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Thrombotic thrombocytopenic purpura and other immune mediated blood disorders following SARS-CoV-2 Vaccination

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Thrombotic thrombocytopenic purpura and other immune
mediated blood disorders following SARS-CoV-2
by Pier Mannuccio Mannucci
Received: July 29, 2021.
Accepted: August 2, 2021.
Citation: Pier Mannuccio Mannucci. Thrombotic thrombocytopenic purpura and other immune
mediated blood disorders following SARS-CoV-2 xaccination.
Haematologica. 2021 Aug 12. doi: 10.3324/haematol.2021.279649. [Epub ahead of print]
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Thrombotic thrombocytopenic purpura and other immune mediated blood disorders
following SARS-CoV-2 Vaccination
Pier Mannuccio Mannucci
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi
Hemophilia and Thrombosis Center, Milan, Italy
Running title: vaccine induced blood disorders
Keywords: immune thrombocytopenic purpura, autoimmune hemophilia, vaccine-
induced immune thrombotic thrombocytopenia, COVID-19 vaccine, acquired bleeding
Correspondence to: P.M. Mannucci
Via Pace 9, 20122 Milano, Italy
Phone +39 0255035421
Giuffrida et al (1) report two cases of new-onset, immune-mediated thrombotic
thrombocytopenic purpura (TTP) in 81-year-old and 30-year-old women diagnosed with
this very rare disease 14 and 18 days after the first dose of the mRNA-based vaccine
against SARS-CoV-2 manufactured by Pfizer-BioNTech. The oldest woman (case 1) had a
history of diabetes and connective tissue disease positive for antinuclear antibodies,
whereas the youngest case 2 had was negative regarding clinical history and laboratory
markers of potential triggers of TTP such as autoimmune, tumoral and infectious diseases.
Both cases were promptly treated with glucocorticoids and daily sessions of plasma
exchange (PEX) each followed by the nanobody caplacizumab. This state-of-the-art
therapeutic approach based upon plasma therapy, immunomodulation and anti-VWF
medicines was successful in the younger woman, with a rapid normalization of the very
low platelet count, even though plasma ADAMTS13 was still unmeasurable on days 14
and 30 after 8 PEX and anti-ADAMTS 13 were still present. In the oldest woman with
comorbidities, there was only a modest improvement of the platelet count and she died
suddenly after the second PEX owing to an ill defined cardiac event, thus witnessing once
again that notwithstanding a prompt and impeccable management TTP is still associated
with a significant mortality toll.
The main interest of these two cases stays with the fact that autoimmune TTP occurred
afresh within two-three weeks from the first dose of an anti-COVID-19 vaccine. Its
administration within this short time window as well as no evidence for other causes (at
least in the youngest woman) are consistent for causality according to the WHO criteria
for post-vaccination adverse events (2). Until now, new-onset TTP was reported as a single
case after the Johnson and Johnson vaccine based upon a human adenovirus vector (3) and
a relapse of recurrent TTP occurred 6 days after the second dose of the Pfizer-BioNTech
vaccine (4). The new-onset cases described herewith by Giuffrida et al (1) of such a rare
immune mediated blood disease associated with a bleeding tendency follow the report of
a mRNA-vaccine (Pfizer-BioNTech)-associated case of autoimmune hemophilia due to
anti-factor VIII antibodies (5) and multiple cases of immune thrombocytopenic purpura
(ITP) owing to platelet autoantibodies occurring after either mRNA-based vaccine
produced by Pfizer and Moderna (6). Common features of these cases are that the
majority of them occurred in women, at young but also at older ages, thus reproducing the
two typical age peaks of occurrence of autoimmune diseases. At variance with the recent
reports of vaccine-induced immune thrombotic thrombocytopenia (VITT) (7), these cases
were not associated with thrombosis in the cerebral and abdominal veins but only with
hemorrhagic symptoms compatible with the degree of thrombocytopenia in ITP and TTP
and of factor VIII deficiency in autoimmune acquired hemophilia. Another feature that
distinguishes from VITT these cases is that they were not accompanied by serological
positivity for autoantibodies directed towards platelet factor 4. Table 1 summarizes the
main clinical symptoms and laboratory findings in the different thrombocytopenias that
did occur post-COVID vaccination.
