Sex: M
Vaccine: COVID19
Symptoms: Hepatitis C virus test, Immune thrombocytopenia, International normalised ratio, Investigation, Minimum inhibitory concentration
Clinical narrative: Severe Immune Thrombocytopenia; This is a literature report for the following literature source(s):   A 25-year-old male with active intravenous drug use presented to the emergency department from a homeless encampment due to fevers and ill appearance. Upon arrival, he was in septic shock and subsequent cultures grew high-grademethicillin-resistant Staphylococcus aureus (MRSA) bacteremia. His initial laboratory work was pertinent for white blood cell count (WBC) of 14.7x103/uL, hemoglobin (Hgb) count of 7.9 g/dL, and platelet (PLT) count of 73x103/uL. Initial coagulation studies showed normal PT/ INR and aPTT. He did not have any history of thrombocytopenia and new onset thrombocytopenia was attributed to sepsis-induced bone marrow suppression. Although he was initially placed on vancomycin for MRSA bacteremia, his antibiotic regimen had to be modified to daptomycin and ceftaroline on hospital day 4 (HD4) given the persistent bacteremia on vancomycin and relatively elevated minimal inhibitory concentration (MIC). Further infectious workup showed negative human immunodeficiency virus (HIV) and EpsteinBarr virus (EBV) serologies and a positive hepatitis C viremia, which was previously documented. Echocardiogram revealed large vegetation (2.8x 3.2 cm) on the anterior leafest of the tricuspid valve with mild tricuspid regurgitation (TR). His repeat echocardiogram after 7 days of antibiotic therapy showed a size change of vegetation to 2.78x1.61 cm (from 2.8 x3.2 cm) and a worsening of TR to moderate-severe from mild. Computed tomography (CT) of the chest showed innumerable cavitary lesions consistent with septic emboli along with multifocal abscesses. He underwent chest tube placement for management of loculated pulmonary e6usion on hospital day 8 and fluid analysis was consistent with empyema with positive cultures for MRSA. His blood cultures finally cleared on day 10, and his repeat laboratory work on day 10 showed a WBC of 12.0 x103/uL, Hgb of 9.4 g/dL, and a PLT count of 174 x103/uL. During the following days, his PLT count ranged between 146 x103/uL and 216 x103/uL with a PLT count of 156 x103/uL on day 15. He received mRNA COVID-19 Pfizer vaccination on the afternoon of hospital day 15 (HD15) and his platelet count the next morning was 0 x103/ uL which was confirmed by repeating the analysis several times with citrated tubes. The peripheral smear was negative for any clumping or hemolysis, and it showed large platelets. Coagulation studies revealed fibrinogen of 384 mg/dL (187-446), PT of 12.4 seconds (9.3-12.1), INR of 1.2 (0.9-1.2), aPTT of 31.9 seconds (23.9-32.8), and D-dimer of 5.90 ug/mlFEU (<0.50). They also calculated the 4T score in this patient and it was found to be 5, which is why prophylactic subcutaneous enoxaparin was discontinued, and a heparin-induced thrombocytopenia panel was sent which later showed negative platelet factor-4 (PF-4) antibodies and negative serotonin release assay (SRA). Infectious disease (ID) service was consulted and ceftaroline was stopped given its link to thrombocytopenia although it was deemed unlikely to be the culprit in this case given the very abrupt drop, single-digit platelet nadir, and atypical temporality as the patient had been on the medication for more than a week. Two units of platelets were transfused without appropriate response as the posttransfusion platelet count was 1 x 103/uL. Given no response to platelet transfusions, the possibility of immune thrombocytopenic purpura (ITP) with ongoing destruction was raised by the hematology service, and he was initiated on intravenous immunoglobulin (IVIG). The patient developed an adverse reaction after the first dose of IVIG which was attributed to the transfusion-related acute lung injury (TRALI); thus, he could not receive the second dose of IVIG. Subsequently, dexamethasone 40 mg daily was started for a total of four days. His PLT count started improving after dexamethasone administration and the daily PLT count trend was as follows: 0 (day 17); 1, 3, 21, 110 (day 20); 90, 155 x103/uL (day 22), and it remained normal afterwards (Figure 1). Coronavirus nucleocapsid protein antibodies (anti-N abs) were sent as per ID request for testing and returned positive which proved suspected previous exposure to SARS-CoV-2 before the vaccine, since nucleocapsid antibodies are triggered only by the infection, whereas spike antibodies are triggered by infection and/or vaccination. This indicated that mRNA COVID-19 vaccination was at least his second encounter with SARS-CoV-2 antigens which likely made a