Subscribe to RSS
DOI: 10.1055/s-0040-1713888
von Willebrand Factor Predicts Mortality in ACS Patients Treated with Potent P2Y12 Antagonists and is Inhibited by Aptamer BT200 Ex Vivo
Funding This trial was funded by the Austrian Science Fund, grant number: SFB54-P04.![](https://www.thieme-connect.de/media/10.1055-s-00035024/202009/lookinside/thumbnails/10-1055-s-0040-1713888_200115-1.jpg)
Abstract
Background von Willebrand factor (VWF) is crucial for arterial thrombosis and its plasma levels are increased in acute coronary syndromes (ACSs). The effects of conventional platelet inhibitors are compromised by elevated VWF under high shear rates. BT200 is a third-generation aptamer that binds and inhibits the A1 domain of human VWF. This article aims to study whether VWF is a predictor of mortality in ACS patients under potent P2Y12 blocker therapy and to examine the effects of a VWF inhibiting aptamer BT200 and its concentrations required to inhibit VWF in plasma samples of patients with ACS.
Methods VWF activity was measured in 320 patients with ACS, and concentration effect curves of BT200 were established in plasma pools containing different VWF concentrations.
Results Median VWF activity in patients was 170% (interquartile range % confidence interval [CI]: 85–255) and 44% of patients had elevated (> 180%) VWF activity. Plasma levels of VWF activity predicted 1-year (hazard ratio [HR]: 2.68; 95% CI: 1.14–6.31; p < 0.024) and long-term (HR: 2.59; 95% CI: 1.10–6.09) mortality despite treatment with potent platelet inhibitors (dual-antiplatelet therapy with aspirin and prasugrel or ticagrelor). Although half-maximal concentrations were 0.1 to 0.2 µg/mL irrespective of baseline VWF levels, increasing concentrations (0.42–2.13 µg/mL) of BT200 were needed to lower VWF activity to < 20% of normal in plasma pools containing increasing VWF activity (p < 0.001).
Conclusion VWF is a predictor of all-cause mortality in ACS patients under contemporary potent P2Y12 inhibitor therapy. BT200 effectively inhibited VWF activity in a target concentration-dependent manner.
Publication History
Received: 02 March 2020
Accepted: 26 May 2020
Article published online:
17 July 2020
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Stuttgart · New York
-
References
- 1 André P, Hainaud P, Bal dit Sollier C, Garfinkel LI, Caen JP, Drouet LO. Relative involvement of GPIb/IX-vWF axis and GPIIb/IIIa in thrombus growth at high shear rates in the guinea pig. Arterioscler Thromb Vasc Biol 1997; 17 (05) 919-924
- 2 Li M, Goto S, Sakai H. , et al. Enhanced shear-induced von Willebrand factor binding to platelets in acute myocardial infarction. Thromb Res 2000; 100 (04) 251-261
- 3 Reininger AJ, Heijnen HFG, Schumann H, Specht HM, Schramm W, Ruggeri ZM. Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress. Blood 2006; 107 (09) 3537-3545
- 4 Ruggeri ZM. The role of von Willebrand factor in thrombus formation. Thromb Res 2007; 120 (Suppl. 01) S5-S9
- 5 Ruggeri ZM, Ware J. von Willebrand factor. FASEB J 1993; 7 (02) 308-316
- 6 Le Behot A, Gauberti M, Martinez De Lizarrondo S. , et al. GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice. Blood 2014; 123 (21) 3354-3363
- 7 Reininger AJ. VWF attributes--impact on thrombus formation. Thromb Res 2008; 122 (Suppl. 04) S9-S13
- 8 Blann AD. Plasma von Willebrand factor, thrombosis, and the endothelium: the first 30 years. Thromb Haemost 2006; 95 (01) 49-55
- 9 Spiel AO, Gilbert JC, Jilma B. von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation 2008; 117 (11) 1449-1459
