# C-reactive protein and D-dimer in cerebral vein thrombosis: Relation to clinical and imaging characteristics as well as outcomes in a French cohort study

Paul Billoir, Virginie Siguret, Elisabeth Masson Fron, Ludovic Drouet, Isabelle Crassard, Raphaël Marlu, Marianne Barbieux-Guillot, Pierre-Emmanuel Morange, Emmanuelle Robinet, Catherine Metzger, et al.

► To cite this version:

Paul Billoir, Virginie Siguret, Elisabeth Masson Fron, Ludovic Drouet, Isabelle Crassard, et al. C-reactive protein and D-dimer in cerebral vein thrombosis: Relation to clinical and imaging characteristics as well as outcomes in a French cohort study. Research and Practice in Thrombosis and Haemostasis, 2023, 7 (3), pp.100130. 10.1016/j.rpth.2023.100130. hal-04083689

HAL Id: hal-04083689

https://u-picardie.hal.science/hal-04083689

Submitted on 30 May 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
ORIGINAL ARTICLE

# C-reactive protein and D-dimer in cerebral vein thrombosis: Relation to clinical and imaging characteristics as well as outcomes in a French cohort study

Paul Billoir PharmD, PhD<fnref n="1" />

<figure><img src="image_1.png" /></figure>

Virginie Siguret PharmD, PhD<fnref n="2" />

<figure><img src="image_2.png" /></figure>

Elisabeth Masson Fron PharmD<fnref n="2" />

Ludovic Drouet MD, PhD<fnref n="2" />

<figure><img src="image_3.png" /></figure>

Isabelle Crassard MD, PhD<fnref n="3" />

Raphaël Marlu MD<fnref n="4" />

Marianne Barbieux-Guillot MD<fnref n="5" />

<figure><img src="image_4.png" /></figure>

Pierre-Emmanuel Morange MD, PhD<fnref n="6" />

<figure><img src="image_5.png" /></figure>

Emmanuelle Robinet MD<fnref n="7" />

<figure><img src="image_6.png" /></figure>

Catherine Metzger PharmD<fnref n="8" />

Valérie Wolff MD<fnref n="9" />

Elisabeth André-Kerneis MD<fnref n="10" />

<figure><img src="image_7.png" /></figure>

Frédéric Klapczynski MD<fnref n="11" />

Brigitte Martin-Bastenaire MD¹²

Fernando Pico MD¹³

<figure><img src="image_8.png" /></figure>

Fanny Menard PharmD¹⁴

Emmanuel Ellie MD¹⁵

Geneviève Freyburger MD, PhD¹⁶

<figure><img src="image_9.png" /></figure>

François Rouanet MD¹⁷

Hong-An Allano MD¹⁸

Gaëlle Godenèche MD¹⁹

<figure><img src="image_10.png" /></figure>

Guillaume Mourey MD²⁰

Thierry Moulin MD, PhD²¹

Micheline Berruyer MD²²

<figure><img src="image_11.png" /></figure>

Laurent Derex MD, PhD²³

Catherine Trichet MD²⁴

Gwénaëlle Runavot MD²⁵

<figure><img src="image_12.png" /></figure>

Agnès Le Querrec MD, PhD²⁶

Fausto Viader MD, PhD²⁷

<figure><img src="image_13.png" /></figure>

Sophie Cluet-Dennetiere MD²⁸

Thomas Tarek Husein MD²⁹

<figure><img src="image_14.png" /></figure>

Magali Donnard PharmD, PhD³⁰

Francisco Macian-Montoro MD³¹

<figure><img src="image_15.png" /></figure>

Catherine Ternisien MD, PhD³²

<figure><img src="image_16.png" /></figure>

Benoît Guillon MD³³

<figure><img src="image_17.png" /></figure>

Mathieu Zuber MD³⁵

Jean-Yves Peltier MD³⁶

Philippe Tassan MD³⁷

<figure><img src="image_18.png" /></figure>

Bertrand Roussel MD³⁸

Sandrine Canaple MD³⁹

Emilie Scavazza PharmD⁴⁰

<figure><img src="image_19.png" /></figure>

Nicolas Gaillard MD⁴¹

Aude Triquenot Bagan MD, PhD⁴²

<figure><img src="image_20.png" /></figure>

Véronique Le Cam Duchez MD, PhD<fnref n="1" />

<figure><img src="image_21.png" /></figure>

<footnote n="1">¹Univ Rouen Normandie, INSERM U1096, Department of Vascular Hemostasis Unit, CHU Rouen, Rouen, France</footnote>

<footnote n="2">²Department of Biological Hematology, Lariboisière University Hospital, Université Paris Cité, Paris, France</footnote>

<footnote n="3">³Department of Neurology, Lariboisière University Hospital, Université Paris Cité, Paris, France</footnote>

<footnote n="4">⁴Department of Biological Hematology, Grenoble University Hospital, Grenoble, France</footnote>

<footnote n="5">⁵Department of Neurology, Grenoble University Hospital, Grenoble, France</footnote>

<footnote n="6">⁶Department of Biological Hematology, Marseille University Hospital, Marseille, France</footnote>

<footnote n="7">⁷Department of Neurology, Marseille University Hospital, Marseille, France</footnote>

<footnote n="8">⁸Department of Biological Hematology, Strasbourg University Hospital, Strasbourg, France</footnote>

<footnote n="9">⁹Department of Neurology, Strasbourg University Hospital, Strasbourg, France</footnote>

<footnote n="10">¹⁰Department of Biological Hematology, Meaux Hospital, Meaux, France</footnote>

<footnote n="11">¹¹Department of Neurology, Meaux Hospital, Meaux, France</footnote>
ORIGINAL ARTICLE

# C-reactive protein and D-dimer in cerebral vein thrombosis: Relation to clinical and imaging characteristics as well as outcomes in a French cohort study

Paul Billoir PharmD, PhD<fnref n="1" /> ⬒

<figure><img src="image_2.png" /></figure>

Virginia Siguret PharmD, PhD<fnref n="2" /> |

Elisabeth Masson Fron PharmD<fnref n="2" /> |

Ludovic Drouet MD, PhD<fnref n="2" /> |

Isabelle Crassard MD, PhD<fnref n="3" /> |

Raphaël Marlu MD<fnref n="4" /> |

Marianne Barbieux-Guillot MD<fnref n="5" /> |

Pierre-Emmanuel Morange MD, PhD<fnref n="6" /> ⬒

<figure><img src="image_3.png" /></figure>

Emmanuelle Robinet MD<fnref n="7" /> |

Catherine Metzger PharmD<fnref n="8" /> |

Valérie Wolff MD<fnref n="9" /> |

Elisabeth André-Kerneis MD<fnref n="10" /> |

Frédéric Klapczynski MD<fnref n="11" /> |

Brigitte Martin-Bastenaire MD¹² |

Fernando Pico MD¹³ |

Fanny Menard PharmD¹⁴ |

Emmanuel Ellie MD¹⁵ |

Geneviève Freyburger MD, PhD¹⁶ |

François Rouanet MD¹⁷ |

Hong-An Allano MD¹⁸ |

Gaëlle Godenèche MD¹⁹ |

Guillaume Mourey MD²⁰ |

Thierry Moulin MD, PhD²¹ |

Micheline Berruyer MD²² |

Laurent Derex MD, PhD²³ |

Catherine Trichet MD²⁴ |

Gwénaëlle Runavot MD²⁵ |

Agnès Le Querrec MD, PhD²⁶ |

Fausto Viader MD, PhD²⁷ |

Sophie Cluet-Dennetiere MD²⁸ |

Thomas Tarek Husein MD²⁹ |

Magali Donnard PharmD, PhD³⁰ |

Francisco Macian-Montoro MD³¹ |

Catherine Ternisien MD, PhD³² ⬒

<figure><img src="image_4.png" /></figure>

Benoît Guillon MD³³ |

Mathieu Zuber MD³⁵ |

Jean-Yves Peltier MD³⁶ |

Philippe Tassan MD³⁷ |

Bertrand Roussel MD³⁸ |

Sandrine Canaple MD³⁹ |

Emilie Scavazza PharmD⁴⁰ |

Nicolas Gaillard MD⁴¹ |

Aude Triquenot Bagan MD, PhD⁴² |

Véronique Le Cam Duchez MD, PhD<fnref n="1" /> ID

<figure><img src="image_5.png" /></figure>

<footnote n="1">¹Univ Rouen Normandie, INSERM U1096, Department of Vascular Hemostasis Unit, CHU Rouen, Rouen, France</footnote>

<footnote n="2">²Department of Biological Hematology, Lariboisière University Hospital, Université Paris Cité, Paris, France</footnote>

<footnote n="3">³Department of Neurology, Lariboisière University Hospital, Université Paris Cité, Paris, France</footnote>

<footnote n="4">⁴Department of Biological Hematology, Grenoble University Hospital, Grenoble, France</footnote>

<footnote n="5">⁵Department of Neurology, Grenoble University Hospital, Grenoble, France</footnote>

<footnote n="6">⁶Department of Biological Hematology, Marseille University Hospital, Marseille, France</footnote>

<footnote n="7">⁷Department of Neurology, Marseille University Hospital, Marseille, France</footnote>

<footnote n="8">⁸Department of Biological Hematology, Strasbourg University Hospital, Strasbourg, France</footnote>

<footnote n="9">⁹Department of Neurology, Strasbourg University Hospital, Strasbourg, France</footnote>

<footnote n="10">¹⁰Department of Biological Hematology, Meaux Hospital, Meaux, France</footnote>

<footnote n="11">¹¹Department of Neurology, Meaux Hospital, Meaux, France</footnote>
¹²Department of Biological Hematology, Versailles Hospital, Versailles, France

¹³Department of Neurology, Versailles Hospital, Versailles, France

¹⁴Department of Biological Hematology, Bayonne Hospital, Bayonne, France

¹⁵Department of Neurology, Bayonne Hospital, Bayonne, France

¹⁶Department of Biological Hematology, Bordeaux University Hospital, Bordeaux, France

¹⁷Department of Neurology, Bordeaux University Hospital, Bordeaux, France

¹⁸Department of Biological Hematology, La Rochelle Hospital, La Rochelle, France

¹⁹Department of Neurology, La Rochelle Hospital, La Rochelle, France

²⁰Department of Biological Hematology, Besançon University Hospital, Besançon, France

²¹Department of Neurology, Besançon University Hospital, Besançon, France

²²Department of Biological Hematology, Lyon University Hospital, Lyon, France

²³Department of Neurology, Lyon University Hospital, Lyon, France

²⁴Department of Biological Hematology, Argenteuil Hospital, Argenteuil, France

²⁵Department of Neurology, Argenteuil Hospital, Argenteuil, France

²⁶Department of Biological Hematology, Caen University Hospital, Caen, France

²⁷Department of Neurology, Caen University Hospital, Caen, France

²⁸Department of Biological Hematology, Compiègne Hospital, Compiègne, France

²⁹Department of Neurology, Compiègne Hospital, Compiègne, France

³⁰Department of Biological Hematology, Limoges University Hospital, Limoges, France

³¹Department of Neurology, Limoges University Hospital, Limoges, France

³²Department of Biological Hematology, Nantes University Hospital, Nantes, France

³³Department of Neurology, Nantes University Hospital, Nantes, France

³⁴Department of Biological Hematology, Saint Joseph Hospital, Paris, France

³⁵Department of Neurology, Saint Joseph Hospital, Paris, France

³⁶Department of Biological Hematology, Poissy Hospital, Poissy, France

³⁷Department of Neurology, Poissy Hospital, Poissy, France

³⁸Department of Biological Hematology, Amiens university Hospital, Amiens, France

³⁹Department of Neurology, Amiens university Hospital, Amiens, France

⁴⁰Department of Biological Hematology, Perpignan Hospital, Perpignan, France

⁴¹Department of Neurology, Perpignan Hospital, Perpignan, France

⁴²Department of Neurology, CHU Rouen, Rouen, France

Correspondence

Véronique Le Cam Duchez, Service
d'Hématologie Biologique, Centre
hospitalier Universitaire Charles Nicolle, 1
rue de Germont, 76031 Rouen, France.
Email: veronique.le-cam@chu-rouen.fr

Handling Editor: Dr Mary Cushman

Abstract

**Introduction:** Cerebral venous sinus thrombosis (CVST) is a rare disease with highly variable clinical presentation and outcomes. Clinical studies suggest a role of inflammation and coagulation in CVST outcomes. The aim of this study was to investigate the association of inflammation and hypercoagulability biomarkers with CVST clinical manifestations and prognosis.

**Methods:** This prospective multicenter study was conducted from July 2011 to September 2016. Consecutive patients referred to 21 French stroke units and who had a diagnosis of symptomatic CVST were included. High-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), D-dimer, and thrombin generation using calibrated automated thrombogram system were measured at different time points until 1 month after anticoagulant therapy discontinuation.

**Results:** Two hundred thirty-one patients were included. Eight patients died, of whom 5 during hospitalization. The day 0 hs-CRP levels, NLR, and D-dimer were higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; NLR: 3.51 [2.15-5.88] vs 4.78 [3.10-9.59], respectively; D-dimer: 950 µg/L [520-2075] vs 1220 µg/L [950-2445],
¹²Department of Biological Hematology, Versailles Hospital, Versailles, France

¹³Department of Neurology, Versailles Hospital, Versailles, France

¹⁴Department of Biological Hematology, Bayonne Hospital, Bayonne, France

¹⁵Department of Neurology, Bayonne Hospital, Bayonne, France

¹⁶Department of Biological Hematology, Bordeaux University Hospital, Bordeaux, France

¹⁷Department of Neurology, Bordeaux University Hospital, Bordeaux, France

¹⁸Department of Biological Hematology, La Rochelle Hospital, La Rochelle, France

¹⁹Department of Neurology, La Rochelle Hospital, La Rochelle, France

²⁰Department of Biological Hematology, Besançon University Hospital, Besançon, France

²¹Department of Neurology, Besançon University Hospital, Besançon, France

²²Department of Biological Hematology, Lyon University Hospital, Lyon, France

²³Department of Neurology, Lyon University Hospital, Lyon, France

²⁴Department of Biological Hematology, Argenteuil Hospital, Argenteuil, France

²⁵Department of Neurology, Argenteuil Hospital, Argenteuil, France

²⁶Department of Biological Hematology, Caen University Hospital, Caen, France

²⁷Department of Neurology, Caen University Hospital, Caen, France

²⁸Department of Biological Hematology, Compiègne Hospital, Compiègne, France

²⁹Department of Neurology, Compiègne Hospital, Compiègne, France

³⁰Department of Biological Hematology, Limoges University Hospital, Limoges, France

³¹Department of Neurology, Limoges University Hospital, Limoges, France

³²Department of Biological Hematology, Nantes University Hospital, Nantes, France

³³Department of Neurology, Nantes University Hospital, Nantes, France

³⁴Department of Biological Hematology, Saint Joseph Hospital, Paris, France

³⁵Department of Neurology, Saint Joseph Hospital, Paris, France

³⁶Department of Biological Hematology, Poissy Hospital, Poissy, France

³⁷Department of Neurology, Poissy Hospital, Poissy, France

³⁸Department of Biological Hematology, Amiens university Hospital, Amiens, France

³⁹Department of Neurology, Amiens university Hospital, Amiens, France

⁴⁰Department of Biological Hematology, Perpignan Hospital, Perpignan, France

⁴¹Department of Neurology, Perpignan Hospital, Perpignan, France

⁴²Department of Neurology, CHU Rouen, Rouen, France

Correspondence

Véronique Le Cam Duchez, Service
d'Hématologie Biologique, Centre
hospitalier Universitaire Charles Nicolle, 1
rue de Germont, 76031 Rouen, France.
Email: veronique.le-cam@chu-rouen.fr

Handling Editor: Dr Mary Cushman

Abstract

**Introduction:** Cerebral venous sinus thrombosis (CVST) is a rare disease with highly variable clinical presentation and outcomes. Clinical studies suggest a role of inflammation and coagulation in CVST outcomes. The aim of this study was to investigate the association of inflammation and hypercoagulability biomarkers with CVST clinical manifestations and prognosis.

