Short Report Received: April 24, 2014 Accepted: June 22, 2014 Published online: October 25, 2014
Eur Neurol 2014;72:375–377 DOI: 10.1159/000365443
Fibrinogen and von Willebrand Factor and Susceptibility Vessel Sign on T2*-Weighted Gradient Echo Imaging Ahmed Farghali a Michel Hanss b Julien Berthiller c, d Laurent Derex a Laura Mechtouff a Thomas Ritzenthaler a Tae-Hee Cho a Yves Berthezene e Anne Marie Schott c Patrick Ffrench b Norbert Nighoghossian a
a
Centre d’Urgences Cerebrovasculaires, Hôpital Pierre Wertheimer, Hospices Civils de Lyon CREATIS, Laboratoire d’Hématologie, CBPE, GHE, Hospices Civils de Lyon, c Pôle Information Médicale Evaluation Recherche, Equipe d’Accueil 4129, Hospices Civils de Lyon et Université de Lyon, d Inserm, CIC201, EPICIME, RIPPS, CNRS UMR 5558 France; CHU Lyon, Hop L. Pradel, Service de Pharmacologie Clinique, Université Lyon and e Service de Neuroradiologie, Hôpital Pierre Wertheimer, Hospices Civils de Lyon, CREATIS CNRS UMR 5220 – INSERM U1044 – Université Lyon 1, Lyon, France
b
Key Words Haemostasis · Stroke · Imaging
Abstract Background: We investigated the relationship between von Willebrand factor (vWF), fibrin monomers (FM), fibrinogen baseline levels and the presence of susceptibility vessel sign (SVS) on T2*-weighted gradient echo imaging in acute ischemic stroke. Methods: SVS was assessed at admission using T2*weighted GRE. Plasmatic levels of vWF, FM and fibrinogen were evaluated before the initiation of intravenous thrombolysis. Results: Forty-four patients were enrolled in this study. SVS was noted in 26 patients. Univariate analysis revealed that vWF >160% (p = 0.02) and fibrinogen >4 g/l (p = 0.03) were associated with a significant decrease in the likelihood of SVS. Multivariate analysis confirmed that higher levels of vWF or fibrinogen predicted the absence of SVS. Conclusions: The increased activity of vWF may promote a fibrin-platelet recruitment mainly contributing to the absence of (SVS).
Introduction
Prior studies have assessed the presence of the so-called susceptibility vessel sign (SVS) on T2*-weighted gradient echo (GRE) imaging [1–3]. High concentrations of von Willebrand factor (vWF) promote platelet plugs [4]. In addition, fibrin monomers (FM) are found at an early stage of thrombosis [5]. We sought to investigate the relationship between von Willebrand factor (vWF) and fibrin monomers (FM) and the presence of SVS on GRE imaging. Methods
Patients From April 2013 through July 2013, consecutive patients treated with intravenous thrombolysis and documented occlusion on magnetic resonance angiography (MRA) were enrolled in this study. Baseline stroke severity and functional outcome at three months were as-
sessed using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin stroke scale (mRS) respectively. Image Analysis MRI examinations were performed using a 1.5-T MR imaging unit (Avento Siemens 1.5T). The imaging protocol included the following sequences: [1] diffusionweighted imaging (DWI) [2] T2* GRE SVS was defined as an area of hypointensity or signal loss on T2* imaging. Two experienced observers, who reviewed all T2*weighted images, rated the presence or absence of SVS, and reached the final decision by consensus. Hemostasis Studies Fibrinogen was measured as a Clauss assay using an ACL TOP® analyser, D-dimers were measured by an automated quantitative microlatex bead immuno-agglutination assay on ACL TOP® (HemosIL D-Dimer HS500, FM (N 160% (p = 0.02) and fibrinogen levels >4 g/l (p = 0.03) were associated with a significant decrease in the likelihood of SVS. Multivariate analyses showed that both vWF: Ag >160% (p = 0.02) and fibrinogen levels >4 g/l (p = 0.03) were predictive of the absence of SVS independently from age and sex. Discussion
