30%) were admitted with chronic heart failure, 1684 (15.12%) with thromboembolic stroke, 3834 (34.43%) with severe lung disease, 1658 (14.89%) with acute infection, and 2367 (21.26%) with cancer. Of the 11,135 patients, 5932 received anticoagulant therapy at some point during their hospitalization and until 30 days after discharge. VTE events occurred in 1.30% of patients who received anticoagulant prophylaxis versus 2.99% of patients who did not. Risk-adjusted total healthcare costs for patients with a VTE or major or minor bleeding event were significantly higher than for those without events (VTE: $52,157 ± 24,389 vs $24,164 ± 11,418; major bleeding: $33,656 ± 18,196 vs $24,765 ± 11,974; minor bleeding: $33,690 ± 14,398 vs $23,610 ± 11,873). In a multivariate analysis, appropriate anticoagulant prophylaxis use was significantly associated with a reduced risk of clinical VTE, compared with no anticoagulant use (hazard ratio: 0.37). Patients admitted with thromboembolic stroke were less likely to have a VTE than patients admitted with cancer (hazard ratio: 0.42). Conclusions In this analysis, VTE and major bleeding event rates were lower for patients who received prophylaxis compared with those who did not. Prophylaxis use was associated with lower healthcare costs.

Background Venous thromboembolism prophylaxis has been shown to safely and cost-effectively reduce the incidence of thromboembolic events in medical inpatients. However, there is a gap between evidence and medical practice. The aim of this study was evaluate the appropriateness of prescribing venous thromboembolism prophylaxis in accordance with local recommendations for medical inpatients. Methods This cross-sectional study included 310 prescriptions of medical general-ward admitted patients of two university hospitals of Buenos Aires, Argentina. Data was collected using filled-out prescriptions, medical records and interviews with the head attending physician. Information was gathered at different times during 16 days randomly selected over September 2007 and January 2008. Results One hundred eighty eight patients' prescriptions (60.6%) were appropriate according to the institutional guidelines. Inappropriateness was due to excessive (14.2%), insufficient (15.8%) and absent (9.4%) prescribing. According to the recommendations of the American College of Chest Physicians, 256 (82.6%) patients received appropriate prophylaxis. Twenty-nine patients (9.4%) were considered at low risk for thromboembolism and did not need pharmacologic or mechanical prophylaxis. One hundred three patients (33.2%) had at least one major risk factor for venous thromboembolism. Compliance with the institutional guidelines was more frequently in the case of high risk patients. Complex preventive measures and low risk patients were related to lower adherence to recommendations. In the multivariate analysis, predictors of inappropriateness were the requirement of a surgical procedure and absence of prophylaxis prescribing at admission. In contrast, patients with a diagnosis of gastrointestinal disorders had lower odds of inappropriateness than those with an infectious disease. Conclusions Most medical inpatients received some thromboprophylaxis measure, but the compliance with recommendations was less frequent. Efforts should be made to improve the appropriate prescription.

Background Left ventricular thrombus(LVT] formation is a frequent complication in patients with acute anterior myocardial infarction(MI). LVT is associated with increased risk of embolism and higher mortality rates after acute MI. Anticardiolipin antibodies (ACA) are immunoglobulins that react with phospholipid-binding proteins interfering with the prothrombin activator complex. The effects of phospholipids on pathophysiology of cardiovascular thrombotic events are well known. In this study, we aimed to evaluate the importance of clinical and biochemical parameters including anticardiolipin antibodies on left ventricular thrombus formation after acute anterior MI. Methods and Results Seventy patients with a first anterior AMI were prospectively and consecutively enrolled. Patients with previous MI, autoimmune disease, collagen vascular disease and arterial or venous thrombosis history were excluded from this study. At the time of hospitalization, key demographic and clinical characteristics were collected including age, gender, ethanol intake and presence of traditional risk factors for atherosclerosis (hypertension, diabetes, smoking, hyperlipidemia, positive family history). Patients were evaluated for echocardiographic data, blood chemistry and ACA. Two-dimensional and Doppler echocardiographic examinations were performed in all patients within the first week and at 14 days after MI. LV thrombus was detected in 30 (42.8%) patients. ACA IgM levels were significantly higher in the patient group with LV thrombus than in the group without thrombus (12.44 ±4.12 vs. 7.69 ± 4.25 mpl, p = 0,01). ACA IgG levels were also found higher in the group with LV thrombus (24.2 ± 7.5 vs.17.98 ± 6.45 gpl, p = 0.02). Multivariate analyses revealed diabetes mellitus, higher WMSI, lower MDT and higher ACA IgM and higher ACA IgG levels as independent predictors of left ventricular thrombus formation. Conclusions Our data demonstrate that beside the low ejection fraction, lower MDT and higher wall motion score index, modestly elevated ACA IgM and ACA IgG levels are associated with LV thrombus formation in patients with anterior MI.

