10.4081/btvb.2022.23
Vaccination with ChAdOx1 nCoV-19 can result in vaccine-induced immune thrombotic thrombocytopenia (VITT). This phenomenon mimics heparin-induced thrombocytopenia, yet it does not require heparin as a trigger. This case report highlights the potentially lifethreatening complication associated with ChAdOx1 nCov-19 vaccine, clinical presentation, diagnostic approach, and treatment. We report two cases of vaccine-induced immune thrombotic thrombocytopenia after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. We attribute these thrombotic conditions to the vaccine due to the remarkable temporal relationship. The proposed mechanism of VITT is a production of antibodies against platelet factor-4 resulting in massive platelet activation. Healthcare providers should be aware of the possibility of such a fatal complication, and the vaccine recipients should be warned about the symptoms of VITT.
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Simona Prejanò
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Bleeding, Thrombosis and Vascular Biology
SARS-CoV-2
Vaccine-induced immune thrombotic thrombocytopenia following AstraZeneca (ChAdOx1 nCoV-19) vaccine: report of two cases
Text.Serial.Journal
https://www.btvb.org/btvb
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Case Reports
2022-05-23
2022-03-01
2022-05-23
2022-07-14
Bleed Thromb Vascul Biol
Simona Prejanò
2022/05/23
10.4081/btvb.2022.23
Hemostasis and Thrombosis Center Unit, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro
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SISET. Database nazionale sui casi di trombosi dopo vaccinazione contro Sars-CoV-2: SISET VAX COVID-19. Available from: https://www.siset.org/sisetvaxcovid-19/ [Accessed 2 September 2021]
Vaccine-induced immune thrombotic thrombocytopenia following AstraZeneca (ChAdOx1 nCoV-19) vaccine: report of two cases
https://www.btvb.org/btvb/article/download/23/26
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                                                                                                                      CASE REPORT

Vaccine-induced immune thrombotic thrombocytopenia following AstraZeneca
(ChAdOx1 nCoV-19) vaccine: report of two cases
Rita Carlotta Santoro,1 Roberto Minici,2 Marzia Leotta,1 Mariapia Falbo,1 Lucia Concetta Elia,1 Francesca Leo,1
Antonella Ierardi,1 Alessandra Strangio,1 Simona Prejanò1
1
    Hemostasis and Thrombosis Center Unit; and 2Diagnostic Radiology Unit, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy



ABSTRACT
     Vaccination with ChAdOx1 nCoV-19 can result in vaccine-induced immune thrombotic thrombocytopenia (VITT). This phenomenon
mimics heparin-induced thrombocytopenia, yet it does not require heparin as a trigger. This case report highlights the potentially life-
threatening complication associated with ChAdOx1 nCov-19 vaccine, clinical presentation, diagnostic approach, and treatment. We re-
port two cases of vaccine-induced immune thrombotic thrombocytopenia after receiving the first dose of the ChAdOx1 nCoV-19 vaccine.
We attribute these thrombotic conditions to the vaccine due to the remarkable temporal relationship. The proposed mechanism of VITT
is a production of antibodies against platelet factor-4 resulting in massive platelet activation. Healthcare providers should be aware of
the possibility of such a fatal complication, and the vaccine recipients should be warned about the symptoms of VITT.




                                                                                                 ly
                                                                                after the first case series was reported in China,1 the number




                                                                                          on
INTRODUCTION                                                                    of new cases increased exponentially. COVID-19 is a seri-
    The Coronavirus Disease 2019 (COVID-19) pandemic                            ous infectious disease with a high mortality rate of up to
has affected health and economic systems globally. Shortly                      3.4% among infected patients.2 Vaccines against severe


                                                                                    e
                                                                                acute respiratory syndrome coronavirus 2 (SARS_CoV-2)
                                                                               us
                                                                                are the most important countermeasure to fight the COVID-
                                                                                19 pandemic. From December 2020 through March 2021,
                                                                               al
     Correspondence: Rita Carlotta Santoro, Hemostasis and Thrombo-             the European Medicines Agency approved four vaccines
     sis Unit, Azienda Ospedaliera “Pugliese Ciaccio”, Viale Pio X 83,          on the basis of randomized, blinded, controlled trials:3 two
                                                            ci

     88100 Catanzaro (CZ), Italy.
                                                                                messenger RNA-based vaccines (Pfizer-BioNTech and
     Tel.: +39.0961722180 - Fax: +39.0961883093.
                                                          er



     E-mail: ritacarlottasantoro@gmail.com                                      Moderna) that encode the spike protein antigen of Sars-
                                                                                CoV-2, encapsulated in lipid nanoparticles; and two aden-
                                                         m




     Key words: Thrombosis, Thrombocytopenia, Vaccine, SARS-CoV-2.              oviral-vector based vaccines, encoding the SARS-CoV-2
                                                                                spike glycoprotein, ChAdOx1 nCoV-19 (Vaxzervria, Astra-
                                             om




