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Abstract

Introduction:

Cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is a severe disease with high mortality. There are few data on sex differences in CVST-VITT. The aim of our study was to investigate the differences in presentation, treatment, clinical course, complications, and outcome of CVST-VITT between women and men.

Patients and methods:

We used data from an ongoing international registry on CVST-VITT. VITT was diagnosed according to the Pavord criteria. We compared the characteristics of CVST-VITT in women and men.

Results:

Of 133 patients with possible, probable, or definite CVST-VITT, 102 (77%) were women. Women were slightly younger [median age 42 (IQR 28–54) vs 45 (28–56)], presented more often with coma (26% vs 10%) and had a lower platelet count at presentation [median (IQR) 50x10⁹/L (28–79) vs 68 (30–125)] than men. The nadir platelet count was lower in women [median (IQR) 34 (19–62) vs 53 (20–92)]. More women received endovascular treatment than men (15% vs 6%). Rates of treatment with intravenous immunoglobulins were similar (63% vs 66%), as were new venous thromboembolic events (14% vs 14%) and major bleeding complications (30% vs 20%). Rates of good functional outcome (modified Rankin Scale 0-2, 42% vs 45%) and in-hospital death (39% vs 41%) did not differ.

Discussion and conclusions:

Three quarters of CVST-VITT patients in this study were women. Women were more severely affected at presentation, but clinical course and outcome did not differ between women and men. VITT-specific treatments were overall similar, but more women received endovascular treatment.

Keywords

VITT CVST sex differences

Introduction

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but severe adverse reaction after adenoviral vaccination for SARS-CoV-2.¹ It may cause thromboses at multiple sites and in multiple vascular beds, cerebral venous sinus thrombosis (CVST) being the most frequent and strongly associated with mortality.² Previous reports on VITT have shown conflicting results, with some reporting a higher frequency in women,^3–5 while others found no difference in frequency of VITT in women and men.^2,6 However, reports on patients with CVST associated with VITT (CVST-VITT) consistently found a higher proportion of affected women than men.^7,8

There is a lack of data about the clinical characteristics of CVST-VITT in women compared to men. The aim of this study was to compare the presentation, treatment, clinical course, complications, and outcome of CVST-VITT in women and men.

Methods

We used data from an ongoing international registry on CVST-VITT, details of which have been reported previously.⁹ In short, this is a registry-based study. Investigators were asked to report consecutive patients who developed CVST within 28 days of any SARS-CoV-2 vaccination.

Data were collected using a standardized electronic case report form (Castor EDC, Ciwit B.V., Amsterdam, The Netherlands). The ethical review committee of the Academic Medical Center in Amsterdam approved this observational cohort study. Each center was responsible for obtaining permission from local authorities if required by national and local law. The study was endorsed by the European Academy of Neurology and European Stroke Organisation.

We included patients reported until January 10, 2023 with possible, probable, or definite CVST-VITT according to the criteria proposed by an expert hematology panel by the British Society for Haematology as described by Pavord et al.² For the assessment of anti-platelet factor 4 (anti-PF4) antibodies, we accepted all types of tests, as reported by the investigators. In all cases, CVST was confirmed radiologically or at autopsy, and symptom onset was within 28 days of SARS-CoV-2 vaccination. Coma was defined as Glasgow Coma Scale score <9 points. Non-haemorrhagic lesions were defined as edema or venous infarction. Major bleeding was defined according to International Society of Thrombosis and Haemostasis criteria.¹⁰ For outcome analysis, we dichotomized the modified Rankin Scale at discharge in 0–2 (favorable outcome) and 3–5 (poor outcome). The VITT-specific treatments included immunomodulatory treatment such as intravenous immunoglobulins or plasma exchange, avoidance of heparins, and avoidance of platelet transfusions, unless required for surgery.¹¹ Female specific risk factors for CVST were defined as oral contraceptive use, pregnancy, or recent childbirth. Conventional risk factors for CVST were defined as infection, previous venous thromboembolism, genetic or acquired thrombophilia, or cancer within the past 10 years. For thrombus load, the number of sinuses or veins that were thrombosed were added.¹²

Data analysis

We used descriptive statistics for baseline characteristics, treatment, complications during hospitalization, and outcome. We used Mann–Whitney U test, Chi-square, Fisher’s exact, or Fisher-Freeman-Holton test, as appropriate, to determine significance and considered a two-sided probability value below 0.05 as significant. Confidence intervals were calculated using Wilson’s method. The number of missing values for each variable is reported. Analyses were performed with IBM SPSS Statistics for Windows, version 28.0 (IBM Corp., Armonk, N.Y., USA).

This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

Results

Of the 255 patients entered in the registry, 22 were excluded due to onset of symptoms more than 28 days after, or prior to vaccination, 5 were duplicates, 93 had unlikely VITT, and 2 had VITT after mRNA vaccination, leaving 133 cases for analysis (Figure 1).

Figure 1.

Flowchart of patient selection.

