The role of ADAMTS13 in acute myocardial infarction:cause or consequence?

ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, is a metalloprotease that cleaves von Willebrand factor (VWF). There is considerable evidence that VWF levels increase and ADAMTS13 levels decrease in ST-elevation myocardial infarction (STEMI) patients. It is unclear whether this contributes to no reflow, infarct size, and intramyocardial haemorrhage (IMH). We aimed to determine the role of ADAMTS13 in STEMI patients and to investigate the benefits of recombinant ADAMTS13 (rADAMTS13) in a porcine model of myocardial ischaemia-reperfusion. In 49 consecutive percutaneous coronary intervention (PCI)-treated STEMI patients, blood samples were collected directly after through 7 days following PCI. Cardiac magnetic resonance was performed 4-6 days after PCI to determine infarct size and IMH. In 23 Yorkshire swine, the circumflex coronary artery was occluded for 75 min. rADAMTS13 or vehicle was administered intracoronary following reperfusion. Myocardial injury and infarct characteristics were assessed using cardiac enzymes, ECG, and histopathology. In patients with IMH, VWF activity and VWF antigen were significantly elevated directly after PCI and for all subsequent measurements, and ADAMTS13 activity significantly decreased at 4 and 7 days following PCI, in comparison with patients without IMH. VWF activity and ADAMTS13 activity were not related to infarct size. In rADAMTS13-treated animals, no differences in infarct size, IMH, or formation of microthrombi were witnessed compared with controls. No correlation was found between VWF/ADAMTS13 and infarct size in patients. However, patients suffering from IMH had significantly higher VWF activity and lower ADAMTS13 activity. Intracoronary administration of rADAMTS13 did not decrease infarct size or IMH in a porcine model of myocardial ischaemia-reperfusion. These data dispute the imbalance in ADAMTS13 and VWF as the cause of no reflow

Prothrombin complex concentrate reverses the anticoagulant effect of rivaroxaban in healthy volunteers

Background: Rivaroxaban is a novel oral antithrombotic agent in the class of specific factor Xa inhibitors, and is licensed in Europe and Canada for the prevention of venous thromboembolism after elective orthopedic surgery. Despite its stable pharmacokinetic and pharmacodynamic profile, immediate reversal may be required in case of a major bleeding or emergency surgery. No specific antidote is currently available, although Prothrombin Complex Concentrate (PCC) seems effective in animal studies. This study is the first to investigate the ability of PCC to reverse the antithrombotic effect of Rivaroxaban in humans. Methods: In a randomized, double-blind, placebo-controlled trial, twelve healthy male subjects received Rivaroxaban 20mg twice daily for two and a half days. One group (n=6) was then randomized to receive a single bolus of 50 IU/kg PCC (Co-fact©, Sanquin, the Netherlands) while the other group (n=6) was given a similar volume of saline. Results: The prothrombin time (PT) was significantly prolonged by Rivaroxaban (15.8 sec ± 1.3 versus 12.3 ± 0.7 at baseline; p<0.001). Immediately after the infusion of PCC, the PT normalised almost completely (12.8 ± 1.0; p<0.001), which was sustained for 24 hours. Saline did not reverse the PT prolongation (16.2 ± 0.8; p= 0.4). Furthermore, Rivaroxaban inhibited the endogenous thrombin potential (ETP) (51% ± 22, baseline 92 ± 22; p= 0.002), with normalisation after administration of PCC (114 ± 26; p<0.001), but not after saline (41 ± 6; p= 0.2). Conclusions: This study provides the first data that Prothrombin Complex Concentrate reverses the anticoagulant effect of Rivaroxaban in humans and may serve as an antidote for the new oral factor Xa inhibitors (Figure Presented)

Response to Letters Regarding Article, "Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects"

Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P <0.001) that was immediately and completely reversed by PCC (12.8±1.0; P <0.001). The endogenous thrombin potential was inhibited by rivaroxaban (51±22%; baseline, 92±22%; P=0.002) and normalized with PCC (114±26%; P <0.001), whereas saline had no effect. Dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time. Administration of PCC did not restore these coagulation tests. Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study. Clinical Trial Registration- URL: http://www.trialregister.nl. Unique identifier: NTR227

Clinical impact of major bleeding in patients with venous thrombo-embolism treated with factor Xa inhibitors or vitamin K antagonists

Factor Xa (fXa)-inhibitors are as effective and safer than vitaminK antagonists (VKA) in the treatment of venous thromboembolism (VTE). We previously classified the severity of clinical presentation and course of all major bleeding events from the EINSTEIN, AMPLIFY and HOKUSAI-VTE trials separately. The current aim was to combine these findings in order to increase precision, assess a class effect and analyse presentation and course for different types of bleeding, i.e. intracranial, gastro-intestinal, and other. We classified the clinical presentation and course of all major bleeding events using pre-defined criteria. Both classifications comprised four categories; one being the mildest, and four the most severe. Odds ratios (OR) were calculated for all events classified as category three or four between fXa-inhibitors and VKA recipients. Also, ORs were computed for different types of bleeding. Major bleeding occurred in 111 fXa-inhibitor recipients and in 187 LMWHNKA recipients. The clinical presentation was classified as category three or four in 35% and 48% of the major bleeds in fXa inhibitor and VKA recipients, respectively (OR 0.59, 95 % CI 0.36-0.97). For intracranial, gastro-intestinal and other bleeding a trend towards a less severe presentation was observed for patients treated with fXa inhibitors. Clinical course was classified as severe in 22 % of the fXa inhibitor and 25% of the VKA associated bleeds (OR 0.83, 95 % CI 0.47-1.46). In conclusion, FXa inhibitor associated major bleeding events had a significantly less severe presentation and a similar course compared to VKA. This finding was consistent for different types of bleedin

The role of ADAMTS13 in acute myocardial infarction:Cause or consequence?

BACKGROUND ADAMTS13 is a metalloprotease that cleaves von Willebrand factor (VWF), thereby reducing its prothrombotic properties. There is considerable evidence that VWF levels increase and ADAMTS13 levels decrease in STEMI patients. It is unclear if this contributes to no reflow, infarct size and intramyocardial hemorrhage (IMH). The aim of this study was to determine the role of ADAMTS13 in patients with acute myocardial infarction; and to investigate the benefits of recombinant (r)ADAMTS13 in a porcine model of myocardial ischemia-reperfusion with dual antiplatelet therapy and heparin. METHODS In 49 consecutive PCI-treated STEMI patients, blood samples were collected directly after and up to 7 days following PCI. Cardiac magnetic resonance was performed 4-6 days after PCI to determine infarct size and IMH. In 23 Yorkshire swine, the circumflex coronary artery was occluded for 75 minutes by a balloon catheter. rADAMTS13 or vehicle was administered intracoronary following reperfusion. Myocardial injury and infarct characteristics were assessed using cardiac enzymes, ECG, and histopathology. RESULTS In patients with IMH, VWF activity and VWF antigen were significantly elevated directly after PCI and for all subsequent measurements, and ADAMTS13 activity significantly decreased at 4 and 7 days following PCI; in comparison to patients without IMH. VWF activity and ADAMTS13 activity were not related to infarct size. For rADAMTS13 treated animals no differences in myocardial infarct size, IMH, or formation of microthrombi were witnessed in comparison to controls. CONCLUSIONS No correlation was witnessed between VWF/ ADAMTS13 and infarct size in patients; and intracoronary administration of rADAMTS13 did not decrease infarct size or IMH in a porcine model of myocardial ischemia-reperfusion. These data dispute the imbalance in ADAMTS13 and VWF as the cause of no reflow. Restoring the imbalance between ADAMTS13 and VWF most likely will not be beneficial in STEMI patients already treated with standard antiplatelet and anticoagulant therapy. (Figure Presented)