Abstract
Heparin-induced thrombocytopenia (HIT) is characterized clinically by thrombocytopenia, hypercoagulability, and increased thrombosis risk, and serologically by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Heparin-“induced” acknowledges that HIT is usually triggered by a proximate immunizing exposure to heparin. However, certain non-heparin medications (pentosan polysulfate, hypersulfated chondroitin sulfate, fondaparinux) can trigger “HIT”. Further, naturally-occurring polyanions (bacterial lipopolysaccharide, DNA/RNA) can interact with PF4 to recapitulate HIT antigens. Indeed, immunologic presensitization to naturally-occurring polyanions could explain why HIT more closely resembles a secondary, rather than a primary, immune response. In 2008 it was first reported that a HIT-mimicking disorder can occur without any preceding exposure to heparin or polyanionic medications. Termed “spontaneous HIT syndrome”, two subtypes are recognized: (a) surgical (post-orthopedic, especially post-total knee arthroplasty, and (b) medical (usually post-infectious). Recently, COVID-19 adenoviral vector vaccination has been associated with a thrombotic thrombocytopenic disorder associated with positive PF4-dependent enzyme-immunoassays and serum-induced platelet activation that is maximal when PF4 is added. Vaccine-induced immune thrombotic thrombocytopenia (VITT) features unusual thromboses (cerebral venous thrombosis, splanchnic vein thrombosis) similar to those seen in spontaneous HIT syndrome. The emerging concept is that classic HIT reflects platelet-activating anti-PF4/heparin antibodies whereas spontaneous HIT syndrome and other atypical “autoimmune HIT” presentations (delayed-onset HIT, persisting HIT, heparin “flush” HIT) reflect heparin-independent platelet-activating anti-PF4 antibodies—although the precise relationships between PF4 epitope targets and the clinical syndromes remain to be determined. Treatment of spontaneous HIT syndrome includes non-heparin anticoagulation (direct oral Xa inhibitors favored over direct thrombin inhibitors) and high-dose immunoglobulin.
Highlights
The concept of spontaneous HIT syndromeSpontaneous HIT syndrome denotes a disorder that has striking clinical and serological similarities to immune heparin-induced throm bocytopenia (HIT) but where a proximate (closely preceding) immu nizing exposure to heparin is unlikely to have occurred
Almost 30 years ago, one of us (AG) reported that certain polyanions other than unfractionated heparin (UFH)—including low-molecular-weight heparin (LMWH), dextran sulfate, and pentosan polysulfate—can contribute to formation of heparin-induced throm bocytopenia (HIT) antigens, as these compounds can substitute for heparin in platelet activation assays used to detect HIT antibodies
This early work occurred prior to the recognition that the antigens of HIT are found on complexes between a chemokine—platelet factor 4 (PF4)—and heparin, a discovery made by Amiral and colleagues in 1992 [29] and corroborated by three other groups [30,31,32]
Summary
Spontaneous HIT syndrome denotes a disorder that has striking clinical and serological similarities to immune heparin-induced throm bocytopenia (HIT) but where a proximate (closely preceding) immu nizing exposure to heparin is unlikely to have occurred. This is probably because asymptomatic thrombocytopenia is uncommon and usually not identified. Thrombosis occurrence is typically the event prompting the blood work that reveals thrombocytopenia; sometimes, suspicion of thrombosis leads to administration of heparin, resulting in an unex pected abrupt platelet count fall. Patient blood contains platelet-activating antibodies that recognize PF4
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