Of the 133 included cases, 102 (77%) were women and 31 (23%) were men. Women were slightly younger than men (median age 42 [IQR 28–54] vs 45 [28–56], respectively). The time from vaccination to symptom onset (9 days [IQR 7–11] vs 10 days [7–11]) and from symptom onset to diagnosis (3 days [IQR 2–6] vs 3 days [1–6]) was similar in women and men. At the time of CVST-VITT diagnosis, 14/102 (14%) women had an intake of oral contraceptives and one was pregnant. Conventional risk factors for CVST did not differ between women and men (Table 1).

Table 1.

Patient characteristics of female and male CVST-VITT patients.

	Female CVST-VITT patients (N = 102)	Male CVST-VITT patients (N = 31)	P value
Baseline characteristics, n/N (%)
Age at diagnosis, median (IQR), years	42 (28–54)	45 (28–56)	0.731
Conventional CVST risk factors
Oral contraceptive use	14/102 (14)	N/A
Pregnancy	1/102 (1)	N/A
Recent delivery^†	0/102	N/A
Infection	4/102 (4)	3/31 (10)	0.353*
Previous VTE	2/102 (2)	0/31	>0.999*
Thrombophilia	1/102 (1)	1/31 (3)	0.413*
Cancer^††	3/102 (3)	2/31 (6)	0.331*
SARS-CoV-2 vaccine			0.160*
ChAdOx1 nCoV-19	91/102 (89)	24/31 (77)
Ad26.COV2.S	5/102 (5)	5/31 (16)
BBIBP-CorV	3/102 (3)	1/31 (3)
Sinovac	3/102 (3)	1/31 (3)
Time from vaccination to symptom onset, median (IQR), days	9 (7–11)	10 (7–11)^a	0.893
Time from symptom onset to diagnosis, median (IQR), days	3 (2–6)	3 (1–6)^b	0.858
Focal neurologic deficits at presentation	57/99 (58)	17/31 (55)	0.788
Coma at presentation (GCS < 9)	25/97 (26)	3/30 (10)	0.069
Seizure at presentation	15/100 (15)	5/31 (16)	>0.999*
Concomitant VTE at presentation^†††	23/97 (24)	6/29 (21)	0.734
Splanchnic vein thrombosis	9/97 (9)	2/29 (7)	>0.999*
Deep vein thrombosis	4/97 (4)	1/29 (3)	>0.999*
Pulmonary embolism	14/97 (14)	3/29 (10)	0.760*
Pelvic vein thrombosis	5/97 (5)	0/29	0.589*
Other thrombosis	1/97 (1)	0/29	>0.999*
Laboratory data, n/N (%)
Thrombocytopenia at any time during admission	100/102 (98)	30/31 (97)	0.552*
Platelet count at presentation, median (IQR), ×10⁹/L	50 (28–79)	68 (30–125)	0.049
Platelet count nadir, median (IQR), ×10⁹/L	34 (19–62)	53 (20–92)	0.163
Anti-PF4 antibodies			0.891*
Positive	72/102 (71)	22/31 (71)
Negative	8/102 (8)	3/31 (10)
Not tested or unknown	22/102 (22)	6/31 (19)
D-dimer level >4 μg/mL FEU
>4 µg/mL FEU	82/102 (80)	24/31 (77)
2–4 µg/mL FEU	8/102 (8)	4/31 (13)
<2 µg/mL FEU	3/102 (3)	1/31 (3)
Not tested or unknown	9/102 (9)	2/31 (6)
INR, median (IQR)	1.1 (1.1–1.3)^c	1.2 (1.1–1.3)^d	0.291
aPTT, median (IQR), seconds	29 (25–34)^e	30 (26–34)^f	0.402
Hemoglobin level, median (IQR), mmol/L	7.9 (7.5–8.5)^g	9.1 (7.9–9.7)^h	<0.001
Baseline imaging, n/N (%)
Thrombosis location^†††
Superior sagittal sinus	53/102 (52)	17/31 (55)	0.779
Transverse or sigmoid sinus	80/102 (78)	23/31 (74)	0.621
Straight sinus	20/102 (20)	2/31 (6)	0.084
Deep venous system^‡	14/102 (14)	0/31	0.039*
Thrombus load, median (IQR)^‡‡	3 (2–4)ⁱ	2 (1–4)	0.239
Intracranial hemorrhagic lesion	68/99 (69)	20/31 (65)	0.665
Non-hemorrhagic lesions	28/96 (29)	7/29 (24)	0.597
Treatment data, n/N (%)
Any anticoagulant treatment	87/101 (86)	28/31 (90)	0.761*
Non-heparin received as first anticoagulant	51/87 (59)	19/28 (68)	0.384
Any immunomodulatory treatment	65/100 (65)	22/29 (76)	0.272
Intravenous immunoglobulin	63/100 (63)	19/29 (66)	0.804
Plasma exchange	6/100 (6)	0/29	0.336*
Corticosteroids	32/100 (32)	7/29 (24)	0.417
Eculizumab	2/100 (2)	0/29	>0.999*
Rituximab	1/100 (1)	0/29	>0.999*
Platelet transfusion	24/100 (24)	8/29 (28)	0.694
Endovascular treatment	15/101 (15)	2/31 (6)	0.358*
Decompressive neurosurgery	27/101 (27)	8/31 (26)	0.919
Intensive care unit admission	79/99 (80)	25/31 (81)	0.918
Clinical events during admission, n/N (%)
New VTE	13/96 (14)	4/28 (14)	>0.999*
Splanchnic vein thrombosis	5/96 (5)	1/28 (4)	>0.999*
Deep vein thrombosis	4/96 (4)	2/28 (7)	0.617*
Pulmonary embolism	4/96 (4)	3/28 (11)	0.190*
Pelvic vein thrombosis	2/96 (2)	0/28	>0.999*
Other thrombosis	1/96 (1)	1/28 (4)	0.402*
Bleeding complication	35/98 (36)	8/30 (27)	0.359
Major bleeding^‡‡‡	29/96 (30)	6/30 (20)	0.276
Discharge data, n/N (%)
Duration hospital admission, median (IQR), days	8 (3–17)^j	6 (2–14)^k	0.560
Discharge disposition			0.780*
Home	44/101 (44)	11/29 (38)
Rehabilitation center	16/101 (16)	6/29 (21)
Other hospital	3/101 (3)	0/29
Deceased	38/101 (38)	12/29 (41)
mRS score at discharge			0.790
mRS 0–2	41/98 (42)	13/29 (45)
mRS 3–5	19/98 (19)	4/29 (14)
mRS 6 (dead)	38/98 (39)	12/29 (41)