- 10 Kovacevic KD, Mayer FJ, Jilma B. , et al. Von Willebrand factor antigen levels predict major adverse cardiovascular events in patients with carotid stenosis of the ICARAS study. Atherosclerosis 2019; 290: 31-36
- 11 Buchtele N, Schwameis M, Gilbert JC, Schörgenhofer C, Jilma B. Targeting von Willebrand factor in ischaemic stroke: focus on clinical evidence. Thromb Haemost 2018; 118 (06) 959-978
- 12 Siller-Matula J, Lang IM, Schoergenhofer C, Roest M, Jilma B. Interdependence between osteoprotegerin and active von Willebrand factor in long-term cardiovascular mortality prediction in patients undergoing percutaneous coronary intervention. Thromb Haemost 2017; 117 (09) 1730-1738
- 13 Siller-Matula JM, Akca B, Neunteufl T. , et al. Inter-patient variability of platelet reactivity in patients treated with prasugrel and ticagrelor. Platelets 2016; 27 (04) 373-377
- 14 Gorog DA, Geisler T. Platelet inhibition in acute coronary syndrome and percutaneous coronary intervention: insights from the past and present. Thromb Haemost 2020; 120 (04) 565-578
- 15 Traby L, Kollars M, Kaider A. , et al. Differential effects of ticagrelor with or without aspirin on platelet reactivity and coagulation activation: a randomized trial in healthy volunteers. Clin Pharmacol Ther 2020; 107 (02) 415-422
- 16 Eyileten C, Soplinska A, Pordzik J, Siller-Matula JM, Postuła M. Effectiveness of antiplatelet drugs under therapeutic hypothermia: a comprehensive review. Clin Pharmacol Ther 2019; 106 (05) 993-1005
- 17 Prüller F, Bis L, Milke OL. , et al. Cangrelor induces more potent platelet inhibition without increasing bleeding in resuscitated patients. J Clin Med 2018; 7 (11) 442
- 18 Derhaschnig U, Pachinger C, Jilma B. Variable inhibition of high-shear-induced platelet plug formation by eptifibatide and tirofiban under conditions of platelet activation and high von Willebrand release: a randomized, placebo-controlled, clinical trial. Am Heart J 2004; 147 (04) E17
- 19 Reiter RA, Mayr F, Blazicek H. , et al. Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Blood 2003; 102 (13) 4594-4599
- 20 Spiel AO, Derhaschnig U, Schwameis M, Bartko J, Siller-Matula JM, Jilma B. Effects of prasugrel on platelet inhibition during systemic endotoxaemia: a randomized controlled trial. Clin Sci (Lond) 2012; 123 (10) 591-600
- 21 Kubisa MJ, Jezewski MP, Gasecka A, Siller-Matula JM, Postuła M. Ticagrelor - toward more efficient platelet inhibition and beyond. Ther Clin Risk Manag 2018; 14: 129-140
- 22 Siller-Matula JM, Lang IM, Neunteufl T. , et al. Interplay between genetic and clinical variables affecting platelet reactivity and cardiac adverse events in patients undergoing percutaneous coronary intervention. PLoS One 2014; 9 (07) e102701
- 23 Marcucci R, Cesari F, Cinotti S. , et al. ADAMTS-13 activity in the presence of elevated von Willebrand factor levels as a novel mechanism of residual platelet reactivity in high risk coronary patients on antiplatelet treatment. Thromb Res 2008; 123 (01) 130-136
- 24 Zhu S, Gilbert JC, Hatala P. , et al. The development and characterization of a long acting anti-thrombotic von Willebrand factor (VWF) aptamer. J Thromb Haemost 2020; 18 (05) 1113-1123
- 25 Winter MP, von Lewinski D, Wallner M. , et al. Incidence, predictors, and prognosis of premature discontinuation or switch of prasugrel or ticagrelor: the ATLANTIS - SWITCH study. Sci Rep 2019; 9 (01) 8194
- 26 Winter MP, Schneeweiss T, Cremer R. , et al. Platelet reactivity patterns in patients treated with dual antiplatelet therapy. Eur J Clin Invest 2019; DOI: 10.1111/eci.13102.
