Diagnostic workup of inherited platelet disorders

Bohyun Kim

doi:10.5045/br.2022.2021223

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Blood Res 2022; 57(S1):

Published online April 30, 2022

https://doi.org/10.5045/br.2022.2021223

Diagnostic workup of inherited platelet disorders

Bohyun Kim

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Department of Laboratory Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea

Correspondence to : Bohyun Kim, M.D., Ph.D.
Department of Laboratory Medicine, Soonchunhyang University Cheonan Hospital, 31, Soonchunhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
E-mail: bhkim@schmc.ac.kr

Received: December 27, 2021; Revised: January 17, 2022; Accepted: January 27, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Inherited platelet disorders (IPDs) can cause mucocutaneous bleeding due to impaired primary hemostatic function of platelets, thrombocytopenia, or both. Recent advances in molecular technology can help identify many genes related to platelet biology, control the overall steps of megakaryopoiesis, and cause IPD. In this article, currently available laboratory tools for diagnosing IPDs with the characteristic laboratory features of each IPD are reviewed, and a general diagnostic approach for the evaluation of IPD patients is presented.

Keywords Inherited platelet disorder, Platelet function tests, Thrombocytopenia, Bernard-Soulier syndrome, MYH9, Gray platelet syndrome, Glanzmann thrombasthenia

Article

Review Article

Blood Res 2022; 57(S1): S11-S19

Published online April 30, 2022 https://doi.org/10.5045/br.2022.2021223

Diagnostic workup of inherited platelet disorders

Bohyun Kim

Department of Laboratory Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea

Correspondence to:Bohyun Kim, M.D., Ph.D.
Department of Laboratory Medicine, Soonchunhyang University Cheonan Hospital, 31, Soonchunhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea
E-mail: bhkim@schmc.ac.kr

Received: December 27, 2021; Revised: January 17, 2022; Accepted: January 27, 2022

Abstract

Keywords: Inherited platelet disorder, Platelet function tests, Thrombocytopenia, Bernard-Soulier syndrome, MYH9, Gray platelet syndrome, Glanzmann thrombasthenia

Abstract

Fig 1.

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Figure 1.Characteristic peripheral blood smear findings in some inherited platelet disorder (IPDS). (A) Döhle like inclusion body in neutrophil and large-sized platelet (arrow) in MYH9-related disorder, one of the macrothrombocytopenic IPDS (Wright-Giemsa stain, ×1,000). (B) Platelet with the absence of normal cytoplasmic color (arrows) in gray platelet syndrome (GPS) (Wright-Giemsa stain, ×1,000) (adapted from [31]). (C, D) Transmission electron microscopy images of platelets from normal (C) and GPS patient (D) with marked deficiency of α-granule (×14,400) (adapted from [31]. (E) Characteristic neutrophilic granules in Chediak- Higashi syndrome (Wright-Giemsa stain, ×1,000) (adapted from [32]).

Blood Research 2022; 57: S11-S19https://doi.org/10.5045/br.2022.2021223

Fig 2.

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Figure 2.Results of light transmission aggregometry in various inherited platelet disorders. (A, B) Normal aggregation patterns to various platelet agonists. (C) Results in Bernard-Soulier syndrome. Note that absence of aggregation to ristocetin, but normal to others. (D) Results in Glanzmann thrombasthenia. Absent aggregation with all agonists except ristocetin. (E) and (F) Results in platelet-type von Willebrand disease. Normal aggregation to all agonists and aggregation also was observed even at low concentrations of ristocetin, which does not occur in normal specimens (adapted from [32]).

Blood Research 2022; 57: S11-S19https://doi.org/10.5045/br.2022.2021223

Fig 3.

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Figure 3.Platelet function pathway and biology related to each stage of megakaryopoiesis, and genes found to be associated with inherited platelet disorder (IPDs) (modified from [1, 7, 10]).
Abbreviations: HSC, hematopoietic stem cell; MK, megakaryocytes.

Blood Research 2022; 57: S11-S19https://doi.org/10.5045/br.2022.2021223

Fig 4.

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Figure 4.Diagnostic algorithm for inherited platelet disorders (modified from [4, 8, 9]).
Abbreviations: 22qDS, 22q deletion syndrome; Ag, antigen; ATRUS, amegakaryocytic thrombocytopenia with radioulnar synostosis; BSS, Bernard-Soulier syndrome; CAMT, congenital amegakaryocytic thrombocytopenia; CBC, complete blood count; FCM, flow cytometry; FPD/AML, familial platelet disorder with predisposition to acute myeloid leukemia; GP, glycoprotein; GPS, gray platelet syndrome; IPDS, inherited platelet disorder; LTA, light transmission aggregometry; MPV, mean platelet volume; P2Y12R, P2Y12 receptor deficiency; PB, peripheral blood; PT/J, Paris-Trousseau/Jacobsen syndrome; SPD, storage pool disease; TAR, thrombocytopenia with absent radii; TXA2R, thromboxane A2 receptor deficiency; vWD, von Willebrand disease; vWF, von Willebrand factor; WAS, Wiskott-Aldrich syndrome; XLT, X-linked thrombocytopenia.

Blood Research 2022; 57: S11-S19https://doi.org/10.5045/br.2022.2021223

Table 1 . Classification of inherited platelet disorders (modified from [8])..