aPTT: activated partial thromboplastin time; CVST: cerebral venous sinus thrombosis; FEU: fibrinogen equivalent units; GCS: Glasgow Coma Scale; INR = international normalized ratio; IQR: interquartile range; mRS: modified Rankin Scale; PF4: platelet factor 4; VITT: vaccine-induced immune thrombotic thrombocytopenia; VTE: venous thromboembolism.

†

within 12 weeks; ^††in the past 10 years; ^†††multiple possible; ^‡vein of Galen, internal cerebral veins, basal vein of Rosenthal, or inferior sagittal sinus; ^‡‡ thrombus load: number of thrombosed sinus/veins (superior sagittal sinus, transverse sinus, sigmoid sinus, torcula, straight sinus, deep venous system, cavernous sinus, cortical vein, cerebellar vein, jugular vein); ^‡‡‡according to the International Society of Thrombosis and Haemostasis (ISTH) criteria.

Missing values: ^aTwo missing values; ^bTwo missing values; ^cFifteen missing values; ^dSeven missing values; ^eTwenty missing values; ^fSeven missing values; ^gNine missing values; ^hThree missing values; ⁱOne missing value; ^jThree missing values; ^kThree missing values.

Fisher’s exact test or Fisher-Freeman-Holton Test. Significant p values are in bold.

More women presented with coma (26% [95%CI 18–35] vs 10% [3–26]) and in women the platelet count at presentation was lower (50 × 10⁹/L [IQR 28–79] vs 68 [30–125], p = 0.049). More women had thrombosis in the deep venous system (14% [95%CI 8–22] vs 0% [0–11], p = 0.039). The thrombus load and presence of haemorrhagic and non-haemorrhagic lesions did not differ between the groups.

The nadir of platelet count was lower in women than in men (median [IQR]: 34 [19–62] vs 53 [20–92]). During hospitalization, occurrence of new venous thromboembolism (14% [95%CI 8–22] vs 14% [6–31]) and bleeding complications (36% [95%CI 27–46] vs 27% [14–44]) had similar proportions in both women and men.

More women received endovascular treatment than men (15% [95%CI 9–23] vs 6% [2–21]). The proportions of VITT-specific treatments such as any immunomodulatory treatment (65% [95%CI 55–74] vs 76% [58–88]), any non-heparins as first anticoagulants (59% [95%CI 48–68] vs 68% [49–82]) or platelet transfusions (24% [95%CI 17–33] vs 28% [15–46]) were similar.

In women and men, functional outcome at discharge for modified Rankin Scale (mRS) 0–2 (41/98 [42%, 95%CI 33–52] vs 13/29 [45% 28–62]), mRS 3–5 (19/98 [19%, 95%CI 13–28] vs 4/29 [14% 5–31]) and in-hospital mortality (38/98 [39%, 95%CI 30–49] vs 12/29 [41% 26–59]) did not differ (Figure 2). Also there were no differences regarding the discharge disposition.

Figure 2.

Modified Rankin Scale (mRS) score of women and men with cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) at discharge. There are four missing values in the female group and two missing values in the male group.

In an exploratory analysis of cases who were comatose and had a severe thrombocytopenia (platelet count <50 × 10⁹/L) at presentation, 20/133 (15%) patients were selected. Of these, 19 were women and one was a man. The male patient had a recent lumbar puncture, but no other risk factors for CVST. Of the female patients, two used prothrombotic medication (one of which oral contraceptives), one patient was pregnant, one patient had a history of auto-immune disease, and one patient was obese without oral contraceptive use. The other patients had no known risk factors for CVST.

Discussion

The main findings of our analysis of sex differences in our multicenter cohort study are: (1) three quarters of CVST-VITT patients were women, (2) women were slightly younger and women appeared to be more severely affected at presentation with higher frequency of coma and lower admission platelet counts, and (3) VITT-specific treatments, complications during hospitalization, clinical outcome, and in-hospital mortality did not differ between sexes.

