Discussion
Thrombotic Thrombocytopenic Purpura (TTP) is a rare blood disorder with
an incidence of 3 to 10 cases per million adults per
year.16 It was first described by Eli Moschcowitz in
1924.18,19 The pathogenesis of this disorder includes
the formation of small-vessel platelet rich thrombi leading to ischemic
end organ injury.20 The historical pentad (fever,
hemolytic anemia, thrombocytopenia, neurological or renal dysfunction)
is only seen in < 10% of the patients.21,22Microangiopathic hemolytic anemia (reduced Hb and haptoglobin, increased
LDH and presence of schistocytes) and thrombocytopenia are sufficient
for presumptive diagnosis of TTP.
The PLASMIC Score derived by
Bendapudi et al 23 stratify patients according to
their risk of having severe ADAMTS-13 deficiency. When dichotomized at
high (score 6-7) vs low-intermediate risk (score 0-5), the PLASMIC Score
predicted severe ADAMTS-13 deficiency with positive predictive value at
72%, negative predictive value at 98%, sensitivity, 90% and
specificity, 92%.24 A severe reduction in the
activity of von Willebrand factor (VWF) cleaving metalloprotease
(ADAMTS-13) (less than 10%) and the presence of inhibitory antibodies
confirm the diagnosis.20
TTP can be classified into two types: congenital or acquired (autoimmune
TTP). Autoimmune TTP can be triggered by infections, malignancy,
pregnancy, medications and vaccines.11,19 Rarely some
vaccines (e.g., Influenza, pneumococcus, rabies and H1N1) have been
reported to induce acquired TTP.11,21,25–27 Vaccines
have been hypothesized to activate the immune system leading to
autoantibody formation and hence the development of an autoimmune
disorders like TTP.21,28
Worldwide, in response to the
COVID-19 pandemic, several
vaccines have been developed using various techniques: messenger RNA
(mRNA) (Pfizer-BioNTech [BNT162b2], Moderna and CureVac), human or
primate adenovirus vectors
(Janssen-Johnson & Johnson
[Ad26.COV2-S], Astra-Zeneca [chAdOx1 nCoV-19], Sputnik-V, and
CanSino) and an inactivated whole-virus SARS-CoV-2 (Bharat Biotech,
Sinopharm and
Sinovac)22. The
emergency use authorization of these vaccines in several countries
increased the risk of safety issues.5,7 In the
literature, there have been some reported cases of TTP following
Adenoviral Vector DNA- and SARS-CoV-2 mRNA-Based Covid-19
Vaccines.11,29 Indeed, vaccines against viral
pathogens have been reported to be associated with onset and/or relapse
of TTP.30 This rare autoimmune disease may occur after
the first or the second dose of
COVID-19 vaccines typically one to
two weeks after vaccination.13
For TTP, vaccine-induced immune thrombotic thrombocytopenia (VITT) is a
differential diagnosis. VITT is another adverse event that has been
recently reported after COVID-19 vaccination. It is a novel clinical
syndrome demonstrating striking similarities to TTP. VITT is diagnosed
clinically by the presence of mild to severe thrombocytopenia,
documented evidence or suspicion of thrombosis and positive antibodies
against platelet factor 4 (PF4).31,32 In the present
two cases, severely reduced ADAMTS-13 activity and the presence of
schistocytes or microangiopathic hemolytic anemia on the blood smear
supports the diagnosis of TTP. Temporal association and absence of other
triggering factors for secondary TTP led to the diagnosis that this
disorder was induced by COVID-19 vaccination. The two cases were
recorded within a two-year-long COVID-19 pandemic including just one
year of active vaccination in Tunisia in which more than five hundred
COVID-19 patients were admitted to a 12-bed medical ICU along with
another 600 non-COVID-19 patients in the same two-year period. This
highlights the scarcity of such complication in our hospital.
On April 5, 2022, a personal literature review based on a 2020–2022
PubMed search [key items: “Thrombotic thrombocytopenic
purpura”
AND
“COVID-19 vaccines” AND “case
report”] found 19 papers including 32 cases published in English
language. Among these studies, TTP was reported as an adverse event of
respectively Pfizer-BioNTech
(n=24), Moderna (n=3),
Astra-Zeneca (n=4) and Janssen-Johnson & Johnson (n=1) (Table
1 ; Results of the 32 Cases, Published During the 2020–2022 Period,
Including Thrombotic thrombocytopenic purpura following
COVID-19
Vaccination).11–14,20–22,26–30,33–39
To our knowledge, this is the first report of acquired TTP after
inactivated virus COVID-19 vaccines. In the current cases, TTP occurred
after 20 days after first dose of Sinopharm and 30 days after second
dose of CoronaVac.
A careful clinical surveillance must be done in the post-vaccine period.
Clinicians should consider the
possibility of TTP when evaluating thrombocytopenia following
vaccination. Without prompt initiation of adequate treatment, TTP is a
life-threatening thrombotic microangiopathy. It is a medical emergency
requiring rapid diagnosis and treatment usually in intensive care units.
According to the International Society of Thrombosis and Haemostasis,
PEX represents the cornerstone of TTP treatment with strong
recommendation for adding corticosteroids.28,40Rituximab (a monoclonal anti-CD20 antibody) and Caplacizumab (an
anti-VWF antibody fragment) can improve TTP outcomes and decrease the
duration of PEX. Caplacizumab is not yet available worldwide and it has
a significant cost.41