Background Tissue factor (TF) and its inhibitor tissue factor pathway inhibitor (TFPI) are the main regulators of the initiation of the coagulation process, important in atherothrombosis. In this study we have investigated the frequency of six known TF and TFPI single nucleotide polymorphisms (SNPs) in CHD patients as compared to healthy individuals. These genotypes and the phenotypes (TF, TFPI free and total antigen) were evaluated with special reference to gender and diabetes in the CHD population. Methods Patients with angiographically verified CHD (n = 1001; 22% women, 20% diabetics), and 204 healthy controls (28% women), were included. The investigated SNPs were: TF -1812C/T and TF -603A/G in the 5'upstream region, TF 5466A/G in intron 2, TFPI -399C/T and TFPI -287T/C in the 5'upstream region and the TFPI -33T/C in intron 7. Results No significant differences in frequencies between the CHD population and the controls of any polymorphisms were observed. In the CHD population, the TF 5466 A/G SNP were significantly more frequent in women as compared to men (p < 0.001). The TF-1812C/T and the TF-603A/G SNPs were significantly more frequent in women without type-2 diabetes compared to those with diabetes (p < 0.018, both), and the heterozygous genotypes were associated with significantly lower TF plasma levels compared to the homozygous genotypes (p < 0.02, both). The TFPI-399C/T and the TFPI-33T/C SNPs were associated with lower and higher TFPI total antigen levels, respectively (p < 0.001, both). Conclusion Genetic variations in the TF and TFPI genes seem to be associated with gender and type-2 diabetes, partly affecting their respective phenotypes.

Background The pathophysiological pathways resulting in Late Stent Thrombosis (LST) remain uncertain. Findings from animal studies indicate a role of the intrinsic coagulation pathway in arterial thrombus formation, while clinical studies support an association with ischemic cardiovascular disease. It is currently unknown whether differences in the state of the contact system might contribute to the risk of LST or Very Late Stent Thrombosis (VLST). We assessed the relation between levels of several components involved in the contact system and a history of LST and VLST, termed (V)LST in a cohort of 20 patients as compared to a matched control group treated with PCI. Methods and Results Activated factor XII (FXIIa), FXII zymogen (FXII), FXIIa-C1-esterase inhibitor (C1-inhibitor), Kallikrein-C1-inhibitor, FXIa-C1-inhibitor and FXIa-α1-antitrypsin (AT-inhibitor) complexes were measured by Enzyme-linked immunosorbent assy (ELISA) methodology. Cases and controls showed similar distributions in sex, age, baseline medications and stent type. Patients with a history of (V)LST had a significantly greater stent burden and a higher number of previous myocardial infarctions than the control patients. There were no significant between-group differences in the plasma levels of the components of the contact system. Conclusion In a cohort of patients with a history of (V)LST, we did not observe differences in the activation state of the intrinsic coagulation system as compared to patients with a history of percutaneous coronary intervention without stent thrombosis.

