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.
Highlights
Inherited platelet disorders (IPD) comprise a heterogenous group of rare diseases caused by molecular anomalies in genes that are relevant in platelet formation and/or function
A recent survey of the frequency in the general population of molecular variants in genes associated with platelet disorders, has revealed that about 3 in 1000 subjects have a clinically meaningful loss-of-function variant in genes involved in IPDs [3]
Accurate molecular diagnosis of IPD undoubtedly facilitates clinical management, in the serious, potentially fatal types, in which genotype is related to prognosis and severity of hematological and/or extra-hematological disease, such as congenital amegakaryocytic thrombocytopenia (CAMT), familial platelet disorder with predisposition to hematological malignancies (FPD/acute myeloblastic leukemia (AML)), MYH9-RD, WiskottAldrich syndrome (WAS), Hermansky-Pudlak syndrome (HPS) or Chediak-Higashi Syndrome (CHS) [8,26]
Summary
Severe thrombocytopenia ( the platelet count may be normal at birth). Moderate to severe thrombocytopenia and giant platelets. Moderate to severe thrombocytopenia with typically grayish platelets. Mild thrombocytopenia (occasionally normal platelet counts); moderate fluctuating neutropenia with low to moderate infectious risk; early sensorineural deafness. Inh: inheritance; AD: autosomal dominant; AR: autosomal recessive; XL: chromosome X-linked; Tcp: IT with mainly isolated thrombocytopenia; S: IT associated with other syndromes or additional diseases; HM:IT predisposing to hematological malignancies and/or solid neoplasm; HSCT: Allogeneic hematopoietic stem cell transplantation. Absent or severely reduced LTA with all agonists (ADP, TxA2, collagen, thrombin). Normal platelet morphology δ and α -granule defect by electron microscopy. Reduced LTA and/or absence of second aggregation wave with weak/low dose agonists (ADP, epinephrine, collagen). Reduced LTA and/or absence of second wave with weak/low dose agonists (ADP, epinephrine, collagen). In this review we will update the general approach to diagnosis of IPD, comment on some IPD that we deem most important given their relative frequency and/or clinical repercussions, and, we will briefly mention management of and treatment options for these diseases
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