A case report of vaccine-induced immune thrombotic thrombocytopenia (VITT) with genetic analysis.

The emergence of the rare syndrome called vaccine-induced immune thrombocytopenia and thrombosis (VITT) after adenoviral vector vaccines, including ChAdOx1 nCov-19, raises concern about one's predisposing risk factors. Here we report the case of a 56-year-old white man who developed VITT leading to death within 9 days of symptom onset. He presented with superior sagittal sinus thrombosis, right frontal intraparenchymal hematoma, frontoparietal subarachnoid and massive ventricular hemorrhage, and right lower extremity arterial and venous thrombosis. His laboratory results showed elevated D-dimer, C-reactive protein, tissue factor, P-selectin (CD62p), and positive anti-platelet factor 4. The patient's plasma promoted higher CD62p expression in healthy donors' platelets than the controls. Genetic investigation on coagulation, thrombophilia, inflammation, and type I interferon-related genes was performed. From rare variants in European or African genomic databases, 68 single-nucleotide polymorphisms (SNPs) in one allele and 11 in two alleles from common SNPs were found in the patient genome. This report highlights the possible relationship between VITT and genetic variants. Additional investigations regarding the genetic predisposition of VITT are needed.

Multiple Electrode Aggregometry (Multiplate): Functional Assay for Vaccine-Induced (Immune) Thrombotic Thrombocytopenia (VITT).

Vaccine-induced immune thrombotic thrombocytopenia (VITT) was first described in 2021 and represents an adverse reaction to adenoviral vector COVID-19 vaccines AstraZeneca ChAdOx1 nCoV-19 (AZD1222) and Johnson & Johnson Ad26.COV2.S vaccine. VITT is a severe immune platelet activation syndrome with an incidence of 1-2 per 100,000 vaccinations. The features of VITT include thrombocytopenia and thrombosis within 4-42 days of first dose of vaccine. Affected individuals develop platelet-activating antibodies against platelet factor 4 (PF4). The International Society on Thrombosis and Haemostasis recommends both an antigen-binding assay (enzyme-linked immunosorbent assay, ELISA) and a functional platelet activation assay for the diagnostic workup of VITT. Here, the application of multiple electrode aggregometry (Multiplate) is presented as a functional assay for VITT.

Serotonin Release Assay: Functional Assay for Heparin- and Vaccine-Induced (Immune) Thrombotic Thrombocytopenia.

The serotonin release assay (SRA) has been the gold-standard assay for detection of heparin-dependent platelet-activating antibodies and integral for the diagnosis for heparin-induced thrombotic thrombocytopenia (HIT). In 2021, a thrombotic thrombocytopenic syndrome was reported after adenoviral vector COVID-19 vaccination. This vaccine-induced thrombotic thrombocytopenic syndrome (VITT) proved to be a severe immune platelet activation syndrome manifested by unusual thrombosis, thrombocytopenia, very elevated plasma D-dimer, and a high mortality even with aggressive therapy (anticoagulation and plasma exchange). While the platelet-activating antibodies in both HIT and VITT are directed toward platelet factor 4 (PF4), important differences have been found. These differences have required modifications to the SRA to improve detection of functional VITT antibodies. Functional platelet activation assays remain essential in the diagnostic workup of HIT and VITT. Here we detail the application of SRA for the assessment of HIT and VITT antibodies.

A Case of Vaccine-Induced Thrombocytopenic Thrombosis Manifesting as Cerebral Venous Thrombosis and Intracerebral Bleed.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but detrimental syndrome that has been most commonly reported after the administration of vaccination for the prevention of viral infections. VITT often presents with thrombosis at unusual sites such as cerebral venous sinuses, portal, splanchnic or hepatic veins, in association with thrombocytopenia and elevated anti-platelet factor 4 (aPF-4) antibodies. We describe the case of a young male patient who developed thrombocytopenia, cerebral sinus venous thrombosis, and intracerebral bleed 12 days after receiving the Ad26.COV2.S (Janssen/Johnson&Johnson) COVID-19 vaccine.