Which general messages may be drawn from these reports of immune-mediated
hematological diseases associated with a bleeding tendency in persons recently vaccinated
to prevent COVID-19? It is well established that a number of diseases due to the formation
of autoantibodies against autologous cells and/or proteins may occur after vaccination
against various infectious agents (8-10): common examples are measles-mumps-rubella
and diphtheria-tetanus-pertussis, but also polio, rabies, influenza and bacterial
pneumonia, especially in children but also in adults. There is no evidence that the
innovative technologies recently developed for anti-COVID vaccine production had a
peculiar role in the dysregulation of the immune system that led to the production of
antibodies other than those towards the spike SARS-CoV-2 protein, because autoimmune
diseases did occur after all types of vaccines, spanning from those traditionally based
upon inactivated virions to those newly employing viral DNA vectors or mRNA
technology (8-10). Among them, only VITT appears to be peculiar, because this
complication was so far described with convincing documentation only in patients
receiving the vaccines based upon adenoviral vectors, such as the AstraZeneca and the
Johnson- and Johnson products. In VITT the very rare but catastrophic
thrombohemorrhagic complications are due to the formation of highly pathogenic
autoantibodies against a complex between platelet factor 4 and a still poorly defined
polyanion that triggers platelet activation, consumptive thrombocytopenia and a
hypercoagulable state perhaps amplified by antibody induced NETosis (7). However, it is
as yet not fully understood why venous thrombi occur in unusual sites, nor is definitely
known the source and composition of the polyanion. Moreover, it is still uncertain
whether or not these rare post-vaccination diseases are more frequent than expected in the
population at large, because epidemiologically-based studies evaluating their incidence in
vaccinated versus non-vaccinated persons are scanty or absent. The reported prevalences
in vaccinated persons, usually affected by limited sample size, range from 1 in 50.000-
100.000 for VITT depending on the age and gender of vaccine recipients to a lower
prevalence (one in one million) for ITP (6,11,12).
An array of innate or adaptive immunological mechanisms may be responsible for these
adverse events, but vaccine-induced danger signals accompanied by inflammation, as well
as antigenic mimicry with activation of quiescent autoreacting B and T cells, are the most
plausible (8,10). It is unlikely that adjuvants, frequently employed in some vaccines in
order to boost antibody production towards the target antigen, played a pathogenic role,
because the currently licensed anti-COVID vaccines do not need nor contain such typical
adjuvants as squalene and aluminum, owing to the fact that their RNA and DNA
components offer intrinsic adjuvanticity.
On the whole, these exceptional cases of immune mediated hematological diseases
associated with bleeding and/or thrombosis that occurred in the current frame of global
vaccination of more than 400 million people should not put in doubt nor jeopardize, in
general and in the specific instance of COVID-19, the effectiveness of vaccines, that are the
only weapon currently available to control this pandemic. The majority of ITP and TTP
cases seem to be less severe than VITT and are usually not life-threatening, except in older
multimorbid persons such as case 2. In addition, it appears that within the limited amount
of available knowledge owing to recent onset and short follow-up of these complications,
responses to state-of-the-art therapies, as well as tendency to recur or become chronic, are
not overtly different from the cases that occur irrespective of vaccination. By the same
token, no prophylactic measure is warranted before nor after vaccination, because useless
and potential dangerous.
1. Giuffrida G, Condorelli A, Di Giorgio MA, et al. Immune-mediated thrombotic
thrombocytopenic purpura following Pfizer-BioNTech COVID-19 vaccine.
Haematologica. 2021 XXX.
2. World Health Organization. Global manual on surveillance of adverse effect
following immunization. 2015 Update. World Health Organization. 2014.
3. Yocum A, Simon EL. Thrombotic thrombocytopenic purpura after Ad26.COV2-S
vaccination. Am J Emerg Med. 2021 May 4. [Online ahead of print]
4. Sissa C, Al-Khaffaf A, Frattini F, et al. Relapse of thrombotic thrombocytopenic
purpura after COVID-19 vaccine. Transfus Apher Sci. 2021 Apr 16. [Onlien ahead of
5. Radwi M, Farsi S. A case report of acquired hemophilia following COVID-19 vaccine.
J Thromb Haemost. 2021;19(6):1515-1518.
6. Lee EJ, Cines DB, Gernsheimer T, et al. Thrombocytopenia following Pfizer and
Moderna SARS-CoV-2 vaccination. Am J Hematol. 2021;96(5):534-537.
7. Cines DB, Bussel JB. SARS-CoV-2 Vaccine-induced immune thrombotic
thrombocytopenia. N Engl J Med. 2021;384(23):2254-2256.
8. Guimarães LE, Baker B, Perricone C, Shoenfeld Y. Vaccines, adjuvants and
autoimmunity. Pharmacol Res. 2015;100:190-209.