**Methods:** This prospective multicenter study was conducted from July 2011 to September 2016. Consecutive patients referred to 21 French stroke units and who had a diagnosis of symptomatic CVST were included. High-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), D-dimer, and thrombin generation using calibrated automated thrombogram system were measured at different time points until 1 month after anticoagulant therapy discontinuation.

**Results:** Two hundred thirty-one patients were included. Eight patients died, of whom 5 during hospitalization. The day 0 hs-CRP levels, NLR, and D-dimer were higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; NLR: 3.51 [2.15-5.88] vs 4.78 [3.10-9.59], respectively; D-dimer: 950 µg/L [520-2075] vs 1220 µg/L [950-2445],
respectively). Patients with ischemic parenchymal lesions (n = 31) had a higher endogenous thrombin potential<sub>5pM</sub> than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min (1646-2441) vs 1629 nM min (1371-2090), respectively (P = .0082). Using unadjusted logistic regression with values >75th percentile, day 0 hs-CRP levels of >29.7 mg/L (odds ratio, 10.76 [1.55-140.4]; P = .037) and day 5 D-dimer levels of >1060 mg/L (odds ratio, 14.63 [2.28-179.9]; P = .010) were associated with death occurrence.

**Conclusion:** Two widely available biomarkers measured upon admission, especially hs-CRP, could help predict bad prognosis in CVST in addition to patient characteristics. These results need to be validated in other cohorts.

### KEYWORDS

cerebral venous sinus thrombosis, D-dimer, high-sensitivity C-reactive protein, thrombin generation assay

### Essentials

* There are several clinical presentations of cerebral venous sinus thrombosis (CVST).

* Association between inflammation and CVST severity has been observed.

* D-dimer and C-reactive protein predicted bad prognosis in CVST.

* Elevated endogenous thrombin potential on admission was associated with ischemic parenchymal lesions.

## 1 | INTRODUCTION

Cerebral venous sinus thrombosis (CVST) is a rare thrombotic disorder with an estimated incidence of 1.3 to 1.57 per 100,000 person-years from studies of various European and Australian populations and 2.85 to 3.16 in the United States [1-4]. Several risk factors for CVST have been identified, including oral contraceptive use; pregnancy; thrombophilia; inflammatory diseases; infections; trauma; malignancy; medications, such as steroids; endocrine, and hematologic disorders [1,3-5]. Delays in diagnosis of CVST are common and substantial, with the first symptoms occurring from less than 48 hours until beyond 30 days [5]. Four main patterns have been identified as CVST clinical manifestations: isolated intracranial hypertension, focal syndrome, diffuse encephalopathy, and cavernous sinus syndrome [6]. Clinical presentation of CVST is affected by the patient's age, the time between the onset of symptoms and the admission to hospital, location of CVST, and the presence of cerebral parenchymal lesions.

Only a few studies have focused on the potential interest of biomarkers in CVST diagnosis and prognosis. Although plasma D-dimer has been widely validated as an effective tool for excluding the diagnosis of deep venous thrombosis or pulmonary embolism, its potential usefulness in the management of patients with suspected CVST is debated [7,8]. Indeed, D-dimer testing is of little use for CVST diagnosis [9]. No study has yet evaluated the association of D-dimer with CVST clinical manifestations. Besides, thrombin generation (TG) has been proposed as a global assay to evidence hypocoagulable

[10,11] and hypercoagulable states [12-14]: increased TG is an independent predictor of recurrent venous thrombosis [15]. Inflammation biomarkers, such as fibrinogen and high-sensitivity C-reactive protein (hs-CRP), have been recently described as possible predictors of poor prognosis in CVST [16]. The neutrophil-to-lymphocyte ratio (NLR) reflects subclinical inflammation, predicting mortality in myocardial infarction and cardiovascular risk [17].

We recently described the clinical and imaging features of patients presenting with CVST enrolled in a French prospective cohort [18]. The aim of the present study was to investigate, in the French prospective cohort, the association of inflammation biomarkers, D-dimer, and TG parameters with clinical or imaging characteristics in the patients with CVST in this cohort at diagnosis and during the follow-up months.

## 2 | METHODS

### 2.1 | Population study

The "French prospective cohort-cerebral vein thrombosis" (FPCCVT) multicenter study was prospectively conducted from July 2011 to September 2016 [18]. Briefly, symptomatic patients with CVST from 21 French stroke unit centers were included. This study was funded through a clinical research program (N° 2010/087/HP) of the French Ministry of Health and registered on clinicaltrials.gov
respectively). Patients with ischemic parenchymal lesions (n = 31) had a higher endogenous thrombin potential<sub>5pM</sub> than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min (1646-2441) vs 1629 nM min (1371-2090), respectively (P = .0082). Using unadjusted logistic regression with values >75th percentile, day 0 hs-CRP levels of >29.7 mg/L (odds ratio, 10.76 [1.55-140.4]; P = .037) and day 5 D-dimer levels of >1060 mg/L (odds ratio, 14.63 [2.28-179.9]; P = .010) were associated with death occurrence.

**Conclusion:** Two widely available biomarkers measured upon admission, especially hs-CRP, could help predict bad prognosis in CVST in addition to patient characteristics. These results need to be validated in other cohorts.

### KEYWORDS

cerebral venous sinus thrombosis, D-dimer, high-sensitivity C-reactive protein, thrombin generation assay

### Essentials

* There are several clinical presentations of cerebral venous sinus thrombosis (CVST).

* Association between inflammation and CVST severity has been observed.

* D-dimer and C-reactive protein predicted bad prognosis in CVST.

* Elevated endogenous thrombin potential on admission was associated with ischemic parenchymal lesions.

## 1 | INTRODUCTION

Cerebral venous sinus thrombosis (CVST) is a rare thrombotic disorder with an estimated incidence of 1.3 to 1.57 per 100,000 person-years from studies of various European and Australian populations and 2.85 to 3.16 in the United States [1-4]. Several risk factors for CVST have been identified, including oral contraceptive use; pregnancy; thrombophilia; inflammatory diseases; infections; trauma; malignancy; medications, such as steroids; endocrine, and hematologic disorders [1,3-5]. Delays in diagnosis of CVST are common and substantial, with the first symptoms occurring from less than 48 hours until beyond 30 days [5]. Four main patterns have been identified as CVST clinical manifestations: isolated intracranial hypertension, focal syndrome, diffuse encephalopathy, and cavernous sinus syndrome [6]. Clinical presentation of CVST is affected by the patient's age, the time between the onset of symptoms and the admission to hospital, location of CVST, and the presence of cerebral parenchymal lesions.

Only a few studies have focused on the potential interest of biomarkers in CVST diagnosis and prognosis. Although plasma D-dimer has been widely validated as an effective tool for excluding the diagnosis of deep venous thrombosis or pulmonary embolism, its potential usefulness in the management of patients with suspected CVST is debated [7,8]. Indeed, D-dimer testing is of little use for CVST diagnosis [9]. No study has yet evaluated the association of D-dimer with CVST clinical manifestations. Besides, thrombin generation (TG) has been proposed as a global assay to evidence hypocoagulable

[10,11] and hypercoagulable states [12-14]: increased TG is an independent predictor of recurrent venous thrombosis [15]. Inflammation biomarkers, such as fibrinogen and high-sensitivity C-reactive protein (hs-CRP), have been recently described as possible predictors of poor prognosis in CVST [16]. The neutrophil-to-lymphocyte ratio (NLR) reflects subclinical inflammation, predicting mortality in myocardial infarction and cardiovascular risk [17].

We recently described the clinical and imaging features of patients presenting with CVST enrolled in a French prospective cohort [18]. The aim of the present study was to investigate, in the French prospective cohort, the association of inflammation biomarkers, D-dimer, and TG parameters with clinical or imaging characteristics in the patients with CVST in this cohort at diagnosis and during the follow-up months.

## 2 | METHODS

### 2.1 | Population study

The "French prospective cohort-cerebral vein thrombosis" (FPCCVT) multicenter study was prospectively conducted from July 2011 to September 2016 [18]. Briefly, symptomatic patients with CVST from 21 French stroke unit centers were included. This study was funded through a clinical research program (N° 2010/087/HP) of the French Ministry of Health and registered on [clinicaltrials.gov](https://clinicaltrials.gov)
(NCT02013635). Patients were included regardless of race/ethnicity, and fully covered by the French health system.

## 2.2 | Clinical and imaging characteristics

The diagnosis of CVST had to be confirmed by cerebral tomodensitometry venography and/or magnetic resonance imaging (MRI) combined with magnetic resonance venography and/or digital subtraction angiography following established diagnostic criteria [19]. Patients' data were recorded. Clinical status was evaluated at admission using the Glasgow Coma Scale and the National Institutes of Health Stroke Scale (NIHSS). Presenting syndromes were categorized as isolated intracranial hypertension and/or isolated headache, focal syndrome, cavernous sinus syndrome, and diffuse encephalopathy. Radiological evolution was evaluated at 3 months using preferably MRI with magnetic resonance venography. "Partial recanalization" was defined as recanalization of at least one previously thrombosed sinus or vein in an individual patient with CVST. "No recanalization" was defined as total absence of any type of recanalization in any previously thrombosed sinus or vein. "Complete recanalization" was considered when all previously thrombosed structures met the criteria of complete recanalization. Three categories were predefined according to the time from the onset of symptoms to diagnosis: within 2 days (acute), between 2 and 30 days (subacute), and beyond 30 days (chronic).

The extent of the parenchymal lesions was classified as minor (≤1/3 of lobe lesions), moderate (between 1/3 and 2/3 of lobe lesions), and severe (>2/3 of lobe lesions). The type of parenchymal lesion was described as ischemic, hemorrhagic, or both. Follow-up visits were planned at 3 months, and one month after stopping an antithrombotic treatment or after a maximum of 13 months if antithrombotic treatment was continued [18].

## 2.3 | Laboratory parameters and assays

Laboratory tests, including whole blood count and plasma fibrinogen, were locally performed for each patient upon admission before any initiation of anticoagulant therapy (D₀). Additional blood was collected on EDTA, 0.109M citrate, and dry tubes to build a plasma and serum bank. In addition to D₀ sampling, blood samples were taken at different times, especially at day 5 (D₅) after the diagnosis.

Anemia was defined by decreased hemoglobin <12.0 g/dL in females and 13.0 g/dL in males.

Platelet-poor plasma (PPP) was prepared as recommended by the "Groupe Français d'études sur l'Hémostase et la Thrombose," ie, doublecentrifuged at 2000 g for 10 minutes, and aliquots were kept frozen at -80 °C (www.geht.org). Samples were transported on dry ice for central analysis. Plasma D-dimer was assessed using Liatect DDI+ (Diagnostica Stago) on a STAR analyzer and serum hs-CRP using C-reactive protein (CRP)-VARIO on a C8000 analyzer (Abbott) at Lariboisière Hospital (Paris). TG was performed on a calibrated automated thrombogram system using a microplate fluorometer (Fluorocan

Ascent, Thermoscientific Labsystems) at Rouen University Hospital. PPP samples were run using either PPP reagent (5pM tissue factor and 4µM phospholipid vesicles) or low PPP reagent (1pM tissue factor and 4µM phospholipid vesicles) (Diagnostica Stago). We recorded and analyzed the following parameters: lag time, time to peak, endogenous thrombin potential (ETP) (area under the thrombin time-concentration curve), maximal thrombin peak, and velocity. TG assay was not performed if patients were on anticoagulant therapy before D₀ sampling; activity was systematically measured to detect anti-Xa inhibitors.

## 2.4 | Statistical analysis

The Shapiro-Wilk test was used to test normality of continuous variables. Normally, distributed data were presented as mean ± standard deviations and non-Gaussian variables as median ± IQR. We performed analyses to test relationships between biomarkers, namely inflammation biomarkers, D-dimer, and TG parameters measured at different times and i/clinical presentation or imaging data upon admission; ii/clinical evolution evaluated by modified Rankin Score, NIHSS, and death occurrence; iii/clinical/imaging evolution on 3 months. Univariate subgroup comparisons were analyzed using the Mann-Whitney U-test. Multiple group comparisons were performed using the Kruskal-Wallis test completed with the two-stage step-up method of Benjamini, Krieger, and Yekutieli. The correlation between clinical and biological parameters was evaluated with Spearman and Pearson correlation. Univariate logistic regression analysis of clinical outcome (death, presence of a parenchymal lesion) was performed using the following variables as predictors: age >75th percentile, sex, body mass index, dyslipidemia, tobacco, diabetes, initial consciousness disturbances, D-dimer >75th percentile, hs-CRP >75th percentile, and maximal thrombin peak. P values of <.05 were considered significant. Data were analyzed using GraphPad Prism 9.4 and the R software, version 4.0.0.

