Download PDF
Thromb Haemost 1988; 59(02): 175-179
DOI: 10.1055/s-0038-1642749
Original Articles
Schattauer GmbH Stuttgart

Impairment of Phosphatidylinositol Metabolism in a Patient with a Bleeding Disorder Associated with Defects of Initial Platelet Responses

Bruce Lages
The Department of Medicine, Division of Hematology and Oncology, St. Luke's-Roosevelt Hospital Center, and Columbia University College of Physicians and Surgeons, New York, N.Y., USA
,
Harvey J Weiss
The Department of Medicine, Division of Hematology and Oncology, St. Luke's-Roosevelt Hospital Center, and Columbia University College of Physicians and Surgeons, New York, N.Y., USA
› Author Affiliations
Further Information

Publication History

Received 21 January 1987

Accepted after revision 05 November 1987

Publication Date:
21 May 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Phosphoinositide/polyphosphoinositide (PI/PPI) metabolism, measured by the increase of 3H-phosphatidic acid (PA) and the decrease of 3H-phosphatidylinositol (PI) in 3H-arachidonate- labeled platelet suspensions, was assessed in five patients whose platelet functional defects included impaired initial rates of ADP, epinephrine and U44069 aggregation in platelet-rich plasma (PRP). In one patient, 3H-PA formation induced by collagen and thrombin was reduced or absent on two of three occasions, and the decrease in 3H-PI was reduced on one of these two occasions in response to collagen and A23187, and on all 3 occasions in response to thrombin. The variations in the formation of 3H-PA in this patient on different occasions broadly paralleled the variations in the initial rates of ADP and U44069 aggregation and in epinephrine aggregation seen in PRP. No such abnormalities of PI metabolism were found in four other patients with similar, but not identical, functional defects. These results suggest an impairment affecting metabolism of PI/PPI via the PI/PPI cycle in this patient's platelets. The association of abnormalities of PI metabolism with defects of initial platelet responses provides further support for a physiological role of phosphoinositide metabolism in the early activation mechanisms of platelets.