The higher proportion of women with CVST-VITT is in-line with previous reports.^7,8 A direct pathophysiological link between female sex and risk of CVST-VITT cannot be inferred from our observational study. Furthermore, we cannot rule out a selection bias, for example because healthcare workers, which comprise predominantly women, were more likely to be vaccinated against COVID-19 in an early stage before restrictions on adenoviral COVID-19 vaccinations were widely implemented.^13–15 In addition, there might have been a higher awareness of CVST-VITT in female patients since the majority of patients in reports on CVST-VITT were women and might therefore be more likely to undergo investigations in case of suspicion of CVST. In general, women are more likely to suffer from autoimmune disease given the more pronounced immune response to antigens and vaccines with higher antibody production and stronger T-cell activation, which could at least partially explain these findings.^16,17 Compared to historical CVST cohorts, a lower proportion of women with CVST-VITT had women-specific risk factors.⁹

In our study, the higher proportion of women with coma and lower platelet count at presentation is not explained by a delayed recognition and diagnosis. The number of days between vaccination to symptom onset and symptom onset to diagnosis was similar in both sexes. The higher proportion of women with thrombosis in the deep venous system might explain the higher rate of coma at presentation.^18,19 Additionally, the lower platelet count at admission and the lower nadir during hospitalization in women might reflect a more severe disease. However, the cerebral venous sinus thrombus load and haemorrhagic lesions at presentation, the new thromboses and bleeding rates during hospitalization as well as outcome were similar in both women and men. This could partially be explained by the similar VITT-specific treatments in both groups, especially the treatment with intravenous immunoglobulins (IVIG).¹¹ IVIG was previously shown to be effective in CVST-VITT.^1,11 The higher proportion of women treated with endovascular treatment might be explained by the more severe clinical presentation.

Our study has several limitations. First, the overall number of patients was low, precluding detection of significant differences, robust statistical comparisons and outcome analyses. Second, there was no central adjudication of reported data, as they have been collected from clinical routine records. Third, local funding and ethical constraints may have influenced the decision to participate in the study, and hence affected the actual consecutiveness of participating centers and reported cases.

In conclusion, in this international cohort, more women than men were reported with CVST-VITT. More women presented with more severe thrombocytopenia and coma compared to men and the nadir platelet count was lower in women. VITT-specific treatments were overall similar. Despite the more severe clinical presentation in women, clinical course and outcome did not differ between women and men.

Supplemental Material

sj-docx-1-eso-10.1177_23969873231185213 – Supplemental material for Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID- 19

Supplemental material, sj-docx-1-eso-10.1177_23969873231185213 for Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID-19 by Adrian Scutelnic, Anita van de Munckhof, Katarzyna Krzywicka, Mayte Sánchez van Kammen, Erik Lindgren, Charlotte Cordonnier, Timothy J Kleinig, Thalia S Field, Sven Poli, Robin Lemmens, Saskia Middeldorp, Sanjith Aaron, Afshin Borhani-Haghighi, Antonio Arauz, Johanna A Kremer Hovinga, Albrecht Günther, Jukka Putaala, Mohammad Wasay, Adriana Bastos Conforto, Diana Aguiar de Sousa, Katarina Jood, Turgut Tatlisumak, José M Ferro, Jonathan M Coutinho, Marcel Arnold, Mirjam R Heldner

