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.