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

Alessandra Strangio

Antonella Ierardi

Francesca Leo

Lucia Concetta Elia

Mariapia Falbo

Marzia Leotta

Rita Carlotta Santoro

Roberto Minici

Simona Prejanò

Undetermined

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Bleeding, Thrombosis and Vascular Biology 2022; 1:23CASE REPORTINTRODUCTIONThe Coronavirus Disease 2019 (COVID-19) pandemichas affected health and economic systems globally. Shortlyafter the first case series was reported in China,1 the numberof new cases increased exponentially. COVID-19 is a seri-ous infectious disease with a high mortality rate of up to3.4% among infected patients.2 Vaccines against severeacute respiratory syndrome coronavirus 2 (SARS_CoV-2)are the most important countermeasure to fight the COVID-19 pandemic. From December 2020 through March 2021,the European Medicines Agency approved four vaccineson the basis of randomized, blinded, controlled trials:3 twomessenger RNA-based vaccines (Pfizer-BioNTech andModerna) that encode the spike protein antigen of Sars-CoV-2, encapsulated in lipid nanoparticles; and two aden-oviral-vector based vaccines, encoding the SARS-CoV-2spike glycoprotein, ChAdOx1 nCoV-19 (Vaxzervria, Astra-Zeneca), with a recombinant chimpanzee adenoviral vectorand Ad26.COV2.S (Johnson & Johnson/Jassen), with a re-combinant adenovirus type 26 vector. In Italy, vaccinationwas started in January 2021, with most adverse event re-ports indicating minor side effects. However, some indi-viduals receiving the ChAdOx1 nCoV-19 vaccine,developed a vaccine type-specific complication named vac-cine-induced immune thrombotic thrombocytopenia(VITT) within 4-28 days after the first dose of vaccine.4-6The mortality rate of VITT was high and reached 18% (71of 390) in the United Kingdom.7 It has been assumed thatthe mechanisms of VITT and autoimmune/spontaneous he-parin-induced thrombocytopenia/thrombosis (HIT/T) aresimilar.6 We present here two cases of VITT which havecome to our observation. Both cases did not present withthe more common cerebral venous thrombosis. CASE REPORT #1We report a case of a 45-year-old male patient who,8 days after the ChAdOx1 nCoV-19 vaccine, presentedto the emergency room (ER) for precordial pain. A non-Vaccine-induced immune thrombotic thrombocytopenia following AstraZeneca(ChAdOx1 nCoV-19) vaccine: report of two casesRita Carlotta Santoro,1 Roberto Minici,2 Marzia Leotta,1 Mariapia Falbo,1 Lucia Concetta Elia,1 Francesca Leo,1Antonella Ierardi,1 Alessandra Strangio,1 Simona Prejanò11Hemostasis and Thrombosis Center Unit; and 2Diagnostic Radiology Unit, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, ItalyABSTRACTVaccination with ChAdOx1 nCoV-19 can result in vaccine-induced immune thrombotic thrombocytopenia (VITT). This phenomenonmimics 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 VITTis a production of antibodies against platelet factor-4 resulting in massive platelet activation. Healthcare providers should be aware ofthe possibility of such a fatal complication, and the vaccine recipients should be warned about the symptoms of VITT.Correspondence: Rita Carlotta Santoro, Hemostasis and Thrombo-sis Unit, Azienda Ospedaliera “Pugliese Ciaccio”, Viale Pio X 83,88100 Catanzaro (CZ), Italy. Tel.: +39.0961722180 - Fax: +39.0961883093.E-mail: ritacarlottasantoro@gmail.com  Key words: Thrombosis, Thrombocytopenia, Vaccine, SARS-CoV-2.Contributions: RS wrote the paper. RS, ML, AI, AS, SP collectedand interpreted data. RM performed all radiological diagnostics.MF, LE, FL performed laboratory diagnostics. All the authors madea significant contribution to the discussion, critically revised thepaper, and approved the final version for publication Conflict of interest: The authors declare no potential conflict of in-terest. Funding: None.Received for publication: 1 March 2022.Accepted for publication: 6 May 2022.Publisher’s note: All claims expressed in this article are solely thoseof the authors and do not necessarily represent those of their affili-ated organizations, or those of the publisher, the editors and the re-viewers. Any product that may be evaluated in this article or claimthat may be made by its manufacturer is not guaranteed or endorsedby the publisher.