Congenital disorders associated with platelet dysfunctions

Paquita Nurden; Alan T. Nurden

doi:10.1160/TH07-09-0568

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 99(02): 253-263
DOI: 10.1160/TH07-09-0568

Theme Issue Article

Schattauer GmbH

Congenital disorders associated with platelet dysfunctions

Autoren

Paquita Nurden

¹CRPP/PTIB, Hôpital Xavier Arnozan, Pessac, France
Alan T. Nurden

¹CRPP/PTIB, Hôpital Xavier Arnozan, Pessac, France

Abstract

Summary

Genetic defects of the megakaryocyte lineage give rise to bleeding syndromes of varying severity. Blood platelets are unable to fulfill their hemostatic function of preventing blood loss on vessel injury. Spontaneous bleeding is mostly mucocutaneous in nature. Most studied are deficiencies of glycoprotein (GP) mediators of adhesion (Bernard-Soulier syndrome) and aggregation (Glanzmann thrombasthenia) which concern the GPIb-IX-V complex and the integrin αIIbβ3, respectively. Defects of primary receptors for stimuli include the P2Y₁₂ ADP receptor pathology. Agonist-specific deficiencies in the platelet aggregation response and abnormalities of signaling pathways are common and lead to trauma-related bleeding. Inherited defects of secretion from storage organelles, of ATP production, and of the generation of procoagulant activity are also encountered. In some disorders, such as the Chediak-Higashi, Hermansky-Pudlak, Wiskott-Aldrich and Scott syndromes, the molecular lesion extends to other cells. In familial thrombocytopenia (FT), platelets are produced in insufficient numbers to assure haemostasis. Some of these disorders affect platelet morphology and give rise to the so-called ‘giant platelet’ syndromes (MYH9-related diseases) with changes in megakaryocyte maturation within the bone marrow and premature release of platelets. Diseases of platelet production may extend to other cells and in some cases interfere with development. Transfusion of platelets remains the most common treatment of severe bleeding, management with desmopressin is common for mild disorders. Substitute therapies are available including rFVIIa and the potential use of TPO analogues for FT. Stem cell or bone marrow transplanation is being used for severe diseases while gene therapy may be on the horizon.

Keywords

Platelets - inherited disorders - platelet function - platelet production - treatment

