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

Abstract

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 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 12 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 mAb 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.

Post-COVID Syndrome: An Insight on Its Pathogenesis

“…In addition, in a previously healthy 56-year-old man with persistent neurological disorders, including short-duration epileptic seizures, and deep depression almost six months after COVID-19, CNS MRI revealed numerous hyperintense focal areas in the periventricular and subcortical white matter and in semioval centers, compatible with gliotic outcomes in association with microvascular injuries [ 71 ]. Endothelial injury, either due to virus invasion or in the context of profound inflammation increased levels of coagulation factors, hypoxia, due to respiratory impairment or anti-platelel factor 4 (PF4)-immune complexes, has been implicated in acute COVID-19 pathogenesis, predisposing to coagulopathy and thromboembolic complications in large blood vessels and microcirculation [ 53 , 72 , 73 ]. Thromboembolism may also complicate the post-COVID period in the context of a hypercoagulate state [ 74 ].…”

Hypotheses behind the very rare cases of thrombosis with thrombocytopenia syndrome after SARS-CoV-2 vaccination

“…The hypothesis that a factor present in the serum of COVID-19 patients, and inhibiting platelet activation induced by anti-PF4 antibodies, was evaluated and not confirmed. [ 28 ] In addition, another report also showed that among COVID-19 patients, the rate of positive EIA is significantly higher than in the general population. [ 29 ]…”

SARS-CoV-2 receptor binding domain-specific antibodies activate platelets with features resembling the pathogenic antibodies in heparin-induced thrombocytopenia

“…Several other studies also detected increased PF4/H-reactive antibodies in COVID-19 patients in the context of heparin treatment and patients are suspected of developing "classical" HIT, i.e. heparin exposure-induced HIT [38][39][40][41][42] . A recent randomized trial reported that therapeutic dose of UFH and LMWH did not improve organ dysfunction in critically ill patients with COVID-19 43 .…”