key: cord-0889040-51uw18qh
authors: Kim, Ah Young; Woo, Wongi; Yon, Dong Keon; Lee, Seung Won; Yang, Jae Won; Kim, Ji Hong; Park, Seoyeon; Koyanagi, Ai; Kim, Min Seo; Lee, Sungsoo; Shin, Jae Il; Smith, Lee
title: Thrombosis patterns and clinical outcome of COVID-19 vaccine-induced immune thrombotic thrombocytopenia: A Systematic Review and Meta-Analysis
date: 2022-03-24
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2022.03.034
sha: 9e14c6f5ab5109a13558a35399c7e2cec1e4fa8f
doc_id: 889040
cord_uid: 51uw18qh

Objectives To meta-analyze the clinical manifestations, diagnosis, treatment, and mortality of vaccine-induced immune thrombotic thrombocytopaenia (VITT) after adenoviral vector vaccination. Methods Eighteen studies of VITT after ChAdOx1 nCoV-19 or Ad26.COV2.S vaccine administration were reviewed from PubMed, Scopus, Embase, and Web of Science. The meta-analysis estimated the summary effects and between-study heterogeneity regarding the incidence, manifestations, sites of thrombosis, diagnostic findings, and clinical outcomes. Results The incidence of total venous thrombosis after ChAdOx1 nCoV-19 was 28 (95% CI 12-52, I2=100%) per 100,000 doses administered. Of 664 patients in quantitative analysis (10 studies), the mean age of VITT patients was 45.6 years (95% CI 43.8-47.4, I2=57%), with a female predominance (70%). Cerebral venous thrombosis (CVT), deep vein thrombosis (DVT)/pulmonary thromboembolism (PE), and splanchnic vein thrombosis occurred in 54%, 36%, 19% of VITT patients, respectively. The pooled incidence rate of cerebral venous thrombosis after ChAdOx1 nCoV-19 (23 per 100,000 person-years) was higher than the pre-pandemic rate (0.9 per 100,000 person-years). Intracranial haemorrhage and extracranial thrombosis accompanied 47% and 33% of all CVT patients, respectively. The antiplatelet factor 4 (anti-PF4) antibody positivity rate was 91% (95% CI 88-94, I2=0%) and the overall mortality was 32% (95% CI 24-41, I2=69%), and no significant difference was observed between heparin- and non-heparin-based anticoagulation treatments (risk ratio 0.84, 95% CI 0.47-1.50, I2=0%). Conclusions VITT patients after SARS-CoV-2 vaccination most frequently presented with CVT following DVT/PE and splanchnic vein thrombosis, and about one-third of patients had a fatal outcome. This meta-analysis should provide a better understanding of VITT and assist clinicians in identifying VITT early to improve outcomes and optimize management.

More than 233 million people have been infected with SARS-CoV-2, and 4.7 million people have died from the disease worldwide (as of 1 October 2021). Several vaccines have been developed concerning this public health problem, and 6.2 billion doses have already been administered (COVID-19 Map -Johns Hopkins Coronavirus Resource Center, October 1, 2021) . A phase-III clinical trial of ChAdOx1 nCoV-19 (Oxford-AstraZeneca) included 12,021 participants from the UK, Brazil, and South Africa, and there was no adverse event related to unusual thrombotic events (Voysey et al., 2021) . However, as the ChAdOx1 nCoV-19 vaccination programs expanded, a rare event of extraordinary thrombosis emerged from March 2021 (Greinacher et al., 2021a; Schultz et al., 2021; Scully et al., 2021) . Due to safety concerns related to thrombosis, several European counties reevaluated the eligibility criteria, and many of them did not recommend ChAdOx1nCoV-19 to people under age 50. After receiving more reports from various countries, clinicians named this rare adverse event vaccine-induced immune thrombotic thrombocytopaenia (VITT), which described its similar pathophysiology to heparin-induced thrombocytopaenia (HIT). A similar adverse events was observed in another adenovirus vector vaccine (Ad26.COV2.S; Johnson & Johnson) (See et al., 2021) .

Subsequently, the first case series of VITT was published in April 2021 (Greinacher et al., 2021) , and it suggested the benefit of the antiplatelet factor 4 (anti-PF4) antibody test for diagnosing VITT.

Later, Hwang et al. summarised case reports related to VITT and introduced several prognostic factors related to mortality (Hwang et al., 2021) . However, because of the different clinical environments among studies, it has been challenging to comprehensively describe VITT.