Footnotes

Acknowledgements

None

**The Thrombosis with Thrombocytopenia Syndrome Study Group

Kateryna Antonenko¹, Joshua Mbroh², Justine Brodard³, Etrat Hooshmandi⁴, Vanessa Dizonno⁵, Annemie Devroye⁶, Alfonso Ciccone⁷, Matthias Wittstock⁸, Julian Zimmermann⁸, Felix J. Bode⁹, Mona Skjelland¹⁰, Jiangang Duan¹¹, Sini Hiltunen¹², Susanna M. Zuurbier¹³, Marco Petruzzellis¹⁴, Aarti R. Sharma¹⁵, Abdoreza Ghoreishi¹⁶, Ahmed Elkady¹⁷, Alberto Negro¹⁸, Alexander Gutschalk¹⁹, Silvia Schoenenberger¹⁹, Simon Nagel¹⁹, Alina Buture²⁰, Alvaro Cervera²¹, Ana Paiva Nunes²², Ana Romina Montané Baños²³, Andreas Tiede²⁴, Anemon Puthuppallil²⁵, Anil M. Tuladhar²⁶, Annerose Mengel², Antonio Medina²⁷, Åslög Hellström Vogel²⁸, Audrey Tawa²⁹, Avinash Aujayeb³⁰, Balakrishnan Ramasamy³¹, Barbara Casolla³², Beng Lim Alvin Chew³³, Bentalhoda Ziaadini³⁴, Boby Varkey Maramattom³⁵, Brian Buck³⁶, Carla Zanferrari³⁷, Carlos Garcia-Esperon³⁸, Caroline Vayne³⁹, Catherine Legault⁴⁰, Christian Jacobi⁴¹, Christian Pfrepper⁴², Johann Pelz⁴², Christoph Wahl⁴³, Rolf Kern⁴³, Clement Tracol⁴⁴, Cristina Soriano⁴⁵, Daniel Guisado-Alonso⁴⁶, David Bougon⁴⁷; Deepti Bal⁴⁸, Domenico Sergio Zimatore⁴⁹, Dominik Michalski⁴², Dylan Blacquiere⁴⁸, Elias Johansson^50,51, Elisa Cuadrado-Godia⁵², Elyar Sadeghi-Hokmabadi⁵³, Emmanuel Carrera⁵⁴, Emmanuel De Maistre⁵⁵, Espen Saxhaug Kristoffersen⁵⁶, Fabrice Bonneville⁵⁷, Thomas Geeraerts⁵⁷, Fabrice Vuillier⁵⁸, Fabrizio Giammello⁵⁹, Florindo D’Onofrio⁶⁰, Francesco Grillo⁶¹, François Caparros⁶², Sophie Susen⁶², Frank Maier⁶³, Georgios Tsivgoulis⁶⁴, Giosue Gulli⁶⁵, Giovanni Frisullo⁶⁶, Guillaume Franchineau⁶⁷, Hakan Cangür⁶⁸, Hans Katzberg⁶⁹, Hossein Mozhdehipanah⁷⁰, Igor Sibon⁷¹, M. Irem Baharoglu⁷², Jaime Masjuan⁷³, Jaskiran Brar⁷⁴, Jean-Francois Payen⁷⁵, Jim Burrow⁷⁶, João Fernandes⁷⁷, Jorge Octavio López Esparza⁷⁸, Joyce Oen⁷⁹, Judith Schouten⁸⁰, Karl Ng⁸¹, Sophie Chatterton⁸¹, Miriam Wronski⁸¹, Katharina Althaus⁸², Katia Garambois⁸³, Laurent Derex⁸⁴, Laurent Puy⁶², Leila Poorsaadat⁸⁵, Lenise Valler⁸⁶, Letícia Januzi de Almeida Rocha⁸⁷, Lisa Humbertjean⁸⁸, Lucia Lebrato Hernandez⁸⁹, Luis Murillo-Bonilla⁹⁰, Lukas Kellermair⁹¹, Mar Morin Martin⁹², Maria Sofia Cotelli⁹³, Maria Hernandez Perez⁹⁴, Marialuisa Zedde⁹⁵, Mariana Carvalho Dias⁹⁶, Marie-Cecile Dubois⁹⁷, Marta Carvalho⁹⁸, Masoud Ghiasian⁹⁹, Meenakshisundaram Umaiorubahan¹⁰⁰, Ravi Kumar Karunakaran¹⁰⁰, Mehrdad Roozbeh¹⁰¹, Michele Romoli¹⁰², Miguel Miranda¹⁰³, Mohammad Saadatnia¹⁰⁴, Monica Bandettini di Poggio¹⁰⁵, Moritz J. Scholz¹⁰⁶, Robert Kahnis¹⁰⁶, Mostafa Almasi-Dooghaee¹⁰⁷, Nahid Hoseininejad Mir¹⁰⁸, Nasli R. Ichaporia¹⁰⁹, Naveen Kumar Paramasivan¹¹⁰, Sapna Erat Sreedharan¹¹⁰, PN Sylaja¹¹⁰, Nicolas Raposo¹¹¹, Nima Fadakar⁴, Nyika Kruyt¹¹², Olivier Detante¹¹³, Pauline Cuisenier¹¹³, Olivier Huet¹¹⁴, Pankaj Sharma¹¹⁵, Paolo Candelaresi¹¹⁶, Pasquale Scoppettuolo¹¹⁷, Peggy Reiner¹¹⁸, Reza Nemati¹¹⁹, Ricardo Vieira¹²⁰, Rudy Goh¹²¹, Seán Murphy²⁰, Serge Timsit¹²², Shelagh Coutts¹²³, Shyam S. Sharma¹²⁴, Simerpreet Bal¹²⁴, Subhash Kaul¹²⁵, Theodoros Karapanayiotides¹²⁶, Thomas Cox¹²⁷, Thomas Gattringer¹²⁸, Thomas Mathew¹²⁹, Thorsten Bartsch¹³⁰, Vahid Shaygannejad¹³¹, Veronica Garcia-Talavera¹³², Vincenzo Palma¹³³, Yıldız Arslan¹³⁴, Zahra Mirzaasgari¹³⁵, Zeinab Yavari¹³⁶, Zohreh Zamani¹³⁷, Tamam Bakchoul¹³⁸, Marcel Levi¹³⁹, Eric C.M. van Gorp¹⁴⁰

¹Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

² Department of Neurology & Stroke, University Hospital Tuebingen, Eberhard-Karls University, Tuebingen, Germany

³Department of Hematology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

⁴ Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

⁵University of British Columbia, Vancouver, Canada

⁶ Department of Neurology, University Hospitals Leuven, Leuven, Belgium

⁷Department of Neurology, Carlo Poma Hospital, Azienda Socio Sanitaria Territoriale di Mantova, Mantua, Italy

⁸University Medicine Rostock, Rostock, Germany

⁹Universitätsklinikum Bonn, Bonn, Germany

¹⁰Oslo University Hospital, Oslo, Norway

¹¹Department of Neurology and Emergency, Xuanwu Hospital, Capital Medical University, Beijing, China

