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AstraZeneca's COVID-19 vaccine is back in action. However, many patients are unsettled about the reported cases of sinus vein thrombosis. In an interview, the hemostaseologist Prof. Oldenburg explains why he would still vaccinate people with an increased risk of thrombosis - and how doctors should react if they suspect sinus vein thrombosis.

Prof. Dr. med. Johannes Oldenburg, Director of the Institute for Experimental Hematology and Transfusion Medicine (IHT) at the University Hospital Bonn,
Chairman of the Board of the Society for Thrombosis and Haemostasis Research (GTH)

Prof. Oldenburg, in connection with an AstraZeneca vaccination, sinus vein thromboses have occurred in rare cases. This has led to a temporary vaccination freeze and caused uncertainty among many patients. Would you recommend this vaccination to a patient who has ever had a thrombosis and is to be vaccinated with the AstraZeneca COVID-19 vaccine?

Prof. Oldenburg:I receive several inquiries about this every day, both personally and in our coagulation clinic. We then tell these patients that such a history does not play a role in the choice of vaccine. The mechanism that is responsible for thrombosis after an AstraZeneca vaccination differs fundamentally from the mechanism of other thromboses, e.g. deep vein thrombosis or pulmonary embolism.

The pathology of vaccine-induced thrombosis is very similar to thatheparin-induced thrombocytopenia, which has been known for many decades - with the difference that no previous exposure to heparin is required. Autoantibodies against its own platelets are formed. These autoantibodies activate the platelets, trigger their aggregation and ultimately lead to the formation of thrombosis. This is an immunological process. And therefore it does not matter whether there are other classic risk factors for thrombosis.

Classic risk factors do not play a role in this mechanism. And what about the pill?

Prof. Oldenburg:Exactly, classic risk factors such as pill, obesity, immobilization or genetic predisposition play a role in the COVID-19 vaccine from AstraZeneca and the thrombosis induced by it - according to current knowledge! - not matter.

Because so far mainly women between the ages of 25 and 55 have been affected, the pill was directly suspected as a promoting risk factor. However, not all women who were affected took the pill. In addition, it is known that such autoimmune phenomena occur more frequently in women than in men. We have discussed it intensively in specialist circles and have come to the conclusion that the pill is unlikely to have an influence on this genesis.

Nevertheless, efforts are being made to establish a register at both European and national level. All cases of sinus vein thrombosis that have occurred in connection with an AstraZeneca vaccination are to be collected centrally there. The aim is of course to find out whether there are any other, previously unknown risk factors and to gain experience with the treatment of this complication.

Would you currently advise any patient group against a COVID-19 vaccination with the AstraZeneca vaccine?

Prof. Oldenburg:There are two groups of patients I would not give the AstraZeneca vaccine to, but they are small groups: one is those who have had heparin-induced thrombocytopenia and the other is those who have already had sinus vein thrombosis. The latter group only if another vaccine is available in the near future. Otherwise I woulddo not advise patients against vaccination because of a specific indication.

Because the benefit of the vaccination is of course still many times higher than the associated risks. Furthermore, one is confident that the mortality of such sinus vein thromboses can be reduced by the increased attention on the part of patients and doctors, because these complications can be diagnosed and treated earlier.

Are there any special features to consider with patients who take anticoagulants, e.g. heparin?

Prof. Oldenburg:No, it doesn't matter for the vaccination. Existing therapy with an anticoagulant or platelet aggregation inhibitor is not a contraindication for vaccination. I would carry out the standard therapy as intended, even if a heparin supplement is used.

There is one important thing that patients taking anticoagulants should be advised of: They should compress the injection site for about ten minutes after the vaccination until it starts to clot.

Has the connection between vaccination and sinus vein thrombosis or thrombocytopenia already been clearly proven?

Prof. Oldenburg:The connection is clear. And the mechanism postulated by the Greifswald working group is more than just an assumption and has already been submitted for publication.The reported cases also appear to be specifically related to the AstraZeneca vaccine. If such side effects also occurred with the mRNA vaccines, such incidents would have been seen.

However, this does not necessarily mean that every case of sinus vein thrombosis that occurs after an AstraZeneca vaccination has been caused by precisely this autoimmune mechanism. In Hanover, for example, there was one case in which an atypical hemolytic-uremic syndrome developed in connection with the vaccination. A sinus vein thrombosis then formed on its floor. The pathogenesis in this case was quite different. In the vast majority of patients, however, the autoimmune thrombocytopenia described by the Greifswald working group will be present.

