Inherited Defects in Platelet Signaling Mechanisms

In the majority of patients with an inherited abnormality in platelet function and a bleeding diathesis, the underlying platelet molecular mechanisms are unknown. The usually considered entities, such as thrombasthenia, the Bernard-Soulier syndrome, and storage pool deficiency, occur in a small proportion of patients. A substantial number of patients present with decreased aggregation and secretion of dense granule contents upon activation, and are lumped in the category of primary secretion defects or platelet activation defects. Evidence is now available that defects in platelet signaling mechanisms may be the basis for the platelet dysfunction in some of these patients. This evidence is presented here. If the key components in signal transduction are the surface receptors, the G-proteins, and the effectors, evidence now exists for specific human platelet abnormalities at each of these levels. There is a pressing need for a concerted effort to delineate the molecular mechanisms in the large group of patients with impaired platelet function who represent an untapped reservoir of new information into normal platelet function.

KEYWORDS

Platelet signal transduction - platelet function disorders - phospholipase C-β₂ - primary secretion defects - signal transduction defects

REFERENCES

• 1 Solum N O. Procoagulant expression in platelets and defects leading to clinical disorders.  Arterioscler Thromb Vasc Biol. 1999;  19 2841-2846
• 2 Weiss H J. Platelet aggregation, adhesion and ADP release in thrombopathia (platelet factor 3 deficiency)-a comparison with Glanzmann's thrombasthenia and von Willebrand's disease.  Am J Med. 1967;  43 570-578
• 3 Hardisty R M, Hutton R A. Bleeding tendency associated with “new” abnormality of platelet behavior.  Lancet. 1967;  1 983-985
• 4 Weiss H J, Chervenick P A, Zalusky R, Factor A. A familial defect in platelet function associated with impaired release of adenosine diphosphate.  N Engl J Med. 1969;  281 1264-1270
• 5 Malmsten C, Hamberg M, Svensson J. Physiological role of an endoperoxide in human platelets: hemostatic defect due to platelet cyclooxygenase deficiency.  Proc Natl Acad Sci USA. 1975;  72 1446-1450
• 6 Rao A K, Willis J, Hassell B, Day H J, Holmsen H. Congenital platelet secretion defects with normal storage pools and arachidonate metabolism.  Circulation. 1982;  66 299 , (Abst)
• 7 Rao A K, Holmsen H. Congenital disorders of platelet function.  Semin Hematol. 1986;  23 102-118
• 8 Day H J, Rao A K. Platelet function testing.  Semin Hematol. 1986;  23 89-101
• 9 Rao A K, Gabbeta J. Congenital disorders of platelet signal transduction.  Arterioscler Thromb Vasc Biol. 2000;  20 285-289
• 10 Cattaneo M, Lombardi R, Zighetti M L, Gachet C, Ohlmann P, Cazenave J. Deficiency of (³³)P-2MeS-ADP binding sites on platelets with secretion defect, normal granule stores and normal thromboxane A₂ production.  Thromb Haemost. 1997;  77 986-990
• 11 Lages B, Weiss H J. Heterogeneous defects of platelet secretion and responses to weak agonists in patients with bleeding disorders.  Br J Haematol. 1988;  68 53-62
• 12 Koike K, Rao A K, Holmsen H, Mueller P S. Platelet secretion defect in patients with the attention deficit disorder and easy bruising.  Blood. 1984;  63 427-433
• 13 Yang X, Sun L, Gabbeta J, Rao A K. Platelet activation with combination of ionophore A23187 and a direct protein kinase C activator induces normal secretion in patients with impaired receptor mediated secretion and abnormal signal transduction.  Thromb Res. 1997;  88 317-328
• 14 Rao A K. Congenital disorders of platelet secretion and signal transduction. In: Colman RW, Hirsh J, Marder VJ, Clowes P, George JN Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 4th ed Philadelphia, PA; JB Lippincott 2001: 890-904
• 15 Hayward C PM. Inherited disorders of platelet α-granules.  Platelets. 1997;  8 197-209
• 16 Hirata T, Kakizuka A, Ushikubi F, Fuse I, Okuma M, Narumiya S. Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder.  J Clin Invest. 1994;  94 1662-1667
