ABSTRACT
Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia. Recently, the pathophysiology and novel drugs of ITP have been the focus of researchers with plenty of publications emerging. Bibliometrics is the process of extracting measurable data through statistical analysis of published research studies to provide an insight into the trends and hotspots. Objective: This study aimed to provide an insight into developing trends and hotspots in the field of ITP by bibliometric analysis. Methods: By using three bibliometric mapping tools (bibliometrix R package, VOSviewer, CiteSpace), we summarized the overview information of retrieved publications, as well as the analysis of keyword co-occurrence and reference co-citation. Results: A total of 3299 publications with 78066 citations on ITP research were included in the analysis. The keyword co-occurrence network identified 4 clusters relating to the diagnosis, pathophysiology, and treatment of ITP respectively. Then the reference co-citation analysis produced 12 clusters with a well-structured and highly credible clustering model, and they can be divided into 5 trends: second-line treatment, chronic ITP, novel therapy and pathogenesis, COVID-19 vaccine. Treg cells, spleen tyrosine kinase, and mesenchymal stem cells were the latest hotspots with strong burstness. Conclusion: This bibliometric analysis provided a comprehensive insight into research hotspots and trends on ITP, which would enrich the review of the ITP research.
Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , Purpura, Thrombocytopenic, Idiopathic/therapy , COVID-19 Vaccines , BibliometricsABSTRACT
SARS-CoV-2-induced immune thrombocytopenia (SARS-CoV-2-induced ITP) is an autoimmune disease secondary to virus infections. Its diagnosis is often based on exclusion of other possible causes of thrombocytopenia in COVID-19 patients. Common laboratory examinations include coagulation function, thrombopoietin and drug-dependent antibodies. Since both bleeding and thrombosis risks are seen in SARS-CoV-2-induced ITP patients, individual remedy is essential for the treatment of this disease. Because thrombopoietin receptor agonist(TPO-RA) has the side effect of accelerating thrombosis and may aggravate the pulmonary embolism symptoms of patients, it should be used for refractory SARS-CoV-2-induced ITP patients only. This review briefly summarizes the recent research progress in the pathogenesis, diagnosis and treatment of SARS-CoV-2-induced ITP.
Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , Humans , Purpura, Thrombocytopenic, Idiopathic/drug therapy , SARS-CoV-2 , COVID-19/complications , Thrombosis/drug therapy , Thrombopoietin/therapeutic use , Recombinant Fusion Proteins/therapeutic useABSTRACT
Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome characterized by high-titer anti-platelet factor 4 (PF4) antibodies, thrombocytopenia and arterial and venous thrombosis in unusual sites, as cerebral venous sinuses and splanchnic veins. VITT has been described to occur almost exclusively after administration of ChAdOx1 nCoV-19 and Ad26.COV2.S adenovirus vector- based COVID-19 vaccines. Clinical and laboratory features of VITT resemble those of heparin-induced thrombocytopenia (HIT). It has been hypothesized that negatively charged polyadenylated hexone proteins of the AdV vectors could act as heparin to induce the conformational changes of PF4 molecule that lead to the formation of anti-PF4/polyanion antibodies. The anti-PF4 immune response in VITT is fostered by the presence of a proinflammatory milieu, elicited by some impurities found in ChAdOx1 nCoV-19 vaccine, as well as by soluble spike protein resulting from alternative splice events. Anti-PF4 antibodies bind PF4, forming immune complexes which activate platelets, monocytes and granulocytes, resulting in the VITT's immunothrombosis. The reason why only a tiny minority of patents receiving AdV-based COVID-19 vaccines develop VITT is still unknown. It has been hypothesized that individual intrinsic factors, either acquired (i.e., pre-priming of B cells to produce anti-PF4 antibodies by previous contacts with bacteria or viruses) or inherited (i.e., differences in platelet T-cell ubiquitin ligand-2 [TULA-2] expression) can predispose a few subjects to develop VITT. A better knowledge of the mechanistic basis of VITT is essential to improve the safety and the effectiveness of future vaccines and gene therapies using adenovirus vectors.
Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , Vaccines , Humans , Antigen-Antibody Complex , COVID-19 Vaccines/adverse effects , Ad26COVS1 , ChAdOx1 nCoV-19 , Ligands , Spike Glycoprotein, Coronavirus , COVID-19/prevention & control , Platelet Factor 4/genetics , Platelet Factor 4/metabolism , Heparin/adverse effects , Thrombocytopenia/chemically induced , Vaccines/adverse effects , Purpura, Thrombocytopenic, Idiopathic/chemically induced , UbiquitinsABSTRACT
Primary immune thrombocytopenia (ITP) is an acquired blood disorder that causes a reduction in circulating platelets with the potential for bleeding. The incidence of ITP is slightly higher in adults and affects more women than men until 60 years, when males are more affected. Despite advances in basic science, primary ITP remains a diagnosis of exclusion. The disease is heterogeneous in its clinical behavior and response to treatment. This reflects the complex underlying pathophysiology, which remains ill-understood. Platelet destruction plays a role in thrombocytopenia, but underproduction is also a major contributing factor. Active ITP is a proinflammatory autoimmune disease involving abnormalities within the T and B regulatory cell compartments, along with several other immunological abnormalities. Over the last several years, there has been a shift from using immunosuppressive therapies for ITP towards approved treatments, such as thrombopoietin receptor agonists. The recent COVID-19 pandemic has hastened this management shift, with thrombopoietin receptor agonists becoming the predominant second-line treatment. A greater understanding of the underlying mechanisms has led to the development of several targeted therapies, some of which have been approved, with others still undergoing clinical development. Here we outline our view of the disease, including our opinion about the major diagnostic and therapeutic challenges. We also discuss our management of adult ITP and our placement of the various available therapies.
Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Adult , Female , Humans , Purpura, Thrombocytopenic, Idiopathic/therapy , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Receptors, Thrombopoietin/agonists , Receptors, Thrombopoietin/therapeutic use , Pandemics , Blood Platelets , COVID-19 TestingABSTRACT
BACKGROUND: Immune thrombocytopenic purpura is a condition associated with an unusual, unexplained, and sometimes very severe reduction in the level of platelets in the blood. Though documented, its association with Graves' disease is not very common and can easily be missed or misdiagnosed, leading to excessive bleeding and mortality. Treatment with steroids and antithyroid medications has been shown to be beneficial in correcting thrombocytopenia in these patients, although the response is varied. We report on a patient with Graves' disease who presents with immune thrombocytopenic purpura. CASE PRESENTATION: A 37-year-old Ghanaian female presented to our hospital's emergency department with a complaint of palpitations, difficulty breathing, easy fatigue, and headaches. She had been referred from a peripheral hospital as a case of thrombocytopenia, severe anemia, and anterior neck swelling. She was diagnosed with Graves' disease 2 years ago, became euthyroid during treatment, but defaulted. On further examination and investigation, she was diagnosed with immune thrombocytopenic purpura and was also found to have elevated free T3 and T4, and suppressed thyroid stimulating hormone. She also had high thyroid autoantibodies. She was initially started on oral prednisolone but there was no stabilization of platelets until methimazole was introduced, which improved and normalized her platelet count. CONCLUSION: The association of Graves' disease with immune thrombocytopenic purpura, though documented, is uncommon, and very few cases have been reported thus far. There have not been any reported cases in Ghana or Sub-Saharan Africa and hence, clinicians should be aware of this association when investigating immune thrombocytopenic purpura and should consider Graves' disease as a possible cause. From this study, we observed that there was no improvement in platelet count following the use of corticosteroid therapy until methimazole was started.
Subject(s)
Graves Disease , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , Female , Adult , Purpura, Thrombocytopenic, Idiopathic/complications , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Methimazole/therapeutic use , Ghana , Graves Disease/complications , Graves Disease/drug therapy , Thrombocytopenia/complicationsABSTRACT
BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but established complication of 1st dose ChAdOx1 nCoV19 vaccination (AZD1222), however this complication after dose 2 remains controversial. OBJECTIVES: To describe the clinicopathological features of confirmed cases of VITT post dose 2 AZD1222 vaccination in Australia, and to compare this cohort to confirmed cases of VITT post 1st dose. METHODS: Sequential cases of clinically suspected VITT (thrombocytopenia, D-Dimer > 5x upper limit normal and thrombosis) within 4-42 days of dose 2 AZD1222 referred to Australia's centralised testing centre underwent platelet activation confirmatory testing in keeping with the national diagnostic algorithm. Final classification was assigned after adjudication by an expert advisory committee. Descriptive statistics were performed on this cohort and comparative analyses carried out on confirmed cases of VITT after 1st and 2nd dose AZD1222. RESULTS: Of 62 patients referred, 15 demonstrated presence of antibody mediated platelet activation consistent with VITT after dose 2 AZD1222. Four were immunoassay positive. Median time to presentation was 13 days (range 1-53) platelet count 116x10^9/L (range 63-139) and D-dimer elevation 14.5xULN (IQR 11, 26). Two fatalities occurred. In each, the dosing interval was less than 30 days. In comparison to 1st dose, dose 2 cases were more likely to be male (OR 4.6, 95% CI 1.3-15.8, p = 0.03), present with higher platelet counts (p = 0.05), lower D-Dimer (p = 01) and less likely to have unusual site thromboses (OR 0.14, 95% CI 0.04-0.28, p = 0.02). CONCLUSIONS: VITT is a complication of dose 2 AZD1222 vaccination. Whilst clinicopathological features are less severe, fatalities occurred in patients with concomitant factors.