Background Postoperative asymptomatic deep venous thromboses (ADVT) can give rise to posttthrombotic syndrome (PTS), but there are still many unresolved issues in this context. For example, there is a lack of knowledge regarding the fate of small ADVT following minor orthopedic surgery. This follow-up study evaluates postthrombotic changes and clinical manifestations of PTS in a group of patients with asymptomatic calf vein DVT after surgery for Achilles tendon rupture. Methods Forty-six consecutive patients with distal ADVT were contacted and enrolled in a follow-up consisting of a single visit at the hospital at a mean time of 5 years postoperatively, including clinical examination and scoring, ultrasonography and venous plethysmography. All patients had participated in DVT-screening with colour duplex ultrasound (CDU) 3 and 6 weeks postoperatively and 80% of them were treated with anticoagulation. Results With CDU postthrombotic changes and deep venous reflux were detected at follow-up in more than 50% of the patients, more commonly in somewhat larger calf DVT:s initially affecting more than one vessel. However, only about 10% of the patients had significant venous reflux according to venous plethysmography. No patient had plethysmographic evidence of remaining outflow obstruction, but presence of postthrombotic changes shown with CDU negatively influenced venous outflow capacity measured with plethysmography. A clinical entity of PTS was rarely found and occurred only in two patients (4%) and then classified by Villalta scoring as of mild degree with few clinical signs of disease. Distal ADVT:s detected in the early postoperative period (3 weeks) showed DVT-progression in 75% of the limbs that were still immobilized and without anticoagulation. Conclusions Asymptomatic postoperative distal DVT:s following surgery for Achilles tendon rupture have a good prognosis and a favourable clinical outcome. In our material of 46 patients the general appearance of the clinical entity of PTS at 5 years follow-up was low (

Objectives and Background Tissue factor (TF) contributes to thrombosis following plaque disruption in acute coronary syndromes (ACS). Aim of the study was to investigate the impact of plasma TF activity on prognosis in patients with ACS. Methods and Results One-hundred seventy-four patients with unstable Angina pectoris (uAP) and 112 patients with acute myocardial infarction (AMI) were included with a mean follow up time of 3.26 years. On admission, plasma TF activity was assessed. Patients were categorized into 2 groups: a high-TF activity group with TF >24 pmol/L and low TF activity group with TF ≤ 24 pmol/L. Fifteen cardiovascular deaths occurred in the uAP group and 16 in the AMI group. In AMI TF activity was 24,9 ± 2,78 pmol/l (mean ± SEM) in survivors and 40,9 ± 7,96 pmol/l in nonsurvivors (P = 0.024). In uAP no differences were observed (25.0 ± 8.04 pmol/L nonsurvivors vs. 25.7 ± 2.14 pmol/L survivors; P = 0.586). Kaplan-Meier estimates of survival at 3.26 years regarding TF activity in AMI were 81.3% and 92.2% with an hazard ratio of 3.02 (95% CI [1.05–8.79], P = 0.03). The Cox proportional hazards model adjusting for correlates of age and risk factors showed that plasma TF activity was an independent correlate of survival (hazard ratio 9.27, 95% CI [1.24–69.12], P = 0.03). In an additional group of patients with uAP and AMI, we identified circulating microparticles as the prevailing reservoir of plasma TF activity in acute coronary syndromes. Conclusion Systemic TF activity in AMI has an unfavorable prognostic value and as a marker for dysregulated coagulation may add to predict the atherothrombotic risk.

Background Anticoagulation with warfarin should be stopped 4–6 days before invasive procedures to avoid bleeding complications. Despite this routine, some patients still have high International Normalized Ratio (INR) values on the day of surgery and the procedure may be cancelled. We sought to identify easily available clinical characteristics that may influence the rate of normalization of prothrombin time when warfarin is stopped before surgery or invasive procedures. Methods Clinical data were collected retrospectively from consecutive cases from two cohorts, who stopped warfarin 6 days before surgery. An INR value of 1.6 or higher on the day of surgery or requirement for reversal with vitamin K the day before surgery were criteria for slow return (S) to normal INR. Results Of 202 patients, 14 (7%) were classified as S. Eight of the S-patients required reversal with vitamin K one day before surgery and in another case surgery was cancelled due to high INR. Baseline INR was the only variable significantly associated with classification as S in stepwise logistic regression analysis (p = 0.003). The odds ratio for being in the normal group was 0.27 (95% confidence interval 0.12–0.62) for each unit baseline INR increased. The positive predictive value of baseline INR with a cut off at > 3.0 was only 15% and for INR > 3.5 it was 33%. Conclusion Baseline INR, but not the size of the maintenance dose, is associated with the rate of normalization of prothrombin time after stopping warfarin, but it has limited utility as predictor in clinical practice. Whenever normal hemostasis is considered crucial for the safety, the INR should be checked again before the invasive procedure.

