Immunogenicity and risks associated with impaired immune responses following SARS-CoV-2 vaccination and booster in hematologic malignancy patients: an updated meta-analysis.

Patients with hematologic malignancies (HM) have demonstrated impaired immune responses following SARS-CoV-2 vaccination. Factors associated with poor immunogenicity remain largely undetermined. A literature search was conducted using PubMed, EMBASE, Cochrane, and medRxiv databases to identify studies that reported humoral or cellular immune responses (CIR) following complete SARS-CoV-2 vaccination. The primary aim was to estimate the seroconversion rate (SR) following complete SARS-CoV-2 vaccination across various subtypes of HM diseases and treatments. The secondary aims were to determine the rates of development of neutralizing antibodies (NAb) and CIR following complete vaccination and SR following booster doses. A total of 170 studies were included for qualitative and quantitative analysis of primary and secondary outcomes. A meta-analysis of 150 studies including 20,922 HM patients revealed a pooled SR following SARS-CoV-2 vaccination of 67.7% (95% confidence interval [CI], 64.8-70.4%; I2 = 94%). Meta-regression analysis showed that patients with lymphoid malignancies, but not myeloid malignancies, had lower seroconversion rates than those with solid cancers (R2 = 0.52, P < 0.0001). Patients receiving chimeric antigen receptor T-cells (CART), B-cell targeted therapies or JAK inhibitors were associated with poor seroconversion (R2 = 0.39, P < 0.0001). The pooled NAb and CIR rates were 52.8% (95% CI; 45.8-59.7%, I2 = 87%) and 66.6% (95% CI, 57.1-74.9%; I2 = 86%), respectively. Approximately 20.9% (95% CI, 11.4-35.1%, I2 = 90%) of HM patients failed to elicit humoral and cellular immunity. Among non-seroconverted patients after primary vaccination, only 40.5% (95% CI, 33.0-48.4%; I2 = 87%) mounted seroconversion after the booster. In conclusion, HM patients, especially those with lymphoid malignancies and/or receiving CART, B-cell targeted therapies, or JAK inhibitors, showed poor SR after SARS-CoV-2 vaccination. A minority of patients attained seroconversion after booster vaccination. Strategies to improve immune response in these severely immunosuppressed patients are needed.

ChAdOx1 nCoV-19 vaccine-associated thrombocytopenia: three cases of immune thrombocytopenia after 107 720 doses of ChAdOx1 vaccination in Thailand.

We reported three cases of immune thrombocytopenia (ITP) that developed within 6 weeks after ChAdOx1 nCoV-19 vaccination. Antiplatelet factor 4 antibodies were undetectable in all three cases. Therefore, vaccine-induced immune thrombotic thrombocytopenia was very unlikely. Other potential causes of thrombocytopenia were excluded. Their clinical presentations, severity of thrombocytopenia and outcomes were varied. Only one ITP case, an 80-year-old man, received ITP treatments and achieved complete response after 2 weeks of eltrombopag. An 84-year-old man had spontaneous complete remission, and a 55-year-old woman had partial platelet recovery without ITP treatments. Among 107 720 Thais administered the ChAdOx1 vaccine between 16 March and 10 May 2021, these three ITP cases resulted in an estimated risk of ITP of at least one per 36 000 doses, which was approximately similar to the risk of ITP after measles-mumps-rubella immunization. This raises the concern of an increased risk of ITP after ChAdOx1 vaccination.

Thrombosis with thrombocytopenia after the second ChAdOx1 nCoV-19 vaccination: A possible immunological mechanism independent of anti-platelet factor 4 antibody.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a distinctive syndrome characterized by unusual site thrombosis accompanied by thrombocytopenia following adenoviral vector vaccines against severe acute respiratory syndrome coronavirus 2. Platelet-activating anti-platelet factor 4-dependent antibodies (anti-PF4 Abs) have been identified as pathogenic antibodies in almost all patients. OBJECTIVE: We proposed an immunological mechanism of VITT independent of anti-PF4 Abs. METHODS: Case report. RESULTS: A 68-year-old Thai woman developed pulmonary embolism and deep vein thrombosis with thrombocytopenia one week after the second ChAdOx1 nCoV-19 vaccination with undetectable anti-PF4 Abs. The platelet count responded rapidly to intravenous immunoglobulin and steroids. Therefore, the high clinical suspicion is essential for early recognition and prompt management irrespective of anti-PF4 Ab results. CONCLUSIONS: We hypothesize that platelet and endothelial activation following ChAdOx1 nCoV-19 vaccination may lead to generation of pathogenic antibodies which account for VITT independent of anti-PF4 Abs.