# 3 | RESULTS

## 3.1 | Clinical characteristics

Two hundred thirty-one patients with a diagnosis of CVST were included. The main demographic and clinical characteristics at baseline are shown in Table 1. Briefly, the median age was 41.2 years (IQR, 28-51). The cohort comprised a majority of women (68.4%), 67.1% of whom took oral contraceptives. The median time from the onset of symptoms to diagnosis was 5 days (range, 0-205). The mode of onset was acute in 82 patients, subacute in 131, and chronic in 18. The median number of vein sinuses with thrombosis was 3 (IQR, 1-15). Twenty-nine (12.5%) had only 1 vein with thrombosis. Thirty-one (13.4%) had isolated thrombotic parenchymal lesions, 31 (13.4%) had isolated hemorrhagic parenchymal lesions, and 27 (11.7%) had both. The median duration of follow-up was 11.9 months (range, 76-543 months) for 197 (88.3%) of 223 surviving patients. Five patients died during hospitalization, 4 of brain herniation (despite
(NCT02013635). Patients were included regardless of race/ethnicity, and fully covered by the French health system.

## 2.2 | Clinical and imaging characteristics

The diagnosis of CVST had to be confirmed by cerebral tomodensitometry venography and/or magnetic resonance imaging (MRI) combined with magnetic resonance venography and/or digital subtraction angiography following established diagnostic criteria [19]. Patients' data were recorded. Clinical status was evaluated at admission using the Glasgow Coma Scale and the National Institutes of Health Stroke Scale (NIHSS). Presenting syndromes were categorized as isolated intracranial hypertension and/or isolated headache, focal syndrome, cavernous sinus syndrome, and diffuse encephalopathy. Radiological evolution was evaluated at 3 months using preferably MRI with magnetic resonance venography. "Partial recanalization" was defined as recanalization of at least one previously thrombosed sinus or vein in an individual patient with CVST. "No recanalization" was defined as total absence of any type of recanalization in any previously thrombosed sinus or vein. "Complete recanalization" was considered when all previously thrombosed structures met the criteria of complete recanalization. Three categories were predefined according to the time from the onset of symptoms to diagnosis: within 2 days (acute), between 2 and 30 days (subacute), and beyond 30 days (chronic).

The extent of the parenchymal lesions was classified as minor (≤1/3 of lobe lesions), moderate (between 1/3 and 2/3 of lobe lesions), and severe (>2/3 of lobe lesions). The type of parenchymal lesion was described as ischemic, hemorrhagic, or both. Follow-up visits were planned at 3 months, and one month after stopping an antithrombotic treatment or after a maximum of 13 months if antithrombotic treatment was continued [18].

## 2.3 | Laboratory parameters and assays

Laboratory tests, including whole blood count and plasma fibrinogen, were locally performed for each patient upon admission before any initiation of anticoagulant therapy ($D_0$). Additional blood was collected on EDTA, 0.109M citrate, and dry tubes to build a plasma and serum bank. In addition to $D_0$ sampling, blood samples were taken at different times, especially at day 5 ($D_5$) after the diagnosis.

Anemia was defined by decreased hemoglobin <12.0 g/dL in females and 13.0 g/dL in males.

Platelet-poor plasma (PPP) was prepared as recommended by the "Groupe Français d'études sur l'Hémostase et la Thrombose," ie, doublecentrifuged at 2000 g for 10 minutes, and aliquots were kept frozen at -80 °C (www.geht.org). Samples were transported on dry ice for central analysis. Plasma D-dimer was assessed using Liatect DDI+ (Diagnostica Stago) on a STAR analyzer and serum hs-CRP using C-reactive protein (CRP)-VARIO on a C8000 analyzer (Abbott) at Lariboisière Hospital (Paris). TG was performed on a calibrated automated thrombogram system using a microplate fluorometer (Fluorocan

Ascent, Thermoscientific Labsystems) at Rouen University Hospital. PPP samples were run using either PPP reagent (5pM tissue factor and 4µM phospholipid vesicles) or low PPP reagent (1pM tissue factor and 4µM phospholipid vesicles) (Diagnostica Stago). We recorded and analyzed the following parameters: lag time, time to peak, endogenous thrombin potential (ETP) (area under the thrombin time-concentration curve), maximal thrombin peak, and velocity. TG assay was not performed if patients were on anticoagulant therapy before $D_0$ sampling; activity was systematically measured to detect anti-Xa inhibitors.

## 2.4 | Statistical analysis

The Shapiro-Wilk test was used to test normality of continuous variables. Normally, distributed data were presented as mean ± standard deviations and non-Gaussian variables as median ± IQR. We performed analyses to test relationships between biomarkers, namely inflammation biomarkers, D-dimer, and TG parameters measured at different times and i/clinical presentation or imaging data upon admission; ii/clinical evolution evaluated by modified Rankin Score, NIHSS, and death occurrence; iii/clinical/imaging evolution on 3 months. Univariate subgroup comparisons were analyzed using the Mann-Whitney U-test. Multiple group comparisons were performed using the Kruskal-Wallis test completed with the two-stage step-up method of Benjamini, Krieger, and Yekutieli. The correlation between clinical and biological parameters was evaluated with Spearman and Pearson correlation. Univariate logistic regression analysis of clinical outcome (death, presence of a parenchymal lesion) was performed using the following variables as predictors: age >75th percentile, sex, body mass index, dyslipidemia, tobacco, diabetes, initial consciousness disturbances, D-dimer >75th percentile, hs-CRP >75th percentile, and maximal thrombin peak. P values of <.05 were considered significant. Data were analyzed using GraphPad Prism 9.4 and the R software, version 4.0.0.

# 3 | RESULTS

## 3.1 | Clinical characteristics

Two hundred thirty-one patients with a diagnosis of CVST were included. The main demographic and clinical characteristics at baseline are shown in Table 1. Briefly, the median age was 41.2 years (IQR, 28-51). The cohort comprised a majority of women (68.4%), 67.1% of whom took oral contraceptives. The median time from the onset of symptoms to diagnosis was 5 days (range, 0-205). The mode of onset was acute in 82 patients, subacute in 131, and chronic in 18. The median number of vein sinuses with thrombosis was 3 (IQR, 1-15). Twenty-nine (12.5%) had only 1 vein with thrombosis. Thirty-one (13.4%) had isolated thrombotic parenchymal lesions, 31 (13.4%) had isolated hemorrhagic parenchymal lesions, and 27 (11.7%) had both. The median duration of follow-up was 11.9 months (range, 76-543 months) for 197 (88.3%) of 223 surviving patients. Five patients died during hospitalization, 4 of brain herniation (despite
<table><caption>TABLE 1 Epidemiologic, demographic, and clinical characteristics of patients with cerebral venous sinus thrombosis.</caption><thead><tr><th>Parameters</th><th>All (n = 231)</th></tr></thead><tbody><tr><td>Demographic characteristics</td><td></td></tr><tr><td>Age (y)</td><td>41.2 (28-51)</td></tr><tr><td>Female</td><td>158 (68.4%)</td></tr><tr><td>Body mass index (kg/m²)</td><td>25.4 (22.6-28.5)</td></tr><tr><td>Underlying comorbidity</td><td></td></tr><tr><td>Dyslipidemia</td><td>27 (11.7%)</td></tr><tr><td>Hypothyroidism</td><td>12 (5.2%)</td></tr><tr><td>Diabetes</td><td>11 (4.8%)</td></tr><tr><td>Smoking history</td><td>32 (13.9%)</td></tr><tr><td>History of thrombosis</td><td>36 (15.6%)</td></tr><tr><td>Contraceptive</td><td>106 (67.1%)</td></tr><tr><td>Initial clinical presentation</td><td></td></tr><tr><td>Time between onset of symptoms and diagnosis (d)</td><td>5 (range, 0-205)</td></tr><tr><td>≤2</td><td>82</td></tr><tr><td>2-30</td><td>131</td></tr><tr><td>>30</td><td>18</td></tr><tr><td>Clinical presentation</td><td></td></tr><tr><td>Isolated intracranial hypertension</td><td>117 (50.6%)</td></tr><tr><td>Focal syndrome</td><td>96 (41.5%)</td></tr><tr><td>Diffuse encephalopathy</td><td>16 (6.9%)</td></tr><tr><td>Initial consciousness disturbances</td><td>35 (15.2%)</td></tr><tr><td>Median GCS score</td><td>15 (8-15)</td></tr><tr><td>Mean NIHSS score</td><td>1.59 (range, 0-26)</td></tr><tr><td>0</td><td>149 (64.5%)</td></tr><tr><td>≤5</td><td>208 (90%)</td></tr><tr><td>>5</td><td>23 (10%)</td></tr><tr><td>Initial imaging</td><td></td></tr><tr><td>Number of sinus thrombosis</td><td></td></tr><tr><td>1</td><td>29 (12.6%)</td></tr><tr><td>2</td><td>33 (14.3%)</td></tr><tr><td>3</td><td>58 (25.1%)</td></tr><tr><td>4</td><td>29 (12.6%)</td></tr><tr><td>5</td><td>26 (11.3%)</td></tr><tr><td>6</td><td>14 (6%)</td></tr><tr><td>7</td><td>9 (3.9%)</td></tr><tr><td>8</td><td>8 (3.5%)</td></tr><tr><td>≥9</td><td>6 (2.6%)</td></tr></tbody></table>

(Continues)

<table><caption>TABLE 1 (Continued)</caption><thead><tr><th>Parameters</th><th>All (n = 231)</th></tr></thead><tbody><tr><td>Parenchymal lesion severity</td><td></td></tr><tr><td>Minor</td><td>57 (24.7%)</td></tr><tr><td>Moderate</td><td>25 (10.8%)</td></tr><tr><td>Severe</td><td>4 (1.7%)</td></tr><tr><td>Type of lesion</td><td></td></tr><tr><td>Ischemic</td><td>31 (13.4%)</td></tr><tr><td>Hemorrhagic</td><td>31 (13.4%)</td></tr><tr><td>both</td><td>27 (11.7%)</td></tr><tr><td>Evolution</td><td></td></tr><tr><td>NIHSS score variation between day 0 and 5</td><td></td></tr><tr><td>Stable</td><td>159 (68.8%)</td></tr><tr><td>Improvement</td><td>59 (25.5%)</td></tr><tr><td>Worsening</td><td>11 (4.8%)</td></tr><tr><td>Modified Rankin Score variation between day 5 and month 3</td><td></td></tr><tr><td>Stable</td><td>95 (41.1%)</td></tr><tr><td>Improvement</td><td>70 (30.3%)</td></tr><tr><td>Worsening</td><td>47 (20.3%)</td></tr></tbody></table>

GCS, Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke Scale.

decompressive craniectomy in 1 patient), and 1 of uncontrolled cancer. Three more patients died because of underlying conditions such as cancer at 3 (n = 2) and 12 months. Twenty-six were lost to follow-up (they did not come to the control visit at 3 and 12 months). Among the 205 survivor patients who had a complete follow-up, 97 (47.3%) were no longer treated with anticoagulants, 85 patients (41.5%) were still on anticoagulants, and 20 (9.8%) were on aspirin. The median duration of antithrombotic treatments was 356 days (IQR, 228-387).

## 3.2 | Laboratory parameters and clinical presentation characteristics

Laboratory results obtained at D₀ are shown in Supplementary Table 1. They are displayed according to the time between the onset of symptoms and diagnosis and the different clinical presentations (Table 2).

### 3.2.1 | Association with the initial clinical presentation

We analyzed the association of biomarkers with symptoms at presentation categorized as isolated intracranial hypertension and/or
<table><caption>**TABLE 1** Epidemiologic, demographic, and clinical characteristics of patients with cerebral venous sinus thrombosis.</caption><thead><tr><th>Parameters</th><th>All (n = 231)</th></tr></thead><tbody><tr><td>Demographic characteristics</td><td></td></tr><tr><td>Age (y)</td><td>41.2 (28-51)</td></tr><tr><td>Female</td><td>158 (68.4%)</td></tr><tr><td>Body mass index (kg/m²)</td><td>25.4 (22.6-28.5)</td></tr><tr><td>Underlying comorbidity</td><td></td></tr><tr><td>Dyslipidemia</td><td>27 (11.7%)</td></tr><tr><td>Hypothyroidism</td><td>12 (5.2%)</td></tr><tr><td>Diabetes</td><td>11 (4.8%)</td></tr><tr><td>Smoking history</td><td>32 (13.9%)</td></tr><tr><td>History of thrombosis</td><td>36 (15.6%)</td></tr><tr><td>Contraceptive</td><td>106 (67.1%)</td></tr><tr><td>Initial clinical presentation</td><td></td></tr><tr><td>Time between onset of symptoms and diagnosis (d)</td><td>5 (range, 0-205)</td></tr><tr><td>≤2</td><td>82</td></tr><tr><td>2-30</td><td>131</td></tr><tr><td>>30</td><td>18</td></tr><tr><td>Clinical presentation</td><td></td></tr><tr><td>Isolated intracranial hypertension</td><td>117 (50.6%)</td></tr><tr><td>Focal syndrome</td><td>96 (41.5%)</td></tr><tr><td>Diffuse encephalopathy</td><td>16 (6.9%)</td></tr><tr><td>Initial consciousness disturbances</td><td>35 (15.2%)</td></tr><tr><td>Median GCS score</td><td>15 (8-15)</td></tr><tr><td>Mean NIHSS score</td><td>1.59 (range, 0-26)</td></tr><tr><td>0</td><td>149 (64.5%)</td></tr><tr><td>≤5</td><td>208 (90%)</td></tr><tr><td>>5</td><td>23 (10%)</td></tr><tr><td>Initial imaging</td><td></td></tr><tr><td>Number of sinus thrombosis</td><td></td></tr><tr><td>1</td><td>29 (12.6%)</td></tr><tr><td>2</td><td>33 (14.3%)</td></tr><tr><td>3</td><td>58 (25.1%)</td></tr><tr><td>4</td><td>29 (12.6%)</td></tr><tr><td>5</td><td>26 (11.3%)</td></tr><tr><td>6</td><td>14 (6%)</td></tr><tr><td>7</td><td>9 (3.9%)</td></tr><tr><td>8</td><td>8 (3.5%)</td></tr><tr><td>≥9</td><td>6 (2.6%)</td></tr></tbody></table>

(Continues)

<table><caption>**TABLE 1** (Continued)</caption><thead><tr><th>Parameters</th><th>All (n = 231)</th></tr></thead><tbody><tr><td>Parenchymal lesion severity</td><td></td></tr><tr><td>Minor</td><td>57 (24.7%)</td></tr><tr><td>Moderate</td><td>25 (10.8%)</td></tr><tr><td>Severe</td><td>4 (1.7%)</td></tr><tr><td>Type of lesion</td><td></td></tr><tr><td>Ischemic</td><td>31 (13.4%)</td></tr><tr><td>Hemorrhagic</td><td>31 (13.4%)</td></tr><tr><td>both</td><td>27 (11.7%)</td></tr><tr><td>Evolution</td><td></td></tr><tr><td>NIHSS score variation between day 0 and 5</td><td></td></tr><tr><td>Stable</td><td>159 (68.8%)</td></tr><tr><td>Improvement</td><td>59 (25.5%)</td></tr><tr><td>Worsening</td><td>11 (4.8%)</td></tr><tr><td>Modified Rankin Score variation between day 5 and month 3</td><td></td></tr><tr><td>Stable</td><td>95 (41.1%)</td></tr><tr><td>Improvement</td><td>70 (30.3%)</td></tr><tr><td>Worsening</td><td>47 (20.3%)</td></tr></tbody></table>

GCS, Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke Scale.

decompressive craniectomy in 1 patient), and 1 of uncontrolled cancer. Three more patients died because of underlying conditions such as cancer at 3 (n = 2) and 12 months. Twenty-six were lost to follow-up (they did not come to the control visit at 3 and 12 months). Among the 205 survivor patients who had a complete follow-up, 97 (47.3%) were no longer treated with anticoagulants, 85 patients (41.5%) were still on anticoagulants, and 20 (9.8%) were on aspirin. The median duration of antithrombotic treatments was 356 days (IQR, 228-387).