Background Venous thromboembolism (VTE) and thromboembolic arterial diseases are usually considered to be distinct entities, but there is evidence to suggest that these disorders may be linked. The aim of this study was to determine whether a diagnosis of VTE increases the long-term risk of myocardial infarction (MI). Methods The incidence rate (IR) and relative risk (RR) of MI in a cohort of patients with a diagnosis of VTE (n = 4890) compared with that of a control cohort without prior VTE (n = 43 382) were evaluated in the UK General Practice Research Database (GPRD). Death during follow-up was also determined. Patients were followed for up to 8 years (mean of 3 years). Results The IR of MI per 1000 person-years was 4.1 (95% CI: 3.1–5.3) for the VTE cohort and 3.5 (95% CI: 3.2–3.8) for the control cohort. The IR of MI was highest in the first year after the VTE episode, but overall differences between the two cohorts were not significant (RR of MI associated with VTE: 1.2; 95% CI: 0.9–1.6). The risk of death was higher in the VTE cohort than the control cohort, even after adjustment for cancer, heart failure and ischaemic heart disease (RR: 2.4; 95% CI: 2.2–2.6), particularly during the first year after VTE (RR: 3.8; 95% CI: 3.4–4.3). Conclusion A VTE episode does not significantly increase the risk of MI, but does increase the risk of death, particularly in the first year following VTE diagnosis.

Neck of femur fractures predispose patients to venous thromboembolism (VTE). NICE has issued guideline 46 to reduce this risk through the use of antithrombic agents. We audited our department's VTE practise by reviewing the clinical notes of 123 consecutive patients with no exclusions. We found our compliance to be a low 6%. We also found that patients were likely to be given low molecular heparin (LMWH) only during their hospital stay. Reasons for the low adherence were probably secondary to confusion caused by the multiple thromboprophylaxis protocols used in our department. The correlation between duration of heparin administration and length of hospital stay was due to logistical difficulty in administering VTE prophylaxis out of hospital setting.

Aim To prospectively determine the role of platelet glycoprotein IIIa (GP IIIa) gene PlA1/PlA2 polymorphism on the long-term clinical outcome in patients with coronary artery disease undergoing coronary stenting. Design and setting Prospective observational study in the University Hospital of Caen (France). Patients and methods 1 111 symptomatic consecutive Caucasian patients treated with percutaneous coronary intervention including stent implantation underwent genotyping for GP IIIa PlA1/A2. Main outcome measures Long-term clinical outcome in terms of the rate of major adverse cardiac events (MACE, ie death from any cause, non-fatal Q wave or non Q wave myocardial infarction, and need for coronary revascularisation) was obtained and subsequently stratified according to the GP IIIa PlA1/A2 polymorphism. Results Three groups of patients were determined according to the GP IIIa PlA1/A2 polymorphism (71.6% had the A1/A1, 25.8% had the A1/A2 and 2.6% had the A2/A2 genotype). These three groups were comparable for all clinical characteristics including sex ratio, mean age, vascular risk factors, previous coronary events, baseline angiographic exam, indication for the percutaneous coronary intervention and drug therapy). The incidence of MACE was similar in these 3 groups of patients during a mean follow-up period of 654+/-152 days. Independent risk factors for MACE were a left ventricular ejection fraction < 40%, absence of treatment with a beta-blocker and absence of treatment with an angiotensin converting enzyme inhibitor during follow-up. Conclusion The GP IIIa PlA1/A2 polymorphism does not influence the clinical long-term outcome in patients with symptomatic coronary disease undergoing percutaneous coronary intervention with stent implantation.

Background The true relationship between methylenetetrahydrofolate reductase C677T homozygosity and risk of recurrent spontaneous abortion is unknown, and it is unclear if women with these mutations should be anticoagulated during pregnancy. Objectives We report a series of 8 patients with this issue and review the current literature. Methods 8 patients (3 of whom were actively pregnant) were referred with histories of spontaneous fetal loss; hypercoaguability work-ups revealed each were homozygous for the MTHFR C677T mutation without other thrombophilias. Results In the 3 women who have conceived, treatment with LMW heparin during pregnancy led to two full-term births and one additional pregnancy without complication. For the 5 who have not, we recommended treatment with LMW heparin upon conception. Conclusion We provide evidence to support the relationship between MTHFR C677T mutations and recurrent fetal loss, and to suggest that anticoagulation of these patients during pregnancy can lead to a successful pregnancy outcome.

