Structural Features and PF4 Functions that Occur in Heparin-Induced Thrombocytopenia (HIT) Complicated by COVID-19

Abstract

Platelet factor 4 (PF4, CXCL4) is a small chemokine protein released by activated platelets. Although a major physiological function of PF4 is to promote blood coagulation, this cytokine is involved in innate and adaptive immunity in events when platelets are activated in response to infections. Coronavirus disease 2019 (COVID-19) patients have abnormal coagulation activities, and severe patients develop higher D-dimer levels. D-dimers are small protein products present in the blood after blood clots are degraded by fibrinolysis. To prevent clotting, heparin is often clinically used in COVID-19 patients. Some clinical procedures for the management of COVID-19 patients may include extracorporeal membrane oxygenation (ECMO) and renal replacement therapy (CRRT), which also require the use of heparin. Anti-PF4 antibodies are frequently detected in severe patients and heparin-induced thrombocytopenia (HIT) can also be observed. PF4 and its role in HIT as well as in pathologies seen in COVID-19 patients define a potential therapeutic option of using blocking antibodies in the treatment of COVID-19.

COVID‐19 vaccine‐associated immune thrombosis and thrombocytopenia (VITT): Diagnostic and therapeutic recommendations for a new syndrome

“…These latter findings are in agreement with the antimicrobial, beyond procoagulant, suggested activity of PF4 25,26 . In response to microorganisms, indeed, activated platelets release PF4 contributes to the recruitment of neutrophils and facilitates neutrophil exocytosis to release myeloperoxidase and lysozyme 27 . In addition, PF4 binds directly to bacteria thus creating a neoantigen which is targeted by anti‐PF4/heparin or anti‐PF4/polyanion antibodies to form immune complexes that play a key role in antibacterial host defense 26 .…”

Is COVID-19 an Independent Risk Factor for Heparin-Induced Thrombocytopenia?

“…4T score is a commonly used clinical scoring system to assess the likelihood of HIT. It includes the degree of thrombocytopenia, timing of the drop in platelet count, associated thrombosis, and presence of other causes of thrombocytopenia with 2 points given to each criterion [ 10 ]. In those with moderate to high probability of HIT, diagnosis can be confirmed with HIT IgG-specific antibodies (anti-PF4/H) and SRA.…”

Targeting SARS-CoV-2-Platelet Interactions in COVID-19 and Vaccine-Related Thrombosis

“…It also plays a protective role in influenza H1N1 infection ( Guo et al, 2017 ). Increased levels of PF4 and anti-PF4 antibodies are found in patients with Covid-19 ( Liu X. et al, 2020 ; Cai et al, 2020 ) and there is a report of a patient who developed immune thrombocytopenia after SARS-CoV-2 infection ( Zulfiqar et al, 2020 ).…”