[en] During the last decade, significant progress has been made in understanding thrombus composition and organization in the setting of acute ischemic stroke (AIS). In particular, thrombus organization is now described as highly heterogeneous but with 2 preserved characteristics: the presence of (1) two distinct main types of areas in the core-red blood cell (RBC)-rich and platelet-rich areas in variable proportions in each thrombus-and (2) an external shell surrounding the core composed exclusively of platelet-rich areas. In contrast to RBC-rich areas, platelet-rich areas are highly complex and are mainly responsible for the thrombolysis resistance of these thrombi for the following reasons: the presence of platelet-derived fibrinolysis inhibitors in large amounts, modifications of the fibrin network structure resistant to the tissue plasminogen activator (tPA)-induced fibrinolysis, and the presence of non-fibrin extracellular components, such as von Willebrand factor (vWF) multimers and neutrophil extracellular traps. From these studies, new therapeutic avenues are in development to increase the fibrinolytic efficacy of intravenous (IV) tPA-based therapy or to target non-fibrin thrombus components, such as platelet aggregates, vWF multimers, or the extracellular DNA network.
Disciplines :
Neurology
Author, co-author :
Desilles, Jean-Philippe; Interventional Neuroradiology Department and Biological Resources Center, Rothschild Foundation Hospital, Paris, France ; Laboratory of Vascular Translational Science, U1148 INSERM, Paris, France ; Université Paris Cité, Paris, France ; FHU Neurovasc, Paris, France
Di Meglio, Lucas; Laboratory of Vascular Translational Science, U1148 INSERM, Paris, France
Delvoye, François ; Université de Liège - ULiège > Département des sciences cliniques > Neuroimagerie des troubles de la mémoire et revalidation cognitive ; Interventional Neuroradiology Department and Biological Resources Center, Rothschild Foundation Hospital, Paris, France
Maïer, Benjamin; Interventional Neuroradiology Department and Biological Resources Center, Rothschild Foundation Hospital, Paris, France ; Université Paris Cité, Paris, France ; FHU Neurovasc, Paris, France
Piotin, Michel; Interventional Neuroradiology Department and Biological Resources Center, Rothschild Foundation Hospital, Paris, France ; Laboratory of Vascular Translational Science, U1148 INSERM, Paris, France
Ho-Tin-Noé, Benoît; Laboratory of Vascular Translational Science, U1148 INSERM, Paris, France ; Université Paris Cité, Paris, France
Mazighi, Mikael; Interventional Neuroradiology Department and Biological Resources Center, Rothschild Foundation Hospital, Paris, France ; Laboratory of Vascular Translational Science, U1148 INSERM, Paris, France ; Université Paris Cité, Paris, France ; FHU Neurovasc, Paris, France ; Department of Neurology, Hopital Lariboisère, APHP Nord, Paris, France
Language :
English
Title :
Composition and Organization of Acute Ischemic Stroke Thrombus: A Wealth of Information for Future Thrombolytic Strategies.
INSERM - French Institute of Health and Medical Research FRM - Fondation pour la Recherche Médicale ANR - Agence Nationale de la Recherche
Funding text :
This work was supported by INSERM, La Fondation pour la Recherche sur les AVC (grant # FR-AVC-003), La Fondation pour la Recherche Médicale (grant #DPC20171138959), La Fondation de l'Avenir (AP-RM-17-005), and by a public grant overseen by the French National Research Agency (ANR) as part of the Investments for the Future program (PIA) under grant agreement nos. ANR-18-RHUS-0001 (RHU Booster) and ANR-16-RHUS-0004 (RHU TRT_cSVD).