Background Deep venous thrombosis (DVT) is an important complication in the peripartal and postpartal period. Methods We followed up prospectively the prevalence of DVT in 34720 prenatal mothers between June 2002 and July 2006 attending the antenatal clinics of two major hospitals in Mumbai, India. Thirty two women (0.1%) presented for the first time with symptomatic DVT i.e. 17 in the first trimester, 6 in the second and 9 in the third trimester of pregnancy. Nine had history of fetal loss while in the remaining twenty three there was no history of fetal loss. Results The evaluation of both acquired and heritable thrombophilia showed a conglomeration of thrombophilia in this group when compared to 100 normal pregnant women who have given birth to at least one healthy baby with no history of fetal death, DVT or other obstetrical complications. The relative risks for all the antiphospholipid antibodies (APA) studied i.e lupus anticoagulant (LA), IgG/IgM antibodies for cardiolipin (ACA), β2 glycoprotein 1 (β2 GP 1) and annexin V were significantly higher in women with pregnancy associated DVT (RR 7.4 95% CI 4.3–11.3 P < 0.05). Among the genetic thrombophilia markers studied, Protein S (PS) deficiency was the strongest risk factor (RR 5.00 95% CI 3.02–5.00 P < 0.05) followed by factor V Leiden (FVL) mutation (RR 4.57 95% CI 2.23–4.57 P < 0.05) and PAI 4G/4G homozygosity (RR 3.24 95% CI 1.85–5.12 P < 0.05). Protein C (PC) and endothelial protein C receptor (EPCR) 23 bp insertion polymorphism was also increased in the patient group as compared to controls but the difference was not statistically significant. The MTHFR C677T, fibrinogen gene β448 Arg/Lys polymorphisms were not significantly different from the normal controls, while antithrombin III (AT III) deficiency and PT G20210A polymorphism were absent in both controls and patients. Two or more risk factors were present in 22 out of 32 cases (68.75%). Conclusion We conclude that the prevalence of DVT in India is more or less similar to other reports published and both acquired and heritable thrombophilia show strong association with DVT associated with pregnancy.

Background Influenza infections have been associated with procoagulant changes. Whether influenza infections lead to an increased risk of pulmonary embolism remains to be established. Methods We conducted a nested case control study in a large cohort of patients with a clinical suspicion of having pulmonary embolism. Blood samples were collected to investigate the presence of influenza A and B by complement fixation assay (CFA). We compared case patients, in whom pulmonary embolism was proven (n = 102), to controls, in whom pulmonary embolism was excluded (n = 395). Furthermore, we compared symptoms of influenza-like illness in both patient groups 2 weeks prior to inclusion in the study, using the influenza-like illness (ILI) score, which is based on a questionnaire. We calculated the risk of pulmonary embolism associated with influenza infection. Results The percentage of patients with influenza A was higher in the control group compared to the case group (4.3% versus 1.0%, respectively, odds ratio 0.22; 95% CI: 0.03–1.72). Influenza B was not detectable in any of the cases and was found in 3 of the 395 controls (0.8%). The ILI score was positive in 24% of the cases and 25% in the control persons (odds ratio 1.16, 95% CI: 0.67–2.01). We did not observe an association between the ILI score and proven influenza infection. Conclusion In this clinical study, influenza infection was not associated with an increased risk of acute pulmonary embolism. The ILI score is non-specific in this clinical setting.

