Anticoagulant-treated Patients Research Articles

Effectiveness and safety of anticoagulants among patients with venous thromboembolism and common cancers or cancers with high venous thromboembolism risk.

Aim: Treatment effects among anticoagulant-treated patients with venous thromboembolism (VTE) and cancer across tumor types were evaluated. Methods: Patients initiating an anticoagulant within 30days after VTE were identified. After inverse probability treatment weighting, patients were stratified by tumor type. Interactions between treatment and tumor type on recurrent VTE, major bleeding and clinically relevant non-major bleeding were assessed using Cox proportional hazard models. Results: Treatment effects were generally not significantly different among patients with or without the following cancer types: prostate, breast, lung, pancreatic or multiple myeloma. Few significant interactions were observed for lung and pancreatic cancer. Conclusion: Anticoagulant treatment effects were generally consistent across tumor types. The significant interactions may indicate tumor-specific effects of anticoagulants, but further research is needed.

Safety of expedited-surgery protocols in anticoagulant-treated patients with hip fracture: a systematic review and meta-analysis.

Perioperative management of patients with hip fracture patients receiving oral anticoagulants requires navigating the risks associated with surgical delay and perioperative hemostasis. The aim of this systematic review and meta-analysis was to evaluate the effect of expedited-surgery protocols on time to surgery and perioperative outcomes in anticoagulant-treated patients with hip fracture. We searched MEDLINE, Embase and CENTRAL from inception to May 5, 2020, to identify English-language studies reporting outcomes after expedited hip fracture surgery in patients receiving vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) before hospital admission. We performed a meta-analysis using Mantel-Haenszel weighting for dichotomous variables and inverse variance weighting for continuous variables. Among the 4253 citations identified, 14 studies were included. In the 6 studies eligible for meta-analysis, compared to hip fracture surgery before implementation of a VKA-reversal protocol, surgery after implementation of such a protocol was associated with a significant reduction in time to surgery (mean difference 45.31 h, 95% confidence interval [CI] 15.81 h to 74.80 h). Expedited surgery (within 48 h) in patients who received DOACs preoperatively was not associated with increased surgical duration (mean difference -7.29 min, 95% CI -22.5 min to 7.95 min) or 30-day mortality (odds ratio [OR] 1.30, 95% CI 0.49 to 3.89) compared to patients who did not receive anticoagulants (control patients). However, expedited surgery in DOAC-treated patients was associated with an increased blood transfusion risk compared to control patients (OR 0.58, 95% CI 0.36 to 0.96). Implementing a VKA-reversal protocol for patients with hip fracture is effective in decreasing time to surgery, without an increased bleeding risk. Performing hip fracture surgery within 48 hours in DOAC-treated patients is also safe, with a small increase in blood transfusion risk.

Thrombin generation in real life bleeding patients on oral anticoagulants reversed (or not) with (activated) prothrombin complex concentrate

BackgroundBleeding during oral anticoagulant therapy is currently codified by expert guidelines. Monitoring of coagulation during bleeding events is challenging. Our study sought to assess thrombin generation assay (TGA) in direct oral anticoagulant-treated patients without bleeding (WB), bleeding without reversal therapy (BR-), and bleeding with reversal therapy (BR+). MethodsWe conducted a prospective, monocentric study from June 2015 to June 2018. For all bleeding groups, TGA was evaluated using platelet-poor plasma collected upon arrival at emergency (T0), and 30 min (T1), 6 h (T2) and 24 h (T3) after reversal therapy (if indicated) following activation by tissue factor 5 pM and phospholipids. ResultsOverall, 292 patients participated, including 91 BR+, 94 BR-, and 107 WB patients. At T0, vitamin K antagonist reversed (VKA-BR+) patients experienced a significant decrease in TGA parameters (ETP and peak) compared with VKA without bleeding (VKA-WB). Compared with healthy controls, VKA-BR+ patients reversed by four-factor prothrombin complex concentrate (4F-PCC) displayed comparable TGA ‘s ETP and peak at T1, T2, and T3, whereas direct anti-Xa BR+ patients reversed by 4F-PCC or activated prothrombin complex concentrate (aPCC) reached thrombin generation parameters that exceeded normal range at T2 and T3. ConclusionsIn VKA-treated patients reversed by 4F-PCC, TGA parameters were normalized, whereas in rivaroxaban or apixaban-treated patients reversed by 4F-PCC or aPCC, TGA parameters exceeded normal range. Further studies are needed to compare the efficacy and safety of a different dose of reversal therapy and the impact on coagulation parameters.

