Treatment of Dabigatran-Associated Bleeding

2012 ◽  
Vol 26 (3) ◽  
pp. 264-269 ◽  
Author(s):  
Lisa M. Harinstein ◽  
Joseph W. Morgan ◽  
Nicholas Russo
Keyword(s):  
Clinical Practice ◽  
Factor Viia ◽  
Thrombus Formation ◽  
Treatment Algorithm ◽  
Bleeding Event ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Thrombin Inhibitor ◽  
Reversal Agents ◽  
Life Threatening

Dabigatran etexilate is a competitive, direct thrombin inhibitor that works in the coagulation cascade to ultimately prevent thrombus formation. It is recommended by the 2012 American College of Chest Physicians evidence-based clinical practice guidelines as first-line therapy over vitamin k antagonists for long-term antithrombotic therapy in patients with paroxysmal or persistent nonrheumatic atrial fibrillation who are at intermediate to high risk of stroke and systemic embolism (grade 2B). However, serious postmarketing events involving life-threatening bleeding are emerging with no antidote for reversal of the anticoagulant effect being available for use. Potential reversal agents are being used in clinical practice with questionable efficacy and safety profiles. We report a case involving an 84-year-old male with acute kidney injury who developed life-threatening gastrointestinal and surgical site bleeding secondary to dabigatran accumulation. Use of the Naranjo probability scale indicated a probable cause between the bleeding event and dabigatran use. After discontinuation of drug therapy, fresh frozen plasma, recombinant coagulation factor VIIa, and cryoprecipitate were administered as potential reversal agents with negligible benefit. However, this patient appeared to slowly benefit with administration of continuous venovenous hemodialysis. Based upon our experience with this patient and literature review, the most effective treatment algorithm for dabigatran-associated bleeding may be to utilize hemodialysis initially.

Abstract 56: Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jenya Zilberman-Rudenko ◽  
Chantal Wiesenekker ◽  
Asako Itakura ◽  
Owen J McCarty
Keyword(s):  
Shear Flow ◽  
Platelet Activation ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Thrombin Inhibitor ◽  
Dependent Manner ◽  
Factor Xi ◽  
Primate Model

Objective: Coagulation factor XI (FXI) has been shown to contribute to thrombus formation on collagen or tissue factor (TF)-coated surfaces in vitro and in vivo by enhancing thrombin generation. Whether the role of the intrinsic pathway of coagulation is restricted to the local site of thrombus formation is unknown. This study was designed to determine whether FXI could promote both proximal and distal platelet activation and aggregate formation in the bloodstream. Approach and Results: Pharmacological blockade of FXI activation or thrombin activity in blood did not affect local platelet adhesion, yet reduced local platelet aggregation, thrombin localization and fibrin formation on immobilized collagen and TF under shear flow, ex vivo . Downstream of the thrombus formed on immobilized collagen or collagen and 10 pM TF, platelet CD62P expression and microaggregate formation and progressive platelet consumption were significantly reduced in the presence of FXI-function blocking antibodies or a thrombin inhibitor in a shear rate- and time-dependent manner. In a non-human primate model of thrombus formation, we found that inhibition of FXI reduced single platelet consumption in the bloodstream distal to a site of thrombus formation. Conclusions: This study demonstrates that the FXI-thrombin axis contributes to distal platelet activation and procoagulant microaggregate formation in the blood flow downstream of the site of thrombus formation. Our data highlights FXI as a novel therapeutic target for inhibiting distal platelet activation without affecting proximal platelet adhesion.

scholarly journals Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant Medications

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Alok Dabi ◽  
Aristides P. Koutrouvelis
Keyword(s):  
Side Effects ◽  
Intracranial Hemorrhage ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Reversal Agents ◽  
United States Food ◽  
Life Threatening

Direct oral anticoagulants (DOACs) are a new class of anticoagulants that directly inhibit either thrombin or factor Xa in the coagulation cascade. They are being increasingly used instead of warfarin or other vitamin K antagonists (VKAs). Adverse side effects of DOACs may result in hemorrhagic complications, including life-threatening intracranial hemorrhage (ICH), though to a much lesser degree than VKAs. Currently there are relatively limited indications for DOACS but their usage is certain to expand with the availability of their respective specific reversal agents. Currently, only idarucizumab (antidote for dabigatran) has been United States Food and Drug Administration- (FDA-) approved, but others (andexanet-α and ciraparantag) may be approved in near future, and the development and availability of such reversal agents have the potential to dramatically change the current anticoagulant use by providing reversal of multiple oral anticoagulants. Until all the DOACs have FDA-approved reversal agents, the treatment of the dreaded side effects of bleeding is challenging. This article is an attempt to provide an overview of the management of hemorrhage, especially ICH, related to DOAC use.

