Should HLA and HPA-matched platelet transfusions for patients with Glanzmann Thrombasthenia or Bernard-Soulier syndrome be standardized care? A Dutch survey and recommendations.

BACKGROUND: Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) patients require frequent platelet transfusions and hence have an increased risk for alloimmunization against donor Human Leukocyte Antigens (HLA) when no HLA-matching is performed. Knowing that Human Platelet Antigens (HPA) are located on the platelet glycoproteins that can be absent in these patients, preventive HPA-matching may also be considered. Uniform recommendations on this topic lack in transfusion guidelines making standard practice unclear, therefore, we aimed to provide a framework for matched platelet transfusions. STUDY DESIGN AND METHODS: We conducted a targeted literature search and a national survey of Dutch (pediatric) hematologists from July to September 2021. RESULTS: We found 20 articles describing platelet transfusion policies in 483 GT-patients and 29 BSS-patients, both adults and children. Twenty surveys were returned for full analysis. All responders treated patients with platelet disorders, including GT (n = 36 reported) and BSS (n = 29 reported). Of respondents, 75% estimated the risk of antibody formation as "likely" for HLA and 65% for HPA. Formation of HLA antibodies was reported in 5 GT and in 5 BSS-patients, including one child. Fifteen respondents gave preventive HLA-matched platelets in elective setting (75%). Three respondents additionally matched for HPA in GT-patients (15%). Main argument for matched platelet transfusions was preventing alloimmunization to safeguard the effectivity of 'random' donor-platelets in acute settings. CONCLUSION: Elective HLA-matching for GT and BSS-patients is already conducted by most Dutch (pediatric) hematologists. HPA-matching is mainly applied when HPA-antibodies are formed. Based on the current literature and the survey, recommendations are proposed.

Transplant-associated thrombotic microangiopathy and immune haematological complications following intestine-containing organ transplantation: experience from over 100 consecutive cases.

Descriptions of passenger lymphocyte syndrome (PLS), immune cytopenias and transplant-associated thrombotic microangiopathy (TA-TMA) after intestine-containing transplants remain scarce. We describe our centre's experience of these complications from 2007 to 2019. Ninety-six patients received 103 transplants. PLS occurred in 9 (9%) patients (median 12 days post-transplant); all due to ABO antibodies. There were 31 minor ABO mismatch transplants. No patient required change in immunosuppression. Immune cytopenias (excluding PLS) occurred in six patients at an incidence of 1·7/100 patient years; three immune haemolysis, one immune thrombocytopenia, one acquired Glanzmann's and one immune neutropenia; 50% occurred with other cytopenias. All cases eventually responded to treatment, with a median of four treatments (range 1-8) and 5/6 were treated with rituximab. One patient with immune haemolysis required bortezomib. Complications were common in patients with immune cytopenias; 4/6 with infection needing intravenous antibiotics and 3/6 with venous thromboembolism. In 3/6 cases, a secondary cause for the immune cytopenia was evident. Switching from tacrolimus to ciclosporin was not necessary. There were five cases of transplant-associated thrombotic microangiopathy (TA-TMA; 1·5/100 patient years) requiring calcineurin inhibitor withdrawal; two cases associated with acute rejection. Two cases were managed with plasma exchange, one with plasma infusions and one with eculizumab. Further research in this patient group is required.