Efficacy and Safety of Antithrombotic Therapy With Oral Anticoagulants in Real-World Elderly Patients With Acute Coronary Syndrome and Atrial Fibrillation.

BackgroundThe efficacy and safety of antithrombotic treatment with oral anticoagulants (OACs) in elderly patients with comorbidities of acute coronary syndrome (ACS) and atrial fibrillation (AF) are unclear.MethodsA cohort of hospitalized elderly patients (≥65 years of age) diagnosed with ACS and AF and treated with oral antithrombotic agents were consecutively recruited. Follow-up was performed for at least 1 year. Major adverse cardiac events (MACEs) were defined as a composite of all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke, and systemic embolism. The safety outcomes of bleeding were defined according to the Bleeding Academic Research Consortium (BARC) criteria.ResultsA cohort of 548 eligible patients (76 ± 6.6 years) was analyzed. Compared to the patients with OAC treatment (n = 184, 33.6%), patients treated without OAC (n = 364, 66.4%) were older, had a lower prevalence of persistent AF and unstable angina (UA), and more often presented with paroxysmal AF, acute myocardial infarction (AMI), stent implantation and dual antiplatelet therapy (DAPT). Compared to the patients without OAC treatment (n = 364, 66.4%), patients treated with OAC (n = 184, 33.6%) had a lower risk of MACEs at both the 1-year (4.3 vs. 15.1%, adjusted HR: 0.34, 95% CI: 0.15–0.80, p = 0.014) and 5-year (17.5 vs. 48.4%, adjusted HR: 0.36, 95% CI: 0.19–0.67, p = 0.001) follow-up. No significant difference was observed for bleeding events of BARC ≥2 between the groups (8.0 vs. 9.0%, adjusted HR: 1.17, 95% CI: 0.58–2.34, p = 0.667). Compared with warfarin-treated patients, the non-vitamin K antagonist oral anticoagulant-treated patients had lower risks of all-cause mortality (2.1 vs. 9.5%, HR: 0.18, 95% CI: 0.03–0.98, p = 0.047) and bleeding events of BARC ≥ 3 (2.1 vs. 4.8%, HR: 0.14, 95% CI: 0.02–1.10, p = 0.062).ConclusionsAntithrombotic therapy with OACs in elderly patients with ACS and AF was associated with a lower risk of ischemic events without an increase in bleeding events. In real-world practice, the clinical awareness of anticoagulation treatments in elderly patients with ACS and AF needs to be strengthened.

Predicting recurrence of venous thromboembolism in anticoagulated cancer patients using real-world data and machine learning.

e18742 Background: The clinical predictors of venous thromboembolism (VTE) recurrence in patients with cancer are not well known. Our objective was to develop a predictive model for risk of VTE recurrence in anticoagulant-treated cancer patients within the first 6 months following VTE diagnosis. Methods: Using the EHRead technology, based on Natural Language Processing (NLP) and machine learning (ML), the unstructured clinical data in EHRs from 9 Spanish hospitals between 2014 and 2018 was extracted and analyzed. The study population, comprising all adult anticoagulated cancer patients with VTE, was downsampled to prevent bias and class imbalance. A total of 94 patient characteristics were explored, and Random Forest (RF) feature selection was performed to identify the most relevant predictors for VTE recurrence. Multiple algorithms were used to train different prediction models, which were subsequently validated in a hold-out dataset. The model with the best performance metrics (i.e., ROC-AUC) was selected as the final model. Results: From a source population of 2,893,208 patients, 21,227 anticoagulant-treated patients with VTE and active cancer (53.9% male, median age of 70 years) were identified. Across the study period, yearly incidence of VTE remained relatively stable, ranging from 2.7 to 3.9%. The most common type of VTE was deep vein thrombosis (68.2% of patients), followed by pulmonary embolism (28.4%). Regarding primary cancer locations, the most frequent were colorectal (10.1%) and lung cancer (8.5%). Of all trained and validated models, the RF approach yielded the best performance, with a ROC-AUC = 0.72. The following predictors of VTE recurrence were identified: pulmonary embolism, deep vein thrombosis, metastasis, adenocarcinoma, hemoglobin values, serum creatinine values, platelet count, leukocyte count, family history of VTE, and patients’ age. Conclusions: Using NLP and ML, we were able to use the real-world data in EHRs to build a predictive model of VTE recurrence in cancer patients based on individual clinical features. These results may improve the clinical management of VTE recurrence in this population.

