Immune thrombocytopenia: options and new perspectives.

Immune thrombocytopenia is a haematological, autoimmune disorder characterized by elevated platelet demolition due to the presence of antiplatelet autoantibodies derived from B cells and to an irregular, deficient process of platelets production in bone marrow. In this review, after a brief presentation of 'old' strategies used nowadays yet, we focused on new drugs used in the treatment of immune thrombocytopenia and their mechanism of action and posology, basing on the last scientific literature. The observation that CoViD-19 can be associated with immune thrombocytopenia is also put in evidence. Particular attention will be dedicated on the concept that the ideal treatment should represent a solution not only for the failure of normal processes of production and survival of platelets, but also it should improve quality of life of patients, with minimum adverse events. Anyway, despite enormous advances of the last years, further investigations are necessary in order to define scrupulously long-term efficacy of new molecules proposed.

COVID-19 and thrombosis: searching for evidence.

Early in the pandemic, COVID-19-related increases in rates of venous and arterial thromboembolism were seen. Many observational studies suggested a benefit of prophylactic anticoagulation for hospitalized patients using various dosing strategies. Randomized trials were initiated to compare the efficacy of these different options in acutely ill and critically ill inpatients as the concept of immune-mediated inflammatory microthrombosis emerged. We present a case-based review of how we approach thromboembolic prophylaxis in COVID-19 and briefly discuss the epidemiology, the pathophysiology, and the rare occurrence of vaccine-induced thrombotic thrombocytopenia.

COVID-19: Vaccine-induced immune thrombotic thrombocytopenia.

In late February 2021, a prothrombotic syndrome was encountered for the first time in some of the recipients of ChAdOx1 CoV-19 vaccine (AstraZeneca, University of Oxford, and Serum Institute of India). Since the hallmark of this syndrome is the development of thrombocytopenia and/or thrombosis between 4 and 42 days after receiving a COVID-19 vaccine, it was named vaccine-induced immune thrombotic thrombocytopenia (VITT). Other names include "vaccine-induced prothrombotic immune thrombocytopenia" and "thrombosis with thrombocytopenia syndrome" by the Centers for Disease Control and the Food and Drug Administration (FDA). VITT appears similar to heparin-induced thrombocytopenia in that "platelet activating" autoantibodies are produced in both these conditions due to prior exposure of COVID-19 vaccine and heparin respectively, in turn causing thrombotic complications and consumptive thrombocytopenia. In this article, recent advances in the understanding of pathobiology, clinical features, investigative work-up, and management of VITT are reviewed.

Autoimmune haemolytic anaemia and immune thrombocytopenia following SARS-CoV-2 and non-SARS-CoV-2 vaccination: 32 Years of passive surveillance data.

Autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenia (ITP) are two uncommon haematologic autoimmune conditions that can rarely arise secondary to vaccination. Prior studies using the US Centers for Disease Control's (CDC) Vaccine Adverse Event Reporting System (VAERS) have demonstrated this infrequency, but contemporary data as well as comparison with current information regarding SARS-CoV-2 vaccination has not been assessed. In this study, we reviewed VAERS database reports from 1990 to 2022 to characterize the incidence and clinical and laboratory findings of non-SARS-CoV-2-associated AIHA and ITP and SARS-CoV-2 vaccine-associated AIHA and ITP. We discovered a total of 863 AIHA and ITP reports following vaccination with 15 non-SARS-CoV-2 and four SARS-CoV-2 vaccines submitted to the CDC VAERS database. AIHA and ITP reporting was low for both groups, with a large proportion excluded due to a lack of clinical details. ITP was reported the most frequently in both groups and was significantly more common with measles-mumps-rubella (MMR) vaccination (p < 0.001) in the non-SARS-CoV-2 group. AIHA and ITP cases were higher in the SARS-CoV-2 vaccine group, though ultimately still very infrequent. Autoimmune haematologic disease is vanishingly rare after immunization and rates are lower than in the general population according to passive reporting.

Autoimmune and autoinflammatory conditions after COVID-19 vaccination. New case reports and updated literature review.

Autoimmunity linked to COVID-19 immunization has been recorded throughout the pandemic. Herein we present six new patients who experienced relapses of previous autoimmune disease (AD) or developed a new autoimmune or autoinflammatory condition following vaccination. In addition, we documented additional cases through a systematic review of the literature up to August 1st, 2022, in which 464 studies (928 cases) were included. The majority of patients (53.6%) were women, with a median age of 48 years (IQR: 34 to 66). The median period between immunization and the start of symptoms was eight days (IQR: 3 to 14). New-onset conditions were observed in 81.5% (n: 756) of the cases. The most common diseases associated with new-onset events following vaccination were immune thrombocytopenia, myocarditis, and Guillain-Barré syndrome. In contrast, immune thrombocytopenia, psoriasis, IgA nephropathy, and systemic lupus erythematosus were the most common illnesses associated with relapsing episodes (18.5%, n: 172). The first dosage was linked with new-onset events (69.8% vs. 59.3%, P = 0.0100), whereas the second dose was related to relapsing disease (29.5% vs. 59.3%, P = 0.0159). New-onset conditions and relapsing diseases were more common in women (51.5% and 62.9%, respectively; P = 0.0081). The groups were evenly balanced in age. No deaths were recorded after the disease relapsed, while 4.7% of patients with new-onset conditions died (P = 0.0013). In conclusion, there may be an association between COVID-19 vaccination and autoimmune and inflammatory diseases. Some ADs seem to be more common than others. Vaccines and SARS-CoV-2 may induce autoimmunity through similar mechanisms. Large, well-controlled studies are warranted to validate this relationship and assess additional variables such as genetic and other environmental factors.

