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.

Keywords: congenital platelet disorders; inherited thrombocytopenias; platelet function disorders.

Figure 1

Inherited Platelet Disorders. The image shows the myriad of IPDs according to the protein and/or platelet function element which is affected by the genetic anomaly.

Figure 2

Diagnostic approach for inherited thrombocytopenias. N: Normal; XLT: X-Linked thrombocytopenia; CYCS-RT: CYCS-related thrombocytopenia (thrombocytopenia type 4); FYB-RT: FYB-related thrombocytopenia (adap-related thrombocytopenia); PTPRJ-RT: Thrombocytopenia due to variants affecting the phosphatase CD148; CAMT: Congenital amegakaryocytic thrombocytopenia (associated to a severe bone marrow aplasia ); THPO-RT: thrombocytopenia due to mutations in THPO encoding thrombopoietin; FPD-AML: Familial platelet disorder with propensity to acute myelogenous leukemia; ANKRD26-RT: Thrombocytopenia due to variants affecting ankyrin repeat domain 26; ETV6-RT: Thrombocytopenia due to variants in the transcription factor ETV6; IKZF5-RT: Thrombocytopenia due to variants in the transcription factor IKZF5; MYH9-RD: Disorders related to variants in MYH9 (neutrophil inclusions, deafness, kidney disease, cataracts); mSBS: monoalellic Bernard-Soulier syndrome (Mediterranean macrothrombocytopenia); PT-VWD: Platelet type von Willebrand disease; ITGA2B/ITGB3-RT: Thrombocytopenia due to variants in ITGA2B/ITGB3; GATA1-RD:GATA1–related disorders (commonly associated to red cells anomalies); GPS: Gray platelet syndrome (myelofibrosis); FLI1-RT: Thrombocytopenia due to variants in the transcription factor FLI1; GFI1-RT: Thrombocytopenia due to variants in GFI1B (abnormal CD34 expression in platelets); FLNA-RT: Thrombocytopenia with filaminopathy (syndromic or only thrombocytopenia); TUBB1-RT; Thrombocytopenia due to variants affecting tubulin b1; ACTN1-RT: Thrombocytopenia due to variants affecting Actinin-1; SLFN14-RT: SLFN14-Related thrombocytopenia; TPM4-RT: Thrombocytopenia due to variants in tropomyosin 4; TRPM7-RT: Thrombocytopenia related with the ionic channel TRPM7; G6b-B: Thrombocytopenia due to variants affecting the immunoreceptor G6b-B (myelofibrosis); WAS: Wiskott-Aldrich syndrome (eczema and severe infections; ARCP1B-RT: Mycrothrombocytopenia linked to a ARCPB; TAR: Thrombocytopenia with absent radii; RUSAT: Radioulnar synostosis with amegakaryocytic thrombocytopenia; SKS: Stormorken syndrome; KDSR-RT: Thrombocytopenia with variable hyperkeratosis due to variants affecting 3-dehydrosphinganine reductase; DIAPH1-RT: Thrombocytopenia associated to dominant deafness and variants in DIAPH1; PT-JS: Paris-Trousseau/Jacobsen syndrome; VCF-DiGeorge syndromes: velocardiofacial/DiGeorge syndrome; SIST: sistosterolemia (elevated plasma levels of plant sterols); SRC: Thrombocytopenia associated to gain-of-function variant in tyrosine kinase SRC; BSS: Bernard-Soulier syndrome; CDC42-RT: CDC42-related thrombocytopenia (Takenouchi-Kosaki syndrome); GNE-RT: GNE-related thrombocytopenia; GALE-RT: GALE-related thrombocytopenia (galactosemia); SLC35A1-RT: Syndromic thrombocytopenia due to variants affecting the CMP-sialic acid transporter; ACTB-RT: Thrombocytopenia due to variants affecting actin beta; * Disorders with high risk of hematological malignancy.

Figure 3

Diagnostic approach for suspected cases of inherited platelet function disorders. BSS: Bernard-Soulier Syndrome; GPS: Gray Platelet Syndrome; GT: Glanzmann thrombasthenia; STD: Signaling transmission defect (deficiencies in enzymes, G-proteins, CalDAG-GEF1, other signaling proteins); Specific defects in platelet receptors P2Y12 (ADP), Tpa (TxA2) or glycoprotein VI (GPVI) (collagen); SS: Scott Syndrome; HPS: Hermansky-Pudlak Syndrome; CHS: Chediak-Higashi Syndrome; QS: Quebec Syndrome. EM: electron microscopy; LTA: light transmission aggregometry; U46619:TxA2 analog; CRP: collagen-related peptide; Figure 2: Figure 2.