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