## 3.2 | Laboratory parameters and clinical presentation characteristics

Laboratory results obtained at D₀ are shown in Supplementary Table 1. They are displayed according to the time between the onset of symptoms and diagnosis and the different clinical presentations (Table 2).

### 3.2.1 | Association with the initial clinical presentation

We analyzed the association of biomarkers with symptoms at presentation categorized as isolated intracranial hypertension and/or
isolated headache, focal syndrome, cavernous sinus syndrome, and diffuse encephalopathy. A lower D₀ hs-CRP was observed in patients with isolated intracranial hypertension (8.7 mg/L [IQR, 2.2-23.3]) and diffuse encephalopathy (31.0 mg/L [13.0-66.5]; P = .0045). The presence of initial consciousness disturbance was considered a factor of severity. D₀ hs-CRP levels were significantly higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; P = .0086).

Concerning the NIHSS score, higher D₀ hs-CRP was associated with worse initial NIHSS score (>5) compared with NIHSS score of ≤5 (P = .0009). No significant differences were observed for NLR, fibrinogen, or TG parameters.

Finally, D₀ NLR (odds ratio [OR], 1.088 [1.011-1.178]; P = .0246) and hs-CRP (OR, 1.013 [1.03-1.025]; P = .01) were associated with parenchymal lesions.

## 3.3 | Laboratory parameters and imaging at presentation

Laboratory parameters on D₀ according to imaging data are displayed in Table 3.

### 3.3.1 | Association with cerebral parenchymal lesions

A significant difference in D-dimer levels was also observed in patients with minor vs moderate-to-severe parenchymal lesions (1070 µg/L [543-2175] vs 2220 [1108-3885], respectively; P = .0058). Patients with parenchymal ischemic parenchymal lesions (n = 31) had higher ETP<sub>5pM</sub> than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min [1646-2441] vs 1629 nM min [1371-2090], respectively; P = .0082).

### 3.3.2 | Association with etiological characteristics

D₀ TG was increased in women under contraceptives: higher ETP<sub>5pM</sub>, maximal thrombin peak<sub>5pM</sub>, and velocity<sub>5pM</sub> (1892 nM min [IQR, 1573-2407] vs 1489 nM min [IQR, 1489-1840], P = .0042; 354 nM [IQR, 255-419] vs 253 [IQR, 189-345], P = .0029; and 127.6 nM/min [IQR, 66.0-160.1] vs 51.2 [IQR, 21.2-82.9], P < .001; respectively).

## 3.4 | Laboratory parameters and evolution

### 3.4.1 | NIHSS evolution from D₀ to D₅ and biomarkers

We calculated the NIHSS variation from D₀ to D₅ (Supplementary Table 2): 11 patients had a worsening score, 159 patients had a stable score, and 59 patients had an improving score. In patients with

worsening scores, the D₀ hs-CRP and NLR were significantly higher than those with stable or improving scores (32.7 mg/L [18.6-105.1] vs 9.6 mg/L [2.8-23.4] vs 13.4 mg/L [5.7-31.4]; 6.9 [4.7-12.7] vs 3.5 [2.1-5.9] vs 3.9 [2.1-6.5]; P = .003 and P = .0041, respectively).

### 3.4.2 | Death occurrences during hospitalization and biomarkers

Five patients died during hospitalization. No significant correlations were observed between D₀ hs-CRP and D-dimer (Supplementary Table 3). The D₀ hs-CRP and D-dimer were significantly higher in patients who died during hospitalization (hs-CRP: 71.2 mg/L [IQR, 9.1-110.8] vs 10.6 mg/L [IQR, 3.6-29.1], P = .017; D-dimer: 2405 µg/L [IQR, 2085-10250] vs 965 µg/L [IQR, 550-2123], P = .020; respectively). On D₅, hs-CRP and D-dimer were also higher (hs-CRP: 223.5 mg/L [IQR, 31.3-393.1] vs 4.3 mg/L [IQR, 1.9-12.7], P < .0001; D-dimer: 1160 µg/L [IQR, 1140-10,450] vs 650 µg/L [IQR, 380-1030], P = .016; respectively). No significant differences were observed for NLR or TG parameters.

## 3.5 | Clinical characteristics and biomarkers as predictors of death occurrence

We evaluated clinical characteristics and biomarkers to predict death occurrence during hospitalization. Age >75th percentile (>51.5 years) was associated with death occurrence (OR, 12.51 [1.98-153.7]; P = .016) (Supplementary Table 4). Dyslipidemia and initial hemorrhagic parenchymal lesion were associated with death occurrence (OR, 25.38 [3.11-524.2], P = .028; OR, 21.32 [2.63-439.2], P = .0045; respectively). No other clinical characteristics were associated with death occurrence. In unadjusted logistic regression, D₀ hs-CRP level >75th percentile (>29.7 mg/L) was associated with odds of death (OR, 10.76 [1.55-140.4], P = .04). D₀ D-dimer level >75th percentile (>2198 mg/L) was not associated with death occurrence (OR, 1.272 [0.20-15.95]; P = .99). The OR of death for D₅ hs-CRP >75th percentile (>13.7 mg/L) was 13.08 (2.06-160.8) (P = .01), and for D₅ D-dimer >75th percentile (>1060 mg/L), it was 14.63 (2.28-179.9) (P = .01).

### 3.5.1 | Evolution at 3 months

Imaging was evaluated at 3 months (Supplementary Table 3): 4 patients had worse imaging findings, 15 patients had no change, and 193 patients had improved imaging findings with partial (n = 112) or complete (n = 81) recanalization. The improvement was associated with a lower D₀ NLR than that with no change (4.10 [2.54-5.76] vs 6.37 [5.02-9.57], respectively; P = .0246). No significant differences were observed for hs-CRP, D-dimer, or TG parameters. No laboratory marker predicted improvement, worsening, or stable modified Rankin Score.
isolated headache, focal syndrome, cavernous sinus syndrome, and diffuse encephalopathy. A lower D₀ hs-CRP was observed in patients with isolated intracranial hypertension (8.7 mg/L [IQR, 2.2-23.3]) and diffuse encephalopathy (31.0 mg/L [13.0-66.5]; P = .0045). The presence of initial consciousness disturbance was considered a factor of severity. D₀ hs-CRP levels were significantly higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; P = .0086).

Concerning the NIHSS score, higher D₀ hs-CRP was associated with worse initial NIHSS score (>5) compared with NIHSS score of ≤5 (P = .0009). No significant differences were observed for NLR, fibrinogen, or TG parameters.

Finally, D₀ NLR (odds ratio [OR], 1.088 [1.011-1.178]; P = .0246) and hs-CRP (OR, 1.013 [1.03-1.025]; P = .01) were associated with parenchymal lesions.

## 3.3 | Laboratory parameters and imaging at presentation

Laboratory parameters on D₀ according to imaging data are displayed in Table 3.

### 3.3.1 | Association with cerebral parenchymal lesions

A significant difference in D-dimer levels was also observed in patients with minor vs moderate-to-severe parenchymal lesions (1070 µg/L [543-2175] vs 2220 [1108-3885], respectively; P = .0058). Patients with parenchymal ischemic parenchymal lesions (n = 31) had higher ETP<sub>5pM</sub> than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min [1646-2441] vs 1629 nM min [1371-2090], respectively; P = .0082).

### 3.3.2 | Association with etiological characteristics

D₀ TG was increased in women under contraceptives: higher ETP<sub>5pM</sub>, maximal thrombin peak<sub>5pM</sub>, and velocity<sub>5pM</sub> (1892 nM min [IQR, 1573-2407] vs 1489 nM min [IQR, 1489-1840], P = .0042; 354 nM [IQR, 255-419] vs 253 [IQR, 189-345], P = .0029; and 127.6 nM/min [IQR, 66.0-160.1] vs 51.2 [IQR, 21.2-82.9], P < .001; respectively).

## 3.4 | Laboratory parameters and evolution

### 3.4.1 | NIHSS evolution from D₀ to D₅ and biomarkers

We calculated the NIHSS variation from D₀ to D₅ (Supplementary Table 2): 11 patients had a worsening score, 159 patients had a stable score, and 59 patients had an improving score. In patients with

worsening scores, the D₀ hs-CRP and NLR were significantly higher than those with stable or improving scores (32.7 mg/L [18.6-105.1] vs 9.6 mg/L [2.8-23.4] vs 13.4 mg/L [5.7-31.4]; 6.9 [4.7-12.7] vs 3.5 [2.1-5.9] vs 3.9 [2.1-6.5]; P = .003 and P = .0041, respectively).

### 3.4.2 | Death occurrences during hospitalization and biomarkers

Five patients died during hospitalization. No significant correlations were observed between D₀ hs-CRP and D-dimer (Supplementary Table 3). The D₀ hs-CRP and D-dimer were significantly higher in patients who died during hospitalization (hs-CRP: 71.2 mg/L [IQR, 9.1-110.8] vs 10.6 mg/L [IQR, 3.6-29.1], P = .017; D-dimer: 2405 µg/L [IQR, 2085-10250] vs 965 µg/L [IQR, 550-2123], P = .020; respectively). On D₅, hs-CRP and D-dimer were also higher (hs-CRP: 223.5 mg/L [IQR, 31.3-393.1] vs 4.3 mg/L [IQR, 1.9-12.7], P < .0001; D-dimer: 1160 µg/L [IQR, 1140-10,450] vs 650 µg/L [IQR, 380-1030], P = .016; respectively). No significant differences were observed for NLR or TG parameters.

## 3.5 | Clinical characteristics and biomarkers as predictors of death occurrence

We evaluated clinical characteristics and biomarkers to predict death occurrence during hospitalization. Age >75th percentile (>51.5 years) was associated with death occurrence (OR, 12.51 [1.98-153.7]; P = .016) (Supplementary Table 4). Dyslipidemia and initial hemorrhagic parenchymal lesion were associated with death occurrence (OR, 25.38 [3.11-524.2], P = .028; OR, 21.32 [2.63-439.2], P = .0045; respectively). No other clinical characteristics were associated with death occurrence. In unadjusted logistic regression, D₀ hs-CRP level >75th percentile (>29.7 mg/L) was associated with odds of death (OR, 10.76 [1.55-140.4], P = .04). D₀ D-dimer level >75th percentile (>2198 mg/L) was not associated with death occurrence (OR, 1.272 [0.20-15.95]; P = .99). The OR of death for D₅ hs-CRP >75th percentile (>13.7 mg/L) was 13.08 (2.06-160.8) (P = .01), and for D₅ D-dimer >75th percentile (>1060 mg/L), it was 14.63 (2.28-179.9) (P = .01).