Bacigaluppi M Semerano A Gullotta GS Strambo D. Insights from thrombi retrieved in stroke due to large vessel occlusion. J Cereb Blood Flow Metab. (2019) 39:1433–51. 10.1177/0271678X1985613131213164
Staessens S François O Brinjikji W Doyle KM Vanacker P Andersson T et al. Studying stroke thrombus composition after thrombectomy: what can we learn? Stroke. (2021) 52:3718–27. 10.1161/STROKEAHA.121.03428934517770
Loyau S Ho-Tin-Noé B Bourrienne M-C Boulaftali Y Jandrot-Perrus M. Microfluidic modeling of thrombolysis. Arterioscler Thromb Vasc Biol. (2018) 38:2626–37. 10.1161/ATVBAHA.118.31117830354249
Li R Elmongy H Sims C Diamond SL. Ex vivo recapitulation of trauma-induced coagulopathy and preliminary assessment of trauma patient platelet function under flow using microfluidic technology. J Trauma Acute Care Surg. (2016) 80:440–9. 10.1097/TA.000000000000091527082706
Whyte CS Swieringa F Mastenbroek TG Lionikiene AS Lancé MD van der Meijden PEJ et al. Plasminogen associates with phosphatidylserine-exposing platelets and contributes to thrombus lysis under flow. Blood. (2015) 125:2568–78. 10.1182/blood-2014-09-59948025712989
Rubiera M Alvarez-Sabín J Ribo M Montaner J Santamarina E Arenillas JF et al. Predictors of early arterial reocclusion after tissue plasminogen activator-induced recanalization in acute ischemic stroke. Stroke. (2005) 36:1452–6. 10.1161/01.STR.0000170711.43405.8115947260
Ducroux C Di Meglio L Loyau S Delbosc S Boisseau W Deschildre C et al. Thrombus neutrophil extracellular traps content impair tPA-induced thrombolysis in acute ischemic stroke. Stroke. (2018) 49:754–7. 10.1161/STROKEAHA.117.01989629866759
Laridan E Denorme F Desender L François O Andersson T Deckmyn H et al. Neutrophil extracellular traps in ischemic stroke thrombi. Ann Neurol. (2017) 82:223–32. 10.1002/ana.2499328696508
Mangold A Alias S Scherz T Hofbauer T Jakowitsch J Panzenböck A et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res. (2015) 116:1182–92. 10.1161/CIRCRESAHA.116.30494433476207
Le Behot A Gauberti M Martinez De Lizarrondo S Montagne A Lemarchand E Repesse Y et al. GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice. Blood. (2014) 123:3354–63. 10.1182/blood-2013-12-54307424553181
Reimann A Li Z Goebel S Fassbender J Holthoff H-P Gawaz M et al. Combined administration of the GPVI-Fc fusion protein Revacept with low-dose thrombolysis in the treatment of stroke. Heart Int. (2016) 11:e10–6. 10.5301/heartint.500022927924212
Denorme F Langhauser F Desender L Vandenbulcke A Rottensteiner H Plaimauer B et al. ADAMTS13-mediated thrombolysis of t-PA–resistant occlusions in ischemic stroke in mice. Blood. (2016) 127:2337–45. 10.1182/blood-2015-08-66265026929275
Martinez de Lizarrondo S Gakuba C Herbig BA Repessé Y Ali C Denis CV et al. Potent thrombolytic effect of N-acetylcysteine on arterial thrombi. Circulation. (2017) 136:646–60. 10.1161/CIRCULATIONAHA.117.02729028487393
Di Meglio L Desilles J-P Ollivier V Nomenjanahary MS Di Meglio S Deschildre C et al. Acute ischemic stroke thrombi have an outer shell that impairs fibrinolysis. Neurology. (2019) 93:e1686–98. 10.1212/WNL.000000000000839531659139
Staessens S Denorme F François O Desender L Dewaele T Vanacker P et al. Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance. Haematologica. (2020) 105:498–507. 10.3324/haematol.2019.21988131048352