Thromboembolic and hemorrhagic risks after vaccination against SARS-CoV-2: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Thromboembolic and bleeding events after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are major public concerns leading to vaccine hesitancy. Due to low incidence, an individual randomized controlled trial (RCT) is underpowered to determine whether SARS-CoV-2 vaccines increase the risks of thromboembolism and hemorrhage. METHODS: We performed a literature search using PubMed, EMBASE, Cochrane, medRxiv databases, and reference lists of relevant articles to identify RCTs that reported thromboembolic, hemorrhagic events, and thromboembolism/hemorrhage-related death after SARS-CoV-2 vaccination. The primary aim of this systematic review and meta-analysis was to estimate the pooled thromboembolic risk related to SARS-CoV-2 vaccines compared to placebo. The secondary outcomes included estimating the risks of arterial thromboembolism (ATE), venous thromboembolisms (VTE), hemorrhage, thrombocytopenia, and thromboembolism/hemorrhage-related death. RESULTS: Eight RCTs of 4 vaccine platforms comprised of 195,196 participants were retrieved. SARS-CoV-2 vaccines were not associated with an increased risk of overall thromboembolism (risk ratio [RR], 1.14; 95% CI [confidence interval], 0.61-2.14; I2 = 35%), ATE (RR, 0.97; 95% CI, 0.46-2.06; I2 = 21%), VTE (RR, 1.47; 95% CI, 0.72-2.99; I2 = 0%), hemorrhage (RR, 0.97; 95% CI, 0.35-2.68; I2 = 0), and thromboembolism/hemorrhage-related death (RR, 0.53; 95% CI, 0.16-1.79; I2 = 0). Compared to the baseline estimated risk of these outcomes in participants administered placebos, the risk differences with vaccines were very small and not statistically significant. These findings were consistent in the subgroup analysis across 4 vaccine platforms. CONCLUSION: Vaccines against SARS-CoV-2 are not associated with an increased risk of thromboembolism, hemorrhage, and thromboembolism/hemorrhage-related death.

Heparin-induced thrombocytopenia in patients with COVID-19: a systematic review and meta-analysis.

Heparin thromboprophylaxis is routinely administered during hospitalization for COVID-19. Because of the immune stimulation related to COVID-19, there is ongoing concern regarding a heightened incidence of heparin-induced thrombocytopenia (HIT). We performed a literature search using PubMed, EMBASE, Cochrane, and medRxiv database to identify studies that reported clinical and laboratory characteristics and/or the incidence of HIT in patients with COVID-19. The primary aim was to systematically review the clinical features and outcomes of patients with COVID-19 with confirmed HIT. The secondary objective was to perform a meta-analysis to estimate the incidence of HIT in hospitalized patients with COVID-19. A meta-analysis of 7 studies including 5849 patients revealed the pooled incidence of HIT in COVID-19 of 0.8% (95% confidence interval [CI], 0.2%-3.2%; I2 = 89%). The estimated incidences were 1.2% (95% CI, 0.3%-3.9%; I2 = 65%) vs 0.1% (95% CI, 0.0%-0.4%; I2 = 0%) in therapeutic vs prophylactic heparin subgroups, respectively. The pooled incidences of HIT were higher in critically ill patients with COVID-19 (2.2%; 95% CI, 0.6%-8.3%; I2 = 72.5%) compared with noncritically ill patients (0.1%; 95% CI, 0.0%-0.4%: I2 = 0%). There were 19 cases of confirmed HIT and 1 with autoimmune HIT for clinical and laboratory characterization. The median time from heparin initiation to HIT diagnosis was 13.5 days (interquartile range, 10.75-16.25 days). Twelve (63%) developed thromboembolism after heparin therapy. In conclusion, the incidence of HIT in patients with COVID-19 was comparable to patients without COVID-19, with higher incidences with therapeutic anticoagulation and in critically ill patients.

