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\begin{document}

\title{Acquired Thrombotic Thrombocytopenic Purpura following inactivated COVID
19 vaccines: Two case-reports and a short literature review}



\author[1]{Imen Ben Saida}%
\author[1]{Iyed Maatouk}%
\author[1]{Radhouane Toumi}%
\author[1]{Emna Bouslama}%
\author[1]{Hajer Ben Ismail}%
\author[2]{Chaker Ben Salem}%
\author[1]{Mohamed Boussarsar}%
\affil[1]{Farhat Hached University Hospital of Sousse}%
\affil[2]{Universite de Sousse Faculte de Medecine de Sousse}%


\vspace{-1em}



  
  \date{March 13, 2025}


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\selectlanguage{english}
\begin{abstract}
The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
outbreak from December 2019 causing millions of deaths all over the
world and the lack of specific treatment for severe forms of coronavirus
disease 2019 (COVID-19) has led to vaccines development in record time
with emergency use authorization in several countries increasing the
risk of vaccine safety issues. Recently, several cases of Thrombotic
Thrombocytopenic Purpura (TTP) have been reported following COVID-19
vaccination. TTP represents a life-threatening consumptive coagulopathy
requiring urgent diagnosis and prompt treatment. It is a rare disease
characterized by thrombocytopenia, microangiopathic hemolytic anemia and
ischemic end-organ lesions. It can be either congenital or acquired.
Various events such viral infections, medication, pregnancy,
malignancies, and vaccinations may cause TTP. Clinicians should consider
this diagnosis when evaluating thrombocytopenia in the post-vaccine
period. Here, we report two cases of acquired TTP following Sinopharm
COVID-19 vaccine (BBIBP-CorV) and Sinovac COVID-19 vaccine (CoronaVac).
Diagnosis was based on clinical presentation and confirmed with severe
reduction in the activity of von Willebrand factor-cleaving protease
ADAMTS-13 and the presence of inhibitory autoantibodies. The two
patients were successfully treated with corticosteroids, plasma exchange
therapy and rituximab in the acute phase. In the literature, the
reported cases of TTP induced by COVID-19 vaccination occurred after
Adenoviral Vector DNA- and SARS-CoV-2 mRNA-Based COVID-19 Vaccines. To
the best of our knowledge, this is the first report of acquired TTP
after inactivated virus COVID-19 vaccines. A short literature review
regarding acquired TTP patients following COVID-19 vaccines is also
included.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel
virus first detected in Wuhan in December 2019. Few months later, the
World Health Organization (WHO) declared a worldwide pandemic. This
virus may cause severe viral pneumonia with acute respiratory distress
syndrome causing millions of deaths.\textsuperscript{1,2} Currently,
there is no effective treatment for coronavirus disease 2019
(COVID-19).\textsuperscript{3} However, several vaccines have been
developed worldwide to reduce COVID-19 mortality and
morbidity.\textsuperscript{4} Those vaccines have obtained emergency use
approval by the WHO in several countries increasing the risk of vaccine
safety issues and some adverse events have been
reported.\textsuperscript{5--7} Most frequent were injection site
reactions or systemic effects (eg, fatigue, headache, body pain, fever),
with rare serious adverse events (eg, anaphylaxis, Guillain-Barr\selectlanguage{ngerman}é,
thrombosis with thrombocytopenia Syndrome).\textsuperscript{8--10}
Several cases of Thrombotic Thrombocytopenic Purpura (TTP) induced by
COVID-19 vaccination have been reported in the
literature.\textsuperscript{11--14} TTP is a rare hematologic disorder
classically characterized by the pentad of fever, hemolytic anemia,
thrombocytopenia, renal failure, and neurologic dysfunction. However,
most patients do not have the entire pentad.\textsuperscript{15} This
disease is caused by a severe decrease in the activity of the von
Willebrand factor-cleaving protease ADAMTS-13 which can be either
congenital or acquired due to anti-ADAMTS-13
autoantibodies.\textsuperscript{11} Various events may initiate the
production of those antibodies such viral infections, medication,
pregnancy, malignancies and occasionally
vaccinations.\textsuperscript{16} Here, we report two cases of acquired
TTP after two inactivated COVID-19 vaccines: BBIBP-CorV vaccine known as
the Sinopharm COVID-19 vaccine and CoronaVac known as the Sinovac
vaccine. To the best of our knowledge, the present cases are the first
reported cases of acquired TTP after inactivated virus COVID-19
vaccines.