Predicting major bleeding events in anticoagulated cancer patients with venous thromboembolism using real-world data and machine learning.

e18744 Background: Evidence regarding the clinical predictors of bleeding risk in patients with cancer and venous thromboembolism (VTE) is lacking. Our aim was to develop a predictive model to assess the risk of major bleeding (MB) in anticoagulant-treated patients with active cancer during the first 6 months following VTE diagnosis. Methods: Observational, retrospective, and multicenter study based on the secondary analysis of unstructured clinical data in electronic health records (EHRs). Using the EHRead technology, based on Natural Language Processing (NLP) and machine learning (ML), data were collected from EHRs from 9 Spanish hospitals between 2014 and 2018. The study population comprised all adult cancer patients with a diagnosis of VTE under anticoagulant treatment and no history of MB. This population was downsampled to prevent bias and class imbalance. A total of 94 patient characteristics were explored, and Random Forest (RF) feature selection was performed to identify the most relevant predictors. Multiple algorithms were used to train different prediction models, which were subsequently validated in a hold-out dataset. The model with the best performance metrics (i.e., ROC-AUC) was selected as the final model. Results: Among a source population of 2,893,208 patients, 21,227 anticoagulant-treated patients with VTE and active cancer were identified from EHRs. Of these, 53.9% men, with a median age (Q1, Q3) of 70 (59,80) years. The median duration of follow up across all patients was 0.7 (0.11, 2.03) years. During the study period, estimated in-hospital prevalence of cancer-related VTE was 5.8 %. The most common type of VTE at baseline was deep vein thrombosis (68.2 % of patients), followed by pulmonary embolism (28.4%). The most frequent primary cancers were colorectal (10.1%) and lung cancer (8.5 %). Of all trained and validated models, the RF approach yielded the best performance, with a ROC-AUC = 0.7. The following predictors of MB were identified: hemoglobin levels, presence of metastasis, patient’s age, platelet count, leukocyte count, and serum creatinine levels. Conclusions: This is the first multicenter study to use NLP to extract the unstructured information from EHRs to develop a predictive model for MB in anticoagulated cancer patients with VTE. These results may improve the prevention and management of bleeding in these patients.

Hematoma duodenal intramural post biopsia endoscópica: una complicación inusual. Reporte de un caso pediátrico

The intramural duodenal hematoma is a rare but well-known collateral complication after an endoscopic biopsy. It is more frequent after abdominal trauma or therapeutic endoscopy and even more in anticoagulant-treated patients or those with coagulation disorders. Clinical presentation consists of the symptoms and the signs of the intestinal obstruction, the pancreatitis and the conjugated hyperbilirubinemia. We report a pediatric case of a five-year-old female patient who was being checked for celiac disease. Without known previous bleeding or coagulation disorders, she presented a intramural duodenal hematoma with pancreatitis as a complication of the endoscopic biopsy procedure. A summary of the symptomatology and the signs, the diagnosis, the conservative treatment and evolution is described and also a reminder to paediatric endoscopists to be aware that this unusual complication can occur. This case presents the possibility that an intramural duodenal hematoma can be a complication of a duodenal endoscopic biopsy in patients with no coagulations disorders. This hematoma subsided with a non-surgical treatment (conservative), assisted by the joint work of a pediatric gastroenterologist and surgeon.