     Contributions: RS wrote the paper. RS, ML, AI, AS, SP collected
     and interpreted data. RM performed all radiological diagnostics.           Zeneca), with a recombinant chimpanzee adenoviral vector
     MF, LE, FL performed laboratory diagnostics. All the authors made          and Ad26.COV2.S (Johnson & Johnson/Jassen), with a re-
                                       -c




     a significant contribution to the discussion, critically revised the       combinant adenovirus type 26 vector. In Italy, vaccination
     paper, and approved the final version for publication
                                                                                was started in January 2021, with most adverse event re-
                              on




     Conflict of interest: The authors declare no potential conflict of in-     ports indicating minor side effects. However, some indi-
     terest.                                                                    viduals receiving the ChAdOx1 nCoV-19 vaccine,
                        N




                                                                                developed a vaccine type-specific complication named vac-
     Funding: None.
                                                                                cine-induced immune thrombotic thrombocytopenia
     Received for publication: 1 March 2022.                                    (VITT) within 4-28 days after the first dose of vaccine.4-6
     Accepted for publication: 6 May 2022.                                      The mortality rate of VITT was high and reached 18% (71
     Publisher’s note: All claims expressed in this article are solely those
                                                                                of 390) in the United Kingdom.7 It has been assumed that
     of the authors and do not necessarily represent those of their affili-     the mechanisms of VITT and autoimmune/spontaneous he-
     ated organizations, or those of the publisher, the editors and the re-     parin-induced thrombocytopenia/thrombosis (HIT/T) are
     viewers. Any product that may be evaluated in this article or claim        similar.6 We present here two cases of VITT which have
     that may be made by its manufacturer is not guaranteed or endorsed         come to our observation. Both cases did not present with
     by the publisher.
                                                                                the more common cerebral venous thrombosis.
     ©
      Copyright: the Author(s), 2022
     Licensee PAGEPress, Italy
     Bleeding, Thrombosis and Vascular Biology 2022; 1:23
                                                                                CASE REPORT #1
     doi:10.4081/btvb.2022.23
                                                                                    We report a case of a 45-year-old male patient who,
     This work is licensed under a Creative Commons Attribution-
     NonCommercial 4.0 International License (CC BY-NC 4.0).                    8 days after the ChAdOx1 nCoV-19 vaccine, presented
                                                                                to the emergency room (ER) for precordial pain. A non-

                                                 Bleeding, Thrombosis and Vascular Biology 2022; 1:23
2                                                              R.C. Santoro et al.




ST elevation myocardial infarction (non-STEMI) heart                         count is normal, 335×103/µL; the patient has fully recov-
attack was diagnosed. Coronary angiography diagnosed                         ered, and he is fine.
coronary thrombosis on uninjured coronaries. A drug-
eluting stent was placed, but 6 hours after the procedure
the patient experienced acute closure, treated with plain                    CASE REPORT #2
old balloon angioplasty (POBA). Later, extensive intra-                           We describe a case of concomitant thrombosis of por-
ventricular thrombosis was diagnosed. The patient was                        tal, superior mesenteric and splenic veins in a 49-year-old
treated with double antiplatelet therapy and enoxaparin                      female patient, with no known risk factors, who had re-
was started. After a further 4 days, due to pain in the                      ceived ChAdOx1 nCoV-19 vaccine, 7 days before.
lower limbs appeared two days after POBA, computed                                The patient went to the ER for abdominal pain and
tomography (CT) with angiography was performed                               melaena. At the time of admission, laboratory data
which highlighted: thrombotic occlusion of the common                        showed prolonged prothrombin time (PT) and activated
right femoral artery and popliteal left, critical thrombotic                 partial thromboplastin time (aPTT), significant reduction
stenosis of the external iliac arteries bilaterally, the hy-                 of plasma fibrinogen (30 mg/dl) and platelet count
pogastric artery and the anterior tibial right, and occlu-                   (30×103 Ul) (Table 1).
sion of a branch of the right hepatic vein at the hepatic                         CT revealed filling defects in the entire spleno-portal
segment. There were also multiple splenic and bilateral                      axis with extension also to the intrahepatic portal




                                                                                                            ly
renal infarcts. A Fogarty catheter embolectomy at the                        branches, to the splenic vein and to the superior mesen-




                                                                                                  on
level of the common femoral artery right was then                            teric vein; and the presence of flap of peritoneal effusion.
performed.                                                                   The patient presented with an episode of extreme brady-
    Three days prior to vaccine administration the platelet                  cardia which required resuscitation. The next day the lab-