Background Hyperhomocysteinemia has been described as a risk factor for unexplained recurrent pregnancy loss. Increased levels of homocysteine may be due to inadequate dietary intake of folate and vitamin B12 and inherited defects within the methionine-homocysteine pathway such as MTHFR C677T gene polymorphism. However, the association between hyperhomocysteinemia and sterility problems have been underlined only for recurrent pregnancy loss while a relationship between hyperhomocysteinemia and female sterility is still matter of discussion. Aim This study sought to find out a possible relationship between sterility (primary sterility or secondary sterility due to recurrent pregnancy loss) and homocysteine metabolism. Patients and Methods We selected 20 patients with recurrent pregnancy loss, 20 patients with unexplained female sterility and 20 healthy women as control group. Several whole blood samples were collected by venipuncture. Firstly homocysteinemia and other related variables were tested (i.e. folate and vitamin B12 levels); thereafter DNA was extracted by a further whole blood sample collected in EDTA in order to screen MTHFR C677T gene polymorphism. Statistical analysis was performed by chi square test; differences were considered to be significant if p < 0.05. Results The median fasting total plasma homocysteine concentration was 19.2 ± 6.14 μM for patients with recurrent pregnancy loss, while was 21.05 ± 8.78 μM for patients with unexplained sterility, vs 7.85 ± 3.31 μM of control group (p < 0.05). Fifteen patients with unexplained female sterility showed MTHFR C677T homozigosity vs 17 with recurrent pregnancy loss and 3 in the control group (p < 0.05). On the other hand no significant differences were found in the levels of vitamin B 12 in the three groups, while reduced folate concentrations were found in women with unexplained female sterility and recurrent pregnancy loss (p < 0.05 vs control group. Discussion MTHFR C677T gene polymorphism is frequent in the studied populations. These data raise questions on the role of the homocysteine metabolism in sterility problems. Even though increased homocysteine (i.e. > 15 μM) and MTHFR C677T homozigosity have already been described as risk factors for recurrent pregnancy loss, few studies evaluated their role in women with unexplained sterility. Further studies on larger series are needed to better understand the role of homocysteine metabolism, including folate metabolism, in this clinical setting.

Background Clinical trials have shown low-molecular weight heparin (LMWH) to be at least as safe and efficacious as unfractionated heparin (UFH) for preventing venous thromboembolism (VTE) in acutely-ill medical inpatients. Objective To compare clinical and economic outcomes among acutely-ill medical inpatients receiving the LMWH enoxaparin versus UFH prophylaxis in clinical practice. Methods Using a large, multi-hospital, US database, we identified persons aged ≥40 years hospitalized for ≥6 days for an acute medical condition (including circulatory disorders, respiratory disorders, infectious diseases, or neoplasms) from Q4 1999 to Q1 2002. From these patients, those who received thromboprophylaxis with either enoxaparin or UFH were identified. Surgical patients and those requiring or ineligible for anticoagulation were excluded. We compared the incidence of deep-vein thrombosis (DVT), pulmonary embolism (PE), and all VTE (i.e., DVT and/or PE). Secondary outcomes were occurrence of side-effects, length of hospital stay and total costs. RESULTS: 479 patients received enoxaparin prophylaxis and 2,837 received UFH. The incidence of VTE was 1.7% with enoxaparin prophylaxis versus 6.3% with UFH (RR = 0.26; p < 0.001). Occurrence of side effects, length of stay (10.00 days with enoxaparin vs. 10.26 days with UFH; p = 0.348) and total costs ($18,777 vs. $17,602; p = 0.463) were similar in the 2 groups. Conclusion We observed a 74% lower risk of VTE among patients receiving enoxaparin prophylaxis versus UFH prophylaxis. There was no significant difference in side effects or economic outcomes. These results provide evidence that the LMWH enoxaparin is more effective than UFH in reducing the risk of VTE in current clinical practice.

Background Previous studies have suggested that exercise in patients with intermittent claudication (IC) may induce a systemic thrombo-inflammatory response. The effect of secondary prevention therapy on this response is unknown. This study aimed to investigate the effects of treadmill exercise on markers of coagulation activation, inflammation and renal function in patients with IC, receiving aspirin and statin therapy compared to healthy controls. Methods Samples were taken before, immediately and 1 hour after exercising on a treadmill in 20 patients with IC and 20 healthy volunteers. Interleukin-6 (IL-6), thrombin-anti-thrombin complex (TAT) and fibrin D-dimer were measured by ELISA. High sensitivity CRP (HsCRP) and urinary albumin were measured via a nephelometric technique, urinary protein via a turbidometric assay and N-acetyl-β-D-glucosaminidase (NAG) via a colorimetric assay. Results Elevated baseline levels of Hs-CRP, IL-6, white cell counts, D-dimer and urinary NAG occurred in patients with IC compared to volunteers (p > 0.05). Following exercise there was no increase in Hs CRP or IL-6. D-dimer levels significantly increased following exercise in the patients and volunteers. TAT levels increased immediately after exercise in the patient group only and were significantly increased at 1 hour in both patients and volunteers. A transient rise in the protein creatinine ratio occurred in both groups (p < 0.007), and in albumin creatinine ratio in the patient group. There was no change in urinary NAG. Conclusion Elevated markers of inflammation occurred in patients with IC on statin and aspirin therapy but these did not increase following exercise. However, acute exercise resulted in a prothrombotic state evident in both groups, although this was more prolonged in patient with IC. The clinical significance of these findings in patients who are known to be at an increased risk of cardiac and other thrombotic event are unclear.

