Application of Activators Ecarin and Factor Xa in Thrombelastography for Measurement of Anticoagulant Effect of Direct Oral Anticoagulants Using TEG 5000.

There are situations where monitoring direct oral anticoagulants (DOACs) would be useful, including bleedings and trauma. The thromboelastographic technique has proven useful in bleeding situations in trauma and heart surgery. The aim of this study was to examine the effect of DOACs on all currently commercially available conventional TEG®5000 assays as well as novel modified assay using Ecarin and human factor Xa (HFXa). Healthy male volunteers were given single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg. Kaolin, RapidTEG, functional fibrinogen, PlateletMapping assay, and novel modified assays using Ecarin and HFXa were prepared. All TEG parameters were recorded. DOAC concentrations were correlated to the parameters with highest response to the DOAC effect. Sensitivity and negative predictive value of the parameter with highest response to DOAC concentration of 50 ng/mL was calculated. None of the conventional TEG assays demonstrated significant response to the effect on apixaban. Using Ecarin, reaction time R was strongly correlated with dabigatran concentrations. Using HFXa assay, R was strongly correlated with rivaroxaban and apixaban concentrations: r = 0.96, 0.84, and 0.86, respectively; p < 0.0001 for all. The R times obtained with the modified assays demonstrated strong sensitivity and negative predictive values for DOAC levels of ≥50 ng/mL. We have demonstrated that TEG®5000 can monitor the DOAC effect on hemostasis when the appropriate activator is used with significant correlation with DOAC concentrations. Larger clinical studies are warranted for correlation of TEG profile and clinical outcomes.

Cancer associated thrombosis in everyday practice: perspectives from GARFIELD-VTE.

Venous thromboembolism (VTE) is common in cancer patients and is an important cause of morbidity and mortality. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE (ClinicalTrials.gov: NCT02155491) is a prospective, observational study of 10,684 patients with objectively diagnosed VTE from 415 sites in 28 countries. We compared baseline characteristics, VTE treatment patterns, and 1-year outcomes (mortality, recurrent VTE and major bleeding) in 1075 patients with active cancer, 674 patients with a history of cancer, and 8935 patients without cancer. Patients with active cancer and history of cancer were older than cancer-free patients, with median ages of 64.8, 68.9, and 58.4 years, respectively. The most common sites of active cancer were lung (14.5%), colorectal (11.0%), breast (10.6%), and gynaecological (10.3%). Active cancer patients had a higher incidence of upper limb and vena cava thrombosis than cancer-free patients (9.0% vs 4.8% and 5.1% vs 1.4%, respectively), and were more likely to receive parenteral anticoagulation as monotherapy than cancer-free patients (57.8% vs 12.1%), and less likely to receive DOACs (14.2% vs 50.6%). Rates of death, recurrent VTE, and major bleeding were higher in active cancer patients than in cancer-free patients, with hazard ratios (95% confidence intervals) of 14.2 (12.1-16.6), 1.6 (1.2-2.0) and 3.8 (2.9-5.0), respectively. VTE was the second most common cause of death in patients with active cancer or history of cancer. In patients with VTE, those with active cancer are at higher risk of death, recurrence, and major bleeding than those without cancer.

Graduated elastic compression stockings in the prevention of post-thrombotic syndrome: A systematic review and meta-analysis.

BACKGROUND: The effect of graduated elastic compression stockings (ECS) in the prevention of post-thrombotic syndrome (PTS) has been questioned since a large randomized trial found no prophylactic effect of ECS. OBJECTIVE: To assess the effect of the wearing time of ECS on the incidence of post-thrombotic syndrome (PTS) after proximal deep venous thrombosis, we performed a meta-analysis of the incidence of PTS across randomized and observational studies. METHOD: PubMed, Embase and Cochrane databases were searched until 12 June 2023 for studies on the effect of ECS on PTS. References of eligible studies were also screened in order to identify other potential studies that might have been missed during the search. RESULTS: Four studies comprising a total of 1467 patients met our inclusion criteria for early initiation and consistent use of ECS in patients with acute proximal DVT. ECS significantly reduced the incidence of mild-moderate PTS (OR: 0.48; 95% CI: 0.36-0.63) as well as severe PTS (OR: 0.44; 95% CI: 0.28-0.58).

Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation.

