Thrombotic and Thromboembolic Complications After Vaccination Against COVID-19: A Systematic Review.

COVID-19 is caused by infection from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the first case was reported from Wuhan, Hubei Province, China, in December 2019 [ 1 ]. COVID-19 was declared a pandemic by the World Health Organization (WHO) on March 11, 2020 [ 1 ]. It is now evident that COVID-19 is associated with prothrombotic complications due to immunothrombosis and endothelial dysfunction. Immunothrombosis is caused by the activation of neutrophils and monocytes and causes dysregulated coagulation cascade activation. This in turn leads to the formation of thrombi in blood vessels [ 2 ]. One way to combat the SARS-CoV-2 pandemic is to develop and distribute vaccines as quickly as possible. The WHO listed various vaccines for emergency use, and the first vaccine listed for WHO emergency use listing (EUL) was the Pfizer/BioNTech vaccine (BNT162b2) on December 31, 2020 [ 3 ]. WHO also listed two versions of the AstraZeneca/Oxford vaccine developed by AstraZeneca/Oxford - the Serum Institute of India/Covishield and AstraZeneca/AZD1222 vaccines (ChAdOx1 nCov-19) on 15 February 2021, produced by the Serum Institute of India (SII) and AstraZeneca-SKBio (Republic of Korea) respectively; the Janssen/Ad26.COV 2.S vaccine developed by Johnson & Johnson/Janssen (J&J/Janssen) on 12 March 2021; the Moderna vaccine (mRNA 1273) on 30 April 2021; the Sinopharm COVID-19 vaccine produced by Beijing Bio-Institute of Biological Products Co Ltd, a subsidiary of China National Biotec Group on 07 May 2021; and the Sinovac-CoronaVac on 01 June 2021 [ 3 ]. Pfizer/BioNTech and Moderna are messenger RNA-based vaccines that encode the spike protein antigen of SARS-CoV-2; AstraZeneca is a recombinant chimpanzee adenoviral vector vaccine that encodes the spike glycoprotein of SARS-CoV-2; and the J&J/Janssen vaccine is a recombinant adenovirus type 26 vector vaccine that encodes the SARS-CoV-2 spike glycoprotein [ 3 ]. According to WHO data, globally as of September 5, 2021, a total of 5,352,927,296 vaccine doses of 13 different types of vaccines have been administered, with 2,018,604,130 people receiving at least one dose and 1,241,236,974 people receiving a full dose of vaccine [ 4 ]. Concerns about possible thrombotic problems following vaccination with the AstraZeneca vaccine were raised after reports from the European Medicines Agency (EMA) on March 10, 2021 [ 5 ]. Following the report, various European governments temporarily suspended the use of the AstraZeneca vaccine, although there was no convincing evidence that vaccination caused these problems [ 6 ]. The EMA's safety committee, the Pharmacovigilance Risk Assessment Committee (PRAC), concluded on March 18th that the benefits outweighed the possible risks in combating the COVID-19 outbreak, that there is no overall risk of thromboembolic events, and that the AstraZeneca vaccine could be used while further investigation and assessment are ongoing [ 7 ]. A Joint Centers for Disease Control and Prevention (CDC) and US Food and Drug Administration (FDA) Statement on the J&J/Janssen vaccine was released on April 13th, 2021, citing six cases of cerebral venous sinus thrombosis (CVST) after receiving the J&J/Janssen vaccine in the United States and recommending that the vaccine be halted until the next review [ 8 ]. The J&J/Janssen vaccine was reintroduced in the United States on April 23, 2021 [ 8 ]. Multiple cases of rare thrombotic events such as CVST have been observed around the world after receiving COVID-19 adenovirus-based vaccines [ 9 , 10 ]. The original designation used to describe COVID-19 vaccine-associated thrombosis with thrombocytopenia was “vaccine-induced prothrombotic immune thrombocytopenia” (VIPIT) [ 11 ]. Other terms used include vaccine-induced immune thrombotic thrombocytopenia (VITT) and vaccine-associated (immune) thrombotic thrombocytopenia (VATT) [ 11 ]. Most reporting agencies now use the term “thrombosis with thrombocytopenia syndrome” (TTS) [ 9 , 11 , 12 ]. The purpose of this systematic review is to identify the thrombotic and thromboembolic complications that can arise after receiving various types of COVID-19 vaccines, their frequency and distinguishing characteristics, as well as the vaccine dose, timing of onset of symptoms after vaccination, clinical features, laboratory and imaging results, treatment received, and outcome.