\textbf{Case presentations}

The Ethics Committee of Farhat Hached hospital approved the publication
of the two-cases retrospectively obtained and anonymized data.

\textbf{Case 1}

A 38-year-old Tunisian woman with no medical history presenting with
dizziness and ecchymosis in her upper limbs was referred to the
hematology department. The patient reported that she had received a
first dose of an inactivated virus COVID-19 vaccine Sinopharm
(BBIBP-CorV) twenty days before symptom onset. Laboratory findings
revealed hemoglobin 6 g/dl, platelet count 6×10\textsuperscript{9}/L,
lactate dehydrogenase (LDH) 1074 UI/L, haptoglobin 0.54 g/l, creatinine
66 \selectlanguage{greek}µ\selectlanguage{english}mol/L, urea 20.7 mg/dl, total bilirubin 3.75 mg/dl and indirect
bilirubin 2.88 mg/dl. Peripheral blood smear showed schistocytes (1 to
2\%). During her hospital stay, the patient presented left hemi-body
heaviness and dysarthria. A brain MRI revealed an ischemic stroke in the
territory of the infero-posterior cerebellar artery. A curative
anticoagulation was started. A few hours after ICU admission, the
patient presented a sudden generalized tonico-clonic seizure with status
epilepticus requiring her intubation. Glycemia and electrolytes were
within the normal ranges. The patient was promptly given clonazepam and
intravenous sodium valproate. Analgo-sedation was prolonged with
remifentanyl and midazolam to achieve a Richmond Agitation Sedation
Scale (RASS)\textsuperscript{17} at -5 to control the status epilepticus
and obtain patient-ventilator synchronization. The presence of
thrombocytopenia, hemolytic anemia and neurologic symptoms were
indicative of a presumptive diagnosis of TTP. The PLASMIC score, used to
identify patients with ADAMTS-13 deficiency in suspected TTP patients,
was at 6 (range, 0-7) indicating a high risk of severe ADAMTS-13
deficiency <\selectlanguage{english}10\%. The patient was promptly treated by methylprednisolone
1000 mg daily for three consecutive days, then 1 mg/kg/day in
combination with daily plasma exchange therapy (PEX).

Infectious screening tests (e.g., Human immunodeficiency virus (HIV),
hepatitis, SARS-CoV-2, Epstein-Barr Virus, and Cytomegalovirus) were
negative. Autoimmunity investigations revealed severe ADAMTS-13
deficiency (6\%) with positive anti ADAMTS-13 autoantibodies more than
15 U/ml (normal\textless{}12 U/ml) confirming the diagnosis of an
acquired TTP.

The patient remained seizure free and was extubated on day 5 of ICU
stay. She had a fully recovery after a 17-day course of glucocorticoids,
12 sessions of PEX and Rituximab. Laboratory parameters improvement
trends (platelet and hemoglobin level) are displayed in \textbf{figure
1} . The patient was discharged with hemoglobin at 10 g/dl and platelet
count at 370 \selectlanguage{ngerman}×10\textsuperscript{9}/L with a follow up at the hematology
department. Prednisone was tapered off over 5 weeks. The patient made a
complete recovery and is currently living a normal life. The latest
ADAMTS-13 activity at the 6-month follow up visit showed 94\%.

