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Covid-19: Rare immune response may cause clots after AstraZeneca vaccine, say researchers

BMJ 2021; 373 doi: https://doi.org/10.1136/bmj.n954 (Published 12 April 2021) Cite this as: BMJ 2021;373:n954

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The Headache of Vaccine. Every clot or Thrombotic event post vaccine is not VIPIT. We must educate the public and clinicians

Dear Editor,

The Headache of Vaccine. Every clot or Thrombotic event post vaccine is not VIPIT. We must educate public and clinicians

Since the MHRA has issued a statement on the potential risk of thrombosis with ChaAdOx1 nCov-19 Astra Zeneca (AZ) vaccine, NHS services have been inundated with calls from anxious public who have had AZ vaccine in the last few months. One report in leading news media reveals hundreds of cases of patients presenting with headache and other nonspecific symptoms to accident and emergency (AE)[1]. Haematologists have been the main point of contact for clinicians. It is however important to distinguish true vaccine induced pro-thrombosis and immune thrombocytopenia (VIPIT) cases from simple thrombocytopenia or isolated thrombosis. It is pleasing to see professional associations responding quickly and providing us with statements and flow charts for the management of these adverse events [2]. The New England Journal of Medicine (NEJM ) has published two reports of eleven and five cases of VIPIT identified in Germany and Norway respectively, nine of whom died mainly due to cerebral venous thrombosis (CVT) or bleeding[3][4]. General Practitioners (GPs) are in dilemma as to which patients to refer to hospital for assessment.

We have to bear in mind that 60% of the population in UK is now already vaccinated, which means anyone coming through the front door with any complaint may lead us to ascribe it to the vaccine when it may not be? I have personally seen several cases of possible vaccine related thrombocytopenia/ venous thrombosis in the recent weeks which is not the same as VIPIT. VIPIT is characterised by severe thrombocytopenia associated with a thrombotic event which could be a CVT or any other thrombosis together with disproportionate rise in d-Dimer levels often above 4000 mcg/ml and hypofibrinogenaemia [2][3]. Most of these patients will have a positive IgG antiplatelet factor-4 antibody. This is a pro-thrombotic condition in spite of thrombocytopenia. UK’S Expert haematology panel on behalf of the British Society for Haematology (BSH) recommend these patients need urgent treatment with intravenous immunoglobulins and non-heparin anticoagulation unless they are bleeding. The anticoagulant of choice recommended by expert panel is either direct oral anticoagulants ( DOACS ), fondaparinux or argatoban depending upon the site of thrombosis. Heparin is contraindicated as it may trigger further immune reaction. Also these patients should not be given any platelet transfusions unless they need neurosurgery or have significant life threatening bleeding [2][3].

However, as is already evident, we are going to see a number of cases that do not fit with this definition. There are clear guidelines for patients who fall in the window period of 4-28 days post AZ vaccine and have following symptoms: persistent headache, visual disturbances, unexplained bruising/bleeding from sites other than at vaccine site or shortness of breath/chest pain/haemoptysis or swelling of legs suggestive of deep vein thrombosis (DVT). GPs must sent them for assessment. Many patients will not fall in with this symptomatology and may have one or the other symptom; the best way to distinguish these cases from true VIPIT is to check full blood count (FBC), and if there is evidence of thrombocytopenia, then an appropriate referral must be done. They must then have their D-Dimer levels checked in the hospital.

An isolated thrombocytopenia is likely ITP and should be managed appropriately with corticosteroids. If D-dimer levels are found to be raised particularly above 2000 mcg/ml, then a platelet factor-4 antibody must be checked and patient must be treated for suspected VIPIT. CTPA /MRI/CT head may be warranted as per symptoms. Patients who present with thrombosis without thrombocytopenia should be treated on usual anticoagulation protocols as it is not VIPIT. Patients who have headaches but without thrombocytopenia, they must be managed on usual headache protocols.