Thus, we conducted a systematic review and meta-analysis to appraise patients' demographics, clinical manifestations, laboratory findings, a pattern of treatments, and mortality for VITT after 6 ChAdOx1 nCoV-19 or Ad26.COV2.S vaccination. We expect our meta-analysis to provide clinicians with a thorough understanding of this rare adverse event.

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for this systematic review (Supplementary Table S1 ), and this study was not registered with PROSPERO due to concerns for idea exposure related to timely important study theme.

Two investigators (A.Y.K. and W.W.) searched PubMed, Scopus, Embase, and Web of Science databases up to 4 October 2021 to identify studies that reported VITT after ChAdOx1 nCoV-19 or Ad26.COV2.S vaccination. Our initial search yielded 725 articles. After a review of individual abstracts and full texts, we identified 18 studies (Abbattista et al., 2021; Gras-Champel et al., 2021; Greinacher et al., 2021b; Hippisley-Cox et al., 2021; Huh et al., 2021; Krzywicka et al., 2021; Pavord et al., 2021; Perry et al., 2021; Pottegård et al., 2021; Rosenblum et al., 2021; Sánchez van Kammen et al., 2021a; Schultz et al., 2021; Schulz et al., 2021; Scully et al., 2021; See et al., 2021; de Simone et al., 2021; Simpson et al., 2021; Tiede et al., 2021) (4 case series, 7 cohort studies, 1 monthly report, 1 brief communication, 2 narrative reviews, 1 observational study, and 2 self-controlled case series) that met our inclusion criteria. The search terms used are described in Supplementary Table S2. Discrepancies regarding the inclusion/exclusion of studies were discussed and resolved by consensus among three investigators (J.I.S., A.Y.K, and W.W.). The full literature search strategy is presented in Supplementary Figure S1. The eligibility criteria for inclusion were as follows: studies in which (1) venous thrombosis, thrombotic thrombocytopenia, or VITT was an adverse event following ChAdOx1 nCoV-19 or Ad26.COV2.S vaccine; (2) cerebral venous thrombosis (CVT) developed after ChAdOx1 nCoV-19 or Ad26.COV2.S vaccine; and (3) an editorial, short survey, or monthly report to identify the most recent comprehensive analysis of incidence was manually added. We excluded (1) studies in which VITT was reported before the COVID-19 pandemic and (2) case series with less than 5 cases, we also excluded (3) review articles, letters to the editors, abstracts, articles that did not contain sufficient information on the patients, and (4) studies with insufficient patients' data. We finally included 18 studies that met the inclusion criteria. Among them, 10 studies with clinical data were subsequently used to analyze clinical manifestations and outcomes. The remaining 8 used to analyze the incidence of VITT. The summary of the findings in included studies are shown in Supplementary   Table S3 .

The inclusion criteria for VITT in each study are described in Supplement Table S4 . All studies suggested several standards such as recent vaccination history, presence of thrombosis, thrombocytopenia, D-dimer level, a result of anti-PF4 antibody test, and additional experts' opinion.

For each eligible clinical trial (or study), we recorded the first author, publication year, journal name, country, a total number of patients, incidence proportion or incidence rate of patients who developed any type of thrombosis, patients' demographics, location of thrombosis, laboratory results, treatment modalities, clinical course, and survival of patients.

The data for each study that was included in the clinical analysis are presented in Table 1 ( Greinacher et al., 2021b; Krzywicka et al., 2021; Pavord et al., 2021; Perry et al., 2021; Sánchez van Kammen et al., 2021a; Schultz et al., 2021; Schulz et al., 2021; Scully et al., 2021; See et al., 2021; Tiede et al., 2021) . To estimate the proportion of VITT patients for each variable, we performed a meta-analysis to estimate the summary effects with a proportion of each variable and 95% confidence interval (CI) using random-effect models (DerSimonian and Laird, 2015; Lau et al., 1997) . The random-effects model provides the weighted average of the effect sizes of a group of studies with the assumption that each study supplies information about a different effect size (Ioannidis et al., 2011) .

We evaluated the between-study heterogeneity using the I 2 metric of inconsistency and P-value of the Cochran Q test. I 2 is the ratio of the between-study variance over the sum of the within-study and between-study variances, and it ranges from 0-100%. I 2 values over 50% usually represent significant heterogeneity (Higgins et al., 2003) .

Publication bias was not assessed because studies included in the proportion meta-analyses were non-comparable except for the mortality comparison between two types of anticoagulation. All analyses were conducted using R version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria).