### 3.5.1 | Evolution at 3 months

Imaging was evaluated at 3 months (Supplementary Table 3): 4 patients had worse imaging findings, 15 patients had no change, and 193 patients had improved imaging findings with partial (n = 112) or complete (n = 81) recanalization. The improvement was associated with a lower D₀ NLR than that with no change (4.10 [2.54-5.76] vs 6.37 [5.02-9.57], respectively; P = .0246). No significant differences were observed for hs-CRP, D-dimer, or TG parameters. No laboratory marker predicted improvement, worsening, or stable modified Rankin Score.
<table><caption>TABLE 2 Laboratory markers on D₀ were associated with the initial clinical presentation.</caption><thead><tr><th rowspan="2">Biomarkers</th><th colspan="3">Time to diagnosis</th><th colspan="3">Clinical presentation</th><th colspan="2">Initial consciousness</th></tr><tr><th>&lt;2 d</th><th>2-30 d</th><th>&gt;30 d</th><th>ICHT</th><th>Focal syndrome</th><th>Diffuse encephalopathy</th><th>No initial consciousness disturbance</th><th>Initial consciousness disturbance</th></tr></thead><tbody><tr><td>hs-CRP (mg/L)</td><td>10.8 (5.0-29.6)</td><td>10.6 (3.2-28.5)</td><td>5.3 (2.2-33.4)</td><td>8.7 (2.2-23.3)α, β</td><td>13.4 (5.6-30.2)α</td><td>31.0 (13.0-66.5)β</td><td>10.17 (3.6-25.5)γ</td><td>23.71 (4.80-60.0)γ</td></tr><tr><td>NLR</td><td>3.40 (2.06-5.42)</td><td>3.40 (2.06-5.42)</td><td>3.46 (2.29-5.83)</td><td>3.32 (2.13-5.87)</td><td>4.13 (2.15-6.46)</td><td>4.00 (2.15-7.19)</td><td>3.51 (2.12-5.88)δ</td><td>4.78 (3.10-9.59)δ</td></tr><tr><td>D-dimer (µg/L)</td><td>830 (475-2365)</td><td>1160 (680-2220)</td><td>655 (413-1535)</td><td>925 (500-1680)</td><td>1170 (670-2425)</td><td>1220 (625-2370)</td><td>950 (520-2075)α</td><td>1220 (950-2445)α</td></tr><tr><td>Fibrinogen (g/L)</td><td>4.1 (3.6-4.7)</td><td>3.8 (3.3-4.6)</td><td>4.7 (3.5-5.5)</td><td>3.9 (3.4-4.8)</td><td>4.3 (3.6-4.7)</td><td>3.9 (3.4-4.8)</td><td>4.0 (3.4-4.7)</td><td>4.3 (3.4-4.8)</td></tr><tr><td colspan="9">Thrombin generation assay 1 pM</td></tr><tr><td>N</td><td>82</td><td>131</td><td>18</td><td>106</td><td>75</td><td>10</td><td>148</td><td>25</td></tr><tr><td>Lagtime<sub>1pM</sub> (min)</td><td>7.9 (5.6-9.2)</td><td>7.7 (6.1-8.8)</td><td>8.33 (6.9-9.5)</td><td>7.5 (5.8-9.0)</td><td>7.9 (6.6-8.9)</td><td>9.4 (5.9-10.3)</td><td>7.8 (6.0-8.9)</td><td>8.0 (5.8-10.3)</td></tr><tr><td>TTP<sub>1pM</sub> (min)</td><td>11.9 (9.0-13.8)</td><td>11.7 (10.1-13.3)</td><td>12.3 (9.8-13.2)</td><td>11.5 (9.8-13.3)</td><td>11.9 (10.2-13.4)</td><td>12.9 (8.5-14.8)</td><td>11.7 (10.0-13.3)</td><td>12.3 (9.1-15.1)</td></tr><tr><td>ETP<sub>1pM</sub> (nM min)</td><td>1370 (922-1793)</td><td>1314 (1068-1726)</td><td>1370 (970-1559)</td><td>1333 (929-1699)</td><td>1440 (1095-1827)</td><td>1141 (998-1463)</td><td>1374 (1023-1753)</td><td>1121 (954-1505)</td></tr><tr><td>Peak<sub>1pM</sub> (nM)</td><td>207 (117-303)</td><td>203 (118-269)</td><td>209 (101-328)</td><td>181 (109-278)</td><td>222 (131-295)</td><td>218 (127-297)</td><td>204 (118-287)</td><td>212 (110-271)</td></tr><tr><td>Velocity<sub>1pM</sub> (nM/min)</td><td>55.3 (27.0-95.0)</td><td>51.6 (24.3-85.5)</td><td>63.0 (21.2-131.1)</td><td>44.3 (22.1-84.2)</td><td>56.2 (29.6-104.1)</td><td>70 (31.1-112.0)</td><td>54.5 (25.7-86.6)</td><td>53.9 (23.9-96.2)</td></tr><tr><td colspan="9">Thrombin generation assay 5 pM</td></tr><tr><td>Lagtime<sub>5pM</sub> (min)</td><td>4.1 (3.3-5.0)</td><td>4.0 (3.3-4.9)</td><td>4.2 (3.9-5.0)</td><td>3.9 (3.3-4.6)</td><td>4.3 (3.5-5.4)</td><td>4.1 (3.8-5.2)</td><td>4.1 (3.3-4.8)</td><td>4.2 (3.8-5.8)</td></tr><tr><td>TTP<sub>5pM</sub> (min)</td><td>7.5 (5.8-8.5)</td><td>7.1 (6.3-8.5)</td><td>7.5 (6.7-7.8)</td><td>7.1 (6.0-7.7)</td><td>7.5 (6.5-9.0)</td><td>7.2 (6.2-8.4)</td><td>7.1 (6.3-8.3)</td><td>7.4 (6.4-9.7)</td></tr><tr><td>ETP<sub>5pM</sub> (nM min)</td><td>1645 (1349-2109)</td><td>1739 (1417-2107)</td><td>1491 (1205-1959)</td><td>1652 (1365-2030)</td><td>1695 (1422-2255)</td><td>1510 (1364-1736)</td><td>1743 (1391-2105)</td><td>1551 (1316-1782)</td></tr><tr><td>Peak<sub>5pM</sub> (nM)</td><td>283 (198-373)</td><td>293 (229-389)</td><td>278 (209-353)</td><td>283 (222-370)</td><td>298 (207-411)</td><td>279 (238-361)</td><td>298 (218-383)</td><td>260 (221-347)</td></tr><tr><td>Velocity<sub>5pM</sub> (nM/min)</td><td>92.2 (50.8-146)</td><td>97.2 (59.6-145.7)</td><td>83.7 (66.4-129.6)</td><td>91.5 (58.6-141)</td><td>97.1 (55.4-148.3)</td><td>96.7 (71.8-137.2)</td><td>97.0 (57.6-145.9)</td><td>80.0 (60.2-124)</td></tr></tbody></table>

Results are expressed as median (IQR).

Statistical analysis was performed using the Mann-Whitney U-test or Kruskal-Wallis test completed with 2-stage step-up method of Benjamini, Krieger, and Yekutieli for multiple comparisons. α: ICHT vs Focal syndrome P value = .039; β: ICTH vs Diffuse encephalopathy P value = .0045; γ: No initial consciousness disturbance vs initial consciousness disturbance P value = .0086; δ: No initial consciousness disturbance vs initial consciousness disturbance P value = .012. N was the number of Thrombin generation assay without anticoagulant treatment at D₀ sampling.

ETP, endogenous thrombin potential; hs-CRP, high-sensitivity C-reactive protein; ICHT, intracranial hypertension; NLR, neutrophil-to-lymphocyte ratio; TTP, time to peak.
<table><caption>TABLE 2 Laboratory markers on D₀ were associated with the initial clinical presentation.</caption><thead><tr><th rowspan="2">Biomarkers</th><th colspan="3">Time to diagnosis</th><th colspan="3">Clinical presentation</th><th colspan="2">Initial consciousness</th></tr><tr><th>&lt;2 d</th><th>2-30 d</th><th>&gt;30 d</th><th>ICHT</th><th>Focal syndrome</th><th>Diffuse encephalopathy</th><th>No initial consciousness disturbance</th><th>Initial consciousness disturbance</th></tr></thead><tbody><tr><td>hs-CRP (mg/L)</td><td>10.8 (5.0-29.6)</td><td>10.6 (3.2-28.5)</td><td>5.3 (2.2-33.4)</td><td>8.7 (2.2-23.3)α, β</td><td>13.4 (5.6-30.2)α</td><td>31.0 (13.0-66.5)β</td><td>10.17 (3.6-25.5)γ</td><td>23.71 (4.80-60.0)γ</td></tr><tr><td>NLR</td><td>3.40 (2.06-5.42)</td><td>3.40 (2.06-5.42)</td><td>3.46 (2.29-5.83)</td><td>3.32 (2.13-5.87)</td><td>4.13 (2.15-6.46)</td><td>4.00 (2.15-7.19)</td><td>3.51 (2.12-5.88)δ</td><td>4.78 (3.10-9.59)δ</td></tr><tr><td>D-dimer (µg/L)</td><td>830 (475-2365)</td><td>1160 (680-2220)</td><td>655 (413-1535)</td><td>925 (500-1680)</td><td>1170 (670-2425)</td><td>1220 (625-2370)</td><td>950 (520-2075)α</td><td>1220 (950-2445)α</td></tr><tr><td>Fibrinogen (g/L)</td><td>4.1 (3.6-4.7)</td><td>3.8 (3.3-4.6)</td><td>4.7 (3.5-5.5)</td><td>3.9 (3.4-4.8)</td><td>4.3 (3.6-4.7)</td><td>3.9 (3.4-4.8)</td><td>4.0 (3.4-4.7)</td><td>4.3 (3.4-4.8)</td></tr><tr><td colspan="9">Thrombin generation assay 1 pM</td></tr><tr><td>N</td><td>82</td><td>131</td><td>18</td><td>106</td><td>75</td><td>10</td><td>148</td><td>25</td></tr><tr><td>Lagtime<sub>1pM</sub> (min)</td><td>7.9 (5.6-9.2)</td><td>7.7 (6.1-8.8)</td><td>8.33 (6.9-9.5)</td><td>7.5 (5.8-9.0)</td><td>7.9 (6.6-8.9)</td><td>9.4 (5.9-10.3)</td><td>7.8 (6.0-8.9)</td><td>8.0 (5.8-10.3)</td></tr><tr><td>TTP<sub>1pM</sub> (min)</td><td>11.9 (9.0-13.8)</td><td>11.7 (10.1-13.3)</td><td>12.3 (9.8-13.2)</td><td>11.5 (9.8-13.3)</td><td>11.9 (10.2-13.4)</td><td>12.9 (8.5-14.8)</td><td>11.7 (10.0-13.3)</td><td>12.3 (9.1-15.1)</td></tr><tr><td>ETP<sub>1pM</sub> (nM min)</td><td>1370 (922-1793)</td><td>1314 (1068-1726)</td><td>1370 (970-1559)</td><td>1333 (929-1699)</td><td>1440 (1095-1827)</td><td>1141 (998-1463)</td><td>1374 (1023-1753)</td><td>1121 (954-1505)</td></tr><tr><td>Peak<sub>1pM</sub> (nM)</td><td>207 (117-303)</td><td>203 (118-269)</td><td>209 (101-328)</td><td>181 (109-278)</td><td>222 (131-295)</td><td>218 (127-297)</td><td>204 (118-287)</td><td>212 (110-271)</td></tr><tr><td>Velocity<sub>1pM</sub> (nM/min)</td><td>55.3 (27.0-95.0)</td><td>51.6 (24.3-85.5)</td><td>63.0 (21.2-131.1)</td><td>44.3 (22.1-84.2)</td><td>56.2 (29.6-104.1)</td><td>70 (31.1-112.0)</td><td>54.5 (25.7-86.6)</td><td>53.9 (23.9-96.2)</td></tr><tr><td colspan="9">Thrombin generation assay 5 pM</td></tr><tr><td>Lagtime<sub>5pM</sub> (min)</td><td>4.1 (3.3-5.0)</td><td>4.0 (3.3-4.9)</td><td>4.2 (3.9-5.0)</td><td>3.9 (3.3-4.6)</td><td>4.3 (3.5-5.4)</td><td>4.1 (3.8-5.2)</td><td>4.1 (3.3-4.8)</td><td>4.2 (3.8-5.8)</td></tr><tr><td>TTP<sub>5pM</sub> (min)</td><td>7.5 (5.8-8.5)</td><td>7.1 (6.3-8.5)</td><td>7.5 (6.7-7.8)</td><td>7.1 (6.0-7.7)</td><td>7.5 (6.5-9.0)</td><td>7.2 (6.2-8.4)</td><td>7.1 (6.3-8.3)</td><td>7.4 (6.4-9.7)</td></tr><tr><td>ETP<sub>5pM</sub> (nM min)</td><td>1645 (1349-2109)</td><td>1739 (1417-2107)</td><td>1491 (1205-1959)</td><td>1652 (1365-2030)</td><td>1695 (1422-2255)</td><td>1510 (1364-1736)</td><td>1743 (1391-2105)</td><td>1551 (1316-1782)</td></tr><tr><td>Peak<sub>5pM</sub> (nM)</td><td>283 (198-373)</td><td>293 (229-389)</td><td>278 (209-353)</td><td>283 (222-370)</td><td>298 (207-411)</td><td>279 (238-361)</td><td>298 (218-383)</td><td>260 (221-347)</td></tr><tr><td>Velocity<sub>5pM</sub> (nM/min)</td><td>92.2 (50.8-146)</td><td>97.2 (59.6-145.7)</td><td>83.7 (66.4-129.6)</td><td>91.5 (58.6-141)</td><td>97.1 (55.4-148.3)</td><td>96.7 (71.8-137.2)</td><td>97.0 (57.6-145.9)</td><td>80.0 (60.2-124)</td></tr></tbody></table>

Results are expressed as median (IQR).

Statistical analysis was performed using the Mann-Whitney U-test or Kruskal-Wallis test completed with 2-stage step-up method of Benjamini, Krieger, and Yekutieli for multiple comparisons. α: ICHT vs Focal syndrome P value = .039; β: ICTH vs Diffuse encephalopathy P value = .0045; γ: No initial consciousness disturbance vs initial consciousness disturbance P value = .0086; δ: No initial consciousness disturbance vs initial consciousness disturbance P value = .012. N was the number of Thrombin generation assay without anticoagulant treatment at D₀ sampling.

