Download PDF
Semin Thromb Hemost 2013; 39(02): 161-171
DOI: 10.1055/s-0032-1333540
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Diagnosis and Management of Inherited Thrombocytopenias

Carlo Luigi Balduini
1   Department of Internal Medicine, University of Pavia-IRCCS, Policlinico San Matteo Foundation, Pavia, Italy
,
Alessandro Pecci
1   Department of Internal Medicine, University of Pavia-IRCCS, Policlinico San Matteo Foundation, Pavia, Italy
,
Patrizia Noris
1   Department of Internal Medicine, University of Pavia-IRCCS, Policlinico San Matteo Foundation, Pavia, Italy
› Author Affiliations
Further Information

Publication History

Publication Date:
08 February 2013 (online)

    Permissions and Reprints

Abstract

The number of recognized causes of inherited thrombocytopenias has grown in the past 10 years and there are now more than 18 thrombocytopenic disorders with characterized genetic mutations. Moreover, the pathogenic mechanisms of many forms of inherited thrombocytopenia have been identified and prognosis of different disorders, ranging from unfavorable to very good, has been defined. In addition, for some inherited thrombocytopenias, therapies are now available to improve both survival and quality of life for persons with these conditions. Therefore, it is important to recognize when a low platelet count reflects an inherited disorder, and establish a correct diagnosis; however, this remains a challenge because documented evidences about these diseases are scarce. In this review, we address how to diagnose inherited thrombocytopenia, how to differentiate these conditions from immune thrombocytopenia, present a new and simple diagnostic algorithm, and discuss the different therapeutic options. We also emphasize that further research on these disorders is needed, as about half of patients with inherited thrombocytopenias have a disease that is not yet characterized.

Keywords

inherited thrombocytopenias - inherited disorders - differential diagnosis - immune thrombocytopenia
 

