key: cord-0730568-62fop1cq authors: Mohseni Afshar, Zeinab; Babazadeh, Arefeh; Janbakhsh, Alireza; Afsharian, Mandana; Saleki, Kiarash; Barary, Mohammad; Ebrahimpour, Soheil title: Vaccine‐induced immune thrombotic thrombocytopenia after vaccination against Covid‐19: A clinical dilemma for clinicians and patients date: 2021-07-01 journal: Rev Med Virol DOI: 10.1002/rmv.2273 sha: 329f1509e05005792b3229daba6243191f1bbe75 doc_id: 730568 cord_uid: 62fop1cq The coronavirus disease 2019 (Covid‐19) pandemic has had devastating effects on public health worldwide, but the deployment of vaccines for Covid‐19 protection has helped control the spread of SARS Coronavirus 2 (SARS‐CoV‐2) infection where they are available. The common side effects reported following Covid‐19 vaccination were mostly self‐restricted local reactions that resolved quickly. Nevertheless, rare vaccine‐induced immune thrombotic thrombocytopenia (VITT) cases have been reported in some people being vaccinated against Covid‐19. This review summarizes the thromboembolic events after Covid‐19 vaccination and discusses its molecular mechanism, incidence rate, clinical manifestations and differential diagnosis. Then, a step‐by‐step algorithm for diagnosing such events, along with a management plan, are presented. In conclusion, considering the likeliness of acquiring severe SARS‐CoV‐2 infection and its subsequent morbidity and mortality, the benefits of vaccination outweigh its risks. Hence, if not already initiated, all governments should begin an effective and fast public vaccination plan to overcome this pandemic. Sedentary lifestyle, air travel, 4 obesity, active smoking, 5 hormonal changes during pregnancy, hormone replacement therapy, neoplasms 6 and nephrotic syndrome can be the underlying cause of thromboembolic events (TE). 7 Moreover, trauma and major surgeries, including hip arthroplasty, autoimmune disorders, such as systemic lupus erythematosus, antiphospholipid antibody syndrome, Behçet's syndrome, 8 and systemic vasculitis, 9 inflammatory disease, including inflammatory bowel disease, can also lead to TE. 10 Furthermore, medications, such as oral contraceptives, 11 chemotherapeutic agents, including thalidomide, cisplatin, bleomycin and gemcitabine, 12 immunomodulatory agents, such as infliximab, 13 and antipsychotic drugs are also proposed to be a cause of clot formation. 14 Additionally, sepsis and infections may also induce TE. 15 Thrombosis is a typical sequel of severe infections. 15 Infectious agents, such as Epstein-Bar virus, Herpesvirus, Cytomegalovirus, H1N1 Influenza virus, 16, 17 Measles morbillivirus, 18 Rubella virus, 19 Varicellazoster virus, 20 Herpes zoster virus, 21 Human immunodeficiency virus, 22, 23 and recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been implicated in the TE incidence. 24, 25 On the other hand, the role of vaccines in preventing or triggering thrombosis has also been reported previously. For example, it was demonstrated that the Quadrivalent HPV vaccine, 26, 27 Influenza vaccine 28, 29 and measles vaccine 30 could cause TE. Moreover, recently, there has been some report of TE incidence after administrations of some of the Covid-19 vaccines, especially, Oxford-AstraZeneca vaccine (ChAdOx1) 31 and Johnson & Johnson (Janssen) vaccine. 32 Hence, in this study, an overview of the vaccine-induced immune thrombotic thrombocytopenia (VITT), along with its molecular mechanism, incidence rate, clinical manifestations, and differential diagnosis, are discussed. Then, a step-by-step algorithm for diagnosing and management of patients with such event are presented. VITT has somehow similar mechanism to that of heparin-induced thrombocytopenia (HIT). HIT is a significant complication that could happen in patients receiving this medication, and physicians should be vigilant to the development of this adverse event. It is caused by the formation of antibodies against platelet factor 4 (PF4)/heparin complexes. 37 While these antibodies are produced in many patients receiving heparin, a few them develop deteriorating clinical manifestations, such as HIT with thrombosis, referred more commonly as HITT. 37 Regardless of whether a patient has an identified thrombus in the setting of HIT, HIT alone is a hypercoagulable state requiring alternative anticoagulation promptly. 37 Nevertheless, prothrombotic disorders can be induced with triggers other than heparin, including polyanionic drugs (such as hypersulfated chondroitin sulfate 38 and pentosan polysulfated). 39 Moreover, it has also been observed that after some orthopedic surgeries, such as knee replacement surgery, 40, 41 and viral and bacterial infections, such calamitous events can be induced even in the absence of any prior exposure to mentioned medications. 38, 42 These non-pharmacologic-induced clinical scenarios were categorized as autoimmune heparininduced thrombocytopenia (aHIT). 