Sep 19, 2023

Findings of the Review Table 3 Characteristics of Participants in the Included Studies Gender and Age Twelve studies identified a total of 63 participants; 46 females (73.02%) 12–16 , 18–20 , 22 and 17 males (26.98%) 15–19 , 21 , 23 who experienced embolism and/or thrombotic event(s). The majority of the studies reported participants’ age ranges from 22 to 49 years (n = 9 studies), 15–23 followed by 50–65 years (n = 6 studies), 12–14 , 18–20 12–21 years (n = 2 studies), 19 , 20 and older than 65 years (n = 2 studies). 19 , 20 Medical History and Prescription Medication Medical history and prescription medication were classified as known and unknown thrombosis risk factors based on previous literature. 26 , 27 There were participants with known thrombosis risk factors shown in five studies (10 participants), 12 , 18–20 , 23 comprising type 2 diabetes mellitus (n = 1 study; 1 participant), 12 hypertension (n = 1 study; 1 participant), 18 single-vessel coronary artery disease (SVD) (n = 1 study; 1 participant), 23 previous deep venous thrombosis (DVT) (n = 1 study; 1 participant), 19 and obesity (n = 1 study; 6 participants). 20 Other medical histories were cited in seven studies (14 participants). 12 , 14–18 , 20 Prescription medications known to cause thrombosis were reported as the following; contraceptive tablets or vaginal rings (n = 4 studies; 5 participants) 12 , 18–20 and hormone-replacement treatment (n = 1 study; 1 participant). 18 Other prescription medications are recorded in Table 3 (n = 4 studies; 14 participants). 12 , 16–18 Vaccine Information Among the 12 studies included, two types and three different brands of COVID-19 vaccines were reported being used; BNT162b2, EP2163 mRNA COVID-19 vaccine, or Pfizer (n = 2 studies; 2 participants), 12 , 23 Ad26.COV2.S COVID-19 viral vector vaccine, or Janssen/Johnson & Johnson (J&J) (n = 1 study; 10 participants), 20 and Oxford-AstraZeneca ChAdOx1 nCoV-19, Covishield, adenoviral vector vaccine, Vaxzevria, or AstraZeneca (AZ) (n = 9 studies; 49 participants). 13–19 , 21 , 22 Forty-seven participants of those included in the literature had embolism and/or thrombotic adverse reaction(s) after the first dose of vaccination (n = 9 studies; 47 participants) 12 , 13 , 15 , 17–21 , 23 and four studies (16 participants) 14–16 , 22 did not provide data about the sequence of dosing of the vaccination. Time duration from vaccination to the admission of embolism and/or thrombotic adverse reaction(s) ranged across studies from 0 to 28 days; 0–7 days (n = 7 studies; 11 participants), 12 , 15 , 17–19 , 21 , 22 8–14 days (n = 8 studies; 35 participants), 13–20 , 22 15 to 21 days (n=5 studies; 12 participants), 15 , 19 , 20 , 22 , 23 22–28 days (n = 3 studies; 5 participants), 16 , 19 , 20 and 29–35 days (n = 1 study; 1 participant). 16 Potential Mechanism Potential mechanisms of embolism and/or thrombotic event(s) after the COVID-19 vaccination are reported in Table 2 . The review found that vaccine-induced thrombotic thrombocytopenia (VITT) was reported as the potential mechanism of embolism and/or thrombotic event(s) after the COVID-19 vaccination most frequently (n = 5 studies). 12 , 15 , 18 , 19 , 21 Amidst these studies, one study reported that VITT occurs due to two possible mechanisms. 15 First, the adenovirus binds to platelets and causes platelet activation, and free DNA in the vaccine could be a potential trigger of these Platelet Factor 4 (PF4) reactive antibodies. Another study demonstrated that exposure to AZ might trigger the expression of antiplatelet antibodies, resulting in VITT. 22 Three studies reported that embolism and/or thrombotic event(s) after the COVID-19 vaccination were conceivably due to the immunological mechanism, autoimmune heparin-induced thrombocytopenia (HIT)-like mechanism in which platelet-activating antibodies develop without heparin exposure is suspected. 13 , 17 , 20 Other potential mechanisms were demonstrated in the included studies. One study showed that COVID-19 vaccine recipients who have a history of allergy to the immunological response to the mRNA vaccine and the dysregulation of the surface receptor may have triggered or activated thrombosis formation. 