Other intriguing question is what exactly causes VIPIT. Current thinking is that it is an autoimmune IgG reaction to vaccine which cross reacts with platelet factor-4 and leads to platelet activation and thrombosis similar to heparin induced thrombocytopenia (HIT). It has not yet been reported with mRNA vaccines like Pfizer or Moderna vaccines. There are now some cases under review following roll out of Johnson and Johnson vaccination [5]. Both of these are vector derived vaccines. Could it have anything to do with the viral vector? Are there any people who are more prone to get it, why only young people and why is there preponderance of females? These are questions which need to be answered.

However, new thoughts are emerging. Could vaccine induced inflammation play a part? The authors in the NEJM postulate free DNA in the vaccine may trigger inflammation. There is some in-vitro evidence for this mechanism. It is has been shown that inflammation and dying cells in the inflamed or infected tissues and inflammatory cells like neutrophils release extracellular DNA and danger associated molecular signals called DAMPS. Neutrophils release DNA by forming neutrophilic extracellular traps (NETs) during inflammation. Extracellular DNA is thought to be highly pro-inflammatory and pro-thrombotic. Does vector based vaccine contain free DNA to trigger inflammation/thrombosis? If proven, this may have therapeutic implications since animal experiments have shown using recombinant DNASes may combat immunothrombosis [6].

This subject is evolving. We will learn more about this rare and intriguing thrombotic disorder as time goes on.

The decision by the Joint Committee on Vaccination and Immunisation (JCVI) to limit the vaccination to above thirty year old people only seems a right one till we learn more.

It is pleasing to note that the UK medicines and healthcare agency (MHRA) and department of health have been transparent about the publication of these potential adverse events [7].This is important as transparency gains the trust of people in science and regulatory bodies. There was an initial apprehension that these reports may have an adverse impact on vaccine uptake in UK. It is however encouraging to see UK vaccination uptake continues at the same pace as before ( 450,000 2nd doses given on 11th April)[8].We hope other countries will follow suit.

References

1. https://www.theguardian.com/society/2021/apr/09/ae-swamped-with-patients...
2. Guidance produced from the Expert Haematology Panel focused on covid-19 vaccine induced thrombosis and thrombocytopenia. 7 April 2021. https://b-s-h.org.uk/media/19530/guidance-version-13-on-mngmt-of-thrombo....
3. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination Andreas Greinacher, M.D., Thomas Thiele, M.D., Theodore E. Warkentin, M.D.,Karin Weisser, Ph.D., Paul A. Kyrle, M.D., and Sabine Eichinger, M.D.DOI: 10.1056/NEJMoa2104840, published on April 9,2021, at NEJM.org.
4. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med2021. doi:10.1056/NEJMoa2104882. pmid:33835768CrossRefPubMedGoogle Scholar
5. EU agency examines reports of blood clots with J&J Covid vac. EMA says four serious cases reported, one fatal, and also expands inquiry into AstraZeneca vaccine, https://www.theguardian.com/world/2021/apr/09/eu-agency-examines-reports... blood-clots-with-jj-covid-vaccine
6. Front. Immunol., 07 October 2020 https://doi.org/10.3389/fimmu.2020.568513.Extracellular DNA—A Danger Signal Triggering Immunothrombosis. Chongxu Shi1*, Luying Yang1, Attila Braun2 and Hans-Joachim Anders1.1Renal Division, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians University Munich, Munich, Germany,2German Center for Lung Research, Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Munich, Germany
7.https://www.theguardian.com/society/2021/apr/07/under-30s-in-uk-should-b...
8. Covid vaccine: How many people in the UK have been vaccinated so far? https://www.bbc.co.uk/news/health-55274833

Competing interests: No competing interests

15 April 2021
Farooq A Wandroo
Consultant Hematologist/Honorary Senior Lecturer
Sandwell and West Birmingham Hospitals, NHS Trust, University of Birmingham
SWBH NHS Trust, Lyndon, West Bromwich