  • References

  • 1 Balduini CL, Savoia A. Genetics of familial forms of thrombocytopenia. Hum Genet 2012; 131 (12) 1821-1832
    CrossrefPubMedSearch in Google Scholar
  • 2 Seri M, Cusano R, Gangarossa S , et al. The May-Heggllin/Fechtner Syndrome Consortium. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. Nat Genet 2000; 26 (1) 103-105
    CrossrefPubMedSearch in Google Scholar
  • 3 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 (Baltimore) 2003; 82 (3) 203-215
    CrossrefPubMedSearch in Google Scholar
  • 4 Jackson SC, Sinclair GD, Cloutier S, Duan Z, Rand ML, Poon MC. The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation. Blood 2009; 113 (14) 3348-3351
    CrossrefPubMedSearch in Google Scholar
  • 5 Rees DC, Iolascon A, Carella M , et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol 2005; 130 (2) 297-309
    CrossrefPubMedSearch in Google Scholar
  • 6 Savoia A, Balduini CL, Savino M , et al. Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome. Blood 2001; 97 (5) 1330-1335
    CrossrefPubMedSearch in Google Scholar
  • 7 Noris P, Pecci A, Di Bari F , et al. Application of a diagnostic algorithm for inherited thrombocytopenias to 46 consecutive patients. Haematologica 2004; 89 (10) 1219-1225
    PubMedSearch in Google Scholar
  • 8 Biino G, Balduini CL, Casula L , et al. Analysis of 12,517 inhabitants of a Sardinian geographic isolate reveals that predispositions to thrombocytopenia and thrombocytosis are inherited traits. Haematologica 2011; 96 (1) 96-101
    CrossrefPubMedSearch in Google Scholar
  • 9 Biino G, Gasparini P, D'Adamo P , et al. Influence of age, sex and ethnicity on platelet count in five Italian geographic isolates: mild thrombocytopenia may be physiological. Br J Haematol 2012; 157 (3) 384-387
    CrossrefPubMedSearch in Google Scholar
  • 10 Santimone I, Di Castelnuovo A, De Curtis A , et al. MOLI-SANI Project Investigators. White blood cell count, sex and age are major determinants of heterogeneity of platelet indices in an adult general population: results from the MOLI-SANI project. Haematologica 2011; 96 (8) 1180-1188
    CrossrefPubMedSearch in Google Scholar
  • 11 Bader-Meunier B, Proulle V, Trichet C , et al. Misdiagnosis of chronic thrombocytopenia in childhood. J Pediatr Hematol Oncol 2003; 25 (7) 548-552
    CrossrefPubMedSearch in Google Scholar
  • 12 Geddis AE, Balduini CL. Diagnosis of immune thrombocytopenic purpura in children. Curr Opin Hematol 2007; 14 (5) 520-525
    CrossrefPubMedSearch in Google Scholar
  • 13 Balduini CL, Pecci A, Savoia A. Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. Br J Haematol 2011; 154 (2) 161-174
    CrossrefPubMedSearch in Google Scholar
  • 14 Notarangelo LD, Miao CH, Ochs HD. Wiskott-Aldrich syndrome. Curr Opin Hematol 2008; 15 (1) 30-36
    CrossrefPubMedSearch in Google Scholar
  • 15 Ciovacco WA, Raskind WH, Kacena MA. Human phenotypes associated with GATA-1 mutations. Gene 2008; 427 (1-2) 1-6
    CrossrefPubMedSearch in Google Scholar
  • 16 Balduini CL, Pecci A, Loffredo G , et al. Effects of the R216Q mutation of GATA-1 on erythropoiesis and megakaryocytopoiesis. Thromb Haemost 2004; 91 (1) 129-140
    PubMedSearch in Google Scholar
  • 17 Liew E, Owen C. Familial myelodysplastic syndromes: a review of the literature. Haematologica 2011; 96 (10) 1536-1542
    CrossrefPubMedSearch in Google Scholar
  • 18 Noris P, Perrotta S, Seri M , et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood 2011; 117 (24) 6673-6680
    CrossrefPubMedSearch in Google Scholar
  • 19 Albers CA, Paul DS, Schulze H , et al. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet 2012; 44 (4) 435-439 , S1–S2
    CrossrefPubMedSearch in Google Scholar
  • 20 Castillo-Caro P, Dhanraj S, Haut P, Robertson K, Dror Y, Sharathkumar AA. Proximal radio-ulnar synostosis with bone marrow failure syndrome in an infant without a HOXA11 mutation. J Pediatr Hematol Oncol 2010; 32 (6) 479-485
    CrossrefPubMedSearch in Google Scholar