Volltext

Referenzen

References
1 Nurden AT, George JN. Inherited abnormalities of the platelet membrane: Glanzmann thrombasthenia, Bernard-Soulier syndrome, and other disorders. Hemostasis and Thrombosis. Lippincott V. Williams & Wilkins; Philadelphia: 2006: 987-1010.
2 Nurden P, George JN, Nurden AT. Inherited thrombocytopenias. Hemostasis and Thrombosis. Lippincott V. Williams & Wilkins; Philadelphia: 2006: 975-986.
3 Nurden AT, Nurden P. Inherited disorders of platelet function. Platelets. II Academic Press; San Diego: 2007: 1025-1050.
4 Huizinga EG, Tsuji S, Romijn RAP. et al. Structures of glycoprotein Ibα and its complex with von Willebrand factor A1 domain. Science 2002; 297: 1176-1179.
5 Celikel R, McClintock RA, Roberts JR. et al. Modulation of α-thrombin function by distinct interactions with platelet glycoprotein Ibα. Science 2003; 301: 218-221.
6 Andrews RK, Berndt MC, Lopez JA. The glycoprotein Ib-IX-V complex. Platelets. II Academic Press; San Diego: 2007: 145-163.
7 Strassel C, Pasquet J-M, Alessi M-C. et al. A novel missense mutation shows that GPIbβ has a dual role in controlling the processing and stability of the platelet GPIb-IX adhesion receptor. Biochemistry 2003; 42: 4452-4462.
8 Othman M, Notley C, Levender F. et al. Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease. Blood 2005; 105: 4330-4336.
9 Shim K, Anderson PJ, Tuley EA. et al. Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood. 2007 Epub ahead of print.
10 Nurden P, Chretien F, Poujol C. et al. Platelet structural abnormalities in three patients with type 2B von Willebrand disease. Br J Haematol 2000; 110: 704-714.
11 Nurden P, Debili N, Vainchenker W. et al. Impaired megakaryocytopoiesis in type 2B Willebrand disease with severe thrombocytopenia. Blood 2006; 108: 2587-2595.
12 Jacquelin B, Rozenshteyn D, Kanaji S. et al. Characterization of inherited differences in transcription of the human integrin α2 gene. J Biol Chem 2001; 276: 23518-23524.
13 Kojima H, Moroi M, Jung SM. et al. Characterization of a patient with glycoprotein (GP) VI deficiency possessing neither anti-GPVI autoantibody nor genetic aberration. J Thromb Haemost 2006; 4: 2433-2442.
14 Watkins NA, O'Connor MN, Rankin A. et al. Definition of GP6 polymorphisms and major differences in haplotype frequencies between populations by a combination of in-depth exon resequencing and genotyping with single tag single nucleotide polymorphisms. J Thromb Haemost 2006; 4: 1197-1205.
15 Andrews RK, Karunakaran D, Gardiner EE, Berndt MC. Platelet receptor proteolysis: a mechanism for downregulating platelet reactivity. Arterioscler Thromb Vasc Biol 2007; 27: 1511-1520.
16 Hollopeter G, Jantzen H-M, Vincent D. et al. Molecular identification of the platelet receptor targeted by antithrombotic drugs. Nature 2001; 409: 202-207.
17 Cattaneo M, Zighetti ML, 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.
18 Fung CYE, Cendana C, Farndale RW. et al. Primary and secondary agonists can use P2X1 receptors as a major pathway to increase intracellular Ca2+ in the human platelet. J Thromb Haemost 2007; 5: 910-917.
19 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.
20 Hirata T, Ushikubi F, Kakizuka A. et al. Two thromboxane A2 receptor isoforms in human platelets. Opposite coupling to adenylate cyclase with different sensitivity to Arg60 to Leu mutation. J Clin Invest 1996; 97: 949-956.
21 Tamponi G, Pannocchia A, Arduino C. et al. Congenital deficiency of alpha2-adrenoceptors on human platelets: description of two cases. Thromb Haemost 1987; 58: 1012-1016.
22 Small KM, Brown KM, Seman CA. et al. Complex haplotypes derived from noncoding polymorphisms of the intronless α_2A-adrenergic gene diversify receptor expression. Proc Natl Acad Sci USA 2006; 103: 5472-5477.
23 Fukunaga K, Ishii S, Asano K. et al. Single nucleotide polymorphism of human platelet-activating factor receptor impairs G-protein activation. J Biol Chem 2001; 16: 43025-43030.
24 Gurguis GNM. Psychiatric disorders. Platelets. II Academic Press; San Diego: 2007: 791-821.
25 Rao AK. Inherited defects in platelet signaling mechanisms. J Thromb Haemost 2003; 1: 671-681.
26 Nurden AT, Nurden P. The Gray platelet syndrome: Clinical spectrum of the disease. Blood Reviews 2007; 21: 21-36.
27 Nurden P, Jandrot-Perrus M, Combrié R. et al. Severe deficiency of glycoprotein VI in a patient with Gray Platelet Syndrome. Blood 2004; 104: 107-114.
28 Tubman VN, Levine JE, Campagna DR. et al. X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation. Blood 2007; 109: 3297-3299.
29 White JG. Medich giant platelet disorder: a unique α granule deficiency I. Structural abnormalities. Platelets 2004; 15: 345-353.
30 Hayward CPM, Rivard GE, Kane WH. et al. An autosomal dominant, qualitative platelet disorder associated with multimerin deficiency, abnormalities in platelet factor V, thrombospondin, von Willebrand factor, and fibrinogen and an epinephrine aggregation defect. Blood 1996; 87: 4967-4978.