¹²Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland

¹³Department of Neurology, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, The Netherlands

¹⁴AOU Consorziale Policlinico di Bari, Bari, Italy

¹⁵Imperial College School of Medicine, London, United Kingdom

¹⁶Stroke Research Group, Head of Stroke Care Unit, Department of Neurology, Vali-e-Asr Hospital, School of Medicine, Zanjan University of Medical Sciences, Iran

¹⁷Saudi German Hospital, Jeddah, Saudi Arabia

¹⁸Ospedale del Mare, Naples, Italy

¹⁹Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany;

²⁰Mater Misericordiae University Hospital, Dublin, Ireland

²¹Royal Darwin Hospital, Tiwi, Australia

²²Lisbon Central University Hospital and Faculdade de Medicina da Universidade de Lisboa

²³Queretaro General Hospital, Santiago de Querétaro, Mexico

²⁴Hannover Medical School, Hannover, Germany

²⁵Hamilton General Hospital, Hamilton, Canada

²⁶Radboud University Medical Center, Department of Neurology, Donders Center for Medical Neurosciences, Nijmegen, The Netherlands

²⁷Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain

²⁸Skåne University Hospital, Lund, Sweden;

²⁹University Hospital of Rennes, Rennes, France;

³⁰ Northumbria Healthcare NHS Foundation Trust, Cramlington, United Kingdom;

³¹PSG Institute of Medical Sciences and Research, Coimbatore, Tamil Nadu, India;

³²Stroke Unit, Hôpital Pasteur 2, URRIS-UR2CA, Unité de Recherche Clinique Cote d’Azur, Cote d’Azur University, Nice, France;

³³Department of Neurology, John Hunter Hospital, Newcastle, Australia;

³⁴Neurology Research Center, Kerman University of Medical Sciences, Kerman, Iran;

³⁵Aster Medcity, Kochi, Kerala, India;

³⁶University of Alberta Hospital, Edmonton, Canada;

³⁷Neurology and Stroke Unit, ASST Melegnano e della Martesana - Milan – Italy

³⁸John Hunter Hospital, New Lambton Heights, Australia;

³⁹Tours University Hospital, Tours, France;

⁴⁰McGill University Health Centre, Montreal, Canada;

⁴¹Department of Neurology, Krankenhaus Nordwest, Frankfurt am Main, Germany;

⁴²Leipzig University Hospital, Leipzig, Germany;

⁴³Kempten Hospital, Kempten, Germany;

⁴⁴CHU Rennes, Rennes, France;

⁴⁵Hospital General de Castellón, Castelló, Spain;

⁴⁶Hospital de La Santa Creu I Sant Pau, Barcelona, Spain;

⁴⁷Annecy Genevois Hospital, Annecy, France;

⁴⁸The Ottawa Hospital, Ottawa, Canada;

⁴⁹Policlinico di Bari, Bari, Italy;

⁵⁰Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden and Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden

⁵¹Department of Clinical Science, Umeå University, Umeå, Sweden;

⁵²Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain;

⁵³NeuroSciences Research Center (NSRC), Imam-Reza hospital, Tabriz University of Medical Sciences, Tabriz, Iran;

⁵⁴Hôpitaux Universitaires de Genève, Geneva, Switzerland;

⁵⁵CHU Dijon, Dijon, France;

⁵⁶Department of Neurology, Akershus University Hospital, Lorenskog, Norway;

⁵⁷Toulouse University Hospital, Toulouse, France;

⁵⁸University Hospital of Besancon, Besancon, France;

⁵⁹Translational Molecular Medicine and Surgery 36th Cycle, Department of BIOMORF, Stroke Unit, Department of Clinical and Experimental Medicine, University Hospital G. Martino, Messina, Italy;

⁶⁰San Giuseppe Moscati Hospital, Avellino, Italy;

⁶¹University Hospital G. Martino, Messina, Italy;

⁶²Université Lille, INSERM, Centre Hospitalier Universitaire (CHU) Lille, U1172–Lille Neuroscience and Cognition, Lille, France⁶³ Caritas Hospital Saarbrücken, Saarbrücken, Germany;

⁶⁴Second Department of Neurology, National & Kapodistrian University of Athens, School of Medicine, Athens, Greece;

⁶⁵Ashford and St Peters Hospital NHS Foundation Trust, Surrey, United Kingdom;

⁶⁶Department of Neurology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy;

⁶⁷Centre Hospitalier Intercommunal de Poissy Saint Germain en Laye, Poissy, France;

⁶⁸Hospital of the city of Wolfsburg, Wolfsburg, Germany;

⁶⁹Toronto General Hospital, Toronto, Canada;

⁷⁰Department of Neurology, Bouali University Hospital, Qazvin, Iran;

⁷¹Bordeaux University Hospital, Bordeaux, France;

⁷²Haaglanden Medisch Centrum, The Hague, Netherlands;

⁷³Ramón y Cajal Hospital, Madrid, Spain;

⁷⁴Surrey Memorial Hospital, Surrey, Canada;

⁷⁵CHU Grenoble, Grenoble, France;

⁷⁶Royal Darwin Hospital, Tiwi, Australia;