Features	Platelet components with abnormalities	Disease
Abnormalities of the platelet receptors for adhesive proteins	GPIb-IX-V complex	Bernard-Soullier syndrome, platelet-type vWD
	GPIIb-IIIa (αIIbβ3)	Glanzmann thrombasthenia
	GPIa-IIa (α2β1)
	GPVI
Abnormalities of the platelet receptors for soluble agonists	P2Y12 receptor	P2Y12 receptor deficiency
	Thromboxane A2 receptor	Thromboxane A2 receptor deficiency
	α2-adrenergic receptor	Thromboxane A2 receptor deficiency
Abnormalities of the platelet granules	δ-granules	Nonsyndromic δ-storage pool deficiency, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, MPR4 deficiency, thrombocytopenia with absent radii syndrome, Wiskott-Aldrich syndrome
	α-granules	Gray platelet syndrome, Quebec platelet disorder, 11q terminal deletion disorder, White platelet syndrome, Medich platelet disorder, X-linked macrothrombocytopenia with thalassemia, arthrogryposis renal dysfunction, and cholestasis syndrome
	α- and δ-granules	α, δ-storage pool deficiency
Defects of signal transduction	Arachinodate/thromboxane A2 pathway
	GTP binding proteins
	Phospholipase C activation
	Transcription factors
	GPVI/FcRc signaling
	Leukocyte adhesion deficiency-III
Abnormalities of membrane phospholipids	Membrane phospholipids	Scott syndrome, Stormorken syndrome
Miscellaneous abnormalities of platelet function	Primary secretion defects
Miscellaneous abnormalities of platelet function	Others	Osteogenesis imperfecta, Ehlers-Danlos syndrome, Marfan syndrome, hexokinase deficiency, glucose-6-phosphate deficiency

Abbreviations: GP, glycoprotein; FcRc, Fc receptor; vWD, von Willebrand disease..

Table 2 . Clinical and laboratory characteristics of inherited platelet disorders (modified from [8])..

Disorder	Platelet count	Platelet size and morphology	Abnormalities in platelet function	Associated clinical phenotypes	Genes affected	Inheritance
Glanzmann thrombasthenia (GT)	Normal	Normal	Absent aggregation with all agonists except ristocetin	None	ITAG2B, ITGB3	AR
GPVI collagen receptor defect	Normal	Normal	Decreased response to collagen	None	GPVI	AR
P2Y12 ADP receptor defect	Normal	Normal	Small and rapidly reversible aggregation induced by ADP; impaired aggregation and secretion induced by other agonists	None	P2Y12	AR
TXA2 receptor defect	Normal	Normal	Absent response to TXA2; impaired aggregation and secretion induced by other agonists	None	TXA2R	AD
Chediak-Higashi syndrome (CHS)	Normal	Deficiency of δ-granules on EM	Impaired aggregation and secretion induced by several agonists	Albinism; eczema; recurrent infections; lymphohistiocytosis	LYST	AR
Hermansky-Pudlak syndrome (HPS)	Normal	Deficiency of δ-granules on EM	Impaired aggregation and secretion induced by several agonists	Albinism; pulmonary fibrosis; lysosomal storage disease	HPS1, HPS3, HPS4, HPS5, HPS6, BLOC1S3	AR
Scott syndrome	Normal	Normal	Normal	None	TMEM16F	AR
Bernard-Soulier syndrome (BSS)	Decreased	Large platelets	Absent aggregation with ristocetin, normal with other agonists	None	GPIBA, GPIBB, GPIX, ITGB3	AR
Gray platelet syndrome (GPS)	Decreased	Large, pale platelets with absence of α granules	Heterogeneity of response to agonists	Myelofibrosis, pulmonary fibrosis	NBEAL2	AR, AD
Wiskott-Aldrich syndrome (WAS)	Decreased	Small platelets; Deficiency of δ-granules on EM	Impaired aggregation and secretion induced by several agonists	Eczema; infections; immunodeficiency; autoimmune disease; malignancy	WAS	X-linked
Congenital amegakaryocytic thrombocytopenia (CAMT)	Decreased	Normal	Normal	Bone marrow failure	MPL	AR
Thrombocytopenia with absent radii (TAR)	Decreased	Normal	Normal	Decreased megakaryocytes, limb abnormalities	Y19	AR
Amegakaryocytic thrombocytopenia with radio-ulnar synostosis (ATRUS)	Decreased	Normal	Normal	Skeletal abnormalities, hearing loss	HOXA11	AD
Familial platelet disorder with predisposition to AML (FPD/AML)	Decreased	Normal	Normal	Myelodysplasia, AML	RUNX1	AD
Paris-Trousseau/Jacobsen syndrome (PT/J)	Decreased	Normal or large size with large granules	Normal	Pancytopenia, mental retardation, facial anomalies, cardiac anomalies	ETS1, FLT1	AD
GATA-1 mutation of X-linked thrombocytopenia with thalassemia	Decreased	Normal	Normal	Anemia	GATA1, FOG1	X-linked

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; EM, electron microscopy; GP, glycoprotein; TXA2, thromboxane A2; vWD, von Willebrand disease; vWF, von Willebrand factor..