Methods Selection Criteria and Search Strategy We searched the following electronic databases for articles published between December 1, 2019, and July 29, 2021: Medline, PubMed, Scopus, EMBASE, Google Scholar, EBSCO, Web of Science, Cochrane Library, CDC database, WHO database, ClinicalTrials.gov , and servers like medRxiv.org and bioRxiv.org . We also looked at the websites of several reporting authorities, including the Vaccine Adverse Event Reporting System (VAERS), the Medicines and Healthcare Products Regulatory Agency (MHRA), and the Ministry of Health and Family Welfare of India (MOHFW). Relevant MeSH terms and keywords were used with an additional filter of “studies in human subjects” (Table 1 ). There were no language restrictions. A primary search was conducted between June 6, 2021, and July 15, 2021, and a final search was conducted on July 29, 2021. To ensure literature saturation, we reviewed the references of all studies included. In May 2021, the protocol for this review was prospectively registered at PROSPERO (ID-CRD42021257862). Inclusion and Exclusion Criteria All case-control studies, cohort studies, retrospective studies, case series, and case reports were included. There were no randomized controlled trials or non-randomized controlled trials. We also incorporated data from various reporting agencies and analyzed it separately. Studies were included if they met the following criteria: (1) use of any type of vaccination for COVID-19; (2) studies that reported thrombosis, thrombocytopenia, or sudden cardiac death as a complication; and (3) no other obvious or confirmed cause for thrombotic complications. Editorials, systematic reviews, meta-analyses, narrative reviews, full texts not available, and commentaries were excluded. Animal and post-mortem studies, as well as those that could not be translated into English, were removed. The same cases can be reported in different databases; however, we made an effort to prevent duplication by comparing the patient's age, sex, date of admission, hospital name, and clinical, laboratory, and radiological characteristics. Additionally, we emailed the relevant corresponding author for clarification if there were any uncertainties. Data Extraction and Study Quality Assessment Two team members (AK and TF) searched and extracted data from various databases. Two reviewers independently reviewed all the articles and selected articles based on inclusion and exclusion criteria. Duplicate studies were excluded from the analysis. Any discrepancies were resolved by discussing them with the third reviewer. Reporting was done according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA). Two investigators (AK and TF) independently assessed the risk of bias in the included studies with the National Institutes of Health (NIH) Quality Assessment Tool [ 13 ]. The following information was extracted: author's name, publication date, study design, sample size, demographic characteristics, age, gender, comorbidities, type of vaccine received, number of doses received, time of onset of symptoms after vaccination, site of thrombosis and incidence, clinical features, laboratory parameters, imaging features, treatment received, patient outcome, study follow-up, and limitations. Outcome Measures and Data Synthesis Strategy We assessed the venous and arterial thromboembolic manifestations reported following different types of vaccination against COVID-19, as well as the vaccine dose, timing of onset of symptoms after vaccination, clinical features, laboratory and imaging results, treatment received, and outcome. Because there were few registries available and to prevent duplication with the reported cases, the descriptive analysis did not include national registries, surveillance, or reporting agencies' data. For the categorical variables, we used simple and relative frequencies and proportions. We employed measures of central tendency (mean or median) and dispersion (standard error and standard deviation) for continuous variables. Results Among the 1859 articles identified through database searching and other sources, 59 studies enrolling 202 patients were included in this systematic review (Figure 1 ). Out of them, one was a retrospective cohort, one was a retrospective survey, 17 were case series (Table 2 ), and the rest were case reports. Most of the studies reported were from the United States, the United Kingdom, and Germany. A population-based cohort study and a