Platelet-Activating Anti-Platelet Factor 4/Polyanion Antibodies without Preceding Heparin Therapy: A Transient Autoimmune Disorder Resembling Heparin-Induced Thrombocytopenia (“Spontaneous HIT”).

Abstract Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder with autoimmune features: its target antigen is a “self” protein, platelet factor 4 (PF4), that is conformationally modified in the presence of heparin or certain other polyanions. A central dogma in HIT is that the antibodies are invariably triggered by treatment with heparin. We report four patients who developed an acute illness strongly resembling immune HIT despite the absence of any preceding heparin administration [Table 1]. Various inflammatory or invasive events were documented during the two-week period prior to each patient’s acute illness, suggesting that factors other than heparin can trigger an immune response against PF4/polyanion complexes. Following onset of their HIT-like illness, three of the patients received unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) to treat proven or suspected thrombosis, which precipitated abrupt platelet count falls in all. Serum from all four patients contained antibodies serologically indistinguishable from those causing HIT, namely platelet-activating immunoglobulin G (IgG) recognizing PF4 bound to heparin or polyvinyl sulfonate [Table 2]. Two patients died from thrombosis; in the two survivors, antibodies became undetectable during follow-up, consistent with the transient nature of the anti-PF4/heparin immune response reported in HIT. Conclusion: These four patient cases suggest that on rare occasions a transient prothrombotic autoimmune disorder strongly resembling immune HIT can occur, “spontaneous HIT”. Table 1. Clinical features: 4 patients with “spontaneous HIT” Case Age M/F Platelet count nadir (× 10^9^/L) Sequelae Event(s) in preceding two weeks * UFH or LMWH were only given for proven or suspected thrombosis after “spontaneous HIT” disorder was established; DIC = disseminated intravascular coagulation 1 69 M 17 (no heparin given) Limb artery thromboses (amputations); pulmonary embolism; DIC; fatal myocardial infarction Ampicillin (sore tooth); corticosteroid injection into wrist 2 40 F 175 (pre-UFH*); 59 (post-UFH*) Stroke; limb artery thrombosis (amputation) Incision & draining procedures (recurrent groin cyst) 3 69 F 33 (pre-UFH*); 11 (post-UFH*) Bilateral adrenal infarction; digital infarcts; deep-vein thrombosis; DIC Knee replacement surgery 4 24 F 301 (pre-LMWH*); 62 (post-LMWH*) Acute systemic reaction after LMWH Pneumonia Table 2. Serologic features: 4 patients with “spontaneous HIT” Case Maximum serotonin release (0.1-0.3 U/mL UFH) (N<10%) Serotonin release (Fc receptor-blocking monoclonal antibody) Serotonin release (100 U/mL UFH) Anti-PF4/H ELISA (IgG) (N<0.450 OD U)* Anti-PF4/polyanion ELISA, GTI (N<0.400 OD U)* * >80% inhibition in presence of 100 U/mL UFH was seen with all 4 blood samples and in both ELISAs (not shown) 1 99% 1% 0% 2.028 2.722 2 95% 0% 0% 2.909 2.284 3 100% 0% 0% 1.888 2.950 4 80% 0% 0% 1.866 2.622