The pooled incidence of VITT (total venous or cerebral venous thrombosis) after SARS-CoV-2 vaccinations (ChAdOx1 nCoV-19, Ad26.COV2.S) was shown in Figure 1 (Supplementary Figure   S2 [a-d]). The incidence of venous thrombosis after the 1 st dose of ChAdOx1 nCoV-19 was 28(95% CI 12-52) per 100,000 doses administered. The incidence of cerebral venous thrombosis after ChAdOx1 nCoV-19 and Ad26.COV2.S were 0.3 (95% CI 0.1-1.4) and 1.14(95% CI 0.96-1.36) per 100,000 administered doses, respectively. Moreover, the CVT incidence rate after ChAdOx1 nCoV-19 seemed to be higher than the general population, based on the pre-pandemic period's data.

Ten studies investigated the clinical manifestation and treatment outcomes of VITT after ChAdOx1 nCoV-19 or Ad26.COV2.S vaccination (Table 1 and 2). Among them, five studies investigated the overall thrombosis in different sites. Since most VITT cases were identified through its unique infiltration of the cerebral venous system, five studies particularly appraised CVT and its clinical outcome.

The result of the meta-analyses of clinical variables is outlined in Table 3 . Regarding demographic variables, the mean age of all VITT patients was 45.6 years (95% CI 43.8-47.4, k=8, n=599, I 2 =57%, p=0.02), and the percentage of females was 65% by overall estimation and 70% (95% CI 57-80, I 2 =82%) by meta-analysis. Venous thrombosis risk factors, such as cancer, use of oral contraceptives, infection, recent surgery, or thrombophilia, were present in 20% of patients by overall estimation and 27% by meta-analysis, and headaches were noted in 90% of patients by overall estimation and in 89% by meta-analysis (Supplementary Figure S3 Regarding all CVT patients, the rate of accompanying ICH was 48% by overall estimation and 47% by meta-analysis. The rate of extracranial thrombosis was 25% by overall estimation and 33% by meta-analysis, and the pooled proportions of pulmonary thromboembolism, splanchnic vein thrombosis, and aorto-limb arterial thrombosis in CVT patients were 16%, 13%, and 6%, respectively (Supplementary Figure S4 [g-n]).

Supplementary Table S5 describes the pooled-mean laboratory values of all VITT patients. The pooled-mean initial and nadir platelet counts were very low (50.0 ×10 9 /L and 33.2×10 9 /L, respectively) and the prothrombin time was prolonged (13.4 s). The nadir fibrinogen and peak Ddimer levels were 1.6 g/L and 26.3 mg/L, respectively. Of note, the anti-PF4-antibody test was conducted in 7 studies, and the positivity rate was 91% (95% CI 88-94, I 2 =0%) in the meta-analysis ( Figure 3 ).

Non-heparin anticoagulation was administered in 64% of patients by overall estimation and in 65% (95% CI 45-73, I 2 =77%) by meta-analysis, whereas 35% (95% CI 23-48, I 2 =68%) of patients received heparin-based anticoagulation. The pooled proportions of patients treated with intravenous immunoglobulin (IVIG), corticosteroid, platelet transfusion, and intervention were 69%, 44%, 25%, and 30%, respectively (Supplementary Figure S4 [o-u]). Notably, the mortality rate was 30% by overall estimation and 32% (95% CI 24-41, I 2 =69%) by meta-analysis ( Figure 4 ). There was no significant difference in mortality rate between heparin-and non-heparin-based anticoagulation (risk ratio 0.84, 95% CI 0.47-1.50, I 2 =0%, p=0.80; Figure 5 ) based on the meta-analysis of three studies, which had available data Perry et al., 2021; Tiede et al., 2021) . Supplementary Figure S5 demonstrated the publication bias of these three included studies.

As the vaccine rollout expands worldwide, more precise information about vaccine safety has become essential. Owing to the lack of a comprehensive understanding of VITT after ChAdOx1-nCoV or Ad26.COV2.S vaccination, we conducted a systematic analysis of published retrospective cohort studies and case series to investigate the clinical features and outcomes of VITT. To our knowledge, this study was the first attempt to meta-analyze recently reported studies from clinical manifestations to treatment outcomes. Therefore, this meta-analysis will provide a more systematic understanding of the current patterns of diagnosis, treatment, and prognosis of adenoviral vector vaccine related thrombosis.

