Munnix Imke C A, Harmsma Marjan, Giddings John C, Collins Peter W, Feijge Marion A H, Comfurius Paul, Heemskerk Johan W M, Bevers Edouard M
Department of Biochemistry, CARIM, Maastricht University, P. O. Box 616, 6200 MD Maastricht, The Netherlands.
Thromb Haemost. 2003 Apr;89(4):687-95.
Scott syndrome is a bleeding disorder, characterized by impaired surface exposure of procoagulant phosphatidylserine (PS) on platelets and other blood cells, following activation with Ca(2+)-elevating agents. Since store-mediated Ca(2+) entry (SMCE) forms an important part of the Ca(2+) response in various blood cells, it has been proposed that deficiencies in Ca(2+) entry may relate to the impaired PS exposure in the Scott syndrome. Here, we have tested this hypothesis by investigating the relationship between Ca(2+) fluxes and PS exposure in platelets as well as B-lymphoblasts derived from the original Scott patient (M.S.), a newly identified Welsh patient (V.W.) with similar bleeding symptoms, and two control subjects. Procoagulant activity of V.W. platelets in suspension, measured after stimulation with collagen/thrombin or Ca(2+)-ionophore, ionomycin, resulted in 52% or 17%, respectively, compared to that of correspondingly activated control platelets. Procoagulant activity of V.W. erythrocytes treated with Ca(2+)-ionophore resulted in less than 6% of the activity of control erythrocytes. Single-cell Ca(2+) responses of M.S. and V.W. platelets, adhering to collagen, were similar to those of platelets from control subjects, while PS exposure was reduced to 7% and 15%, respectively, compared to controls. Stimulation of non-apoptotic B-lymphoblasts derived from both patients and controls with Ca(2+)-ionophore or agents causing Ca(2+) mobilization and SMCE, resulted in similar Ca(2+) responses. However, in lymphoblasts from M.S. and V.W. Ca(2+)-induced PS exposure was reduced to 7% and 13% of the control lymphoblasts, respectively. We conclude that i. patient V.W. is a new case of Scott syndrome, ii. Ca(2+) entry in the platelets and lymphoblasts from both Scott patients is normal, and iii. elevated Ca(2+) as caused by SMCE is not sufficient to trigger PS exposure.
斯科特综合征是一种出血性疾病，其特征是在用钙离子升高剂激活后，血小板和其他血细胞上促凝血磷脂酰丝氨酸（PS）的表面暴露受损。由于储存介导的钙离子内流（SMCE）是各种血细胞中钙离子反应的重要组成部分，因此有人提出钙离子内流缺陷可能与斯科特综合征中PS暴露受损有关。在此，我们通过研究来自最初的斯科特患者（M.S.）、新确诊的有类似出血症状的威尔士患者（V.W.）以及两名对照受试者的血小板和B淋巴细胞母细胞中钙离子通量与PS暴露之间的关系，对这一假设进行了验证。与相应激活的对照血小板相比，用胶原蛋白/凝血酶或钙离子载体离子霉素刺激后，悬浮状态下V.W.血小板的促凝血活性分别为52%或17%。用钙离子载体处理的V.W.红细胞的促凝血活性不到对照红细胞活性的6%。粘附在胶原蛋白上的M.S.和V.W.血小板的单细胞钙离子反应与对照受试者的血小板相似，而与对照相比，PS暴露分别降至7%和15%。用钙离子载体或引起钙离子动员和SMCE的试剂刺激来自患者和对照的非凋亡B淋巴细胞母细胞，会产生相似的钙离子反应。然而，在来自M.S.和V.W.的淋巴细胞母细胞中，钙离子诱导的PS暴露分别降至对照淋巴细胞母细胞的7%和13%。我们得出以下结论：i. 患者V.W.是斯科特综合征的一个新病例；ii. 两名斯科特患者的血小板和淋巴细胞母细胞中的钙离子内流正常；iii. 由SMCE引起的细胞内钙离子浓度升高不足以触发PS暴露。