43 Unlike HIT, patients with aHIT have remarkably severe thrombocytopenia, increased chances of disseminated intravascular coagulation (DIC), and atypical TE. Although heparin can significantly activate the platelets of these patients, their platelets are also unusually active in the absence of heparin. Consequently, when these abnormal antibodies were detected in thrombocytopenic patients without prior history of heparin administration, the term spontaneous HIT was proposed. 43, 44 Recently, a similar phenomenon was diagnosed in some patients after being vaccinated for Covid-19, which was then named VITT, formerly known as vaccine-induced prothrombotic immune thrombocytopenia (VIPIT). 45 Unfortunately, the predisposing factors behind this calamitous event are not yet fully understood. 46 The currently proposed mechanisms of VITT are HIT-similar increased antiplatelet factor 4 (PF4), or PF4-dependent platelet activation, an inflammatory process of antibody formation against platelet antigens to massive platelet activation via the Fc receptor, leading to platelet consumption with thrombus formation and thrombocytopenia. 33 These antibodies tend to form between 4 and 16 days after vaccination. 35 Whether the vaccine itself or the vaccine-induced high immune response is the factor promoting the formation of platelets-activating antibodies is not yet understood. Possibly, adenovirus attachment to platelets leads to platelet preactivation contributing in part to this inflammatory process. 33 Another theory is the potential role of free DNA in the vaccine in forming reactive antibodies to PF4. 47 Previously in a murine model, it has been illustrated that DNA and RNA can bind to PF4, forming multimolecular complexes which, alternatively, can attach to host anti-PF4-heparin antibodies ( Figure 1 ). 48 It is estimated that the incidence rate of VITT is between one in 125,000 to one in a million vaccinated people. This adverse event can affect any age and sex group. However, the risk has been higher in younger individuals, particularly those aged 20-29 years, for whom the risk-benefit should be weighed very carefully. 49 In a preprint study conducted on 537,913 cases with Covid-19, the incidence of CSVT and portal vein thrombosis (PVT) af- 50 Also, it was determined that CSVT incidence was significantly correlated with higher D-dimer levels, while PVT incidence was significantly correlated with low fibrinogen levels and thrombocytopenia. 50 Interestingly, when dividing the study timeline into three twoweek periods and comparing them (weeks 1 and 2 vs. weeks 3 and 4, and weeks 1 and 2 vs. weeks 5 and 6), valuable data were obtained regarding CSVT/PVT incidence risk in the course of Covid-19. The risk of CSVT incidence were significantly decreased in the following weeks than the first 2 weeks after Covid-19 diagnosis (weeks 3 and 4: RR = 0.24, 95% CI: 0.098-0.59, p < 0.001; weeks 5 and 6: RR = 0.12, 95% CI: 0.036-0.40, p < 0.001). 50 Similarly, the incidence risk of PVT was also significantly decreased in the following weeks compared to the first 2 weeks post-Covid-19 diagnosis (weeks 3 and 4: RR = 0.19, 95% CI: 0.14-0.27, p < 0.001; weeks 5 and 6: RR = 0.12, 95% CI: 0.080-0.18, p < 0.001). 50 Various thrombotic events have been reported after vaccination, including intracranial venous sinus thrombosis or cerebral venous sinus thrombosis (CVST), 51 hepatic and splenic vein thrombosis, 52 PVT, 50,53 deep vein thrombosis (DVT), 54 pulmonary thromboembolism, 47 DIC, 55 left inferior ophthalmic vein thrombosis, 56 and bilateral superior ophthalmic vein thrombosis. 57 Surprisingly, as recently approved in a presentation by the Centers for Disease Control and Prevention (CDC), for unknown reasons, it has been a trend that VITT complications mainly involve cerebral vessels. 58 As it can be inferred from Table 1 , the incidence of thrombotic and thrombocytopenia events is higher in adenoviral-vector vaccines, that is, Johnson & Johnson and AstraZeneca vaccines, than the mRNA vaccines, that is, Pfizer/BioNTech, and Moderna vaccines. Moreover, no thrombotic event was reported so far following administration of mRNA vaccines, and these vaccines mainly were related to the exacerbation of the pre-existing bleeding disorders, for example, immune thrombocytopenia (ITP) 59-60 and acquired haemophilia A. 61 On the other hand, the adenoviral-vector vaccines are chiefly related to thrombotic events, such as CVST, PVT and pulmonary thromboembolism. Furthermore, for the adenoviral-vector vaccine, there was no report of vaccine-related thrombotic and thrombocytopenia events before 5 days post-vaccination, whereas, for the mRNA vaccines, such events were reported as soon as two days after vaccination. It is also noteworthy that the platelet count was reported to be as low as 2 � 10 9 /L after administration of mRNA vaccines, while the platelet count mainly was not below 20 � 10 9 /L regarding adenoviral-vector vaccines administration. 