23 Another study showed that disseminated intravascular coagulation (DIC) is the possible mechanism of embolism and/or thrombotic event(s) that occur with COVID-19 recipients after getting vaccinated. 14 One study reported as unclear mechanism. 16 Clinical Presentation, Embolism and/or Thrombotic Event(s), Coexisting Conditions The ICD-10 WHO Version 2016 was utilized to classify as shown in Table 4 . Table 4 Clinical Presentations, Embolism and/or Thrombotic Events, and Coexisting Conditions Classified by ICD10 (Version 2016) Clinical Presentation Not all included studies provided data regarding presenting symptoms of embolism and/or thrombotic event(s). Of the 12 studies with data available, conditions related to diseases of the musculoskeletal system and connective tissue were reported in five studies (8 events), 12 , 16–18 , 20 and conditions related to diseases of the circulatory system were reported in three studies (4 events). 12 , 16 , 20 Other findings included conditions related to diseases of eye and adnexa (n = 6 studies; 10 events), 13 , 17 , 18 , 20 , 22 diseases of nervous system (n = 4 studies, 7 events), 14 , 17 , 18 , 22 general symptoms and signs (n = 7 studies; 26 events), 15 , 17 , 18 , 20–23 and symptoms and signs involving the digestive system and abdomen (n = 4 studies; 9 events). 15 , 18 , 20 , 21 Embolism and/or Thrombotic Event(s) Ten studies reported 49 incidents of cerebrovascular diseases. 13–15 , 17–23 Other embolism and/or thrombotic events were intracardiac thrombosis (n = 2 studies; 2 events), 15 , 19 ischemic heart diseases (n = 2 studies; 2 events), 14 , 19 pulmonary heart disease and diseases of pulmonary circulation (n = 5 studies; 13 events), 12 , 14 , 15 , 19 , 20 and diseases of arteries, arterioles and capillaries (n = 2 studies; 2 events). 15 , 19 Also, diseases of veins, lymphatic vessels and lymph nodes were reported as embolism and/or thrombotic events, and this category included phlebitis and thrombophlebitis (n = 5 studies; 9 events), 12 , 15 , 16 , 19 , 20 portal vein thrombosis (n = 4 studies; 7 events), 14 , 18–20 and other venous embolism and thrombosis (n = 6 studies; 21 events). 13–15 , 18–20 Coexisting Conditions Among coexisting conditions based on data available, diseases of the circulatory system were most frequently cited (n = 7 studies; 22 events). 14 , 15 , 17–21 Subsequently, diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism were reported in one study (5 events). 19 Clinical Management Figure 2 Clinical management of embolism and/or thrombotic event(s) after the COVID-19 vaccination identified from the included studies. This figure summarizes the clinical management reported in the majority of the included participants who had suggestive symptoms following COVID-19 vaccination. The figure shows the number of studies that reported using different laboratory and imaging to make diagnosis, and receiving different types of interventions, such as anticoagulation therapy, corticosteroids, or interventional therapies for blood clot. Laboratory and Imaging Findings COVID-19 and coagulation tests, including platelet, D-dimer, fibrinogen, INR, aPTT, and heparin-PF4 ELISA test, were assessed in 12 studies, 12–23 as demonstrated in Table 5 . The data showed that nine studies (59 participants) 13–15 , 17–22 reported thrombocytopenia. Another three studies had a normal level of platelet count. 12 , 16 , 23 Additionally, ten studies (71.43%) 12 , 14–16 , 18–23 assessed D-dimer levels, which showed elevated D-dimer levels in eight studies (51 participants) 12 , 14 , 15 , 18–22 and normal level in two studies (3 participants). 16 , 23 However, eight studies 12 , 14 , 15 , 17–21 that assessed fibrinogen levels reported a variety of ranges from low (n = 6 studies, 31 participants) 15 , 17–21 to normal (n= 5 studies; 16 participants), 14 , 15 , 18–20 and high (n = 3 studies; 4 participants). 12 , 15 , 19 Table 5 Laboratory Findings of Included Studies INR and aPTT were assessed in six studies. 12 , 15 , 18–20 , 23 Seven participants had a normal INR level (3 studies), 15 , 18 , 23 and one study (5 participants) had a high INR level. 