SVS appears to be associated with erythrocyte-rich thrombi, whereas the absence of SVS may indicate a fibrinoplatelets dominant clot [1]. Marder et al. [3] showed that thromboemboli retrieved from the MCA or intracranial ICA of patients with acute ischemic stroke have similar histological components, whether derived from cardiac or arterial sources. Accordingly, the prediction of clot composition from MRI may therefore be difficult. Acute coronary syndromes are the archetype of the clinical conditions associated with a pattern of increased vWF [6]. We found higher plasmatic levels of vWF in patients without SVS, which may reflect an increase in platelet recruitment. Inhibiting the early steps of
376
Table 1. Clinical, imaging and biological parameters
Age, years Sex Female Male BA No Yes Baseline NIHSS Recanalization No Yes Day 90 mRS Etiology Atheroma Cardioembolic Unknown Arterial dissection Diabetes No Yes Hypertension No Yes Fibrinogen 1.8–4 g/l >4 g/l Fibrin monomers 6 mg/l von Willebrand factor 50–160% >160% D-Dimer INR HCT CRP
n (%)
Mean ± SD
No SVS n = 17
SVS n = 27
p
44
67.6±12.1
65.7 (12.5)
68.8 (12.0)
0.28*
5 12
11 16
0.45#
13±6.1
13.1 (6.6)
13.0 (5.9)
0.95*
15 12 2.2 (1.9)
0.58#
2.0±1.9
8 9 1.8 (1.9)
8 18 16 2
4 5 7 1
4 13 9 1
34 10
14 40
20 6
0.68##
44 20
12 8
11 13
0.36#
30 14
8 8
23 5
18 26
9 8
9 18
0.20#
14 14 1.5 (1.6) 1.0 (0.04) 0.4 (0.04) 9.1 (16.4)
0.02##
16 28 18 26 44 23 21 44
16 28 44 44 44 44
1.25±1.30 1.03±0.06 0.43±0.04 9.3±14.0
2 14 0.9 (0.5) 1.0 (0.1) 0.4 (0.04) 9.6 (9.4)
0.45* 0.65##
0.03#
0.40* 0.22* 0.58* 0.21*
SVS = Susceptibility vessel sign; mRS = modified Rankin score; INR = international normalized ratio; HCT = hematocrit; CRP = C-reactive protein. # Chi 2 test; ## Fisher exact test; * Wilcoxon test.
platelet adhesion to the ischemic endothelium and the subendothelial matrix, using selective monoclonal antibodies, may offer a novel therapeutic strategy in acute stroke.
Sources of Funding
No. Disclosure Statement
Conclusions
None declared. The study was limited to the baseline biomarkers of hemostasis and susceptibility vessel sign. It would be appropriate to clarify the relationship between these latter and stroke outcome.
Eur Neurol 2014;72:375–377 DOI: 10.1159/000365443
Farghali et al.
References 1 Liebeskind DS, Sanossian N, Yong WH, Starkman S, Tsang MP, Moya AL, et al: CT and MRI early vessel signs reflect clot composition in acute stroke. Stroke 2011; 5: 1237– 1243. 2 Tomsick T, Brott T, Barsan W, Broderick J, Haley EC, Spilker J, et al: Prognostic value of the hyperdense middle cerebral artery sign and stroke scale score before ultra early thrombolytic therapy. AJNR Am J Neuroradiol 1996;17:79–85.
Haemostasis Biomarker and Susceptibility Vessel Sign
3 Marder VJ, Chute DJ, Starkman S, Abolian AM, Kidwell C, Liebeskind D, et al: Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke. Stroke 2006;37:2086–2093. 4 Sadler JE: Von Willebrand factor. J Biol Chem 1991;266:22777–22784.
5 Budzynski AZ, Olexa SA, Pandya BV: Fibrinogen polymerization site in fibrinogen and fibrin fragment. Ann N Y Acad Sci 1983; 408: 301–314. 6 Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G: Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation 2007; 17: 2323– 2330.