scholarly journals Next-Generation Antithrombotics in Ischemic Stroke: Preclinical Perspective on ‘Bleeding-Free Antithrombosis’

2012 ◽  
Vol 32 (10) ◽  
pp. 1831-1840 ◽  
Author(s):  
Peter Kraft ◽  
Simon F De Meyer ◽  
Christoph Kleinschnitz
Keyword(s):  
Ischemic Stroke ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Bleeding Complications ◽  
Factor Xii ◽  
Platelet Inhibitors ◽  
Platelet Surface ◽  
Surface Receptors ◽  
Glycoprotein Vi

The present antithrombotic drugs used to treat or prevent ischemic stroke have significant limitations: either they show only moderate efficacy (platelet inhibitors), or they significantly increase the risk for hemorrhages (thrombolytics, anticoagulants). Although most strokes are caused by thrombotic or embolic vessel occlusions, the pathophysiological role of platelets and coagulation is largely unclear. The introduction of novel transgenic mouse models and specific coagulation inhibitors facilitated a detailed analysis of molecular pathways mediating thrombus formation in models of acute ischemic stroke. Prevention of early platelet adhesion to the damaged vessel wall by blocking platelet surface receptors glycoprotein Ib alpha (GPIb α) or glycoprotein VI (GPVI) protects from stroke without provoking bleeding complications. In addition, downstream signaling of GPIb α and GPVI has a key role in platelet calcium homeostasis and activation. Finally, the intrinsic coagulation cascade, activated by coagulation factor XII (FXII), has only recently been identified as another important mediator of thrombosis in cerebrovascular disease, thereby disproving established concepts. This review summarizes the latest insights into the pathophysiology of thrombus formation in the ischemic brain. Potential clinical merits of novel platelet inhibitors and anticoagulants as powerful and safe tools to combat ischemic stroke are discussed.

scholarly journals Chronically Elevated Interleukin-6 Disturbs the Coagulation Cascade in Mice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2065-2065
Author(s):  
Tanja Knopp ◽  
Jeremy Lagrange ◽  
Rebecca Jung ◽  
Johannes Wild ◽  
Heidi Rossmann ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Interleukin 6 ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Coagulation Cascade ◽  
Bleeding Complications ◽  
Thrombin Inhibitor ◽  
Advisory Committees ◽  
Hemostatic System

Abstract Introduction: Pro-inflammatory cytokines play an essential role as activators of the hemostatic system and in the regulation of physiological antithrombotic mechanisms. Interleukin-6 (IL-6) influences platelet production and platelet activation. It was associated with accelerated clotting and intravascular coagulation in tissue factor (TF)-driven murine thrombosis models. However, the precise role of myeloid cell-derived IL-6 on thrombosis formation and the hemostatic system is still unknown. Methods and Results: To better understand the role of IL-6 in thrombosis and the hemostatic system, we developed a new mouse strain with Cre-recombinase driven constitutive IL-6 expression specifically in myeloid cells (LysM-IL-6 OE, Control mice: IL-6 OE). LysM-IL-6 OE mice had a prolonged tail bleeding time and lacked venous thrombus formation induced by inferior vena cava (IVC) stenosis. There were no differences in D-Dimer levels in LysM-IL-6 OE mice neither on baseline level nor after IVC ligation. However, we found unstoppable post-operative bleedings in LysM-IL-6 OE. They showed a prolonged aPTT, a significantly increased INR and a prolonged thrombin converting time. The Factor V and IX expression were reduced, but von Willebrand factor, antithrombin and fibrinogen expression were up-regulated and could not explain the missing thrombus formation. We found significantly elevated erythrocyte sedimentation in line with erythrocytes aggregates, which seemed to be mediated by IL-6 and α2M. Most importantly, hepatic levels of thrombin inhibitor α2 macroglobulin (α2M) mRNA and protein were increased in LysM-IL-6 OE/+ mice compared to control mice. In parallel, Platelet erythrocyte interaction seemed to be essential in the development of the bleeding phenotype. Conclusions: These findings show the role of chronically elevated IL-6 in driving the accumulation of A2m on the surface of erythrocytes, thereby mediating a phenotype of increased bleeding complications. This work was supported by the DFG KA4035/1-1 and by the German Ministry for Education and Research (BMBF 01EO1503) Disclosures Lämmle: Takeda: Membership on an entity's Board of Directors or advisory committees; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Baxter: Other: Travel Support, Speakers Bureau; Alexion: Other: Travel Support, Speakers Bureau; Siemens: Other: Travel Support, Speakers Bureau; Bayer: Other: Travel Support, Speakers Bureau; Roche: Other: Travel Support, Speakers Bureau; Sanofi: Other: Travel Support, Speakers Bureau. Ruf: ARCA bioscience: Consultancy, Patents & Royalties; ICONIC Therapeutics: Consultancy; MeruVasimmune: Current holder of individual stocks in a privately-held company.

