|Year : 2021 | Volume
| Issue : 5 | Page : 3-5
Vaccination ‘Hit’ by Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)
Department of Vascular and Endovascular Surgery, Kauvery Hospital, Chennai, Tamil Nadu, India
|Date of Submission||21-Jul-2021|
|Date of Acceptance||22-Jul-2021|
|Date of Web Publication||30-Aug-2021|
Department of Vascular and Endovascular Surgery, Kauvery Hospital, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sekar N. Vaccination ‘Hit’ by Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT). Indian J Vasc Endovasc Surg 2021;8, Suppl S1:3-5
Agreed that India celebrated the end of pandemic prematurely and lowered its guard. Reasons for the resurgence of the virus were higher transmissibility of the new variants, several religious and political gatherings, and poor adherence to public health and social measures. Vaccination and masking were offered as the only solution to contain this pandemic. Thankfully, the second wave has been more or less contained.
As of now (July 2021), 399 million people have received one dose of vaccine in India which is more than what has been achieved in the UK, USA, and other western countries. One of the reasons for slowing of the vaccination drive was the misinformation campaign done by various platforms both in India and abroad. The cases of thrombosis which were seen after AstraZeneca vaccine (Covishield) were highlighted and made to look as though this vaccine is deadly. Some of the European nations showed a knee-jerk reaction of banning it only to reverse it a few days later saying that the incidence is negligible and the usefulness of the vaccine far outweighs the risks involved. However, by then, the damage was done. Even doctors and other health-care workers were scared and were reluctant to take the vaccine.
A survey in 15 countries published in the Guardian showed that the majority of people were apprehensive about vaccines because of fear of side effects and that the vaccines have not been adequately tested. The survey which has been running since last year found that until March 2021, AZ vaccine was the most trusted vaccine in the UK but confidence level dropped significantly since publication of the complication.
All the vaccines were approved by the respective regulatory bodies under an emergency use authorization without long-term safety data.
It is well known that all vaccines can have adverse reactions.
Smadja et al. have published a descriptive analysis of the anti-SARS-CoV-2 vaccination thrombotic risk reported to the World Health Organization (WHO) Global Database for Individual Case Safety Reports (VigiBase). VigiBase is a databank developed and maintained by the Uppsala Monitoring Centre, Sweden. It is the world's largest pharmacovigilance database with submission from member states since the establishment of the WHO Program for International Drug Monitoring in 1968.
Between December 13, 2020, and March 16, 2021 (94 days), 361,734,967 people received vaccination in the International COVID-19 vaccination dataset and 2161 thrombotic events (795 venous and 1374 arterial thrombotic event) were reported in Vigibase on March 16, 2021. Thrombotic events were seen in 1197 for Comirnaty from Pfizer, 325 for COVID-19 vaccine of Moderna, and 639 for AZD1222 vaccine. Thus, the rate was 0.21 (95% confidence interval [CI]: 0.19–0.22) cases of thrombotic events per 1 million person vaccinated-days. For venous thromboembolism (VTE) and arterial thromboembolism (ATE), rates were, respectively, 0.075 (95% CI: 0.07–0.08) and 0.13 (95% CI: 0.12–0.14) cases per 1 million person vaccinated-days.
Data analysis showed an imbalance between venous (VTE) and arterial (ATE) thrombotic adverse events in mRNA vaccines, respectively, 31.8% (381/1197) and 67.9% (813/1197) for Comirnaty (Pfizer); 24.6% (80/325) and 77.6% (253/325) for Moderna vaccine whereas for AZD1222 data showed that VTE and ATE were evenly shared (52.2% [334/639] vs. 48.2%) (308/639), respectively. The timeframe between vaccination and ATE is the same for three vaccines (median of 2 days). Concerning ATE, the patients' profile for the three vaccines appeared to be similar.
Moreover, they observed unexpected cerebral venous thrombosis (CVT) for COVID-19 vaccine with all the three vaccines. Majority were younger females. Five out of seven CVT cases observed after AZD1222 were associated with thrombocytopenia. Moreover, they noticed thrombocytopenia associated with thrombotic events and/or disseminated intravascular coagulation and/or antiphospholipid antibodies for all three vaccines and one thrombocytopenia associated with heparin-induced thrombocytopenia (HIT)-positive tests after AZD1222. Since March 2021, several other cases of HIT have also been described after AZ1222 vaccination and this phenomenon has now been named vaccine-induced immune thrombotic thrombocytopenia (VITT).
These data have suggested that thrombotic events, including CVT, can occur in association with all three vaccines.
Recently, other side effects such as myocarditis and hearing loss with deafness and other neurological manifestations have also been reported with mRNA vaccines.
The incidence of VITT is unknown but it appears to be exceedingly rare.
Majority of the cases have been reported after two adenoviral vector-based vaccines, namely ChAdOx1 nCoV-19 (AstraZeneca, University of Oxford, and Serum Institute of India) and Ad26.COV2.S (Janssen; Johnson and Johnson).
VITT is caused by antibodies that recognize platelet factor 4 (PF4, also called CXCL4) bound to platelets. These antibodies are immunoglobulins (Igs) that activate platelets through low-affinity platelet FcγIIa receptors (receptors on the platelet surface that binds the Fc portion of IgG).
