ORIGINAL ARTICLE Rare bleeding disorders Natural history of platelet antibody formation against aIIbb3 in a French cohort of Glanzmann thrombasthenia patients M. FIORE,* N. FIRAH,  X. PILLOIS,* P. NURDEN,* R. HEILIG à and A. T. NURDEN* *Centre de Re ´fe ´rence des Pathologies Plaquettaires (CRPP), Plateforme Technologique d’Innovation Biome ´dicale, Ho ˆ pital Xavier Arnozan, Pessac;  Ho ˆ pital des Enfants - Ho ˆ pital Pellegrin – CHU Bordeaux, Unite ´ d’He ´matologie Pe ´diatrique, Bordeaux; and àGenoscope, Centre National de Se ´quenc ¸age, 91000, Evry, France Summary. Treatment of the bleeding syndrome in Glanz- mann thrombasthenia (GT) is often complicated by naturally occurring isoantibodies directed against the aIIbb3 integrin that cause the removal of or render ineffective transfused donor platelets. Such antibodies are produced after transfusion or pregnancy when the patient’s immune system comes into contact with normal platelets. Despite many reports of anti-aIIbb3 antibodies in GT patients, there is no consensus pertaining to their frequency, their long-term evolution in the circulation, or their formation in relation to either (i) the extent of the aIIbb3 deficiency in the patient’s platelets or (ii) the nature of the genetic defect (ITGA2B or ITGB3 genes). Antibody screening was performed on a large series of 24 GT patients in South-West France dividing the patients into two cohorts: (i) 16 patients with the French gypsy mutation (c.1544 + 1G>A) within ITGA2B that gives platelets totally lacking aIIbb3 and (ii) 8 patients carrying other defects of ITGA2B or ITGB3 with different expression levels of aIIbb3. Our results confirm that patients with premature termination mutations resulting in platelets lacking aIIbb3 are the most susceptible to form isoantibodies, a finding that may be useful in deciding the choice of therapy between platelet transfu- sion and the use of recombinant factor VIIa (FVIIa). Keywords: isoimmunization, platelet antibody, rFVIIa, thrombasthenia, aIIbb3 Introduction Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder caused by inherited defects of the genes encoding the platelet integrin, aIIbb3 [1,2]. The disease is characterized by a lack of platelet aggregation in response to all physiological stimuli. GT has been classified into three subtypes, platelets of types I and II show quantitative abnormalities, with aIIbb3 either absent or in trace amounts (<5%, type I) or at levels varying from 5% to 20% of those of normal donors (type II). Variant GT is given by qualitative abnormalities preventing function but allowing reduced or even normal surface expression of aIIbb3 in platelets. Generally, in GT, bleeding is largely mucocutaneous in nature and if minor, local measures, sometimes in conjunction with anti-fibrinolytics, are sufficient; in contrast, platelet transfusions or recombinant factor VIIa are used to control or to prevent life-threatening blood loss [3–5]. Platelet transfusion therapy in GT can be followed by an immune response that is usually directed against the deficient aIIbb3 (isoimmunization) and/or against MHC-Class I molecules (alloimmunization) [6–9]. Immune-mediated foetal thrombocytopenia can also occur in rare cases where a mother with GT bears a child whose platelets express aIIbb3 [10,11]. The presence of anti-aIIbb3 antibodies is a crucial problem for the management of GT patients [12,13]. However, it remains unclear how frequently they occur, whether they are persistent or indeed why the complication develops in some but not all transfused patients. Previous detailed characterizations of isoantibodies from GT patients show that they recognize epitopes located on aIIbb3 or b3 and that some can block platelet function as well as cause platelet elimination [14–16]. Although the epidemiology of neutralizing antibodies (inhibitors) is well known in patients with haemophilia A [17], it has been relatively poorly studied in GT. Little is known of the risk factors associated with antibody production although a direct relation between their formation and the type of GT has been suggested [18]. While the development of antibodies in GT patients is a result of transfusion therapy in most cases, the degree of exposure to platelet concentrates or red Correspondence: Mathieu Fiore, CRPP, Laboratoire d’he ´matolo- gie, Ho ˆ pital Cardiologique, 33604 Pessac, France. Tel.: +33 55 710 2850; fax: +33 55 710 2864; e-mail: mathieu.fiore@chu-bordeaux.fr Accepted after revision 13 December 2011 Haemophilia (2012), 18, e201–e209 DOI: 10.1111/j.1365-2516.2011.02744.x Ó 2012 Blackwell Publishing Ltd e201