The overall objectives are two-fold: 1) to continue to explore the biochemical, rheologic, and physiologic factors responsible for congenital disorders of hemostasis due to platelet dysfunction and 2) to utilize patients with well-characterized platelet dysfunction as a means of further defining the mechanisms which regulate normal platelet function. The specific studies toward these objectives are: 1) to examine activation mechanisms which could be abnormal in 7 patients with a new type of platelet dysfunction characterized by impaired platelet responses to weak platelet agonists, including studies on fibrinogen receptor exposure, calcium mobilization and responses, phospholipase C-mediated pathways, Na+/H+ exchange, and G-protein interactions. 2) to study, in patients with dense granule storage pool deficiency (delta-SPD), the basis for the storage defect and to examine no further detail (by measuring alpha-granule release and activation pathways linked to receptor occupancy) the secretion defect in these patients. 3) in SPD patients with combined defects of dense and alpha-granules (alpha/delta-SPD), to study whether the alpha- granule is absent (as distinct form the functionally defective granule in the gray platelet syndrome, alpha-SPD) by utilizing monoclonal antibodies to an alpha-granule specific protein, GMP-140. 4) to study further mechanisms involved in platelet adhesion and thrombus formation on subendothelium under conditions of controlled flow by examining a) the role of von Willebrand factor (vWf) and other adhesion molecules binding to GPIIb-IIIa in platelet adhesion and thrombus formation on subendothelium, utilizing antibodies to the 1737-1750 RGD-containing sequence in vWf, and homologous sequences in other adhesion molecules, which bind uniquely to each adhesive protein; b) the role and mechanism of platelet vWf utilizing platelets from patients with various types of von Willebrand's disease (vWd); c) the structure-function relationships of vWf that may be important for adhesion and thrombus formation utilizing plasmas from vWd patients (Type I, II variants, IIB, I-NY, and pseudo-vWd) that have been carefully characterized for vWf content, multimer characteristics, and platelet- binding properties; d) the hematocrit-dependent platelet adhesion defect in delta-SPD in order to assess further the role of ADP and red cells in promoting platelet adhesion. 4) to investigate further the basis for impaired platelet procoagulant activity (PPA) in Scott Syndrome (reduced Factor Xa binding and impaired phosphatidylserine expression) and to utilize platelets from Scott Syndrome and alpha/delta-SPD to test the hypothesis that the expression of PPA in response to agonists may be related to the fusion of alpha-granules with the plasma membrane and the formation of microvesicles with procoagulant activity. 5) to utilize a newly developed technique for assessing primary hemostasis, by obtaining, in a wide variety of patients with prolonged bleeding times and/or known platelet dysfunction, time-course studies on blood volume, thromboxane B2, platelet factor 4 and fibrinopeptide A in bleeding time blood.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
St. Luke's-Roosevelt Institute for Health Sciences
New York
United States
Zip Code
Lages, B; Weiss, H J (1997) Enhanced increases in cytosolic Ca2+ in ADP-stimulated platelets from patients with delta-storage pool deficiency--a possible indicator of interactions between granule-bound ADP and the membrane ADP receptor. Thromb Haemost 77:376-82
Lages, B; Sussman, I I; Levine, S P et al. (1997) Platelet alpha granule deficiency associated with decreased P-selectin and selective impairment of thrombin-induced activation in a new patient with gray platelet syndrome (alpha-storage pool deficiency). J Lab Clin Med 129:364-75
Weiss, H J; Lages, B (1997) Platelet prothrombinase activity and intracellular calcium responses in patients with storage pool deficiency, glycoprotein IIb-IIIa deficiency, or impaired platelet coagulant activity--a comparison with Scott syndrome. Blood 89:1599-611
Stout, J G; Basse, F; Luhm, R A et al. (1997) Scott syndrome erythrocytes contain a membrane protein capable of mediating Ca2+-dependent transbilayer migration of membrane phospholipids. J Clin Invest 99:2232-8
Weiss, H J; Lages, B; Hoffmann, T et al. (1996) Correction of the platelet adhesion defect in delta-storage pool deficiency at elevated hematocrit--possible role of adenosine diphosphate. Blood 87:4214-22
Weiss, H J (1995) Flow-related platelet deposition on subendothelium. Thromb Haemost 74:117-22
Lages, B; Weiss, H J (1994) Evidence for a role of glycoprotein IIb-IIIa, distinct from its ability to support aggregation, in platelet activation by ionophores in the presence of extracellular divalent cations. Blood 83:2549-59
Kojima, H; Newton-Nash, D; Weiss, H J et al. (1994) Production and characterization of transformed B-lymphocytes expressing the membrane defect of Scott syndrome. J Clin Invest 94:2237-44
Weiss, H J; Hoffmann, T; Turitto, V T et al. (1994) Further studies on the presence of functional tissue factor activity on the subendothelium of normal human and rabbit arteries. Thromb Res 73:313-26
Weiss, H J (1994) Scott syndrome: a disorder of platelet coagulant activity. Semin Hematol 31:312-9

Showing the most recent 10 out of 34 publications