Background An increased incidence of deep venous thrombosis (DVT) has been described in multiple myeloma (MM). A recently described mechanism of hypercoagulability in cancer patients including MM patients is acquired activated protein C resistance (APC-R). The purpose of the present study was to examine the association between the combination of thalidomide plus chemotherapy and DVT development in a cohort of patients with newly diagnosed multiple myeloma. We also evaluated the association between acquired activated protein C resistance and DVT. Methods Patients with newly diagnosed and symptomatic MM (untreated or with one cycle of preceding chemotherapy) were evaluated. The present study is a prospective, descriptive, longitudinal and observational one. The coagulations tests were performed including: prothrombin time, activated partial thromboplastic time (aPTT), fibrinogen, anticardiolipin antibodies, lupus anticoagulant, antithrombin, protein C and protein S activities, factor VIII, activated protein C (APC) resistance, factor V Leiden, and quantitative D-dimers. Factor V Leiden mutation was detected by analysis of the polymerase chain reaction amplification of genomic DNA. Results Fifty newly diagnosed multiple myeloma patients were included in the study. DVT was developed in 8 patients (16%). Six patients were confirmed to have acquired activated C protein resistance. All of them were tested twice. Four out of 6 patients developed DVT (66%), all of them received thalidomide at a median dose of 200 mg qd. Conclusion APC-R appears to be a transitional condition that may be related to myeloma status. Thrombotic complications can affect morbidity and even mortality in these patients. To fully evaluate the potential synergistic anticancer activity of combinations of chemotherapy and thalidomide, effective prophylactic anticoagulation should be implemented in all controlled trials, at least during the first few cycles of treatment.

Background Hyperhomocysteinemia is an important and independent risk factor for vascular disease. About 35% of patients with stroke and 47% of patients with peripheral arterial disease have elevated plasma homocysteine (HCY) concentrations. The relationship between plasma HCY and the methylentetrahydrofolate reductase (MTHFR) C677T polymorphism is still unclear, especially in regard to screening/diagnostic power. Methods This case-control study was performed on 96 patients, who underwent surgery due to asymptomatic or symptomatic high grade stenosis of the internal carotid artery (ICA), and 96 healthy age and sex-matched, controls. Plasma HCY concentration was determined using a commercial kit for fully automated analysis (AxSYM, Abbott). The C677T polymorphism of the MTHFR-gene was assessed by PCR. Results The mean plasma HCY concentration was significantly higher in the group with stenosis of ICA compared to the controls, 12.43 ± 6.96 μM and 10.16 ± 3.16 μM, respectively, (p < 0.05). An HCY plasma concentration of 1.5 SD above the mean value of the control group, was defined as cut-off for a pathological versus physiological plasma concentration. The sensitivity and specificity of HCY was 0.27 and 0.94, respectively. The positive predictive value was 0.82. There was no significant difference in the frequency of the MTHFR 677 CT and TT genotype between patients and controls (47% vs. 47% and 8.3% vs. 11.4%, respectively). Carriers of the T-allele (CT and TT genotypes) have significantly higher plasma HCY concentrations than CC patients, 14.1 ± 7.6 μM and 10.29 ± 5.2 μM, respectively, p < 0.05. Sensitivity and specificity of the MTHFR C677T polymorphism (T-allele) were 0.56 and 0.40, respectively. The positive predictive value was 0.48. There was no significant difference in plasma HCY or genotype frequency of the MTHFR C677T polymorphism between asymptomatic and symptomatic patients. Conclusion Our study shows that in a population with a given pretest disease probability of 50%, the determination of plasma HCY concentration, with a positive predictive value of 0.82, is more suitable for screening of patients at risk than analysis of the MTHFR C677T polymorphism.