76 It is noteworthy that some symptoms, such as headaches for one or 2 days and other flu-like symptoms like myalgia and arthralgia, are expected consequences of vaccination and should not be overestimated or concerning. Nonetheless, if any of the symptoms mentioned above last for more than three days, further assessments are mandated. 35 MOHSENI AFSHAR ET AL. In all TE settings, other thrombocytopenic thrombosis causes, including antiphospholipid syndrome, paroxysmal nocturnal haemoglobinuria, and thrombotic microangiopathies, such as immune thrombocytopenic purpura, or atypical haemolytic uremic syndrome, and underlying haematological malignancies should be excluded. 77 Therefore, in all patients with a suspicion of such events, the following assessments should always be performed before confirming VITT: The thrombophilia screening should be negative; antiphospholipid and anticardiolipin IgG antibodies should not be detected; complement levels (C1q, C3 and C4), their activation products (sC5b-9), and ADAMTS13 activity are expected to be within F I G U R E 1 Possible link of different Covid-19 vaccines with thrombotic and thrombocytopenia events. Structure type and platform for four SARS-CoV2 vaccines have been provided. Although more studies are required to reach a common point, thrombotic events have been reported for several specific vaccines but not for others. Prothrombotic thrombocytopathy mimicking heparin-induced thrombocytopenia has been found in severe cases of Covid-19 and after vaccination with some vaccines. This process may involve ACE2 and CD147, SARS-CoV2 receptors. PGs and PF4 from platelets interact with B cells. Next, produced antibodies bind the endothelial surface (RCSB.org; PDB ID: 3QQN). ACE2, angiotensin-converting enzyme 2; CD, cluster of differentiation; nCoV, novel coronavirus; PF4, platelet factor 4; PG, proteoglycan; SARS-CoV2, severe acute respiratory syndrome coronavirus 2. Created with BioRender.com (1) CVST (1) ICH (7) JVT (6) PVT (2) PTE (3) DVT (3) Discharged (4) Continue hos-pitalization venography, brain CT scan, MRI venography or colour Doppler ultrasound, should be performed. 46 In these patients, a reduction in platelet count to <150 � 10 9 /L, 46 an elevation of D-dimer > 4000 ng/ml FEU, 69 and confirmation of thrombosis by appropriate imaging suggest VITT. 46 This condition should trigger an urgent haematology consultation in order to request testing and initiate empirical treatment. The diagnosis is confirmed by identifying antibodies against the complex of PF4 and heparin. 46 Figure 2 illustrates a step-by-step algorithm for diagnosing VITT. Any patient with a suspected or confirmed VITT must be followed up and managed similar to HIT. It is vital to prohibit any heparin-based anticoagulants and platelet transfusions until VITT is excluded. Furthermore, warfarin is not recommended in this condition due to a paradoxical increase in thrombotic tendency. However, other nonheparin-based anticoagulants, such as direct thrombin inhibitors (including bivalirudin, argatroban and dabigatran), direct factor X a inhibitors (e.g., rivaroxaban, apixaban and edoxaban), and indirect (antithrombin-dependent) X a inhibitors (such as fondaparinux) are not contraindicated in these settings. These medications should be initiated empirically while awaiting laboratory confirmation. 68 This patient had a past medical history of familial thrombocytopenia classified as ITP. c For this study, the median nadir of platelet count (n = 11), INR peak (n = 7), aPTT peak (n = 7), fibrinogen nadir (n = 6) and D-dimer peak (n = 5) were reported. d For this study, the median nadir of platelet count, INR peak, aPTT peak, fibrinogen nadir and D-dimer peak were reported. MOHSENI AFSHAR ET AL. 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Diagnosis and management of cerebral venous sinus thrombosis with vaccine-induced thrombotic thrombocytopenia Vaccine-induced prothrombotic immune thrombocytopenia (VIPIT): consider IVIG batch in the treatment Vaccine-induced immune thrombotic thrombocytopenia after vaccination against Covid-19: A clinical dilemma for clinicians and patients The authors would like to thank the clinical research development centre of Imam Reza Hospital, Kermanshah University of Medical Sciences, for their kind support. Figure 2 is created with BioRender.com. All authors declare no conflict of interest. Zeinab Mohseni Afshar: Data collection and writing the manuscript.Arefeh Babazadeh: Data collection and helped with manuscript writing. Alireza Janbakhsh: Data collection and helped with manuscript writing. Mandana Afsharian: Data collection and helped with F I G U R E 2 A step-by-step algorithm for diagnosing VIPIT, which is now changed to VITT (Courtesy of 2021 Ontario Covid-19 Science Advisory Table 46 ). VIPIT, vaccine-induced prothrombotic immune thrombocytopenia; VITT, vaccine-induced immune thrombotic thrombocytopenia The data that support the findings of this study are available from the corresponding author upon reasonable request.