9. Perricone C, Ceccarelli F, Nesher G, et al. Immune thrombocytopenic purpura (ITP)
associated with vaccinations: a review of reported cases. Immunol Res. 2014;60(2-
10. Watad A, De Marco G, Mahajna H, et al. Immune-mediated disease flares or new-
onset disease in 27 subjects following mRNA/DNA SARS-CoV-2 Vaccination.
Vaccines (Basel). 2021;9(5):435.
11. Simpson CR, Shi T, Vasileiou E, et al. First-dose ChAdOx1 and BNT162b2 COVID-19
vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in
Scotland. Nat Med. 2021;27(7):1290-1297.
12. Pottegård A, Lund LC, Karlstad Ø, et al. Arterial events, venous thromboembolism,
thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca
ChAdOx1-S in Denmark and Norway: population based cohort study. BMJ.
Table 1: Main features of vaccine-induced, immune mediated thrombocytopenias
Disease (and acronym) Severe
(< 10x109/L)
hemorrhage Associated
thrombosis Thrombosis
sites Laboratory
Immune thrombocytopenic
purpura (ITP)
Thrombotic thrombocytopenic
purpura (TTP) Frequent Rare Rare
microvascular Microcirculation
of heart, brain
and GI tract
deficiency and
thrombotic thrombocytopenia
Cerebral and
abdominal veins
... [9][10][11][12][13] Given the current massive vaccination due to the SARS-CoV-2 pandemic, new onset iTTP has been documented following a vector based Ad26.COV2-S vaccine 14 and we recently described two new onset cases following the first dose of the Pfizer-BioNTech COVID-19 vaccine. 15,16 Here we describe our real-life single center experience of iTTP monitoring following mRNA COVID-19 vaccination in order to early detect any disease relapse. ...
... 20 Since the beginning of the global COVID-19 vaccination various cases of autoimmune activations, both as new-onset and disease flares, were reported. 16 Watad and colleagues described 27 subjects with different autoimmune reactions that occurred on average 4 days following SARS-CoV-2 vaccination, including 17 flares and 10 new onsets. Twenty-three of 27 cases had received Pfizer-BioNTech, while Moderna and ChAdOx1 vaccines were received in two cases each. ...
Full-text available
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease. Vaccination has been reported to be a trigger of onset and relapse of autoimmune diseases. We evaluated after mRNA COVID-19 vaccination 32 adult patients previously diagnosed with iTTP by means of weekly monitoring of complete blood count and ADAMTS13 testing. Thirty of 32 patients received at least one dose of Pfizer-BioNTech, the remaining two received Moderna. A total of five patients, all vaccinated with Pfizer-BioNTech, had a biochemical relapse at a median post-vaccination time of 15 days following the second or third vaccine dose, presenting with unmeasurable ADAMTS13 activity and a median anti-ADAMTS13 autoantibody value of 34 U/ml. Four of five cases had concomitant clinical relapse and were treated with corticosteroids alone or daily sessions of plasma exchange and caplacizumab, while one patient was closely monitored with ADAMTS13 with no onset of anemia and thrombocytopenia. Although the benefits of vaccination exceed its potential risks, clinicians should be aware that iTTP relapse might follow COVID-19 vaccination. Therefore, laboratory and clinical monitoring of iTTP patients should be done in the first post-vaccination month, in order to promptly diagnose and treat any relapse.
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U hrvatskim je medijima sve više govora o cijepljenju djece protiv covid-19, unatoč maloj ulozi djece u prijenosu novog koronavirusa i njihovom malom riziku od teških simptoma, postojanju drugih oblika prevencije, činjenici da klinička ispitivanja nisu dovršena, raznih problema u provedenim ispitivanjima i rastućoj zabrinutosti oko sigurnosti cjepiva i mogućih štetnih učinaka. Cilj je ovog kratkog pregleda odabrane znanstvene literature potaknuti kvalitetnu javnu raspravu prije donošenja potencijalno ishitrenih odluka.
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Reports of ChAdOx1 vaccine–associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0–27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41–13.83), with an estimated incidence of 1.13 (0.62–1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29–3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12–1.34) 0–27 d after vaccination, with an SCCS RR of 0.97 (0.93–1.02). For hemorrhagic events 0–27 d after vaccination, the aRR was 1.48 (1.12–1.96), with an SCCS RR of 0.95 (0.82–1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events. New data from the EAVE II cohort in Scotland suggests that a first dose of the ChAdOx1 nCoV-19 vaccine might be associated with a small increase in the risk of idiopathic thrombocytopenic purpura between 0 and 27 d after vaccination.