• 17 Ushikubi F, Okuma M, Kanaji K et al.. Hemorrhagic thrombocytopathy with platelet thromboxane A2 receptor abnormality: defective signal transduction with normal binding activity.  Thromb Haemost. 1987;  57 158-164
• 18 Fuse I, Mito M, Hattori A et al.. Defective signal transduction induced by thromboxane A2 in a patient with a mild bleeding disorder: impaired phospholipase C activation despite normal phospholipase A2 activation.  Blood. 1993;  81 994-1000
• 19 Ushikubi F, Ishibashi T, Narumiya S, Okuma M. Analysis of the defective signal transduction mechanism through the platelet thromboxane A₂ receptor in a patient with polycythemia vera.  Thromb Haemost. 1992;  67 144-146
• 20 Fuse I, Hattori A, Mito M et al.. Pathogenetic analysis of five cases with a platelet disorder characterized by the absence of thromboxane A2 (TXA2)-induced platelet aggregation in spite of normal TXA2 binding activity.  Thromb Haemost. 1996;  76 1080-1085
• 21 Kahn M L. Platelet-collagen responses: molecular basis and therapeutic promise.  Semin Thromb Hemost. 2004;  30 419-426
• 22 Nieuwenhuis H K, Akkerman J WN, Houdijk W PM, Sixma J J. Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia.  Nature. 1985;  318 470-472
• 23 Nieuwenhuis H K, Sakariassen K S, Houdijk W PM, Nievelstein PF EM, Sixma J J. Deficiency of platelet membrane glycoprotein Ia associated with a decreased platelet adhesion to subendothelium: a defect in platelet spreading.  Blood. 1986;  68 692-695
• 24 Kehrel B, Balleisen L, Kokott R et al.. Deficiency of intact thrombospondin and membrane glycoprotein Ia in platelets with defective collagen-induced aggregation and spontaneous loss of disorder.  Blood. 1988;  71 1074-1078
• 25 Moroi M, Jung S M, Okuma M, Shinmyozu K. A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion.  J Clin Invest. 1989;  84 1440-1445
• 26 Ryo R, Yoshida A, Sugano W et al.. Deficiency of P62, a putative collagen receptor, in platelet from a patient with defective collagen-induced platelet aggregation.  Am J Hematol. 1992;  38 25-31
• 27 Arai M, Yamamoto N, Moroi M, Akamatsu N, Fukutake K, Tanoue K. Platelets with 10% of the normal amount of glycoprotein VI have an impaired response to collagen that results in a mild bleeding tendency.  Br J Haematol. 1995;  89 124-130
• 28 Diaz-Ricart M, Tandon N N, Carretero M, Ordinas A, Bastida E, Jamieson G A. Platelets lacking functional CD36 (glycoprotein IV) show reduced adhesion to collagen in flowing whole blood.  Blood. 1993;  82 491-496
• 29 Yamamoto N, Ikeda H, Tandon N N et al.. A platelet membrane glycoprotein (GP) deficiency in healthy blood donors: Nak^a- platelets lack detectable GPIV (CD36).  Blood. 1990;  76 1698-1703
• 30 Daniel J L, Dangelmaier C, Strouse R, Smith J B. Collagen induces normal signal transduction in platelets deficient in CD36 (platelet glycoprotein IV).  Thromb Hemost. 1994;  71 353-356
• 31 Kashiwagi H, Honda S, Tomiyama Y et al.. A novel polymorphism in glycoprotein IV (replacement of proline-90 by serine) predominates in subjects with platelet GPIV deficiency.  Thromb Haemost. 1993;  69 481-484
• 32 Lipsky R, Sobieski D A, Tandon N N, Herman J, Ikeda H, Jamieson G A. Detection of GPIV (CD36) mRNA in Nak^a- platelets.  Thromb Haemost. 1991;  65 456-457
• 33 Dorsam R T, Kunapuli S P. Central role of the P2Y12 receptor in platelet activation.  J Clin Invest. 2004;  113 340-345
• 34 Cattaneo M, Lecchi A, Randi A M, McGregor J L, Mannucci P M. Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate.  Blood. 1992;  80 2787-2796
• 35 Cattaneo M, Lecchi A, Lombardi R, Gachet C, Zighetti M L. Platelets from a patient heterozygous for the defect of P2(CYC) receptors for ADP have a secretion defect despite normal thromboxane A(2) production and normal granule stores: further evidence that some cases of platelet ‘Primary Secretion Defect’ are heterozygous for a defect of P2(CYC) receptors.  Arterioscler Thromb Vasc Biol. 2000;  20 E101-E106
• 36 Nurden P, Savi P, Heilmann E et al.. An inherited bleeding disorder linked to a defective interaction between ADP and its receptor on platelets. Its influence on glycoprotein IIb-IIIa complex function.  J Clin Invest. 1995;  95 1612-1622
• 37 Levy-Toledano S, Maclouf J, Rosa J P et al.. Abnormal tyrosine phosphorylation linked to a defective interaction between ADP and its receptor on platelets.  Thromb Haemost. 1998;  80 463-468