scholarly journals An Update on the Reversal of Non-Vitamin K Antagonist Oral Anticoagulants

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Mark Terence P. Mujer ◽  
Manoj P. Rai ◽  
Varunsiri Atti ◽  
Ian Limuel Dimaandal ◽  
Abigail S. Chan ◽  
...  
Keyword(s):  
Vitamin K ◽  
Oral Anticoagulants ◽  
Coagulation Factor ◽  
Heart Association ◽  
Vitamin K Antagonist ◽  
Thrombin Inhibitor ◽  
Minor Bleeding ◽  
Onset Of Action ◽  
Reversal Agents ◽  
Andexanet Alfa

Non-vitamin K antagonist oral anticoagulants (NOACs) include thrombin inhibitor dabigatran and coagulation factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban. NOACs have several benefits over warfarin, including faster time to the achieve effect, rapid onset of action, fewer documented food and drug interactions, lack of need for routine INR monitoring, and improved patient satisfaction. Local hemostatic measures, supportive care, and withholding the next NOAC dose are usually sufficient to achieve hemostasis among patients presenting with minor bleeding. The administration of reversal agents should be considered in patients on NOAC's with major bleeding manifestations (life-threatening bleeding, or major uncontrolled bleeding), or those who require rapid anticoagulant reversal for an emergent surgical procedure. The Food and Drug Administration (FDA) has approved two reversal agents for NOACs: idarucizumab for dabigatran and andexanet alfa for apixaban and rivaroxaban. The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) have released an updated guideline for the management of patients with atrial fibrillation that provides indications for the use of these reversal agents. In addition, the final results of the ANNEXA-4 study that evaluated the efficacy and safety of andexanet alfa were recently published. Several agents are in different phases of clinical trials, and among them, ciraparantag has shown promising results. However, their higher cost and limited availability remains a concern. Here, we provide a brief review of the available reversal agents for NOACs (nonspecific and specific), recent updates on reversal strategies, lab parameters (including point-of-care tests), NOAC resumption, and agents in development.

scholarly journals The relationship between tissue factor and cancer progression: insights from bench and bedside

Blood ◽  
2012 ◽  
Vol 119 (4) ◽  
pp. 924-932 ◽  
Author(s):  
Yascha W. van den Berg ◽  
Susanne Osanto ◽  
Pieter H. Reitsma ◽  
Henri H. Versteeg
Keyword(s):  
Tumor Growth ◽  
Tissue Factor ◽  
Cancer Progression ◽  
Tumor Angiogenesis ◽  
Factor Viia ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Cancer Subtypes ◽  
Tumor Cell Behavior

Abstract It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TF-dependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF.

scholarly journals Dirofilaria immitis possesses molecules with anticoagulant properties in its excretory/secretory antigens

Parasitology ◽  
2020 ◽  
Vol 147 (5) ◽  
pp. 559-565 ◽  
Author(s):  
Alicia Diosdado ◽  
Fernando Simón ◽  
Rodrigo Morchón ◽  
Javier González-Miguel
Keyword(s):  
Dirofilaria Immitis ◽  
Thrombus Formation ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Circulatory System ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Blood Clots ◽  
Key Enzyme

AbstractDirofilaria immitis is a parasitic nematode that survives in the circulatory system of suitable hosts for many years, causing the most severe thromboembolisms when simultaneous death of adult worms occurs. The two main mechanisms responsible for thrombus formation in mammals are the activation and aggregation of platelets and the generation of fibrin through the coagulation cascade. The aim of this work was to study the anticoagulant potential of excretory/secretory antigens from D. immitis adult worms (DiES) on the coagulation cascade of the host. Anticoagulant and inhibition assays respectively showed that DiES partially alter the coagulation cascade of the host and reduce the activity of the coagulation factor Xa, a key enzyme in the coagulation process. In addition, a D. immitis protein was identified by its similarity to the homologous serpin 6 from Brugia malayi as a possible candidate to form an inhibitory complex with FXa by sodium dodecyl sulfate polyacrylamide gel electrophoresis and mass spectrometry. These results indicate that D. immitis could use the anticoagulant properties of its excretory/secretory antigens to control the formation of blood clots in its immediate intravascular habitat as a survival mechanism.

Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers

2004 ◽  
Vol 91 (06) ◽  
pp. 1090-1096 ◽  
Author(s):  
Marcel Levi ◽  
Troy Sarich ◽  
Stig Boström ◽  
Ulf Eriksson ◽  
Maria Eriksson-Lepkowska ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Thrombin Generation ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Venous Blood ◽  
Active Form ◽  
Coagulation Cascade ◽  
Thrombin Inhibitor ◽  
Shed Blood ◽  
Inhibition Of Thrombin

SummaryThe objectives were to investigate whether activation of the extrinsic coagulation cascade by recombinant factor VIIa (rFVIIa) reverses the inhibition of thrombin generation and platelet activation by melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. In a single-blind, randomized, parallel-group study, volunteers (20 per group) received a 5-hour intravenous (iv) infusion to achieve steadystate melagatran plasma concentrations of approximately 0.5 µmol/L, with a single iv bolus of rFVIIa (90 µg/kg) or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-antithrombin complex, fibrinopeptide A, β-thromboglobulin, and thrombin-activatable fibrinolysis inhibitor were quantified for venous and shed blood. Activated partial thromboplastin time (APTT), prothrombin time (PT), endogenous thrombin potential, thrombus precursor protein (TpP), and plasmin-α2-antiplasmin complex concentrations were determined in venous blood. Shed blood volume was measured. Melagatran reduced markers of thrombin generation and platelet activation in shed blood and prolonged APTT. rFVIIa increased FVIIa activity, PT, and TpP in venous blood. All other parameters were unaffected. In conclusion, rFVIIa did not reverse the anticoagulant effects of high constant concentrations of melagatran. However, the potential value of higher, continuous or repeated doses of rFVIIa or its use with lower melagatran concentrations has not been excluded.

scholarly journals Reversing targeted oral anticoagulants

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 518-523 ◽  
Author(s):  
Maureane Hoffman ◽  
Dougald M. Monroe
Keyword(s):  
Factor Viia ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Novel Oral Anticoagulants ◽  
Factor Xa Inhibitors ◽  
Invasive Procedures ◽  
Prothrombin Complex Concentrates ◽  
Reversal Agents ◽  
Life Threatening ◽  
Orally Active

Abstract Dabigatran, rivaroxaban, and apixaban are orally active anticoagulants that are approved in many countries. Dabigatran inhibits thrombin, whereas rivaroxaban and apixaban are factor Xa inhibitors. In clinical trials, these novel oral anticoagulants were at least as effective as warfarin for preventing stroke in patients with atrial fibrillation, but with a lower rate of serious bleeding. However, the lack of true antidotes for these agents has caused concern when patients suffer life-threatening bleeding or trauma or require emergent invasive procedures. True antidotes are under development for all of these agents. In the meantime, activated and nonactivated prothrombin complex concentrates have been used as reversal agents. Factor VIIa may also be effective for reversal of the factor Xa inhibitors. Reversal of novel oral anticoagulants by these hemostatic agents has not been studied in bleeding human patients, so their true efficacy and appropriate dosing are not known.

Use of recombinant factor VIIa in the perioperative period

2009 ◽  
Vol 29 (01) ◽  
pp. 68-70 ◽  
Author(s):  
M. Levi
Keyword(s):  
Blood Loss ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Coagulation Factor ◽  
Perioperative Period ◽  
Factor Vii ◽  
Clinical Settings ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Life Threatening

SummaryRecombinant activated factor VII (rFVIIa) is a pro-haemo -static agent that can be used for patients with haemophilia and inhibiting antibodies towards a coagulation factor. Recombinant factor VIIa is, however, increasingly used for several other indications, including patients who experience serious and life-threatening bleeding. In addition, rFVIIa has been evaluated for the prevention of major blood loss in patients undergoing surgical procedures that are known to be associated with major blood loss. In this manuscript we review the data on efficacy and safety of rFVIIa in the prevention of excessive blood loss and trans-fusion requirements in the perioperative period.We conclude that recombinant factor VIIa is a promising agent for perioperative prevention of major blood loss but that its efficacy will probably vary between specific clinical settings. Its exact place in surgery warrants further clinical trials in various situations that will also more precisely determine the safety of this intervention.

Sign in / Sign up

Export Citation Format

Share Document