Division of Genome Science and Cancer, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
Department of Clinical Haematology, Canberra Health Services, Canberra, ACT, Australia.
Blood Adv. 2024 Nov 12;8(21):5542-5555. doi: 10.1182/bloodadvances.2024014190.
Clinical features in patients with the B-cell lymphoma, Waldenström macroglobulinemia (WM), include cytopenias, immunoglobulin M (IgM)-mediated hyperviscosity, fatigue, bleeding, and bruising. Therapeutics such as Bruton's tyrosine kinase inhibitors (BTKis) exacerbate bleeding risk. Abnormal hemostasis arising from platelet dysfunction, altered coagulation or vascular impairment have not yet been investigated in patients with WM. Therefore, this study aimed to evaluate hemostatic dysfunction in samples from these patients. Whole blood (WB) samples were collected from 14 patients with WM not receiving therapy, 5 patients receiving BTKis and 15 healthy donors (HDs). Platelet receptor levels and reticulation were measured by flow cytometry, plasma thrombin generation with or without platelets by fluorescence resonance energy transfer assay, WB clotting potential by rotational thromboelastometry, and plasma soluble glycoprotein VI (sGPVI) and serum thrombopoietin (TPO) by enzyme-linked immunosorbent assay. Donor platelet spreading, aggregation, and ability to accelerate thrombin generation in the presence of WM-derived IgM were assessed. WM platelet receptor levels, responses to physiological agonists, and plasma sGPVI were within normal ranges. WM platelets had reduced reticulation (P = .0012) whereas serum TPO levels were increased (P = .0040). WM plasma displayed slower thrombin generation (P = .0080) and WM platelets contributed less to endogenous thrombin potential (ETP; P = .0312). HD plasma or platelets incubated with IgM (50-60 mg/mL) displayed reduced spreading (P = .0002), aggregation (P < .0001), and ETP (P = .0081). Thus, alterations to thrombin potential and WB coagulation were detected in WM samples. WM IgM significantly impaired hemostasis in vitro. Platelet and coagulation properties are disturbed in patients with well-managed WM.
临床表现为伴有 B 细胞淋巴瘤的 Waldenström 巨球蛋白血症 (WM) 患者的血细胞减少、免疫球蛋白 M (IgM)介导的高粘滞血症、疲劳、出血和瘀斑。布鲁顿酪氨酸激酶抑制剂 (BTKi) 等治疗方法会加剧出血风险。WM 患者的血小板功能障碍、凝血改变或血管损伤引起的异常止血尚未得到研究。因此，本研究旨在评估这些患者样本中的止血功能障碍。采集 14 名未接受治疗的 WM 患者、5 名接受 BTKi 治疗的患者和 15 名健康供体 (HD) 的全血 (WB) 样本。通过流式细胞术测量血小板受体水平和网织化，通过荧光共振能量转移测定法测量有无血小板的血浆凝血酶生成，通过旋转血栓弹性测定法测量 WB 凝血潜能，通过酶联免疫吸附法测量血浆可溶性糖蛋白 VI (sGPVI) 和血清血小板生成素 (TPO)。评估供体血小板的铺展、聚集以及在 WM 衍生的 IgM 存在下加速凝血酶生成的能力。WM 血小板受体水平、对生理激动剂的反应和血浆 sGPVI 均在正常范围内。WM 血小板的网织化减少 (P =.0012)，而血清 TPO 水平升高 (P =.0040)。WM 血浆的凝血酶生成较慢 (P =.0080)，WM 血小板对内源性凝血酶潜能 (ETP; P =.0312)的贡献较小。用 50-60mg/mL 的 IgM 孵育 HD 血浆或血小板后，铺展 (P =.0002)、聚集 (P <.0001) 和 ETP (P =.0081) 均减少。因此，在 WM 样本中检测到血栓潜能和 WB 凝血的改变。WM IgM 显著损害了体外止血功能。在经过良好管理的 WM 患者中，血小板和凝血特性受到干扰。
