Platelet Granules Â•• Secretory and Secretive

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Platelet granules – secretory and secretive

Kerstin Jurk Center for Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany

Keywords Schlüsselwörter δ-granules, which are highly electron dense platelets, secretory granules, storage pool Thrombozyten, sekretorische Granula, (▶ Fig. 1) secrete ADP, ATP, polyphos- 2+ 2+ disease Storage-Pool-Erkrankung phates, Ca and Mg cations, serotonin and histamine, thereby amplifying platelet Summary Zusammenfassung aggregation and platelet-dependent coagu- The article reviews three recent publications Der Beitrag gibt eine Übersicht über drei lation. addressing physiological and pathological aktuelle Publikationen zu physiologischen Activated platelets release distinct acid aspects of platelet granules and release as und pathologischen Aspekten von Thrombo - glycohydrolases, cathepsins and heparinase well as limitations of recent screening tests zyten- Granula und -Freisetzung sowie den Li - from lysosomes, which contribute to extra- for diagnosis of non-syndromic inherited mita tionen der Screening-Tests zur Diagnose cellular matrix degradation and cell mi- δ-storage pool disease (1-3). von nicht-syndromalen erblichen δ-Storage- gration. Pool-Erkrankungen (1-3). Platelet α-granules are most abundant (▶ Fig. 1) and packed with multifunctional proteins and peptides, synthesised in Korrespondenzadresse Plättchen-Granula – sekretorisch und geheimnis- megakaryocytes or endocytosed from plas- PD Dr. rer. nat. Kerstin Jurk voll ma. In addition to adhesion proteins such Center for Thrombosis and Hemostasis (CTH) Hämostaseologie 2017; 37: 208–210 University Medical Center Mainz https://doi.org/10.5482/HAMO-16-07-0023 as fibrinogen and von Willebrand factor, Langenbeckstr. 1, 55131 Mainz, Germany received: July 15, 2016 α-granules contain factors with supporting E-Mail: [email protected] accepted in revised form: September 7, 2016 or inhibiting functions of coagulation, fi- epub ahead of print: September 21, 2016 brinolysis and angiogenesis.

There is increasing evidence that α-gra - In response to injury activated platelets to moderate bleeding diathesis, which nules are not equal, but rather hetero - release a bulk of proteins and small bio- may occur as life-threatening compli- geneous in cargo packing and / or secretion molecules from the storage pool of differ- cations upon surgery or trauma. Platelet kinetics. ent granules in a coordinated manner. storage pool diseases (SPD) are characte- Fusion of granule membranes with the rised by defects of granule secretion or Recently, Crescente and co-workers identi- plasma membrane and membrane of the by defects of granule biogenesis, e. g. fied a potential novel granule-independent surface-connected or open canalicular sys- decreased / absent numbers or content of release mechanism of the thiol isomerases tem (OCS) leads to secretion of granule α-granules (α-SPD), δ-granules (δ-SPD) or protein disulphide isomerase (PDI) and cargos, which facilitate platelet aggregation both (α-δ-SPD). endoplasmic reticulum protein 57 (ERp57) and platelet-based coagulation, thereby (1). In resting platelets, PDI and ERp57

contributing crucially to haemostatic plug They can present as isolated or syndromic represent important endoplasmic reticular This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. and thrombus formation. forms, i. e. in association with other disease chaperones and are important surface- Beside their role in haemostasis and manifestations, with normal or altered pla- located regulators of platelet activation. thrombosis, secreted granule contents con- telet count and volume (4–6). The authors of this study demonstrated tribute to wound healing, immune res- that PDI and ERp57 are mobilised to the ponse and inflammation and they are in- surface of activated platelets through a volved in pathologic processes of Platelet granules and dense tubular membrane system near the • arteriosclerosis, release – update needed inner surface of the plasma membrane in • infection, an actin-polymerisation-dependent but • cancer and Classically, three prominent granule types secretory-membrane-fusion-independent • metastasis (4). are described in platelets: manner. • α-granules, This study suggests a new model of dif- Inherited or acquired platelet granule dis- • δ-granules and ferent platelet compartments that enable orders are frequently associated with mild • lysosomes. protein release onto the platelet surface: On

the one hand, secretory proteins are packed and small platelets without any type of into granules when megakaryocytes form granules and lacking internal membranes pro-platelets. On the other hand, distinct is not typical for classical GPS. It remains proteins from megakaryocytic endoplas- exciting to see which further genes, so far mic reticulum move to developing mem- not known or expected to be involved in branes of the dense tubular system and lo- megakaryopoiesis, will regulate α-granule calise adjacent to the surface membrane of biogenesis. forming platelets.

