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Inherited platelet function disorders
continued from the previuos page
Disease - Name - OMIM
Aspirin-like syndrome
AR (biallelic
and monoallelic) 176805
Ghosal syndrome 231095
Gene
- Transmission - Protein
PTGS1
ADorAR COX-1
TBXAS1
AR(biallelic) Thromboxane synthetase
Platelets - count
- volume - granules
N/N/N
N/N/N
Isolated or syndromic -bleeding severity
Isolated Aspirin-like Mild bleeding
Osteopetrosis Mild bleeding
Principle platelet function defects
Defect of platelet response to AA, collagen, no second wave with ADP Normal response to TXA2 agonists
Defect of platelet response to AA, collagen and no second wave with ADP
Normal response to TXA2 agonists
Biology Ref
Signaling pathway defect Defect of conversion of AA into prostaglandin
87-89
Signaling pathway defect due to absent 90 thromboxane synthesis
OMIM: Online Mendelian Inheritance in Man: Ref: references; RD: related disease; AR: autosomal recessive; AD: autosomal dominant; N: normal; Fg: fibrinogen; CalDAG-GEFI: calcium and diacyl- glycerol-regulated guanine nucleotide exchange factor I; PMA: phorbol 12-myristate 13-acetate; PS: phosphatidylserine; ADP: adenine disphosphate; AA: arachidonic acid; VASP: vasodilator stimu- latedphosphoprotein; PI3-kinase:phosphoinositide3-kinase;Cvx:convulxin;CRP:collagen-relatedpeptide;PLCγ2:phospholipaseCγ2;TXA2:thromboxaneA2;TPα:thromboxanereceptorα;PLCβ: phospholipase Cβ; OCA: oculocutaneous albinism; BLOC1-3: biogenesis of lysosome-related organelles complex 1-3; GI: gastrointestinal; PLA2: phospholipase-A2; Cox-1: cyclooxygenase-1
this was accompanied by the emergence of a new catego- ry of powerful anti-ischemic drugs.13,14
Definition
Classically, GT is a severe bleeding diathesis with auto- somal recessive transmission caused by an absence of platelet aggregation induced by all physiologic agonists.
Clinical phenotype
The clinical phenotype is marked by life-long sponta- neous easy bruising, epistaxis and gum bleeding, often requiring platelet transfusions. Gastro-intestinal hemor- rhage, menorrhagia and severe bleeding at menarche fea- ture prominently, as does trauma-related hemorrhage. The first signs usually appear at birth, are intense during childhood but tend to decrease in later life. GT is prevalent in ethnic communities.15
Biological phenotype
Patients have a normal platelet count and morphology. Most have platelets lacking αIIbβ3 although some express residual amounts but insufficient to support platelet aggre- gation: these have been termed type I and type II throm- basthenia.12 A third category consists of phenotypic vari- ants in which platelets have reduced to normal amounts of αIIbβ3 unable to function. While type I GT patients pos- sess platelets that fail to promote clot retraction, this can be subnormal or normal for some with residual or variant αIIbβ3. Platelets respond to ristocetin and adhere to subendothelial matrix components under flow yet fail to spread; intriguingly they can attach to fibrin. If bleeding first occurs late in life, care must be taken to exclude acquired GT, which often has an immune origin.16 The severity of bleeding in GT is independent of the subtype.
Genotype
Several hundred GT patients and their families have undergone gene sequencing.12,17,18 Mutations extend across both ITGA2B and ITGB3 and include missense mutations, stop codons, small deletions, inserts or duplications, splice defects often with frame-shifts. In classic GT, defects pre- vent or greatly limit the passage of the affected subunit (and the pro-αIIbβ3 precursor) across the endoplasmic reticulum and the Golgi apparatus. The absence or incorrect confor- mation of one subunit results in the destruction of both the
mutated and the unused normal subunit in maturing megakaryocytes. An exception is the ability of β3 to com- plex with αv, forming αvβ3, which is present in small amounts in platelets but is a major integrin of endothelial and other cells. For both ITGA2B and ITGB3 defects the bleeding phenotype predominates and the absence of αvβ3 does not lead to major additive defects. Large gene dele- tions are rare.17 Recent haplotype analysis suggests that the mutational landscape of GT is constantly renewing.19
Missense mutations in domains such as the terminal β- propeller of αIIb and in the βI (or βA) region of β3 have helped to identify interfaces where αIIb and β3 are in con- tact (Figure 1).19 Rare non-synonymous missense substitu- tions such as the classic p.D145N/Y and p.R240Q/W sub- stitutions permit αIIbβ3 expression and give rise to variant GT in which the integrin fails to function (Figure 1). These have been vital to the identification of key residues within the metal ion-dependent adhesion site (MIDAS) and adja- cent domains of β3 that are essential for Ca2+ and ligand binding.12,13,18 Variant GT can also involve intracellular domains abrogating “inside-out” signaling linked to inte- grin activation; these include the p.S778P and p.R750ter mutations in β3.18 Resting αIIbβ3 has a bent configuration; on platelet activation; conformational changes emanating from the cytoplasmic domains promote exposure of the ligand-binding epitopes and lead to its extension.20,21 Fibrinogen is the principal ligand for aggregation although other adhesive proteins can participate. Occupied αIIbβ3 undergoes further conformational changes, including clus- tering, providing “outside-in” signaling pathways essential for thrombus consolidation, platelet spreading and clot retraction.13 Variants within the cytoplasmic domains of αIIb or β3 interfere with the binding of talin and kindlin-3 during early αIIbβ3 activation.12 Rare gain-of-function monoallelic variants in cytoplasmic and membrane proxi- mal domains promote spontaneous conformational changes that result in macrothrombocytopenia, as detailed in our companion paper.11 Significantly, recent data obtained by next-generation sequencing have begun to reveal combinations of variants in different genes that modify the GT phenotype.22
Target for anti-platelet therapy
Because of the importance of αIIbβ3 in the formation of arterial thrombi, a generation of antiplatelet drugs block-
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