The Risk of Major Bleeding in Patients with Suspected Heparin-Induced Thrombocytopenia (HIT)

Introduction: Without prompt treatment, heparin-induced thrombocytopenia (HIT) is associated with a daily rate of life- and limb-threatening thrombosis of 6.1%. Current recommendations are to empirically treat a patient with an intermediate or high pre-test likelihood of HIT with a non-heparin (alternative) anticoagulant while awaiting HIT laboratory test results. The real-world bleeding rates of empiric treatment with an alternative anticoagulant in patients with suspected HIT have not been well-described. We assessed the rates of major bleeding in a prospective cohort of patients with suspected HIT. Because HIT is generally considered a prothrombotic and not a prohemorrhagic disorder, we hypothesized that major bleeding would be less common in alternative anticoagulant-treated patients with HIT than in treated patients who were ultimately determined not to have HIT.Methods: From June 2012 to January 2015, we enrolled 310 patients with suspected HIT at the Hospital of the University of Pennsylvania and an affiliated community hospital. All patients underwent HIT laboratory testing with a poly-specific PF4/heparin ELISA and in-house serotonin release assay. Patients were adjudicated to be HIT-positive or HIT-negative by an independent adjudication panel of HIT experts based on clinical course and results of HIT laboratory testing. We retrospectively reviewed the electronic health record to assess for the presence of a major bleeding event from the time of suspicion of HIT until hospital discharge or death. Major bleeding events were defined by International Society on Thrombosis and Haemostasis (ISTH) criteria (fall in hemoglobin ≥2 g/dL, transfusion of ≥2 units of packed red blood cells, fatal bleed, bleed occurring in a critical organ and/or requiring a repeat surgical intervention). Secondary outcomes of progressive or new thrombosis following suspicion of HIT testing, in-hospital and 30-day mortality were also assessed. Patients were considered to be treated for suspicion for HIT if they received an alternative anticoagulant following a HIT laboratory test order. The demographics and clinical features of patients defined by adjudicated HIT status were compared using the Wilcoxon test and chi-square tests for continuous and for categorical variables, respectively. The proportion of bleeding and thrombotic events were compared between groups using a chi-square test. All analyses were performed using Stata v14.2.Results:The demographics of our cohort by adjudicated HIT status are displayed in Table 1. 44 patients in the cohort were adjudicated to be HIT-positive and 266 were adjudicated HIT-negative. 42/44 (95.5%) HIT-positive patients and 116 of 266 (43.6%) HIT-negative patients received an alternative anticoagulant.Of those who were empirically treated with an alternative anticoagulant, the median duration of treatment was 3 days (IQR 2-5.5) in HIT-negative patients, compared with 11.5 days (IQR 6-16) in the HIT-positive group (p=0.001). The majority of treated patients received argatroban (88.0% of HIT-positive patients and 76.7% of HIT-negative patients). In those patients who received an alternative anticoagulant, a major bleeding event occurred in 40.9% of HIT positive patients and 44.8% HIT negative patients (p=0.45).The majority of major bleeding events met ISTH criteria based on hemoglobin fall or blood transfusion (Table 2). New or progressive thrombosis following suspicion for HIT was more common in HIT-positive patients (35.7%) than in patients who were HIT-negative and treated (15.5%) or not treated (11.3%) (p=0.001) (Table3).Conclusions:Contrary to our hypothesis, HIT was not protective against bleeding. A similar proportion of HIT-positive patients had ISTH major bleeding compared with HIT-negative patients treated with an alternative anticoagulant. The current paradigm for empiric treatment of patients with suspected HIT may need to be reconsidered in light of our findings of greater than expected bleeding associated with treatment. Limitations of our study include relatively small size, recruitment from a single health system, and predominant use of a single alternative anticoagulant (argatroban). Further studies are needed to determine whether our results apply to other centers and other alternative anticoagulants. [Display omitted] DisclosuresPishko:Novo Nordisk: Research Funding. Cuker:Synergy: Consultancy; Genzyme: Consultancy; Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Research Funding.