Autar ASA Hund HM Ramlal SA Hansen D Lycklama à Nijeholt GJ Emmer BJ et al. High-resolution imaging of interaction between thrombus and stent-retriever in patients with acute ischemic stroke. J Am Heart Assoc. (2018) 7:e008563. 10.1161/JAHA.118.00856329934420
Cines DB Lebedeva T Nagaswami C Hayes V Massefski W Litvinov RI et al. Clot contraction: compression of erythrocytes into tightly packed polyhedra and redistribution of platelets and fibrin. Blood. (2014) 123:1596–603. 10.1182/blood-2013-08-52386024335500
Mereuta OM Fitzgerald S Christensen TA Jaspersen AL Dai D Abbasi M et al. High-resolution scanning electron microscopy for the analysis of three-dimensional ultrastructure of clots in acute ischemic stroke. J Neurointerv Surg. (2021) 13:906–11. 10.1136/neurintsurg-2020-01670933361274
Rossi R Molina S Mereuta OM Douglas A Fitzgerald S Tierney C et al. Does prior administration of rtPA influence acute ischemic stroke clot composition? Findings from the analysis of clots retrieved with mechanical thrombectomy from the RESTORE registry. J Neurol. (2022) 269:1913–20. 10.1007/s00415-021-10758-534415423
Auboire L Fouan D Grégoire J-M Ossant F Plag C Escoffre J-M et al. Acoustic and elastic properties of a blood clot during microbubble-enhanced sonothrombolysis: hardening of the clot with inertial cavitation. Pharmaceutics. (2021) 13:1566. 10.3390/pharmaceutics1310156634683859
Collet JP Park D Lesty C Soria J Soria C Montalescot G et al. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol. (2000) 20:1354–61. 10.1161/01.ATV.20.5.135410807754
Walsh CT Garneau-Tsodikova S Gatto GJ. Protein posttranslational modifications: the chemistry of proteome diversifications. Angew Chem Int Ed Engl. (2005) 44:7342–72. 10.1002/anie.20050102316267872
Karve TM Cheema AK. Small changes huge impact: the role of protein posttranslational modifications in cellular homeostasis and disease. J Amino Acids. (2011) 2011:207691. 10.4061/2011/20769122312457
Weisel JW Litvinov RI. Mechanisms of fibrin polymerization and clinical implications. Blood. (2013) 121:1712–9. 10.1182/blood-2012-09-30663923305734
Rijken DC Abdul S Malfliet JJMC Leebeek FWG Uitte de. Willige S. Compaction of fibrin clots reveals the antifibrinolytic effect of factor XIII. J Thromb Haemost. (2016) 14:1453–61. 10.1111/jth.1335427148673
Booth NA. Regulation of fibrinolytic activity by localization of inhibitors to fibrin(ogen). Fibrinolysis Proteolysis. (2000) 14:206–13. 10.1054/fipr.2000.0071
Brownlee M Vlassara H Cerami A. Nonenzymatic glycosylation reduces the susceptibility of fibrin to degradation by plasmin. Diabetes. (1983) 32:680–4. 10.2337/diabetes.32.7.6806222931
Pretorius E Lipinski B. Differences in morphology of fibrin clots induced with thrombin and ferric ions and its pathophysiological consequences. Heart Lung Circ. (2013) 22:447–9. 10.1016/j.hlc.2012.10.01023219312
Binder V Bergum B Jaisson S Gillery P Scavenius C Spriet E et al. Impact of fibrinogen carbamylation on fibrin clot formation and stability. Thromb Haemost. (2017) 117:899–910. 10.1160/TH16-09-070428382370
Amelot AA Tagzirt M Ducouret G Kuen RL Le Bonniec BF. Platelet factor 4 (CXCL4) seals blood clots by altering the structure of fibrin. J Biol Chem. (2007) 282:710–20. 10.1074/jbc.M60665020017090548
Macrae FL Duval C Papareddy P Baker SR Yuldasheva N Kearney KJ et al. A fibrin biofilm covers blood clots and protects from microbial invasion. J Clin Invest. (2018) 128:3356–68. 10.1172/JCI9873429723163
