VIPIT Flashcards
Features
NACI rapid response: Recommended use of AstraZeneca COVID-19 vaccine in younger adults - Canada.ca
Rare cases of serious blood clots, including cerebral venous sinus thrombosis, associated with thrombocytopenia have been recently reported in Europe following post-licensure use of AstraZeneca COVID-19 vaccineFootnote 1Footnote 2. Cases identified so far have been primarily in women under the age of 55 years; although cases in men have also been reported and have mostly occurred between 4 and 16 days after receipt of vaccine. This adverse event is being referred to as Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT)Footnote 3. This entity is associated with the development of antibodies that “activate” platelets, which stimulate the formation of clots and result in thrombocytopenia. The mechanism of action is similar to heparin-induced thrombocytopenia (HIT). The exact mechanism by which the AstraZeneca vaccine triggers VIPIT is still under investigation. At this time, no other risk factors have consistently been identified in patients who develop VIPIT. This adverse event has not been identified following receipt of mRNA COVID-19 vaccines to date.
The rate of this adverse event is still to be confirmed. Based on information from the European Medicines Agency on March 18, 2021 it was originally estimated at approximately 1 per 1,000,000 people vaccinated with the AstraZeneca vaccine, however a higher rate of 1 per 100,000 was reported by the Paul-Ehrlich Institut in GermanyFootnote 4. Additional information is currently being gathered to characterize more accurately the rate of VIPIT. Based on available information, the case fatality of VIPIT is approximately 40%, however, the case fatality may decrease with increased awareness of the adverse event and appropriate early treatment.
Treatment
Treating Blood Clots in Patients with Presumptive or Confirmed VIPIT
- No heparin
- No platelet transfusions
- First line anticoagulants: direct oral anti-Xa inhibitors (e.g., rivaroxaban, apixaban, edoxaban)
- Consult hematology (in person, virtually, by phone)
- IVIG 1 g/kg daily for 2 days for severe or life-threatening blood clots
Article summary
The clinical picture of moderate-to-severe thrombocytopenia and thrombotic complications at unusual sites beginning approximately 1 to 2 weeks after vaccination against SARS-CoV-2 with ChAdOx1 nCov-19 suggests a disorder that clinically resembles severe heparin-induced thrombocytopenia, a well-known prothrombotic disorder caused by platelet-activating antibodies that recognize multimolecular complexes between cationic PF4 and anionic heparin.6 However, unlike the usual situation in heparin-induced thrombocytopenia, these vaccinated patients did not receive any heparin to explain the subsequent occurrence of thrombosis and thrombocytopenia.
In recent years, it has been recognized that triggers other than heparin can cause a prothrombotic disorder that strongly resembles heparin-induced thrombocytopenia on both clinical and serologic grounds, including certain polyanionic drugs (e.g., pentosan polysulfate,7 antiangiogenic agent PI-88,8 and hypersulfated chondroitin sulfate8). Such a prothrombotic syndrome has also been observed in the absence of preceding exposure to any polyanionic medication, such as after both viral and bacterial infections9,10 and knee-replacement surgery.11,12 These various clinical scenarios with apparent nonpharmacologic triggers have been classified under the term autoimmune heparin-induced thrombocytopenia.13 Unlike patients with classic heparin-induced thrombocytopenia, patients with autoimmune heparin-induced thrombocytopenia have unusually severe thrombocytopenia, an increased frequency of disseminated intravascular coagulation, and atypical thrombotic events. Serum from these patients strongly activate platelets in the presence of heparin (0.1 to 1.0 IU per milliliter) but also in the absence of heparin (heparin-independent platelet activation). When these unusual antibodies are observed in patients who have thrombocytopenia without preceding heparin exposure, the term “spontaneous” heparin-induced thrombocytopenia syndrome13,14 has been used. Sometimes, patients in whom heparin-induced thrombocytopenia develops after exposure to heparin present with atypical clinical features, such as an onset of thrombocytopenia beginning several days after stopping heparin (delayed-onset heparin-induced thrombocytopenia15,16) or thrombocytopenia that persists for several weeks despite the discontinuation of heparin (persisting or refractory heparin-induced thrombocytopenia17,18). Serum from these patients also shows the phenomenon of heparin-independent platelet-activating properties.
