Covid Alert


Print ISSN:-2394-6784

Online ISSN:-2394-6792

CODEN : IJPOF3

Current Issue

Year 2020

Volume: 7 , Issue: 2

  • Article highlights
  • Article tables
  • Article images

Article Access statistics

Viewed: 106

Emailed: 0

PDF Downloaded: 74


Jamal: Clinico-hematological profile of inherited macrothrombocytopenia


Introduction

Platelets derived from megakaryocytes are involved in primary hemostasis.1 Macrothrombocytopenia is defined as reduced platelet count (less than 1.5 lacs/cumm) with significant increase in platelet size (more than 12fl).2 It can be acquired or inherited with acquired cases comprising the majority. Inherited macrothrombocytopenia (IMTP) are rare clinical conditions showing an increasing trend of occurrence affecting 2.7 per 1 lac individuals with mild to absent bleeding manifestations.3 Indian population especially the eastern and north eastern side are more prone to suffer from such conditions.4

Materials and Methods

A Pubmed search of articles with keywords like macrothrombocytopenia, asymptomatic macrothrombocytopenia, syndromic macrothrombocytopenia, platelet disorders was done from January 2000 to October 2019. Reviewed articles provided additional references. Recent reviews in high impact journals and those decibing Indian population were given extra weightage. Out of total 210 articles, 58 articles were shortlisted and read.

In IMTP more than 12 genes have been found to be involved. These genetic mutations can be further categorised according to their mode of inheritance like autosomal dominant (AD), autosomal recessive (AR) and X-linked.

Autosomal dominant IMTP

Most common gene involved is Myosin heavy chain 9 (MYH9) gene leading to premature release of platelets from bone marrow causing macrothrombocytopenia and cytoplasmic inclusions in leucocytes.5 MYH9 gene was discovered back in 1909.6 May and Hegglin discovered an AD IMTP known as May -Hegglin anomaly (MHA) that decribes a triad of thrombocytopenia, giant platelets and leucocyte inclusion bodies.7 This syndrome occurs due to deletion in region 11 of the long arm of chromosome 22. Other syndromes like MHA, Epstein syndrome, Fechtner syndrome and Sebastian syndrome are also associated with MYH9 gene.8

Di George syndrome

This syndrome manifests due to deletion in region 11 of long arm of chromosome 22 in which platelet count is decreased, Mean platelet volume (MPV) is increased and there is reduced expression of platelet surface GP1b/IXb required for platelet adhesion.9, 10

Autosomal recessive IMPTs

Bernard Soulier syndrome (BSS)

It was discovered by Bernard and Soulier as inherited bleeding disorder associated with platelet dysfunction.11 There is absent to decreased expression of Von Willebrand factor (VWF) on platelets resulting in platelet dysfuctioning in the form of defective platelet adhesion. VWF receptors are GP1b-α, GP1b-β, GPV and GP IX.12

Gray platelet syndrome

It occurs due to inability of megakaryocytes to pack endogenously synthesized secretory proteins into developing α granules. As a result granules deficient platelet is decreased leading to thrombocytopenia.

X linked IMPT

It occurs due to mutations in GATA1 and ACTN1 genes. The GATA1 gene is responsible for megakaryocyte and erythroid development. Due to this mutation there is interference with the association of GATA1 with teanscriptional factor FOG1.13, 14, 15

ACTN1 mutation interferes with platelet and megakaryocyte cytoskeleton organisation.

Other less common mutations are TPM4, PRKACG, FLNA etc.16, 17, 18, 19, 20 Many other mutations are still unknown which prevents proper diagnosis and treatment.

Clinical features

Majority of the patients are either symptomatic or have minor bleeding symptoms. In most cases it is just an incidental discovery. In other IMTPs association with other phenotypic abnormalities contribute to early diagnosis.

Diagnsotic modalities

  1. Investigations should start with detailed bleeding history, family history, past history, drug and nutritional history.

  2. Complete hemogram including MPV, Platelet distribution width (PDW) should be included.

  3. Immature platelet fraction, platelet scatter plot and platelet histogram should be taken into account.

  4. Peripheral smear examination to confirm thrombocytopenia and presence of megathrombocytes.

  5. Platelet function studies.

  6. Flow cytometry to detect lack of GP1B/IX.

  7. SDS PAGE for diagnosis BSS, GPS and other X linked IMPTs.

  8. Electron microscopy, DNA analysis and Next generation sequencing.

Ali et al. reported over 112 cases of macrothrombocytopenia having low platelet counts, high MPV and showed presence of giant platelets without any inclusion bodies in peripheral smear.21

Kakkar et al. detected macrothrombocytopenia in 75 patients having MPV ranging from 10.9 to 23.3.22

Naina et al. screened 203 blood donors to analyse platelet and RBC indices. Among 101 donors were form northern India and rest from Southern India. A significant difference was observed between platelet count among northern and southern population.23

Conclusion

IMTPs are not uncommon conditions but their subtle manifestations and lack of specialised diagnostic tools have led to under reporting of such disorders. Not much is known about its exact prevalence in India. Limited studies from India have shown increased frequency in Bengali and Kashmiri population. There is a real need of exploring its prevalence in different parts of India. A major challenge is diagnosing asymptomatic IMPTs and these should be differentiated from Immune thrombocytopenia as treatment modality of both these diverse group is different.