Kidney Transplantation From Deceased Donors With Vaccine-induced Immune Thrombocytopenia and Thrombosis: An Updated Analysis of the UK Experience.

BACKGROUND: The emergence and attendant mortality of vaccine-induced immune thrombocytopenia and thrombosis (VITT) as a consequence of vaccination against severe acute respiratory syndrome coronavirus 2 have resulted in some patients with VITT being considered as deceased organ donors. Outcomes after kidney transplantation in this context are poorly described. Because the disease seems to be mediated by antiplatelet factor 4 antibodies, there is a theoretical risk of transmission via passenger leukocytes within the allograft. METHODS: We analyzed the experience of kidney transplantation from donors with VITT in the United Kingdom between January and June 2021. We followed-up all recipients of kidney-only transplants from donors with VITT to detect major postoperative complications or features of disease transmission and assess graft survival and function. RESULTS: There were 16 kidney donors and 30 single kidney transplant recipients in our study period. Of 11 preimplantation biopsies, 4 showed widespread glomerular microthrombi. After a median of 5 mo, patient and graft survival were 97% and 90%, respectively. The median 3-mo estimated glomerular filtration rate was 51 mL/min/1.73 m 2 . Two recipients had detectable antiplatelet factor 4 antibodies but no evidence of clinical disease after transplantation. Major hemorrhagic complications occurred in 3 recipients, all of whom had independent risk factors for bleeding, resulting in the loss of 2 grafts. The involvement of VITT could not be completely excluded in one of these cases. CONCLUSIONS: The UK experience to date shows that favorable outcomes are possible after kidney transplantation from donors with VITT but highlights the need for ongoing vigilance for donor-related complications in these patients.

Thrombosis patterns and clinical outcome of COVID-19 vaccine-induced immune thrombotic thrombocytopenia: A Systematic Review and Meta-Analysis.

OBJECTIVES: To meta-analyse the clinical manifestations, diagnosis, treatment, and mortality of vaccine-induced immune thrombotic thrombocytopenia (VITT) after adenoviral vector vaccination. METHODS: Eighteen studies of VITT after ChAdOx1 nCoV-19 or Ad26.COV2.S vaccine administration were reviewed from PubMed, Scopus, Embase, and Web of Science. The meta-analysis estimated the summary effects and between-study heterogeneity regarding the incidence, manifestations, sites of thrombosis, diagnostic findings, and clinical outcomes. RESULTS: The incidence of total venous thrombosis after ChAdOx1 nCoV-19 vaccination was 28 (95% CI 12-52, I2=100%) per 100,000 doses administered. Of 664 patients included in the quantitative analysis (10 studies), the mean age of patients with VITT was 45.6 years (95% CI 43.8-47.4, I2=57%), with a female predominance (70%). Cerebral venous thrombosis (CVT), deep vein thrombosis (DVT)/pulmonary thromboembolism (PE), and splanchnic vein thrombosis occurred in 54%, 36%, and 19% of patients with VITT, respectively. The pooled incidence rate of CVT after ChAdOx1 nCoV-19 vaccination (23 per 100,000 person-years) was higher than that reported in the pre-pandemic general population (0.9 per 100,000 person-years). Intracranial haemorrhage and extracranial thrombosis accompanied 47% and 33% of all patients with CVT, respectively. The antiplatelet factor 4 antibody positivity rate was 91% (95% CI 88-94, I2=0%) and the overall mortality was 32% (95% CI 24-41, I2=69%), and no significant difference was observed between heparin- and non-heparin-based anticoagulation treatments (risk ratio 0.84, 95% CI 0.47-1.50, I2=0%). CONCLUSIONS: Patients with VITT after SARS-CoV-2 vaccination most frequently presented with CVT following DVT/PE and splanchnic vein thrombosis, and about one-third of patients had a fatal outcome. This meta-analysis should provide a better understanding of VITT and assist clinicians in identifying VITT early to improve outcomes and optimise management.

