The complicated relationships of heparin‐induced thrombocytopenia and platelet factor 4 antibodies with COVID‐19

Abstract

COVID‐19 (coronavirus disease 2019) represents a prothrombotic disorder, and there have been several reports of platelet factor 4/heparin antibodies being present in COVID‐19‐infected patients. This has thus been identified in some publications as representing a high incidence of heparin‐induced thrombocytopenia (HIT), whereas in others, findings have been tempered by general lack of functional reactivity using confirmation assays of serotonin release assay (SRA) or heparin‐induced platelet aggregation (HIPA). Moreover, in at least two publications, data are provided suggesting that antibodies can arise in heparin naïve patients or that platelet activation may not be heparin‐dependent. From this literature, we would conclude that platelet factor 4/heparin antibodies can be observed in COVID‐19‐infected patients, and they may occur at higher incidence than in historical non‐COVID‐19‐infected cohorts. However, the situation is complex, since not all platelet factor 4/heparin antibodies may lead to platelet activation, and not all identified antibodies are heparin‐dependent, such that they do not necessarily reflect “true” HIT. Most recently, a “HIT‐like” syndrome has reported in patients who have been vaccinated against COVID‐19. Accordingly, much more is yet to be learnt about the insidious disease that COVID‐19 represents, including autoimmune outcomes in affected patients.

COVID‐19 coagulopathies: Human blood proteins mimic SARS‐CoV‐2 virus, vaccine proteins and bacterial co‐infections inducing autoimmunity

“…The obvious conclusion, which has been reached previously in studies of other autoimmune diseases, is that molecular mimicry may be necessary to induce auto‐reactive B and T cells but is clearly not sufficient to induce autoimmune disease . [ 22 , 83 , 84 , 85 , 86 ] This point is essential for understanding how many hospitalized COVID‐19 patients are found transiently to express anti‐phospholipid antibodies (aPL), anti‐PL4, b2GPI, and other blood cell antibodies [ 7 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 87 , 88 ] but only a fraction of these develop coagulopathies [ 25 , 30 , 87 , 88 ] and also why SARS‐CoV‐2 vaccines (to be discussed in “Implications of bacterial and viral coinfections for understanding vaccine‐induced coagulopathies”) often induce autoantibodies but rarely autoimmune disease. Mimicry may frequently induce autoantibody production but rarely leads to overt autoimmune disease or, alternatively, mimics may be perceived by the immune system as “self” antigens resulting in T cell tolerance.…”

“…Autoantibodies against platelet factor 4 (PF4), a platelet activating factor that binds heparin (as well as bacterial antigens), have also been documented in thrombotic COVID‐19 patients [ 26 , 27 ] as well as in vaccinees who have developed thrombotic thrombocytopenia [ 28 , 29 ] but, again, are found in many patients who do have not developed clinically‐evident coagulopathies. [ 28 , 30 ] Severity of COVID‐19 also correlates with significant alterations in the function and expression of a range of other clotting factors including significant increases in von Willebrand factor (VWF), Factors IX, X, and Xa, and significant decreases in ADAMTS13 (VWF‐cleaving protease or VWFCP) [ 31 , 32 , 33 ] and autoantibodies against these proteins are found in some SARS‐CoV‐2 infected patients. [ 24 ] This range of autoantigen targets is a key point that any explanation of COVID‐19 coagulopathies must address.…”

Antibodies against Platelet Factor 4 and Their Associated Pathologies: From HIT/HITT to Spontaneous HIT-Like Syndrome, to COVID-19, to VITT/TTS

“…In COVID-19, multiple hemostatic pathways can be affected, including primary hemostasis (platelets and von Willebrand factor [VWF]), secondary hemostasis (‘coagulation’), and fibrinolysis. Moreover, anti-PF4 antibodies do not arise in the majority of COVID-19 patients [ 20 ] and so cannot be considered a major driver of COVID-19-associated coagulopathy.…”

“…Nevertheless, of relevance to the current review, beside direct platelet activation resulting from direct interaction of SARS-CoV-2 spike protein with platelet receptors [ 15 ], ‘HIT-like’ events may occur in a small proportion of patients with COVID-19, and there have been several reports of anti-PF4 antibodies in COVID-19 patients, as recently reviewed by some of us [ 20 ]. In some cases, these were identified as involving heparin (i.e., anti-PF4/H antibodies were identified); however, in other cases, they did not involve prior heparin exposure (i.e., they were not anti-PF4/H antibodies, and so can be considered anti-PF4/X antibodies).…”

Untangling the Intricacies of Infection, Thrombosis, Vaccination, and Antiphospholipid Antibodies for COVID-19

“…Regardless, Preti et al propose that the incidence of heparin-induced thrombocytopenia is higher in COVID-19 than the background control population [88]. Others rightfully caution in deriving immediate conclusions in regards to pathogenesis [91]. Apart from the above, COVID-19 has been associated with de novo immune thrombocytopenia that may otherwise occur with various viral infections [92,93].…”