Outcomes of Cerebral Venous Thrombosis due to Vaccine-Induced Immune Thrombotic Thrombocytopenia After the Acute Phase.

BACKGROUND: Cerebral venous thrombosis (CVT) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe condition, with high in-hospital mortality rates. Here, we report clinical outcomes of patients with CVT-VITT after SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccination who survived initial hospitalization.
METHODS: We used data from an international registry of patients who developed CVT within 28 days of SARS-CoV-2 vaccination, collected until February 10, 2022. VITT diagnosis was classified based on the Pavord criteria. Outcomes were mortality, functional independence (modified Rankin Scale score 0-2), VITT relapse, new thrombosis, and bleeding events (all after discharge from initial hospitalization).
RESULTS: Of 107 CVT-VITT cases, 43 (40%) died during initial hospitalization. Of the remaining 64 patients, follow-up data were available for 60 (94%) patients (37 definite VITT, 9 probable VITT, and 14 possible VITT). Median age was 40 years and 45/60 (75%) patients were women. Median follow-up time was 150 days (interquartile range, 94-194). Two patients died during follow-up (3% [95% CI, 1%-11%). Functional independence was achieved by 53/60 (88% [95% CI, 78%-94%]) patients. No new venous or arterial thrombotic events were reported. One patient developed a major bleeding during follow-up (fatal intracerebral bleed).
CONCLUSIONS: In contrast to the high mortality of CVT-VITT in the acute phase, mortality among patients who survived the initial hospitalization was low, new thrombotic events did not occur, and bleeding events were rare. Approximately 9 out of 10 CVT-VITT patients who survived the acute phase were functionally independent at follow-up.

Cerebral venous thrombosis (CVT) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse event of adenovirus-based SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccines.[1-3] CVT-VITT has substantially higher in-hospital mortality rates (20%–50%), compared with CVT unrelated to VITT (4%).[2-4] We aimed to report clinical and functional outcomes of patients with CVT-VITT who survived initial hospitalization.

Methods

We used data from an international registry on CVT after COVID-19 vaccination collected until February 10, 2022. Details have been described.[3] Inclusion criteria were radiologically or autopsy-confirmed CVT and symptom onset within 28 days of any SARS-CoV-2 vaccine. The ethical review committee of Amsterdam UMC waived formal approval for this observational study. This article follows the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines. Original data are available upon reasonable request.

VITT classification was based on the Pavord criteria[2] (Table S1). We included cases with definite, probable, or possible CVT-VITT. We excluded CVT-VITT patients who died during initial hospitalization, patients with missing follow-up data, and cases with CVT after mRNA vaccines, which do not cause VITT.[5]

We used the information from the last available visit. Outcome measures were mortality, functional independence (modified Rankin Scale score 0–2), VITT relapse after initial clinical remission, new thrombosis, and new major bleeding events according to the criteria of the International Society on Thrombosis and Haemostasis.

Clinical remission was defined as fulfilling the following criteria at any time during follow-up: (1) platelet count >150×109/L; (2) no clinical evidence of new or progressive ischemic organ injury; and (3) no immunomodulatory treatment for 30 days. Relapse was defined as a decrease in platelet count to <150×109/L (with other causes of thrombocytopenia ruled out), with or without clinical evidence of new ischemic organ injury, at any time after achieving clinical remission.

We calculated 95% CI using Wilson score method for main outcomes. Analyses were performed with IBM SPSS Statistics, version 28.0.1.0, RStudio version 1.3.1093 and R version 4.0.3 using the Hmisc package.

Results

Of 208 reported cases, 107 had CVT-VITT. In total, 43 (40%) died during initial hospitalization (Figure S1 and Table S2). Of the remaining 64 patients, follow-up data were available for 60 (94%) patients: 37 (62%) with definite VITT, 9 (15%) probable VITT, and 14 (23%) possible VITT.

Median age was 40 years (interquartile range, 27–56) and 45/60 (75%) patients were women (Table 1). Median follow-up time was 150 days (interquartile range, 94–194, Table 2). Two patients died during follow-up (3% [95% CI, 1%–11%]): one due to a new intracerebral hemorrhage and one of unknown causes (details in Table S3). The latter patient had a new thrombocytopenia during readmission for a COVID-19 infection, fulfilling the criteria for a VITT relapse. No other relapses or bleeding events were reported. No new venous or arterial thrombotic events were reported in any patient. Hospital readmission occurred in 9/54 (17%) cases, 4 of which were for a planned cranioplasty following decompressive hemicraniectomy (Table 2).

