Inherited Platelet Disorders: An Updated Overview

Abstract

Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 1011 platelet per day as well as appropriate survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either platelet count or platelet functions, comprise a heterogenous group of about sixty rare diseases caused by molecular anomalies in many culprit genes. Their clinical relevance is highly variable according to the specific disease and even within the same type, ranging from almost negligible to life-threatening. Mucocutaneous bleeding diathesis (epistaxis, gum bleeding, purpura, menorrhagia), but also multisystemic disorders and/or malignancy comprise the clinical spectrum of IPDs. The early and accurate diagnosis of IPDs and a close patient medical follow-up is of great importance. A genotype–phenotype relationship in many IPDs makes a molecular diagnosis especially relevant to proper clinical management. Genetic diagnosis of IPDs has been greatly facilitated by the introduction of high throughput sequencing (HTS) techniques into mainstream investigation practice in these diseases. However, there are still unsolved ethical concerns on general genetic investigations. Patients should be informed and comprehend the potential implications of their genetic analysis. Unlike the progress in diagnosis, there have been no major advances in the clinical management of IPDs. Educational and preventive measures, few hemostatic drugs, platelet transfusions, thrombopoietin receptor agonists, and in life-threatening IPDs, allogeneic hematopoietic stem cell transplantation are therapeutic possibilities. Gene therapy may be a future option. Regular follow-up by a specialized hematology service with multidisciplinary support especially for syndromic IPDs is mandatory.

Assessment of a complete and classified platelet proteome from genome-wide transcripts of human platelets and megakaryocytes covering platelet functions

“…To further establish the coverage for platelet-related disorders, we extracted the databases Online Mendelian Inheritance in Man (OMIM) 34 and Bloodomics 23 in combination with a recent overview paper 35 for genes associated with bleeding, thrombocythemia or thrombophilia. This resulted in 138 genes, of which 9 were absent in the platelet transcriptome but present in the proteome (coagulation factor and other plasma proteins), and 5 were absent in both (Table 4 ).…”

“… Listed are per platelet function class genes expressed in the (non)identified platelet proteome, which according to recent OMIM, Bloodomics and overviews 23 , 34 , 35 in man contribute to bleeding, thrombocytopenia or thrombophilia. Coding as follows.…”

Megakaryopoiesis and Platelet Biology: Roles of Transcription Factors and Emerging Clinical Implications

“…By investigating congenital thrombocytopenia, more than 30 genes have been implicated in megakaryopoiesis and platelet biogenesis [67]. Among them, seven genes, including RUNX1, GATA1, FLI1, GFI1B, MECOM, ETV6, and NFE2, are transcription factors [68][69][70]. During megakaryopoiesis, transcription factors are activated in a stepwise manner, and thus, different mutations induce different disease characteristics.…”

Screening platelet function in blood donors

“…Unlike severe platelet defects that often occur early in life, some less severe disorders that cause only minor bleeding symptoms may persist undetected 2 . As a result, potential blood donors may be unaware of a moderate platelet disorder, especially if they have not experienced a traumatic injury or undergone surgery.…”

“…1 Unlike severe platelet defects that often occur early in life, some less severe disorders that cause only minor bleeding symptoms may persist undetected. 2 As a result, potential blood donors may be unaware of a moderate platelet disorder, especially if they have not experienced a traumatic injury or undergone surgery. Although the clinical consequences of defective platelets in transfusion recipients remain unknown, platelet function defects may play a role in the hemostasis ineffectiveness of some platelet concentrates.…”