Inherited Thrombocytopenias: Molecular Mechanisms

Each megakaryocyte forms 10[3] platelets and 10[11] platelets are replenished daily. The unique and amazing mechanisms that allow megakaryocytes to become giant and polyploid and to release such a large number of platelets are still poorly understood. The study of inherited thrombocytopenias offers the possibility to gain new information on these processes because several different forms, deriving from defective megakaryocytic commitment, differentiation, maturation, or platelet formation, have been identified. Moreover, in the presence of some genetic defects, megakaryocytes produce platelets with a shortened life span. In this review, we summarize what we have learned about inherited thrombocytopenias in the last few years.

Platelets - megakaryocytes - inherited thrombocytopenias - bleeding - pathogenesis

REFERENCES

• 1 Balduini C L, Iolascon A, Savoia A. Inherited thrombocytopenias: from genes to therapy.  Haematologica. 2002;  87 860-880
• 2 Kuter D J, Begley C G. Recombinant human thrombopoietin: basic biology and evaluation of clinical studies.  Blood. 2002;  100 3457-3469
• 3 Ballmaier M, Germeshausen M, Schulze H et al.. c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia.  Blood. 2001;  97 139-146
• 4 Ihara K, Ishii E, Eguchi M et al.. Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia.  Proc Natl Acad Sci USA. 1999;  96 3132-3136
• 5 Fox N, Priestley G, Papayannopoulou T et al.. Thrombopoietin expands hematopoietic stem cells after transplantation.  J Clin Invest. 2002;  110 389-394
• 6 Carver-Moore K, Broxmeyer H E, Luoh S M et al.. Low levels of erythroid and myeloid progenitors in thrombopoietin- and c-mpl-deficient mice.  Blood. 1996;  88 803-808
• 7 Greenhalgh K L, Howell R T, Bottani A et al.. Thrombocytopenia-absent radius syndrome: a clinical genetic study.  J Med Genet. 2002;  39 876-881
• 8 Letestu R, Vitrat N, Masse A et al.. Existence of a differentiation blockage at the stage of a megakaryocyte precursor in the thrombocytopenia and absent radii (TAR) syndrome.  Blood. 2000;  95 1633-1641
• 9 Strippoli P, Savoia A, Iolascon A et al.. Mutational screening of thrombopoietin receptor gene (c-mpl) in patients with congenital thrombocytopenia and absent radii (TAR).  Br J Haematol. 1998;  103 311-314
• 10 Fleischman R A, Letestu R, Mi X et al.. Absence of mutations in the HoxA10, HoxA11 and HoxD11 nucleotide coding sequences in thrombocytopenia with absent radius syndrome.  Br J Haematol. 2002;  116 367-375
• 11 Thompson A A, Woodruff K, Feig S A et al.. Congenital thrombocytopenia and radio-ulnar synostosis: a new familial syndrome.  Br J Haematol. 2001;  113 866-870
• 12 Thorsteinsdottir U, Sauvageau G, Hough M R et al.. Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia.  Mol Cell Biol. 1997;  17 495-505
• 13 Davis A P, Witte D P, Hsieh-Li H M et al.. Absence of radius and ulna in mice lacking hoxa-11 and hoxd-11.  Nature. 1995;  375 791-795
• 14 Thompson A A, Nguyen L T. Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation.  Nat Genet. 2000;  26 397-398
• 15 Small K M, Potter S S. Homeotic transformations and limb defects in Hox A11 mutant mice.  Genes Dev. 1993;  7 2318-2328
• 16 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
• 17 Harada H, Harada Y, Tanaka H et al.. Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia.  Blood. 2003;  101 673-680
• 18 Imai Y, Kurokawa M, Izutsu K et al.. Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis.  Blood. 2000;  96 3154-3160
• 19 Michaud J, Wu F, Osato M et al.. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis.  Blood. 2002;  99 1364-1372
• 20 Okuda T, van Deursen J, Hiebert S W et al.. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis.  Cell. 1996;  84 321-330
• 21 Wang Q, Stacy T, Binder M et al.. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis.  Proc Natl Acad Sci USA. 1996;  93 3444-3449
• 22 Chang A N, Cantor A B, Fujiwara Y et al.. GATA-factor dependence of the multitype zinc-finger protein FOG-1 for its essential role in megakaryopoiesis.  Proc Natl Acad Sci USA. 2002;  99 9237-9242
• 23 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
• 24 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. 2002;  11 147-152
