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| PF4 disorders including pediatric issues Ted Warkentin. |
Abstract
The prototypic anti-platelet factor 4 (PF4) disorder, heparin-induced thrombocytopenia and thrombosis (HITT), features IgG class antibodies that activate platelets, monocytes, and neutrophils in a predominantly heparin-dependent fashion via Fcγ receptor-dependent
cellular activation. Atypical presentations of HITT with proximate heparin triggers that however evince heparin-independent platelet-activating properties (“autoimmune HITT”) have been recognized since 2001; heparin-independent platelet-activating properties also characterize HITT-mimicking disorders with undefined non-heparin triggers (e.g., “spontaneous HITT” [SpHITT] following bacterial infection or total knee arthroplasty). The identification in 2021 of an ultrarare HITT-mimicking disorder, vaccine-induced immune thrombocytopenia and thrombosis (VITT), triggered by adenoviral vector vaccines, abruptly broadened the spectrum of recognized anti-PF4 disorders. Surprisingly, antibodies identical to those of (vaccine-induced) VITT can also be triggered rarely by natural adenovirus infection, including in children. Recently, the immunopathogenesis of VITT has been solved, namely a specific acquired somatic mutation (K31E) that misdirects an anti-adenovirus core protein VII immune response against PF4. HITT and VITT antibodies recognize different epitopes on PF4, and have somewhat different reaction profiles in PF4-dependent laboratory diagnostic assays. All the aforementioned anti-PF4 disorders are acute, transient, and self-limited. Recently, however, chronic anti-PF4 disorders featuring potent VITT-like properties of monoclonal proteins (M-proteins) have been identified: this oftentimes treatment-refractory entity, named “VITT-like monoclonal gammopathy of thrombotic significance” (VITT-like MGTS), significantly expands the clinical spectrum of recognized anti-PF4 disorders. Anti-PF4 disorders with heparin-independent platelet-activating antibodies, whether HITT or VITT, may require management strategies beyond anticoagulation alone, including high-dose intravenous immunoglobulin (IVIG) or (for VITT-like MGTS) the Bruton's tyrosine kinase inhibitor, ibrutinib. Even for pediatricians, HITT and VITT warrant diagnostic consideration in the appropriate clinical context: pediatric HITT as an uncommon but recognized potential complication of heparin administration to children; VITT is a well-documented complication of adenovirus infection in children; and neonatal stroke and thrombocytopenia due to VITT-like MGTS attributed to transplacental passage of maternal VITT-like M-protein has been described (single case report).
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