• 38 Hollopeter G, Jantzen H M, Vincent D et al.. Identification of the platelet ADP receptor targeted by antithrombotic drugs.  Nature. 2001;  409 202-207
• 39 Cattaneo M, Zighetti M L, Lombardi R et al.. Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding.  Proc Natl Acad Sci USA. 2003;  100 1978-1983
• 40 Conley P B, Jurek M M, Vincent D, Lecchi A, Cattaneo M. Unique mutations of the P2Y₁₂ locus of patients with previously described defects in ADP-dependent aggregation.  Blood. 2001;  98 43B
• 41 Oury C, Lenaerts T, Peerlinck K, Vermylen J, Hoylearts M F. Congenital deficiency of the phospholipase C coupled platelet P2Y1 receptor leads to a mild bleeding disorder.  Thromb Haemost. 1999;  (suppl) 20-21
• 42 Oury C, Toth-Zsamboki E, Van Geet C et al.. A natural dominant negative P2X1 receptor due to deletion of a single amino acid residue.  J Biol Chem. 2000;  275 22611-22614
• 43 Weiss H J, Lages B. The response of platelets to epinephrine in storage pool deficiency-evidence pertaining to the role of adenosine diphosphate in mediating primary and secondary aggregation.  Blood. 1988;  72 1717-1725
• 44 Propping P, Friedl W. Genetic control of adrenergic receptors on human platelets. A twin study.  Hum Genet. 1983;  64 105-109
• 45 Rao A K, Willis J, Kowalska M A, Wachtfogel Y, Colman R W. Differential requirements for epinephrine induced platelet aggregation and inhibition of adenylate cyclase. Studies in familial α₂-adrenergic receptor defect.  Blood. 1988;  71 494-501
• 46 Tamponi G, Pannocchia A, Arduino C et al.. Congenital deficiency of α-2-adrenoreceptors on human platelets: description of two cases.  Thromb Haemost. 1987;  58 1012-1016
• 47 Yang J, Wu J, Kowalska M A et al.. Loss of signaling through the G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs.  Proc Natl Acad Sci USA. 2000;  97 9984-9989
• 48 Gabbeta J, Yang X, Kowalska M A, Sun L, Dhanasekaran N, Rao A K. Platelet signal transduction defect with Gα subunit dysfunction and diminished Gα_q in a patient with abnormal platelet responses.  Proc Natl Acad Sci USA. 1997;  94 8750-8755
• 49 Rao A K, Disa J, Yang X. Concomitant defect in internal release and influx of calcium in patients with congenital platelet dysfunction and impaired agonist-induced calcium mobilization: thromboxane production is not required for internal release of calcium.  J Lab Clin Med. 1993;  121 52-63
• 50 Rao A K, Koike K, Willis J et al.. Platelet secretion defect associated with impaired liberation of arachidonic acid and normal myosin light chain phosphorylation.  Blood. 1984;  64 914-921
• 51 Gabbeta J, Vaidyula V R, Dhanasekaran D N, Rao A K. Human platelet Gα_q deficiency is associated with decreased Gα_q gene expression in platelets but not neutrophils.  Thromb Haemost. 2002;  87 129-133
• 52 Freson K, Hoylaerts M F, Jaeken J et al.. Genetic variation of the extra-large stimulatory G protein alpha-subunit leads to Gs hyperfunction in platelets and is a risk factor for bleeding.  Thromb Haemost. 2001;  86 733-738
• 53 Freson K, Thys C, Wittevrongel C et al.. Pseudohypoparathyroidism type Ib with disturbed imprinting in the GNAS1 cluster and Gsalpha deficiency in platelets.  Hum Mol Genet. 2002;  11 2741-2750
• 54 Patel Y M, Patel K, Rahman S et al.. Evidence for a role for Galphai1 in mediating weak agonist-induced platelet aggregation in human platelets: reduced Galphai1 expression and defective Gi signaling in the platelets of a patient with a chronic bleeding disorder.  Blood. 2003;  101 4828-4835
• 55 Yang X, Sun L, Ghosh S, Rao A K. Human platelet signaling defect characterized by impaired production of 1,4,5 inositoltrisphosphate and phosphatic acid, and diminished pleckstrin phosphorylation. Evidence for defective phospholipase C activation.  Blood. 1996;  88 1676-1683
• 56 Lee S B, Rao A K, Lee K-H, Yang X, Bae Y S, Rhee S G. Decreased expression of phospholipase C-β2 isozyme in human platelets with impaired function.  Blood. 1996;  88 1684-1691
