{"doi":"10.1002/ajh.70078","title":"Third‐Generation <scp>Bruton tyrosine kinase</scp>  Inhibitors for the Treatment of Monoclonal Gammopathy of Thrombotic Significance ( <scp>MGTS)</scp>","abstract":"Monoclonal gammopathy of thrombotic significance (MGTS) is a persistent prothrombotic state caused by monoclonal anti-platelet factor-4 (PF4) antibodies [1-4]. Recently, plasma cell-directed therapy and the first-generation covalent Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, have been used in persistent anti-PF4 antibody-mediated thrombotic syndromes [1-3, 5]. However, some patients may not be able to tolerate myeloma treatments. Additionally, the use of ibrutinib, especially in the setting of MGTS-associated thrombocytopenia, can be challenging due to bleeding risks. Relative to ibrutinib, non-covalent, highly-selective BTKis such as pirtobrutinib offer pharmacokinetic advantages including higher target specificity, significantly longer half-life, and fewer reported bleeding side effects [6, 7]. A 66-year-old male was diagnosed with heparin-induced thrombocytopenia (HIT) 15 years ago (ELISA optical density, OD 1.341) when he experienced thrombocytopenia and suffered recurrent deep vein thromboses (DVTs) and adrenal hemorrhage (Figure 1A). When “HIT” was initially diagnosed, he most recently received low molecular weight heparin (LMWH) a year prior for the treatment of DVTs. Notably, such a prolonged time between LMWH exposure and the development of thrombocytopenia and thrombosis is highly unusual for HIT. Subsequently, he developed recurrent iliofemoral DVTs and required thrombectomy, thrombolysis, or both on multiple occasions as well as bilateral iliac vein stenting (Figure 1A). During this period with recurrent DVTs, he was managed with various anticoagulants, including fondaparinux 7.5–10 mg subcutaneous (SQ) daily, dabigatran 150 mg BID, and rivaroxaban 20 mg/day. Aspirin 81 mg/day was also maintained through these anticoagulant regimen changes, but despite this, thromboses occurred. Approximately 9 years before his current admission, platelet counts stabilized at borderline-normal levels while on apixaban 5 mg BID and aspirin 81 mg/day (Figure 1A). Following elective hernia surgery during his current admission, the patient developed acute iliac vein DVT with significant thrombocytopenia (47 × 109/L; Figure 1B), relative to a platelet count of 150 × 109/L 1 week prior to surgery. He received no heparin products perioperatively. HIT ELISA (OD 1.445) and serotonin-release assay (SRA, 75%) were positive, and a small (0.1%) lambda-restricted plasma cell population and IgG lambda monoclonal protein (0.23 g/dL) were noted. He underwent a thrombectomy, and despite treatment with methylprednisolone, romiplostim, and intravenous immunoglobulin, his thrombocytopenia worsened (12 × 109/L), and vessel occlusion recurred. Therapeutic plasma exchange, high-dose prednisone, and rituximab did not improve platelet counts. He underwent angioplasty, mechanical thrombectomy of bilateral iliac and femoral veins, as well as catheter-directed thrombolysis (Figure S1). Within days, he required recanalization of the right common iliac vein stents, angioplasty, and re-lining of the stents (Figure S1). Recurrent thromboses with a monoclonal gammopathy prompted the initiation of daratumumab for suspected monoclonal gammopathy of thrombotic significance (MGTS). After four doses of daratumumab, bortezomib was added to the treatment regimen, but stopped prematurely (after four doses) due to severe thrombocytopenia (12 × 109/L; Figure 1B). Following 10 doses of daratumumab, platelets improved from their nadir but plateaued at 38–52 × 109/L. HIT serology remained positive. Thus, additional therapy was considered. A recent report described the use of the first-generation non-selective BTKi, ibrutinib, as rescue therapy in persistent anti-PF4 antibody-mediated thrombotic syndromes [5]. The decision was made to start the third-generation BTKi pirtobrutinib due to its advantages over ibrutinib, which resulted in normalization of platelet counts within 2 weeks. An inadvertent 4-day treatment break of pirtobrutinib coincided with a platelet count de","journal":"American Journal of Hematology","year":2025,"id":524423,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":806800,"name":"Adam J. Kanack","orcid":"0000-0002-6077-0475","position":1,"is_corresponding":false},{"id":1398456,"name":"Emily Mauch","orcid":null,"position":2,"is_corresponding":false},{"id":857258,"name":"Noah P. Splinter","orcid":null,"position":3,"is_corresponding":false},{"id":409240,"name":"Anand Padmanabhan","orcid":"0000-0003-2519-4377","position":4,"is_corresponding":false},{"id":1153119,"name":"Louise Man","orcid":"0000-0001-8053-5336","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:50:12.083054Z","pmid":"40944630","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}