Session: 330. Vascular Biology, Thrombosis, and Thrombotic Microangiopathies: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Bleeding and Clotting, Translational Research, Plasma Cell Disorders, Thromboembolism, Diseases, Thrombocytopenias, Thrombotic disorders, Lymphoid Malignancies
Methods. An administrative database search was performed of Mayo Clinic records to identify patients who had a diagnosis of MGUS, and thrombosis. Research samples from 134 MGUS patients with IgG monoclonal protein and thrombosis were obtained from Mayo Clinic’s dysproteinemia biobank and subjected to PF4 antigen-based and functional screening. Research studies were approved by the Institutional Review Board of Mayo Clinic.
Results. Of the 134 patients, 17 (12.7%) activated platelets in the PEA (≥19%). To exclude non-specific activation (e.g. due to HLA antibodies), secondary PEA testing was performed to assess whether platelet activation was mediated by a HIT-like antibody (i.e., PF4- and IgG-dependent, and inhibitable with high concentrations of heparin). Four patients, hereafter referred to as patients 1-4, were identified as having a HIT-like antibody, as demonstrated by PF4-dependent platelet activation that could be inhibited with high concentrations of heparin (100 U/mL), and blockade of the platelet IgG receptor, FcγRIIa.
Patients 1 and 2 had persistent, platelet-activating anti-PF4 antibodies based on PEA testing of multiple samples obtained several years apart. Patient 1 had a recurrent, multi-year history of deep venous thrombosis (DVT), while patient 2 had one DVT episode. Patient 3 demonstrated a HIT antibody-like profile in the PEA in two of three samples available for testing and had a history of thrombotic cerebrovascular accident (CVA). Patient 4 demonstrated a HIT-like platelet-activating antibody in only one of four samples tested, and consistent with this finding, had an MGUS identified on clinical testing at only one time point (“small” IgG lambda, not quantified), 3 months prior to the platelet-activating sample. This patient experienced multiple thrombotic events including DVTs, left atrial thrombus and embolic CVA, pulmonary embolism and acute limb ischemia. All patients tested negative in two FDA-approved antigen-based HIT assays tested (Immucor PF4 IgG and Zymutest HIA IgG), similar to a recent MGTS case (submitted). SRA was negative in both Patients 1 & 2, weakly positive in Patient 3 (33%, with high CV), and positive (72%) in Patient 4.
Conclusions. Definitive diagnosis of patients with MGTS provides insight into a mechanism of “unexplained” thrombosis and may offer additional treatment pathways for these patients with recurrent thrombosis (New Eng J of Med, 2024 Aug 8). Serologic testing in two patients correlated strongly with observations of thrombosis, and the study confirmed recent findings that anti-PF4 antibodies may present with unusual serology that is neither HIT- nor VITT-like (with negative results in both ELISA and SRA). The incidence of confirmed/suspected MGTS was 3% (4/134) in this population of MGUS patients with thrombosis. Prospective studies are needed to confirm these observations.
Disclosures: Padmanabhan: Retham technologies, Mayo Clinic, Versiti: Divested equity in a private or publicly-traded company in the past 24 months, Other: Officer, Patents & Royalties. Pruthi: CSL Behring: Consultancy, Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Instrumentation Laboratories: Membership on an entity's Board of Directors or advisory committees. Dispenzieri: Pfizer: Research Funding; Takeda: Consultancy, Research Funding; Alexion: Consultancy, Research Funding; BMS: Consultancy, Research Funding; HaemaloiX: Research Funding; Alnylam: Research Funding; Janssen: Research Funding. Kumar: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Other: Independent review committee participation; MedImmune/AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Roche: Research Funding. Houghton: Bayer: Research Funding; Veralox: Research Funding.