\textbf{Case 2}

A previously healthy 30-year-old male presented to the emergency
department with headache, fever, dysarthria and right hemiparesis. He
had received a second dose of an inactivated COVID-19 vaccine CoronaVac
one month prior to consultation. Laboratory findings showed hemoglobin
7.2 g/dL, platelet count, 9×10\textsuperscript{9}/L, LDH 1268 UI/L,
D-dimer 1890\selectlanguage{greek}µ\selectlanguage{english}g/L, haptoglobin 0.26 g/L and creatinine 105 \selectlanguage{greek}µ\selectlanguage{english}mol/L.
Peripheral blood smear showed schistocytes (2\%). PLASMIC score was at 5
(range, 0-7). A presumptive diagnosis of TTP was made. The patient was
admitted to the ICU. On the initial examination, the patient had a
fluctuating consciousness, dysarthria and right hemiparesis without any
petechiae or purpura. The brain CT scan revealed no abnormalities. No
triggering factors such as viral infections or medication, alcohol or
illicit drugs use were identified. Infectious screening tests were
negative. Investigations revealed severe ADAMTS-13 deficiency
(\textless{} 0.2 \%) with positive anti ADAMTS-13 autoantibodies (12
U/ml). All other autoimmune tests returned negative.

The patient received methylprednisolone 1000 mg daily for three
consecutive days followed by prednisone 1 mg/kg/day in combination with
daily PEX. Weekly infusion of Rituximab for 4 weeks was started two
weeks after admission due to issues concerning the patient's health
insurance.

The patient had a fully recovery after 31-day course including 26
sessions of PEX (\textbf{figure 2} ). The patient was discharged with
hemoglobin at 10 g/dl and platelets at 180 \selectlanguage{ngerman}×10\textsuperscript{9}/L with
a follow up at the hematology department. The steroids dose was tapered
off over 4 weeks. One month later, the control of activity of ADAMTS-13
was 74\%.

\textbf{Discussion}

Thrombotic Thrombocytopenic Purpura (TTP) is a rare blood disorder with
an incidence of 3 to 10 cases per million adults per
year.\textsuperscript{16} It was first described by Eli Moschcowitz in
1924.\textsuperscript{18,19} The pathogenesis of this disorder includes
the formation of small-vessel platelet rich thrombi leading to ischemic
end organ injury.\textsuperscript{20} The historical pentad (fever,
hemolytic anemia, thrombocytopenia, neurological or renal dysfunction)
is only seen in \textless{} 10\% of the
patients.\textsuperscript{21,22}Microangiopathic 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 \textsuperscript{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\%.\textsuperscript{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.\textsuperscript{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.\textsuperscript{11,19} Rarely some
vaccines (e.g., Influenza, pneumococcus, rabies and H1N1) have been
reported to induce acquired TTP.\textsuperscript{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.\textsuperscript{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)\textsuperscript{22}. The emergency use authorization of these
vaccines in several countries increased the risk of safety
issues.\textsuperscript{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.\textsuperscript{11,29} Indeed, vaccines
against viral pathogens have been reported to be associated with onset
and/or relapse of TTP.\textsuperscript{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.\textsuperscript{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).\textsuperscript{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)
(\textbf{Table 1} ; Results of the 32 Cases, Published During the
2020--2022 Period, Including Thrombotic thrombocytopenic purpura
following COVID-19
Vaccination).\textsuperscript{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.\textsuperscript{28,40}Rituximab (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.\textsuperscript{41}

\textbf{Conclusion}

This report highlights potential safety issues that can be encountered
after COVID-19 vaccination. The benefits of vaccination in fighting the
ongoing pandemic outweigh the risk of side effects. Additional
surveillance is required in the post vaccine period to detect adverse
events in a timely fashion. TTP is a very rare life-threatening
complication of COVID-19 vaccination. It is a medical emergency that is
almost always fatal if adequate treatment is not initiated early.
Further research should be conducted to correctly identify the mechanism
linking thrombotic microangiopathic disorders with COVID-19 vaccines.

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