• 57 Sun L, Mao G, Rao A K. Association of CBFA2 mutation with decreased platelet PKC-{theta} and impaired receptor-mediated activation of GPIIb-IIIa and pleckstrin phosphorylation: proteins regulated by CBFA2 play a role in GPIIb-IIIa activation.  Blood. 2004;  103 948-954
• 58 Lages B, Weiss H J. Impairment of phosphatidylinositol metabolism in a patient with a bleeding disorder associated with defects of initial platelet responses.  Thromb Haemost. 1988;  59 175-179
• 59 Speiser-Ellerton S, Weiss H J. Studies on platelet protein phosphorylation in patients with impaired responses to platelet agonists.  J Lab Clin Med. 1990;  115 104-111
• 60 Rao A K, Kowalska M A, Disa J. Impaired cytoplasmic ionized calcium mobilization in inherited platelet secretion defects.  Blood. 1989;  74 664-672
• 61 Mao G F, Vaidyula V R, Kunapuli S P, Rao A K. Lineage-specific defect in gene expression in human platelet phospholipase C-beta2 deficiency.  Blood. 2002;  99 905-911
• 62 Holmsen H, Walsh P N, Koike K et al.. Familial bleeding disorder associated with deficiencies in platelet signal processing and glycoproteins.  Br J Haematol. 1987;  67 335-344
• 63 Cartwright J, Hampton K K, Macneil S, Colvin B T, Preston F E. A haemorrhagic platelet disorder associated with altered stimulus-response coupling and abnormal membrane phospholipid composition.  Br J Haematol. 1994;  88 129-136
• 64 Mitsui T. Defective signal transduction through the thromboxane A₂ receptor in a patient with a mild bleeding disorder. Deficiency of the inositol 1,4,5-triphosphate formation despite normal G-protein activation.  Thromb Haemost. 1997;  77 991-995
• 65 Gabbeta J, Yang X, Sun L, McLane M A, Niewiarowski S, Rao A K. Abnormal inside-out signal transduction-dependent activation of glycoprotein IIb-IIIa in a patient with impaired pleckstrin phosphorylation.  Blood. 1996;  87 1368-1376
• 66 Pareti F I, Mannucci P M, D'Angelo A, Sautebin L, Galli G. Congenital deficiency of thromboxane and prostacyclin.  Lancet. 1980;  1 898-901
• 67 Rak K, Boda Z. Hemostatic balance in congenital deficiency of platelet cyclooxygenase.  Lancet. 1980;  2 44
• 68 Roth G J, Machuga R. Radioimmune assay of human platelet prostaglandin synthetase.  J Lab Clin Med. 1982;  99 187-196
• 69 Matijevic-Aleksic N, McPhedran P, Wu K K. Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency.  Br J Haematol. 1996;  92 212-217
• 70 Defryn G, Machin S J, Carreras L D, Danden M V, Chamone D AF, Vermylen J. Familial bleeding tendency with partial platelet thromboxane synthetase deficiency: Reorientation of cyclic endoperoxide metabolism.  Br J Haematol. 1981;  49 29-41
• 71 Mestel F, Oetliker O, Beck E. al e. Severe bleeding associated with defective thromboxane synthetase.  Lancet. 1980;  1 157
• 72 Rao A K, Koike K, Day H J, Smith J B, Holmsen H. Bleeding disorder associated albumin-dependent partial deficiency in platelet thromboxane production. Effect of albumin on arachidonate metabolism in platelets.  Am J Clin Pathol. 1985;  83 687-696
• 73 Remold-O'Donnell E, Rosen F S, Kenney D M. Defects in Wiskott-Aldrich syndrome blood cells.  Blood. 1996;  87 2621-2631
• 74 Semple J W, Siminovitch K A, Mody M et al.. Flow cytometric analysis of platelets from children with the Wiskott-Aldrich syndrome reveals defects in platelet development, activation and structure.  Br J Haematol. 1997;  97 747-754
• 75 Shcherbina A, Rosen F S, Remold-O'Donnell E. Pathological events in platelets of Wiskott-Aldrich syndrome patients.  Br J Haematol. 1999;  106 875-883
• 76 Zhu Q, Watanabe C, Liu T et al.. Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype.  Blood. 1997;  90 2680-2689
• 77 Zigmond S H. How WASP regulates actin polymerization.  J Cell Biol. 2000;  150F 117-120
• 78 Song W J, Sullivan M G, Legare R D et al.. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.  Nat Genet. 1999;  23 166-175
• 79 Freson K, Devriendt K, Matthijs G et al.. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation.  Blood. 2001;  98 85-92
• 80 Shivdasani R A. Molecular and transcriptional regulation of megakaryocyte differentiation.  Stem Cells. 2001;  19 397-407
• 81 Shiraga M, Ritchie A, Aidoudi S et al.. Primary megakaryocytes reveal a role for transcription factor NF-E2 in integrin αIIbβ3 signaling.  J Cell Biol. 1999;  147 1419-1430