Risk factors for hepatic veno-occlusive disease caused by Gynura segetum: a retrospective study

BackgroundHepatic veno-occlusive disease (HVOD) caused by Gynura segetum has been increasingly reported in China in recent years. The aim of this retrospective study was to identify independent prognostic markers for survival in patients with Gynura segetum-induced HVOD and to evaluate the effect of anticoagulants and transjugular intrahepatic portosystemic shunt (TIPS) on survival rate.MethodsClinical data including symptoms, signs, imaging characteristics, laboratory test results, results of liver tissue biopsies, type of treatment during follow-up and clinical outcomes were collected. Univariate, multivariate and time-dependent Cox regression analyses were performed.ResultsSurvival rates were 91% (95% confidence interval [CI], 82–95%), 64% (95% CI, 53–69%) and 57% (95% CI, 51–65%) at 1, 3 and 60 months, respectively. Total bilirubin, albumin and hepatic encephalopathy were independent prognostic markers of survival. Anticoagulants were administered to 76% of the patients. Among 75 patients treated with anticoagulants, 49 patients (65.3%) were cured, whereas 26 patients (34.7%) died; the cure rate in anticoagulant-treated patients was higher than that of those not treated with anticoagulants (χ2 = 9.129, P = 0.004). Cure rate of the anticoagulation + TIPS treatment group was 64.3%, which was also higher than that of the non-anticoagulation group; however, this was not significantly different (χ2 = 3.938, P = 0.096).ConclusionsThe presence of hepatic encephalopathy, serum bilirubin and albumin levels were major prognostic factors for Gynura segetum-induced HVOD. Anticoagulation therapy significantly increased the cure rate; however, TIPS treatment did not have a beneficial effect on the cure rate.

Anticoagulation in patients with isolated distal deep vein thrombosis: a meta‐analysis

Background The optimal management of patients with isolated distal deep vein thrombosis (IDDVT), concerning both the need for anticoagulation and its duration, is undefined. Objectives We performed a meta-analysis of randomized and cohort studies in patients with IDDVT to assess the clinical benefit of: (i) anticoagulation versus no anticoagulation; and (ii) anticoagulant treatment for 6weeks versus for >6weeks. Methods The primary outcome of this analysis was recurrent venous thromboembolism (proximal propagation, recurrence of deep vein thrombosis, and pulmonary embolism). Data were pooled and compared by the use of odds ratio (OR) and 95% confidence interval (CI). Results A reduction in the rate of recurrent venous thromboembolism was observed in patients who received anticoagulation relative to those who did not receive anticoagulation (either therapeutic or prophylactic) (20 studies, 2936 patients; OR0.50, 95%CI0.31-0.79), without an increase in the risk of major bleeding (OR0.64, 95%CI0.15-2.73). The rate of pulmonary embolism was lower in anticoagulant-treated patients than in controls (15 studies, 1997 patients; OR0.48, 95%CI0.25-0.91). A lower rate of recurrent venous thromboembolism was observed in patients who received >6weeks of anticoagulant therapy than in those who received 6weeks of anticoagulant therapy (four studies, 1136 patients; OR0.39, 95%CI0.17-0.90). Conclusions In patients with IDDVT, anticoagulation (both therapeutic and prophylactic) reduces the rate of recurrent venous thromboembolism and the incidence of pulmonary embolism as compared with no anticoagulation, without an increased risk of major bleeding. Anticoagulation for >6weeks should be preferred over shorter durations.

Traumatic events involving elderly patients treated with anticoagulants for atrial fibrillation: the downside of stroke prevention

A group of oral anticoagulant-treated patients affected by permanent atrial fibrillation was evaluated after their access to the emergency room as a result of a traumatic accident. In these patients, the re-evaluation of their risk of thromboembolism and bleeding was performed together with the evaluation of their risk of falling and institutionalization. Results show that the emergency department identifies a cohort of very elderly frail patients, who should be carefully reconsidered for anticoagulant therapy after a traumatic event.