©Copyright: the Author(s), 2022Licensee PAGEPress, ItalyBleeding, Thrombosis and Vascular Biology 2022; 1:23doi:10.4081/btvb.2022.23This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).Non-commercial use onlyR.C. Santoro et al.2ST elevation myocardial infarction (non-STEMI) heartattack was diagnosed. Coronary angiography diagnosedcoronary thrombosis on uninjured coronaries. A drug-eluting stent was placed, but 6 hours after the procedurethe patient experienced acute closure, treated with plainold balloon angioplasty (POBA). Later, extensive intra-ventricular thrombosis was diagnosed. The patient wastreated with double antiplatelet therapy and enoxaparinwas started. After a further 4 days, due to pain in thelower limbs appeared two days after POBA, computedtomography (CT) with angiography was performedwhich highlighted: thrombotic occlusion of the commonright femoral artery and popliteal left, critical thromboticstenosis of the external iliac arteries bilaterally, the hy-pogastric artery and the anterior tibial right, and occlu-sion of a branch of the right hepatic vein at the hepaticsegment. There were also multiple splenic and bilateralrenal infarcts. A Fogarty catheter embolectomy at thelevel of the common femoral artery right was thenperformed. Three days prior to vaccine administration the plateletcount was 280×103/µL. On admission in ER the plateletscount was halved (163×103/µL). Five days after drug-elut-ing stent placement and one day after embolectomy, theplatelet count was 55×103 Ul. Finally, tests HIT (Werfen,Barcelona, Spain) were carried out at our center that ex-cluded the presence of heparin PF4 antibodies (0.01 U/ml;normal value 0-1 U/ml), but at the time of the examinationthe platelets were already increasing. However, it shouldbe noted that these tests are often false negative. It wasnot possible to perform functional platelet activationassay, heparin-induced platelet aggregation (HIPA). Ex-cept for the DDimer, all other tests, including investiga-tions for thrombophilia, were normal.The patient switched to fondaparinux therapy andstarted dexamethasone 40 mg/kg body weight for 4 days.Three months after the onset of symptoms, the plateletcount is normal, 335×103/µL; the patient has fully recov-ered, and he is fine.CASE REPORT #2We describe a case of concomitant thrombosis of por-tal, superior mesenteric and splenic veins in a 49-year-oldfemale patient, with no known risk factors, who had re-ceived ChAdOx1 nCoV-19 vaccine, 7 days before.The patient went to the ER for abdominal pain andmelaena. At the time of admission, laboratory datashowed prolonged prothrombin time (PT) and activatedpartial thromboplastin time (aPTT), significant reductionof plasma fibrinogen (30 mg/dl) and platelet count(30×103 Ul) (Table 1). CT revealed filling defects in the entire spleno-portalaxis with extension also to the intrahepatic portalbranches, to the splenic vein and to the superior mesen-teric vein; and the presence of flap of peritoneal effusion.The patient presented with an episode of extreme brady-cardia which required resuscitation. The next day the lab-oratory data from blood sampling sent to our centershowed positivity for heparin-PF4 antibodies (1,55 U/ml),low platelet count (32×103/µL), confirming abnormalitiesof PT (PT 41%; INR 1.93), aPTT (aPTT 42.2 sec; ratio1.33) , and fibrinogen levels (116 mg/dl), together withsignificantly elevated DDimer (61697 ng/ml), reducedlevels of protein C and protein S, lupus anticoagulantslightly positive, but not univocal interpretation, anticar-diolipin antibodies and Beta-2 glycoprotein 1 (B2GP1)antibodies negative, absence of Factor V Leiden and Fac-tor II G20210A mutation. Treatment with fondaparinux, intravenous high doseimmunoglobulins, methylprednisolone and replacementtherapy with antithrombin, fibrinogen concentrate, andprothrombin complex concentrate were initiated.Ten days after the event, the patient was in intensiveBleeding, Thrombosis and Vascular Biology 2022; 1:23Table 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/mlPz 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-STEMIPz 2                                   -                   -               30×10³          32×10³               -                    -                    -                    -                    -             152×10³Pz 2 thrombosis                -                   -                7 days                -                    -                    -                    -                    -                    -               Death                                                                             after the                                                                          vaccine SVTH, hospitalization; N-STEMI, non-ST elevation myocardial infarction; SVT, splanchnic vein thrombosis.No-commercial us