• 25 Mehaffey M G, Newton A L, Gandhi M J et al.. X-linked thrombocytopenia caused by a novel mutation of GATA-1.  Blood. 2001;  98 2681-2688
• 26 Nichols K E, Crispino J D, Poncz M et al.. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1.  Nat Genet. 2000;  24 266-270
• 27 Balduini C L, Pecci A, Loffredo G et al.. Effects of R216Q mutation of GATA-1 on erythropoiesis and platelet production.  Thromb Haemost. 2004;  91 129-140
• 28 Yu C, Niakan K K, Matsushita M et al.. X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction.  Blood. 2002;  100 2040-2045
• 29 McDevitt M A, Shivdasani R A, Fujiwara Y et al.. A “knockdown” mutation created by cis-element gene targeting reveals the dependence of erythroid cell maturation on the level of transcription factor GATA-1.  Proc Natl Acad Sci USA. 1997;  94 6781-6785
• 30 Vyas P, Ault K, Jackson C W et al.. Consequences of GATA-1 deficiency in megakaryocytes and platelets.  Blood. 1999;  93 2867-2875
• 31 Breton-Gorius J, Favier R, Guichard J et al.. A new congenital dysmegakaryopoietic thrombocytopenia (Paris-Trousseau) associated with giant platelet alpha-granules and chromosome 11 deletion at 11q23.  Blood. 1995;  85 1805-1814
• 32 Penny L A, Dell’Aquila M, Jones M C et al.. Clinical and molecular characterization of patients with distal 11q deletions.  Am J Hum Genet. 1995;  56 676-683
• 33 Gangarossa S, Mattina T, Romano V et al.. Micromegakaryocytes in a patient with partial deletion of the long arm of chromosome 11 [del(11)(q24.2qter)] and chronic thrombocytopenic purpura.  Am J Med Genet. 1996;  62 120-123
• 34 Krishnamurti L, Neglia J P, Nagarajan R et al.. Paris-Trousseau syndrome platelets in a child with Jacobsen’s syndrome.  Am J Hematol. 2001;  66 295-299
• 35 Bartel F O, Higuchi T, Spyropoulos D D. Mouse models in the study of the Ets family of transcription factors.  Oncogene. 2000;  19 6443-6454
• 36 Eisbacher M, Holmes M L, Newton A et al.. Protein-protein interaction between Fli-1 and GATA-1 mediates synergistic expression of megakaryocyte-specific genes through cooperative DNA binding.  Mol Cell Biol. 2003;  23 3427-3441
• 37 Iolascon A, Perrotta S, Amendola G et al.. Familial dominant thrombocytopenia: clinical, biologic, and molecular studies.  Pediatr Res. 1999;  46 548-552
• 38 Savoia A, Del Vecchio M, Totaro A et al.. An autosomal dominant thrombocytopenia gene maps to chromosomal region 10p.  Am J Hum Genet. 1999;  65 1401-1405
• 39 Drachman J G, Jarvik G P, Mehaffey M G. Autosomal dominant thrombocytopenia: incomplete megakaryocyte differentiation and linkage to human chromosome 10.  Blood. 2000;  96 118-125
• 40 Gandhi M J, Cummings C L, Drachman J G. FLJ14813 missense mutation: a candidate for autosomal dominant thrombocytopenia on human chromosome 10.  Hum Hered. 2003;  55 66-70
• 41 Von Behrens W E. Mediterranean macrothrombocytopenia.  Blood. 1975;  46 199-208
• 42 Najean Y, Lecompte T. Genetic thrombocytopenia with autosomal dominant transmission: a review of 54 cases.  Br J Haematol. 1990;  74 203-208
• 43 Fabris F, Cordiano I, Salvan F et al.. Chronic isolated macrothrombocytopenia with autosomal dominant transmission: a morphological and qualitative platelet disorder.  Eur J Haematol. 1997;  58 40-45
• 44 Savoia A, Balduini C L, Savino M et al.. Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome.  Blood. 2001;  97 1330-1335
• 45 Fabris F, Fagioli F, Basso G, Girolami A. Autosomal dominant macrothrombocytopenia with ineffective thrombopoiesis.  Haematologica. 2002;  87 ELT27
• 46 Hartwig J, Italiano J R. The birth of the platelet.  J Thromb Haemost. 2003;  1 1580-1586
• 47 Ware J W, Ruggeri Z M. Platelet receptors: von Willebrand factor. In: Gresele P, Page CP, Fuster V, Vermylen J Platelets Cambridge, UK; Cambridge University Press 2002: 179-187
• 48 Jackson S P, Nesbitt W S, Kulkurni S. Signaling events underlying thrombus formation.  J Thromb Haemost. 2003;  1 1602-1612
• 49 Lopez J A, Andrews R K, Afshar-Kharghan V, Berndt M C. Bernard-Soulier syndrome.  Blood. 1998;  91 4397-4418
• 50 Bernard J. History of congenital hemorrhagic thrombocytopathic dystrophy.  Blood Cells. 1983;  9 179-193
• 51 White J G, Burris S M, Tukey D, Smith C, Clawson C C. Micropipette aspiration of human platelets: influence of microtubules and actin filaments on deformability.  Blood. 1984;  64 210-214