Humoral immunity and thrombosis in COVID-19

Coronavirus disease 2019 (COVID-19) is due to the infection of the upper and lower airways by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is characterized by different clinical manifestations ranging from paucisymptomatic conditions to life-threatening acute respiratory distress syndrome and may present multisystem involvement. A hyperinflammatory response to the virus and the associated prothrombotic state (immunothrombosis) are the major causes of tissue/organ damage. Several humoral mediators have been described to mediate the immunothrombosis in COVID-19;among them, a lot of attention has been paid to the synthesis of nonorgan specific procoagulant autoantibodies, the hyperproduction of proinflammatory cytokines, and to the activation of the complement cascade. All the above-mentioned pathogenic pathways are affecting the endothelium as one of the main targets of the disease and contribute to the clinical manifestations. © 2023 Elsevier Inc. All rights reserved.

Renal Vein Thrombosis and Pulmonary Embolism Secondary to Vaccine-induced Thrombotic Thrombocytopenia (VITT).

The Medicines and Healthcare products Regulatory Agency (MHRA) of the UK has approved the use of three vaccines to combat COVID-19 (SARS-CoV-2). There have been rare reports of thrombosis after vaccination with the AstraZeneca vaccine. We present three cases of vaccine-induced thrombotic thrombocytopenia (VITT) in one UK district general hospital following administration of this vaccine. Two of the patients had asymptomatic pulmonary emboli, while the other is the first known case of both renal vein thrombosis and pulmonary embolism. LEARNING POINTS: Vaccine-induced thrombotic thrombocytopenia (VITT) can be associated with unusual and multiple sites of thrombosis.Clinicians should have a low threshold for requesting anti-PF4 antibody tests and imaging (especially pulmonary imaging) in thrombocytopenic patients after administration of the AstraZeneca vaccine.We describe a localised cluster of VITT despite its rarity according to current statistics, highlighting the need for an efficient data collection system to ensure the incidence of VITT is accurately reported.

Concurrence of immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura: a case report and review of the literature.

BACKGROUND: Immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura are both causes of thrombocytopenia. Recognizing thrombotic thrombocytopenic purpura is crucial for subsequent treatment and prognosis. In clinical practice, corticosteroids and rituximab can be used to treat both immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura; plasma exchange therapy is the first-line treatment in thrombotic thrombocytopenic purpura, while corticosteroids are strongly recommended as first-line treatment in immune thrombocytopenic purpura. The differential diagnosis of immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura is essential in clinical practice. However, case reports have suggested that immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura can occur concurrently. CASE PRESENTATION: We report the case of a 32-year-old Asian female without previous disease who presented with pancytopenia, concurrent with immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura. The morphology of the megakaryocytes in the bone marrow indicated immune-mediated thrombocytopenia. The patient received glucocorticoid treatment, and her platelet count increased; however, schistocytes remained high during the course of the therapy. Further investigations revealed ADAMTS13 activity deficiency and positive ADAMTS13 antibodies. The high titer of antinuclear antibody and positive anti-U1-ribonucleoprotein/Smith antibody indicated a potential autoimmune disease. However, the patient did not fulfill the current criteria for systemic lupus erythematosus or mixed connective tissue disease. The patient responded well to plasma exchange therapy, and her platelet count remained normal on further follow-up. CONCLUSIONS: Concurrence of immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura is rare, but clinicians should be aware of this entity to ensure prompt medical intervention. Most of the reported cases involve young women. Human immunodeficiency virus infection, pregnancy, and autoimmune disease are the most common underlying conditions.

An Unusual Case of Combined Thrombosis and Amegakaryocytopenia Resembling Thrombosis With Thrombocytopenia Syndrome Following COVID-19 Infection in an Unvaccinated Patient.

As a global community, we have learned that the manifestations of severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2), infection, or coronavirus disease 2019 (COVID-19), extends far beyond respiratory compromise. Thrombocytopenia is thought to occur secondary to increased platelet consumption. Platelet activation and platelet-mediated immune inflammation contribute towards the thromboembolic complications seen in COVID-19 patients. In this report, the authors present the unusual case of a 75-year-old female with a history of COVID-19 infection who presented with a transient ischemic attack, thrombocytopenia, and amegakaryocytopenia.