A systematic review on the effect of aspirin in the prevention of post-operative arterial thrombosis in patients undergoing total hip and total knee arthroplasty

IntroductionMajor surgery is associated with increased risk of venous thromboembolism (VTE), which is decreased by anticoagulant drugs. Evidence is growing that major surgery is associated with increased risk of arterial thrombosis (AT). With the aim of testing aspirin ability in reducing the risk of post-operative AT, we performed a systematic review of studies in which acetylsalicylic acid (ASA) was compared to anticoagulant drugs in VTE prophylaxis of patients undergoing total hip replacement (THR) or total knee replacement (TKR). Materials and MethodsStudies were identified by reviewing the reference of the ACCP guidelines and by electronic search of MEDLINE database from January 2012 to December 2013 and of the web database www.trialresultscenter.org. ResultsWe analyzed 5 of the 78 studies that were identified by our search strategy; they included 5179 patients; the median follow-up was 90days. The incidence of post-operative AT tended to be lower in ASA-treated patients, compared to anticoagulant-treated patients, although the difference did not reach statistical significance (OR 0.56, 95%CI 0.23-1.35). In contrast, the incidence of post-operative VTE tended to be higher in ASA-treated patients, compared to anticoagulant-treated patients (1.48, 95% CI 0.93-2.36). ConclusionsDue to the heterogeneity and low quality of the studies, which do not allow firm conclusions, it is uncertain whether aspirin is effective in reducing the incidence of postoperative AT. Our results do emphasize the need for developing specifically designed studies to test the safety and efficacy of ASA in the prevention of post-operative AT.

Introduction of Point-of-Care Testing in Japanese Outpatient Clinics Is Associated With Improvement in Time in Therapeutic Range in Anticoagulant-Treated Patients

Warfarin reduces the risk of stroke in patients with atrial fibrillation, but requires a moderate-to-high time in therapeutic range (TTR). We hypothesized that point-of-care (POC) testing for prothrombin time-internationalized normalized ratio (PT-INR) could improve the TTR in patients receiving warfarin. Eight outpatient clinics that introduced POC testing for PT-INR participated in this study. We identified 148 consecutive patients who received warfarin for at least 12 months before and after the introduction of POC testing. We compared the TTR before and after the introduction of POC testing for each patient. TTR after the introduction of POC testing was significantly higher than that beforehand (51.9%±33.0% vs. 69.3%±26.3%; P<0.0001). The improvement in TTR was statistically significant in patients who had low TTR (<70%) before the introduction of POC testing. After the introduction of POC, the time spent above the target INR showed no significant change (3.7%±10.6% vs. 3.3%±6.3%, P=0.7322), while that spent below the target INR improved significantly (44.4%±34.4% vs. 27.4%±27.6%, P<0.0001). The introduction of POC testing was associated with an improvement in TTR, mainly through a reduction in the time spent below the target INR.

GENETIC FACTORS INFLUENCING THE EFFECTIVENESS AND SAFETY OF LONG-TERM ANTICOAGULANT THERAPY

Late postoperative thrombotic and haemorrhagic complications in anticoagulant-treated patients remain one of the key problems of the modern clinical medicine. At present, the most widely used anticoagulant is warfarin, a vitamin K antagonist. One of the reasons for a pathological reaction to the therapeutic concentration of warfarin could be individual features of warfarin metabolism, determined by relevant genes. The literature data suggest that protein-coding CYP2C9 and VKORC1 genes play an important role in the development of postoperative complications. However, the individual warfarin dosage can be influenced by a wide range of other genetic polymorphisms.

Effect of New Direct Oral Anticoagulants on Ex Vivo Platelet and Fibrin Thrombus Formation in Blood Flowing Over Fibrillar Type I Collagen