Subject(s)
COVID-19 Vaccines , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , Female , Humans , Male , Antibodies , ChAdOx1 nCoV-19 , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Thrombocytopenia/chemically induced , Vaccination/adverse effects , Vaccines , COVID-19 Vaccines/adverse effectsABSTRACT
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.
Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/complications , Purpura, Thrombocytopenic, Idiopathic/etiology , Thrombosis/etiology , Anticoagulants/therapeutic use , Blood Coagulation/drug effects , COVID-19/blood , Critical Illness , Humans , Male , Middle Aged , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Risk Factors , Thrombosis/blood , Thrombosis/drug therapyABSTRACT
BACKGROUND Thrombosis with thrombocytopenia syndrome (TTS), including vaccine-induced immune thrombotic thrombocytopenia (VITT), is an extremely rare adverse effect, mostly seen after initial vaccination with the viral vector-based AstraZeneca-Oxford COVID-19 vaccine. It is characterized by mild to severe thrombocytopenia and venous or arterial thrombosis. CASE REPORT Herein, we present a case of an 18-year-old male patient who developed Level 1 TTS (probable VITT) eight days after immunization with the ChADOx1 nCOV-19 vaccine (Covishield; AZ-Oxford). Initial investigations revealed severe thrombocytopenia, hemiparesis, and intracranial hemorrhage, after which the patient was treated conservatively. However, a decompressive craniotomy was performed later due to patient deterioration. One week after surgery, the patient developed bilious vomiting, lower-gastrointestinal bleeding, and abdominal distension. An abdominal CT scan was performed that showed thrombosis of the portal vein with occlusion of the left iliac vein. The patient underwent an exploratory laparotomy followed by resection and anastomosis of the small bowel due to massive gut gangrene. Due to persistent thrombocytopenia after surgery, intravenous immune globulin (IVIG) was administered. The platelet count increased thereafter, and the patient stabilized. He was discharged on the 33rd day after admission and was followed up for a year. No post-hospitalization complications were observed in the follow-up period. CONCLUSIONS Although vaccines have been proven to be highly safe and effective to end the Coronavirus Disease 2019 (COVID-19) caused pandemic, there is still a small risk of developing rare complications, including TTS and VITT. Early diagnosis and prompt intervention are key for patient management.
Subject(s)
COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Adolescent , Humans , Male , ChAdOx1 nCoV-19 , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Immunization , Thrombocytopenia/etiology , VaccinationABSTRACT
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.
Subject(s)
Anemia, Hemolytic, Autoimmune , COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , Anemia, Hemolytic, Autoimmune/epidemiology , Anemia, Hemolytic, Autoimmune/etiology , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Purpura, Thrombocytopenic, Idiopathic/etiology , Purpura, Thrombocytopenic, Idiopathic/chemically induced , SARS-CoV-2 , Thrombocytopenia/chemically induced , Vaccination/adverse effectsABSTRACT
Hematologic complications, including vaccine-induced immune thrombotic thrombocytopenia (VITT), immune thrombocytopenia (ITP), and autoimmune hemolytic anemia (AIHA), have been associated with the original severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. However, on August 31, 2022, new formulations of the Pfizer-BioNTech and Moderna vaccines were approved for use without clinical trial testing. Thus, any potential adverse hematologic effects with these new vaccines remain unknown. We queried the US Centers for Disease Control Vaccine Adverse Event Reporting System (VAERS), a national surveillance database, through February 3, 2023, all reported hematologic adverse events that occurred within 42 days of administration of either the Pfizer-BioNTech or Moderna Bivalent COVID-19 Booster vaccine. We included all patient ages and geographic locations and utilized 71 unique VAERS diagnostic codes pertaining to a hematologic condition as defined in the VAERS database. Fifty-five reports of hematologic events were identified (60.0% Pfizer-BioNTech, 27.3% Moderna, 7.3% Pfizer-BioNTech bivalent booster plus influenza, 5.5% Moderna bivalent booster plus influenza). The median age of patients was 66 years, and 90.9% (50/55) of reports involved a description of cytopenias or thrombosis. Notably, 3 potential cases of ITP and 1 case of VITT were identified. In one of the first safety analyses of the new SARS-CoV-2 booster vaccines, we identified few adverse hematologic events (1.05 per 1,000,000 doses), most of which could not be definitively attributed to vaccination. However, three reports of possible ITP and one report of possible VITT highlight the need for continued safety monitoring of these vaccines as their use expands and new formulations are authorized.
