Blood, Vol. 90 No. 1 (July 1), 1997:
pp. 475-476
CORRESPONDENCE
Family Studies in Scott Syndrome
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LETTER |
To the Editor:
Scott syndrome refers to a relatively severe bleeding disorder associated with an isolated defect in the expression in stimulated platelets of the membrane catalytic tenase activity (complex of coagulation factors VIIIa and IXa) and prothrombinase activity (complex of coagulation factors Va and Xa).1-4 Studies on the originally described patient, MS,1,4 have shown that this defect results from an impaired binding of coagulation factors Va2,5 and VIIIa6 by activated platelets, reflecting a diminished surface exposure of phosphatidylserine (PS),3 and is also associated with reduced shedding of microparticles from the platelet surface.5 Similar defects have also been found in stimulated erythrocytes7 and Epstein-Barr virus (EBV)-transformed lymphocytes8 from this patient. Recently, Toti et al9 reported a new patient with a relatively severe bleeding disorder who may have defects similar to those in patient MS. Family studies in this newly reported patient suggested an autosomal recessive inheritance pattern, in that somewhat reduced prothrombinase activities were observed in the stimulated platelets, red blood cells, and EBV-transformed B cells obtained from her clinically unaffected son and daughter.9
To obtain information on the inheritance pattern of the platelet coagulant activity defect in patient MS, we measured prothrombinase activity in stirred and unstirred platelets stimulated by collagen plus thrombin in the propositus MS (age 57) and in her asymptomatic mother (age 82), father (age 91), and only child, a 33-year-old son. Three asymptomatic siblings were not studied. Results are shown in Fig 1. Prothrombinase activity in MS was 30% of normal, similar to results reported in previous studies.2,3 Reduced values were obtained in the three other family members. In both stirred and unstirred platelets, the values obtained for the father and son (55% to 63% of controls) were at, or just below, the mean - 2SD values of the controls. The value obtained in unstirred platelets from the mother (75% of controls) was also at the lower 2SD limit of normals, whereas that obtained in stirred platelets (80% of controls) was well within the 2SD limit. In previous studies of the parents by Miletich et al,2 thrombin-induced prothrombinase activities in platelet suspensions (109 platelets/mL) were observed to be within the normal range (4.3 to 7.2 U thrombin/mL/min), although the values of 4.6 in the father and 4.3 in the mother were in the lower end of this range. As percents of normal, the somewhat low platelet prothrombinase activities that we obtained in the unaffected family members of patient MS appear to be similar to those obtained in the unaffected children of the newly reported patient described by Toti et al.9 From the data presented in their Fig 2, the prothrombinase activities in platelets activated by the calcium ionophore A23187 were approximately 55% of the control value for the daughter and 66% for the son, both values being just within the 2SD range of their controls, as calculated from the data presented.
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| Fig 1.
Collagen plus thrombin-induced platelet prothrombinase activity. Prothrombinase activity in activated platelets was determined as described previously.10 Briefly, 280 µL of gel-filtered platelets (7 × 107 platelets per mL), 7.5 µL of 100 mmol/L Ca2+, and 2.5 µL of Ca-free Tyrode-HEPES elution buffer was activated with (+) or without (-) stirring by addition of 5 µL each of "Horm" collagen (10 µg/mL, final concentration [f.c.]) and thrombin (0.1 U/mL, f.c.). After 10 minutes of incubation at 37°C, 50 µL each of 27 µmol/L prothrombin, 20 nmol/L factor Va, and 20 nmol/L factor Xa was added, and prothrombinase activity measured as the amount of thrombin generated in 1 minute, as described previously.10 Results are shown for MS, the propositus (P), her father (F ), mother (M), and son (S) as percent of mean normal control (C) values, which were 1,831 pmol/108 platelets/min for stirred platelets and 1,450 for unstirred platelets (n = 8). The error bars indicate the mean - 2SD.
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Recent studies by Kojima et al8 have provided evidence for a gene defect in the original Scott syndrome patient. They observed impaired procoagulant activity in all of the EBV-transformed lymphoblasts derived from MS's B cells. This abnormal phenotype could be isolated by single cell cloning, was propagated in culture through many generations,8 and could be corrected by hybridoma fusion with a cell exhibiting the normal procoagulant activity phenotype. The corrected phenotype was sustained when these hybridomas were subsequently propagated through many generations. The results of these studies strongly suggest that the Scott syndrome defect in patient MS is caused by the deletion or mutation of a gene that is involved in the transmigration of PS to the cell surface, which is passed to daughter cells via mitosis.8 The findings of somewhat reduced platelet prothrombinase values that we obtained in her clinically unaffected parents and son are certainly consistent with an autosomal recessive inheritance pattern. However, the precise mode of inheritance of this hemostatic disorder awaits the identification of the defect in the gene(s) responsible for agonist-induced exposure of binding sites for factors Va and VIIIa on cell membranes. As suggested previously, this could have important implications for the development of new antithrombotic agents.4,10,11
Harvey J. Weiss
Bruce Lages
Department of Medicine St Luke's-Roosevelt Hospital Center and Columbia University College of Physicians and Surgeons New York, NY
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