Plasma levels of direct oral anticoagulants in atrial fibrillation patients at the time of embolic stroke: a pilot prospective multicenter study.

BACKGROUND: Patients with atrial fibrillation (AF) who are on long-term direct oral anticoagulants (DOAC) with low anti-Xa or anti-IIa levels may be at higher risk of recurrent stroke. However, no prospective post-marketing study has investigated these DOAC plasma levels at the time of embolic stroke. The aim of this study was to assess the anti-Xa (rivaroxaban, apixaban) and anti-IIa (dabigatran) plasma levels in DOAC-treated AF patients at the time of acute embolic stroke. PATIENTS AND METHODS: We prospectively identified 43 patients with AF on long-term DOAC who experienced embolic strokes. We compared the DOAC plasma levels of these patients with a control sample of 57 patients who tolerated long-term therapeutic dose DOAC therapy without any adverse event. DOAC levels were assessed with drug-specific anti-Xa chromogenic analysis (rivaroxaban, apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). RESULTS: Dabigatran-treated patients with stroke had significantly lower anti-IIa levels when compared with the trough (40.7 ± 36.9 vs. 85.4 ± 57.2 ng/mL, p < 0.05) and peak samples of the controls (40.7 ± 36.9 vs. 138.8 ± 78.7 ng/mL, p < 0.001). Similarly, there were significantly lower anti-Xa levels in apixaban-treated patients with stroke compared to the trough control samples (72.4 ± 46.7 vs. 119.9 ± 81.7 ng/mL, p < 0.05), and in rivaroxaban- and apixaban-treated patients when compared to peak control samples (rivaroxaban: 42.7 ± 31.9 vs. 177.6 ± 38.6 ng/mL, p < 0.001; apixaban: 72.4 ± 46.7 vs. 210.9 ± 88.7 ng/mL, p < 0.001). CONCLUSION: This observational study showed significantly lower anti-IIa and anti-Xa plasma levels in AF patients with embolic stroke compared to those who tolerated long-term therapeutic dose DOAC therapy.

Direct Oral Anticoagulants Plasma Levels in Patients with Atrial Fibrillation at the Time of Bleeding: A Pilot Prospective Study.

ABSTRACT: Patients with atrial fibrillation (AF) on long-term direct oral anticoagulants (DOACs) may be at higher risk of bleeding because of higher anti-Xa or anti-IIa levels. However, there is no postmarketing study investigating these DOAC plasma levels at the time of bleeding. The aim of this study was to evaluate DOAC levels at the time of a bleeding emergency. We analyzed 5440 patients examined at our Emergency Department in from April 1, 2019, to September 30, 2019. During this period, we prospective identified 105 consecutive patients with bleeding while on long-term antithrombotic therapy; 49 patients had AF on DOACs. We compared DOAC levels in patients who bled against a control sample of 55 patients who tolerated long-term high dose DOAC therapy without any emergency. Samples of these patients were tested with drug-specific anti-Xa chromogenic analysis (rivaroxaban and apixaban) and with Hemoclot Thrombin Inhibitor assay (dabigatran). Dabigatran-treated patients who bled had significantly higher anti-IIa levels when compared with trough (261.4 ± 163.7 vs. 85.4 ± 57.2 ng/mL, P < 0.001) and peak samples of controls (261.4 ± 163.7 vs. 138.8 ± 78.7 ng/mL, P < 0.05). Similarly, there were significantly higher anti-Xa levels in rivaroxaban-treated and apixaban-treated patients with bleeding compared with trough control samples (rivaroxaban: 245.9 ± 150.2 vs. 52.5 ± 36.4 ng/mL, P <0.001 and apixaban: 311.8 ± 142.5 vs. 119.9 ± 81.7 ng/mL, P < 0.001), as well as in apixaban-treated patients when compared with peak control samples (311.8 ± 142.5 vs. 210.9 ± 88.7 ng/mL, P < 0.05). Finally, rivaroxaban anti-Xa levels in patients who bled tended to be higher compared with peak control samples (245.9 ± 150.2 vs. 177.6 ± 38.6 ng/mL, P = 0.13). This observational study showed a significant difference in anti-IIa and anti-Xa plasma levels in patients with AF with bleeding complications compared with those who tolerated long-term high-dose DOAC therapy without bleeding complications.

Apixaban: An Optimal Agent for the Treatment of Cancer-Associated Venous Thromboembolism?