AIMS: It is presently unknown whether patients with atrial fibrillation (AF) are at increased risk of thrombo-embolic adverse events after interruption of warfarin treatment. The purpose of this study was to assess the risk and timing of thrombo-embolism after warfarin treatment interruption. METHODS AND RESULTS: A retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with AF in the period 1997-2008. Incidence rate ratios (IRRs) of thrombo-embolic events and all-cause mortality were calculated using the Poisson regression analyses. In total, 48 989 AF patients receiving warfarin treatment were included. Of these, 35 396 patients had at least one episode of warfarin treatment interruption. In all, 8255 deaths or thrombo-embolic events occurred during treatment interruption showing an initial clustering of events with 2717, 835, 500, and 427 events occurring during 0-90, 91-180, 181-270, and 271-360 days after treatment interruption, respectively. Correspondingly, the crude incidence rates were 31.6, 17.7, 12.3, and 11.4 events per 100 patient-years. In a multivariable analysis, the first 90-day interval of treatment interruption was associated with a markedly higher risk of death or thrombo-embolism (IRR 2.5; 95% confidence interval 2.3-2.8) vs. the interval of 271-360 days. CONCLUSION: In patients with AF, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thrombo-embolic events within the first 90 days of treatment interruption.

Inadequate use of prophylaxis against venous thromboembolism in Danish medical departments.

INTRODUCTION: Venous thromboembolism (VTE) constitutes a major risk factor in hospitalized acutely ill medical patients. It has been demonstrated in numerous papers that by using different forms of prophylaxis, a significant reduction of the incidence of VTE can be achieved. In this article we assessed the tendencies in the use of venous thromboprophylaxis (TP) at internal medicine departments in Denmark. The results were compared with results from a similar study conducted in 2005. MATERIAL AND METHODS: All medical departments in Denmark received a two-page questionnaire on TP. The recipients were asked to evaluate the frequency, use of local instructions, form of administration, side-effects and duration of TP at their departments. One reminder was sent out. RESULTS: A total of 188 responses were received (90% response rate), 16 were excluded. Virtually all departments indicated that they used TP (92%). At intensive care units, the TP was used according to local guidelines at 77% of the wards and at the other subspecialties of internal medicine, TP was used in less than 50%. By far the most frequently used prophylaxis method was low molecular weight heparin, which was used by more than 80% of the departments. Side-effects, most often superficial bleeding and haematomas, were reported in 25% of the cases. The following serious side-effects were reported: heparininduced thrombocytopenia (n = 2), stroke (n = 1) and gastrointestinal bleeding (n = 3). No difference was observed between the hospitals of larger cities and those of smaller cities. CONCLUSION: In Denmark, no significant increase in the use of TP at internal medicine departments has been observed since 2005. The guideline's strong recommendation of TP is still not reflected in daily practice. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

[Perioperative heparin bridging is rarely indicated].

Numerous studies have shown that perioperative heparin bridging in patients treated with a vitamin K antagonist leads to an increased incidence of bleeding and so far, there is no evidence that it leads to a significant reduction in postoperative thromboembolism as summarised in this review. Prophylactic dosage of heparin is recommended after major surgery. Heparin bridging is not relevant in patients receiving a direct oral anticoagulant due to the rapid onset and offset of action of DOACs.

Risk profile, antithrombotic treatment and clinical outcomes of patients in Nordic countries with atrial fibrillation - results from the GARFIELD-AF registry.

AIMS: The objective was to evaluate the clinical characteristics, management and two-year outcomes of patients with newly diagnosed non-valvular atrial fibrillation at risk for stroke in Nordic countries. METHODS: We examined the baseline characteristics, antithrombotic treatment, and two-year clinical outcomes of patients from four Nordic countries. RESULTS: A total of 52,080 patients were enrolled in the GARFIELD-AF. Out of 29,908 European patients, 2,396 were recruited from Nordic countries. The use of oral anticoagulants, alone or in combination with antiplatelet (AP), was higher in Nordic patients in all CHA2DS2-VASc categories: 0-1 (72.8% vs 60.3%), 2-3 (78.7% vs 72.9%) and ≥4 (79.2% vs 74.1%). In Nordic patients, NOAC ± AP was more frequently prescribed (32.0% vs 27.7%) and AP monotherapy was less often prescribed (10.4% vs 18.2%) when compared with Non-Nordic European patients. The rates (per 100 patient years) of all-cause mortality and non-haemorrhagic stroke/systemic embolism (SE) were similar in Nordic and Non-Nordic European patients [3.63 (3.11-4.23) vs 4.08 (3.91-4.26), p value = .147] and [0.98 (0.73-1.32) vs 1.02 (0.93-1.11), p value = .819], while major bleeding was significantly higher [1.66 (1.32-2.09) vs 1.01 (0.93-1.10), p value < .001]. CONCLUSION: Nordic patients had significantly higher major bleeding than Non-Nordic-European patients. In contrast, rates of all-cause mortality and non-haemorrhagic stroke/SE were comparable. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT01090362. URL: http://www.clinicaltrials.gov. KEY MESSAGE: Nordic countries had significantly higher major bleeding than Non-Nordic-European countries. Rates of mortality and non-haemorrhagic stroke/SE were similar .