Subject(s)
COVID-19 , Drug-Related Side Effects and Adverse Reactions , Influenza, Human , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , Aged , COVID-19/epidemiology , COVID-19/prevention & control , SARS-CoV-2 , Vaccination/adverse effects , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/epidemiology , COVID-19 Vaccines/adverse effectsABSTRACT
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.
Subject(s)
Lupus Erythematosus, Systemic , Purpura, Thrombocytopenic, Idiopathic , Purpura, Thrombotic Thrombocytopenic , Pregnancy , Female , Humans , Adult , Purpura, Thrombotic Thrombocytopenic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/complications , Platelet Count , Rituximab/therapeutic use , Lupus Erythematosus, Systemic/complicationsABSTRACT
RATIONALE: The use of ChAdOx1 nCoV-19 (Astra Zeneca) vaccine has proven beneficial, but in a limited number of the general population, it was found to be associated with vaccine-induced immune thrombotic thrombocytopenia (VITT). However, there have been no reports of this complication occurring in a microsurgical free tissue transfer. PATIENT CONCERNS: A 49-year-old man developed an acute myocardial infarction 3 weeks after receiving his first dose of ChAdOx1 nCoV-19 in June 2021. Three months later, he presented with right third toe wet gangrene with extension into the plantar foot nine days after receiving his second dose of ChAdOx1 nCoV-19 vaccine. DIAGNOSIS: Based on recent exposure to vaccination, the timing of inoculation before the development of his symptoms, and serology tests (platelet, D-dimer, and anti-PF4 antibodies), the patient was diagnosed with VITT. INTERVENTIONS: Fasciectomy and sequestrectomy were performed for wound bed preparation. Limb salvage was done using free vastus lateralis muscle flap and skin graft for reconstruction. OUTCOME: The flap was complicated by persistent microthrombi leading to superficial necrosis without vascular pedicle compromise. Repeated debridement of the superficial necrosis was done. Three months after the development of VITT, no further new superficial necrosis was seen. A well-contoured flap was seen 5 months after the initial surgery. LESSONS: We believe this is the first case describing microthrombi in the free flap due to VITT after microsurgical reconstruction. Patients and surgeons should be advised of this possible risk when contemplating microsurgery once VITT has developed after ChAdOx1 nCoV-19 administration.
Subject(s)
ChAdOx1 nCoV-19 , Free Tissue Flaps , Purpura, Thrombocytopenic, Idiopathic , Thrombosis , Humans , Male , Middle Aged , ChAdOx1 nCoV-19/adverse effects , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Thrombosis/chemically induced , COVID-19/prevention & controlABSTRACT
In our facility, anti-SARS-CoV-2 mRNA vaccines were given to 21 patients, including 8 with aplastic anemia (AA), 3 with pure red cell aplasia (PRCA), and 10 with immune thrombocytopenic purpura (ITP), and IgG antibody titers were assessed one month after vaccinations. After receiving both a second vaccine and a booster shot, all patients with AA/PRCA treated with cyclosporine A aside from one, had IgG titers that were lower than the median levels of healthy controls. Even if prednisolone (PSL) doses did not go over 10 mg/day, ITP patients receiving PSL therapy were unable to achieve adequate levels of IgG after booster immunizations.
Subject(s)
Anemia, Aplastic , COVID-19 , Hematologic Diseases , Purpura, Thrombocytopenic, Idiopathic , Red-Cell Aplasia, Pure , Humans , COVID-19/prevention & control , Anemia, Aplastic/therapy , Antibodies, Viral , Immunoglobulin G , Prednisolone , Purpura, Thrombocytopenic, Idiopathic/drug therapy , RNA, Messenger , VaccinationABSTRACT
Immune thrombocytopenia (ITP) was reported as a rare complication of COVID-19 vaccines. We conducted a retrospective single-center analysis of all ITP cases detected in 2021 and compared the quantity with the pre-vaccination years, from 2018 to 2020. In 2021, a two-fold increase in ITP cases was identified compared to previous years; 11 of 40 cases (27.5%) were considered COVID-19-vaccine related. Our study highlights an increase in ITP cases at our institution, probably related to COVID-19 vaccinations. Further studies are needed to investigate this finding globally.
