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P. Gresele et al.
Figure 3. A suggested clinical surveillance and diagnostic approach to suspected vaccine-induced immune thrombotic thrombocytopenia. Subjects receiving the Vaxzevria and the Janssen vaccines who develop new onset headache, especially if severe or with unprecedented characteristics, and/or associated with other clin- ical manifestations (blurred vision, gait disturbance, focal neurological symptoms and/or abdominal pain, vomiting, bloody stool, shortness of breath, petechiae or ecchymoses) should be referred for immediate laboratory evaluation (platelet count and D-dimer measurement). If thrombocytopenia is detected they should under- go anti-PF4 antibody testing, imaging and evaluation for cerebral vein sinus thrombosis, splanchnic vein thrombosis or pulmonary embolism. If confirmed, therapy for vaccine-induced immune thrombocytopenic thrombosis (VITT) should be immediately started according to the statement from the Italian Society for the Study of Haemostasis and Thrombosis (SISET)13 Although almost one quarter of the reported patients with VITT in whom unfractionated or low-molecular weight heparin was used apparently responded well to treatment (Table 2), subjects positive for anti-PF4 antibodies, as determined by a heparin-induced platelet aggregation (HIPA) test and/or enzyme-linked immunosorbent assay, or who have not been tested should, for prudence, be treated with alternative anticoagulants, until new information becomes available. In subjects in whom these anti-PF4 antibodies do not cross-react with heparin, as shown by a HIPA test in the presence of a low concentration of heparin, the use of heparin as anticoagulant may be allowed. ELISA: enzyme-linked immunosorbent assay; MRI: magnetic resonance imaging; CT: computed tomography; US: ultrasound.
ity anti-PF4 antibodies. Furthermore, there is no evidence that the anti-PF4 antibodies isolated from patients with VITT cause thrombosis and thrombocytopenia in animal models.49,83 Finally, recent observations show that 1.2% to 8.0% of subjects receiving a first dose of Vaxzevria devel- op circulating anti-PF4 antibodies while the prevalence of VITT ranges from 0.0006% to 0.00125%.84,85
Other possible pathogenic mechanisms of vaccine-induced immune thrombotic thrombocytopenia
Very recently a preliminary report, published in a non- peer-reviewed repository, provided an interesting alterna- tive potential pathogenic mechanism of VITT.86 COVID- 19 is caused by SARS-CoV-2 which is a single-strand RNA virus that is translated and replicates only in the cytosol of infected cells in the absence of processes which are necessary when nuclear-encoded genes are tran- scribed, and in particular of mRNA splicing. Nuclear
encoded genes have intronic sequences, thus their tran- scripts require splice reactions at consensus RNA sequences to eliminate them. When an Ad-vectored viral RNA sequence is administered the vector infects host cells, adenoviral DNA enters the nucleus and is then tran- scribed by the host transcription machinery. However, the viral piece of DNA deriving from the SARS-CoV-2 virus is not optimized to be transcribed into the nucleus and its open reading frame may thus be disrupted by arbi- trary splice events. These splice events would produce shorter spike protein variants, including forms missing the C-terminal membrane anchor, thus leading to soluble circulating spike protein molecules. The soluble spike protein may cause a strong activation of endothelial cells expressing ACE2.87 Moreover, when the host immune system starts to produce antibodies against the spike pro- tein, endothelial cells binding soluble spike would also be decorated by these antibodies, triggering a strong inflam- matory reaction through antibody-dependent or comple- ment-dependent cytotoxicity, thus eliciting VITT. With this hypothesis, the preferential involvement of cerebral
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haematologica | 2021; 106(12)