Improving antithrombotic management in patients with atrial fibrillation: current status and perspectives.

Despite overwhelming evidence of the benefits of risk-adjusted oral anticoagulation on stroke reduction in patients with atrial fibrillation (AF), there is still considerable undertreatment. A multidisciplinary expert group was formed to discuss issues surrounding anticoagulant treatment of patients with AF to try and achieve consensus on various aspects of the implementation of guidelines on oral anticoagulation therapy in AF. Panel members were cardiologists, hematologists, and laboratory and primary care physicians with specific expertise from Europe and the United States. One of the most important conclusions of the meeting was to enhance guideline adherence by better communication of the data showing that the benefits of stroke reduction outweigh the risk of bleeding associated with treatment with vitamin K antagonists. Management of oral anticoagulation therapy by dedicated centers, such as anticoagulation clinics, or by patient self-management may improve the quality of anticoagulation and facilitate the management of these patients and thereby further facilitate optimal antithrombotic management in patients with AF.

Application of basic and composite thrombelastography parameters in monitoring of the antithrombotic effect of the low molecular weight heparin dalteparin: an in vivo study.

BACKGROUND: Low molecular weight heparin (LMWH) is in vast usage for treatment of thromboembolic diseases such as deep venous thrombosis and acute coronary syndromes. There are certain clinical situations where a quick point of care testing of the effect of LMWH would be useful. At this point there are no point of care devices available in the market for monitoring the effect of LMWH. Thrombelastography (TEG) evaluates the viscoelastic properties of blood during coagulation. The clinical application of TEG in monitoring LMWH treatment is not yet well defined. The purpose of this in vivo study was to systematically evaluate the most suitable TEG parameters for evaluation of the antithrombotic effect of LMWH. We furthermore evaluated for the first time the usefulness of the composite TEG parameter the Thrombodynamic Ratio (TDR) in monitoring LMWH treatment. METHODS: Healthy male volunteers (n = 7) were injected subcutaneously with the LMWH dalteparin 120 IU/kg. TEG parameters and antifactor Xa levels were measures at baseline, 2, 4, 5 and 24 hours after the injection. Correlation between TEG parameters and antiXa were calculated. The sensitivity and specificity of the TEG parameters for plasma levels of antiXa in the therapeutic range of 0.5 - 1.0 U/ml were calculated. RESULTS: All basic TEG parameters correlated significantly with antiXa levels. Among the basic parameters, the TEG reaction time R had the best correlation with antiXa levels with the most favorable combination of sensitivity and specificity for the therapeutic range of antiXa levels (r = 0.82, p < 0.0001, sensitivity 68%, specificity 100%). The composite TEG parameter TDR demonstrated the best correlation with antiXa levels, and an even more favorable combination of sensitivity and specificity compared to any of the basic parameters (r = - 0.87, p < 0.0001, sensitivity 95%, specificity 79%). CONCLUSION: The TEG reaction time R and TDR are the most suitable TEG parameters for evaluation of the antithrombotic effect of dalteparin with a highly significant correlation with antiXa levels in healthy male volunteers. Measures for uniform clinical use of these parameters are proposed. Larger clinical trials are needed to correlate R and TDR with clinical outcomes.

[Recurrence of venous thromboembolism].

Recurrence of venous thromboembolism (VTE) is seen in approximately one third of the patients after discontinuation of therapy with anticoagulants. The duration of treatment seems to be of minor importance, as several studies have shown the same recurrence rate over years after treatment for three months and up to 24 months. In patients with reversible risk factors, three months of treatment seems to be sufficient. Treatment duration should be determined by physicians with special expertise in risk factors for VTE recurrence and bleeding complications.

The management of thrombosis in pregnancy: role of low-molecular-weight heparin.