Clinical care pathway for the evaluation of patients with suspected VITT after ChAdOx1 nCoV-19 vaccination.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) adenoviral vector vaccination. In British Columbia (BC), Canada, a provincial clinical care pathway was developed to guide clinicians in evaluating for VITT among patients who present with thrombocytopenia or thrombosis symptoms within 4 to 28 days after adenoviral vector vaccine exposure. All patients had enzyme-linked immunosorbent assay (ELISA) testing for platelet factor 4 (PF4) antibodies, and all cases with positive PF4-ELISA or d-dimer levels ≥2.0 mg/L fibrinogen equivalent units (FEU) had further testing for platelet-activating PF4 antibodies using a modified serotonin release assay (SRA). Between 1 May and 30 June 2021, 37% of 68 patients investigated for VITT had thrombosis, but only 3 had VITT confirmed by PF4-ELISA and SRA. Platelet counts, d-dimer levels, and ELISA optical density values were significantly different between those with and without VITT. Three patients had thrombocytopenia and thrombosis with d-dimer levels >4.0 mg/L FEU but had negative PF4-ELISA and SRA results. Patients with VITT were treated successfully with IV immunoglobulin, nonheparin anticoagulants, and corticosteroids. Our pathway demonstrated that thrombosis is common among patients investigated for VITT and that PF4-ELISA testing is necessary to confirm VITT in those presenting with thrombosis and thrombocytopenia.

Simultaneous Occurrence of Immune-Mediated Thrombocytopenia and Myocarditis After mRNA-1273 COVID-19 Vaccination: A Case Report.

With the global spread of severe acute respiratory syndrome coronavirus 2, several vaccines were developed; messenger RNA (mRNA) vaccines have recently been widely used worldwide. However, the incidence of myocarditis following mRNA vaccination is increasing; although the cause of myocarditis has not yet been clearly identified, it is presumed to be caused by a problem in the innate immune system. Immune-mediated thrombocytopenia (ITP) after vaccination is rare but has been reported and is also assumed to occur by the same mechanism. We report the first case of simultaneous myocarditis and ITP after mRNA vaccination. A 38-year-old woman presented with chest pain, mild dyspnea, and sweating after vaccination with mRNA-1273 vaccine (Moderna) 4 days prior to admission. Upon admission to the emergency department, cardiac enzymes were elevated; blood test performed 5 months ago showed normal platelet count, but severe thrombocytopenia was observed upon admission. After administration of intravenous immunoglobulin, the platelet count improved; subsequently, myocarditis was observed on endomyocardial biopsy. Thus, myocarditis and ITP were judged to have occurred simultaneously due to the expression of the innate immune system markers after mRNA vaccination. The patient was discharged on day 6 of admission.

Severe Immune Thrombocytopenia after COVID-19 Vaccination: Two Case Reports and a Literature Review.

We herein report two cases of coronavirus disease 2019 (COVID-19) vaccine-induced immune thrombocytopenia (ITP). A 69-year-old Japanese man developed severe thrombocytopenia after COVID-19 vaccination. He had oral bleeding and hemoptysis but no thrombotic symptoms. He improved rapidly with oral prednisolone therapy. A 34-year-old Japanese woman had generalized purpura after COVID-19 vaccination. Her platelet count improved rapidly after treatment with prednisolone and eltrombopag. The occurrence of two cases of ITP after COVID-19 vaccination at a single institution suggests that there could be more such undiagnosed cases, especially cases of mild secondary ITP.

A Case Report of Thrombotic Thrombocytopenia After ChAdOx1 nCov-19 Vaccination and Heparin Use During Hemodialysis.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but life-threatening complication. VITT strongly mimics heparin-induced thrombocytopenia (HIT) and shares clinical features. Heparin is commonly used to prevent coagulation during hemodialysis. Therefore, nephrologists might encounter patients needing dialysis with a history of heparin exposure who developed thrombotic thrombocytopenia after vaccination. A 70-year-old male presented with acute kidney injury and altered mental status due to lithium intoxication. He needed consecutive hemodialysis using heparin. Deep vein thrombosis of left lower extremity and accompanying severe thrombocytopenia of 15,000/µL on 24 days after vaccination and at the same time, nine days after heparin use. Anti-platelet factor 4 antibody test was positive. Anticoagulation with apixaban and intravenous immunoglobulin (IVIG) infusion resolved swelling of his left calf and thrombocytopenia. There were no definitive diagnostic tools capable of differentiating between VITT and HIT in this patient. Although VITT and HIT share treatment with IVIG and non-heparin anticoagulation, distinguishing between VITT and HIT will make it possible to establish a follow-up vaccination plan in a person who has had a thrombocytopenic thrombotic event. Further research is needed to develop the tools to make a clear distinction between the clinical syndromes.

Successful mRNA SARS-Cov-2 vaccine rechallenge after a first episode of immune thrombocytopenic purpura.

In 2021, the world experienced the most extensive vaccination campaign to defeat COVID-19. Many cases of idiopathic thrombocytopenia have been reported following injections of SARS-Cov-2 mRNA vaccine. We present the case of a 73-year-old woman with de novo ITP after a first injection of SARS-Cov-2 mRNA vaccine (Moderna vaccine) who experienced a successful rechallenge of SARS-Cov-2 mRNA vaccine (Pfizer vaccine) a few months later.