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Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination

Our take —

Reports of rare severe thrombotic events (blood clotting), associated with the Oxford-AstraZeneca vaccine have led to temporary suspensions of its use in several countries. This study reported on 11 patients (9 of whom were female, with a median age of 36 years) in Germany and Austria who had thrombotic events and low platelet counts. Antibodies against platelet factor 4 (PF4) were present in these patients, and platelet activation was enhanced by the presence of PF4. The clinical presentation of these cases resembled heparin-induced thrombocytopenia; however, none of the patients had been exposed to heparin before symptom onset. The following inhibited platelet activation in vitro: immune globulin, antibodies against platelet receptor factor IIA, and heparin. These results provide some detail on vaccine-induced thrombosis and thrombocytopenia, reports of which remain quite rare, though many questions about pathogenesis, risk factors, and treatment remain unanswered.

Study design

Case Series

Study population and setting

This study reported on clinical and laboratory characteristics of 11 patients who received the Oxford-AstraZeneca (ChAdOx1 nCov-19) vaccine in Germany and Austria and who developed thrombosis or thrombocytopenia. Laboratory testing was conducted on blood samples from 9 of the 11 patients, with ELISA used to test for the presence of platelet factor 4 (PF4)-heparin antibodies, and a modified (PF4-enhanced) platelet activation assay used for detection of platelet-activating antibodies under a range of conditions. Samples from 24 additional patients with suspected thrombocytopenia related to vaccination were also tested for validation purposes.

Summary of Main Findings

Nine of the 11 patients were women, with a median age of 36 years. Thrombotic complications began 5 to 16 days after vaccination, and all patients presented with moderate-to-severe thrombocytopenia (median platelet count nadir: 20,000 per cubic millimeter). Five patients had more than one thrombotic event; events included cerebral venous thrombosis (n=9), splanchnic-vein thrombosis (splenic, mesenteric, portal and hepatic veins; n=3), pulmonary embolism (n=3), and other types (n=4). One patient presented with fatal cerebral hemorrhage. Six patients died, and one had an unknown clinical outcome. None of the patients had received heparin before symptom onset, and only one patient was known to have prothrombotic blood disorder before symptom onset. There was evidence of disseminated intravascular coagulation in five patients, who all had d-dimer levels above 10mg/L and one or more of the following abnormalities: fibrinogen levels below 200ng/mL, elevation of the international normalized ratio (INR), and elevation of partial thromboplastin time(PTT). All samples that tested positive for PF4-heparin antibodies (n=24) showed strong reactivity; PF4-dependent platelet activation occurred in the absence of heparin. Platelet activation was enhanced by PF4 and inhibited by heparin, monoclonal antibody against platelet receptor FC gamma IIA, and immune globulin (10 mg/mL).

Study Strengths

Platelet activation patterns were assessed for additional samples from 24 patients suspected of thrombosis and/or thrombocytopenia, which allowed for comparison with the case series. The authors used two assays to measure antibodies against PF4.

Limitations

The sample of patients was small and detailed information on risk factors was not available. As this was a case series, data are needed on the prevalence of PF4-heparin antibodies among all individuals receiving the ChAdOx1 vaccine. More attention may have been paid to unusual thrombotic events, and so these may have been overrepresented (i.e., it is possible that the profile of thrombotic events associated with the ChAdOx1 vaccine is different from that observed in this study due to under-ascertainment). Detailed laboratory results are reported for only a subsample (n=4) of the 11 patients.

Value added

This study provides more detail about the mechanism of thrombotic adverse events that have led to pauses in the global rollout of the Oxford-AstraZeneca vaccine.

This review was posted on: 14 May 2021