• 52 Nurden A T, Combriè R, Claeyssens S, Nurden P. Heterozygotes in the Bernard-Soulier syndrome do not necessarily have giant platelets or thrombocytopenia.  Br J Haematol. 2003;  120 716-719
• 53 Ware J, Russell S, Ruggeri Z M. Generation and rescue of a murine model of platelet dysfunction: the Bernard-Soulier syndrome.  Proc Natl Acad Sci USA. 2000;  97 2803-2808
• 54 Berg S B, Powell B C, Cheney R E. A millennial myosin census.  Mol Biol Cell. 2001;  12 780-794
• 55 Leala A, Endelea S, Stengela C et al.. A novel myosin heavy chain gene in human chromosome 19q13.3  Gene. 2003;  312 165-171
• 56 Maupin P, Phillips C L, Adelstein R S, Pollard T D. Differential localization of myosin-II isozymes in human cultured cells and blood cells.  J Cell Sci. 1994;  107 3077-3090
• 57 Mansfield P J, Shayman J A, Boxer L A. Regulation of polymorphonuclear leukocyte phagocytosis by myosin light chain kinase after activation of mitogen-activated protein kinase.  Blood. 2000;  95 2407-2412
• 58 Seri M, Pecci A, Di Bari F et al.. MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness.  Medicine. 2003;  82 203-215
• 59 Pecci A, Noris P, Invernizzi R et al.. Immunocytochemistry for the heavy chain of the non-muscle myosin IIA as a diagnostic tool for MYH9-related disorders.  Br J Haematol. 2002;  117 164-167
• 60 Hu A, Wang F, Sellers J R. Mutations in human nonmuscle myosin IIA found in patients with May-Hegglin anomaly and Fechtner syndrome result in impaired enzymatic function.  J Biol Chem. 2002;  277 46512-46517
• 61 Deutsch S, Rideau A, Bochaton-Piallat M et al.. Asp1424Asn MYH9 mutation results in an unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome.  Blood. 2003;  102 529-534
• 62 Kunishima S, Matsushita T, Kojima T et al.. Nonmuscle myosin heavy chain-A in MYH9 disorders: Association of subcellular localization with MYH9 mutations.  Lab Invest. 2003;  83 115-122
• 63 Ghiggeri G M, Caridi G, Magrini U et al.. Genetics, clinical and pathological features of glomerulonephritis associated with mutations of non-muscle myosin IIA (Fechtner syndrome).  Am J Kidney Dis. 2003;  41 95-104
• 64 Kunishima S, Heaton D C, Naoe T et al.. De novo mutation of the platelet glycoprotein Ib alpha gene in a patient with pseudo-von Willebrand disease.  Blood Coagul Fibrinolysis. 1997;  8 311-315
• 65 Nurden P, Chretien F, Poujol C et al.. Platelet ultrastructural abnormalities in three patients with type 2B von Willebrand disease.  Br J Haematol. 2000;  110 704-714
• 66 Snapper S B, Rosen F S. A family of WASPs.  N Engl J Med. 2003;  348 350-351
• 67 Haddad E, Cramer E, Riviere C et al.. The thrombocytopenia of Wiskott Aldrich syndrome is not related to a defect in proplatelet formation.  Blood. 1999;  94 509-518
• 68 Kajiwara M, Nonoyama S, Eguchi M et al.. WASP is involved in proliferation and differentiation of human haemopoietic progenitors in vitro.  Br J Haematol. 1999;  107 254-262
• 69 Zhang J, Shehabeldin A, Cruz L A et al.. Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes.  J Exp Med. 1999;  190 1329-1342
• 70 Schmitt A, Jouault H, Drouin A et al.. Pathological interaction between megakaryocytes and PMN leukocytes in myelofibrosis.  Blood. 2000;  96 1342-1347
• 71 Jantunen E, Hanninen A, Naukkarinen A, Vornanen M, Lahtinen R. Gray platelet syndrome with splenomegaly and signs of extramedullary hematopoiesis: a case report with review of the literature.  Am J Hematol. 1994;  46 218-224
• 72 Falik-Zaccai T C, Anikster Y, Rivera C E et al.. A new genetic isolate of gray platelet syndrome (GPS): clinical, cellular, and hematologic characteristics.  Mol Genet Metab. 2001;  74 303-313
• 73 Kohler M, Hellstern P, Morgenstern E et al.. Gray platelet syndrome: selective alpha-granules deficiency and thrombocytopenia due to increased platelet turnover.  Blut. 1985;  50 331-340
• 74 Pestina T I, Jackson C W, Stenberg P E. Abnormal subcellular distribution of myosin and talin in Wistar Furth rat platelets.  Blood. 1995;  85 2436-2446
• 75 Lacombe M, d’Angelo G. Etudes sur une thrombopathie familiale.  Nouv Rev Fr Hematol. 1963;  3 611-614
• 76 Okita J R, Frojmovic M M, Kristopet S, Wong T, Kunicki T J. Montreal platelet syndrome: a defect in calcium-activated neutral proteinase (calpain).  Blood. 1989;  74 715-721