Acute limb ischemia secondary to vaccine-induced thrombotic thrombocytopenia.

Vaccine-associated thrombosis has previously been described in patients presenting with cerebral sinus thrombosis, deep venous thrombosis/pulmonary embolism, or mesenteric venous thrombosis. Only recently has arterial thrombosis gained attention. A new entity known as vaccine-induced thrombotic thrombocytopenia (VITT) has been associated with the coronavirus disease of 2019 (COVID-19) vaccines produced by AstraZeneca and Johnson & Johnson. We describe a case series of three patients who presented with acute limb ischemia with vaccine-associated arterial occlusions, one of whom was diagnosed with VITT.

Pituitary apoplexy and COVID-19 vaccination: a case report and literature review.

A 50-year-old man was admitted to our hospital for vomit, nausea, diplopia, and headache resistant to analgesic drugs. Symptoms started the day after his third COVID-19 mRNA vaccine (Moderna) whereas SARS-CoV-2 nasal swab was negative. Pituitary MRI showed recent bleeding in macroadenoma, consistent with pituitary apoplexy. Adverse Drug Reaction was reported to AIFA (Italian Medicines Agency).A stress dexamethasone dose was administered due to the risk of adrenal insufficiency and to reduce oedema. Biochemistry showed secondary hypogonadism; inflammatory markers were elevated as well as white blood cells count, fibrinogen and D-dimer. Pituitary tumour transsphenoidal resection was performed and pathology report was consistent with pituitary adenoma with focal haemorrhage and necrosis; we found immunohistochemical evidence for SARS-CoV-2 proteins next to pituitary capillaries, in the presence of an evident lymphocyte infiltrate.Few cases of pituitary apoplexy after COVID-19 vaccination and infection have been reported. Several hypotheses have been suggested to explain this clinical picture, including cross-reactivity between SARS-CoV-2 and pituitary proteins, COVID-19-associated coagulopathy, infection-driven acutely increased pituitary blood demand, anti-Platelet Factor 4/heparin antibodies development after vaccine administration. Ours is the first case of SARS-CoV-2 evidence in pituitary tissue, suggesting that endothelial infection of pituitary capillaries could be present before vaccination, possibly due to a previous asymptomatic SARS-CoV-2 infection. Our case underlines that SARS-CoV-2 can associate with apoplexy by penetrating the central nervous system, even in cases of negative nasal swab. Patients with pituitary tumours may develop pituitary apoplexy after exposure to SARS-CoV-2, therefore clinicians should be aware of this risk.

Thrombotic outcomes in patients in a large clinical enterprise following COVID-19 vaccination.

Vaccination against COVID-19 reduces infection-related mortality. Unfortunately, reports of vaccine-induced immune thrombotic thrombocytopenia (VITT) in individuals administered adenovirus-vector-based vaccines (ChAdOx1 nCoV-19 and Ad26.COV2.S) have spurred side effect concerns. To address vaccine hesitancy related to this, it is essential to determine the incidence of VITT (defined by a 50% decrease in platelet count and positive anti-PF4 immunoassay within 4-28 days after vaccination) among patients administered two doses of an mRNA-based COVID-19 vaccination. We identified a retrospective cohort of 223,345 patients in the Cleveland Clinic Enterprise administered a COVID-19 vaccine at any location in Northeast Ohio and Florida from 12/4/2020 to 6/6/2021. 97.3% of these patients received an mRNA-based vaccination. Patients with: (1) a serial complete blood count both before and after vaccination and (2) a decrease in platelet count of ≥ 50% were selected for chart review. The primary outcome was the incidence of thrombotic events, including venous thromboembolism (VTE) and arterial thrombosis, 4-28 days post vaccination. Of 74 cohort patients with acute thrombosis, 72 (97.3%) demonstrated clear etiologies, such as active malignancy. Of two patients with unprovoked thrombosis, only one had findings concerning for VITT, with a strongly positive anti-PF4 antibody assay. In this large, multi-state, retrospective cohort, of 223,345 patients (97.2% of whom received the mRNA-based mRNA-1273 or BNT162b2 vaccines), we detected a single case that was concerning for VITT in a patient who received an mRNA vaccine. The overwhelming majority of patients with a thrombotic event 4-28 days following vaccination demonstrated clear etiologies.

