Demystifying autoimmune HIT: what it is, when to test, and how to treat

Abstract

Antibodies to platelet factor 4 (PF4) have been primarily linked to classical heparin-induced thrombocytopenia (cHIT). However, during the rollout of the COVID-19 vaccine program a new condition, vaccine-induced thrombocytopenia and thrombosis (VITT), was identified, related to adenoviral-based COVID-19 vaccines. The differences between these 2 conditions, both clinically and in laboratory testing, set the scene for the development of a new rapid anti-PF4 assay that is not linked with heparin (as relevant for cHIT). Concurrently, there has been a reassessment of those cases described as autoimmune HIT. Such scenarios do not follow cHIT, but there is now a clearer differentiation of heparin-dependent and heparin-independent anti-PF4 conditions. The importance of this distinction is the identification of heparin-independent anti-PF4 antibodies in a new subgroup termed VITT-like disorder. Cases appear to be rare, precipitated by infection and in a proportion of cases, orthopaedic surgery, but are associated with high mortality and the need for a different treatment pathway, which includes immunomodulation therapy.

Graphical abstract

Figure 1.

Treatment in anti-F4 antibody disorders. A summary of the pathway associated with anti-PF4 disorders. In cHIT, stopping heparin and initiating an alternative anticoagulant is associated with an increment in platelet count and halting of the thrombotic risk. In aHIT, related to heparin-dependent antibodies, the pathway would be comparable to cHIT. But in those developing non–heparin-dependent antibodies, further therapy is required. It is related to progression in the immune response, requiring IVIg or occasionally additional immunomodulation, such as PEX for platelet count increase and prevention of further thrombosis. In VITT and VITT-like disorder, there is no heparin exposure. Heparin can be used, but there are alternative anticoagulants. The prompt initiation of IVIg and/or plasma exchange or alternate immunosuppressive therapy is required. *Alternative, non–heparin-based anticoagulation must be started. PEX, plasma exchange.

Figure 2.

Categorization of anti-PF4 antibody disorders. The 4 identified conditions related to HIT presentation. Differentiation is related to the presence of heparin-dependent or heparin- independent anti-PF4 antibodies. Classical HIT/a HIT require stopping heparin, a change in anticoagulation, and occasionally further therapy such as high-dose IVIg. Conversely, VITT or VITT-like disorder require intensive immunomodulatory therapy, such as plasma exchange (PEX).

Figure 3.

Laboratory diagnosis of anti-PF4 antibody syndromes. Utilizing rapid PF4 or PF4 heparin assays, ELISAs, or confirmation by specialized platelet activation studies, the 4 scenarios are differentiated based on their relation to heparin exposure.