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Objective: To assess rates of cardiovascular and haemostatic events in the first 28 days after vaccination with the Oxford-AstraZeneca vaccine ChAdOx1-S in Denmark and Norway and to compare them with rates observed in the general populations. Design: Population based cohort study. Setting: Nationwide healthcare registers in Denmark and Norway. Participants: All people aged 18-65 years who received a first vaccination with ChAdOx1-S from 9 February 2021 to 11 March 2021. The general populations of Denmark (2016-18) and Norway (2018-19) served as comparator cohorts. Main outcome measures: Observed 28 day rates of hospital contacts for incident arterial events, venous thromboembolism, thrombocytopenia/coagulation disorders, and bleeding among vaccinated people compared with expected rates, based on national age and sex specific background rates from the general populations of the two countries. Results: The vaccinated cohorts comprised 148 792 people in Denmark (median age 45 years, 80% women) and 132 472 in Norway (median age 44 years, 78% women), who received their first dose of ChAdOx1-S. Among 281 264 people who received ChAdOx1-S, the standardised morbidity ratio for arterial events was 0.97 (95% confidence interval 0.77 to 1.20). 59 venous thromboembolic events were observed in the vaccinated cohort compared with 30 expected based on the incidence rates in the general population, corresponding to a standardised morbidity ratio of 1.97 (1.50 to 2.54) and 11 (5.6 to 17.0) excess events per 100 000 vaccinations. A higher than expected rate of cerebral venous thrombosis was observed: standardised morbidity ratio 20.25 (8.14 to 41.73); an excess of 2.5 (0.9 to 5.2) events per 100 000 vaccinations. The standardised morbidity ratio for any thrombocytopenia/coagulation disorders was 1.52 (0.97 to 2.25) and for any bleeding was 1.23 (0.97 to 1.55). 15 deaths were observed in the vaccine cohort compared with 44 expected. Conclusions: Among recipients of ChAdOx1-S, increased rates of venous thromboembolic events, including cerebral venous thrombosis, were observed. For the remaining safety outcomes, results were largely reassuring, with slightly higher rates of thrombocytopenia/coagulation disorders and bleeding, which could be influenced by increased surveillance of vaccine recipients. The absolute risks of venous thromboembolic events were, however, small, and the findings should be interpreted in the light of the proven beneficial effects of the vaccine, the context of the given country, and the limitations to the generalisability of the study findings.
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Background: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs. Methods: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes. Findings: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Other immune-mediated conditions included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare. Interpretation: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred. Funding: none.
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Acquires haemophilia A (AHA) is rare bleeding condition commonly associated with malignancy, autoimmune disease, or pregnancy. We report a case of a 69‐year‐old gentleman who developed bleeding symptoms after receiving COVID‐19 vaccine. Laboratory testing showed isolated prolongation of the activated partial thromboplastin time, and normal Von‐Willebrand factor. Further testing confirmed the presence of factor eight inhibitor. To date, no cases of AHA have been reported after exposure to COVID‐19 vaccine. There have been two cases of AHA following seasonal flu and H1N1 vaccination, as well two cases of AHA following COVID‐19 infection. We present a summary of these cases and review of literature of autoimmune reactions following vaccination.
The U.S. Food and Drug Administration (FDA) recently issued an Emergency Use Authorization (EUA) for two highly effective Sars-CoV-2 (COVID-19) vaccines from Pfizer-BioNTech and Moderna. More recently, Emergency Use Authorization was granted for the Johnson and Johnson COVID-19 vaccine which uses traditional virus-based. In this vaccine, researchers added the gene for the coronavirus spike protein to modified Adenovirus 26 and named it Ad26.COV2-S. Nearly 7 million doses of the Ad26.COV2-S have been administered as of mid-April 2021. Recently the Federal Drug Administration and Center for Disease Control and Prevention reviewed data involving six reported cases in the United States of cerebral venous sinus thrombosis in combination with thrombocytopenia in people who received the vaccination. All cases were in women between 18 and 48, with symptoms developing six to 13 days after vaccination. A recent study in the United Kingdom reported similar events in 23 patients age 21 to 77, 61% of which were female with cases of presumed vaccine induced thrombosis and thrombocytopenia occurring six to 24 days after vaccination. We report a 62-year-old female who presented to the ED with acute onset of altered mental status. She had received the Ad26.COV2-S vaccine 37 days prior to ED presentation. She developed thrombotic thrombocytopenic purpura (TTP) and no other cause was found. To our knowledge this is the first case in the United States of thrombotic thrombocytopenic purpura after receiving the Ad26.COV2-S COVID-19 vaccine.