olyVaccine-induced immune thrombotic thrombocytopenia following AstraZeneca (ChAdOx1 nCoV-19) vaccine 3care unit, sedated and intubated, she had renal insuffi-ciency, heparin-PF4 antibodies negative, platelet countand blood clotting parameters normalized. However, thepatient died 18 days after the onset of symptoms.DISCUSSION Since the first reports of case series were published inApril 2021, the number of patients diagnosed with VITTassociated with the ChAdOx1 nCoV-19 vaccine developedby AstraZeneca has grown and continues to grow.4-6 TheAd26.COV2.S vaccine (Johnson & Johnson) with similaradenovirus viral vector technology, was also reported to in-duce thrombocytopenia and thrombosis in the UnitedStates.7Most patients with VITT present with thrombosis at un-usual sites, such as the cerebral venous sinus or the splanch-nic vein, with concomitant severe thrombocytopenia.4-7Thrombosis reported are predominantly venous thrombo-sis, but sporadic cases of arterial thrombosis are also re-ported.8-12 The onset of VITT is usually 4–28 days aftervaccination.4-7 Although the exact pathogenesis and riskfactors of VITT are still unknown, many laboratory find-ings support the hypothesis that the mechanism of throm-bocytopenia and thrombosis is similar to that ofautoimmune HIT/T in that the anti-PF4 antibody may beinduced by polyanions, including lipid A, in bacterial sur-face nucleic acids instead of heparin.6 For VITT, some com-ponents of the vaccine, for example, the adenovirus DNA,spike protein, and/or neoantigen induced by the vaccine,have been proposed to be key components that could in-duce PF4 release and anti-PF4 antibody production.13In our first case we cannot entirely exclude that we arefaced with a HIT, but there are some considerations to bemade. At the time of admission in ER, even before anytherapy, the patient had platelet values almost halved,compared to the platelet count taken immediately beforethe vaccine (280×103/mmc → 163×103/mmc. Further-more, the patient had no risk factors for heart attack andon coronary angiography there was a coronary arterythrombosis on uninjured coronaries. He immediately un-derwent PTCA with drug eluting stent placement, withfondaparinux, lysine acetylsalicylate and then concomi-tant administration of cangrelor and ticagrelor. After only6 hours from stent placement, pain in the shoulder and leftarm with evidence of ST displacement and acute stent clo-sure. POBA was performed and only after this second ma-neuver therapy with enoxaparin was started. Immediatelyafter there was echocardiographic evidence of multipleextensive apical thrombotic manifestations.Two days after POBA (30 hours after the admission toER), pain in the lower limbs and abdomen appeared, whichworsened the next day, becoming more and more intense,but unfortunately the angio-CT which showed all otherthromboses was only performed after a further two days.Therefore, although it is not possible to exclude heparin-induced thrombocytopenia, it should be emphasized thatthe temporal criterion would not be respected (the patientwould have presented arterial thrombotic manifestationsand splenic infarcts after only 2 days from the start ofenoxaparin, while the heart attack, stent closure and intra-ventricular thrombosis would have occurred prior to the ad-ministration of enoxaparin). The patient had neverpreviously been treated with heparin; therefore, rapid onsetis not justified. These are the reasons why we believe thatthe diagnosis of VITT is more likely than that of HIT.VITT is a rapidly fatal disorder if not recognized andtreated early. A recent post-mortem report showed exten-sive involvement of large venous vessels with thromboticocclusions in the microcirculation of multiple organs.These findings indicated the progression of an inflamma-tory process that culminates in microvascular injury ofmultiple organs by iatrogenic activation of the innate im-mune system along with the complement pathway.14The Italian Society for the Study of Hemostasis andThrombosis – SISET, as well as other scientific societies,have provided some recommendations based on the con-sensus of experts for the management of cerebral andsplanchnic venous thrombotic events associated withthrombocytopenia occurred in subjects vaccinated within30 days with the Vaxzervria vaccine.15 In accordance withthese recommendations, we have diagnosed and managedtwo cases of VITT. Both the patients presented to hospital1-2 weeks after their first dose of the AstraZeneca vaccine,although the second patient was hospitalized three