Source of Funding

None.

Conflict of Interest

None.

References

1 

S R Patel J H Hartwig J E Italiano The biogenesis of platelets from megakaryocyte proplateletsJ Clin Invest2005115334854

2 

S Kunushima H Saito Congenital macrothrombocytopeniasBlood Rev20062011121

3 

Guy Young Naomi Luban James G. White Giant Platelet Disorders in African-American Children Misdiagnosed as Idiopathic Thrombocytopenic PurpuraJ Pediatr Hematol/Oncol19992132316

4 

A Pecci P Noris C L Balduini Inherited thrombocytopeniasHämostaseol2012320425970

5 

Majed J. Dasouki Syed K. Rafi Adam J. Olm-Shipman Nathan R. Wilson Sunil Abhyankar Brigitte Ganter Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemiaBlood20131222034409

6 

Kim E. Nichols John D. Crispino Mortimer Poncz James G. White Stuart H. Orkin John M. Maris Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1Nat Genet200024326670

7 

Channing Yu Kathy K. Niakan Mark Matsushita George Stamatoyannopoulos Stuart H. Orkin Wendy H. Raskind X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interactionBlood2002100620405

8 

Adam Hart Fabrice Melet Paul Grossfeld Kenneth Chien Christopher Jones Alan Tunnacliffe Fli-1 Is Required for Murine Vascular and Megakaryocytic Development and Is Hemizygously Deleted in Patients with ThrombocytopeniaImmun200013216777

9 

L Noetzli R W Lo A B Lee-Sherick Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemiaNat Genet2015475358

10 

M Djaldetti D Creter Y Bujanover E Elian Ultrastructural and functional studies of the platelets in patients with May-Hegglin anomalyHaematologica1982675308

11 

W. S. Stevenson M.-C. Morel-Kopp Q. Chen H. P. Liang C. J. Bromhead S. Wright GFI1Bmutation causes a bleeding disorder with abnormal platelet functionJ Thromb Haemost20131111203947

12 

Jennifer L. Richardson Ramesh A. Shivdasani Chad Boers John H. Hartwig Joseph E. Italiano Mechanisms of organelle transport and capture along proplatelets during platelet productionBlood200510613406675

13 

J E Italiano S Patel-Hett J H Hartwig Mechanics of proplatelet elaborationJ Thromb Haemost 200751823

14 

M Seri R Cusano S Gangarossa The May-Hegglin/Fechtner Syndrome Consortium. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromesNat Genet2000261035

15 

S Kunishima Y Okuno K Yoshida ACTN1 mutations cause congenital macrothrombocytopeniaAm J Hum Genet2013924318

16 

P Nurden N Debili I Coupry Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndromeBlood2011118592837

17 

Shinji Kunishima Ryoji Kobayashi Tomohiko J. Itoh Motohiro Hamaguchi Hidehiko Saito Mutation of the β1-tubulin gene associated with congenital macrothrombocytopenia affecting microtubule assemblyBlood2009113245861

18 

S Stritt P Nurden E Turro A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing lossBlood2016127290314

19 

Karen E. Heath Angel Campos-Barros Amos Toren Galit Rozenfeld-Granot Lena E. Carlsson Judy Savige Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromesAm J Human Genet2001695103345

20 

Karina Althaus Andreas Greinacher MYH-9 related platelet disorders: strategies for management and diagnosisTransfus Med Hemother20103752607

21 

Shahnaz Ali Shrimati Shetty Kanjaksha Ghosh Bengal macrothrombocytopenia is not totally an innocuous conditionBlood Cells Mol Dis20166036

22 

Naveen Kakkar M. Joseph John Amrith Mathew Macrothrombocytopenia in North India: Role of Automated Platelet Data in the Detection of an Under Diagnosed EntityIndian J Hematol Blood Transfus2015311617

23 

H V K Naina S C Nair S Harris G Woodfield M I Rees Harris syndrome - a geographic perspectiveJ Thromb Haemost200531125812



jats-html.xsl

© 2020 Published by Innovative Publication Creative Commons Attribution - NonCommercial 4.0 International (CC BY-NC 4.0) license (creativecommons.org)