BACKGROUND: Apixaban, a direct inhibitor of activated coagulation factor X (FXaI), is being frequently selected for treatment and prevention of venous thromboembolism (VTE). Several reports about possible use of oral FXaI in patients with cancer-associated VTE (CA-VTE) have been published recently. AREAS OF UNCERTAINTY: The efficacy/safety profile of oral FXaI anticoagulation in patients with CA-VTE seems promising; however, several problems remain unanswered. The pharmacologic profile of apixaban could prefer this agent for the treatment of CA-VTE. DATA SOURCES: Currently available medical literature was searched and reviewed to summarize data regarding the use of apixaban for the prevention and treatment of cancer-associated VTE. RESULTS: Apixaban therapy in patients with cancer and VTE is expected to increase as clinicians gain more experience and reassurance with data from real-world studies that are generally promising. Several studies demonstrated that apixaban exhibits noninferiority to warfarin and low molecular weight heparin in preventing recurrent thrombosis in cancer-associated VTE. Nevertheless, there are still concerns regarding the bleeding associated with apixaban therapy, and regarding the optimal management of these bleeding emergencies. THERAPEUTIC OPINION: Although currently available evidence confirms the noninferiority of apixaban for reduction of the risk of recurrent VTE in patients with cancer; there are still concerns regarding the safety, especially in selected subpopulations of these patients.

The Impact of Proton Pump Inhibition on Dabigatran Levels in Patients With Atrial Fibrillation.

BACKGROUND: Proton pump inhibition (PPI) administrated together with dabigatran reduces the risk of gastrointestinal hemorrhage. However, there is a discussion regarding possible PPI-dabigatran interaction that may reduce the efficacy of this therapy. STUDY QUESTION: To determine the impact of concomitant PPI on dabigatran plasma levels in patients with nonvalvular atrial fibrillation (NV-AF). STUDY DESIGN: A pilot prospective study in patients with NV-AF on dabigatran therapy was performed; 31 patients were enrolled. PPI with either omeprazole or pantoprazole was administrated in 19 patients. MEASURES AND OUTCOMES: Blood samples were taken for the assessment of the dabigatran trough and peak levels. Dabigatran concentration was measured with the Hemoclot Thrombin Inhibitor Assay. RESULTS: There were significant differences in dabigatran trough level comparing patients treated with PPI and patients without PPI (58.86 ± 36.76 ng/mL vs. 110.72 ± 88.47 ng/mL, P < 0.05). Similarly, there were significant differences in dabigatran peak level between compared groups (88.0 ± 20.5 ng/mL vs. 174.4 ± 139.64 ng/mL, P < 0.05). CONCLUSIONS: This pilot study demonstrated the interaction between PPI and dabigatran levels in patients with NV-AF.

Does proton pump inhibition change the on-treatment anti-Xa activity in xabans-treated patients with atrial fibrillation? A pilot study.

Proton pump inhibition (PPI) reduces gastrointestinal bleeding on direct oral anticoagulants. However, PPI may affect dabigatran on-treatment levels; and there is no information regarding the effect of PPI on xabans on-treatment activity. Thus, the aim of this study was to determine the impact of PPI on therapeutic anti-Xa activity in rivaroxaban- and apixaban-treated patients with atrial fibrillation (AF). This single-centre pilot prospective study enrolled 77 consecutive xabans-treated patients (42 rivaroxaban-treated and 35 apixaban-treated patients) with AF. PPI was administrated in 44 patients. Trough and peak anti-Xa activity was assessed with factor Xa-calibrated anti-Xa chromogenic analysis. There were no significant differences in trough anti-Xa activity comparing PPI-treated patients and patients without PPI (80.5 ± 66.5 ng/mL in PPI group vs. 71.6 ± 64.1 ng/mL in non-PPI group, p = 0.57, Table 2). Similarly, there were no significant differences in peak anti-Xa activity between compared groups (175.2 ± 102.5 ng/mL in PPI group vs. 202.9 ± 84.1 ng/mL in non-PPI group, p = 0.21). This pilot study did not reveal significant changes in xabans on-treatment anti-Xa activity according the PPI status.

Direct Oral Anticoagulants: Novel Approach for the Treatment of Thrombosis in Pediatric Patients?

Venous thromboembolism (VTE) is a rare, but life-threatening disease in those who have not reached their adulthood. This condition is usually treated with heparin or low molecular weight heparins which require parenteral administration and, in case of unfractionated heparin, also frequent laboratory monitoring and dose adjustment. Direct oral anticoagulants (DOACs)-direct thrombin inhibitor dabigatran, and direct oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban-are currently frequently used for the prevention and treatment of VTE in adult population. In fact, these agents offer several advantages compared to traditional agents, such as oral route of administration, short on-set and off-set of action, predictable pharmacologic profile with low risk of food and drug interactions, and no need for routine laboratory assessment of anticoagulant activity. However, clinical experience with these directly acting oral anticoagulants in pediatric population is very limited as these drugs had been tested and are used mostly in adult individuals. This article reviews the current data from pre- and post-marketing studies reporting the use of DOACs for the treatment of VTE in pediatric patients.