daysafter the onset of symptoms. Positive anti-PF4 antibodieswere detected only in one of two cases, probably due to thedelay in sending the sample for determination of anti-PF4antibodies. In neither case was it possible to carry out theHIPA confirmation test. Both patients were treated with anon-heparin anticoagulant and dexamethasone. CONCLUSIONSClinicians must be alerted to the possibility of such aprecipitously fatal complication while vaccine recipientsshould be warned about the symptoms of VITT. The rapidrecognition of the pathology is fundamental, in factprompt treatment can improve the patient’s outcome.More research data, data collections, reports, registries,especially about the risk factors and pathogenesis of thesyndrome, are needed to encourage patients to be vacci-nated confidently. In Italy, the SISET VAX COVID 19 study promotedby SISET aims to consecutively record all thrombosisevents associated or not associated with thrombocytope-nia arising after vaccines against SARS-CoV-2, to collectas much information as possible on the events, to ade-Bleeding, Thrombosis and Vascular Biology 2022; 1:23Non-commercial ue onlyR.C. Santoro et al.4quately characterize them, provide useful data for the for-mulation of pathogenetic hypotheses and for the designof any intervention studies.16REFERENCES1. Huang C, Wang Y, Li X, et al. Clinical features of patientsinfected with 2019 novel coronavirus in Wuhan. ChinaLancet 2020;395:497–506.2. Worldometers. Coronavirus (COVID-19) Mortality Rate.Available from: https://www.worldometers.info/coron-avirus/coronavirus-death-rate/ [Accessed 14 September2021].3. Forni G, Mantovani A, Forni G, et al. COVID-19 vaccines:where we stand and challenges ahead. Cell Death Differ2021;28:626-39.4. Scully M, Singh D, Lown R, et al. Pathologic antibodies toplatelet factor 4 after ChAdOx1 nCoV-19 vaccination. NEngl J Med 2021;384:2202-11.5. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosisand thrombocytopenia after ChAdOx1 nCoV-19 vaccina-tion. N Engl J Med 2021;384:2124-30.6. Greinacher A, Thiele T, Warkentin TE, et al. Thromboticthrombocytopenia after ChAdOx1 nCov-19 vaccination. NEngl J Med 2021;384:2092-101.7. See I, Su JR, Lale A, et al. US Case Reports of Cerebral Ve-nous Sinus Thrombosis With Thrombocytopenia AfterAd26.COV2.S Vaccination, March 2 to April 21, 2021.JAMA 2021;325:2448-56.8. Kenda J, Lovric D, Skerget M, Milivojevic N. Treatment ofChAdOx1 nCoV-19 Vaccine-Induced Immune ThromboticThrombocytopenia Related Acute Ischemic Stroke. J StrokeCerebrovasc Dis 2021;30:106072.9. Al-Mayhani T, Saber S, Stubbs MJ, et al. Ischaemic strokeas a presenting feature of ChAdOx1 nCoV-19 vaccine-in-duced immune thrombotic thrombocytopenia. J Neurol Neu-rosurg Psychiatry 2021;92:1247-8.10. De Michele M, Iacobucci M, Chistolini A, et al. Malignantcerebral infarction after ChAdOx1 nCoV-19 vaccination: acatastrophic variant of vaccine-induced immune thromboticthrombocytopenia. Nat Commun 2021;12:4663.11. Blauenfeldt RA, Kristensen SR, Ernstsen SL, et al. Throm-bocytopenia with acute ischemic stroke and bleeding in apatient newly vaccinated with an adenoviral vector-basedCOVID-19 vaccine. J Thromb Haemost 2021;19:1771-5.12. Walter U, Fuchs M, Grossmann A, et al. Adenovirus-vec-tored COVID-19 vaccine-induced immune thrombosis ofcarotid artery: a case report. Neurology 2021;10:1212.13. Arepally GM, Ortel TL. Vaccine-Induced Immune Throm-botic Thrombocytopenia (VITT): What We Know and Don’tKnow. Blood 2021;138:293-8.14. Ponero C, Sessa F, Ciaccio M et al. Post-mortem findingsin vaccine-induced thrombotic thrombocytopenia. Haema-tologica 2021;106:2291-3.15. Gresele P, Marietta M, Ageno W, et al. Management of cere-bral and splanchnic vein thrombosis associated with throm-bocytopenia in subjects previously vaccinated withVaxrevria: a position statement from the Italian Society forthe Study of Haemostasis and Thrombosis (SISET). BloodTransf 2021;19:281-3.16. SISET. Database nazionale sui casi di trombosi dopo vacci-nazione contro Sars-CoV-2: SISET VAX COVID-19. Avail-able from: https://www.siset.org/sisetvaxcovid-19/ [Accessed2 September 2021].Bleeding, Thrombosis and Vascular Biology 2022; 1:23Non-commercial use only

Vaccine-induced immune thrombotic thrombocytopenia following AstraZeneca (ChAdOx1 nCoV-19) vaccine: report of two cases

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Vaccine-induced immune thrombotic thrombocytopenia following AstraZeneca (ChAdOx1 nCoV-19) vaccine: report of two cases

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