nested incident-matched case-control study were also included. These two investigations reported a total of 6347 venous and arterial thromboembolic events. We also looked at three independent registries from the United States, the United Kingdom, and India. Abbreviations: CVST, cerebral venous sinus thrombosis; DVT, deep vein thrombosis; DIC, disseminated intravascular coagulation; IVIG, intravenous immunoglobulin; LMWH, low molecular weight heparin; HTN, hypertension; DM, diabetes mellitus; SAH, subarachnoid haemorrhage; MCA, middle cerebral artery; UFH, unfractionated Heparin; TIA, transient ischemic attack; ICA, internal carotid artery; PE, plasmapheresis/plasma exchange; CT, Computed tomography; NA, not available N=total number of patients Patient and Study Characteristics Thromboembolic (venous and arterial) and hemorrhagic complications following COVID-19 vaccination were reported in 202 patients. The age group with the highest incidence was 20-40 years (39-7%; 46/116), followed by 41-60 years. The majority of patients were female (71.1%; 143/201). The mean age of presentation was 47 ± 15.5 (mean ± SD) years and ranged from 21 to 86 years. Comorbidity and Risk Factors Comorbidities and risk factors were documented in 122 patients, and 28 (23%) patients had significant and specific risk factors for the events; 29 (23.8%) patients had at least one medical condition prior to the onset of events. Significant risk factors included a history of deep vein thrombosis (DVT) (n = 2), a history of relapsing thrombotic thrombocytopenic purpura (TTP) (n=1), a family history of unprovoked pulmonary embolism (n = 1), previous other thrombotic events (n = 1), oral contraceptive pill use (n = 5), hormone replacement therapy (n = 3), obesity (n = 12), antiphospholipid antibodies (n = 6), Factor V Leiden mutation (n = 5), prothrombin G20210A mutation (n = 2), low antithrombin III (n = 1), heterozygous methylenetetrahydrofolate reductase (MTHFR) mutation (n = 1), low ADAMTS13 activity (n = 4), hypothyroidism (n = 4), cancer (n = 4), smoker and ex-smoker (n = 11), hypertension (n = 14), diabetes mellitus (n = 8), and atrial fibrillation (n = 2). In 72 cases, heparin exposure status was documented, and only one patient among them had a history of prior heparin exposure nine months ago; 94 (77%) of the patients had no significant risk factors for any events. The majority of studies reported that there has not been a recent COVID-19 infection and that SARS-CoV-2-PCR test results were negative. Dosage and Vaccination In 199 of the reported cases, information on the type of vaccine received was available. One hundred fifty-three of them received the AstraZeneca vaccine, 26 received the Pfizer/BioNTech vaccine, 16 received the J&J/Janssen vaccine, and four received the Moderna vaccine. The vaccine dose was documented in 152 patients, with 138 patients experiencing complications after the first dose (most common with the AstraZeneca vaccine) and another 14 experiencing complications after the second dose. Among the patients who developed complications with the second dose, most (11 patients) received the Pfizer/BioNTech vaccine. Events Reported The total number of thrombotic, thromboembolic, and hemorrhagic events reported among 202 patients was 306. Of those, 229 (74.8%) were venous thromboembolic events, and 39 (12.7%) were arterial thromboembolic events. Among them, in 174 patients for whom data was available, the mean duration of the onset of symptoms after vaccination was 9.8 ± 5 days. The majority of patients (79.9%) reported their initial symptoms between six and 14 days after vaccination, with the duration ranging from 30 minutes to 37 days. CVST was the most commonly reported form among all thromboembolic events, followed by pulmonary embolism and splanchnic thrombosis. Multiple thromboses were reported in 59 individuals (29.2%). Nature of the Reported Events CVST was reported in 133 patients (65.8%), and among them, 33 (24.8%) had associated brain parenchymal haemorrhage secondary to CVST. Also, 12 patients also had coexisting internal jugular vein thrombosis (IJVT). Other common systemic thromboses reported were pulmonary embolism (17.8%), splanchnic vein thrombosis (12.9%), and DVT (7.4%). Twenty patients presented with ischemic stroke, and the most common territory involved was the MCA territory (3/5 of reported cases). Other territories reported were the basilar artery and cerebellar infarcts. Two patients had transient