Subject(s)
COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Immunization Programs , Incidence , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/epidemiology , Retrospective Studies , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Vaccination/adverse effectsABSTRACT
There are currently three thrombopoietin receptor agonists (TPO-RAs) approved in Europe for treating patients with immune thrombocytopenia (ITP): romiplostim (Nplate®), eltrombopag (Revolade®), and avatrombopag (Doptelet®). However, comparative clinical data between these TPO-RAs are limited. Therefore, the purpose of this study was to perform a literature review and seek expert opinion on the relevance and strength of the evidence concerning the use of TPO-RAs in adults with ITP. A systematic search was conducted in PubMed and Embase within the last 10 years and until June 20, 2022. A total of 478 unique articles were retrieved and reviewed for relevance. The expert consensus panel comprised ITP senior hematologists from eight countries across Central Europe. The modified Delphi method, consisting of two survey rounds, a teleconference and email correspondence, was used to reach consensus. Forty articles met the relevancy criteria and are included as supporting evidence, including five meta-analyses analyzing all three European-licensed TPO-RAs and comprising a total of 31 unique randomized controlled trials (RCTs). Consensus was reached on seven statements for the second-line use of TPO-RAs in the management of adult ITP patients. In addition, the expert panel discussed TPO-RA treatment in chronic ITP patients with mild/moderate COVID-19 and ITP patients in the first-line setting but failed to reach consensus. This work will facilitate informed decision-making for healthcare providers treating adult ITP patients with TPO-RAs. However, further studies are needed on the use of TPO-RAs in the first-line setting and specific patient populations.
Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , Adult , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Receptors, Thrombopoietin/agonists , Consensus , Thrombocytopenia/chemically induced , Thrombopoietin/therapeutic use , Receptors, Fc/therapeutic use , Benzoates/therapeutic use , Hydrazines/therapeutic use , Recombinant Fusion Proteins/therapeutic useABSTRACT
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious complication of adenoviral vector-based COVID-19 vaccines. Similar to heparin-induced thrombocytopenia (HIT), antibodies reacting to platelet factor 4 (PF4) are responsible for platelet activation in VITT. The diagnosis of VITT includes the detection of anti-PF4 antibodies. Particle gel immunoassay (PaGIA) is one of the rapid immunoassays that is commonly used in the diagnosis of HIT to detect anti-PF4 antibodies. The aim of this study was to investigate the diagnostic performance of PaGIA in patients suspected of VITT. In this retrospective, single-center study, the correlation between PaGIA, enzyme immunoassay (EIA), and modified heparin-induced platelet aggregation assay (HIPA) in patients with findings suggestive of VITT was investigated. A commercially available PF4 rapid immunoassay (ID PaGIA H/PF4, Bio-Rad-DiaMed GmbH, Switzerland) and an anti-PF4/heparin EIA (ZYMUTEST HIA IgG, Hyphen Biomed) were used according to manufacturer's instructions. Modified HIPA was accepted as the gold standard test. Between March 8 and November 19, 2021, a total of 34 samples from clinically well-characterized patients (14 males, 20 females, mean age: 48.2 ± 18.2 years) were analyzed with PaGIA, EIA, and modified HIPA. VITT was diagnosed in 15 patients. Sensitivity and specificity of PaGIA were 54 and 67%, respectively. Anti-PF4/heparin optical density values were not significantly different between PaGIA positive and negative samples (p = 0.586). The sensitivity and specificity of EIA, on the other hand, were 87 and 100%, respectively. In conclusion, PaGIA is not reliable in the diagnosis of VITT because of its low sensitivity and specificity.