- 27 Spiel AO, Mayr FB, Ladani N. , et al. The aptamer ARC1779 is a potent and specific inhibitor of von Willebrand Factor mediated ex vivo platelet function in acute myocardial infarction. Platelets 2009; 20 (05) 334-340
- 28 Goodall AH, Jarvis J, Chand S. , et al. An immunoradiometric assay for human factor VIII/von Willebrand factor (VIII:vWF) using a monoclonal antibody that defines a functional epitope. Br J Haematol 1985; 59 (04) 565-577
- 29 Murdock PJ, Woodhams BJ, Matthews KB, Pasi KJ, Goodall AH. von Willebrand factor activity detected in a monoclonal antibody-based ELISA: an alternative to the ristocetin cofactor platelet agglutination assay for diagnostic use. Thromb Haemost 1997; 78 (04) 1272-1277
- 30 Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction. J Lab Clin Med 2001; 138 (03) 152-163
- 31 Jilma-Stohlawetz P, Gilbert JC, Gorczyca ME, Knöbl P, Jilma B. A dose ranging phase I/II trial of the von Willebrand factor inhibiting aptamer ARC1779 in patients with congenital thrombotic thrombocytopenic purpura. Thromb Haemost 2011; 106 (03) 539-547
- 32 Homoncik M, Blann AD, Hollenstein U, Pernerstorfer T, Eichler HG, Jilma B. Systemic inflammation increases shear stress-induced platelet plug formation measured by the PFA-100. Br J Haematol 2000; 111 (04) 1250-1252
- 33 Kazianka L, Drucker C, Skrabs C. , et al. Ristocetin-induced platelet aggregation for monitoring of bleeding tendency in CLL treated with ibrutinib. Leukemia 2017; 31 (05) 1117-1122
- 34 Spiel AO, Bartko J, Schwameis M. , et al. Increased platelet aggregation and in vivo platelet activation after granulocyte colony-stimulating factor administration. A randomised controlled trial. Thromb Haemost 2011; 105 (04) 655-662
- 35 Tóth O, Calatzis A, Penz S, Losonczy H, Siess W. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006; 96 (06) 781-788
- 36 Yan AT, Yan RT, Tan M. , et al; Canadian Acute Coronary Syndromes Registry Investigators. In-hospital revascularization and one-year outcome of acute coronary syndrome patients stratified by the GRACE risk score. Am J Cardiol 2005; 96 (07) 913-916
- 37 Yan AT, Tan M, Fitchett D. , et al; Canadian Acute Coronary Syndromes Registry Investigators. One-year outcome of patients after acute coronary syndromes (from the Canadian Acute Coronary Syndromes Registry). Am J Cardiol 2004; 94 (01) 25-29
- 38 Wallentin L, Becker RC, Budaj A. , et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
- 39 Hochman JS, Tamis JE, Thompson TD. , et al. Sex, clinical presentation, and outcome in patients with acute coronary syndromes. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes IIb Investigators. N Engl J Med 1999; 341 (04) 226-232
- 40 Sanders YV, Eikenboom J, de Wee EM. , et al; WiN Study Group. Reduced prevalence of arterial thrombosis in von Willebrand disease. J Thromb Haemost 2013; 11 (05) 845-854
- 41 Jilma-Stohlawetz P, Gorczyca ME, Jilma B, Siller-Matula J, Gilbert JC, Knöbl P. Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura. Thromb Haemost 2011; 105 (03) 545-552
- 42 Hasper D, Schrage D, Niesporek S, Knollmann F, Barckow D, Oppert M. Extensive coronary thrombosis in thrombotic-thrombocytopenic purpura. Int J Cardiol 2006; 106 (03) 407-409
- 43 Knoebl P, Cataland S, Peyvandi F. , et al. Efficacy and safety of open-label caplacizumab in patients with exacerbations of acquired thrombotic thrombocytopenic purpura in the HERCULES study. J Thromb Haemost 2020; 18 (02) 479-484
- 44 Reininger AJ. Function of von Willebrand factor in haemostasis and thrombosis. Haemophilia 2008; 14 (Suppl. 05) 11-26
- 45 Paulinska P, Spiel A, Jilma B. Role of von Willebrand factor in vascular disease. Hamostaseologie 2009; 29 (01) 32-38
- 46 Carter AM, Catto AJ, Mansfield MW, Bamford JM, Grant PJ. Predictive variables for mortality after acute ischemic stroke. Stroke 2007; 38 (06) 1873-1880
- 47 Nichols TC, Bellinger DA, Tate DA. , et al. von Willebrand factor and occlusive arterial thrombosis. A study in normal and von Willebrand's disease pigs with diet-induced hypercholesterolemia and atherosclerosis. Arteriosclerosis 1990; 10 (03) 449-461
