Nissen C, Genitsch A, Sendelov S, Dalle Carbonare V, Wodnar-Filipowicz A
Department of Research and Department of Internal Medicine, Division of Haematology, University Hospital, Basel, Switzerland.
Acta Haematol. 2000;103(1):33-40. doi: 10.1159/000041002.
Severe aplastic anaemia (SAA) causes permanent stem cell damage from which patients do not recover after treatment with antilymphocyte globulin (ALG). To produce peripheral blood values compatible with life, the few remaining stem and precursor cells are put under stress. We defined a 'stress factor' (SF) for various haematopoietic lines as the ratio of the corresponding peripheral blood (PB) value to the total colony number in short-term bone marrow cultures from 86 patients with different outcomes. Both values are expressed as percentage of normal, hence SF averages 1 in normal steady-state haematopoiesis. SF was elevated in all patients, from 2-to 40-fold, with wide variations in different patient groups and striking differences between haematopoietic lineages. In long-term disease-free survivors after ALG (group 1) the mean total colony count was 19% of normal, with a significantly higher proportion of erythroid burst-forming units compared to normal. They had ineffective erythropoiesis with haemoglobin (Hb) values below, and reticulocyte counts above normal; platelet counts were 67% of normal. In contrast, monocyte counts were in the high normal range, resulting in a high SF (18.7 +/- 1.9) for monocytes. In patients who developed paroxysmal nocturnal haemoglobinuria (PNH) after ALG (group 2), ineffective erythropoiesis, reflecting haemolysis, was more pronounced and they had striking relative monocytosis, resulting in a significantly higher SF for monocytes (33.7 +/- 5.7) compared with group 1 (p < 0.0001). High monocyte counts most likely reflect the relative resistance of nucleated cells to complement, compared with red cells and platelets. Patients who developed myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) after ALG, with or without PNH (group 3), had the highest SF for monocytes (39 +/- 10). They also had neutrophil counts in the upper range, or above normal, resulting in a high SF for neutrophils: 32 +/- 19. In patients with persisting or relapsing-remitting pancytopenia without a clinically detectable clonal disorder (group 4), all values were strikingly similar to those of the PNH group. In patients who achieved normal PB values after uncomplicated bone marrow transplantation (group 5), the SF averaged 3, but they also had ineffective erythropoiesis and mild relative monocytosis, a possible sign of occult PNH. We conclude that all patients after treatment of SAA have ineffective erythropoiesis and relative monocytosis, and that these abnormalities probably reflect PNH. We suggest that the resulting high SF for the leukocyte - particularly the monocyte line - predisposes to the development of MDS/AML. We discuss how these results may provide some of the missing pieces in the puzzle of SAA/PNH.
重型再生障碍性贫血（SAA）会导致永久性干细胞损伤，患者接受抗淋巴细胞球蛋白（ALG）治疗后无法恢复。为了使外周血指标维持在可维持生命的水平，仅存的少量干细胞和前体细胞会承受压力。我们将86例不同预后患者短期骨髓培养中相应外周血（PB）值与总集落数之比定义为各种造血系的“应激因子”（SF）。两个指标均以正常水平的百分比表示，因此在正常稳态造血过程中，SF平均为1。所有患者的SF均升高，为正常水平的2至40倍，不同患者组间差异很大，造血系之间也存在显著差异。接受ALG治疗后长期无病生存的患者（第1组），平均总集落数为正常水平的19%，与正常情况相比，红系爆式集落形成单位的比例显著更高。他们存在无效红细胞生成，血红蛋白（Hb）值低于正常，网织红细胞计数高于正常；血小板计数为正常水平的67%。相比之下，单核细胞计数处于高正常范围，导致单核细胞的SF较高（18.7±1.9）。接受ALG治疗后发生阵发性睡眠性血红蛋白尿（PNH）的患者（第2组），反映溶血的无效红细胞生成更为明显，且存在显著的相对性单核细胞增多，导致单核细胞的SF显著高于第1组（33.7±5.7，p<0.0001）。与红细胞和血小板相比，高单核细胞计数很可能反映了有核细胞对补体的相对抗性。接受ALG治疗后发生骨髓增生异常综合征（MDS）或急性髓系白血病（AML）的患者，无论有无PNH（第3组），单核细胞的SF最高（39±10）。他们的中性粒细胞计数也处于较高范围或高于正常水平，导致中性粒细胞的SF较高：32±19。持续性或复发缓解性全血细胞减少且无临床可检测到的克隆性疾病的患者（第4组），所有指标与PNH组非常相似。在无并发症的骨髓移植后外周血指标恢复正常的患者（第5组）中，SF平均为3，但他们也存在无效红细胞生成和轻度相对性单核细胞增多，这可能是隐匿性PNH的迹象。我们得出结论，SAA治疗后的所有患者均存在无效红细胞生成和相对性单核细胞增多，这些异常可能反映了PNH。我们认为，由此导致的白细胞尤其是单核细胞系的高SF易引发MDS/AML的发生。我们讨论了这些结果如何可能为SAA/PNH之谜提供一些缺失的环节。
