Summary
The integrin αIIbβ3 is the major fibrinogen receptor on the platelet membrane and
plays a crucial role for platelet aggregation. The β3-subunit carries the human platelet
alloantigen (HPA)-1a, which is the main target for alloantibodies (alloabs) responsible
for foetal and neonatal alloimmune thrombocytopenia (FNAIT) and post-transfusion purpura
(PTP).Whereas PTP is almost invariably associated with severe bleeding, the clinical
presentation of FNAIT ranges from mild thrombocytopenia to severe haemorrhagic diathesis.
However, this clinical heterogeneity is not fully understood as it is not explained
solely by the variability of the platelet count. Here, we examined the ability of
HPA-1a alloabs from mothers with FNAIT (n = 43) and PTP patients (n = 8) to inhibit
cell adhesion to fibrinogen and asked if this inhibition was correlated with the heterogeneity
of the clinical picture. Stably transfected cells expressing HPA-1a (β3-Leu33) and
–1b (β3-Pro33) isoforms were incubated with sera containing HPA-1a alloabs and were
allowed to adhere to immobilised fibrinogen. The inhibitory activity was measured
as percentage of cell adhesion in the presence of patient sera versus normalAB serum.
Only two FNAIT sera specifically inhibited the adhesion of HPA-1a, but not HPA-1b
cells. Two other FNAIT sera blocked the adhesion of HPA-1a as well as HPA-1b cells.
Interestingly, all four neonates with inhibitory HPA-1a alloabs (9% of all sera) suffered
severe bleeding. In comparison, the majority of PTP sera (75%) inhibited cell binding
to fibrinogen, four PTP sera selectively inhibited the adhesion of HPA-1a cells whilst
2 sera impaired the binding of both allotypes. Our observations indicate that 1) HPA-1a
alloabs are heterogeneous in their ability to interfere with fibrinogen binding, and
2) inhibition of the αIIbβ3 fibrinogen receptor by HPA-1a alloabs may contribute to
pronounced bleeding in patients with alloimmune thrombocytopenia.
Keywords
HPA-1a - alloimmune thrombocytopenia - integrin αIIbβ3
