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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
xaccination
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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1
Editorial
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
disorders
Correspondence to: P.M. Mannucci
Via Pace 9, 20122 Milano, Italy
Phone +39 0255035421
Email: piermannuccio.mannucci@policlinico.mi.it
2
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
3
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
4
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
5
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.
References
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.
6
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
print]
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-
3):226-35.
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.
20215;373:n1114.
7
Table 1: Main features of vaccine-induced, immune mediated thrombocytopenias
Disease (and acronym) Severe
thrombocytopenia
(< 10x109/L)
Mucocutaneous
bleeding
symptoms
Intracerebral
hemorrhage Associated
thrombosis Thrombosis
sites Laboratory
diagnosis
Immune thrombocytopenic
purpura (ITP)
Frequent
Frequent
-
Anti
-
platelet
antibodies
Thrombotic thrombocytopenic
purpura (TTP) Frequent Rare Rare
Frequent,
microvascular Microcirculation
of heart, brain
and GI tract
ADAMTS-13
deficiency and
ADAMTS-13
antibody
Vaccine
-
induce
d
immune
thrombotic thrombocytopenia
(VITT)
Frequent
F
requent
Frequent
,
macrovascular
Cerebral and
abdominal veins
Anti
-
PF4 ELISA
positivity
... [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. ...
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