Ultimately, platelet activation (and possibly activation of other cells such as neutrophils) results in marked stimulation of the coagulation system and clinically significant thromboembolic complications.
This antibody is not heparin dependent (not induced by heparin exposure and does not require heparin for detection in in vitro platelet activation assays). This is a major difference from antibodies found in HIT, which are heparin dependent.
The key feature that distinguishes VITT from other thrombocytopenic disorders is that anti-PF4 antibodies in these disorders are able to activate platelets and cause thrombosis. In other disorders such as immune thrombocytopenia, antiplatelet antibodies bind platelets but do not cause platelet activation and hence do not cause thrombosis.
| Clinical Features|| |
VITT seems to be slightly more common among younger females and many of them were on estrogen hormones.
VITT strongly mimics autoimmune HIT, with typical clinical features. Symptoms usually start by 5–30 days after vaccination.
Flu-like symptoms, petechiae, and mucosal bleeding due to thrombocytopenia are the common symptom recorded. Usual presentation is due to thrombosis rather than bleed. Intense headache should alert to the possibility of CVT. Cerebral bleed can happen after treatment with anticoagulation for CVT.
Thrombosis in VITT can occur in typical sites of VTE such as pulmonary embolism or deep vein thrombosis in the leg; however, a distinctive feature of the syndrome is thrombosis in unusual sites including the splanchnic (splenic, portal, mesenteric) veins, adrenal veins (risk for adrenal failure), and the cerebral and ophthalmic veins. Arterial thrombosis including ischemic stroke (often, middle cerebral artery) and peripheral arterial occlusion has also occurred, often in individuals with venous thrombosis. The pathophysiologic explanation for these unusual sites of thrombosis is unknown.
Laboratory findings are
- Moderate-to-severe thrombocytopenia, or a significant decrease from the individual's baseline platelet count
- Elevated D-dimer (often greatly elevated, >10 mg/L [>10,000 ng/mL])
- Decreased fibrinogen
- Normal or mildly increased prothrombin time, international normalized ratio, and activated partial thromboplastin timePF4 antibody testing (ELISA) – positive testing is confirmatory.
High index of suspicion is needed to diagnose this condition and early treatment improves the outcome. Since confirmatory test PF4 antibody testing by ELISA may not be available or may take time, treatment may have to be initiated based on clinical suspicion.
Therapeutic anticoagulation using nonheparin anticoagulants is one of the primary treatments for VITT and is used unless there is a contraindication such as expanding intracerebral hemorrhage.
Direct oral anticoagulation is preferred (Factor Xa inhibitors apixaban, edoxaban, rivaroxaban or the oral direct thrombin inhibitor dabigatran). Fondaparinux or danaparoid has also been found useful. Parenteral direct thrombin inhibitor such as argatroban or bivalirudin can also be used if available.
High-dose intravenous Ig along with high dose of steroids and anticoagulation is recommended as a means of interrupting VITT antibody-induced platelet activation.
Platelet transfusions are generally avoided and should be reserved for critical bleeding (bleeding into a critical anatomical site or that causes hemodynamic or respiratory compromise). In such cases, it may be reasonable to transfuse platelets and/or a source of fibrinogen (fibrinogen concentrate, plasma, or cryoprecipitate), depending on the platelet count and fibrinogen level. Apheresis to remove circulating VITT antibodies may be warranted in patients who continue to deteriorate despite treatment.,,
The appropriate duration of anticoagulation is unknown since thrombocytopenia can be prolonged. A reasonable approach for VITT with thrombosis would be to continue anticoagulation for 3 months after normalization of the platelet count, as long as no further thrombosis occurs. For VITT without thrombosis, anticoagulation until platelet count recovery and perhaps longer if tolerated (4–6 weeks after platelet count recovery) appears prudent. The reported mortality has been around 20%–50%. Early recognition and treatment can certainly bring down the mortality rate.
| Conclusion|| |
Vaccination remains the primary means of preventing SARS-CoV-2 infection and curbing the COVID-19 pandemic. The risk of life-threatening thrombosis from COVID-19 greatly exceeds the risk of VITT. There are no known preventive strategies for VITT. Available vaccines have proved to be highly safe and effective. However, there is a need for maintaining a high index of suspicion when patients present with central nervous system or abdominal symptoms after receiving any SARSCoV-2 vaccine However, it is important to remember that these side-effects are rare and much less common than both CVT and ischemic stroke associated with COVID-19 infection itself. Better understanding of how the vaccine induces these platelet-activating antibodies will help to improvements in vaccine design.
| References|| |
Smadja DM, Yue QY, Chocron R, Sanchez O, Lillo-Le Louet A. Vaccination against COVID-19: Insight from arterial and venous thrombosis occurrence using data from VigiBase. Eur Respir J 2021; 58:2100956. doi: 10.1183/13993003.00956-2021.
Sholzberg M, Arnold DM, Laupacis A. Recognizing, managing and reporting vaccine-induced immune thrombotic thrombocytopenia. CMAJ 2021;193:E913-5.
Cines DB, Bussel JB. SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia. N Engl J Med 2021;384:2254-6.
Guetl K, Gary T, Raggam RB, Schmid J, Wölfler A, Brodmann M. SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia treated with immunoglobulin and argatroban. Lancet 2021;397:e19.