COVID-19 in Patients with Hematologic Diseases.

The COVID-19 outbreak had a strong impact on people's lives all over the world. Patients with hematologic diseases have been heavily affected by the pandemic, because their immune system may be compromised due to anti-cancer or immunosuppressive therapies and because diagnosis and treatment of their baseline conditions were delayed during lockdowns. Hematologic malignancies emerged very soon as risk factors for severe COVID-19 infection, increasing the mortality rate. SARS-CoV2 can also induce or exacerbate immune-mediated cytopenias, such as autoimmune hemolytic anemias, complement-mediated anemias, and immune thrombocytopenia. Active immunization with vaccines has been shown to be the best prophylaxis of severe COVID-19 in hematologic patients. However, the immune response to vaccines may be significantly impaired, especially in those receiving anti-CD20 monoclonal antibodies or immunosuppressive agents. Recently, antiviral drugs and monoclonal antibodies have become available for pre-exposure and post-exposure prevention of severe COVID-19. As adverse events after vaccines are extremely rare, the cost-benefit ratio is largely in favor of vaccination, even in patients who might be non-responders; in the hematological setting, all patients should be considered at high risk of developing complications due to SARS-CoV2 infection and should be offered all the therapies aimed to prevent them.

Pilot Findings on SARS-CoV-2 Vaccine-Induced Pituitary Diseases: A Mini Review from Diagnosis to Pathophysiology.

Since the emergence of the COVID-19 pandemic at the end of 2019, a massive vaccination campaign has been undertaken rapidly and worldwide. Like other vaccines, the COVID-19 vaccine is not devoid of side effects. Typically, the adverse side effects of vaccination include transient headache, fever, and myalgia. Endocrine organs are also affected by adverse effects. The major SARS-CoV-2 vaccine-associated endocrinopathies reported since the beginning of the vaccination campaign are thyroid and pancreas disorders. SARS-CoV-2 vaccine-induced pituitary diseases have become more frequently described in the literature. We searched PubMed/MEDLINE for commentaries, case reports, and case series articles reporting pituitary disorders following SARS-CoV-2 vaccination. The search was reiterated until September 2022, in which eight case reports were found. In all the cases, there were no personal or familial history of pituitary disease described. All the patients described had no previous SARS-CoV-2 infection prior to the vaccination episode. Regarding the type of vaccines administered, 50% of the patients received (BNT162b2; Pfizer-BioNTech) and 50% received (ChAdOx1 nCov-19; AstraZeneca). In five cases, the pituitary disorder developed after the first dose of the corresponding vaccine. Regarding the types of pituitary disorder, five were hypophysitis (variable clinical aspects ranging from pituitary lesion to pituitary stalk thickness) and three were pituitary apoplexy. The time period between vaccination and pituitary disorder ranged from one to seven days. Depending on each case's follow-up time, a complete remission was obtained in all the apoplexy cases but in only three patients with hypophysitis (persistence of the central diabetes insipidus). Both quantity and quality of the published data about pituitary inconveniences after COVID-19 vaccination are limited. Pituitary disorders, unlike thyroid disorders, occur very quickly after COVID-19 vaccination (less than seven days for pituitary disorders versus two months for thyroid disease). This is partially explained by the ease of reaching the pituitary, which is a small gland. Therefore, this gland is rapidly overspread, which explains the speed of onset of pituitary symptoms (especially ADH deficiency which is a rapid onset deficit with evocative symptoms). Accordingly, these pilot findings offer clinicians a future direction to be vigilant for possible pituitary adverse effects of vaccination. This will allow them to accurately orient patients for medical assistance when they present with remarkable symptoms, such as asthenia, polyuro-polydipsia, or severe headache, following a COVID-19 vaccination.

