Pathogenicity of Heparin Dependent Antibodies

Many of the heparin dependent antibodies, including those with the IgG isotype, are asymptomatic, and only a subgroup of antibodies is positive in platelet activation assays. What differentiates pathogenic from asymptomatic antibodies is not fully understood, with the exception that there is some relationship between antibody concentration and occurrence of HIT, and that antibodies with the highest affinity to HPF4 are those with the strongest capacity to activate platelets. Probably, the immune response is first targeted to HPF4 complexes, but in some patients, antibodies can also react with PF4 alone as the consequence of epitope spreading, and then the deleterious antibodies` effect is higher. In most of cases, pathogenic antibodies are of the IgG isotype. Interestingly, patients who develop HIT generate directly and rapidly IgG isotypes, although IgM and IgA isotypes can be present. Conversely, in unselected UFH or LMWH treated patients, development of IgM, and IgA anti-HP4 antibodies, and sometimes IgG isotype, is a frequent feature, with a much higher incidence in patients with Extra Corporeal Circulation (ECO, without thrombocytopenia. If HIT does not develop, which is the usual context, antibody concentration tends then to decrease with continuation of heparin treatment. Follow-up of the development kinetics of IgG isotypes in non-thrombocytopenic, heparin-treated, patients shows that the first generated antibodies are mainly IgM and IgA isotypes, few IgG isotypes being formed slightly later. The rapid generation of IgG isotypes in patients developing HIT is in line with the studies suggesting that the HIT immune response could be secondary and anamnestic (after an earlier PF4-dependent immune stimulation). A possible example is the association between periodontitis and the early development of antibodies to HPF4. For distinguishing asymptomatic from symptomatic antibodies, their presence and concentration must be compared with the clinical probability of HIT, and they must be tested for platelet activation with platelet functional assays. The unresolved question is to know if asymptomatic antibodies can become  symptomatic if exposure to heparin is prolonged (although the risk of developing HIT decreases with time of heparin therapy, and becomes rare after 15 days of treatment), or if they can be pathogenic if the target antigen (ultra-large HPF4 complexes) is formed and exposed onto blood and endothelial cells, focusing the deleterious immune attack.