Although most studies used similar criteria to diagnose VITT, there was also significant variability among them. Recently published studies Perry et al., 2021) used objective measures excluding specialists' opinion in diagnosis. However, whether all five criteria (recent vaccination, thrombosis, thrombocytopenia, elevated D-dimer, and anti-PF4 antibody positivity) should be met to be categorized into VITT still needs to be addressed. Adopting a strict cut-off for thrombocytopaenia (150 × 10⁹/L), for instance, could exclude patients with sufficient evidence of VITT in manifestations and other criteria (Perry et al., 2021) . Studies published between April and July used clinical intuitions from specialists in neurology or haematology as one of the inclusion criteria (Greinacher et al., 2021b; Krzywicka et al., 2021; Sánchez van Kammen et al., 2021a; Schultz et al., 2021; Schulz et al., 2021; Scully et al., 2021; See et al., 2021; Tiede et al., 2021) . Subsequently, this could introduce biases with regard to the local level of SARS-CoV-2 infection, clinical environments, or available tests among those specialists. A more precise and uniformly constructed consensus on VITT diagnosis must be addressed via a higher-level collaboration of experts.

As noted in this study, VITT occurred more commonly in females, and more than half of patients were under age 50. After it was found that young female individuals were vulnerable to VITT from early reports, many countries have modified the eligibility criteria for the adenoviral vector vaccine.

However, as recent studies described Perry et al., 2021) , male and older people are not spared from VITT. Although some patients had risk factors related to venous thrombosis, VITT occurred even in people without these predispositions, as it was previously reported (Idiculla et al., 2020; Marjot et al., 2011) . Therefore, regardless of patients' pre-existing risk factors for thrombosis, clinicians should consider the possibility of VITT diagnosing patients with suspected thrombosis after SARS-CoV-2 vaccinations.

When CVT was first reported after vaccination, it was uncertain whether this rare disease was indeed an adverse event of the vaccine or coincidental cases of CVT, and all different types of thrombosis after vaccination were also reviewed by experts. In the attempts to understand this disease, the connection between VITT and anti-PF4 positivity was used to differentiate this rare phenomenon (Greinacher et al., 2021) . Later, it was suggested that inter-reactivity between the adenoviral vaccine and platelets or PF4 could be related to the pathogenesis of VITT. The free nucleic acid in the vaccines could adhere to PF4 and trigger the formation of PF4-reactive autoantibodies resulting in VITT (Greinacher et al., 2021b; Jaax et al., 2013) . Although many experts suggest that there would be a similar process between VITT and HIT (Cines and Bussel, 2021; Vayne et al., 2021 ), VITT appears to cause more frequent thrombotic events in the cerebral venous system than HIT. Though VITT and HIT are anti-PF4 disorders, they represented different binding amino acids in PF4 according to alanine-scanning mutagenesis, and VITT anti-PF4 antibodies had a more robust binding response to PF4 and PF4-heparin complexes than HIT anti-PF4 antibodies (Huynh et al., 2021) . The high frequency of CVT in VITT was comparable to the clinical phenomenon in medical spontaneous HIT syndrome, which occurs in post-infection scenarios or where no proximate illness or surgery is identified (Warkentin et al., 2021) . Thus, the connection between VITT and CVT might be related to the difference in binding site on PF4 compared to HIT. Moreover, the molecular mimicry between the vaccine-induced proteins of SARS-CoV-2 and human components might increase the risk of adverse effects by leading to the production of pathological autoantibodies, resulting in vaccine-induced autoimmunity (Dotan and Shoenfeld, 2021; Segal and Shoenfeld, 2018) . Furthermore, the reason why these thrombotic events occur frequently as CVT or splanchnic vein thrombosis remains uncertain, and further studies are warranted. However, as these were unusual locations for thrombosis, clinicians speculated VITT when patients with recent SARS-CoV-2 vaccination history presented with these thrombotic patterns (CVT or splanchnic vein thrombosis). (Ciccone, 2021) .

The introduction of an anti-PF4 antibody test to diagnose this rare disease was first described in Germany (Greinacher et al., 2021) . Although patients were not previously exposed to heparin, they exhibited a pattern of clinical manifestations similar to that of HIT. Later, the anti-PF4 antibody test was frequently used in other studies Perry et al., 2021; Sánchez van Kammen et al., 2021a; Scully et al., 2021; See et al., 2021; Schultz et al., 2021) , and our meta-analysis revealed a high positivity rate (91%). In the CVT patients prior to the COVID-19 pandemic, the anti-PF4 positivity rate was extremely low compared to VITT-related CVT patients (Sánchez van . The cut-off value of optical density in the test, which was measured to display the positivity, has not been determined, but it seems to have a higher value in VITT than in the normal population (Hursting et al., 2010; Schultz et al., 2021) . This pooled effect could be less informative due to a high proportion of a single study ; further analysis on this value would be warranted.