Background Systemic sclerosis (SSc) is an autoimmune disorder of the connective tissue characterized by widespread vascular lesions and fibrosis. Little is known so far on the activation of the hemostatic and fibrinolytic systems in SSc, and most preliminary evidences are discordant. Methods To verify whether SSc patients might display a prothrombotic condition, plasma D-dimer was assessed in 28 consecutive SSc patients and in 33 control subjects, matched for age, sex and environmental habit. Results and discussion When compared to healthy controls, geometric mean and 95% confidence interval (IC95%) of plasma D-dimer were significantly increased in SSc patients (362 ng/mL, IC 95%: 361–363 ng/mL vs 229 ng/mL, IC95%: 228–231 ng/mL, p = 0.005). After stratifying SSc patients according to disease subset, no significant differences were observed between those with limited cutaneous pattern and controls, whereas patients with diffuse cutaneous pattern displayed substantially increased values. No correlation was found between plasma D-dimer concentration and age, sex, autoantibody pattern, serum creatinine, erythrosedimentation rate, nailfold videocapillaroscopic pattern and pulmonary involvement. Conclusion We demonstrated that SSc patients with diffuse subset are characterized by increased plasma D-dimer values, reflecting a potential activation of both the hemostatic and fibrinolytic cascades, which might finally predispose these patients to thrombotic complications.

Background Benign Intracranial Hypertension (BIH) may be caused, at least in part, by intracranial sinus thrombosis. Thrombosis is normally due to derangements in blood coagulation cascade which may predispose to abnormal clotting activation or deficiency in natural inhibitors' control. The aim of the study is to examine the strength of the association between risk factors for thrombosis and BIH. Patients and methods The incidence of prothrombotic abnormalities among a randomly investigated cohort of 17 patients with BIH, was compared with 51 healthy subjects matched for sex, age, body mass index, height and social background. Results The number of subjects with protein C deficiency was significantly higher in patients than in controls (3 vs 1, p < .001; Fisher Exact Test). Moderate to high titers of anticardiolipin antibodies (β2-Glycoprotein type I) were found in 8 out of 17 patients. Increased plasma levels of prothrombin fragment 1+2, fibrinopeptide A (FPA), and PAI-1 were demonstrated in patients group (5.7 ± 1.15 nM vs 0.45 ± 0.35 nM; 8.7 ± 2.5 ng/mL vs 2.2 ± 1.25 ng/mL; 45.7 ± 12.5 ng/mL vs 8.5 ± 6.7 ng/mL, respectively; p < .001; Fisher Exact Test). Gene polymorphisms for factor V Leiden mutation, prothrombin mutation 20210 A/G, MTHFR 677 C/T, PAI-1 4G/5G, ACE I/D were detected in 13 patients. Discussion In agreement with other authors our data suggest a state of hypercoagulability in BIH associated with gene polymorphisms. Our findings also showed that mutations in cardiovascular genes significantly discriminate subjects with a BIH history. The association between coagulation and gene derangements, usually regarded to as cryptogenic, may suggest a possible pathogenetic mechanism in BIH. So, a prothrombotic tendency may exist that would, at least in part, explain some cases of BIH. Although based on a small population, these findings raise the exciting possibility of using these haemostatic factors as markers for selecting high-risk subjects in BIH disease.

Background There are controversial evidences on the effect of different types and workloads of physical exercise on primary hemostasis. In particular, little is known on the chronic influence of a strenuous and regular aerobic training regimen on platelet function. Methods The aim of this investigation was to compare platelet function between sedentary controls and trained athletes at rest and to evaluate whether a greater amount of exercise performed in professional cyclists may contribute to increased platelet chronic responsiveness compared to both elite cyclists and sedentary individuals. Platelet's ability to adhere and aggregate was assayed following a 12–24 h resting period in 49 active professional male road cyclists, 40 elite male cyclists and 43 matched sedentary healthy male volunteers, by the platelet function analyzer 100 (PFA-100). Results and discussion Mean values of the collagen-epinephrine test did not differ between controls and athletes (sedentary controls: 111 ± 33 s; elite athletes: 113 ± 26 s, p = 0.93; professional athletes: 120 ± 33 s; p = 0.33), whereas mean values of the collagen-ADP test displayed a slightly but significant trend towards decreased values when comparing sedentary controls (83 ± 21 s) with either elite (77 ± 11 s, p < 0.01) or professional (75 ± 16 s, p < 0.01) athletes. Conclusion The trend towards slightly lower collagen-ADP values are suggestive for a modest but significant chronic activation of primary hemostasis, highlighting the need to set appropriate reference ranges for the PFA-100 when evaluating primary hemostasis in physically active subjects.