ETP, endogenous thrombin potential; hs-CRP, high-sensitivity C-reactive protein; ICHT, intracranial hypertension; NLR, neutrophil-to-lymphocyte ratio; TTP, time to peak.
<table><caption>TABLE 3 Laboratory markers on day 0 were associated with initial imaging results.</caption><thead><tr><th rowspan="2">Biomarkers</th><th colspan="2">Cerebral parenchymal lesions</th><th colspan="3">Parenchymal lesion severity</th><th colspan="3">Type of lesion</th></tr><tr><th>Absence of a lesion</th><th>Presence of a lesion</th><th>Minor</th><th>Moderate</th><th>Severe</th><th>Ischemic</th><th>Hemorrhagic</th><th>Both</th></tr></thead><tbody><tr><td>hs-CRP (mg/L)</td><td>9.5 (2.6-23.2)α</td><td>15.3 (5.4-31.8)α</td><td>13.4 (5.7-28.5)</td><td>18.3 (4.0-52.6)</td><td>68.3 (19.8-134.4)</td><td>16.1 (7.8-27.5)</td><td>10.8 (5.4-30.3)</td><td>19.9 (3.6-55.8)</td></tr><tr><td>NLR</td><td>3.25 (2.08-6.07)β</td><td>4.32 (2.70-6.42)β</td><td>4.32 (2.7-5.9)</td><td>4.3 (3.2-10.8)</td><td>5.1 (4.1-9.5)</td><td>4.0 (2.7-6.0)</td><td>5.4 (2.5-6.8)</td><td>4.2 (2.8-7.3)</td></tr><tr><td>D-dimer (µg/L)</td><td>930 (530-1660)</td><td>1240 (645-2423)</td><td>1070 (543-2175)γ</td><td>2220 (1108-3885)γ</td><td>1760 (900-2620)</td><td>1640 (575-2990)</td><td>1430 (640-2425)</td><td>1050 (733-2313)</td></tr><tr><td>Fibrinogen (g/L)</td><td>3.8 (3.3-4.7)</td><td>4.3 (3.6-4.7)</td><td>4.3 (3.6-4.7)</td><td>4.3 (3.6-5.2)</td><td>4.2 (3.8-4.6)</td><td>4.5 (3.7-4.9)</td><td>4.1 (3.6-4.6)</td><td>4.4 (3.6-5.2)</td></tr><tr><td colspan="9">Thrombin generation assay 1 pM</td></tr><tr><td>N</td><td>123</td><td>74</td><td>40</td><td>18</td><td>4</td><td>25</td><td>26</td><td>22</td></tr><tr><td>Lagtime<sub>1pM</sub> (min)</td><td>7.8 (5.8-9.0)</td><td>7.9 (6.7-9.3)</td><td>8.0 (7.3-9.4)</td><td>7.5 (5.0-9.1)</td><td>7.1 (5.6-10.0)</td><td>8.1 (7.3-9.4)</td><td>7.8 (6.4-8.7)</td><td>7.5 (5.0-9.2)</td></tr><tr><td>TTP<sub>1pM</sub> (min)</td><td>11.8 (9.9-13.5)</td><td>11.9 (10.2-13.4)</td><td>12.3 (10.7-13.7)</td><td>11.0 (8.3-13.1)</td><td>10.0 (8.3-13.3)</td><td>12.3 (10.6-13.8)</td><td>11.9 (10.1-13.7)</td><td>11.0 (8.3-12.9)</td></tr><tr><td>ETP<sub>1pM</sub> (nM min)</td><td>1269 (938-1701)</td><td>1442 (1090-1835)</td><td>1442 (1092-1836)</td><td>1454 (1081-1833)</td><td>1835 (1349-2176)</td><td>1448 (1180-1854)</td><td>1406 (1081-1555)</td><td>1280 (913-2042)</td></tr><tr><td>Peak<sub>1pM</sub> (nM)</td><td>185 (109-279)</td><td>221 (139-304)</td><td>222 (136-308)</td><td>218 (118-292)</td><td>336 (217-392)</td><td>228 (145-291)</td><td>215 (139-284)</td><td>218 (89.7-359)</td></tr><tr><td>Velocity<sub>1pM</sub> (nM/min)</td><td>44.4 (22.06-84.2)</td><td>57.3 (31.4-110.6)</td><td>54.3 (27.8-102.4)</td><td>56.0 (31.5-110.6)</td><td>121.5 (65.2-146)</td><td>55.3 (32.2-84.1)</td><td>52.5 (31.9-114.8)</td><td>67 (20.0-125.7)</td></tr><tr><td colspan="9">Thrombin generation assay 5 pM</td></tr><tr><td>Lagtime<sub>5pM</sub> (min)</td><td>3.96 (3.3-4.8)</td><td>4.17 (3.54-5.00)</td><td>4.2 (3.4-5.0)</td><td>4.2 (3.5-5.4)</td><td>4.6 (3.6-5.8)</td><td>3.9 (3.5-4.6)</td><td>4.2 (3.8-6.0)</td><td>4.2 (3.2-5.6)</td></tr><tr><td>TTP<sub>5pM</sub> (min)</td><td>7.1 (6.0-8.5)</td><td>7.3 (6.5-8.1)</td><td>7.3 (6.6-8)</td><td>7.3 (6.0-9.0)</td><td>7.1 (5.8-9.4)</td><td>7.2 (6.5-7.9)</td><td>7.5 (6.8-9.4)</td><td>7.3 (6.0-9.1)</td></tr><tr><td>ETP<sub>5pM</sub> (nM min)</td><td>1627 (1348-2000)</td><td>1716 (1422-2163)</td><td>1844 (1424-2155)</td><td>1477 (1356-2185)</td><td>2373 (1469-2450)</td><td>2025 (1646-2441)δ</td><td>1629 (1433-1797)δ</td><td>1663 (1080-2124)</td></tr><tr><td>Peak<sub>5pM</sub> (nM)</td><td>278 (206-366)</td><td>311 (228-419)</td><td>337 (237-425)</td><td>269 (191-411)</td><td>421 (231-485)</td><td>361 (264-428)</td><td>268 (196-356)</td><td>299 (178-427)</td></tr><tr><td>Velocity<sub>5pM</sub> (nM/min)</td><td>89.8 (54.7-139)</td><td>101.1 (66.0-150.8)</td><td>109.2 (70.0-149.0)</td><td>92.1 (50.8-173.9)</td><td>168.5 (65.4-214.7)</td><td>124 (80.6-150.1)</td><td>84.9 (50.0-131.3)</td><td>85.0 (51.1-185)</td></tr></tbody></table>

Statistical analysis were Mann-Whitney U test or Kruskal-Wallis test completed with two-stage step-up method of Benjamini, Krieger and Yekutieli for multiple comparisons. α: Absence of lesion vs presence of lesion P value = .035; β: Absence of lesion vs presence of lesion P value = .0013; γ: Minor lesion vs moderate lesion P value = .0058; δ: Ischemic lesion vs hemorrhagic lesion P value = .048. N was the number of Thrombin generation assay without anticoagulant treatment at D₀ sampling.

ETP, endogenous thrombin potential; hs-CRP, high-sensitivity C-reactive protein; ICHT, intracranial hypertension; NLR, neutrophil-to-lymphocyte ratio; TTP, time to peak.
<table><caption>TABLE 3 Laboratory markers on day 0 were associated with initial imaging results.</caption><thead><tr><th rowspan="2">Biomarkers</th><th colspan="2">Cerebral parenchymal lesions</th><th colspan="3">Parenchymal lesion severity</th><th colspan="3">Type of lesion</th></tr><tr><th>Absence of a lesion</th><th>Presence of a lesion</th><th>Minor</th><th>Moderate</th><th>Severe</th><th>Ischemic</th><th>Hemorrhagic</th><th>Both</th></tr></thead><tbody><tr><td>hs-CRP (mg/L)</td><td>9.5 (2.6-23.2)α</td><td>15.3 (5.4-31.8)α</td><td>13.4 (5.7-28.5)</td><td>18.3 (4.0-52.6)</td><td>68.3 (19.8-134.4)</td><td>16.1 (7.8-27.5)</td><td>10.8 (5.4-30.3)</td><td>19.9 (3.6-55.8)</td></tr><tr><td>NLR</td><td>3.25 (2.08-6.07)β</td><td>4.32 (2.70-6.42)β</td><td>4.32 (2.7-5.9)</td><td>4.3 (3.2-10.8)</td><td>5.1 (4.1-9.5)</td><td>4.0 (2.7-6.0)</td><td>5.4 (2.5-6.8)</td><td>4.2 (2.8-7.3)</td></tr><tr><td>D-dimer (µg/L)</td><td>930 (530-1660)</td><td>1240 (645-2423)</td><td>1070 (543-2175)γ</td><td>2220 (1108-3885)γ</td><td>1760 (900-2620)</td><td>1640 (575-2990)</td><td>1430 (640-2425)</td><td>1050 (733-2313)</td></tr><tr><td>Fibrinogen (g/L)</td><td>3.8 (3.3-4.7)</td><td>4.3 (3.6-4.7)</td><td>4.3 (3.6-4.7)</td><td>4.3 (3.6-5.2)</td><td>4.2 (3.8-4.6)</td><td>4.5 (3.7-4.9)</td><td>4.1 (3.6-4.6)</td><td>4.4 (3.6-5.2)</td></tr><tr><td colspan="9">Thrombin generation assay 1 pM</td></tr><tr><td>N</td><td>123</td><td>74</td><td>40</td><td>18</td><td>4</td><td>25</td><td>26</td><td>22</td></tr><tr><td>Lagtime<sub>1pM</sub> (min)</td><td>7.8 (5.8-9.0)</td><td>7.9 (6.7-9.3)</td><td>8.0 (7.3-9.4)</td><td>7.5 (5.0-9.1)</td><td>7.1 (5.6-10.0)</td><td>8.1 (7.3-9.4)</td><td>7.8 (6.4-8.7)</td><td>7.5 (5.0-9.2)</td></tr><tr><td>TTP<sub>1pM</sub> (min)</td><td>11.8 (9.9-13.5)</td><td>11.9 (10.2-13.4)</td><td>12.3 (10.7-13.7)</td><td>11.0 (8.3-13.1)</td><td>10.0 (8.3-13.3)</td><td>12.3 (10.6-13.8)</td><td>11.9 (10.1-13.7)</td><td>11.0 (8.3-12.9)</td></tr><tr><td>ETP<sub>1pM</sub> (nM min)</td><td>1269 (938-1701)</td><td>1442 (1090-1835)</td><td>1442 (1092-1836)</td><td>1454 (1081-1833)</td><td>1835 (1349-2176)</td><td>1448 (1180-1854)</td><td>1406 (1081-1555)</td><td>1280 (913-2042)</td></tr><tr><td>Peak<sub>1pM</sub> (nM)</td><td>185 (109-279)</td><td>221 (139-304)</td><td>222 (136-308)</td><td>218 (118-292)</td><td>336 (217-392)</td><td>228 (145-291)</td><td>215 (139-284)</td><td>218 (89.7-359)</td></tr><tr><td>Velocity<sub>1pM</sub> (nM/min)</td><td>44.4 (22.06-84.2)</td><td>57.3 (31.4-110.6)</td><td>54.3 (27.8-102.4)</td><td>56.0 (31.5-110.6)</td><td>121.5 (65.2-146)</td><td>55.3 (32.2-84.1)</td><td>52.5 (31.9-114.8)</td><td>67 (20.0-125.7)</td></tr><tr><td colspan="9">Thrombin generation assay 5 pM</td></tr><tr><td>Lagtime<sub>5pM</sub> (min)</td><td>3.96 (3.3-4.8)</td><td>4.17 (3.54-5.00)</td><td>4.2 (3.4-5.0)</td><td>4.2 (3.5-5.4)</td><td>4.6 (3.6-5.8)</td><td>3.9 (3.5-4.6)</td><td>4.2 (3.8-6.0)</td><td>4.2 (3.2-5.6)</td></tr><tr><td>TTP<sub>5pM</sub> (min)</td><td>7.1 (6.0-8.5)</td><td>7.3 (6.5-8.1)</td><td>7.3 (6.6-8)</td><td>7.3 (6.0-9.0)</td><td>7.1 (5.8-9.4)</td><td>7.2 (6.5-7.9)</td><td>7.5 (6.8-9.4)</td><td>7.3 (6.0-9.1)</td></tr><tr><td>ETP<sub>5pM</sub> (nM min)</td><td>1627 (1348-2000)</td><td>1716 (1422-2163)</td><td>1844 (1424-2155)</td><td>1477 (1356-2185)</td><td>2373 (1469-2450)</td><td>2025 (1646-2441)δ</td><td>1629 (1433-1797)δ</td><td>1663 (1080-2124)</td></tr><tr><td>Peak<sub>5pM</sub> (nM)</td><td>278 (206-366)</td><td>311 (228-419)</td><td>337 (237-425)</td><td>269 (191-411)</td><td>421 (231-485)</td><td>361 (264-428)</td><td>268 (196-356)</td><td>299 (178-427)</td></tr><tr><td>Velocity<sub>5pM</sub> (nM/min)</td><td>89.8 (54.7-139)</td><td>101.1 (66.0-150.8)</td><td>109.2 (70.0-149.0)</td><td>92.1 (50.8-173.9)</td><td>168.5 (65.4-214.7)</td><td>124 (80.6-150.1)</td><td>84.9 (50.0-131.3)</td><td>85.0 (51.1-185)</td></tr></tbody></table>

Statistical analysis were Mann-Whitney U test or Kruskal-Wallis test completed with two-stage step-up method of Benjamini, Krieger and Yekutieli for multiple comparisons. α: Absence of lesion vs presence of lesion *P* value = .035; β: Absence of lesion vs presence of lesion *P* value = .0013; γ: Minor lesion vs moderate lesion *P* value = .0058; δ: Ischemic lesion vs hemorrhagic lesion *P* value = .048. N was the number of Thrombin generation assay without anticoagulant treatment at D₀ sampling.

ETP, endogenous thrombin potential; hs-CRP, high-sensitivity C-reactive protein; ICHT, intracranial hypertension; NLR, neutrophil-to-lymphocyte ratio; TTP, time to peak.
4 | DISCUSSION

In our prospective study including 231 patients with CVST, we iden-
tified several biomarkers associated with clinical presentation char-
acteristics and/or predictors of evolution. We confirmed, in a limited
number of events, that hemorrhage and elevation of inflammation
biomarkers, particularly hs-CRP and D-dimer, were associated with
early death.

CVST is a rare thrombotic disorder caused by systemic or local imbalances in hemostasis [9]. Prognosis is usually good, with more than 80% of the patients making a complete recovery [5,6]. Despite the highly favorable prognosis, identification of patients with CVST having a possible unfavorable outcome can be challenging. For example, in a large cohort of 642 patients from the International Study on Cerebral Vein and Dural Sinus Thrombosis, clinical factors of unfavorable outcome have been identified: namely, male sex, age <37 years, coma, mental status disorder, intracranial hemorrhage on admission, thrombosis of the deep cerebral venous system, central nervous system infection, and cancer [5]. More recently, a practical clinical score was established to predict outcomes after CVST [20]. The clinical score associating parenchymal lesion size of >6 cm, bilateral Babinski signs, male sex, parenchymal hemorrhage, and level of consciousness are associated with unfavorable outcomes. However, no laboratory marker had been evaluated in these 2 studies. We confirmed that age >52 years and hemorrhagic parenchymal lesions were associated with unfavorable outcomes. We also found that dyslipidemia was associated with unfavorable outcomes; this abnormality has never been reported before. However, the confidence interval of the odds ratio is very wide, and this result deserves to be cautiously interpreted.

The association of inflammation biomarkers with diagnosis, severity, and poor prognosis of cerebrovascular events has already been reported, especially in patients with CVST [15,20–25]. Recently, a multicenter prospective observational study was conducted in Portugal: the Pathophysiology of Venous Infarction – Prediction of Infarction and Recanalization in CVT (PRIORITy-CVT) study, including 62 patients, demonstrated that biomarkers associated with inflammation predicted poor prognosis in cerebral vein thrombosis (CVT) [15]. In this study, patients had more unfavorable outcomes than the FPCCVT cohort (21% vs 3% of deaths, respectively). Three biomarkers, namely NLR, CRP, and interleukin (IL)-6, were evaluated as predictors of evolution. As reported in our study, NRL was associated with initial parenchymal brain lesions [16]. A higher baseline NLR, CRP, and IL-6 levels were predictors of unfavorable functional outcome at 90 days [16,24]. We demonstrated in our cohort that baseline systemic inflammation biomarkers were also associated with poor outcomes during hospitalization. Finally, we reported a non-significant fibrinogen increase associated with parenchymal lesions and an increasing number of sinus veins with thrombosis, as well as a lower baseline NLR in patients with improvement in imaging findings at 3 months. Noteworthy, in the PRIORITy-CVT, higher NLR, CRP, and IL-6 levels at admission were not associated with the early evolution of brain lesions or early recanalization. In a recent study including 52 CVST, the hs-CRP level was significantly higher in patients with acute or

subacute CVT than in patients with chronic CVT [25]. However, in our
study, including a much higher number of patients, we did not find a
significant difference.