The consensus of treating VITT has been evolved throughout the pandemic compared to the early period when different modalities were introduced to manage this rare adverse event. In our metaanalysis, there was no significant difference in mortality between heparin-based and non-heparinbased anticoagulation strategies. However, only 3 studies were included in the meta-analysis because of data availability issues; thus, the result should be interpreted with caution, and there was a trend of lower mortality in the non-heparin group. As more VITT cases are reported, this trend will be clearer and further analyses would be needed to confirm the benefit of non-heparin-based anticoagulants.

Immunoglobulins were also widely used (73%) to manage VITT, although there were no available data comparing the use and non-use of IVIG. As the current consensus from experts recommends the administration of IVIG and non-heparin anticoagulation for the initial management (Cines and Bussel, 2021; Makris et al., 2021; Perry et al., 2021) , clinicians should be cautious in interpreting this result considering the shift in clinical practices during the pandemic.

The overall mortality from all VITTs was 29% in the meta-analysis, suggesting a high fatality.

Since most VITT cases were identified due to their involvement in the cerebral venous system, which frequently led to a fatal outcome, this rate could be overestimated regarding all sites of thrombosis, including extracranial involvement. A sub-analysis of extracranial involvement according to the pattern of each thrombosis seems necessary.

The incidence of CVT appeared to be higher for ChAdOx1 nCoV-19 recipients than for the public in the pre-pandemic era. This result follows previous reports of high thromboembolism and CVT after ChAdOx1 nCoV-19 vaccine administration in several European countries (Hippisley-Cox et al., 2021; Simpson et al., 2021) . However, the incidence in South Korea (Huh et al., 2021) seems to be lower than that in other reports from European countries. This could be related to the protective genetic traits against venous thromboembolism in Asians (Klatsky et al., 2000) . However, due to insufficient data from other Asian countries, it is premature to describe this tendency. As the vaccine rollout expands in Asia and Africa, further analysis of incidence by geographical and demographical difference would be necessary. Furthermore, even though adenoviral vector-based vaccines pose a risk of having VITT, clinicians and the public should acknowledge of much greater thromboembolism risk after contracting the SARS-CoV-2 (Terpos et al., 2020) .

There are several limitations to this study. First, the included studies had some degree of discrepancy in defining VITT though thrombosis and thrombocytopenia were commonly mentioned.

As this was a rare adverse event after vaccinations, early case series had heterogenic characteristics of included patients. Additionally, two studies from database analysis did not have enough clinical information in terms of patients' severity. These issues could overestimate the mortality rate and might pose a risk of bias in generalizing the results to the public.Therefore, additional clinical trials or multicentre studies based on the current definition of VITT should be performed to address clinical outcomes in VITT. Second, despite our comprehensive approach, there is limited evidence for generalization since the included studies were retrospectively designed. Though mortality rate and laboratory variables were presented after incorporation, this should be cautiously interpreted as study diversity was not sufficiently assessed in this process. Because of variabilities in the inclusion criteria, under or over-reporting of cases could also have biased our results. Third, the heterogeneity among outcomes was substantial, and cautious interpretation is necessary according to different clinical settings. This heterogeneity may be due to differences between studies in design, disease severity, age distribution, local policy of vaccinations, or other unidentified variables. Additionally, there is a possibility of double-counted cases among included studies. We could not match everyone's data due to the lack of medical records for all patients, so it could overestimate the real-world clinical data.

This is the first systematic review to analyze VITT incidence after adenovirus-based vaccinations and evaluate the manifestations, treatments, and outcomes of this rare adverse event. This unusual thrombosis infiltrated in various sites; CVT (54%), deep vein thrombosis (DVT) or pulmonary thromboembolism (PE) (36%), and splanchnic thrombosis (19%), and the anti-PF4 test was positive in 91%. Considering the relatively high mortality of VITT, early recognition based on current clinical evidence is essential to improve its clinical outcomes.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ⸹ During whole period of hospitalization, 6 additional patients shifted to non-heparin anti-coagulation, 10/12 (83.3%) ⁂ Including patients received decompressive craniectomy or endovascular treatments Data are n (%) or n/N (%) * Additional laboratory findings with continuous variables were delineated in Table 4 

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