Fatal pulmonary embolism remains the most common cause of mortality among pregnant women in many Western countries. The physiological changes of pregnancy produce a hypercoagulable state that increases the risk of venous thromboembolism (VTE). Women with inherited or acquired thrombophilias are at particularly high risk of VTE during pregnancy, and thromboprophylaxis may be advisable in some cases. Thrombophilia is also associated with complications of pregnancy, including fetal loss, pre-eclampsia, intra-uterine growth restriction, and placental abruption. The antithrombotic agents available for the prevention and treatment of VTE during pregnancy, and pregnancy complications, include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and aspirin. Vitamin K antagonists are contra-indicated in pregnancy. Low-dose aspirin may have a role in the prevention of some pregnancy complications, although its safety in early and late pregnancy is uncertain. The efficacy and safety of LMWHs have been demonstrated for the prevention and treatment of VTE in pregnancy. These agents are increasingly being used in place of UFH, which is associated with a higher incidence of side effects compared with LMWH, in addition to the need for regular laboratory monitoring. Evidence is also emerging to support the use of LMWH in the prevention of recurrent fetal loss, although further trials are needed to explore the role of LMWHs in this indication and in the prevention of other complications of pregnancy.

Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage.

INTRODUCTION: Diffuse alveolar hemorrhage (DAH) is a serious pulmonary complication seen in patients with autoimmune disorders and patients treated with chemotherapy or after hematopoietic stem cell transplantation. The clinical management of DAH is complex and the condition has a high mortality rate. Tissue factor is expressed in the lung alveoli during inflammation and therefore pulmonary administration of human recombinant activated factor VIIa (rFVIIa) could be a rational treatment option. METHODS: Six patients with acute, bronchoscopically confirmed DAH from a single intensive care unit university hospital center were included in the study of acute DAH in critically ill patients. The patients were treated with intrapulmonary administration of 50 microg/kg rFVIIa in 50 ml of sodium chloride by bronchoalveolar lavage (BAL) with 25 ml in each of the main bronchi, which was repeated after 24 hours in case of treatment failure. RESULTS: An excellent response, defined as complete and sustained hemostasis after a single dose of rFVIIa, was seen in three patients. A good response, meaning that sustained hemostasis was achieved by a repeated rFVIIa administration, was seen in the remaining three patients. In one of these patients, the BAL treatment was repeated twice; in another patient, the second dose of rFVIIa was administered by nebulizer after extubation after the initial BAL. The hemostatic effect was statistically significant (p = 0.031). The oxygenation capacity, as reflected by the PaO2/FiO2 (arterial oxygen pressure/inspiratory fractional oxygen content) ratio, increased significantly (p = 0.024) in all six patients following the local rFVIIa therapy. CONCLUSION: Symptomatic therapy of DAH after intrapulmonary administration of one or more doses of rFVIIa was found to have a good to excellent hemostatic effect in six consecutive patients with DAH. The intrapulmonary administration of rFVIIa seemed to have a high benefit-to-risk ratio. Larger series should confirm the safety of this approach.

[Perioperative heparin bridging is rarely indicated]. / Perioperativ heparin-bridging er sjældent indiceret.

Meta-analyses of cohort studies and a recent randomized, placebo-controlled study have shown that perioperative bridging of warfarin therapy with therapeutic doses of heparin results in a multi-fold increase in major bleeding but no reduction in the incidence of thromboembolism. It is time to reconsider heparin bridging: When is heparin bridging superfluous? When is prophylactic dosage indicated? And when is it safe to use therapeutic dosing?

[Effect of Coenzyme Q10 and Ginkgo biloba on warfarin dosage in patients on long-term warfarin treatment. A randomized, double-blind, placebo-controlled cross-over trial]. / Effekten af Coenzym Q10 og Ginkgo biloba på warfarindosis hos patienter i laengerevarende warfarinbehandling. Et randomiseret, dobbeltblindt, placebokontrolleret overkrydsningsforsøg.

INTRODUCTION: A few case-stories claim that the anti-oxidant Coenzyme Q10 and possibly also Ginkgo biloba interact with warfarin treatment. A decreased response to warfarin in the Coenzyme Q10 cases and an increased response in the Ginkgo biloba case have been described. MATERIAL AND METHODS: Twenty-four outpatients on stable, long-term warfarin treatment were included in a randomised, double blind, placebo-controlled crossover trial. Coenzyme Q10 100 mg daily, Ginkgo-Biloba 100 mg daily and placebo were given in random order over treatment periods of four weeks, each followed by a two week wash out period. The international normalized ratio (INR) INR was kept between 2.0 and 4.0 by appropriate adjustment of the warfarin dosage. RESULTS: Fourteen women and ten men, median ages 64.5 years (33-79) were included. Three patients withdrew from the study for personal reasons. The INR was stable during all treatment periods. The geometric mean dosage of warfarin did not change during the treatment periods: Ginkgo biloba 36.7 mg/week (95% confidence interval: 29.2-46.0); CoQ10 36.5 mg/week (29.1-45.8); placebo 36.0 mg/week (28.6-45.1). CONCLUSION: The study indicated that Coenzyme Q10 and Ginkgo biloba do not influence the clinical effect of warfarin.

Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors.

Dabigatran has been associated with greater risk of myocardial infarction (MI) than warfarin. It is unknown whether the increased risk is unique to dabigatran, an adverse effect shared by other oral direct thrombin inhibitors (DTIs), or the result of a protective effect of warfarin against MI. To address these questions, we systematically searched MEDLINE and performed a meta-analysis on randomized trials that compared oral DTIs with warfarin for any indication with end point of MIs after randomization. We furthermore performed a secondary meta-analysis on atrial fibrillation stroke prevention trials with alternative anticoagulants compared with warfarin with end point of MIs after randomization. A total of 11 trials (39,357 patients) that compared warfarin to DTIs (dabigatran, ximelagatran, and AZD0837) were identified. In these trials, patients treated with oral DTIs were more likely to experience an MI than their counterparts treated with warfarin (285 of 23,333 vs 133 of 16,024, odds ratio 1.35, 95% confidence interval 1.10 to 1.66, p = 0.005). For secondary analysis, 8 studies (69,615 patients) were identified that compared warfarin with alternative anticoagulant including factor Xa inhibitors, DTIs, aspirin, and clopidogrel. There was no significant advantage in the rate of MIs with the use of warfarin versus comparators (odds ratio 1.06, 95% confidence interval 0.85 to 1.34, p = 0.59). In conclusion, our data suggest that oral DTIs were associated with increased risk of MI. This increased risk appears to be a class effect of these agents, not a specific phenomenon unique to dabigatran or protective effect of warfarin. These findings support the need for enhanced postmarket surveillance of oral DTIs and other novel agents.

Local pulmonary administration of factor VIIa (rFVIIa) in diffuse alveolar hemorrhage (DAH) - a review of a new treatment paradigm.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a clinical syndrome with typical symptoms dyspnea and hemoptysis. DAH is a complication of specific diseases, in some cases with acute catastrophic hemoptysis, while other patients present low grade alveolar bleeding with a need of chronic transfusion as in pulmonary hemosiderosis. METHODS: Current literature in the PubMed database and other sources was reviewed in order to evaluate the current treatment recommendations, efficacy of this treatment, and finally the risk of complications after off-label use of rFVIIa in respect to DAH. OBJECTIVES: (i) To elucidate the clinical aspects of alveolar hemorrhage, (ii) to develop a simple diagnostic algorithm in order to separate DAH from other important pulmonary diseases with similar clinical picture and comparably high mortality. Such an algorithm has important therapeutic consequences because these diseases: acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and bronchiolitis obliterans organizing pneumonia (BOOP) have different therapies, (iii) to evaluate and discuss whether local pulmonary administration may improve outcome and reduce mortality in DAH, and (iv) to suggest a treatment schedule. RESULTS: Hitherto the diagnosis and treatment of DAH has been based on anecdotal reports. The treatment has relied on different unspecific treatment modalities based on a mixture of treatment of the underlying disease and treatment without evidence targeted to stop the alveolar bleeding. However, recently a number of publications have advocated the use of intrapulmonary rFVIIa. Even in severe bleeding DAH has been shown to respond promptly without thromboembolic complication when FVIIa was administered locally via the air side, because the FVIIa does not penetrate the alveolo-capillary membrane to the blood-side. The incidence of DAH (in the US and Europe is 100,000-150,000, and 50,000 patients annually are at risk of developing DAH following hematopoietic stem cell transplant (HSCT) and autoimmune diseases. Finally 50,000-100,000 patients may be falsely categorized as having acute respiratory distress syndrome/acute lung injury (ARDS/ALI) because DAH and ARDS cannot be separated clinically. A new treatment paradigm of DAH is proposed as no other intervention has been able to ensure pulmonary hemostasis in DAH. The diagnosis of DAH is simple, a series of broncho-alveolar washes which become increasingly bloody. This test should be performed in all patients with pulmonary opacities in order to separate ARDS/ALI from DAH. FVIIa administrated via pulmonary route is "drug of choice", because it stops bleeding in the life-threatening syndrome DAH. Hemostasis is obtained after only one to two small doses of FVIIa (50 µg/kg body weight per dose) and after hemostasis the oxygen transport quickly improves. CONCLUSION: Intrapulmonary administration of rFVIIa is recommended as the treatment of choice for DAH and blast lung injury (BLI) because the treatment has been shown to be successful and uncomplicated in spite of the fact that only a small series of DAH has been documented.