However, the molecular mechanisms of dif- Non-syndromic forms of ferential protein trafficking need to be inherited δ-platelet- further characterised to classify new platelet granule types and subtypes as well as granule defects – often other platelet release compartments. missed by routine Fig. 1 Thin-section transmission electron image screening tests of a human platelet. Platelets from a healthy donor were prepared at the Center for Thrombosis In contrast to the syndromic Hermansky- Inherited disorders of and Hemostasis in Mainz and analysed by trans- Pudlak or Chediak-Higashi syndromes, α-platelet -granule mission electron microscopy in M. Schaller’s core facility, University Department of Dermatology in isolated inherited platelet δ-granule dis- formation = Grey platelet Tübingen. Abundant α-granules are coloured in orders are much more common than syndrome? brown. Sparser δ-granules are indicated as δ. appreciated. The analyses of stained blood Lysosomes are not detected. OCS: surface- smears and light transmission aggrego- Originally, grey platelet syndrome (GPS) connected or open canalicular system. Scale bar metry (LTA) are recommended as first-step has been identified as autosomal recessive 1 µm. tests for diagnosis of SPD and are available inherited disorder of α-granule biogen- in most clinical centres. esis caused by mutations in NBEAL2 However, δ-granule defects cannot be coding for the vesicle trafficking relevant nia, myelofibrosis and bone pathologies detected by examination of blood smears. neurobeachin-like 2 (NBEAL-2) protein with facial dysmorphism and premature In case of suspected δ-SPD, impaired sec- (7). Platelets from patients with GPS are edentulism. ondary wave aggregation in response to enlarged and appear “grey” in blood Using genome sequencing and human epinephrine and ADP and reduced col- smears due to α-granule deficiency. In ad- phenotype ontology, the authors identified lagen response are expected but not always dition to the bleeding tendency, myelofi- a E527K substitution of SRC that causes in- present. Indeed, LTA may not be sensitive brosis and splenomegaly are frequently creased SRC activity leading to enhanced for δ-SPD and therefore complex analyses associated with GPS. However, distinct overall tyrosine phosphorylation especially of platelet granule secretion is still necess- mutations in the transcription factor in patients’ megakaryocytes and platelets. ary (9), but usually restricted to specialised genes growth-factor-independence-1b SRC is involved in platelet signalling path- centres. (GFI1B) and GATA1 are also known to ways mediated by cause platelet α-granule deficiency as- • integrins αIIbβ3 and α2β1, In addition to platelet phenotyping, next- sociated with large platelets, but with • Gq-coupled thrombin protease-acti- generation sequencing is recommended to autosomal dominant and X-linked in- vated receptors 1 and 4, complement the diagnosis of inherited heritance, respectively (8). • Gi-coupled ADP receptor P2Y12 and plate let function and number disorders.

Based on the increasing use of high • von Willebrand factor receptor GPIbα. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. throughput sequencing to identify further The ThromboGenomics Consortium pub- novel genes involved in α-granule biogen- The study showed that the E527K variant lished recently that targeted high through- esis, the question arises whether GPS is of SRC results in defective pro-platelet put sequencing of 63 genes involved in caused by different gene defects of α-gran- formation and more immature megakaryo- bleeding, thrombotic and platelet disorders ules. A recent study by E. Turro and co- cytes. In addition, E527K-transduced is a sensitive genomic approach to validate workers nicely demonstrated that a gain- megakaryocytes presented with altered pathogenic variants in patients with sus- of-function mutation in the proto-onco- organisation of the actin cytoskeleton, pected aetiology, such as gene tyrosine-protein-kinase-SRC-gene which might contribute to the α-granule • Glanzmann thrombasthenia, causes a GPS-like disorder but not classical defect. Although patients’ platelets showed • May-Hegglin disorder or GPS (2). The authors studied a three-gen- a GPS-like phenotype (e. g. α-granule pau- • syndromic platelet δ-granule defects, eration pedigree including 9 affected city, decreased α-granule storage pool, e. g. Hermansky-Pudlak syndrome (3). members with a dominant inheritance of abundant OCS-like vacuoles and dysfunc- bleeding associated with thrombocytope- tion), the presence of both unusually large

In contrast, pathogenic variants in patients Conflict of interest 4. Golebiewska EM, Poole AW. Platelet secretion: From haemostasis to wound healing and beyond. with bleeding diathesis, but with uncertain Blood Rev 2015; 29: 153–162. aetiology based on normal coagulation or The author declares that there is no conflict 5. Nurden AT, Nurden P. Inherited disorders of pla- platelet function tests and those with ab- of interest. telet function: selected updates. J Thromb Hae- normal platelet function tests indicating most 2015; 13 Suppl 1: S2–9. 6. Sandrock-Lang K, Wentzell R, Santoso S et al. In- SPD, were not frequently detected. One herited platelet disorders. Hämostaseologie 2016; pathogenic variant in TUBB1 as well as in References 36: 178–186. MYH9 and two cases with mutations in 1. Crescente M, Pluthero FG, Li L et al. Intracellular 7. Gunay-Aygun M, Falik-Zaccai TC, Vilboux T et al. RUNX1 could be detected in this group of trafficking, localization, and mobilization of pla- NBEAL2 is mutated in gray platelet syndrome and telet-borne thiol isomerases. Arterioscler Thromb is required for biogenesis of platelet alpha-gran- 62 unrelated patients with unclear bleed- Vasc Biol 2016; 36: 1164–1173. ules. Nat Genet 2011; 43: 732–734. ing disorder. This sequencing platform 2. Turro E, Greene D, Wijgaerts A et al. A dominant 8. Daly ME. Transcription factor defects causing pla- targets 36 platelet disorder-related genes, gain-of-function mutation in universal tyrosine telet disorders. Blood Rev 2016. In press. but only a few genes, which are known to kinase SRC causes thrombocytopenia, myelofibro- 9. Gresele P, Subcommittee on Platelet Physiology of sis, bleeding, and bone pathologies. Sci Transl Med the International Society on Thrombosis and He- be associated with non-syndromic pla- 2016; 8: 328ra330. mostasis. Diagnosis of inherited platelet function telet-granule secretion defects, such as 3. Simeoni I, Stephens JC, Hu F et al. A high- disorders: guidance from the SSC of the ISTH. NBEA, RUNX1 and FLI1 (10), were in- throughput sequencing test for diagnosing in- J Thromb Haemost 2015; 13: 314–322. cluded. This targeted sequencing study herited bleeding, thrombotic, and platelet dis- 10. Stockley J, Morgan NV, Bem D et al. Enrichment orders. Blood 2016; 127: 2791–2803. of FLI1 and RUNX1 mutations in families with ex- demonstrates its current limitation for di- cessive bleeding and platelet dense granule secre- agnosis of isolated δ-SPD. tion defects. Blood 2013; 122: 4090–4093.

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