Abstract 2318 Background.Studies have shown that 40–85% of patients undergoing total knee replacement develop venographically confirmed deep vein thrombosis (DVT) if not given post-operative thromboprophylaxis; approximately 0.1 to 1.7% of these patients will suffer fatal pulmonary embolism (PE). Oral anti-vitamin K anticoagulants are effective for the prevention and treatment of venous thrombosis, but have limitations. In particular, they have multiple food and drug interactions as well as variable pharmacokinetics and pharmacodynamics, such that regular laboratory monitoring and dose adjustments are required to maintain an optimal therapeutic range as defined with the International Normalized Ratio (INR). New oral agents that inhibit coagulation factor Xa or thrombin have been developed and shown to be effective and safe without requiring laboratory monitoring. In view of the relevance of the latter point, we have studied patients treated with an oral anti factor Xa agent (Rivaroxaban) or Coumadin, and evaluated the antithrombotic efficacy of the respective drugs by measuring platelet aggregation and fibrin deposition in patient blood perfused over fibrillar collagen type I. Material and Methods. Blood drawn from an antecubital vein and containing 0.011 M trisodium citrate as anticoagulant was recalcified with 5 mM calcium chloride and immediately perfused through a rectangular chamber mounted on the stage of a confocal microscope and presenting a surface coated with fibrillar collagen type I under laminar flow conditions at the wall shear rate of 300 1/s. Platelets and fibrin were specifically detected in situ through distinct fluorochromes. We tested 8 normal controls, 8 patients treated with Coumadin and a stable INR value between 1.94 and 2.90 (mean 2.34; standard deviation 0.34), and 7 patients treated with Rivaroxaban at between 8 and 16 days (mean 12.14; standard deviation 2.48 days) from the initiation of therapy. The volume of platelet aggregates and fibrin deposited onto the collagen fibrils was measured distinctly from stacks of confocal sections by integrating surface coverage of each thrombus component in consecutive optical planes separated by 2 micrometers in height. Results and Discussion. There was no significant difference in the volume of platelet and fibrin aggregates formed in blood of normal control and patients treated with either Coumadin or Rivaroxaban. This result was surprising because the patients treated with Coumadin had a laboratory demonstration of significantly retarded coagulation. We reasoned, however, that coagulation tests are typically performed in platelet-poor plasma, while in the perfusion assay coagulation occurs in whole blood and on a surface onto which flowing platelets are fully activated, thus increasing the local procoagulant potential. For this reason, we performed a series of experiments in which a variable amount of a highly specific thrombin inhibitor, lepirudin, was titrated into the recalcified blood before perfusion. We thus determined that with 50 nM lepirudin added to blood there was no decrease in the volume of platelet aggregates and fibrin deposited onto collagen in blood of normal individuals, while the volume of fibrin was decreased in patients receiving either Coumadin or Rivaroxaban. The corresponding values for normal controls, Coumadin-treated and Rivaroxaban-treated patients, in the order, were (mean volume ± standard error of the mean in cubic micrometers): Platelet aggregates = 28,592±3,354; 36,959±4,973; 44,448±7,110; Fibrin = 84,190±9,740; 47,298±7,308; 35,780±5,091. The differences in platelet aggregate volumes were not significant, while fibrin volume was significantly smaller in the anticoagulant-treated patients as compared to normal (p<0.01 for Coumadin and p<0.001 for Rivaroxaban); the difference between patients treated with one or the other anticoagulant was not significant. These results show that Rivaroxaban and Coumadin at therapeutically effective dosage have comparable effect in reducing thrombin generation, as evidenced by the reduced volume of fibrin formed in flowing blood exposed to collagen. This, however, is accompanied by an increased volume of platelet aggregates on the highly thrombogenic collagen surface. The relevance of these experimental results with respect to prevention of arterial as opposed to venous thrombosis deserves further investigation. Disclosures:No relevant conflicts of interest to declare.

A modified method of prothrombin time/International Normalised Ratio determination in capillary blood and monitoring oral anticoagulant therapy

Oral anticoagulant therapy is monitored by a prothrombin time (PT) assay. The PT is standardised by the International Normalised Ratio (INR). The purpose of this study was to work out a modified method of PT/INR measurement in capillary blood for monitoring anticoagulation treatment. Healthy donors, subjects with high or low haematocrit values, and oral anticoagulant-treated patients were included in the study. Plasma and capillary blood PT/INRs were determined by the standard Quick clotting assay, by the modified approach and with the CoaguChek S analyser. The performance characteristics of the developed method were accuracy, due to taking into account whole capillary blood haematocrit values, and precision, due to a decrease in the viscosity of the analysed samples. Implementation of the modified method showed that it is possible to use PT values of normal plasma for capillary blood INR calculation. The developed method allowed the determination of PT in capillary blood within the haematocrit value range from 0.15 up to 0.7. For capillary blood, the results of the modified method closely correlated with PT/INR values determined by the reference Quick method in venous plasma (r=0.99) and with the CoaguChek S analyser (r=0.97). The modified method of capillary blood PT/INR determination could be recommended for oral anticoagulant therapy monitoring.