31 Hayward CP, Cramer EM, Kane WH. et al. Studies on a second family with the Quebec platelet disorder: evidence that the degradation of the alpha-granule membrane and its soluble contents are not secondary to a defect in targeting proteins to alpha-granules. Blood 1997; 15: 1243-1253.
32 Kahr WHA, Zheng S, Sheth PM. et al. Platelets from patients with the Quebec platelet disorder contain and secrete abnormal amounts of urokinase-type plasminogen activator. Blood 2001; 98: 257-265.
33 Lo B, Li L, Gissen P. et al. Requirement of VPS33B, a member of the Sec1/Munc 18 protein family, in megakaryocyte and platelet α-granule biogenesis. Blood 2005; 106: 4159-4166.
34 Weiss HJ, Witte LD, Kaplan KL. et al. Heterogenity in storage pool deficiency: Studies on granule-bound substances in 18 patients including variants deficient in α-granules, platelet factor 4, β-thromboglobulin, and platelet-derived growth factor. Blood 1979; 54: 1296-1319.
35 Gunay-Ayqun M, Huizing M, Gahl WA. Molecular defects that affect platelet dense granules. Semin Thromb Hemost 2004; 30: 537-547.
36 Di Pietro SM, Falçon-Pérez JM, Tenza D. et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17: 4027-4038.
37 Fontana S, Parolini S, Vermi W. et al. Innate immunity defects in Hermansky-Pudlak type 2 syndrome. Blood 2006; 107: 4857-4864.
38 Certain S, Barrat F, Pastural E. et al. Protein truncation test of LYST reveals heterogeneous mutations in patients with Chediak-Higashi syndrome. Blood 2000; 96: 979-983.
39 Karim MA, Suzuki K, Fukai K. et al. Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. Am J Med Genet 2002; 108: 16-22.
40 Enders A, Ziegler B, Schwartz K. et al. Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II. Blood 2006; 108: 81-87.
41 Burns S, Cory GO, Vainchenker W. et al. Mechanisms of WASp-mediated hematologic and immunologic disease. Blood 2004; 104: 3454-3462.
42 Imai K, Morio T, Zhu Y. et al. Clinical course of patients with WASP gene mutations. Blood 2004; 103: 456-464.
43 Sabri S, Foudi A, Boukour S. et al. Deficiency in the Wiskott-Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment. Blood 2006; 108: 134-140.
44 Ancliff PJ, Blundell MP, Cory GO. et al. Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia. Blood 2006; 108: 2182-2189.
45 Patel D, Väänänen H, Jirouskova M. et al. Dynamics of GPIIb/IIIa-mediated platelet-platelet interactions in platelet adhesion/thrombus formation on collagen in vitro as revealed by videomicroscopy. Blood 2003; 101: 929-936.
46 Mitchell WB, Li J, Murcia M. et al. Mapping early conformational changes in αIIb and β3 during biogenesis reveals a potential mechanism for αIIbβ3 adopting its bent conformation. Blood 2007; 109: 3725-3732.
47 Peretz H, Rosenberg N, Landau M. et al. Molecular diversity of Glanzmann thrombasthenia in Southern India: New insights into mRNA splicing and structurefunction correlations of αIIbβ3 integrin (ITGA2B, ITGB3). Hum Mutat 2006; 27: 359-369.
48 Shpilberg O, Rabi I, Schiller K. et al. Patients with Glanzmann thrombasthenia lacking platelet glycoprotein αIIbβ3 (GPIIb/IIIa) and αvβ3 receptors are not protected from atherosclerosis. Circulation 2002; 105: 1044-1048.
49 Chen P, Melchior C, Brons NH. et al. Probing conformational changes in the I-like domain and the cysteine-rich repeat of human β3 integrins following disulfide bond disruption by cysteine mutations: identification of cysteine 598 involved in αIIbβ3 activation. J Biol Chem 2001; 276: 38628-38635.
50 Ruiz C, Liu C-Y, Sun Q-H. et al. A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (αIIbβ3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia-like phenotype. Blood 2001; 98: 2432-2441.
51 Xiao T, Takagi J, Coller BS. et al. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 2004; 432: 59-67.
52 Peyruchaud O, Nurden AT, Pannochia A. et al. An Arg⁹⁹⁵ (R) to Gln (Q) amino acid substitution in the GFFKR sequence of the cytoplasmic domain of the integrin αIIb subunit in a patient with an unusual variant form of Glanzmann's thrombasthenia. Blood 1998; 92: 4178-4187.
53 Pasvolsky R, Feigelson SW, Kilic SS. et al. A LADIII syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med 2007; 204: 1571-1582.
54 Weiss HJ, Turitto VT, Baumgartner HR. Role of shear rate and platelets in promoting fibrin formation on rabbit subendothelium. Studies utilizing patients with quantitative and qualitative platelet defects. J Clin Invest 1986; 78: 1072-1082.
55 Zwaal RF, Comfurius P, Bevers EM. Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids. Biochim Biophys Acta 2004; 1636: 119-128.
56 Albrecht C, McVey JH, Elliott JI. et al. A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome. Blood 2005; 106: 542-549.
57 Geddis AE, Kaushansky K. Inherited thrombocytopenias: toward a molecular understanding of disorders of platelet production. Curr Opin Pediatr 2004; 16: 15-22.
58 Horvat-Switzer RD, Thompson AA. HOXA11 mutation in amegakaryocytic thrombocytopenia with radio-ulnar synosis syndrome inhibits megakaryocytic differentiation in vitro. Blood Cells Mol Dis 2006; 37: 55-63.
59 Favier R, Jondeau K, Boutard P. et al. Paris-Trussaud syndrome: clinical, hematological, molecular data of ten new cases. Thromb Haemost 2003; 90: 893-897.