  • 21 Pecci A, Biino G, Fierro T , et al. Italian Registry for MYH9-releated diseases. Alteration of liver enzymes is a feature of the MYH9-related disease syndrome. PLoS ONE 2012; 7 (4) e35986
    CrossrefPubMedSearch in Google Scholar
  • 22 Savoia A, De Rocco D, Panza E , et al. Heavy chain myosin 9-related disease (MYH9 -RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder. Thromb Haemost 2010; 103 (4) 826-832
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Noris P, Klersy C, Zecca M , et al. Platelet size distinguishes between inherited macrothrombocytopenias and immune thrombocytopenia. J Thromb Haemost 2009; 7 (12) 2131-2136
    CrossrefPubMedSearch in Google Scholar
  • 24 Balduini CL, Cattaneo M, Fabris F , et al. Italian Gruppo di Studio delle Piastrine. Inherited thrombocytopenias: a proposed diagnostic algorithm from the Italian Gruppo di Studio delle Piastrine. Haematologica 2003; 88 (5) 582-592
    PubMedSearch in Google Scholar
  • 25 Glembotsky AC, Marta RF, Pecci A , et al. International collaboration as a tool for diagnosis of patients with inherited thrombocytopenia in the setting of a developing country. J Thromb Haemost 2012; 10 (8) 1653-1661
    CrossrefPubMedSearch in Google Scholar
  • 26 Raccuglia G. Gray platelet syndrome. A variety of qualitative platelet disorder. Am J Med 1971; 51 (6) 818-828
    CrossrefPubMedSearch in Google Scholar
  • 27 Noris P, Spedini P, Belletti S, Magrini U, Balduini CL. Thrombocytopenia, giant platelets, and leukocyte inclusion bodies (May-Hegglin anomaly): clinical and laboratory findings. Am J Med 1998; 104 (4) 355-360
    CrossrefPubMedSearch in Google Scholar
  • 28 Othman M. Platelet-type von Willebrand disease: a rare, often misdiagnosed and underdiagnosed bleeding disorder. Semin Thromb Hemost 2011; 37 (5) 464-469
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Savoia A, Pastore A, De Rocco D , et al. Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations. Haematologica 2011; 96 (3) 417-423
    CrossrefPubMedSearch in Google Scholar
  • 30 Noris P, Perrotta S, Bottega R , et al. Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation). Haematologica 2012; 97 (1) 82-88
    CrossrefPubMedSearch in Google Scholar
  • 31 Nurden AT, Pillois X, Fiore M, Heilig R, Nurden P. Glanzmann thrombasthenia-like syndromes associated with Macrothrombocytopenias and mutations in the genes encoding the αIIbβ3 integrin. Semin Thromb Hemost 2011; 37 (6) 698-706
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Kunishima S, Kobayashi R, Itoh TJ, Hamaguchi M, Saito H. Mutation of the beta1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assembly. Blood 2009; 113 (2) 458-461
    PubMedSearch in Google Scholar
  • 33 Pecci A, Panza E, Pujol-Moix N , et al. Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease. Hum Mutat 2008; 29 (3) 409-417
    CrossrefPubMedSearch in Google Scholar
  • 34 George JN, Shattil SJ. The clinical importance of acquired abnormalities of platelet function. N Engl J Med 1991; 324 (1) 27-39
    CrossrefPubMedSearch in Google Scholar
  • 35 Heller PG, Pecci A, Glembotsky AC , et al. Unexplained recurrent venous thrombosis in a patient with MYH9-related disease. Platelets 2006; 17 (4) 274-275
    CrossrefPubMedSearch in Google Scholar
  • 36 Peaceman AM, Katz AR, Laville M. Bernard-Soulier syndrome complicating pregnancy: a case report. Obstet Gynecol 1989; 73 (3 Pt 2) 457-459
    PubMedSearch in Google Scholar
  • 37 Ballmaier M, Germeshausen M. Congenital amegakaryocytic thrombocytopenia: clinical presentation, diagnosis, and treatment. Semin Thromb Hemost 2011; 37 (6) 673-681
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 Moratto D, Giliani S, Bonfim C , et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. Blood 2011; 118 (6) 1675-1684
    CrossrefPubMedSearch in Google Scholar
  • 39 Locatelli F, Rossi G, Balduini C. Hematopoietic stem-cell transplantation for the Bernard-Soulier syndrome. Ann Intern Med 2003; 138 (1) 79
    PubMedSearch in Google Scholar
  • 40 Rieger C, Rank A, Fiegl M , et al. Allogeneic stem cell transplantation as a new treatment option for patients with severe Bernard-Soulier Syndrome. Thromb Haemost 2006; 95 (1) 190-191