Table 1.

Patient Details of Initial Hospitalization

Table 2.

Outcomes of Patients Who Survived the Acute Phase of CVT-VITT

Functional independence was achieved by 53/60 (88% [95% CI, 78%–94%]) patients at follow-up, compared with 41/58 (71% [95% CI, 58%–81%]) at hospital discharge (Figure and Figure S2). Overall, 21/40 (53%) patients had returned to work or school at follow-up.

Modified Rankin Scale (mRS) score of 60 patients with cerebral venous thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVT-VITT) who survived the acute phase, at discharge and at follow-up. Note that CVT-VITT patients who died during initial hospitalization (43/107, 40%) are not included in the Figure. There are 2 missing mRS scores at discharge; both had mRS 0 at follow-up.

Platelet count at follow-up was available for 39/60 (65%) patients, details of which are provided in Figure S3. At least one D-dimer value at follow-up was available for 27/60 (45%) CVT-VITT patients. D-dimer levels declined from >4 mg/L in the acute phase to ≤0.5 mg/L at follow-up in 19/27 (70%) patients (Figure S4).

Discussion

This study indicates that—in sharp contrast to the high mortality rate during the acute phase—mortality of patients with CVT-VITT who survive initial hospitalization is low and new thrombotic and bleeding events rarely occur after discharge. Almost 90% of patients who survived the acute phase were functionally independent at follow-up and half of the patients had returned to work and/or school. One VITT relapse was reported, although not all patients had achieved clinical remission of VITT at follow-up.

The proportion of patients in our study who were functionally independent at follow-up is comparable to the proportion of patients with long-term functional independence after CVT not related to VITT, as reported in the ISCVT (International Study on Cerebral Vein and Dural Sinus Thrombosis; 88% versus 89%, respectively).[4] The low number of adverse outcomes in surviving CVT-VITT patients may be explained by the fact that anti-PF4 (platelet factor 4) antibodies, which cause VITT,[1] are transient.[6] With the disappearance of the anti-PF4 antibodies, the triggering factor for VITT may have resolved.

In a study on the immune type of heparin-induced thrombocytopenia, a disorder that resembles VITT,[1] 5/28 (18%) patients developed new venous or arterial thrombosis.[7] A systematic review on CVT due to heparin-induced thrombocytopenia reported full recovery in only 4/18 (22%) cases, while all other cases had neurological sequelae.[8] The higher median age of the patients with CVT due to heparin-induced thrombocytopenia may be one of the explanatory factors for the worse outcome.

This study has limitations. First, because data were collected as part of routine clinical care, duration of follow-up varied and there was no central adjudication of study outcomes. In addition, laboratory tests were often not repeated during follow-up. Second, while follow-up rate was over 90%, we cannot exclude the possibility that clinical events occurred in the 4 patients for which follow-up was missing. Third, the median time from diagnosis to follow-up was ≈5 months. In CVT not related to VITT, recovery can occur up to 1 year after diagnosis, which may indicate that the CVT-VITT patients in this study may still recover further.[4]

In summary, in contrast to the severity of CVT-VITT during the acute phase, mortality of patients who survived initial hospital admission was low and new thrombotic and bleeding events were rare. Approximately 9 out of 10 CVT-VITT survivors were functionally independent at follow-up.

Article Information

Acknowledgments

The conceptualization was done by Drs Jood, Tatlisumak, Heldner, Arnold, Aguiar de Sousa, Ferro, and Coutinho. The methodology was done by Drs van de Munckhof, Lindgren, Ferro, and Coutinho. The validation was done by Dr van de Munckhof. The formal analysis was done by Dr van de Munckhof. The investigation was done by all authors. The resources were done by Drs Ferro and Coutinho. The data curation was done by Drs van de Munckhof, Krzywicka, and Sánchez van Kammen. The writing-original drafted by Drs van de Munckhof, Lindgren, Ferro, and Coutinho. The writing-review and editing were done by all authors. The visualization was done by Drs van de Munckhof, Lindgren, Ferro, and Coutinho. The supervision was done by Drs Ferro and Coutinho. The project administration was done by Drs van de Munckhof, Lindgren, Krzywicka, Poli, Sánchez van Kammen, Scutelnic, Günther, Jood, Tatlisumak, Heldner, Arnold, Aguiar de Sousa, Ferro, and Coutinho. The funding acquisition by Drs Putaala and Coutinho. Drs van de Munckhof and Coutinho had full access to the data in the study and take responsibility for the accuracy of the data analysis.