Complementary Sets of Autoantibodies Induced by SARS-CoV-2, Adenovirus and Bacterial Antigens Cross-React with Human Blood Protein Antigens in COVID-19 Coagulopathies.

COVID-19 patients often develop coagulopathies including microclotting, thrombotic strokes or thrombocytopenia. Autoantibodies are present against blood-related proteins including cardiolipin (CL), serum albumin (SA), platelet factor 4 (PF4), beta 2 glycoprotein 1 (ß2GPI), phosphodiesterases (PDE), and coagulation factors such as Factor II, IX, X and von Willebrand factor (vWF). Different combinations of autoantibodies associate with different coagulopathies. Previous research revealed similarities between proteins with blood clotting functions and SARS-CoV-2 proteins, adenovirus, and bacterial proteins associated with moderate-to-severe COVID-19 infections. This study investigated whether polyclonal antibodies (mainly goat and rabbit) against these viruses and bacteria recognize human blood-related proteins. Antibodies against SARS-CoV-2 and adenovirus recognized vWF, PDE and PF4 and SARS-CoV-2 antibodies also recognized additional antigens. Most bacterial antibodies tested (group A streptococci [GAS], staphylococci, Escherichia coli [E. coli], Klebsiella pneumoniae, Clostridia, and Mycobacterium tuberculosis) cross-reacted with CL and PF4. while GAS antibodies also bound to F2, Factor VIII, Factor IX, and vWF, and E. coli antibodies to PDE. All cross-reactive interactions involved antibody-antigen binding constants smaller than 100 nM. Since most COVID-19 coagulopathy patients display autoantibodies against vWF, PDE and PF4 along with CL, combinations of viral and bacterial infections appear to be necessary to initiate their autoimmune coagulopathies.

Vaccine-induced immune thrombotic thrombocytopenia and patients with cancer.

Vaccines to combat SARS-CoV-2 infection and the COVID-19 pandemic were quickly developed due to significant and combined efforts by the scientific community, government agencies, and private sector pharmaceutical and biotechnology companies. Following vaccine development, which took less than a year to accomplish, randomized placebo controlled clinical trials enrolled almost 100,000 people, demonstrating efficacy and no major safety signals. Vaccination programs were started, but shortly thereafter a small number of patients with a constellation of findings including thrombosis in unusual locations, thrombocytopenia, elevated D-dimer and often low fibrinogen led another intense and concentrated scientific effort to understand this syndrome. It was recognized that this occurred within a short time following administration of adenoviral vector SARS-CoV-2 vaccines. Critical to the rapid understanding of this syndrome was prompt communication among clinicians and scientists and exchange of knowledge. Now known as vaccine-induced immune thrombotic thrombocytopenia syndrome (VITT), progress has been made in understanding the pathophysiology of the syndrome, with the development of diagnostic criteria, and most importantly therapeutic strategies needed to effectively treat this rare complication of adenoviral vector vaccination. This review will focus on the current understanding of the pathophysiology of VITT, the findings that affected patients present with, and the rational for therapies, including for patients with cancer, as prompt recognition, diagnosis, and treatment of this syndrome has resulted in a dramatic decrease in associated mortality.

Cerebral Venous Sinus Thrombosis Following COVID-19 and Otogenic Infection: A Diagnostic and Therapeutic Dilemma Followed by mRNA COVID-19 Vaccination.

IntroductionCerebral venous sinus thrombosis (CVST) is a rare neurovascular emergency that has been observed following COVID-19 infection, as well as following the use of non-mRNA COVID-19 vaccines. Case PresentationThe authors report a case of CVST in a 67-year-old woman, unvaccinated for COVID-19, who presented with acute otitis externa. It remains unclear whether the CVST was a following COVID-19 infection complication, otogenic CVST, or a combination of both. ConclusionThis case demonstrates the diagnostic and therapeutic dilemmas in managing this patient's challenging anticoagulation and antibiotic duration, as well as subsequent COVID-19 vaccination recommendations.

Safety of COVID-19 Vaccines: Spotlight on Neurological Complications.