⁷⁷Norra Älvsborgs Länssjukhus, Trollhättan, Sweden;

⁷⁸Centenario Hospital Miguel Hidalgo, Aguascalientes, México;

⁷⁹Department of Neurology, Antonius Ziekenhuis, Sneek, The Netherlands;

⁸⁰Rijnstate Hospital Arnhem, Arnhem, The Netherlands;

⁸¹Department of Neurology, Royal North Shore Hospital, Sydney, Australia;

⁸²Ulm University Hospital, Ulm, Germany;

⁸³University Hospital of Grenoble, Grenoble, France;

⁸⁴Hospices Civils de Lyon, Lyon, France;

⁸⁵Department of Neurology, Arak University of Medical Sciences, Arak, Iran;

⁸⁶UNICAMP Universidade Estadual de Campinas, Campinas, Brazil;

⁸⁷Hospital Universitário Professor Alberto Antunes, Universidade Federal de Alagoas (HUPAA/UFAL/EBSERH), Maceió, Brazil

⁸⁸University Hospital of Nancy, Nancy, France;

⁸⁹Virgen del Rocio University Hospital, Seville, Spain;

⁹⁰Instituto Panvascular de Occidente, Guadalajara, Jalisco, México;

⁹¹Johannes Kepler University Linz, Linz, Austria;

⁹²Hospital complex of Toledo, Toledo, Spain;

⁹³Neurology Unit ASST Valcamonica, Esine, Brescia-Italy;

⁹⁴Stroke Unit, Department of Neurosciences, Germans Trias i Pujol University Hospital, Badalona, Spain;

⁹⁵Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy;

⁹⁶Department of Neurosciences and Mental Health, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte, University of Lisbon, Lisbon, Portugal;

⁹⁷University Hospital of Poitiers, Poitiers, France;

⁹⁸Department of Neurology, Centro Hospitalar Universitario São João and Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Portugal;

⁹⁹Sina Hospital, Hamadan University of Medical Sciences, Hamadan, Iran;

¹⁰⁰Institute of Neurosciences, SIMS hospital, Chennai, Tamil Nadu, India;

¹⁰¹Brain Mapping Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran;

¹⁰²Neurology and Stroke Unit, Department of Neuroscience, Bufalini Hospital, Cesena, Italy;

¹⁰³Hospital de Cascais Dr. José de Almeida, Cascais, Portugal;

¹⁰⁴Isfahan Neurosciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran;

¹⁰⁵IRCSS Ospedale Policlinico San Martino, Genoa, Italy;

¹⁰⁶Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany;

¹⁰⁷Firoozgar hospital, School of Medicine, Iran University of Medical sciences, Tehran, Iran;

¹⁰⁸Department of Neurology, Lorestan University of Medical Sciences, Khorramabad, Iran;

¹⁰⁹Sahyadri Superpeciality Hospital, Pune, Maharashtra, India;

¹¹⁰Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India;

¹¹¹Department of Neurology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France;

¹¹²Leiden University Medical Centre, Leiden, The Netherlands;

¹¹³Department of Neurology, CHU Grenoble Alpes, Grenoble, France;

¹¹⁴Hospital de la Cavale Blanche, CHRU de Brest, Brest, France;

¹¹⁵Institute of Cardiovascular Disease, Royal Holloway University of London, London, United Kingdom;

¹¹⁶Neurology and Stroke Unit, Cardarelli Hospital, Naples, Italy;

¹¹⁷Department of Neurology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Hippocrate 10, 1200, Brussels, Belgium;

¹¹⁸Lariboisière Hospital, Neurology Department, Assistance Publique Hopitaux de Paris, France;

¹¹⁹Department of Neurology, Bushehr University of medical science, Bushehr, Iran;

¹²⁰Universidade Federal do Cariri, Juazeiro do Norte, Brazil;

¹²¹Department of Neurology, Royal Adelaide Hospital, Adelaide, Australia

¹²²Department of Neurology & stroke unit, Hôpital de la Cavale Blanche, CHRU de Brest (University Hospital), Université de Bretagne Occidentale, Inserm1078, Brest, France;

¹²³Foothills Medical Centre, Calgary, Canada;

¹²⁴Edinburgh Medical School, University of Edinburgh, Edinburgh, Scotland;¹²⁵KIMS Hospital, Hyderabad, Telangana, India;

¹²⁶2nd Department of Neurology, Aristotle University of Thessaloniki, School of Medicine, AHEPA University Hospital, Greece;

¹²⁷University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom;

¹²⁸Department of Neurology and Division of Neuroradiology, Vascular and Interventional Radiology, Department of Radiology, Medical University of Graz, Austria;

¹²⁹St John’s Medical College Hospital, Bengaluru, Karnataka, India;

¹³⁰Dept. of Neurology, University Medical Center Schleswig-Holstein, Campus Kiel, Germany;

¹³¹Isfahan University of Medical Sciences (IUMS) and Isfahan Neurosciences Research Center (INRC), Isfahan, Iran;

¹³²Unidad medica de alta especialidad No. 25. Monterrey Nuevo León, Mexico;

¹³³Department of Neurology, Stroke Unit, Ospedale del Mare, ASL Napoli 1 Centro, Napoli, Italy;