- 48 Wong CB, Schreiber TL. Acute myocardial infarction in a patient with von Willebrand disease. Cathet Cardiovasc Diagn 1996; 38 (03) 287-288
- 49 Franchini M, Veneri D. Are only haemophiliacs protected against ischemic heart disease?. Thromb Haemost 2004; 92 (06) 1455
- 50 Fragasso G, Camba L, Pizzetti G, Pagnotta P, Chierchia SL. Successful thrombolysis for acute myocardial infarction in Type I von Willebrand's disease (vWD). Am J Hematol 1998; 57 (02) 180
- 51 Lim MY, Pruthi RK. Outcomes of management of acute coronary syndrome in patients with congenital bleeding disorders: a single center experience and review of the literature. Thromb Res 2012; 130 (03) 316-322
- 52 Meyer SC, Armstrong E, Perdrizat C, Schmid H-R, Lassila R, Beer JH. Management strategies of stroke and acute coronary syndrome in von Willebrand disease and hemophilia: experience from a case series and a Swiss survey of frequencies. Blood 2010; 116 (21) 1406-1406
- 53 Goodnough LT, Saito H, Ratnoff OD. Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases. Medicine (Baltimore) 1983; 62 (04) 248-255
- 54 Fuchs I, Frossard M, Spiel A, Riedmüller E, Laggner AN, Jilma B. Platelet function in patients with acute coronary syndrome (ACS) predicts recurrent ACS. J Thromb Haemost 2006; 4 (12) 2547-2552
- 55 Firbas C, Siller-Matula JM, Jilma B. Targeting von Willebrand factor and platelet glycoprotein Ib receptor. Expert Rev Cardiovasc Ther 2010; 8 (12) 1689-1701
- 56 van Loon JE, de Jaegere PP, Ulrichts H. , et al. The in vitro effect of the new antithrombotic drug candidate ALX-0081 on blood samples of patients undergoing percutaneous coronary intervention. Thromb Haemost 2011; 106 (01) 165-171
- 57 Muller O, Bartunek J, Hamilos M. , et al. von Willebrand factor inhibition improves endothelial function in patients with stable angina. J Cardiovasc Transl Res 2013; 6 (03) 364-370
- 58 Kageyama S, Yamamoto H, Nakazawa H. , et al. Pharmacokinetics and pharmacodynamics of AJW200, a humanized monoclonal antibody to von Willebrand factor, in monkeys. Arterioscler Thromb Vasc Biol 2002; 22 (01) 187-192
- 59 Takahashi M, Yamashita A, Moriguchi-Goto S. , et al. Critical role of von Willebrand factor and platelet interaction in venous thromboembolism. Histol Histopathol 2009; 24 (11) 1391-1398
- 60 Gilbert JC, DeFeo-Fraulini T, Hutabarat RM. , et al. First-in-human evaluation of anti von Willebrand factor therapeutic aptamer ARC1779 in healthy volunteers. Circulation 2007; 116 (23) 2678-2686
- 61 Cataland SR, Peyvandi F, Mannucci PM. , et al. Initial experience from a double-blind, placebo-controlled, clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura. Am J Hematol 2012; 87 (04) 430-432
- 62 Jilma B, Paulinska P, Jilma-Stohlawetz P, Gilbert JC, Hutabarat R, Knöbl P. A randomised pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease. Thromb Haemost 2010; 104 (03) 563-570
- 63 Jilma-Stohlawetz P, Knöbl P, Gilbert JC, Jilma B. The anti-von Willebrand factor aptamer ARC1779 increases von Willebrand factor levels and platelet counts in patients with type 2B von Willebrand disease. Thromb Haemost 2012; 108 (02) 284-290
- 64 Markus HS, McCollum C, Imray C, Goulder MA, Gilbert J, King A. The von Willebrand inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy: a randomized trial. Stroke 2011; 42 (08) 2149-2153
- 65 Zhu S, Gilbert JC, Liang Z. , et al. Potent and rapid reversal of the von Willebrand factor inhibitor aptamer BT200. J Thromb Haemost 2020 DOI: . Doi: 10.1111/jth.14822.
- 66 Nichols TC, Bellinger DA, Merricks EP. , et al. Porcine and canine von Willebrand factor and von Willebrand disease: hemostasis, thrombosis, and atherosclerosis studies. Thrombosis 2010; 2010: 461238
- 67 Verhenne S, Denorme F, Libbrecht S. , et al. Platelet-derived VWF is not essential for normal thrombosis and hemostasis but fosters ischemic stroke injury in mice. Blood 2015; 126 (14) 1715-1722