Sources of Funding

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).

Disclosures

Dr Lindgren 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 Neurological Society, Elsa and Gustav Lindh’s Foundation, Wennerströms’ Foundation, P-O Ahl’s Foundation and Rune and Ulla Amlöv’s Foundation for research on cerebral venous thrombosis (CVT). Dr Kleinig has received educational meeting cost assistance from Boehringer Ingelheim. Dr Field receives in-kind study medication from Bayer Canada, advisory board honoraria from HLS Therapeutics, compensation from BMS-Pfizer for consultant services, grants from Heart and Stroke Foundation of Canada, stock holdings in Destine Health, and service as Board Member for Destine Health. Dr Cordonnier 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. Dr Poli 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). Dr Lemmens reports fees paid to his institution for consultancy by Boehringer Ingelheim, Genentech, Ischemaview, Medtronic, and Medpass. Dr Scutelnic has received a grant from Swiss Heart Foundation. Dr Ciccone received speaker grants from Alexion Pharma, Italfarmaco, and Daiichi Sankyo. Dr Gattringer has received travel grants and speaker honoraria from Boehringer Ingelheim, Bayer, Novartis, BMS/Pfizer, and Alexion. Dr Wittstock has received consulting fees from Portola/Alexion. Dr Günther has received personal fees from Bayer Vital, Bristol Myers Squibb, and Daiichi Sankyo, and compensation from Boehringer Ingelheim, Ipsen Pharma SAS, and PFIZER PHARMA GMBH for other services. Dr Jacobi has received speaker honoraria from Alexion, CSL Behring, TEVA, and Sanofi-Aventis and personal fees for advisory board participation from Alexion, Roche, Sanofi-Aventis, and Merck Serono. Dr Johansson reports grants from Hjärt-Lungfonden, STROKE-Riksförbundet, Knut och Alice Wallenbergs Stiftelse, Jeanssons Stiftelser, the Research fund for Neurological Research at the University Hospital of Northern Sweden, The Northern Swedish fund for stroke research, Region Västerbotten, and the research fund at Umeå University. Dr Katzberg has received personal fees for consulting and data safety monitoring board activities for Octapharma, Grifols, CSL Behring, UCB, Argenx, Takaeda, and Alexion, compensation from Alnylam Pharmaceuticals and Merz Pharma (Schweiz) AG for consultant services, and his institution has received clinical trial support from Takaeda. Dr Nagel has received consulting fees from Brainomix and lecture fees from Boehringer Ingelheim and BMS-Pfizer. Dr Middeldorp reports grants from Bayer, Pfizer, Boehringer Ingelheim, and Daiichi Sankyo paid to her institution, personal fees from Bayer, BMS/Pfizer, Boehringer Ingelheim, Abbvie, Portola/Alexion, and Daiichi Sankyo paid to her institution, and compensation from Sanofi and Viatris for other services. Dr Jood 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. Dr Tatlisumak has received personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva, and Portola Pharma. Dr Heldner reports grants from the Swiss Heart Foundation, the Bangerter Foundation, Swiss National Science Foundation, and SITEM Research Funds, and Advisory Board participation for Amgen. Dr Arnold reports compensation from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Covidien, Daiichi Sankyo, Novartis, Sanofi, Pfizer, Medtronic and research grants from the Swiss National Science Foundation and the Swiss Heart Foundation. Dr Aguiar de Sousa reports travel support from Boehringer Ingelheim, speaker fees from Bayer, Advisory Board participation for AstraZeneca, compensation from University of British Columbia for data and safety monitoring services, and compensation from Faculdade de Medicina da Universidade de Lisboa for other services. Dr Ferro has received personal fees from Boehringer Ingelheim, Bayer, and Daiichi Sankyo as well as grants from Bayer. Dr Coutinho has received grants paid to his institution from Boehringer Ingelheim, Medtronic, and Bayer, compensation from PORTOLA PHARMACEUTICALS LLC for consultant services, and payments paid to his institution for data safety monitoring board participation by Bayer. The other authors report no conflicts.

Supplemental Material

Figures S1–S4

Tables S1–S3

References 9,10