Page 24 - 2021_02-Haematologica-web

P. Nurden et al.
Table 1. Principal named inherited platelet function disorders with a normal platelet count
Disease - name - OMIM
Glanzmann thrombasthenia 273800
RASGRP2- (CalDAG-GEFI)- RD
615888
Leukocyte adhesion deficiency-III (LAD-III syndrome) 612840
Scott syndrome 262890
EPHB2-RD 618462
Gene
- transmission - protein
ITGA2B/ ITGB3
AR (biallelic) αIIbβ3 integrin
RASGRP2
AR (biallelic) CalDAG-GEFI
FERMT3
AR (biallelic) Kindlin-3
ANO6 (TREM16F)
AR (biallelic)
Anoctamin-6
EPHB2
AR (biallelic) EPHB2
Platelets - count
- volume - granules
N/N/N
N/N/N
N/N/N Leukocytosis
N/N/N
N/some elongated platelets/N
N/N/N
N/N/N
N/N/N
N/N/defect of dense granules
Isolated or syndromic - bleeding severity
Isolated
Major bleeding
Isolated
Major bleeding syndrome
Syndromic with severe infections Osteopetrosis (inconstant) Major bleeding
Isolated Bleeding after surgery
Isolated Spontaneous bleeding and after lesions
Isolated Bleeding can be severe. For AD disease bleeding frequently mild
Isolated Bleeding absent or mild.
Isolated Post-surgery bleeding
Syndromic
OCA HPS1-10 -Pulmonary fibrosis and granulomatous colitis, HPS1,4 -Immunodeficiency and neutropenia, HPS2,10
-Mild or severe bleeding syndrome HPS1-10
Mild bleeding Multi-syndromic OCA, recurrent infections, immune dysregulation with lymphoproliferative histiocytosis
Isolated
Moderate bleeding Recurrent GI ulceration
Principal platelet function defects
Absence of platelet aggregation with all agonists. Positive response to ristocetin
Clot retraction often defective
Reduced or absent aggregation Positive response to ristocetin Normal response with PMA
Absence of platelet aggregation with all agonists
Positive response to ristocetin. Defective white cell functions
Defective platelet-derived thrombin formation
Defect of microvesiculation
Defective platelet response to collagen, ADP, AA and TXA2 analogs
ADP reversible aggregation even at high doses. Response reduced
with collagen, AA; reversible. with TRAP. Defective VASP de-phosphorylation after ADP stimulation
Absence of response with collagen, Cvx or CRP.
Decreased binding of fibrin and other ligands
Absence of response to AA
and TXA analogs. 2
Defect of aggregation to ADP, collagen, AA
Defect of secretion whatever the agonist used Decreased or absence of dense granules
Defect of CD63
Defect of aggregation to ADP, collagen, AA
Defect of secretion whatever the agonist
Decrease or absence of dense granules
Defect of platelet response to AA, collagen, and absence of second wave with ADP
Biology
Defects of the αIIbβ3 integrin: Type 1: <5%
Type 2: 5% -20%
Variant: >20% but non functional No binding of Fg
Normal presence but defective activation of αIIbβ3.
Normal presence of αIIbβ3. Defect of β1, β2 and β3 activation
Lack of Ca2+-dependent translocation of PS to the surface of platelets and red cells
Ref
12-22
25-28
29-34
35-42
P2Y12receptor-RD P2RY12
Defect of Giα-coupled P2Y12 receptor linked to adenylate cyclase and PI3-kinase activation
Lack or nonfunctioning of GPVI in complex with FcRγ. Impaired signaling through a pathway involving PLCγ2
Defective TPα-coupled signaling via Gq-protein; signaling pathway involves PLCβ
Platelet storage pool disease affecting dense granules member of the lysosomal-related organelle family. Gene defects manifested via altered function of BLOC1-3 and AP-3 complexes during organelle biogenesis
44-53
54-59
60-64
67-73
Tyrosine phosphorylation of intermediates 43 involved in GPVI and G-protein-coupled receptor mediating signaling
609821 AD
GPVI-RD 614201
TBXA2 receptor- RD 614009
Hermansky- Pudlak syndrome (HPS): 10 subtypes OMIM: HPS1:203300 HPS2:608233
HPS3: 614072 HPS4: 614073 HPS5: 614074 HPS6: 614075 HPS7: 614076 HPS8: 614077 HPS9: 614171 HPS10: 617050
Chediak-Higashi syndrome (CHS) 214500
Cytosolic phospholipase A2- syndrome 600522
AR (biallelic) P2Y12
GP6
AR (biallelic) GPVI
TBXA2R
10 Genes according subtypes HPS1,3,4,5,6 encoded for HPS1,3,4,5,6
HPS2 for AP3B1 HPS7 for Dysbindin HPS8 for BLOS3 HPS9 for Pallidin HPS10 for AP3D1
LYST
AR (biallelic) LYST
PLA2G4A
AR (biallelic) cPLA2
AD
TPα
AR (biallelic)
N/N/defect of dense granules
N/N/N
Lysosomal storage disorder affecting platelet dense (d) granules, member of the lysosomal-related organelle family. LYST is a member of the BEACH protein family
Signaling pathway defect Impaired liberation of AA from membrane phospholipids
67,69,74
84-86
continued on the next page
338
haematologica | 2021; 106(2)