What can we learn from histology of brain clots to improve acute phase treatment of ischemic stroke?
By Barbara Casolla, MD, PhD, Univ. Lille, Inserm U1171, Degenerative and Vascular Cognitive Disorders, CHU Lille, Department of Neurology, France, Twitter: @BarbaraCasolla
Clot histology and behaviour are active areas of research in vascular neurology. In patients with acute ischaemic stroke, mechanical thrombectomy has allowed clot physical removal, opening the access to a new variety of histological data that will probably impact, in the next years, the way we treat patients.
It has been observed that thrombus composition is highly heterogeneous, and it contains crucial pathophysiological information that could influence its susceptibility to i.v. fibrinolysis and mechanical removal.
Under the microscope, the main thrombus components in patients with ischaemic stroke are red blood cells (RBC), platelets (PLT) and leukocytes. RBC/PLT ratio varies, distinguishing RBC-rich vs. PLT-rich thrombi1.
PLT are distributed in different ways: they can be either in the middle of the thrombus or compacted on its surface, in dense structures connected by fibrin and fibrinogen, that are, in turn, bridged by von Willebrand factor (vWF). Interestingly, it has been observed that this outer shell, made of compacted aggregated platelets, fibrin, and vWF, confers resistance to tissue plasminogen activator(rtPA)-mediated thrombolysis2. Indeed, rtPA cleaves plasminogen, and plasmin cleaves fibrin, but in the presence of vWF, PLT remain linked even when fibrin is cleaved. Indeed, vWF could be another therapeutic target in the acute phase of ischaemic stroke. Good news: we know an enzyme that cleaves vWF, and its name is ADAMTS133.
RBC-rich area seems simpler: RBC are linked by a network of fibrin and, from a therapeutic point of view, it is more drug permeable and rtPA susceptible.
What about leukocytes? Neutrophils accumulate in the boundary zone between PLT and RBC. For innate immunity, neutrophils use extrapodes composed by extracellular DNA, the so called neutrophil extracellular traps (NETs), to explore and recognize new antigens. The PLT-RBC interphase is surrounded by NETs, derived from neutrophils. NETs promote thrombosis4 and they seem to confer resistance to pharmacological and mechanical clot lyses5,6,7. Could we add DNAase in a new thrombolytic cocktail? An intriguing question yet to be answered.
Mechanical thrombectomy can be impacted by thrombus composition as well: it has been shown that thrombus fragments removed in the first 2 passes tended to have higher RBC fraction. Fibrin-rich thrombus fragments are retrieved in later passes, suggesting that the fibrino- and PLT-dominant portions of the thrombus contributed to the resistance of mechanical removal8.
We are identifying molecular mechanisms of clot resistance to pharmacological and mechanical lysis, and more evidence will come soon. New targeted lytic therapies and thrombectomy devices could be personalized. Nevertheless, little is known about thrombus composition before therapy, and currently similar treatment approaches are undertaken with all clot subtypes.
Tailoring specific interventions according to the type of thrombus: can neuroimaging help? Beat the clot, part 2, is coming.
Acknowledgments for the musical title: Dr Michele Cavallari, Harvad University, USA
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;39:1433–1451.
- 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–e1698.
- 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;127:2337–2345.
- Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD, et al. Extracellular DNA traps promote thrombosis. Proc. Natl. Acad. Sci. U.S.A. 2010;107:15880–15885.
- Laridan E, Denorme F, Desender L, François O, Andersson T, Deckmyn H, et al. Neutrophil extracellular traps in ischemic stroke thrombi. Ann. Neurol. 2017;82:223–232.
- 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;49:754–757.
- Peña-Martínez C, Durán-Laforet V, García-Culebras A, Ostos F, Hernández-Jiménez M, Bravo-Ferrer I, et al. Pharmacological Modulation of Neutrophil Extracellular Traps Reverses Thrombotic Stroke tPA (Tissue-Type Plasminogen Activator) Resistance. Stroke. 2019;50:3228–3237.
- Duffy S, McCarthy R, Farrell M, Thomas S, Brennan P, Power S, et al. Per-Pass Analysis of Thrombus Composition in Patients With Acute Ischemic Stroke Undergoing Mechanical Thrombectomy. Stroke. 2019;50:1156–1163.