                                                                                             e
count was 280×103/µL. On admission in ER the platelets                       oratory data from blood sampling sent to our center
                                                                                     us
count was halved (163×103/µL). Five days after drug-elut-                    showed positivity for heparin-PF4 antibodies (1,55 U/ml),
ing stent placement and one day after embolectomy, the                       low platelet count (32×103/µL), confirming abnormalities
platelet count was 55×103 Ul. Finally, tests HIT (Werfen,                    of PT (PT 41%; INR 1.93), aPTT (aPTT 42.2 sec; ratio
                                                                           al

Barcelona, Spain) were carried out at our center that ex-                    1.33) , and fibrinogen levels (116 mg/dl), together with
                                                              ci

cluded the presence of heparin PF4 antibodies (0.01 U/ml;                    significantly elevated DDimer (61697 ng/ml), reduced
normal value 0-1 U/ml), but at the time of the examination                   levels of protein C and protein S, lupus anticoagulant
                                                            er



the platelets were already increasing. However, it should                    slightly positive, but not univocal interpretation, anticar-
                                                           m




be noted that these tests are often false negative. It was                   diolipin antibodies and Beta-2 glycoprotein 1 (B2GP1)
not possible to perform functional platelet activation                       antibodies negative, absence of Factor V Leiden and Fac-
                                               om




assay, heparin-induced platelet aggregation (HIPA). Ex-                      tor II G20210A mutation.
cept for the DDimer, all other tests, including investiga-                        Treatment with fondaparinux, intravenous high dose
tions for thrombophilia, were normal.                                        immunoglobulins, methylprednisolone and replacement
                                          -c




    The patient switched to fondaparinux therapy and                         therapy with antithrombin, fibrinogen concentrate, and
                                 on




started dexamethasone 40 mg/kg body weight for 4 days.                       prothrombin complex concentrate were initiated.
Three months after the onset of symptoms, the platelet                            Ten days after the event, the patient was in intensive
                             N




Table 1. Temporal correlation between platelet count and thrombosis.
                       Basal      Vaccine Hospitalization,      1           3            5              8      11         13         17
                      platelet                   U/ml        dpost-H,   dpost-H,     dpost-H,     dpost-H,   dpost-H,   dpost-H,   dpost-H,
                      count,                                  U/ml        U/ml         U/ml         U/ml      U/ml       U/ml       U/ml
                       U/ml
Pz 1                  280×10³         -        163×10³       152×10³     118×10³      55×10³       76×10³    85×10³     142×10³    164×10³
Pz 1 thrombosis          -            -         8 days   Acute-stent        -         All other         -       -          -          -
                                               after the  closure                    thrombosis
                                               vaccine
                                              N-STEMI
Pz 2                     -            -         30×10³       32×10³         -            -              -       -          -       152×10³
Pz 2 thrombosis          -            -         7 days          -           -            -              -       -          -        Death
                                               after the
                                             vaccine SVT
H, hospitalization; N-STEMI, non-ST elevation myocardial infarction; SVT, splanchnic vein thrombosis.


                                          Bleeding, Thrombosis and Vascular Biology 2022; 1:23
           Vaccine-induced immune thrombotic thrombocytopenia following AstraZeneca (ChAdOx1 nCoV-19) vaccine                3



care unit, sedated and intubated, she had renal insuffi-           thromboses was only performed after a further two days.
ciency, heparin-PF4 antibodies negative, platelet count            Therefore, although it is not possible to exclude heparin-
and blood clotting parameters normalized. However, the             induced thrombocytopenia, it should be emphasized that
patient died 18 days after the onset of symptoms.                  the temporal criterion would not be respected (the patient
                                                                   would have presented arterial thrombotic manifestations
                                                                   and splenic infarcts after only 2 days from the start of
DISCUSSION                                                         enoxaparin, while the heart attack, stent closure and intra-
                                                                   ventricular thrombosis would have occurred prior to the ad-
    Since the first reports of case series were published in
                                                                   ministration of enoxaparin). The patient had never
April 2021, the number of patients diagnosed with VITT
                                                                   previously been treated with heparin; therefore, rapid onset
associated with the ChAdOx1 nCoV-19 vaccine developed
                                                                   is not justified. These are the reasons why we believe that
by AstraZeneca has grown and continues to grow.4-6 The
                                                                   the diagnosis of VITT is more likely than that of HIT.
Ad26.COV2.S vaccine (Johnson & Johnson) with similar
                                                                       VITT is a rapidly fatal disorder if not recognized and
adenovirus viral vector technology, was also reported to in-
                                                                   treated early. A recent post-mortem report showed exten-
duce thrombocytopenia and thrombosis in the United
                                                                   sive involvement of large venous vessels with thrombotic
States.7
                                                                   occlusions in the microcirculation of multiple organs.
    Most patients with VITT present with thrombosis at un-
                                                                   These findings indicated the progression of an inflamma-
usual sites, such as the cerebral venous sinus or the splanch-