Whyte C Mitchell J Mutch N. Platelet-mediated modulation of fibrinolysis. Semin Thromb Hemost. (2017) 43:115–28. 10.1055/s-0036-159728328215042
Jang IK Gold HK Ziskind AA Fallon JT Holt RE Leinbach RC et al. Differential sensitivity of erythrocyte-rich and platelet-rich arterial thrombi to lysis with recombinant tissue-type plasminogen activator. A possible explanation for resistance to coronary thrombolysis. Circulation. (1989) 79:920–8. 10.1161/01.CIR.79.4.9202494006
Booth NA Simpson AJ Croll A Bennett B MacGregor IR. Plasminogen activator inhibitor (PAI-1) in plasma and platelets. Br J Haematol. (1988) 70:327–33. 10.1111/j.1365-2141.1988.tb02490.x3264718
Kasahara K Kaneda M Miki T Iida K Sekino-Suzuki N Kawashima I et al. Clot retraction is mediated by factor XIII-dependent fibrin-αIIbβ3-myosin axis in platelet sphingomyelin-rich membrane rafts. Blood. (2013) 122:3340–8. 10.1182/blood-2013-04-49129024002447
Sabovic M Lijnen HR Keber D Collen D. Effect of retraction on the lysis of human clots with fibrin specific and non-fibrin specific plasminogen activators. Thromb Haemost. (1989) 62:1083–7. 10.1055/s-0038-16471222515603
Blinc A Keber D Lahajnar G Zupancic I Zorec-Karlovsek M Demsar F. Magnetic resonance imaging of retracted and nonretracted blood clots during fibrinolysis in vitro. Haemostasis. (1992) 22:195–201. 10.1159/0002163191468722
Tomkins AJ Schleicher N Murtha L Kaps M Levi CR Nedelmann M et al. Platelet rich clots are resistant to lysis by thrombolytic therapy in a rat model of embolic stroke. Exp Transl Stroke Med. (2015) 7:2. 10.1186/s13231-014-0014-y25657829
Douglas A Fitzgerald S Mereuta OM Rossi R O'Leary S Pandit A et al. Platelet-rich emboli are associated with von Willebrand factor levels and have poorer revascularization outcomes. J NeuroInterv Surg. (2020) 12:557–62. 10.1136/neurintsurg-2019-01541031685695
Pfeiler S Stark K Massberg S Engelmann B. Propagation of thrombosis by neutrophils and extracellular nucleosome networks. Haematologica. (2017) 102:206–13. 10.3324/haematol.2016.14247127927771
Martinod K Wagner DD. Thrombosis: tangled up in NETs. Blood. (2014) 123:2768–76. 10.1182/blood-2013-10-46364624366358
Fuchs TA Brill A Duerschmied D Schatzberg D Monestier M Myers DD et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA. (2010) 107:15880–5. 10.1073/pnas.100574310720798043
Desilles J-P Solo Nomenjanahary M Consoli A Ollivier V Faille D Bourrienne M-C et al. Impact of COVID-19 on thrombus composition and response to thrombolysis: Insights from a monocentric cohort population of COVID-19 patients with acute ischemic stroke. J Thromb Haemost. (2022) 20:919–28. 10.1111/jth.1564635032088
Lapergue B Blanc R Costalat V Desal H Saleme S Spelle L et al. Effect of thrombectomy with combined contact aspiration and stent retriever vs stent retriever alone on revascularization in patients with acute ischemic stroke and large vessel occlusion: the ASTER2 randomized clinical trial. JAMA. (2021) 326:1158–69.34581737
Staessens S François O Desender L Vanacker P Dewaele T Sciot R et al. Detailed histological analysis of a thrombectomy-resistant ischemic stroke thrombus: a case report. Thromb J. (2021) 19:11. 10.1186/s12959-021-00262-133618719
Abbasi M Arturo Larco J Mereuta MO Liu Y Fitzgerald S et al. Diverse thrombus composition in thrombectomy stroke patients with longer time to recanalization. Thromb Res. (2022) 209:99–104. 10.1016/j.thromres.2021.11.01834906857