These clinical features that resemble those of autoimmune heparin-induced thrombocytopenia were observed in the patients with vaccine-induced immune thrombotic thrombocytopenia. The serum usually showed strong reactivity on the PF4–heparin ELISA. Moreover, serum showed variable degrees of platelet activation in the presence of buffer that was in most cases greatly enhanced in the presence of PF4 (Figure 1A and 1B). More strikingly, most serum showed inhibition, rather than increased activation, in the presence of low-dose low-molecular-weight heparin (0.2 U per milliliter of anti–factor Xa). In addition, antibodies from two patients, which were affinity purified on either immobilized PF4 or immobilized PF4–heparin, strongly activated platelets but only in the presence of PF4. Enhancement of platelet activation by PF4 is also a feature of heparin-induced thrombocytopenia19,20 and has been used to enhance detection of platelet-activating antibodies in diagnostic testing for this adverse drug reaction.21 Whether these antibodies are autoantibodies against PF4 induced by the strong inflammatory stimulus of vaccination or antibodies induced by the vaccine that cross-react with PF4 and platelets requires further study.
Although we found enhanced reactivity of patient serum with platelets in the presence of ChAdOx1 nCov-19, this is likely to be an in vitro artifact. It is well known that adenovirus binds to platelets22 and causes platelet activation.22,23 Furthermore, the amount of adenovirus in a 500-microliter vaccine injection administered 1 or 2 weeks earlier would seem unlikely to contribute to subsequent platelet activation observed in these patients. However, interactions between the vaccine and platelets or between the vaccine and PF4 could play a role in pathogenesis. One possible trigger of these PF4-reactive antibodies could be free DNA in the vaccine. We have previously shown that DNA and RNA form multimolecular complexes with PF4, which bind antibodies from patients with heparin-induced thrombocytopenia and also induce antibodies against PF4–heparin in a murine model.24 Unfortunately, other Covid-19 vaccines were not available to us for testing.
Our findings have several important clinical implications. First, clinicians should be aware that in some patients, venous or arterial thrombosis can develop at unusual sites such as the brain or abdomen, which becomes clinically apparent approximately 5 to 20 days after vaccination. If such a reaction is accompanied by thrombocytopenia, it can represent an adverse effect of the preceding Covid-19 vaccination. To date, this reaction has been reported only with the ChAdOx1 nCov-19 vaccine, which has been used in approximately 25% of vaccine recipients in Germany and in 30% of those in Austria.
Second, ELISA to detect PF4–heparin antibodies in patients with heparin-induced thrombocytopenia is widely available and can be used to investigate patients for potential postvaccination thrombocytopenia or thrombosis associated with antibodies against PF4.25 A strongly positive ELISA result that is obtained in a patient who has not been recently exposed to heparin would be a striking abnormality.
Third, we have shown that these antibodies recognize PF4 and that the addition of PF4 greatly enhances their detectability in a platelet-activation assay. Since vaccination of millions of persons will be complicated by a background of thrombotic events unrelated to vaccination, a PF4-dependent ELISA or a PF4-enhanced platelet-activation assay may be used to confirm the diagnosis of vaccine-induced immune thrombotic thrombocytopenia through this novel mechanism of postvaccination formation of platelet-activating antibodies against PF4. Although treatment decisions such as administering intravenous immune globulin and starting anticoagulation do not need to await laboratory diagnosis, detection of these unusual platelet-activating antibodies will be highly relevant for case identification and future risk–benefit assessment of this and other vaccines.
Figure 2. Potential Diagnostic and Therapeutic Strategies for Management of Suspected Vaccine-Induced Immune Thrombotic Thrombocytopenia.
Figure 2 shows a potential diagnostic and therapeutic
Flowchart