In addition, we studied D-dimer levels. The D-dimer increase at diagnosis was associated with neurological deficit [22]. In our FPCCVT cohort, the initial D-dimer levels were associated with initial consciousness disturbance, early death occurrence, and the severity of parenchymal lesions. Together with hs-CRP, D-dimer measured at D5 predicted early death. The association between inflammatory biomarkers and clinical outcomes has been reported in different studies [16,26]. Interestingly, a previous study demonstrated that the D-dimer decrease between D0 and day 180 was associated with complete sinus recanalization in MRI findings at 6 months [21]. In a study evaluating fibrin clot properties, an increase in D-dimer was observed in patients who had developed recurrent CVST [27]. An altered fibrin clot and fibrinogen increase were observed in patients with recurrent CVST [28] and in patients with CVST-related pregnancy [29]. The combined activation of inflammatory and hemostatic responses after infection or tissue injury is a defense mechanism. This process is referred to as immunothrombosis: within this novel concept, inflammatory cells such as leukocytes and platelets directly drive the progression of venous thrombosis [30]. Under pathological conditions, an increase in tissue factor expression and increased levels of the plasminogen activation inhibitor 1, blocking fibrinolysis, amplify coagulation [31]. The elevation of D-dimer in our patients at baseline in parallel to that of other inflammation biomarkers shows that D-dimer is an acute phase reactant [32,33]. Once anticoagulant treatment had been initiated, the subsequent D-dimer decrease makes the interpretation of D-dimer more complex, although D-dimer measured on D5 still predicted early death.

Finally, in our cohort, TG parameters measured on D₀, namely, ETP and velocity, were predictive of the presence of ischemic parenchymal lesions and a greater number of thrombosed sinuses. In the literature, to our knowledge, no study had previously evaluated TG as a predictor of CVST evolution. TG assay is a global coagulation assay that may be altered in hypercoagulable states [12,33] or different types of endothelial injury [34–36]. In our study, lower ETP₅₀M was associated only with hemorrhagic parenchymal lesion development.

The strengths of our study were a prospective study design, with a prolonged follow-up, together with clinical and imaging evaluation at similar time points, including the evolution of parenchymal brain lesions and functional outcomes. However, our study has some limitations. Whereas inflammation markers and D-dimer are routinely performed, TG assay is performed only in some laboratories, and the calibrated automated thrombogram system is poorly standardized. We had a few severe clinical presentations. However, Coutinho et al. [37] showed an improvement over time in initial CVT presentations due to improved diagnostic methods. We have demonstrated that the FPCCVT cohort had similar clinical, radiological, biological, and etiological characteristics to the historical International Study on Cerebral Vein and Dural Sinus Thrombosis cohort, suggesting the generalizability of our results. Contrarily, clinical prediction of CVST outcomes is likely complicated, involving several patient characteristics,
4 | DISCUSSION

In our prospective study including 231 patients with CVST, we iden-
tified several biomarkers associated with clinical presentation char-
acteristics and/or predictors of evolution. We confirmed, in a limited
number of events, that hemorrhage and elevation of inflammation
biomarkers, particularly hs-CRP and D-dimer, were associated with
early death.

CVST is a rare thrombotic disorder caused by systemic or local imbalances in hemostasis [9]. Prognosis is usually good, with more than 80% of the patients making a complete recovery [5,6]. Despite the highly favorable prognosis, identification of patients with CVST having a possible unfavorable outcome can be challenging. For example, in a large cohort of 642 patients from the International Study on Cerebral Vein and Dural Sinus Thrombosis, clinical factors of unfavorable outcome have been identified: namely, male sex, age <37 years, coma, mental status disorder, intracranial hemorrhage on admission, thrombosis of the deep cerebral venous system, central nervous system infection, and cancer [5]. More recently, a practical clinical score was established to predict outcomes after CVST [20]. The clinical score associating parenchymal lesion size of >6 cm, bilateral Babinski signs, male sex, parenchymal hemorrhage, and level of consciousness are associated with unfavorable outcomes. However, no laboratory marker had been evaluated in these 2 studies. We confirmed that age >52 years and hemorrhagic parenchymal lesions were associated with unfavorable outcomes. We also found that dyslipidemia was associated with unfavorable outcomes; this abnormality has never been reported before. However, the confidence interval of the odds ratio is very wide, and this result deserves to be cautiously interpreted.

The association of inflammation biomarkers with diagnosis, severity, and poor prognosis of cerebrovascular events has already been reported, especially in patients with CVST [15,20–25]. Recently, a multicenter prospective observational study was conducted in Portugal: the Pathophysiology of Venous Infarction – Prediction of Infarction and Recanalization in CVT (PRIORITy-CVT) study, including 62 patients, demonstrated that biomarkers associated with inflammation predicted poor prognosis in cerebral vein thrombosis (CVT) [15]. In this study, patients had more unfavorable outcomes than the FPCCVT cohort (21% vs 3% of deaths, respectively). Three biomarkers, namely NLR, CRP, and interleukin (IL)-6, were evaluated as predictors of evolution. As reported in our study, NRL was associated with initial parenchymal brain lesions [16]. A higher baseline NLR, CRP, and IL-6 levels were predictors of unfavorable functional outcome at 90 days [16,24]. We demonstrated in our cohort that baseline systemic inflammation biomarkers were also associated with poor outcomes during hospitalization. Finally, we reported a non-significant fibrinogen increase associated with parenchymal lesions and an increasing number of sinus veins with thrombosis, as well as a lower baseline NLR in patients with improvement in imaging findings at 3 months. Noteworthy, in the PRIORITy-CVT, higher NLR, CRP, and IL-6 levels at admission were not associated with the early evolution of brain lesions or early recanalization. In a recent study including 52 CVST, the hs-CRP level was significantly higher in patients with acute or

subacute CVT than in patients with chronic CVT [25]. However, in our
study, including a much higher number of patients, we did not find a
significant difference.

In addition, we studied D-dimer levels. The D-dimer increase at diagnosis was associated with neurological deficit [22]. In our FPCCVT cohort, the initial D-dimer levels were associated with initial consciousness disturbance, early death occurrence, and the severity of parenchymal lesions. Together with hs-CRP, D-dimer measured at D5 predicted early death. The association between inflammatory biomarkers and clinical outcomes has been reported in different studies [16,26]. Interestingly, a previous study demonstrated that the D-dimer decrease between D0 and day 180 was associated with complete sinus recanalization in MRI findings at 6 months [21]. In a study evaluating fibrin clot properties, an increase in D-dimer was observed in patients who had developed recurrent CVST [27]. An altered fibrin clot and fibrinogen increase were observed in patients with recurrent CVST [28] and in patients with CVST-related pregnancy [29]. The combined activation of inflammatory and hemostatic responses after infection or tissue injury is a defense mechanism. This process is referred to as immunothrombosis: within this novel concept, inflammatory cells such as leukocytes and platelets directly drive the progression of venous thrombosis [30]. Under pathological conditions, an increase in tissue factor expression and increased levels of the plasminogen activation inhibitor 1, blocking fibrinolysis, amplify coagulation [31]. The elevation of D-dimer in our patients at baseline in parallel to that of other inflammation biomarkers shows that D-dimer is an acute phase reactant [32,33]. Once anticoagulant treatment had been initiated, the subsequent D-dimer decrease makes the interpretation of D-dimer more complex, although D-dimer measured on D5 still predicted early death.

Finally, in our cohort, TG parameters measured on D₀, namely, ETP and velocity, were predictive of the presence of ischemic parenchymal lesions and a greater number of thrombosed sinuses. In the literature, to our knowledge, no study had previously evaluated TG as a predictor of CVST evolution. TG assay is a global coagulation assay that may be altered in hypercoagulable states [12,33] or different types of endothelial injury [34–36]. In our study, lower ETP₅₀M was associated only with hemorrhagic parenchymal lesion development.

The strengths of our study were a prospective study design, with a prolonged follow-up, together with clinical and imaging evaluation at similar time points, including the evolution of parenchymal brain lesions and functional outcomes. However, our study has some limitations. Whereas inflammation markers and D-dimer are routinely performed, TG assay is performed only in some laboratories, and the calibrated automated thrombogram system is poorly standardized. We had a few severe clinical presentations. However, Coutinho et al. [37] showed an improvement over time in initial CVT presentations due to improved diagnostic methods. We have demonstrated that the FPCCVT cohort had similar clinical, radiological, biological, and etiological characteristics to the historical International Study on Cerebral Vein and Dural Sinus Thrombosis cohort, suggesting the generalizability of our results. Contrarily, clinical prediction of CVST outcomes is likely complicated, involving several patient characteristics,
especially underlying comorbid conditions. Also, we could not assess race or ethnicity as a social determinant related to our findings for regulatory reasons. The power was limited in that we only had 5 deaths and therefore could not perform age-adjusted or multivariable analysis.

In conclusion, we reported here that 2 widely available bio-
markers, namely hs-CRP and D-dimer, could help predict early death
in CVST in addition to patient characteristics. These results need to be
validated in external cohorts.

ACKNOWLEDGMENTS

The authors thank the Direction de la Recherche Clinique et de l'In-
novation of the Rouen University hospital for its help in the elabo-
ration and management of this study and the biostatistics unit of
Rouen University hospital for its help in the statistical analysis of this
study. They thank Claire Auditeau and Geoffrey Foulon-Pinto for their
technical assistance. They are grateful to Pr Benoît Polack from
Grenoble University Hospital for his proofreading of the manuscript.

FUNDING

This work was supported by the research program (No. 2010/087/HP) funded by the French Ministry of Health.

ETHICS STATEMENT

The study was performed in accordance with the Declaration of
Helsinki. The institutional review board (person committee protection
of Rouen University Hospital) and a national ethical committee
approved the study. An informed consent was obtained from all
subjects.

AUTHOR CONTRIBUTIONS

P.B., V.S. and E.M.F. performed analysis, drafted manuscript. A.T.B. and V.L.C.D. are the principal investigators of this research program and revised the manuscript for important intellectual content, and are accountable for all aspects of the work. All other authors are in- vestigators from the different centers. They are listed in order of the number of inclusions and participated in the proofreading of the manuscript. All authors contributed to the article and approved the submitted version.

RELATIONSHIP DISCLOSURE

There are no competing interests to disclose.

ORCID

Véronique Le Cam Duchez https://orcid.org/0000-0003-0429-8222

TWITTER

Paul Billoir @BilloirP

Pierre-Emmanuel Morange @morange_pierre

Catherine Ternisien @CatherineTerni1

REFERENCES

[1] Payne AB, Adamski A, Abe K, Reyes NL, Richardson LC, Hooper WC, et al. Epidemiology of cerebral venous sinus thrombosis and cerebral venous sinus thrombosis with thrombocytopenia in the United States, 2018 and 2019. *Res Pract Thromb Haemost.* 2022;6:e12682. https://doi.org/10.1002/rth2.12682

[2] Kristoffersen ES, Harper CE, Vetvik KG, Zarnovicky S, Hansen JM, Faiz KW. Incidence and mortality of cerebral venous thrombosis in a Norwegian population. *Stroke*. 2020;51:3023-9.

[3] Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of cerebral venous thrombosis: a cross-sectional study. *Stroke*. 2012;43:3375-7.

[4] Stam J. Thrombosis of the cerebral veins and sinuses. *N Engl J Med.* 2005;352:1791-8.

[5] Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). *Stroke*. 2004;35:664-70.

[6] Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. *Lancet Neurol.* 2007;6:162-70.

[7] Alons IM, Jellema K, Wermer MJ, Algra A. D-dimer for the exclusion of cerebral venous thrombosis: a meta-analysis of low-risk patients with isolated headache. *BMC Neurol.* 2015;15:1-7.

[8] Dentali F, Squizzato A, Marchesi C, Bonzini M, Ferro JM, Ageno W. D-dimer testing in the diagnosis of cerebral vein thrombosis: a systematic review and a meta-analysis of the literature. *J Thromb Haemost.* 2012;10:582-9.

[9] Silvis SM, de Sousa DA, Ferro JM, Coutinho JM. Cerebral venous thrombosis. *Nat Rev Neurol.* 2017;13:555-65.

[10] Kasonga F, Feugray G, Chamouni P, Barbay V, Fresel M, Chretien MH, et al. Evaluation of thrombin generation assay in factor XI deficiency. *Clin Chim Acta.* 2021;523:348-54.

[11] Feugray G, Kasonga F, Chamouni P, Barbay V, Fresel M, Chretien MH, et al. Factor XII deficiency evaluated by thrombin generation assay. *Clin Biochem.* 2021;100:42-7.

[12] Billoir P, Duflot T, Fresel M, Chrétien MH, Barbay V, Le Cam Duchez V. Thrombin generation profile in non-thrombotic factor V Leiden carriers. *J Thromb Thrombolysis.* 2019;47:473-7.

[13] Billoir P, Le Cam Duchez V, Miranda S, Richard V, Benhamou Y. Thrombin generation assay in autoimmune disease. *Rev Med Intern.* 2021;42:862-8.

[14] Billoir P, Miranda S, Levesque H, Benhamou Y, Le Cam Duchez V. Hypercoagulability evaluation in antiphospholipid syndrome without anticoagulation treatment with thrombin generation assay: a preliminary study. *J Clin Med.* 2021;10:2728.

[15] Sonnevi K, Tchaikovski SN, Holmström M, Rosing J, Bremme K, Lårfars G. Thrombin generation and activated protein C resistance in the absence of factor V Leiden correlates with the risk of recurrent venous thromboembolism in women aged 18-65 years. *Thromb Haemost.* 2011;106:901-7.

[16] Aguiar de Sousa D, Pereira-Santos MC, Serra-Caetano A, Lucas Neto L, Sousa AL, Gabriel D, et al. Blood biomarkers associated with inflammation predict poor prognosis in cerebral venous thrombosis: a multicenter prospective observational study. *Eur J Neurol.* 2021;28:202-8.

[17] Kaya H, Ertaş F, İslamoğlu Y, Kaya Z, Atılgan ZA, Çil H, et al. Association between neutrophil to lymphocyte ratio and severity of coronary artery disease. *Clin Appl Thromb Hemost.* 2014;20:50-4.

[18] Triquenot Bagan A, Crassard I, Drouet L, Barbieux-Guillot M, Marlu R, Robinet-Borgomino E, et al. Cerebral venous thrombosis: clinical, radiological, biological, and etiological characteristics of a French prospective cohort (FPCCVT)—comparison with ISCVT cohort. *Front Neurol.* 2021;12:753110.

[19] Bousser M, Russel RR. Cerebral venous thrombosis. In: Warlow CP, Van Gijn J, eds. *Major problems in neurology*. London, UK: WB Saunders; 1997:27-9.
especially underlying comorbid conditions. Also, we could not assess race or ethnicity as a social determinant related to our findings for regulatory reasons. The power was limited in that we only had 5 deaths and therefore could not perform age-adjusted or multivariable analysis.