Monitoring of Hemostasis and Management of Anticoagulant Thromboprophylaxis in Pregnant Women with Increased Risk of Fetal Loss.

Physiological prothrombotic changes during pregnancy and the postpartum period, along with other preexisting maternal risk factors, increase the risk of both venous thromboembolism (VTE) and adverse pregnancy outcomes. Pregnancy complications that develop due to placental insufficiency as a result of inappropriate activation of coagulation are present in more than 5% of pregnancies and can contribute to significant maternal morbidity and mortality. Therefore, anticoagulant prophylaxis in women with congenital and acquired thrombophilic conditions should be actively considered. According to the Guidelines of American College of Chest Physicians, the use of low-molecular-weight heparin is suggested for prophylaxis of VTE and pregnancy complications in high-risk pregnant women. However, personalized refinements of such thromboprophylaxis remains unspecified, despite the necessity of better targeted recommendations for life-threatening conditions. We, therefore, review the possibilities of longitudinal monitoring and comprehensive assessment of changes in hemostasis in the group of high-risk pregnant women, which can then be used for early prediction and individualization of the optimal anticoagulant thromboprophylaxis of pregnancy complications. Simultaneously, we present our single-center experience with such monitoring and our first series of results.

Heparin-induced Thrombocytopenia Presenting With Deep Venous Thrombosis and Pulmonary Embolism Successfully Treated With Rivaroxaban: Clinical Case Report and Review of Current Experiences.

Heparin-induced thrombocytopenia (HIT) is a life or limb-threatening thrombotic thrombocytopenia. HIT is traditionally treated with factor-IIa inhibitors such as bivalirudin, lepirudin, or argatroban. However, these agents usually require parenteral administration and are not generally available in all countries. Recently, several experiences with novel oral anticoagulants (NOACs) administration to treat HIT had been reported. NOACs generally offer advantages such as consistent and predictable anticoagulation, oral administration with good patient compliance, and a good safety profile. We report a case of HIT with severe thrombotic complications successfully treated with rivaroxaban and discuss the current knowledge about the use of NOACs for the treatment of this potentially fatal thrombocytopenia.

Monitoring of dabigatran therapy using Hemoclot(®) Thrombin Inhibitor assay in patients with atrial fibrillation.

Dabigatran, a new direct thrombin inhibitor, achieves strong anticoagulation that is more predictable than warfarin. Nevertheless, a patient on dabigatran therapy (DT) may suffer from thrombotic or bleeding events. The routine monitoring of DT is not recommended, and standard coagulation tests are not sensitive enough for the assessment of DT activity. The aim of this study was to examine the clinical usefulness of the Hemoclot(®) Thrombin Inhibitor (HTI) assay in the assessment of dabigatran plasma levels in patients with non-valvular AF. Nineteen patients (12 men, 7 women) on DT were included in this preliminary prospective observational study. Dabigatran was administrated twice daily in a two dose regimens: 150 mg (5 patients) and 110 mg (14 patients). Blood samples were taken for the assessment of trough and peak levels of dabigatran. Dabigatran concentrations were measured with the HTI assay. The average dabigatran trough level was 69.3 ± 55.5 ng/ml and the average dabigatran peak level was 112.7 ± 66.6 ng/ml. The dabigatran trough plasma concentration was in the established reference range in 15 patients and the dabigatran peak plasma concentration was in the established reference range in 9 patients, respectively. Despite the fact that the activated partial thromboplastin and thrombin times were generally changed (prolonged), these tests failed to identify the patients with too low or too high dabigatran concentrations. The study confirmed the high sensitivity of the HTI assay for the assessment of dabigatran plasma levels. When compared to standard coagulation tests, the HTI is a more suitable assay for the monitoring of patients treated with dabigatran. Monitoring of DT may be beneficial in selected patients; however, further studies will be needed for the final clarification of this issue.

Management of Venous and Arterial Thrombosis.

A thrombus is a hemostatic plug localized in a blood vessel [...].

Evaluating Thromboprophylaxis Strategies for High-Risk Pregnancy: A Current Perspective.