Nothing can currently be said about the specific trigger of this autoimmune reaction: In other words, whether it was specifically due to the vaccine vector, its formulation or the special type of immune reaction. It could also be related to the protein made by vaccination - the spike protein. Although I think that's unlikely, because this protein is also formed in mRNA vaccines. The exact cause will now certainly be investigated in further investigations.

Due to the media presence, it is to be expected that many patients come to the practices / clinics because they are concerned about a sinus vein thrombosis. How can doctors differentiate the “real” suspected cases from the “classic” vaccine reactions?

Prof. Oldenburg:It is very important that the typical vaccination reactions, which occur in around half of those vaccinated on the first or second day after vaccination, are completely harmless. These are general vaccination reactions. They have nothing to do with it!

The vaccine-induced thrombosis is - as already described - an immunological process. It takes some time. The previously known cases all occurred between day 4 and day 16 after the vaccination. In the case of heparin-induced thrombocytopenia, it usually lasts 5 to 14 days, so the period is very comparable.

So if symptoms appear from the fourth day after the vaccination that can be associated with a thrombotic event, they need to be clarified. These can be headaches in the case of a sinus vein thrombosis, visual disturbances, but also abdominal complaints in the case of a splanchnic thrombosisis present. Theoretically, leg vein thromboses or pulmonary embolisms can also be triggered by such a phenomenon. So if patients have pain in the extremities or have shortness of breath, these also require clarification.

Now a doctor actually has a patient with suspicious symptoms. Which diagnostics should he then initiate?

Prof. Oldenburg:First you should do a blood count to determine the platelet count. Depending on the localization of the symptoms, specific diagnostics are also appropriate, e.g. a cranial MRI in the case of headaches.

You should also determine the D-dimers and take a blood smear. In the aforementioned case from Hanover, for example, the blood smear made it possible to diagnose an atypical hemolytic-uremic syndrome, since the schistocytes typical of the syndrome - that is, fragmented erythrocytes - could be seen under the microscope.

Next, a platelet factor 4 (PF4- / heparin) ELISA should be performed,especially if a decrease in the platelet count is detectable. The PF4 / heparin test is a screening test for heparin-induced thrombocytopenia. However, this is also positive in the case of vaccine-induced thrombocytopenia. The test is available in practically all coagulation laboratories and is easy to perform.

Let's assume this screening test is positive, what does it mean and what should be done in the next step?

Prof. Oldenburg:If the screening test turns out positive, there can be three reasons: Either the patient has autoantibodies that look like those in heparin-induced thrombocytopenia, or he has antibodies with the special characteristics that Prof. Greinacher and his team determine after exposure to the vaccine could, or it has a third antibody variant. All three antibody variants can be triggered by vaccination.

In order to find out whether the antibodies activate platelets dependently or independently of exogenously supplied heparin, should be in the case of a positive PF4 / heparin tests a functional confirmation test, the so-called HIPA test.

If the HIPA test is positive, no heparin should be given in the case of sinus vein thrombosis - for which anticoagulation is indicated. Instead, other anticoagulants should be used. In addition, immunoglobulins should be administered intravenously to affected patients in order to break the process of platelet aggregation.

If the HIPA test is negative, you can give heparin.

In addition to this test, there is now a modified HIPA test that can be used to specifically detect autoantibodies that have the characteristics typical of the vaccination reaction. It was developed by Prof. Greinacher and his team from Greifswald. If this test is positive, the diagnosis “vaccine-induced prothrombotic immune thrombocytopenia”, or VIPIT for short, can be made.

So there is a new test that can be used to specifically detect thrombocytopenia induced by the vaccine. What are the therapeutic consequences of this?

Prof. Oldenburg:At present, this test has no direct relevance for the therapeutic procedure, but is primarily of scientific interest. With a positive HIT screening test (PF4 / Heparin ELISA)the patient can be treated with heparins and immunoglobulins - unless the HIPA test is positive, in which case heparin is, as already mentioned, contraindicated.

In the case of sinus vein thrombosis, anticoagulation should be continued for about six months. Thereafter, the therapy can be terminated because the mechanism described prevents the spontaneous formation of thrombosis again.

Info:

The GTH statement can be found under this link, including a diagnostic algorithm in the event of a suspected vaccine-induced prothrombotic immune thrombocytopenia,