ischemic attacks (TIAs), and one patient had an ICA non-occlusive thrombus. Seven patients had hemorrhagic strokes at admission. One patient had cardiac arrest, and three patients had myocardial infarction, including one case of triple coronary artery thrombosis and one case of right coronary artery thrombosis. Systemic venous system thromboses, such as iliac, inferior vena cava, iliofemoral, basivertebral, and bilateral superior ophthalmic vein thrombosis, were identified in seven cases. Other arterial systemic thromboses were found in 13 patients, with the most common being aortic thrombosis, followed by celiac, splenic, iliac, spinal, and femoral artery thrombosis. In five patients, cutaneous thrombosis associated with skin necrosis, dermal petechiae, and subdermal hematoma was reported. Five individuals had immune thrombocytopenic purpura (ITP), although one of them had a history and a family history of thrombocytopenia. Four patients were diagnosed with TTP. Six patients developed DIC during the course of the illness. Adrenal haemorrhage was reported in five patients. Thromboses and bleeding caused more neurological events (CVST, stroke, and TIAs) than non-neurological events (Figure 2 ). Investigations The majority of patients (78.6%) had thrombocytopenia, with the lowest platelet count reported being 1 × 10 9 /L. A large number of individuals (87.4%) had elevated D-dimer. Heparin-induced thrombocytopenia (HIT) screen/anti-PF4 antibodies were tested in 150 patients and were positive in 86% of them. Four individuals had a heterozygous Factor V Leiden mutation, two had a prothrombin G20210A mutation, and one had a methylenetetrahydrofolate reductase (MTHFR) mutation. Five individuals tested positive for lupus anticoagulant, and one patient each had low protein S and low antithrombin III levels. Treatment and Outcome Treatment data were available for 161 patients. The majority of patients (128; 79.5%) received heparin or non-heparin anticoagulants. Intravenous immunoglobulin (IVIG) was given to 61 patients, steroids to 42 patients, and plasmapheresis (PE) to 11 patients. Intravenous methylprednisolone was the corticosteroid most frequently used, but data were scarce. Rituximab and eculizumab were administered to four and two patients, respectively, and one patient received caplacizumab. Out of the nine patients who improved completely, five received IVIG, one received PE, seven received IVIG or PE with steroids and heparin or other non-heparin anticoagulants, and two received only anticoagulants. In four cases, neurosurgical decompression procedures were performed. In 185 patients, data on their outcomes were available. At the time of publication, 110 patients were still being treated in the hospital, four patients were critical or in ICU care, and 49 patients (26.5%) had died. Twenty-two patients were discharged, and nine of those patients had fully recovered. The rest of the patients had focal neurological deficits. Data on the cause of death was available for 35 of the 49 patients who died. 15/35 patients had thrombosis in two or more organs. In total, 26/35 patients had CVST, and 15 of them had isolated CVST. Other events reported as causes of death are pulmonary embolism (8), splanchnic vein thrombosis (7), cardiac events (3), adrenal haemorrhage (2), hemorrhagic stroke (2), and ischemic stroke (2). Out of the 27 patients who expired and whose treatment data was documented, 14 patients didn’t receive any steroids, IVIG, anticoagulants, or immunosuppressants. Although data was lacking, patients with normal D-dimer and platelet counts had better outcomes. Only six patients received IVIG, and eight patients received combination therapy. Five patients received only heparin. Data on the type of vaccine administered among those who died was available in 48 patients, and 41 (85.4%) patients received the AstraZeneca vaccine, three patients each received the Pfizer/BioNTech and J&J/Janssen vaccines, and only one received the Moderna vaccine. National Registries, Surveillance, and Reporting Agencies' Data According to a population-based cohort study conducted by Pottegård et al. using data from the nationwide healthcare registers of Denmark and Norway, 281264 patients received their first dosage of the AstraZeneca vaccine between February 9 and March 11, 2021. There were 59 venous thromboembolic events and 83 arterial events recorded in this vaccination group. DVT and ischemic heart disease were the most common