Venous thromboembolism (VTE) represents one of the leading causes of death during pregnancy. The greatest risk for it is the presence of medical or family history of VTE, stillbirth, cesarean section and selected thrombophilia. Appropriate thromboprophylaxis has the potential to decrease the risk of VTE in at-risk pregnant patients by 60-70%. Based on this, the authors reviewed the PubMed, Web of Science and Scopus databases to identify the possibilities of thromboprophylaxis in pregnant patients with a high risk of VTE. Moreover, they summarized its management in specific situations, such as cesarean delivery or neuraxial blockade. Currently, low-molecular-weight heparins (LMWH) are the preferred drugs for anticoagulant thromboprophylaxis in the course of pregnancy and postpartum due to easy administration and a lower rate of adverse events.

How to Treat Today? Oral and Facial Cancer-Associated Venous Thromboembolism.

The exact incidence of cancer-associated venous thromboembolism (CA-VTE) in patients with oral and facial cancer (OFC) is not exactly known, and this risk is empirically considered to be low. However, this suggestion may result in disease underdiagnosis, prolong the initiation of adequate therapy, and consecutively increase CA-VTE-related morbidity and mortality. In addition, there might be specific clinical problems in the treatment of CA-VTE in patients with oral and facial cancer, such as swallowing difficulties, that might limit the possibilities of oral anticoagulation. Finally, there are limited data regarding the optimal treatment of CA-VTE in patients with oral and facial cancer, and this includes data on novel therapeutic strategies, including the use of direct oral anticoagulants. This article reviews current data on the optimal treatment strategy for CA-VTE in patients with OFC.

COVID-19 and the Response to Antiplatelet Therapy.

The coronavirus SARS-CoV2 disease (COVID-19) is connected with significant morbidity and mortality (3.4%), disorders in hemostasis, including coagulopathy, activation of platelets, vascular injury, and changes in fibrinolysis, which may be responsible for an increased risk of thromboembolism. Many studies demonstrated relatively high rates of venous and arterial thrombosis related to COVID-19. The incidence of arterial thrombosis in severe/critically ill intensive care unit-admitted COVID-19 patients appears to be around 1%. There are several ways for the activation of platelets and coagulation that may lead to the formation of thrombi, so it is challenging to make a decision about optimal antithrombotic strategy in patients with COVID-19. This article reviews the current knowledge about the role of antiplatelet therapy in patients with COVID-19.

A Functional Assay for the Determination of Heparin-Induced Thrombocytopenia via Flow Cytometry.

Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin therapy (both unfractionated heparin and low-molecular-weight heparin). In our study, we examined a group of 122 patients with suspected HIT. The samples of all patients were analyzed in the first step using an immunoassay (ID-PaGIA Heparin/PF4, Hemos1L-Acustar HIT IgG, ZYMUTEST HIA Monostrip IgG) to detect the presence of antibodies against heparin-PF4 complexes (platelet factor 4). When the immunoassay was positive, the sample was subsequently analyzed for HIT with a functional flow cytometry assay, the HITAlert kit, the purpose of which was to demonstrate the ability of the antibodies present to activate platelets. A diagnosis of HIT can be made only after a positive functional test result. In this article, we present an overview of our practical experience with the use of the new functional method of analysis, HIT, with flow cytometry. In this work, we compared the mutual sensitivity of two functional tests, SRA and the flow cytometry HITAlert kit, in patients perceived as being at risk for HIT. This work aims to delineate the principle, procedure, advantages, pitfalls, and possibilities of the application of the functional test HITAlert using flow cytometry.

Resistance on the Latest Oral and Intravenous P2Y12 ADP Receptor Blockers in Patients with Acute Coronary Syndromes: Fact or Myth?

Novel P2Y12 ADP receptor blockers (ADPRB) should be preferred in dual-antiplatelet therapy in patients with acute coronary syndrome. Nevertheless, there are still patients who do not respond optimally to novel ADP receptor blocker therapy, and this nonoptimal response (so-called "high on-treatment platelet reactivity" or "resistance") could be connected with increased risk of adverse ischemic events, such as myocardial re-infarction, target lesion failure and stent thrombosis. In addition, several risk factors have been proposed as factors associated with the phenomenon of inadequate response on novel ADPRB. These include obesity, multivessel coronary artery disease, high pre-treatment platelet reactivity and impaired metabolic status for prasugrel, as well as elderly, concomitant therapy with beta-blockers, morphine and platelet count for ticagrelor. There is no literature report describing nonoptimal therapeutic response on cangrelor, and cangrelor therapy seems to be a possible approach for overcoming HTPR on prasugrel and ticagrelor. However, the optimal therapeutic management of "resistance" on novel ADPRB is not clear and this issue requires further research. This narrative review article discusses the phenomenon of high on-treatment platelet reactivity on novel ADPRB, its importance in clinical practice and approaches for its therapeutic overcoming.