15 Among these five studies, the majority of those participants had a normal aPTT (n = 23 participants) 12 , 15 , 18 , 19 , 23 followed by high (n = 2 studies, 11 participants) 15 , 19 and low level of aPTT (n = 1 study; 3 participants). 19 To determine the cause of bleeding disorder and embolism and/or thrombotic event(s), the heparin-PF4 ELISA test was tested in seven studies (26 participants), and the results were positive. 12 , 15 , 17 , 19–21 For other bleeding disorder tests, IgG and IgM antiplatelet antibodies, platelet suspension immunofluorescence test, monoclonal antibody-specific immobilization of platelet antigens assay, and serotonin release assay (SRA) were positive in the 4 patients (n = 2 studies). 13 , 20 Also, in some studies, the participants were further tested (n = 3 studies; 15 participants) 13 , 20 , 22 in thrombophilia, immunologic and functional HIT assays, and IgG antibodies against PF4, which showed negative. In addition, embolism and/or thrombotic event(s) were evaluated with imaging studies, such as positive duplex ultrasonography (n = 1 study; 1 participant) 12 and ultrasound (n = 1 study; 2 participants) 16 for evidence of DVT. For those who were diagnosed with CVST after vaccination with COVID-19 vaccine, they were tested with magnetic resonance imaging (MRI) (n = 3 studies; 5 participants), 14 , 20 , 22 computed tomography (CT) (n = 5 studies; 12 participants), 14 , 18 , 20 , 21 , 23 and digital subtraction angiography (DSA) (n = 1 study; 3 participants). 22 Medical Treatment Most participants were clinically managed by anticoagulation treatment and other treatments, including intravenous steroids, blood products, intravenous immunoglobulin (IVIG), thrombolysis procedures, and symptom management. Participants in eight studies (21 participants) received heparin therapy and low molecular weight heparin (LMWH). 12 , 13 , 15 , 17 , 18 , 20 , 22 , 23 Of eight studies, six studies (11 participants) received heparinization therapy and LMWH as an initial treatment. Then, the participants’ treatment was subsequently switched to non-heparin treatment, such as rivaroxaban, phenprocoumon, apixaban, and dabigatran. 12 , 13 , 15 , 20 , 22 , 23 Some studies (n = 4 studies; 10 participants) were continued on heparin and LMWH from the beginning of treatment. 15 , 17 , 18 , 22 Also, some studies (n = 4 studies; 8 participants) reported that participants were initially treated with non-heparinization treatment, such as rivaroxaban, apixaban, dabigatran, and clopidogrel after diagnosis of embolism and/or thrombosis was made. 16 , 20 , 21 , 23 In addition to anticoagulation, other treatments were used to manage the patient with embolism and/or thrombotic event(s) after COVID-19 vaccination, indicating in some studies that additional treated with systemic corticosteroids. Moreover, immunoglobulin therapy was used in some participants (n = 4 studies; 13 participants). 17 , 18 , 20 , 21 Discussion VITT or TTS may result in embolism and/or thrombotic event(s) after vaccine administration. 5 Several types of vaccines were documented to develop a rare adverse effect of acute thrombocytopenia after vaccinations, such as live-attenuated (MMR and varicella-zoster), recombinant DNA (hepatitis B virus), and inactivated vaccines (influenza). 6 In terms of COVID-19 vaccination, it is thought to be due to autoantibodies directed against PF4 that activate platelets and cause venous and arterial thromboembolism in the absence of heparin exposure, similar to other types of spontaneous HIT. 28 Despite unclear mechanisms of embolism and/or thrombotic event(s) following COVID-19 vaccination, thrombocytopenia is a condition reported in the majority of included studies. 12 , 13 , 15 , 17–22 Approach to the Clients A previous study regarding the management of thrombocytopenia suggested performing a detailed history taking, including a family history of thrombocytopenia, medical history (recent viral and bacterial infections, vaccinations, malignancies, recent travels, and recent transfusions), and concomitant medications (heparin), in order to find causes and treat appropriately. 