venous thromboembolic and arterial events, respectively. The case fatality rate was 10.6% (15/142) [ 33 ]. A nested incident-matched case-control study from Scotland found that 1.71 million people received the first dose of the AstraZeneca vaccine and 0.82 million people received the Pfizer/BioNTech vaccine. The AstraZeneca vaccination was linked to 893 venous thromboembolic events and 3288 arterial thromboembolic events. There were 421 venous thromboembolic events and 1603 arterial thromboembolic events linked to the Pfizer/BioNTech vaccine. They didn't provide any information on the case fatality rate (Table 3 ) [ 34 ]. Abbreviations: CVST, cerebral venous sinus thrombosis; DVT, deep vein thrombosis; SAH, subarachnoid haemorrhage; ITP, immune thrombocytopenic purpura, NA, not available n=total number of patients As of September 1, 2021, data from the US Vaccine Adverse Event Reporting System (VAERS) reported by the CDC and FDA revealed that more than 14.3 million doses of the J&J/Janssen vaccine and more than 356 million doses of the Moderna vaccine had been administered. There were 45 events of TTS following the J&J/Janssen vaccine and two cases after the Moderna vaccine [ 9 ]. According to safety update data from the UK, 24.8 million first doses and 24.1 million second doses of the AstraZeneca vaccine were administered up to September 1, 2021, based on yellow cards reported and reviewed by the Medicines and Healthcare Products Regulatory Agency (MHRA). After the AstraZeneca vaccine, 416 cases of major thromboembolic events with concomitant thrombocytopenia were documented, with 148 of these being CVST. Overall incidence following first or unknown doses was 14.9 per million doses, and second doses were 1.9 cases per million doses. A total of 21.9 million first doses and 18.1 million second doses of Pfizer/BioNTech were administered, with 17 occurrences of similar events recorded. Only two cases of such events were recorded out of the total 1.4 million initial doses and 0.9 million second doses of the Moderna vaccine administered. The case fatality rate reported was 17% with the AstraZeneca vaccine and 12% with the Pfizer/BioNTech vaccine [ 10 ]. A case of hemorrhagic stroke (no prior comorbidities) was reported after COVAXIN vaccine administration in India (MOHFW, AEFI (adverse events following immunization) report, National AEFI Committee) (Table 4 ) [ 35 ]. Abbreviations: TTS, Thrombosis with thrombocytopenia syndrome; CVST, cerebral venous sinus thrombosis; NA, not available; MOHFW: Ministry of Health and Family Welfare; AEFI: adverse events following immunization Risk of Bias In our study, 26/59 of the papers were of fair quality (NIH Quality Assessment Tool) [ 13 ]. There were 17 good-quality articles and 16 poor-quality ones (Tables 5 - 6 ). Abbreviations: CD, cannot determine; NA, not applicable; NR, not reported; Y, yes; N, no Abbreviations: CD, cannot determine; NA, not applicable; NR, not reported; Y, yes; N, no Discussion In this systematic review, we assessed the thrombotic and thromboembolic complications after receiving the COVID-19 vaccination, which included 59 articles with 202 patients and 306 events. Apart from that, data from two nationwide registries and surveillance revealed 6347 venous and arterial thromboembolic incidents. We also analyzed data from various reporting agencies separately. To the best of our knowledge, this is the most comprehensive review of the subject. Data on the underlying mechanism of the AstraZeneca vaccine initiating TTS supports a two-step mechanism similar to the pathogenesis of autoimmune heparin-induced thrombocytopenia (HIT). As a result of a pronounced B-cell response triggered by vaccine-induced PF4/adenovirus aggregates and pro-inflammatory reactions, anti-PF4 antibodies are formed. These are IgG antibodies that activate platelets via low-affinity platelet FcγIIa receptors and the high-titer anti-PF4 antibodies that, in turn, stimulate platelets and neutrophils, causing neutrophils to release NETs (neutrophil extracellular traps). This leads to thrombosis in TTS [ 36 ]. The mechanism through which other types of vaccinations cause TTS is unknown. For a definitive diagnosis of TTS, the American Society of Hematology requires that all five points listed below be met [ 12 ] (1) administratration of the COVID vaccine four to 42 days prior to symptom onset; (2) any venous or arterial thrombosis (often cerebral or abdominal); (3) thrombocytopenia (platelet count < 150 × 10 9 /L) (4) positive PF4 HIT ELISA; (5) markedly elevated D-dimer (more than four times the upper limit of normal). The vast majority of our patients met all five criteria, although a few did not, owing to an insufficient evaluation in many studies, such as anti-PF4 antibodies, D-dimer, etc. The WHO interim guidance case definition of TTS includes the COVID vaccine 30 days before symptom onset [ 37 ]. TTS appears to be extremely uncommon. According to CDC and FDA data, the J&J/Janssen vaccine caused 3.1 cases per million doses, and the Moderna vaccine caused 0.006 cases per million doses [ 9 ]. The MHRA in the United Kingdom reported an overall incidence of major thromboembolic events with concurrent thrombocytopenia of 8.5 cases per million doses after the AstraZeneca vaccine, but 14.9 cases per million doses after first or unknown doses, 1.9 cases per million doses after second doses, and 0.4 cases per million doses after the Pfizer/BioNTech vaccine [ 10 ]. Only two cases of TTS were reported by the CDC and FDA after more than 356 million doses of Moderna vaccine were administered in the United States, and only two cases of major thromboembolic events with concurrent thrombocytopenia were reported by the MHRA after 1.4 million first doses and 0.9 million second doses of Moderna vaccine were administered in the United Kingdom [ 9 , 10 ]. So the highest incidence of TTS is with AstraZeneca, followed by J&J/Janssen, and the least with the Moderna vaccine. The majority of people who received the AstraZeneca vaccine experienced complications after the first dose. The majority of those who developed complications after the second dose of the vaccine received the Pfizer/BioNTech vaccine. Other adenoviral vaccines, such as Gam-COVID-Vac/SputnikV and Ad5-nCOV, have not been linked to thromboembolic complications. It's possible that this is related to the usage of different adenovirus species serotypes or insufficient reporting [ 38 ]. As previously stated, thrombotic and thromboembolic complications were more common in our study with the AstraZeneca vaccination. However, it is too early to comment on vaccine type and predisposition to these side effects, as the majority of people received the AstraZeneca vaccine, and thus the events reported were higher with the same vaccine. More research is needed to compare the risk of thromboembolic complications among different types of vaccines. The most common events reported were venous thromboembolic events, with CVST being the most common, followed by pulmonary embolism and splanchnic thrombosis. Compared to this, the most common venous thromboembolic events recorded in HIT are pulmonary embolism and DVT [ 39 ]. Other events reported in TTS were DVT, internal jugular vein thrombosis, ischemic stroke, TIA, hemorrhagic stroke, cardiac arrest, myocardial infarction, thrombosis in the iliac, inferior vena cava, iliofemoral, basivertebral, bilateral superior ophthalmic veins, and arterial thrombosis in the aorta, celiac, splenic, iliac, spinal, femoral, and leg arteries, cutaneous thrombosis associated with skin necrosis and dermal petechiae, subdermal hematoma, ITP, TTP, DIC, and adrenal hemorrhage. TTS, therefore, occurs more frequently in atypical regions, such as the cerebral venous sinuses and splanchnic circulation, and HIT more frequently manifests as DVT and pulmonary embolism. Furthermore, DVT and pulmonary embolism are the most often observed thrombotic complications associated with COVID-19 infection [ 40 ]. In individuals with minor symptoms or who do not require hospitalization, the reported incidence of thrombotic complications after COVID-19 was reported to be very low. The reported incidence of venous thromboembolism (VTE) was only 0.09% [ 41 ]. In a study by Hill et al., only 3.1% of 2748 patients hospitalized with COVID-19 developed VTE, including DVT (1.5%) and pulmonary embolism (1.3%), while only 0.3% had arterial thromboses [ 41 ]. Another meta-analysis found a 14.1% in-hospital prevalence of VTE (pulmonary embolism or DVT), with a greater frequency in ICU patients (22.7%) [ 42 ]. Various other studies found the pooled incidence of ischemic stroke in COVID-19 patients to be 1.2%, CVST to be 0.08%, and myocardial infarction to be 0.5% in hospitalized, non-ICU-treated patients [ 43 ]. Hence, the prevalence of thrombotic complications, notably VTE, is substantially higher after COVID-19 infection than after COVID-19 vaccination, with a much higher