De Meyer SF Deckmyn H Vanhoorelbeke K. von Willebrand factor to the rescue. Blood. (2009) 113:5049–57. 10.1182/blood-2008-10-16562119318682
Wieberdink RG van Schie MC Koudstaal PJ Hofman A Witteman JCM de Maat MPM et al. High von Willebrand factor levels increase the risk of stroke: the Rotterdam Study. Stroke. (2010) 41:2151–6. 10.1161/STROKEAHA.110.58628921293019
Andersson HM Siegerink B Luken BM Crawley JTB Algra A Lane DA et al. High VWF, low ADAMTS13, and oral contraceptives increase the risk of ischemic stroke and myocardial infarction in young women. Blood. (2012) 119:1555–60. 10.1182/blood-2011-09-38061822110247
Bustamante A Ning M García-Berrocoso T Penalba A Boada C Simats A et al. Usefulness of ADAMTS13 to predict response to recanalization therapies in acute ischemic stroke. Neurology. (2018) 90:e995–1004. 10.1212/WNL.000000000000516230397046
Tanswell P Modi N Combs D Danays T. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction: Clin. Pharmacokinet. (2002) 41:1229–45. 10.2165/00003088-200241150-0000112452736
Huang X Moreton FC Kalladka D Cheripelli BK MacIsaac R Tait RC et al. Coagulation and fibrinolytic activity of tenecteplase and alteplase in acute ischemic stroke. Stroke. (2015) 46:3543–6. 10.1161/STROKEAHA.115.01129026514192
Burgos AM Saver JL. Evidence that tenecteplase is noninferior to alteplase for acute ischemic stroke: meta-analysis of 5 randomized trials. Stroke. (2019) 50:2156–62. 10.1161/STROKEAHA.119.02508031318627
Campbell BCV Mitchell PJ Churilov L Yassi N Kleinig TJ Dowling RJ et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. (2018) 378:1573–82.29694815
Powers WJ Rabinstein AA Ackerson T Adeoye OM Bambakidis NC Becker K et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. (2019) 50:e344–418. 10.1161/STR.000000000000021131765293
Turc G Bhogal P Fischer U Khatri P Lobotesis K Mazighi M et al. European Stroke Organisation (ESO)- European Society for Minimally Invasive Neurological Therapy (ESMINT) guidelines on mechanical thrombectomy in acute ischemic stroke. J Neurointerv Surg. (2019) 11:535–8. 10.1136/neurintsurg-2018-01456831152058
Varna M Juenet M Bayles R Mazighi M Chauvierre C Letourneur D. Nanomedicine as a strategy to fight thrombotic diseases. Future Sci OA. (2015) 1:FSO46. 10.4155/fso.15.4628031907
Wyseure T Declerck PJ. Novel or expanding current targets in fibrinolysis. Drug Discov Today. (2014) 19:1476–82. 10.1016/j.drudis.2014.05.02524886765
Denorme F Wyseure T Peeters M Vandeputte N Gils A Deckmyn H et al. Inhibition of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 reduces ischemic brain damage in mice. Stroke. (2016) 47:2419–22. 10.1161/STROKEAHA.116.01409127470988
Wyseure T Rubio M Denorme F Martinez de Lizarrondo S Peeters M Gils A et al. Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke. Blood. (2015) 125:1325–32. 10.1182/blood-2014-07-58831925540192
Chan S-L Bishop N Li Z Cipolla MJ. Inhibition of PAI (plasminogen activator inhibitor)-1 improves brain collateral perfusion and injury after acute ischemic stroke in aged hypertensive rats. Stroke. (2018) 49:1969–76. 10.1161/STROKEAHA.118.02205629991657
Durand A Chauveau F Cho T-H Kallus C Wagner M Boutitie F et al. Effects of a TAFI-inhibitor combined with a suboptimal dose of rtPA in a murine thromboembolic model of stroke. Cerebrovasc Dis Basel Switz. (2014) 38:268–75. 10.1159/00036626625401979