Keywords

Platelets - Phosphoinositides - Phosphatidic acid - Blood platelet disorders
 

  • References

  • 1 Rittenhouse SE. Inositol lipid metabolism in the response of stimulated platelets. Cell Calcium 1982; 3: 311-322
    CrossrefPubMedGoogle Scholar
  • 2 Lapetina EG. Metabolism of inositides and the activation of platelets. Life Sci 1983; 32: 2069-2082
    CrossrefPubMedGoogle Scholar
  • 3 Kishimoto A, Takai Y, Mori T, Kikkawa U, Nishizuka Y. Activation of calcium and phospholipid-dependent protein kinase by diacyl glycerol: its possible relation to phosphatidylinositol turnover. J Biol Chem 1980; 255: 2273-2276
    PubMedGoogle Scholar
  • 4 O’Rourke FA, Halenda SP, Zavoico GB, Feinstein MB. Inositol 1,4,5-trisphosphate releases Ca + 2 from a Ca + 2-transporting membrane vesicle fraction from human platelets. J Biol Chem 1985; 260: 956-962
    PubMedGoogle Scholar
  • 5 Adunyah SE, Dean WL. Inositol triphosphate-induced Ca + 2 release from human platelet membranes. Biochem Biophys Res Commun 1985; 128: 1274-1280
    CrossrefPubMedGoogle Scholar
  • 6 Lapetina EG, Watson SP, Cuatrecasas P. Myo-Inositol 1,4,5- Irisphosphate stimulates protein phosporylation in saponin-per- meabilized human platelets. Proc Natl Acad Sci USA 1984; 81: 7431-7435
    CrossrefPubMedGoogle Scholar
  • 7 Gerrard JM, Butler AM, Peterson DA, White JG. Phosphatidic acid releases calcium from a platelet membrane fraction in vitro. Prosta- gland Med 1978; 1: 387-396
    PubMedGoogle Scholar
  • 8 Gerrard JM, Kindom SE, Peterson DA, Peller J, Krantz KE, White JG. Lysophosphatidic acids. Influence on platelet aggregation and intracellular calcium flux. Am J Pathol 1979; 96: 423-438
    PubMedGoogle Scholar
  • 9 Lages B, Weiss HJ. Heterogeneous defects of platelet activation/secretion in patients with bleeding disorders. Thromb Haemostas. 1985 54. 11 Abstr
    PubMedGoogle Scholar
  • 10 Lages B, Weiss HJ. Heterogeneous defects of platelet secretion and responses to weak agonists in patients with bleeding disorders. Brit J Haematol 1988; 68: 53-62
    CrossrefPubMedGoogle Scholar
  • 11 White JG. Interaction of membrane systems in blood platelets. Am J Pathol 1972; 66: 295-312
    PubMedGoogle Scholar
  • 12 Walsh PN, Mills DC B, White JG. Metabolism and function of human platelets washed by albumin density gradient centrifugation. Brit J Haematol 1977; 36: 281-296
    CrossrefPubMedGoogle Scholar
  • 13 Lages B, Scrutton MC, Holmsen H. Studies on gel-filtered human platelets: isolation and characterization in a medium containing no added Ca2+, Mg2+, or K+ . J Lab Clin Med 1975; 85: 811-825
    PubMedGoogle Scholar
  • 14 Holmsen H, Setkowsky-Dangelmaier CA. Adenine nucleotide metabolism of blood platelets. X. Formaldehyde stops centrifugation- induced secretion after A23187 stimulation and causes breakdown of metabolic ATP. Biochim Biophys Acta 1977; 497: 46-61
    CrossrefPubMedGoogle Scholar
  • 15 Lapetina EG, Cuatrecasas P. Stimulation of phosphatidic acid formation in platelets precedes the formation of arachidonate and parallels the release of serotonin. Biochim Biophys Acta 1979; 573: 394-402
    CrossrefPubMedGoogle Scholar
  • 16 Lages B, Malmsten C, Weiss HJ, Samuelsson B. Impaired platelet response to thromboxane A2 and defective calcium mobilization in a patient with a bleeding disorder. Blood 1981; 57: 545-552
    PubMedGoogle Scholar
  • 17 Rittenhouse SE, Allen CL. Synergistic activation by collagen and 15- hydroxy-9a, lla-peroxidoprosta-5, 13-dienoic acid (PGH2) of phosphatidyl inositol metabolism and arachidonic acid release in human platelets. J Clin Invest 1982; 70: 1216-1224
    CrossrefPubMedGoogle Scholar
  • 18 Broekman MJ, Ward JW, Marcus AJ. Phospholipid metabolism in stimulated human platelets. Changes in phosphatidylinositol, phosphatidic acid, and lyso phospholipids. J Clin Invest 1980; 66: 275-283
    CrossrefPubMedGoogle Scholar
  • 19 Rittenhouse-Simmons S. Differential activation of platelet phospholipases by thrombin and ionophore A23187. J Biol Chem 1981; 256: 4153-4155
    PubMedGoogle Scholar
  • 20 Imai A, Nozawa Y. The rapid Pi-turnover is not coupled with the aggregation in A23187-activated human platelets. Biochem Biophys Res Commun 1982; 105: 236-243
    CrossrefPubMedGoogle Scholar
  • 21 Lapetina EG, Billah MM, Cuatrecasas P. The initial action of thrombin on platelets. Conversion of phosphatidylinositol to phosphatidic acid preceding the production of arachidonic acid. J Biol Chem 1981; 256: 5037-5040
    PubMedGoogle Scholar
  • 22 Rittenhouse SE. Activation of human platelet phospholipase C by ionophore A23187 is totally dependent upon cyclo-oxygenase products and ADP. Biochem J 1984; 190: 103-110
    PubMedGoogle Scholar
  • 23 Lapetina EG, Silio J, Ruggiero M. Thrombin induces serotonin secretion and aggregation independently of inositol phospholipids hydrolysis and protein phosphorylation in human platelets per- meabilized with saponin. J Biol Chem 1985; 260: 7078-83
    PubMedGoogle Scholar
  • 24 Pollock WK, Armstrong RA, Brydon LJ, Jones RL, MacIntyre DE. Thromboxane-induced phosphatidate formation in human platelets. Relationship to receptor occupancy and to changes in cytosolic free calcium. Biochem J 1984; 219: 833-842
    CrossrefPubMedGoogle Scholar
  • 25 Holmsen H. Platelet metabolism and activation. Sem Hemat 1985; 22: 219-240
    PubMedGoogle Scholar
  • 26 Prescott SM, Majerus PW. Characterization of 1,2-diacyl glycerol hydrolysis in human platelets. J Biol Chem 1983; 258: 764-769
    PubMedGoogle Scholar
  • 27 Brass LF, Laposata M, Banga HS, Rittenhouse SE. Regulation of the phosphoinositide hydrolysis pathway in thrombin-stimulated platelets by a pertussis toxin-sensitive guanine nucleotide-binding protein. J Biol Chem 1986; 261: 16838-16847
    PubMedGoogle Scholar
  • 28 Lapetina EG. Effect of pertussis toxin on the phosphodiesteratic cleavage of the polyphosphoinositides by guanine 5’-0-thiotriphos- phate and thrombin in permeabilized human platelets. Biochim Biophys Acta 1986; 884: 219-224
    CrossrefPubMedGoogle Scholar
  • 29 Banga HS, Simons ER, Brass LF, Rittenhouse SE. Activation of phospholipases A and C in human platelets exposed to epinephrine: role of glycoproteins Ilb/IIIa and dual role of epinephrine. Proc Natl Acad Sci USA 1986; 83: 9197-9201
    CrossrefPubMedGoogle Scholar