¹³⁴Medicana İzmir International Hospital, Izmir, Turkey;

¹³⁵Department of Neurology, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran;

¹³⁶Neurology, public Imam Hossein Hospital, Kermanshah, Iran;

¹³⁷Department of Neurology, Firoozabadi Hospital, Iran University of Medical Sciences, Tehran, Iran;

¹³⁸Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tuebingen, University Hospital of Tuebingen, Tuebingen, Germany;

¹³⁹Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands;

¹⁴⁰Department of Viroscience, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.S. has received a grant from Swiss Heart Foundation; C.C. has received speaker honoraria from Boehringer Ingelheim, personal fees for advisory board participation from AstraZeneca and Biogen, and personal fees for steering committee participation from Biogen and Bristol Myers Squibb; T.J.K. has received educational meeting cost assistance from Boehringer Ingelheim; T.S.F. receives in-kind study medication from Bayer Canada and advisory board honoraria from HLS Therapeutics; S.P. received research support from BMS/Pfizer, Boehringer-Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, Helena Laboratories and Werfen as well as speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen (all outside the submitted work); R.L. reports fees paid to his institution for consultancy by Boehringer Ingelheim, Genentech, Ischemaview, Medtronic and Medpass; E.L. has received academic grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG 942851), Swedish Neurologic Society, Elsa and Gustav Lindh’s Foundation, Wennerströms’ Foundation, P-O Ahl’s Foundation and Rune and Ulla Amlöv’s Foundation for research on CVT; A.C. received speaker grants from Alexion Pharma, Italfarmaco, and Daiichi-Sankyo; M.W. has received consulting fees from Portola/Alexion; C.J. has received speaker honoraria from Alexion, CSL Behring, TEVA and Sanofi Genzyme, personal fees for advisory board participation from Alexion, Roche, Novartis and Merck Serono; H.K. has received personal fees for consulting and data safety monitoring board activities for Octapharma, Grifols, CSL Behring, UCB, Argenx, Takaeda, Alexion and his institution has received clinical trial support from Takaeda; S.N. has received consulting fees from Brainomix and lecture fees from Boehringer Ingelheim and BMS Pfizer; T.G. has received travel grants and speaker honoraria from Boehringer Ingelheim, Bayer, Novartis, BMS / Pfizer and Alexion; A.G. has received personal fees from Bayer Vital, Bristol Myers Squibb, and Daiichi Sankyo; K.J. has received academic grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG 965417) for research on CVT; T.T. has received personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva, and Portola Pharma; D.A.S. reports travel support from Boehringer Ingelheim, speaker fees from Bayer, and Advisory Board participation for AstraZeneca; J.M.F. has received personal fees from Boehringer Ingelheim, Bayer, and Daiichi Sankyo as well as grants from Bayer; J.M.C. has received grants paid to his institution from Boehringer Ingelheim and Bayer, and payments paid to his institution for data safety monitoring board participation by Bayer; M.A. reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Covidien, Daiichi Sankyo, Medtronic, Novartis, Pfizer, and Amgen; M.R.H. reports grants from the Swiss Heart Foundation and from the Bangerter Foundation, and Advisory Board participation for Amgen. All other authors have nothing to disclose.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by The Netherlands Organisation for Health Research and Development (ZonMw, grant number 10430072110005), the Dr. C.J. Vaillant Foundation, and Hospital District of Helsinki and Uusimaa (grant TYH2022223).

Informed consent

Not applicable

Ethical approval

The ethical review committee of the Academic Medical Center in Amsterdam approved this study. Each center was responsible for obtaining permission from local authorities if required by national and local law.

Guarantor

M.A.

Contributorship

Conceptualization: M.A., M.R.H., J.M.C., J.M.F., A.S, A.M.. Methodology: M.A., M.R.H., A.M., A.S., J.M.F., J.M.C. Validation: A.M., A.S.. Formal analysis: A.S., A.M.. Investigation: All authors. Resources: J.M.C. Data Curation: A.M., K.K., M.S.K. Writing-Original Draft: A.S., A.M., J.M.F., J.M.C., M.R.H., M.A. Writing-Review & Editing: All authors. Visualization: A.S., A.M., J.M.F., J.M.C., M.A., M.R.H.. Supervision: M.A., M.R.H., D.A.S., K.J., S.P., J.P., T.T., J.M.F., J.M.C.. Project administration: A.M., A.S., K.K., M.S.K., S.P., A.S., E.L., A.G., K.J., T.T., M.R.H., M.A., D.A.S., J.M.F., J.M.C. Funding acquisition: J.P., J.M.C., A.S., A.M., M.R.H. and M.A. directly accessed and verified the underlying data reported in the manuscript.

ORCID iDs

Adrian Scutelnic

Timothy J Kleinig

Diana Aguiar de Sousa

Data sharing

The de-identified, individual participant data that underlie the results reported in this article can be made available to investigators whose proposed use of the data has been approved by the International Cerebral Venous Thrombosis Consortium Leadership. Proposals should be directed to the study’s Principal Investigator (Dr. Jonathan Coutinho, email: j.coutinho@amsterdamumc.nl).

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