Summary

The integrin α IIbß 3 is the major fibrinogen receptor on the plateletmembrane and plays a crucial role for platelet aggregation.The ß 3-subunit carries the human platelet alloantigen (HPA)-1 a,which is the main target for alloantibodies (alloabs) responsiblefor foetal and neonatal alloimmune thrombocytopenia (FNAIT)and post-transfusion purpura (PTP).Whereas PTP is almost invariablyassociated with severe bleeding, the clinical presentationof FNAIT ranges from mild thrombocytopenia to severehaemorrhagic diathesis. However, this clinical heterogeneity isnot fully understood as it is not explained solely by the variabilityof the platelet count. Here, we examined the ability ofHPA-1 a alloabs from mothers with FNAIT (n = 43) and PTP patients(n = 8) to inhibit cell adhesion to fibrinogen and asked ifthis inhibition was correlated with the heterogeneity of the clinicalpicture. Stably transfected cells expressing HPA-1 a( ß 3-Leu33) and – 1 b (ß 3-Pro33) isoforms were incubated with sera containing HPA- 1 a alloabs and were allowed to adhere toimmobilised fibrinogen.The inhibitory activity was measured aspercentage of cell adhesion in the presence of patient sera versusnormalAB serum.Only two FNAIT sera specifically inhibitedthe adhesion of HPA-1 a, but not HPA-1 b cells.Two other FNAITsera blocked the adhesion of HPA-1 a as well as HPA- 1 b cells. Interestingly,all four neonates with inhibitory HPA- 1 a alloabs (9%of all sera) suffered severe bleeding. In comparison, the majorityof PTP sera (75%) inhibited cell binding to fibrinogen, four PTPsera selectively inhibited the adhesion of HPA-1 a cells whilst 2sera impaired the binding of both allotypes.Our observations indicatethat 1) HPA-1 a alloabs are heterogeneous in their abilityto interfere with fibrinogen binding, and 2) inhibition of thea IIbß 3 fibrinogen receptor by HPA-1 a alloabs may contribute topronounced bleeding in patients with alloimmune thrombocytopenia.