29 In particular COVID-19 vaccination, there are several aspects to consider VITT. Age, Gender, and Prescription Medications Individuals who had thromboembolic events reported following COVID-19 vaccination occurred most frequently in participants aged 22–49, followed by 50–65 years, and least frequently in participants aged 12–21 and 65 years and older. 12 , 13 , 15 , 17–22 The scoping review’s findings, similar to current statistics from other studies, indicated that younger individuals (18–55 years old) are more likely to develop thrombosis with thrombocytopenia syndrome (TTS) following COVID-19 adenovirus vector-based (AZ and J&J) vaccinations than older adults (56 years and older). 5 Additionally, there are gender-specific risk factors among females, such as oral contraceptive pill usage and pregnancy/postpartum period. 30 To our knowledge, estrogen-containing oral contraceptive pills (EOCP) are well known for increasing the risk of VTE. The risk is greater with early usage, particularly within the first 6–12 months. 12 Types of Vaccines Ten of the 12 studies reviewed 13–22 reported embolism and/or thrombotic event(s) after viral vector vaccines (AZ and J&J), while the other two included studies on mRNA vaccines (Pfizer). 12 , 23 Vaccine technologies and manufacturing among these potential COVID-19 vaccines are different, suggesting that clot adverse reactions are more prevalent following one type of vaccine than any other type. Among the included studies, viral vector vaccines are the most predominant type of vaccine causing embolism and/or thrombotic event(s). 13–22 Sequence of Dose In all 12 studies reviewed, embolism and/or thrombotic event(s) occurred after the first dose of the COVID-19 vaccination, consistent with other research findings. In contrast, one case report described a worsening symptom of CVST after the second dose of mRNA Pfizer vaccine. 23 In this case, the participant presented with mild to moderate headache and giddiness 16 days after the first dose but refused medical treatment due to the participant’s consideration from the exertion of working. The second dose was administered, and the participant reported worsening symptoms in the following two days. The symptoms may either progress or are induced by the second dose. In addition, as COVID-19 has constantly been evolving, the CDC encouraged to receive a booster dose. 31 After the first, second, and booster doses of COVID-19 vaccination, individuals and health-care providers should be aware of and closely observe any adverse reactions. A further investigation comparing an individual who received the first, second, additional, and booster doses should be done. Suggested Interval for VITT Surveillance VITT is suspected in individuals who develop thrombocytopenia and/or thrombosis following vaccine administration. 32 The suggested interval for VITT surveillance following COVID-19 vaccination recommended by Warkentin and Cuker is 5–30 days post-vaccination. 32 As mentioned in previous studies reviewed of the 12, the time interval 5–30 days post-vaccination may be an appropriate surveillance period for VITT for individuals and health-care providers. 22 , 33 In the studies reviewed, the most commonly reported time frame after viral vector vaccination events occurred during 8–14 days. The longest time frame found after viral vector vaccination to admission was 29 days after the first dose of the AZ. 16 Among the 12 studies reviewed, individuals with VITT were likely to seek medical assistance when more aggressive symptoms developed, such as sudden onset leg pain, orbital pain, severe headache, visual disturbance, and hemiparesis. For these reasons, recent vaccination status should be assessed. In summary, monitoring for any adverse reactions up to 30 days post-vaccination may be appropriate. Specifically, embolism and/or thrombotic event(s) may need close observation during initially 8–14 days post-vaccination. Any adverse signs and symptoms need to be reported immediately to health-care providers. Physical Examination General physical examination, including inspection, palpation, percussion, and auscultation, was indicated in previous management of thrombocytopenia. 