60 Raslova H, Komura E, Le Couédic JP. et al. FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trusseau/Jacobsen thrombopenia. J Clin Invest 2004; 114: 77-84.
61 Hughan SC, Senis Y, Best D. et al. Selective impairment of platelet activation to collagen in the absence of GATA1. Blood 2005; 105: 4369-4376.
62 Freson K, Matthijs G, Thys C. et al. Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation. Hum Mol Genet 202 11: 147-152.
63 Balduini CL, Pecci A, Loffredo G. et al. Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost 2004; 91: 129-140.
64 Ichikawa M, Asai T, Saito T. et al. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med 2004; 10: 299-304.
65 Sun L, Mao G, Rao AK. Association of CBFA2 mutation with decreased platelet PKC-theta and impaired receptor-mediated activation of GPIIb-IIIa and plekstrin phosphorylation: proteins regulated by CBFA2 play a role in GPIIb-IIIa activation. Blood 2004; 103: 948-954.
66 Sun L, Gorospe JR, Hoffman EP, Rao AK. Decreased platelet expression of myosin regulatory light chain polypeptide (MYL9) and other genes with platelet dysfunction and CBFA2/Runx1 mutation: insights from platelet expression profiling. J Thromb Haemost 2007; 5: 146-154.
67 Germeshausen M, Ballmaier M, Welte K. MPL mutations in 23 patients suffering from congenital amegakaryocytic thrombocytopenia: The type of mutation predicts the course of the disease. Hum Mutat 2006; 27: 296-301.
68 Savoia A, Dufour C, Locatelli F. et al. Congenital amegakaryocytic thrombocytopenia: Clinical and biological consequences of five novel mutations. Haematologica 2007; 92: 1186-1193.
69 Ding J, Komatsu H, Wakita A. et al. Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 2004; 103: 4198-4200.
70 Klpocki E, Schulze H, Strauss G. et al. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet 2007; 80: 232-40.
71 Pecci A, Canobbio I, Balduini A. et al. Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. Hum Mol Genet 2005; 14: 3169-3178.
72 Heath KE, Campos-Barros A, Toren A. et al. Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am J Hum Genet 2001; 69: 1033-1045.
73 Dong F, Li S, Pujol-Moix N. et al. Genotype-phenotype correlation in MYH9-related thrombocytopenia. Br J Haematol 2005; 130: 620-627.
74 Marigo V, Nigro A, Pecci A. et al. Correlation between the clinical phenotype of MYH9-related disease and tissue distribution of class II nonmuscle myosin heavy chains. Genomics 2004; 83: 1125-1133.
75 Chen Z, Naveiras O, Balduini A. et al. The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway. Blood 2007; 110: 171-179.
76 Nurden P, Nurden A, Solé G. et al. Platelet abnormalities in patients with constitutional defects in filamin A. XXI Congress of the International Society on Thrombosis and Haemostasis. 2007 abstract CDROM.
77 Rees DC, Icolascon A, Carella M. et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol 2005; 130: 297-309.
78 Kile BT, Panopoulos AD, Stirzaker RA. et al. Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia. Blood 2007; 110: 2371-2380.
79 Mason KD, Carpinelli MR, Fletcher JI. et al. Programmed anuclear cell death delimits platelet lifespan. Cell 2007; 128: 31173-31186.
80 Alexander WS, Viney EM, Zhang J-G. et al. Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene. Proc Natl Acad Sci USA 2006; 103: 16442-16447.
81 Bolton-Maggs PHB, Chalmers EA, Collins PW. et al. A review of platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol 2006; 135: 603-633.
82 Hayward CP, Rao AK, Cattaneo M. Congenital platelet disorders: overview of their mechanisms, diagnostic evaluation and treatment. Haemophilia 2006; 12: 128-136.
83 Balduini CL, Cattaneo M, Fabris F. et al. Inherited thrombocytopenias: a proposed diagnostic algorithm from the Italian Gruppo di studio delle Plastrine. Haematologica 2003; 88: 582-592.
84 Dargaud Y, Bordet JC, Trzeciak MC. et al. A case of Glanzmann's thrombasthenia successfully treated with recombinant factor VIIa during a surgical procedure: observations on the monitoring and the mechanism of action of this drug. Haematologica 2006; 91 (Suppl. 06) e58-e61.
85 Lisman T, Adelmeijer J, Heijnen HFG, de Groot PG. Recombinant factor VIIa restores aggregation of αIIbβ3-deficient platelets via tissue factor-independent fibrin generation. Blood 2004; 103: 1720-1727.
86 Coppola A, De Stefano V, Tufano A. et al. Longlasting intestinal bleeding in an old patient with multiple mucosal vascular abnormalities and Glanzmann's thrombasthenia: 3-year pharmacological mangement. J Intern Med 2002; 252: 271-275.
87 Bussel JB, Kuter DJ, George JN. et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 2006; 355: 1672-1681.
88 Tardieu M, Lacroix C, Neven B. et al. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome. Blood 2005; 106: 40-42.
89 Charrier S, Dupré L, Scaramuzza S. et al. Lentviral vectors targeting WASp expression to hematopoietic cells, efficiently transduce and correct cells from WAS patients. Gene Ther 2007; 14: 415-428.
90 Fang J, Hodivala-Dilke K, Johnson BD. et al. Therapeutic expression of the platelet-specific integrin, αIIbβ₃, in a murine model for Glanzmann thrombasthenia. Blood 106: 2671-2679.