Prevalence of thrombocytopenia, anti-platelet factor 4 antibodies and D-dimer elevation in Thai people After ChAdOx1 nCoV-19 vaccination.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare distinctive syndrome characterized by unusual site thrombosis accompanied by thrombocytopenia after ChAdOx1 nCoV-19 vaccination. Platelet-activating anti-platelet factor 4-dependent antibodies (anti-PF4 Abs) were detected in most cases of VITT. To date, data from Asian countries are lacking. OBJECTIVES: To determine the prevalence of thrombocytopenia, anti-PF4 Abs, and D-dimer elevation in Thai people administered the ChAdOx1 vaccine. PATIENTS/METHODS: A total of 521 vaccinated and 146 nonvaccinated subjects were enrolled. Blood samples were collected to determine platelet counts, anti-PF4 Abs using ELISA and D-dimer levels 5 to 30 days after the first vaccination. RESULTS: None of the participants developed thrombocytopenia or had significantly decreased platelet counts from baseline after ChAdOx1 vaccination. The frequencies of anti-PF4 Abs between vaccinated (16/521; 3.1%; 95% confidence interval [CI], 1.8-4.9) and nonvaccinated Thai people (6/146; 4.1%; 95% CI, 1.5-8.7) were similar. None of the detectable anti-PF4 Abs activated platelets in vitro. The average D-dimer levels between vaccinated and control groups were similar (282.2 ± 286.3 vs 267.8 ± 219.3 ng/mL; P = 0.58). Four vaccinated and one nonvaccinated participants had markedly elevated D-dimer levels >2000 ng/mL without detectable anti-PF4 Abs. Imaging studies of these asymptomatic subjects revealed incidental pulmonary embolism in a vaccinated elderly woman. CONCLUSIONS: This study demonstrated a low prevalence of thrombocytopenia and pathogenic anti-PF4 Abs after ChAdOx1 vaccination. D-dimer testing revealed no significant coagulation activation. Routine tests for platelet counts, anti-PF4 Abs, and D-dimer levels are not recommended for VITT screening without clinical suspicion.

Anticoagulation and In-Hospital Mortality From Coronavirus Disease 2019: A Systematic Review and Meta-Analysis.

Hypercoagulability in coronavirus disease 2019 (COVID-19) may aggravate disease severity during hospitalization but the reported survival benefits from anticoagulation (AC) vary among studies. We performed a literature research to estimate pooled odds ratios (ORs) of in-hospital mortality and major bleeding comparing among intermediate-to-therapeutic dose AC, prophylactic dose AC, and no AC. Until October 22, 2020, PubMed, EMBASE, and Cochrane Library Database were searched for studies reporting AC utilization and mortality in COVID-19. Studies with suspected risk of bias were excluded before the synthesis of pooled ORs with 95% confidence intervals (CIs) using random-effects models. Of 37 identified studies (N = 19,510), 17 (N = 17,833) were aggregated in the meta-analysis. The overall mortality rate was 23.1% (95% CI 18.7-28.2). The pooled odds of mortality comparing anticoagulated to non-anticoagulated patients were similar, but lower in prophylactic dose AC group (OR 0.83; 95% CI 0.73-0.95). Notably, intermediate-to-therapeutic dose AC increased mortality (OR 1.60; 95% CI 1.11-2.31) and major bleeding compared to prophylactic dose AC (OR 3.33; 95% CI 2.34-4.72). Our findings support the optimal efficacy and safety profiles of prophylactic dose AC in hospitalized COVID-19 patients.

Systemic Coagulopathy in Hospitalized Patients With Coronavirus Disease 2019: A Systematic Review and Meta-Analysis.

Coagulation activation has been reported in several cohorts of patients Coronavirus Disease 2019 (COVID-19). However, the true burden of systemic coagulopathy in COVID-19 remains unknown. In this systematic review and meta-analysis, we performed a literature search using PubMed, EMBASE, and Cochrane Database to identify studies that reported the prevalence of systemic coagulopathy using established criteria in patients with COVID-19. The primary outcome was the prevalence of systemic coagulopathy (disseminated intravascular coagulation [DIC] and/or sepsis-induced coagulopathy [SIC]). Pooled prevalences and 95% confidence intervals [CIs] were calculated using random-effects model. A total of 5 studies including 1210 patients with confirmed COVID-19 were included. The pooled prevalence of systemic coagulopathy was 7.1% (95%CI: 3.2%,15.3%, I2 = 93%). The pooled prevalence of DIC (N = 721) and SIC (N = 639) were 4.3% (95%CI 1.7%, 10.4%, I2 = 84%) and 16.2% (95%CI: 9.3%, 26.8%, I2 = 74%), respectively. Only 2 studies reported the prevalence of elevated D-dimer levels with the pooled prevalence of 84.6% (95%CI: 52.0%,96.5%, I2 = 94%). Average D-dimer and fibrinogen levels were remarkably increased, while platelet counts, PT, and aPTT ratios were minimally affected in COVID-19. The estimated prevalence of systemic coagulopathy in patients with COVID-19 was low despite D-dimer elevation in most patients. Relatively low systemic coagulopathy in COVID-19 may contribute to the high incidence of thrombosis rather than bleeding in patients with COVID-19.