Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia in middle-income countries.

BACKGROUND: Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). Remarkably, cases of cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) have rarely been reported from LMICs. AIMS: We studied the frequency, manifestations, treatment, and outcomes of CVST-VITT in LMICs. METHODS: We report data from an international registry on CVST after COVID-19 vaccination. VITT was classified according to the Pavord criteria. We compared CVST-VITT cases from LMICs to cases from high-income countries (HICs). RESULTS: Until August 2022, 228 CVST cases were reported, of which 63 were from LMICs (all middle-income countries [MICs]: Brazil, China, India, Iran, Mexico, Pakistan, Turkey). Of these 63, 32 (51%) met the VITT criteria, compared to 103 of 165 (62%) from HICs. Only 5 of the 32 (16%) CVST-VITT cases from MICs had definite VITT, mostly because anti-platelet factor 4 antibodies were often not tested. The median age was 26 (interquartile range [IQR] 20-37) versus 47 (IQR 32-58) years, and the proportion of women was 25 of 32 (78%) versus 77 of 103 (75%) in MICs versus HICs, respectively. Patients from MICs were diagnosed later than patients from HICs (1/32 [3%] vs. 65/103 [63%] diagnosed before May 2021). Clinical manifestations, including intracranial hemorrhage, were largely similar as was intravenous immunoglobulin use. In-hospital mortality was lower in MICs (7/31 [23%, 95% confidence interval (CI) 11-40]) than in HICs (44/102 [43%, 95% CI 34-53], p = 0.039). CONCLUSIONS: The number of CVST-VITT cases reported from LMICs was small despite the widespread use of adenoviral vaccines. Clinical manifestations and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs.

The potential impact of Covid-19 on the capacity of routine laboratory tests to detect heparin-induced thrombocytopenia.

In Covid-19, anticoagulation with heparin is often administered to prevent or treat thromboembolic events. Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin treatment, caused by heparin-dependent, platelet activating anti-platelet factor 4 (PF4)/heparin antibodies. Diagnosis of HIT is based on the combination of clinical parameters, allowing to determine the pretest probability, and laboratory testing for anti-PF4/heparin antibodies and confirmatory functional assays, such as the heparin-induced platelet activation (HIPA) test.We report the case of a patient with severe Covid-19 pneumonia requiring ECMO treatment, who developed recurrent clotting of the ECMO filter and a drop in platelet count under heparin treatment. He was therefore suspected to have HIT and the anticoagulation was switched to argatroban. Despite high clinical probability and high titres of anti-PF4/heparin antibodies, the functional HIPA test was negative. Nevertheless, argatroban was continued rather than to reinstate anticoagulation with heparin. Reevaluation 7 days later then demonstrated a strongly positive functional HIPA test and confirmed the diagnosis of HIT. Under anticoagulation with argatroban the patient gradually improved and was finally weaned off the ECMO.In conclusion, this case highlights the critical importance of clinical judgement, exploiting the 4 T score, given that Covid-19 patients may present a different pattern of routine laboratory test results in HIT diagnostics. The possibility of a false negative HIPA test has to be considered, particularly in early phases of presentation. In cases of a discrepancy with high clinical probability of HIT and/or high titre anti-PF4/heparin antibodies despite a negative HIPA test, a reevaluation within 3 to 5 days after the initial test should be considered in order to avoid precipitant reestablishment of unfractionated heparin, with potentially fatal consequences.

Immune-Mediated Thrombotic Thrombocytopenic Purpura Following mRNA-Based COVID-19 Vaccine BNT162b2: Case Report and Mini-Review of the Literature.

Introduction: An increasing number of case reports have associated vaccinations against coronavirus disease 2019 (COVID-19) with immune-mediated thrombotic thrombocytopenic purpura (iTTP), a very rare but potentially life-threatening thrombotic microangiopathy, which leads to ischemic organ dysfunction. Thrombus formation in iTTP is related to a severe deficiency of the specific von Willebrand-factor-cleaving protease ADAMTS13 due to ADAMTS13 autoantibodies. Methods: We present a case of iTTP following exposure to the mRNA-based COVID-19 vaccine BNT162b2 (Comirnaty®, Pfizer-BioNTech). In addition, we review previously reported cases in the literature and assess current evidence. Results: Apart from our case, twenty cases of iTTP occurring after COVID-19 vaccination had been published until the end of November 2021. There were 11 male and 10 female cases; their median age at diagnosis was 50 years (range 14-84 years). Five patients (24%) had a preexisting history of iTTP. Recombinant adenoviral vector-based vaccines were involved in 19%, mRNA-based vaccines in 81%. The median onset of symptoms after vaccination was 12 days (range 5-37), with 20 cases presenting within 30 days. Treatment included therapeutic plasma exchange in all patients. Additional rituximab, caplacizumab, or both these treatments were given in 43% (9/21), 14% (3/21), and 24% (5/21) of cases, respectively. One patient died, despite a prolonged clinical course in one patient, all surviving patients were in clinical remission at the end of the observational period. Conclusion: Clinical features of iTTP following COVID-19 vaccination were in line with those of pre-pandemic iTTP. When timely initiated, an excellent response to standard treatment was seen in all cases. ADAMTS13 activity should be determined pre-vaccination in patients with a history of a previous iTTP episode. None of the reported cases met the WHO criteria for assessing an adverse event following immunization (AEFI) as a consistent causal association to immunization. Further surveillance of safety data and additional case-based assessment are needed.