prevalence rate among severe COVID-19 cases. It might be attributed to longer hospital stays among COVID-19 patients who are severely ill. The majority of patients who developed thromboembolic events were young and female. HIT, which has a similar underlying mechanism, is also more common in females than in males [ 44 ]. The majority of the patients had no prior medical history or risk factors for the events. Most of the patients in our study had the onset of symptoms within 14 days of receiving the vaccine dose, ranging from 30 minutes to 37 days post-vaccination. A complete blood count, peripheral smear, D-dimer, fibrinogen, anti-PF4 heparin antibodies on the enzyme-linked immunosorbent assay (ELISA), and imaging (computed tomography or magnetic resonance imaging with venography or angiography) should be used to rule out thrombosis in individuals suspected of having TTS. In the absence of heparin treatment, anti-PF4 antibodies are highly indicative of TTS. Our patients showed thrombocytopenia, high D-dimer levels, and positive HIT screens or anti-PF4 antibodies in the majority of cases. The platelet count and D-dimer levels were normal in a couple of the cases. Patients with normal D-dimer and platelet counts had better outcomes, despite the dearth of available data. A systematic review of VIIT and CVST after AstraZeneca and J&J/Janssen vaccines, which included 14 articles and 49 patients, was recently published [ 45 ]. The majority of the patients in that study were female, and the PF4 IgG assay and D-dimer were both positive in the majority of the cases. Our research yielded comparable results. Symptoms emerged in the majority of patients one week after the first vaccine dosage (range, 4-19 days) in their study. However, the majority of patients in our research developed symptoms within 14 days of receiving the vaccination dose (a range of 30 minutes to 37 days). It's possible that this is related to the fact that we incorporated more publications. In patients with suspected TTS, a multidisciplinary approach is suggested, comprising physicians from neurology, neurosurgery, hematology, critical care, internal medicine, radiology, and the emergency department [ 37 ]. Heparin is not advised in any of the recommendations. Platelet infusion should be avoided because of its similarities to HIT, except in emergencies where surgery is strongly indicated or severe thrombocytopenia is present. IVIG and non-heparin-based anticoagulants are recommended. The recommended IVIG dose is 1 g/kg per day for two days or 0.4 g/kg per day for five days. Parenteral direct thrombin inhibitors (argatroban or bivalirudin), direct oral anticoagulants (dabigatran, rivaroxaban, apixaban), fondaparinux, and danaparoid are non-heparin anticoagulants that are recommended [ 12 , 37 , 46 ]. If IVIG treatment is ineffective, the NICE guideline also suggests adding short courses of high-dose corticosteroids (methylprednisolone 1 g for three days or dexamethasone 20 to 40 mg for four days) [ 46 ]. Aspirin should be avoided because it can increase the risk of bleeding and is ineffective in preventing TTS [ 12 ]. Plasma exchange, eculizumab, and rituximab can be considered as treatment options in patients not responding to IVIG and anticoagulation [ 12 , 46 ]. Only a small number of individuals received these treatments (plasma exchange, eculizumab, and rituximab), and the prognosis was good. Those who received IVIG had a better prognosis as compared to others. The limitation of our study was that the majority of the research in our review was case reports. The likelihood of thromboembolic complications reported following COVID-19 vaccination may be greater due to the potential underreporting of side effects. The strength of our analysis is that we used data from national registries, monitoring agencies, and reporting agencies, as well as observational studies and case reports, to compile it. The majority of the studies were of fair to good quality.

COVID-19 vaccines are generally safe, and the risk of death from COVID-19 disease far outweighs the risk of TTS from the COVID-19 vaccine. Thrombotic complications are more likely due to COVID-19 infection than post-vaccination, so concern about these events should not deter patients from getting the COVID-19 vaccine. Clinicians should be aware of TTS as it is potentially fatal, and early diagnosis and appropriate treatment can save lives. Vaccine side-effect profiles must be evaluated in future trials.