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P. Nurden et al.
ing αIIbβ3 function was developed some 20 years ago.13 The main drugs are abciximab, a humanized Fab fragment of the murine monoclonal antibody 7E3 (c7E3), integrilin, a KGD-based cyclic heptapeptide and tirofiban a synthetic non-peptide inhibitor; all are given intravenously.13,23 These inhibitors have basically been used in acute coro- nary syndromes. While the associated bleeding risk has now restricted their use, they are still recommended for bailout in shunt thrombosis or as a bridge to supplement platelet inhibition by orally taken drugs such as anti- P2Y12 inhibitors.24
RASGRP2-(CalDAG-GEFI)-related disease
In 2014 a missense mutation (p.G248W) in RASGRP2 coding for calcium and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) was reported for siblings with a severe bleeding disorder and much reduced platelet aggregation despite normal αIIbβ3 lev- els.25 Since this report, a characteristic GT-like defect of platelet function has been confirmed worldwide for 23 cases, as recently reviewed by Canault and Alessi.26
Definition
Gene variants of RASGRP2 represent a new autosomal recessive inherited bleeding disorder linked to major defects of platelet signaling resulting in impaired αIIbβ3 activation (Figure 2). CalDAG-GEFI activates Rap1, which initiates “inside-out” signaling for αIIbβ3 promoting the binding of talin to shift the integrin into its high-affinity state.27 Both mouse and human platelets lacking functional CalDAG-GEFI undergo a slow but sustained activation that supports the formation of small thrombi at low shear
such as those found in the venous system but not the large thrombi characteristic of arterial blood flow.
Clinical phenotype
Bleeding manifestations start early in life and can be severe. Epistaxis is common and most patients have other cutaneous bleeds. Gastrointestinal bleeding has been reported in four patients and menorrhagia in seven out of nine women.26 The bleeding diathesis is not truly syn- dromic; CalDAG-GEFI is found in other blood cell lineag- es, vascular cells and the brain striatum and has been implicated in Huntington disease.26 It often occurs in eth- nic groups. One case, a male of Jamaican origin, success- fully underwent surgery for a brain tumor under recombi- nant activated factor VII administration despite inefficacy of platelet transfusions.28
Biological phenotype and genetics
A critical characteristic is that residual platelet aggrega- tion and elevation of Ca2+ level, which is key for CalDAG- GEFI activity, is retained for high doses of some physio- logical agonists.26 Furthermore, αIIbβ3 fails to activate normally with decreased binding of the PAC1 IgM mono- clonal antibody. Phorbol 12-myristate 13-acetate (PMA) activates Rap1 independently of surface receptors and CalDAG-GEFI and PMA-induced platelet aggregation is a diagnostic test for this disease. Interestingly, platelet spreading on a collagen surface is much decreased and while platelets attach to fibrinogen, lamellipodia are not formed. In the profile of RASGRP2 variants updated by Canault & Alessi in 2020,26 12 of the 23 families had a pre- mature stop codon or frameshift mutations while the oth- ers possessed missense mutations in functional domains important for CaLDAG-GEFI activity.
Figure 1. Integrin αIIbβ3 and Glanzmann thrombasthenia. The model illustrates the bent resting mature integrin and shows the many interactions between αIIb (green) and β3 (violet). Much information has been obtained from variant forms (noted in blue) that block functional sites in the extracellular and cytoplasmic domains while allowing αIIbβ3 expression. Other rare mutations (in red) give rise to activated integrin. Full information on mutations giving rise to Glanzmann throm- basthenia is found in Nurden & Pillois.18 Fg: fibrinogen; GT: Glanzmann thrombasthenia.
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haematologica | 2021; 106(2)