Cerebral Venous Sinus Thrombosis Associated with Vaccine-Induced Thrombotic Thrombocytopenia-A Narrative Review

In March 2021, cerebral venous sinus thrombosis and thrombocytopenia after vaccination with adenovirus-based vaccine against SARS-CoV-2 were first reported. The underlining condition has been termed vaccine-induced immune thrombocytopenia (VITT). Anti-platelet factor 4 antibodies have been proposed as a central component of the pathomechanism. Treatment recommendations entailed immunomodulation with intravenous immunoglobulins, avoidance of heparins and avoidance of platelet transfusions. Although mortality from VITT-associated cerebral venous sinus thrombosis has decreased over time, it remains high. The aim of this narrative review is to describe different aspects of this disease according to the current state of knowledge.

Characteristics and Outcomes of Patients With Cerebral Venous Sinus Thrombosis in SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia.

Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson). Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS. Design, Setting, and Participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination. Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria. Main Outcomes and Measures: Clinical characteristics and mortality rate. Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later. Conclusions and Relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.

Declining mortality of cerebral venous sinus thrombosis with thrombocytopenia after SARS-CoV-2 vaccination.

BACKGROUND AND PURPOSE: High mortality rates have been reported in patients with cerebral venous sinus thrombosis (CVST) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) after vaccination with adenoviral vector SARS-CoV-2 vaccines. The aim of this study was to evaluate whether the mortality of patients with CVST-VITT has decreased over time. METHODS: The EudraVigilance database of the European Medicines Agency was used to identify cases of CVST with concomitant thrombocytopenia occurring within 28 days of SARS-CoV-2 vaccination. Vaccines were grouped based on vaccine type (adenoviral or mRNA). Cases with CVST onset until 28 March were compared to cases after 28 March 2021, which was the day when the first scientific paper on VITT was published. RESULTS: In total, 270 cases of CVST with thrombocytopenia were identified, of which 266 (99%) occurred after adenoviral vector SARS-CoV-2 vaccination (ChAdOx1 nCoV-19, n = 243; Ad26.COV2.S, n = 23). The reported mortality amongst adenoviral cases with onset up to 28 March 2021 was 47/99 (47%, 95% confidence interval 37%-58%) compared to 36/167 (22%, 95% confidence interval 16%-29%) in cases with onset after 28 March (p < 0.001). None of the four cases of CVST with thrombocytopenia occurring after mRNA vaccination died. CONCLUSION: The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector-based SARS-CoV-2 vaccines has significantly decreased over time, which may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after VITT.

Frequency of Thrombocytopenia and Platelet Factor 4/Heparin Antibodies in Patients With Cerebral Venous Sinus Thrombosis Prior to the COVID-19 Pandemic.

Importance: Cases of cerebral venous sinus thrombosis in combination with thrombocytopenia have recently been reported within 4 to 28 days of vaccination with the ChAdOx1 nCov-19 (AstraZeneca/Oxford) and Ad.26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccines. An immune-mediated response associated with platelet factor 4/heparin antibodies has been proposed as the underlying pathomechanism. Objective: To determine the frequencies of admission thrombocytopenia, heparin-induced thrombocytopenia, and presence of platelet factor 4/heparin antibodies in patients diagnosed with cerebral venous sinus thrombosis prior to the COVID-19 pandemic. Design, Setting, and Participants: This was a descriptive analysis of a retrospective sample of consecutive patients diagnosed with cerebral venous sinus thrombosis between January 1987 and March 2018 from 7 hospitals participating in the International Cerebral Venous Sinus Thrombosis Consortium from Finland, the Netherlands, Switzerland, Sweden, Mexico, Iran, and Costa Rica. Of 952 patients, 865 with available baseline platelet count were included. In a subset of 93 patients, frozen plasma samples collected during a previous study between September 2009 and February 2016 were analyzed for the presence of platelet factor 4/heparin antibodies. Exposures: Diagnosis of cerebral venous sinus thrombosis. Main Outcomes and Measures: Frequencies of admission thrombocytopenia (platelet count <150 ×103/µL), heparin-induced thrombocytopenia (as diagnosed by the treating physician), and platelet factor 4/heparin IgG antibodies (optical density >0.4, in a subset of patients with previously collected plasma samples). Results: Of 865 patients (median age, 40 years [interquartile range, 29-53 years], 70% women), 73 (8.4%; 95% CI, 6.8%-10.5%) had thrombocytopenia, which was mild (100-149 ×103/µL) in 52 (6.0%), moderate (50-99 ×103/µL) in 17 (2.0%), and severe (<50 ×103/µL) in 4 (0.5%). Heparin-induced thrombocytopenia with platelet factor 4/heparin antibodies was diagnosed in a single patient (0.1%; 95% CI, <0.1%-0.7%). Of the convenience sample of 93 patients with cerebral venous sinus thrombosis included in the laboratory analysis, 8 (9%) had thrombocytopenia, and none (95% CI, 0%-4%) had platelet factor 4/heparin antibodies. Conclusions and Relevance: In patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, and heparin-induced thrombocytopenia and platelet factor 4/heparin antibodies were rare. These findings may inform investigations of the possible association between the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines and cerebral venous sinus thrombosis with thrombocytopenia.

Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency.

BACKGROUND AND PURPOSE: Cerebral venous sinus thrombosis (CVST) has been described after vaccination against SARS-CoV-2. The clinical characteristics of 213 post-vaccination CVST cases notified to the European Medicines Agency are reported. METHODS: Data on adverse drug reactions after SARS-CoV-2 vaccination notified until 8 April 2021 under the Medical Dictionary for Regulatory Activities Term 'Central nervous system vascular disorders' were obtained from the EudraVigilance database. Post-vaccination CVST was compared with 100 European patients with CVST from before the COVID-19 pandemic derived from the International CVST Consortium. RESULTS: In all, 213 CVST cases were identified: 187 after AstraZeneca/Oxford (ChAdOx1 nCov-19) vaccination and 26 after a messenger RNA (mRNA) vaccination (25 with Pfizer/BioNTech, BNT162b2, and one with Moderna, mRNA-1273). Thrombocytopenia was reported in 107/187 CVST cases (57%, 95% confidence interval [CI] 50%-64%) in the ChAdOx1 nCov-19 group, in none in the mRNA vaccine group (0%, 95% CI 0%-13%) and in 7/100 (7%, 95% CI 3%-14%) in the pre-COVID-19 group. In the ChAdOx1 nCov-19 group, 39 (21%) reported COVID-19 polymerase chain reaction tests were performed within 30 days of CVST symptom onset, and all were negative. Of the 117 patients with a reported outcome in the ChAdOx1 nCov-19 group, 44 (38%, 95% CI 29%-47%) had died, compared to 2/10 (20%, 95% CI 6%-51%) in the mRNA vaccine group and 3/100 (3%, 95% CI 1%-8%) in the pre-COVID-19 group. Mortality amongst patients with thrombocytopenia in the ChAdOx1 nCov-19 group was 49% (95% CI 39%-60%). CONCLUSIONS: Cerebral venous sinus thrombosis occurring after ChAdOx1 nCov-19 vaccination has a clinical profile distinct from CVST unrelated to vaccination. Only CVST after ChAdOx1 nCov-19 vaccination was associated with thrombocytopenia.

COVID-19 patients often show high-titer non-platelet-activating anti-PF4/heparin IgG antibodies.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a severe adverse reaction to heparin caused by heparin-dependent, platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Heparin is a cornerstone of treatment in critically ill COVID-19 patients. HIT antibodies can be detected by antigen tests and functional tests. Often strong reactivity in the antigen test is used as a surrogate marker for the presence of clinically relevant, platelet-activating antibodies. We observed an unexpectedly high percentage of COVID-19 patients, clinically suspected to have HIT, with high titer anti-PF4/heparin antibodies, but a negative functional test. OBJECTIVE: We investigated whether in COVID-19 patients a serum-derived factor inhibits the heparin-induced platelet activation test (HIPA). METHODS AND RESULTS: Twelve COVID-19 patients with suspected HIT were tested. Three samples tested negative in all assays; nine samples tested positive by antigen tests, among which only three tested also positive by HIPA. When we spiked COVID-19 serum or control serum with the human HIT antibody like monoclonal antibody 5B9, reactivity of 5B9 remained the same. Also, the purified IgG fractions of COVID-19 sera testing strongly positive in the PF4/heparin antigen test but negative in the functional test did not show increased reactivity in the functional test in comparison to the original serum. Both results make a functionally inhibitory factor in the serum/plasma of COVID-19 patients highly unlikely. CONCLUSION: COVID-19 patients often present with strong reactivity in PF4/heparin antigen tests without the presence of platelet-activating antibodies. Diagnosis of HIT requires confirmation of heparin-dependent, platelets activating antibodies to avoid overdiagnosis and overtreatment with non-heparin anticoagulants.