Boulaftali Y Ho-Tin-Noe B Pena A Loyau S Venisse L François D et al. Platelet protease nexin-1, a serpin that strongly influences fibrinolysis and thrombolysis. Circulation. (2011) 123:1326–34. 10.1161/CIRCULATIONAHA.110.00088521403095
Kawecki C Aymonnier K Ferrière S Venisse L Arocas V Boulaftali Y et al. Development and characterization of single-domain antibodies neutralizing protease nexin-1 as tools to increase thrombin generation. J Thromb Haemost. (2020) 18:2155–68. 10.1111/jth.1494032495984
Boulaftali Y Adam F Venisse L Ollivier V Richard B Taieb S et al. Anticoagulant and antithrombotic properties of platelet protease nexin-1. Blood. (2010) 115:97–106. 10.1182/blood-2009-04-21724019855083
Duval C Baranauskas A Feller T Ali M Cheah LT Yuldasheva NY et al. Elimination of fibrin γ-chain cross-linking by FXIIIa increases pulmonary embolism arising from murine inferior vena cava thrombi. Proc Natl Acad Sci USA. (2021) 118:e2103226118. 10.1073/pnas.210322611834183396
Siebler M Hennerici MG Schneider D von Reutern GM Seitz RJ Röther J et al. Safety of tirofiban in acute ischemic stroke: the SaTIS trial. Stroke. (2011) 42:2388–92. 10.1161/STROKEAHA.110.59966221852609
Adams HP Effron MB Torner J Dávalos A Frayne J Teal P et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: abciximab in emergency treatment of stroke trial (AbESTT-II). Stroke. (2008) 39:87–99. 10.1161/STROKEAHA.106.47664818032739
Voors-Pette C Lebozec K Dogterom P Jullien L Billiald P Ferlan P et al. Safety and Tolerability, pharmacokinetics, and pharmacodynamics of ACT017, an antiplatelet GPVI (Glycoprotein VI) Fab: first-in-human healthy volunteer trial. Arterioscler Thromb Vasc Biol. (2019) 39:956–64. 10.1161/ATVBAHA.118.31231431017822
Akers WS Oh JJ Oestreich JH Ferraris S Wethington M Steinhubl SR. Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor: a direct, parenteral P2Y12 receptor antagonist. J Clin Pharmacol. (2010) 50:27–35. 10.1177/009127000934498619779037
Sorvillo N Mizurini DM Coxon C Martinod K Tilvawala R Cherpokova D et al. Plasma peptidylarginine deiminase IV promotes VWF-platelet string formation and accelerates thrombosis after vessel injury. Circ Res. (2019) 125:507–19. 10.1161/CIRCRESAHA.118.31457131248335
Elliott W Guda MR Asuthkar S Teluguakula N Prasad DVR Tsung AJ et al. Inhibitors as a potential treatment for SARS-CoV-2 immunothrombosis. Biomedicines. (2021) 9:1867. 10.3390/biomedicines912186734944683
Prochazka V Jonszta T Czerny D Krajca J Roubec M Macak J et al. The role of von Willebrand factor, ADAMTS13, and cerebral artery thrombus composition in patient outcome following mechanical thrombectomy for acute ischemic stroke. Med Sci Monit Int Med J Exp Clin Res. (2018) 24:3929–45. 10.12659/MSM.90844129887594
Grosse GM Blume N Abu-Fares O Götz F Ernst J Leotescu A et al. Endogenous deoxyribonuclease activity and cell-free deoxyribonucleic acid in acute ischemic stroke: a cohort study. Stroke. (2022) 53:1235–44. 10.1161/STROKEAHA.121.03629934991335
Zang N Lin Z Huang K Pan Y Wu Y Wu Y et al. Biomarkers of unfavorable outcome in acute ischemic stroke patients with successful recanalization by endovascular thrombectomy. Cerebrovasc Dis Basel Switz. (2020) 49:583–92. 10.1159/00051080433105129
Di Meglio L Desilles J-P Solonomenjanahary M Labreuche J Ollivier V Dupont S et al. DNA Content in ischemic stroke thrombi can help identify cardioembolic strokes among strokes of undetermined cause. Stroke. (2020) 51:2810–6. 10.1161/STROKEAHA.120.02913432811390