Spontaneous HIT syndrome: Knee replacement, infection, and parallels with vaccine-induced immune thrombotic thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is characterized clinically by thrombocytopenia, hypercoagulability, and increased thrombosis risk, serologically platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Heparin-“induced” acknowledges that HIT usually triggered 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) interact with PF4 recapitulate antigens. Indeed, immunologic presensitization could explain why more closely resembles secondary, rather than primary, immune response. In 2008 it was first reported HIT-mimicking disorder occur without any preceding heparin or polyanionic medications. Termed “spontaneous syndrome”, two subtypes are recognized: (a) surgical (post-orthopedic, especially post-total knee arthroplasty, (b) medical (usually post-infectious). Recently, COVID-19 adenoviral vector vaccination has been associated thrombotic thrombocytopenic positive PF4-dependent enzyme-immunoassays serum-induced platelet activation maximal when added. Vaccine-induced (VITT) features unusual thromboses (cerebral venous thrombosis, splanchnic vein thrombosis) similar those seen in spontaneous syndrome. The emerging concept classic reflects anti-PF4/heparin antibodies whereas syndrome other atypical “autoimmune HIT” presentations (delayed-onset HIT, persisting “flush” HIT) reflect heparin-independent anti-PF4 antibodies—although the precise relationships between epitope targets clinical syndromes remain be determined. Treatment of includes anticoagulation (direct oral Xa inhibitors favored over direct thrombin inhibitors) high-dose immunoglobulin.