In conclusion, we reported here that 2 widely available bio-
markers, namely hs-CRP and D-dimer, could help predict early death
in CVST in addition to patient characteristics. These results need to be
validated in external cohorts.

ACKNOWLEDGMENTS

The authors thank the Direction de la Recherche Clinique et de l'In-
novation of the Rouen University hospital for its help in the elabo-
ration and management of this study and the biostatistics unit of
Rouen University hospital for its help in the statistical analysis of this
study. They thank Claire Auditeau and Geoffrey Foulon-Pinto for their
technical assistance. They are grateful to Pr Benoît Polack from
Grenoble University Hospital for his proofreading of the manuscript.

FUNDING

This work was supported by the research program (No. 2010/087/HP) funded by the French Ministry of Health.

ETHICS STATEMENT

The study was performed in accordance with the Declaration of
Helsinki. The institutional review board (person committee protection
of Rouen University Hospital) and a national ethical committee
approved the study. An informed consent was obtained from all
subjects.

AUTHOR CONTRIBUTIONS

P.B., V.S. and E.M.F. performed analysis, drafted manuscript. A.T.B. and V.L.C.D. are the principal investigators of this research program and revised the manuscript for important intellectual content, and are accountable for all aspects of the work. All other authors are in- vestigators from the different centers. They are listed in order of the number of inclusions and participated in the proofreading of the manuscript. All authors contributed to the article and approved the submitted version.

RELATIONSHIP DISCLOSURE

There are no competing interests to disclose.

ORCID

Véronique Le Cam Duchez

<figure><img src="image_6.png" /></figure>

https://orcid.org/0000-0003-0429-8222

TWITTER

Paul Billoir

<figure><img src="image_7.png" /></figure>

@BilloirP

Pierre-Emmanuel Morange

<figure><img src="image_8.png" /></figure>

@morange_pierre

Catherine Ternisien

<figure><img src="image_9.png" /></figure>

@CatherineTerni1

REFERENCES

[1] Payne AB, Adamski A, Abe K, Reyes NL, Richardson LC, Hooper WC, et al. Epidemiology of cerebral venous sinus thrombosis and cerebral venous sinus thrombosis with thrombocytopenia in the United States, 2018 and 2019. *Res Pract Thromb Haemost.* 2022;6:e12682. https://doi.org/10.1002/rth2.12682

[2] Kristoffersen ES, Harper CE, Vetvik KG, Zarnovicky S, Hansen JM, Faiz KW. Incidence and mortality of cerebral venous thrombosis in a Norwegian population. *Stroke*. 2020;51:3023-9.

[3] Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of cerebral venous thrombosis: a cross-sectional study. *Stroke*. 2012;43:3375-7.

[4] Stam J. Thrombosis of the cerebral veins and sinuses. *N Engl J Med.* 2005;352:1791-8.

[5] Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). *Stroke*. 2004;35:664-70.

[6] Bousser MG, Ferro JM. Cerebral venous thrombosis: an update. *Lancet Neurol.* 2007;6:162-70.

[7] Alons IM, Jellema K, Wermer MJ, Algra A. D-dimer for the exclusion of cerebral venous thrombosis: a meta-analysis of low-risk patients with isolated headache. *BMC Neurol.* 2015;15:1-7.

[8] Dentali F, Squizzato A, Marchesi C, Bonzini M, Ferro JM, Ageno W. D-dimer testing in the diagnosis of cerebral vein thrombosis: a systematic review and a meta-analysis of the literature. *J Thromb Haemost.* 2012;10:582-9.

[9] Silvis SM, de Sousa DA, Ferro JM, Coutinho JM. Cerebral venous thrombosis. *Nat Rev Neurol.* 2017;13:555-65.

[10] Kasonga F, Feugray G, Chamouni P, Barbay V, Fresel M, Chretien MH, et al. Evaluation of thrombin generation assay in factor XI deficiency. *Clin Chim Acta.* 2021;523:348-54.

[11] Feugray G, Kasonga F, Chamouni P, Barbay V, Fresel M, Chretien MH, et al. Factor XII deficiency evaluated by thrombin generation assay. *Clin Biochem.* 2021;100:42-7.

[12] Billoir P, Duflot T, Fresel M, Chrétien MH, Barbay V, Le Cam Duchez V. Thrombin generation profile in non-thrombotic factor V Leiden carriers. *J Thromb Thrombolysis.* 2019;47:473-7.

[13] Billoir P, Le Cam Duchez V, Miranda S, Richard V, Benhamou Y. Thrombin generation assay in autoimmune disease. *Rev Med Intern.* 2021;42:862-8.

[14] Billoir P, Miranda S, Levesque H, Benhamou Y, Le Cam Duchez V. Hypercoagulability evaluation in antiphospholipid syndrome without anticoagulation treatment with thrombin generation assay: a preliminary study. *J Clin Med.* 2021;10:2728.

[15] Sonnevi K, Tchaikovski SN, Holmström M, Rosing J, Bremme K, Lårfars G. Thrombin generation and activated protein C resistance in the absence of factor V Leiden correlates with the risk of recurrent venous thromboembolism in women aged 18-65 years. *Thromb Haemost.* 2011;106:901-7.

[16] Aguiar de Sousa D, Pereira-Santos MC, Serra-Caetano A, Lucas Neto L, Sousa AL, Gabriel D, et al. Blood biomarkers associated with inflammation predict poor prognosis in cerebral venous thrombosis: a multicenter prospective observational study. *Eur J Neurol.* 2021;28:202-8.

[17] Kaya H, Ertaş F, İslamoğlu Y, Kaya Z, Atılgan ZA, Çil H, et al. Association between neutrophil to lymphocyte ratio and severity of coronary artery disease. *Clin Appl Thromb Hemost.* 2014;20:50-4.

[18] Triquenot Bagan A, Crassard I, Drouet L, Barbieux-Guillot M, Marlu R, Robinet-Borgomino E, et al. Cerebral venous thrombosis: clinical, radiological, biological, and etiological characteristics of a French prospective cohort (FPCCVT)—comparison with ISCVT cohort. *Front Neurol.* 2021;12:753110.

[19] Bousser M, Russel RR. Cerebral venous thrombosis. In: Warlow CP, Van Gijn J, eds. *Major problems in neurology*. London, UK: WB Saunders; 1997:27-9.
[20] Barboza MA, Chiquete E, Arauz A, Merlos-Benitez M, Quiroz-Compeán A, Barinagarrementería F, et al. A practical score for prediction of outcome after cerebral venous thrombosis. *Front Neurol*. 2018;9:882.

[21] Meng R, Wang X, Hussain M, Dornbos D, Meng L, Liu Y, et al. Evaluation of plasma D-dimer plus fibrinogen in predicting acute CVST. *Int J Stroke*. 2014;9:166-73.

[22] Juli C, Amalia L, Gamayani U, Atik N. D-dimer level associates with the incidence of focal neurological deficits in cerebral venous thrombosis patients. *J Blood Med*. 2020;11:449-55.

[23] Akboga YE, Bektas H, Anlar O. Usefulness of platelet to lymphocyte and neutrophil to lymphocyte ratios in predicting the presence of cerebral venous sinus thrombosis and in-hospital major adverse cerebral events. *J Neurol Sci*. 2017;380:226-9.

[24] Wang L, Duan J, Bian T, Meng R, Wu L, Zhang Z, et al. Inflammation is correlated with severity and outcome of cerebral venous thrombosis. *J Neuroinflammation*. 2018;15:1-8.

[25] Duan J, Leng X, Han Z, Cai Y, Wang C, Rajah G, et al. Identifying biomarkers associated with venous infarction in acute/subacute cerebral venous thrombosis. *Aging Dis*. 2021;12:93-101.

[26] de Sousa DA, Pereira-Santos MC, Serra-Caetano A, Neto LL, Sousa AL, Gabriel D, et al. Matrix metalloproteinase-9 levels are associated with brain lesion and persistent venous occlusion in patients with cerebral venous thrombosis. *Thromb Haemost*. 2021;121:1476-82.

[27] Skuza AA, Polak M, Undas A. Elevated lipoprotein(a) as a new risk factor of cerebral venous sinus thrombosis: association with fibrin clot properties. *J Thromb Thrombolysis*. 2019;47:8-15.

[28] Siudut J, Świat M, Undas A. Altered fibrin clot properties in patients with cerebral venous sinus thrombosis: association with the risk of recurrence. *Stroke*. 2015;46:2665-8.

[29] Liang ZW, Gao WL, Feng LM. Clinical characteristics and prognosis of cerebral venous thrombosis in Chinese women during pregnancy and puerperium. *Sci Rep*. 2017;7:1-6.

[30] Heestermans M, Poenou G, Duchez AC, Hamzeh-Cognasse H, Bertoletti L, Cognasse F. Immunothrombosis and the role of platelets in venous thromboembolic diseases. *Int J Mol Sci*. 2022;23:13176.

[31] Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. *Blood*. 2019;133:906-18.

[32] Prucha M, Bellingan G, Zazula R. Sepsis biomarkers. *Clin Chim Acta*. 2015;440:97-103.

[33] Billoir P, Alexandre K, Duflot T, Roger M, Miranda S, Goria O, et al. Investigation of coagulation biomarkers to assess clinical deterioration in SARS-CoV-2 infection. *Front Med*. 2021;8:782.

[34] Billoir P, Miranda S, Damian L, Richard V, Benhamou Y, Duchez VL. Development of a thrombin generation test in cultured endothelial cells: evaluation of the prothrombotic effects of antiphospholipid antibodies. *Thromb Res*. 2018;169:87-92.

[35] Billoir P, Blandinières A, Gendron N, Chocron R, Gunther S, Philippe A, et al. Endothelial colony-forming cells from idiopathic pulmonary fibrosis patients have a high procoagulant potential. *Stem Cell Rev Rep*. 2021;17:694-9.

[36] Détriché G, Gendron N, Philippe A, Gruest M, Billoir P, Rossi E, et al. Gonadotropins as novel active partners in vascular diseases: insight from angiogenic properties and thrombotic potential of endothelial colony-forming cells. *J Thromb Haemost*. 2022;20:230-7.

[37] Coutinho JM, Zuurbier SM, Stam J. Declining mortality in cerebral venous thrombosis: a systematic review. *Stroke*. 2014;45:1338-41.

SUPPLEMENTARY MATERIAL

The online version contains supplementary material available at
https://doi.org/10.1016/j.rpth.2023.100130
[20] Barboza MA, Chiquete E, Arauz A, Merlos-Benitez M, Quiroz-Compeán A, Barinagarrementería F, et al. A practical score for prediction of outcome after cerebral venous thrombosis. *Front Neurol*. 2018;9:882.

[21] Meng R, Wang X, Hussain M, Dornbos D, Meng L, Liu Y, et al. Evaluation of plasma D-dimer plus fibrinogen in predicting acute CVST. *Int J Stroke*. 2014;9:166-73.

[22] Juli C, Amalia L, Gamayani U, Atik N. D-dimer level associates with the incidence of focal neurological deficits in cerebral venous thrombosis patients. *J Blood Med*. 2020;11:449-55.

[23] Akboga YE, Bektas H, Anlar O. Usefulness of platelet to lymphocyte and neutrophil to lymphocyte ratios in predicting the presence of cerebral venous sinus thrombosis and in-hospital major adverse cerebral events. *J Neurol Sci*. 2017;380:226-9.

[24] Wang L, Duan J, Bian T, Meng R, Wu L, Zhang Z, et al. Inflammation is correlated with severity and outcome of cerebral venous thrombosis. *J Neuroinflammation*. 2018;15:1-8.

[25] Duan J, Leng X, Han Z, Cai Y, Wang C, Rajah G, et al. Identifying biomarkers associated with venous infarction in acute/subacute cerebral venous thrombosis. *Aging Dis*. 2021;12:93-101.

[26] de Sousa DA, Pereira-Santos MC, Serra-Caetano A, Neto LL, Sousa AL, Gabriel D, et al. Matrix metalloproteinase-9 levels are associated with brain lesion and persistent venous occlusion in patients with cerebral venous thrombosis. *Thromb Haemost*. 2021;121:1476-82.

[27] Skuza AA, Polak M, Undas A. Elevated lipoprotein(a) as a new risk factor of cerebral venous sinus thrombosis: association with fibrin clot properties. *J Thromb Thrombolysis*. 2019;47:8-15.

[28] Siudut J, Świat M, Undas A. Altered fibrin clot properties in patients with cerebral venous sinus thrombosis: association with the risk of recurrence. *Stroke*. 2015;46:2665-8.

[29] Liang ZW, Gao WL, Feng LM. Clinical characteristics and prognosis of cerebral venous thrombosis in Chinese women during pregnancy and puerperium. *Sci Rep*. 2017;7:1-6.

[30] Heestermans M, Poenou G, Duchez AC, Hamzeh-Cognasse H, Bertoletti L, Cognasse F. Immunothrombosis and the role of platelets in venous thromboembolic diseases. *Int J Mol Sci*. 2022;23:13176.

[31] Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. *Blood*. 2019;133:906-18.

[32] Prucha M, Bellingan G, Zazula R. Sepsis biomarkers. *Clin Chim Acta*. 2015;440:97-103.

[33] Billoir P, Alexandre K, Duflot T, Roger M, Miranda S, Goria O, et al. Investigation of coagulation biomarkers to assess clinical deterioration in SARS-CoV-2 infection. *Front Med*. 2021;8:782.

[34] Billoir P, Miranda S, Damian L, Richard V, Benhamou Y, Duchez VL. Development of a thrombin generation test in cultured endothelial cells: evaluation of the prothrombotic effects of antiphospholipid antibodies. *Thromb Res*. 2018;169:87-92.

[35] Billoir P, Blandinières A, Gendron N, Chocron R, Gunther S, Philippe A, et al. Endothelial colony-forming cells from idiopathic pulmonary fibrosis patients have a high procoagulant potential. *Stem Cell Rev Rep*. 2021;17:694-9.

[36] Détriché G, Gendron N, Philippe A, Gruest M, Billoir P, Rossi E, et al. Gonadotropins as novel active partners in vascular diseases: insight from angiogenic properties and thrombotic potential of endothelial colony-forming cells. *J Thromb Haemost*. 2022;20:230-7.

[37] Coutinho JM, Zuurbier SM, Stam J. Declining mortality in cerebral venous thrombosis: a systematic review. *Stroke*. 2014;45:1338-41.

SUPPLEMENTARY MATERIAL

The online version contains supplementary material available at
https://doi.org/10.1016/j.rpth.2023.100130