The COVID-19 pandemic has led to unprecedented demand on the global healthcare system. Remarkably, at the end of 2021, COVID-19 vaccines received approvals for human use in several countries worldwide. Since then, a solid base for response in the fight against the virus has been placed. COVID-19 vaccines have been shown to be safe and effective drugs. Nevertheless, all kinds of vaccines may be associated with the possible appearance of neurological complications, and COVID-19 vaccines are not free from neurological side effects. Neurological complications of COVID-19 vaccination are usually mild, short-duration, and self-limiting. However, severe and unexpected post-vaccination complications are rare but possible events. They include the Guillain-Barré syndrome, facial palsy, other neuropathies, encephalitis, meningitis, myelitis, autoimmune disorders, and cerebrovascular events. The fear of severe or fatal neurological complications fed the "vaccine hesitancy" phenomenon, posing a vital communication challenge between the scientific community and public opinion. This review aims to collect and discuss the frequency, management, and outcome of reported neurological complications of COVID-19 vaccines after eighteen months of the World Health Organization's approval of COVID-19 vaccination, providing an overview of safety and concerns related to the most potent weapon against the SARS-CoV-2.

A Case of COVID-19 Vaccine-Induced Thrombotic Thrombocytopenia.

This report discusses a case of a 37-year-old female who developed vaccine-induced thrombotic thrombocytopenia (VITT) after receiving the Johnson and Johnson COVID-19 vaccination. The patient first presented to the ED with complaints of a worsening headache. Labs were significant for thrombocytopenia with a platelet count of 22,000, and the patient was admitted to the inpatient unit for monitoring. The day after admission, the patient was found to have a right common femoral artery embolus, left distal popliteal trifurcation embolism, a small pulmonary embolism in the right lower lobe, and a mural thrombus of the infrarenal abdominal aorta. Following these findings, the patient underwent emergent thrombectomy of the common and superficial femoral arteries. Over the hospital course of six days, the patient received steroids and IV immunoglobulin (IVIG), which led to the resolution of the thrombocytopenia. The patient was given argatroban followed by apixaban for anticoagulation. She was instructed to follow up with hematology within one to two weeks post-discharge for monitoring of anticoagulation and thrombus surveillance. This case report outlines the clinical course, diagnosis, and treatment of a case of VITT, which will assist physicians in early recognition and adequate treatment of this condition as the COVID-19 pandemic continues.

Vaccine-Induced Thrombotic Thrombocytopenia: A Case of Splanchnic Veins Thrombosis.

Vaccines have been vital in preventing and curbing the spread of SARS-CoV-2 infection. Adenoviral vector-based vaccines, namely the ChAdOx1-S vaccine (AstraZeneca, Cambridge, UK) and Ad26.COV2.S (Janssen; Johnson & Johnson, New Brunswick, NJ, USA), have been associated with a possibly fatal adverse event known as vaccine-induced thrombotic thrombocytopenia (VITT), wherein thrombi form in unusual sites, mainly the cerebral and splanchnic veins. With the female gender predominantly affected, patients present with headache, abdominal pain, neurological symptoms and fever. It is hypothesized that certain components of the vaccine, including the adenovirus vector, may trigger the formation of antibodies against platelet factor 4 (PF4). The antigen-antibody complexes that form thereafter then activate a cascade of reactions eventually leading to the consumptive coagulopathy. This pathogenesis closely resembles a well-understood complication of heparin, known as heparin-induced thrombocytopenia. The lab results in VITT are reflective of its proposed pathophysiology: low platelets, low fibrinogen and high D-dimer, in addition to elevated anti-PF4 titers are classic findings. Treatment mainly includes non-heparin anticoagulants, intravenous immune globulin (IVIG) and plasma exchange. There is some role for surgical intervention, such as mechanical thrombectomy. Mortality due to VITT is usually caused by cerebral hemorrhage. We describe a case of a 36-year-old female who presented with epigastric pain two weeks after receiving her first dose of the AstraZeneca vaccine, and upon workup, was subsequently found to have thrombosis of her right portal and right common iliac vein.