very rapid onset immunological process possible. His thrombocytopenia did not recur afterwards, and he is currently completing his daptomycin course with a plan to follow up with cardiothoracic surgery for valve surgery evaluation. Discussion: In this patient's clinical presentation, the platelet drop onset was very rapid (within 24 hours) and one could argue possible predisposing etiologies such as drug-induced and sepsis-induced thrombocytopenia from bone marrow suppression. He initially presented with sepsis from tricuspid valve endocarditis and was started on vancomycin, followed by daptomycin and ceftaroline for the antibiotic regimen which led to resolution of initial thrombocytopenia from 78 x103/uL up to 146 x103/uL, with the sudden drop of PLT count to 0 the next day after mRNA COVID-19 Pfizer vaccination. As known, several infections have been associated with ITP including but not limited to Helicobacter pylori, hepatitis C virus, and HIV. Our patient did have a history of chronic hepatitis C; however, his platelet count was normal throughout the hospital course until the rapid drop following the vaccine. Previous data have also identified daptomycin-induced ITP as a probable entity of thrombocytopenia; however, in this patient, this drug was continued during his hospitalization course and was maintained even after ITP resolution, making it unlikely to be the cause of the ITP. It was difficult to determine if any of these conditions were contributing factor(s) to his rapid onset of ITP but deemed unlikely to be a causative factor(s) in his case. The leading theory to explain the phenomenon of ITP is that the viral antigens cross-react with normal platelet antigens in molecular mimicry, causing the destruction of these cells. Reactions can occur shortly after exposure to the trigger. For example, if the patient has been previously sensitized to an antigen, the onset of thrombocytopenia can be as early as hours after re-exposure. This seems to be the case in our patient as he tested positive for anti-N abs, which is the standard assay to determine previous infection, confirming prior COVID-19 exposure. It is important to note that anti-N abs are not elicited by COVID-19 vaccines that target the spike protein, including all vaccines used in the existing country. Other authors propose that the mRNA component of the Pfizer-BioNTech vaccine is unlikely to cause an allergic reaction by itself, but rather the modified RNA trace impurities that are present in this vaccine could explain thrombocytopenia. It is also reported that there is a possibility that these aberrant proteins could initiate an immune response that would lead to this adverse reaction. Vaccines prepared from dead bacteria or viruses are potent stimulators of the immune system in general, and many adjuvants (DNA, lipids, and aluminum salts) are commonly added to other vaccines to enhance the immune system. The potent immune activator is mRNA, as this is the nanoparticle lipid component of the COVID-19 vaccines. Recent publications show that mRNA is taken up by cellular RNA receptors leading to the upregulation of toll-like receptors (TLR) 7 and 8 followed by the activation and maturation of immune cells and secretion of cytokines and chemokines. Nonetheless, data show that a second COVID-19 vaccination using a different mRNA vaccine can be considered safe for selected patients who had experienced de novo ITP after the administration of a first dose.; Sender's Comments: Considering the plausible drug-event temporal association, event of Immune thrombocytopenia is assessed as related to BNT162B2 vaccine and unrelated to co-suspect daptomycin. As per the publication it was noted that "patient developed severe thrombocytopenia within twenty-four hours following the Pfizer-BioNTech vaccination. He initially presented with sepsis from tricuspid valve endocarditis and was started on vancomycin, followed by daptomycin and ceftaroline for the antibiotic regimen which led to resolution of initial thrombocytopenia from 78 ×103/uL up to 146 ×103/uL, with the sudden drop of PLT count to 0 the next day after mRNA COVID-19 Pfizer vaccination". In regards to Daptomycin author stated that "Previous data have also identified daptomycin-induced ITP as a probable entity of thrombocytopenia, however, in our patient, this drug was continued during his hospitalization course and was maintained even after ITP resolution, making it unlikely to be the cause of the ITP". The impact of this report on the benefit/risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to Regulatory Authorities, Ethics committees and Investigators, as appropriate.,Linked Report(s) : US-PFIZER INC-202300155509 Same article /patient; Different event /drug;