Novel hemostatic alternatives in reconstructive surgery

Congenital vascular lesions are classed as hemangiomas, vascular malformations, or vascular tumors according to their histology and etiology. The majority of hemangiomas are benign and often involute before the child reaches the age of 12. Severe hemangiomas and vascular malformations were historically viewed as effectively inoperable due to the high risk of potentially catastrophic bleeding during surgery. An effective system of classification and increasing range of therapeutic options have improved the prognosis for many patients, but surgical resection of these lesions remains a serious undertaking. Topical hemostatic agents are widely used and effective in many cases for the control of intraoperative bleeding. The main limitations of these agents are their variability and lack of efficacy in severe bleeding, or in coagulopathic or anticoagulant-treated patients. This paper reviews recent developments in this field, including the possible placental origin of hemangiomas, and discusses current approaches to hemostasis during reconstructive surgery. We also discuss the recent introduction of recombinant activated factor VII (rFVIIa) as a systemic hemostatic agent, including our own experience using this treatment.

Comparing r-Tissue Factor and Mammalian Tissue Reagents for Prothrombin Time

We compared two recombinant human tissue factor (r-TF) prothrombin time (PT) reagents with two commercially available mammalian PT reagents. The two r-TF reagents were more sensitive to the lower concentrations of factors II, VII, IX, andX. The r-TF preparations were found to give longer clotting times than the mammalian thromboplastins when plasma samples from oral anticoagulant–treated patients were tested. When international normalized ratios (INRs) were calculated, however, no significant differences were noted among reagents when INR values were less than or equal to 3.0; however, at INR values greater than 3.0, differences were noted. The r-TF was more sensitive to the thrombin inhibitors than were heparins. Because of different origins and composition, the currently available thromboplastin reagents are not equivalent, and the results obtained from these should be interpreted carefully.

Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction

The use of long-term oral anticoagulant treatment after myocardial infarction remains controversial because of conflicting findings on mortality in previous trials and the increased risk of bleeding associated with anticoagulants. We have carried out a randomised, placebo-controlled, double-blind, multicentre trial in 3404 hospital survivors of myocardial infarction. Eligible patients were randomly assigned to anticoagulant (nicoumalone or phenprocoumon) or placebo treatment within 6 weeks of discharge. The target prothrombin time was 2·8-4·8 international normalised ratio. During mean follow-up of 37 (range 6-76) months there were 170 deaths among 1700 anticoagulant-treated patients and 189 in 1704 placebo-treated patients (hazard ratio 0·90 [95% Cl 0·73-1·11]). Anticoagulant treatment led to significant reductions by comparison with placebo treatment in recurrent myocardial infarction (114 vs 242 patients; hazard ratio 0·47 [0·38-0·59]) and cerebrovascular events (37 vs 62; 0·60 [0·40-0·90]). Major bleeding complications were seen in 73 patients who received anticoagulants and 19 who received placebo. We conclude that long-term oral anticoagulant treatment after myocardial infarction in low-risk patients has a limited effect on mortality but achieves substantial benefit by reducing the risk of cerebrovascular events and recurrent myocardial infarction.

Tranexamic acid as a mouthwash in anticoagulant-treated patients undergoing oral surgery: An alternative method to discontinuing anticoagulant therapy

A double-blind randomized study was carried out to evaluate the clinical hemostatic effect of tranexamic acid mouthwash after dental extraction in 30 patients who received anticoagulant agents. Surgery was performed with a reduction in the level of anticoagulant therapy in the control group and with no change in the level of anticoagulant therapy in the group who received the tranexamic acid. After the extraction the surgical field was irrigated with a 5% solution of tranexamic acid in the group of 15 patients whose anticoagulant treatment had not been discontinued and with a placebo solution in the group of 15 patients for whom the anticoagulant therapy was reduced. Patients were instructed to rinse their mouths with 10 ml of the assigned solution for 2 minutes four times a day for 7 days. There was no significant difference between the two treatment groups in the bleeding incidence after oral surgery. We conclude that the anticoagulant treatment does not need to be withdrawn before oral surgery provided that local antifibrinolytic therapy is instituted.