    PubMedSearch in Google Scholar
  • 41 Kuter DJ. New thrombopoietic growth factors. Blood 2007; 109 (11) 4607-4616
    CrossrefPubMedSearch in Google Scholar
  • 42 Pecci A, Gresele P, Klersy C , et al. Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. Blood 2010; 116 (26) 5832-5837
    CrossrefPubMedSearch in Google Scholar
  • 43 Pecci A, Barozzi S, d'Amico S, Balduini CL. Short-term eltrombopag for surgical preparation of a patient with inherited thrombocytopenia deriving from MYH9 mutation. Thromb Haemost 2012; 107 (6) 1188-1189
    Thieme ConnectPubMedSearch in Google Scholar
  • 44 Kuter DJ, Mufti GJ, Bain BJ, Hasserjian RP, Davis W, Rutstein M. Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim. Blood 2009; 114 (18) 3748-3756
    CrossrefPubMedSearch in Google Scholar
  • 45 Léon C, Evert K, Dombrowski F , et al. Romiplostim administration shows reduced megakaryocyte response-capacity and increased myelofibrosis in a mouse model of MYH9-RD. Blood 2012; 119 (14) 3333-3341
    CrossrefPubMedSearch in Google Scholar
  • 46 Mullen CA, Anderson KD, Blaese RM. Splenectomy and/or bone marrow transplantation in the management of the Wiskott-Aldrich syndrome: long-term follow-up of 62 cases. Blood 1993; 82 (10) 2961-2966
    PubMedSearch in Google Scholar
  • 47 Albert MH, Bittner TC, Nonoyama S , et al. X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options. Blood 2010; 115 (16) 3231-3238
    CrossrefPubMedSearch in Google Scholar
  • 48 Conley ME, Saragoussi D, Notarangelo L, Etzioni A, Casanova JL. PAGID; ESID. An international study examining therapeutic options used in treatment of Wiskott-Aldrich syndrome. Clin Immunol 2003; 109 (3) 272-277
    CrossrefPubMedSearch in Google Scholar
  • 49 Balduini CL, Noris P, Belletti S, Spedini P, Gamba G. In vitro and in vivo effects of desmopressin on platelet function. Haematologica 1999; 84 (10) 891-896
    PubMedSearch in Google Scholar
  • 50 Tosetto A, Balduini CL, Cattaneo M , et al. Italian Society for Haemostasis and Thrombosis. Management of bleeding and of invasive procedures in patients with platelet disorders and/or thrombocytopenia: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2009; 124 (5) e13-e18
    CrossrefPubMedSearch in Google Scholar
  • 51 Mattina T, Perrotta CS, Grossfeld P. Jacobsen syndrome. Orphanet J Rare Dis 2009; 4: 9
    CrossrefPubMedSearch in Google Scholar
  • 52 Di Paola J, Johnson J. Thrombocytopenias due to gray platelet syndrome or THC2 mutations. Semin Thromb Hemost 2011; 37 (6) 690-697
    Thieme ConnectPubMedSearch in Google Scholar
  • 53 Hamilton A, Ozelo M, Leggo J , et al. Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study. Thromb Haemost 2011; 105 (3) 501-508
    Thieme ConnectPubMedSearch in Google Scholar
  • 54 Nurden P, Debili N, Coupry I , et al. Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome. Blood 2011; 118 (22) 5928-5937
    CrossrefPubMedSearch in Google Scholar
  • 55 Gresele P, Falcinelli E, Giannini S , et al. Dominant inheritance of a novel integrin beta3 mutation associated with a hereditary macrothrombocytopenia and platelet dysfunction in two Italian families. Haematologica 2009; 94 (5) 663-669
    CrossrefPubMedSearch in Google Scholar
  • 56 Geddis AE. Congenital amegakaryocytic thrombocytopenia. Pediatr Blood Cancer 2011; 57 (2) 199-203
    CrossrefPubMedSearch in Google Scholar
  • 57 Pippucci T, Savoia A, Perrotta S , et al. Mutations in the 5′ UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am J Hum Genet 2011; 88 (1) 115-120
    CrossrefPubMedSearch in Google Scholar
  • 58 Castillo-Caro P, Dhanraj S, Haut P, Robertson K, Dror Y, Sharathkumar AA. Proximal radio-ulnar synostosis with bone marrow failure syndrome in an infant without a HOXA11 mutation. J Pediatr Hematol Oncol 2010; 32 (6) 479-485
    CrossrefPubMedSearch in Google Scholar
  • 59 Morison IM, Cramer Bordé EM, Cheesman EJ , et al. A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nat Genet 2008; 40 (4) 387-389
    CrossrefPubMedSearch in Google Scholar