Eur Neurol 2014;72:375–377 DOI: 10.1159/000365443
377
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Eur Neurol 2014;72:375–377 DOI: 10.1159/000365443
Fibrinogen and von Willebrand Factor and Susceptibility Vessel Sign on T2*-Weighted Gradient Echo Imaging Ahmed Farghali a Michel Hanss b Julien Berthiller c, d Laurent Derex a Laura Mechtouff a Thomas Ritzenthaler a Tae-Hee Cho a Yves Berthezene e Anne Marie Schott c Patrick Ffrench b Norbert Nighoghossian a
a
Centre d’Urgences Cerebrovasculaires, Hôpital Pierre Wertheimer, Hospices Civils de Lyon CREATIS, Laboratoire d’Hématologie, CBPE, GHE, Hospices Civils de Lyon, c Pôle Information Médicale Evaluation Recherche, Equipe d’Accueil 4129, Hospices Civils de Lyon et Université de Lyon, d Inserm, CIC201, EPICIME, RIPPS, CNRS UMR 5558 France; CHU Lyon, Hop L. Pradel, Service de Pharmacologie Clinique, Université Lyon and e Service de Neuroradiologie, Hôpital Pierre Wertheimer, Hospices Civils de Lyon, CREATIS CNRS UMR 5220 – INSERM U1044 – Université Lyon 1, Lyon, France
b
Key Words Haemostasis · Stroke · Imaging
Abstract Background: We investigated the relationship between von Willebrand factor (vWF), fibrin monomers (FM), fibrinogen baseline levels and the presence of susceptibility vessel sign (SVS) on T2*-weighted gradient echo imaging in acute ischemic stroke. Methods: SVS was assessed at admission using T2*weighted GRE. Plasmatic levels of vWF, FM and fibrinogen were evaluated before the initiation of intravenous thrombolysis. Results: Forty-four patients were enrolled in this study. SVS was noted in 26 patients. Univariate analysis revealed that vWF >160% (p = 0.02) and fibrinogen >4 g/l (p = 0.03) were associated with a significant decrease in the likelihood of SVS. Multivariate analysis confirmed that higher levels of vWF or fibrinogen predicted the absence of SVS. Conclusions: The increased activity of vWF may promote a fibrin-platelet recruitment mainly contributing to the absence of (SVS).
Introduction
Prior studies have assessed the presence of the so-called susceptibility vessel sign (SVS) on T2*-weighted gradient echo (GRE) imaging [1–3]. High concentrations of von Willebrand factor (vWF) promote platelet plugs [4]. In addition, fibrin monomers (FM) are found at an early stage of thrombosis [5]. We sought to investigate the relationship between von Willebrand factor (vWF) and fibrin monomers (FM) and the presence of SVS on GRE imaging. Methods
Patients From April 2013 through July 2013, consecutive patients treated with intravenous thrombolysis and documented occlusion on magnetic resonance angiography (MRA) were enrolled in this study. Baseline stroke severity and functional outcome at three months were as-
sessed using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin stroke scale (mRS) respectively. Image Analysis MRI examinations were performed using a 1.5-T MR imaging unit (Avento Siemens 1.5T). The imaging protocol included the following sequences: [1] diffusionweighted imaging (DWI) [2] T2* GRE SVS was defined as an area of hypointensity or signal loss on T2* imaging. Two experienced observers, who reviewed all T2*weighted images, rated the presence or absence of SVS, and reached the final decision by consensus. Hemostasis Studies Fibrinogen was measured as a Clauss assay using an ACL TOP® analyser, D-dimers were measured by an automated quantitative microlatex bead immuno-agglutination assay on ACL TOP® (HemosIL D-Dimer HS500, FM (N 160% (p = 0.02) and fibrinogen levels >4 g/l (p = 0.03) were associated with a significant decrease in the likelihood of SVS. Multivariate analyses showed that both vWF: Ag >160% (p = 0.02) and fibrinogen levels >4 g/l (p = 0.03) were predictive of the absence of SVS independently from age and sex. Discussion