29 Moreover, special attention for the physical examination can be performed based on different embolisms and/or thrombotic event(s) resulting from different clinical presentations and coexisting conditions. Although not all the included studies specify clinical presentations and coexisting conditions, some specific incidents can be discussed based on the data available. CVST was reported in 9 studies (46 events), 14 , 15 , 17–23 and the reported data shared similar clinical presentations. Headache was the most frequent symptom stated among the reported cases. 17–23 In addition, a review of practical guidelines for CVST reported that red flags for headache from CVST included new-onset, persistent, worse with the Valsalva maneuver, and not improved with regular analgesia. 34 The time interval from vaccination to the presentation of CVST is also relevant to CVST which is possibly associated with the COVID-19 vaccine. A study about clinical characteristics of CVST with VITT showed that symptoms onset began 5–24 days after the first dose of COVID-19 vaccination and congruent with the review’s findings that the time interval was 2–25 days after vaccination. 14 , 17 , 18 , 20–23 , 35 Coexisting condition also consistent with a previous study demonstrated that approximately one-third of CVST patients experienced parenchymal hemorrhage along with more severe symptoms onset. 36 DVT was found in four studies with 8 events reported, 12 , 16 , 19 , 20 but this review also notes clinical presentation and coexisting conditions in two included studies (3 events). 12 , 16 General presentations indicated in included studies are leg pain and swelling as revealed in other DVT cases. 12 , 16 , 37 Furthermore, participants developed signs and symptoms of DVT at day 7, 27, and 29 after the first dose of Pfizer and two unknown sequences of doses of AZ, respectively. 12 , 16 In contrast, an article revealed a participant who experienced DVT shortly after the second dose of the mRNA vaccine. 38 For coexisting conditions of DVT, one study reported that a participant developed PE. 12 Clinical Management The previous management of thrombocytopenia indicated that one treatment approach is removing the potential cause of thrombocytopenia, such as discontinuing medication and treating infection. 29 This is consistent with the review’s findings that management from included studies did not continue the second dose of COVID-19 vaccination. 13 , 15–19 , 21 , 22 In addition, there was evidence of positive COVID-19 cases following 14–27 days after the first dose of the COVID-19 vaccine, which is difficult to determine if they were infected prior to vaccination. 39 Therefore, COVID-19 RT-PCR or serology testing should be considered to evaluate the potential exposure from COVID-19 virus that may cause the thrombosis complication. Laboratory testing is essential for differential diagnosis between isolated thrombocytopenia and pancytopenia, and CBC must be taken. Apart from platelet count that can get from CBC, the review’s findings reported that D-dimer concentration, fibrinogen level, and clotting time are the initial blood tests that have been used to detect abnormal clotting activity. 13–22 Additionally, the coagulation blood tests found in the included studies were consistent with the guideline for clinical management of thrombosis with TTS following vaccination to prevent coronavirus disease from WHO. 5 , 12 , 15 , 19–21 According to the guidelines established by WHO, the recommendation has been suggested that the individual presenting with the symptoms of TTS occurred within 30 days after the COVID-19 vaccination to be referred to a tertiary-care hospital and be managed by a multidisciplinary team. 5 Initial assessment should include a CBC before starting empiric administration of IVIG and anticoagulation. If the patient has thrombocytopenia, such patients are considered a suspect case of VITT; the patients should be further evaluated through D-dimer, fibrinogen, heparin-PF4 ELISA, and imaging for thrombosis. When the proper diagnosis has been made, or while waiting for heparin-PF4 ELISA results, non-heparin therapy and IVIG are recommended. Although there is no evidence to confirm that using heparin in the suspected VITT case will result in an aggravated condition, five included studies have been switched the treatments from heparin to non-heparin therapy after positive results of heparin-PF4 ELISA were detected. 