Subject(s)
COVID-19 Vaccines , Immunoassay , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Adult , Aged , Female , Humans , Male , Middle Aged , COVID-19/prevention & control , COVID-19 Testing , COVID-19 Vaccines/adverse effects , Heparin/adverse effects , Platelet Factor 4 , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Retrospective Studies , Thrombocytopenia/chemically inducedABSTRACT
Within the first months of the COVID-19 vaccination campaign, previously healthy recipients who developed severe thrombosis (often cerebral and/or splanchnic vasculature) and thrombocytopenia typically after adenoviral vector-based vaccination were identified. Similarities between this syndrome, vaccine-induced immune thrombotic thrombocytopenia (VITT), and heparin-induced thrombocytopenia prompted recognition of the role of antiplatelet factor 4 (PF4) antibodies and management strategies based on IV immunoglobulin and nonheparin anticoagulants, which improved outcome. We update current understanding of VITT and potential involvement of anti-PF4 antibodies in thrombotic disorders.
Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , Vaccines , Humans , COVID-19 Vaccines/adverse effects , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/therapy , Thrombocytopenia/chemically induced , Thrombosis/etiology , Platelet Factor 4ABSTRACT
INTRODUCTION: This systematic review aimed to retrieve patients diagnosed with de novo immune thrombocytopenic purpura (ITP) after COVID-19 immunization to determine their epidemiological characteristics, clinical course, therapeutic strategies, and outcome. MATERIALS AND METHODS: We conducted the review using four major databases, comprising PubMed, Scopus, Web of Science, and the Cochrane library, until April 2022. A systematic search was performed in duplicate to access eligible articles in English. Furthermore, a manual search was applied to the chosen papers' references to enhance the search sensitivity. Data were extracted and analyzed with the SPSS 20.1 software. RESULTS: A total of 77 patients with de novo COVID-19 vaccine-associated ITP were identified from 41 studies, including 31 case reports and 10 case series. The median age of patients who developed COVID-19 vaccine-associated ITP was 54 years (IQR 36-72 years). The mRNA-based COVID-19 vaccines, including BNT16B2b2 and mRNA-1273, were most implicated (75.4%). Those were followed by the adenovirus vector-based vaccines, inclusive of ChAdOx1 nCoV-19 and vAd26.COV2.S. No report was found relating ITP to other COVID-19 vaccines. Most cases (79.2%) developed ITP after the first dose of COVID-19 vaccination. 75% of the patients developed ITP within 12 days of vaccination, indicating a shorter lag time compared to ITP after routine childhood vaccinations. Sixty-seven patients (87%) patients were hospitalized. The management pattern was similar to primary ITP, and systemic glucocorticoids, IVIg, or both were the basis of the treatment in most patients. Most patients achieved therapeutic goals; only two individuals required a secondary admission, and one patient who presented with intracranial hemorrhage died of the complication. CONCLUSIONS: De novo ITP is a rare complication of COVID-19 vaccination, and corresponding reports belong to mRNA-based and adenovirus vector-based vaccines, in order of frequency. This frequency pattern may be related to the scale of administration of individual vaccines and their potency in inducing autoimmunity. The more the COVID-19 vaccine is potent to induce antigenic challenge, the shorter the lag time would be. Most patients had a benign course and responded to typical treatments of primary ITP.
Subject(s)
COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Adult , Aged , Humans , Middle Aged , ChAdOx1 nCoV-19 , COVID-19/complications , COVID-19 Vaccines/adverse effects , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Vaccination/adverse effectsABSTRACT
Platelet factor 4 (PF4), also known as chemokine (C-X-C motif) ligand 4 (CXCL4), is a specific protein synthesized from platelet α particles. The combination of PF4 and heparin to form antigenic complexes is an important mechanism in the pathogenesis of heparin-induced thrombocytopenia (HIT), but vaccine-induced immune thrombotic thrombocytopenia (VITT) related to the COVID-19 vaccine makes PF4 a research hotspot again. Similar to HIT, vaccines, bacteria, and other non-heparin exposure, PF4 can interact with negatively charged polyanions to form immune complexes and participate in thrombosis. These anions include cell surface mucopolysaccharides, platelet polyphosphates, DNA from endothelial cells, or von Willebrand factor (VWF). Among them, PF4-VWF, as a new immune complex, may induce and promote the formation of immune-associated thrombosis and is expected to become a new target and therapeutic direction. For both HIT and VITT, there is no effective and targeted treatment except discontinuation of suspected drugs. The research and development of targeted drugs based on the mechanism of action have become an unmet clinical need. Here, this study systematically reviewed the characteristics and pathophysiological mechanisms of PF4 and VWF, elaborated the potential mechanism of action of PF4-VWF complex in immune-associated thrombosis, summarized the current status of new drug research and development for PF4 and VWF, and discussed the possibility of this complex as a potential biomarker for early immune-associated thrombosis events. Moreover, the key points of basic research and clinical evaluation are put forward in the study.