SVS appears to be associated with erythrocyte-rich thrombi, whereas the absence of SVS may indicate a fibrinoplatelets dominant clot [1]. Marder et al. [3] showed that thromboemboli retrieved from the MCA or intracranial ICA of patients with acute ischemic stroke have similar histological components, whether derived from cardiac or arterial sources. Accordingly, the prediction of clot composition from MRI may therefore be difficult. Acute coronary syndromes are the archetype of the clinical conditions associated with a pattern of increased vWF [6]. We found higher plasmatic levels of vWF in patients without SVS, which may reflect an increase in platelet recruitment. Inhibiting the early steps of
376
Table 1. Clinical, imaging and biological parameters
Age, years Sex Female Male BA No Yes Baseline NIHSS Recanalization No Yes Day 90 mRS Etiology Atheroma Cardioembolic Unknown Arterial dissection Diabetes No Yes Hypertension No Yes Fibrinogen 1.8–4 g/l >4 g/l Fibrin monomers 6 mg/l von Willebrand factor 50–160% >160% D-Dimer INR HCT CRP
n (%)
Mean ± SD
No SVS n = 17
SVS n = 27
p
44
67.6±12.1
65.7 (12.5)
68.8 (12.0)
0.28*
5 12
11 16
0.45#
13±6.1
13.1 (6.6)
13.0 (5.9)
0.95*
15 12 2.2 (1.9)
0.58#
2.0±1.9
8 9 1.8 (1.9)
8 18 16 2
4 5 7 1
4 13 9 1
34 10
14 40
20 6
0.68##
44 20
12 8
11 13
0.36#
30 14
8 8
23 5
18 26
9 8
9 18
0.20#
14 14 1.5 (1.6) 1.0 (0.04) 0.4 (0.04) 9.1 (16.4)
0.02##
16 28 18 26 44 23 21 44
16 28 44 44 44 44
1.25±1.30 1.03±0.06 0.43±0.04 9.3±14.0
2 14 0.9 (0.5) 1.0 (0.1) 0.4 (0.04) 9.6 (9.4)
0.45* 0.65##
0.03#
0.40* 0.22* 0.58* 0.21*
SVS = Susceptibility vessel sign; mRS = modified Rankin score; INR = international normalized ratio; HCT = hematocrit; CRP = C-reactive protein. # Chi 2 test; ## Fisher exact test; * Wilcoxon test.
platelet adhesion to the ischemic endothelium and the subendothelial matrix, using selective monoclonal antibodies, may offer a novel therapeutic strategy in acute stroke.
Sources of Funding
No. Disclosure Statement
Conclusions
None declared. The study was limited to the baseline biomarkers of hemostasis and susceptibility vessel sign. It would be appropriate to clarify the relationship between these latter and stroke outcome.
Eur Neurol 2014;72:375–377 DOI: 10.1159/000365443
Farghali et al.
References 1 Liebeskind DS, Sanossian N, Yong WH, Starkman S, Tsang MP, Moya AL, et al: CT and MRI early vessel signs reflect clot composition in acute stroke. Stroke 2011; 5: 1237– 1243. 2 Tomsick T, Brott T, Barsan W, Broderick J, Haley EC, Spilker J, et al: Prognostic value of the hyperdense middle cerebral artery sign and stroke scale score before ultra early thrombolytic therapy. AJNR Am J Neuroradiol 1996;17:79–85.
Haemostasis Biomarker and Susceptibility Vessel Sign
3 Marder VJ, Chute DJ, Starkman S, Abolian AM, Kidwell C, Liebeskind D, et al: Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke. Stroke 2006;37:2086–2093. 4 Sadler JE: Von Willebrand factor. J Biol Chem 1991;266:22777–22784.
5 Budzynski AZ, Olexa SA, Pandya BV: Fibrinogen polymerization site in fibrinogen and fibrin fragment. Ann N Y Acad Sci 1983; 408: 301–314. 6 Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G: Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation 2007; 17: 2323– 2330.
Eur Neurol 2014;72:375–377 DOI: 10.1159/000365443
377
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