12 , 13 , 15 , 20 , 22 Another critical recommendation from the WHO guideline is to oppose platelet infusion for those who have VITT in all cases except that the patients have severe thrombocytopenia and were required to proceed with emergency surgery. For patients who have incompatible initial laboratory results with VITT, the American Society of Hematology suggests continuing assessment for VITT and using non-heparin treatment since the patients might be in an early stage of VITT. 40 Once VITT has been ruled out, or a plausible alternative diagnosis has been made, the standard treatment of embolism and/or thrombotic event(s) could be consequently given. The findings from this review are also consistent with other guidelines published during the early phase, such as the guidelines from National Institute for Health Care Excellence and the International Society on Thrombosis and Haemostasis. 41 , 42 As more information became available about VITT, diagnostic guidelines would also improve. However, due to the varied and often subtle presentations of VITT, diagnostic accuracy remain limited. The help from health-care professionals undertaking the research on this topic would be crucial to ensure that the vaccine works safely to increase vaccine confidence and trustworthiness of the healthcare system. Scoping Review Limitations Several limitations were identified in this scoping review. This scoping review included only English-language studies, so studies reported in other languages were not included in this scoping review, which may exclude some types of vaccines. For example, Sinopharm and Sinovac (inactivated virus vaccines) were developed by China, and Sputnik V (a viral vector vaccine) was developed by Russia. 43 In terms of the reliability of result findings, the majority of included studies are case reports and case series due to limited information in the early stage of the COVID-19 vaccine, so the results of the review should be interpreted with caution. Additionally, the majority of included studies gathered data in Europe, so the results may not be generalizable to other countries in aspects of management and variety of vaccines. Another limitation is the limited time frame only during the early development of the vaccine, which excludes a protein-based COVID-19 vaccine type (Novavax) that develops later. 44 Conclusion The review results suggested monitoring up to 30 days post COVID-19 vaccination, especially the first dose, would be critical to observe any adverse reactions; however, embolism and/or thrombotic event(s) can also occur after that period and requires close monitoring. These suggestions were consistent with WHO guidelines for diagnosis and management of TTS following the COVID-19 vaccination developed and other guidelines at that time. The timely development of guidelines to manage VITT and other serious side effects from newly developed guidelines is a crucial part for vaccine safety surveillance to ensure that the health-care profession will be able to identify and adequately manage the unexpected events. Meanwhile, the health-care profession is the key person to identify the incidence of side effects and the population at risk to help refine the guideline. Then, vaccine safety surveillance should be continued to ensure that the benefit still outweighs the risk for people receiving the vaccine and help build public trust and protect lives from serious infectious diseases. Acknowledgments All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Funding Disclosure References 1. Avila J, Long B, Holladay D, Gottlieb M. Thrombotic complications of COVID-19. Am J Emerg Med. 2021;39:213–218. doi:10.1016/j.ajem.2020.09.065 2. Dyer O. Covid-19: US reports low rate of new infections in people already vaccinated. BMJ. 2021;373:n1000. doi:10.1136/bmj.n1000 3. Shahcheraghi SH, Ayatollahi J, Aljabali AA, et al. An overview of vaccine development for COVID-19. Ther Deliv. 2021;12(3):235–244. doi:10.4155/tde-2020-0129 4. World Health Organization. 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