                                                                                    ly
                                                                   tory process that culminates in microvascular injury of
nic vein, with concomitant severe thrombocytopenia.4-7




                                                                             on
                                                                   multiple organs by iatrogenic activation of the innate im-
Thrombosis reported are predominantly venous thrombo-
                                                                   mune system along with the complement pathway.14
sis, but sporadic cases of arterial thrombosis are also re-
                                                                       The Italian Society for the Study of Hemostasis and
ported.8-12 The onset of VITT is usually 4–28 days after


                                                                        e
                                                                   Thrombosis – SISET, as well as other scientific societies,
vaccination.4-7 Although the exact pathogenesis and risk         ushave provided some recommendations based on the con-
factors of VITT are still unknown, many laboratory find-
                                                                   sensus of experts for the management of cerebral and
ings support the hypothesis that the mechanism of throm-
                                                                   splanchnic venous thrombotic events associated with
bocytopenia and thrombosis is similar to that of
                                                            al
                                                                   thrombocytopenia occurred in subjects vaccinated within
autoimmune HIT/T in that the anti-PF4 antibody may be
                                                                   30 days with the Vaxzervria vaccine.15 In accordance with
                                               ci

induced by polyanions, including lipid A, in bacterial sur-
                                                                   these recommendations, we have diagnosed and managed
face nucleic acids instead of heparin.6 For VITT, some com-
                                             er



                                                                   two cases of VITT. Both the patients presented to hospital
ponents of the vaccine, for example, the adenovirus DNA,
                                                                   1-2 weeks after their first dose of the AstraZeneca vaccine,
                                            m




spike protein, and/or neoantigen induced by the vaccine,
                                                                   although the second patient was hospitalized three days
have been proposed to be key components that could in-
                                   om




                                                                   after the onset of symptoms. Positive anti-PF4 antibodies
duce PF4 release and anti-PF4 antibody production.13
                                                                   were detected only in one of two cases, probably due to the
    In our first case we cannot entirely exclude that we are
                                                                   delay in sending the sample for determination of anti-PF4
faced with a HIT, but there are some considerations to be
                             -c




                                                                   antibodies. In neither case was it possible to carry out the
made. At the time of admission in ER, even before any
                                                                   HIPA confirmation test. Both patients were treated with a
                      on




therapy, the patient had platelet values almost halved,
                                                                   non-heparin anticoagulant and dexamethasone.
compared to the platelet count taken immediately before
the vaccine (280×103/mmc → 163×103/mmc. Further-
                 N




more, the patient had no risk factors for heart attack and
                                                                   CONCLUSIONS
on coronary angiography there was a coronary artery
thrombosis on uninjured coronaries. He immediately un-                 Clinicians must be alerted to the possibility of such a
derwent PTCA with drug eluting stent placement, with               precipitously fatal complication while vaccine recipients
fondaparinux, lysine acetylsalicylate and then concomi-            should be warned about the symptoms of VITT. The rapid
tant administration of cangrelor and ticagrelor. After only        recognition of the pathology is fundamental, in fact
6 hours from stent placement, pain in the shoulder and left        prompt treatment can improve the patient’s outcome.
arm with evidence of ST displacement and acute stent clo-          More research data, data collections, reports, registries,
sure. POBA was performed and only after this second ma-            especially about the risk factors and pathogenesis of the
neuver therapy with enoxaparin was started. Immediately            syndrome, are needed to encourage patients to be vacci-
after there was echocardiographic evidence of multiple             nated confidently.
extensive apical thrombotic manifestations.                            In Italy, the SISET VAX COVID 19 study promoted
    Two days after POBA (30 hours after the admission to           by SISET aims to consecutively record all thrombosis
ER), pain in the lower limbs and abdomen appeared, which           events associated or not associated with thrombocytope-
worsened the next day, becoming more and more intense,             nia arising after vaccines against SARS-CoV-2, to collect
but unfortunately the angio-CT which showed all other              as much information as possible on the events, to ade-

                                      Bleeding, Thrombosis and Vascular Biology 2022; 1:23
4                                                         R.C. Santoro et al.




quately characterize them, provide useful data for the for-                  Thrombocytopenia Related Acute Ischemic Stroke. J Stroke
mulation of pathogenetic hypotheses and for the design                       Cerebrovasc Dis 2021;30:106072.
of any intervention studies.16                                          9.   Al-Mayhani T, Saber S, Stubbs MJ, et al. Ischaemic stroke
                                                                             as a presenting feature of ChAdOx1 nCoV-19 vaccine-in-
                                                                             duced immune thrombotic thrombocytopenia. J Neurol Neu-
                                                                             rosurg Psychiatry 2021;92:1247-8.
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                                                     m
                                            om
                                      -c
                               on
                          N




                                       Bleeding, Thrombosis and Vascular Biology 2022; 1:23