Naturally occurring point mutation Cys460Trp located in the I-EGF1 domain of integrin ß3 alters the binding of some anti-HPA-1a antibodies.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by the destruction of platelets in the fetus or newborn by maternal platelet alloantibodies, mostly against human platelet antigen (HPA)-1a. Recent studies indicate that two anti-HPA subtypes exist: Type I reacts with epitopes residing on the plexin-semaphorin-integrin (PSI) and type II with plexin-semaphorin-integrin/integrin epidermal growth factor 1 (I-EGF1) domains of the ß3 integrin. Here, we evaluated whether a Cys460Trp mutation in the I-EGF1 domain found in a patient with Glanzmann thrombasthenia can alter the binding of anti-HPA-1a. METHODS: Stable HEK293 cell lines expressing wild-type and mutant αIIbß3 and αvß3 were generated to prove the reactivity of different antibodies against HPA-1a. RESULTS: Flow cytometry analysis of wild-type (Cys460) and mutant (Trp460) expressed on HEK293 cells showed equal surface expression of αIIbß3 and αvß3. When tested with mutant αIIbß3 cells, reduced binding was observed in Type II but not in Type I anti-HPA-1a. These results could be confirmed with platelets carrying Cys460Trp mutation. Interestingly, reduced binding of Type I antibodies was detected with mutant αvß3 cells. Both antibody types were found in maternal sera from FNAIT cases by an antigen-capture assay with use of HEK293 transfected cells. CONCLUSIONS: These observations confirm the existence of Type I and Type II anti-HPA-1a. Furthermore, this study underlines different immunogenicity of HPA-1a antigen(s) residing on either αIIbß3 or αvß3. Further analysis of FNAIT cases from mothers having a fetus with and without intracranial bleedings with use of such an approach may highlight the functional relevance of different anti-HPA-1a subtypes.

A Successful Renal Transplant in a Pediatric Patient With Glanzmann Thrombasthenia and Hyperimmunization.

We report the case of a patient with type 2 Glanzmann thrombasthenia who underwent successful kidney transplant with his mother's kidney. He started dialysis at 13 months. The patient had been diagnosed with Glanzmann thrombasthenia at 9 years old, after hemorrhagic shock, during which multiple transfusions were required and hyperimmunization had developed. At 12 years old, he received a kidney transplant. Before transplant, ABO- and HLA-compatible platelet donors were identified and convened to donate forthe surgery and in case of emergency. Bleeding was prevented withprophylacticHLA-matched platelet transfusion and tranexamic acid. After transplant, diuresis started immediately with excellent graft function and no severe bleeding. However, after week 5, several episodes of macroscopic hematuria occurred, with obstruction and anuria. The double J ureteric stent was replaced 4 times in 2 months. Finally, the ureteric stent was removed 9 months later. At 22 months after kidney transplant, the patient has a normal graft function and no further bleeding has occurred, underlying the importance of multidisciplinary management.

First description of an IgM monoclonal antibody causing αIIb ß3 integrin activation and acquired Glanzmann thrombasthenia associated with macrothrombocytopenia.

Essentials Acquired Glanzmann thrombasthenia (GT) is generally caused by anti-αIIb ß3 autoantibodies. We report the case of a man with an acquired GT phenotype associated with macrothrombocytopenia. Perturbed platelet function were associated with an activating anti-αIIb ß3 IgM autoantibody. This novel clinical entity raises interesting questions about the αIIb ß3 integrin signaling. SUMMARY: Background Acquired Glanzmann thrombasthenia (GT) is a bleeding disorder generally caused by anti-αIIb ß3 autoantibodies. Objectives We aimed to characterize the molecular mechanism leading to a progressive GT-like phenotype in a patient with chronic immune thrombocytopenia. Patient, Methods, and Results The patient suffered from repeated episodes of gastrointestinal bleeding; further studies indicated a moderate platelet aggregation defect. A few months later, platelet function showed abolished aggregation using all agonists, but normal agglutination with ristocetin. No platelet-bound antibodies were detected, but the presence of large amounts of an IgM type antibody detected together with αIIb ß3 in the patient permeabilized platelets suggested that this IgM was an autoantibody causing the internalization of the complex. This was confirmed by the fact that the patient IgM bound to normal platelets but not to platelets from GT type I patients. Moreover, patient's plasma activated αIIb ß3 on controls' platelets as evidenced by increased PAC-1 binding. We also demonstrated that the patient plasma triggered αIIb ß3 outside-in signaling, as ß3 Tyr773 and FAK were phosphorylated, and increased the rate of actin polymerization in resting platelets reflecting an impairment of cytoskeletal reorganization. Because different signs of dysmegakaryopoiesis were also observed in our patient, we evaluated the ability of its serum to impair proplatelets formation and showed that it significantly decreased the number of proplatelet-bearing megakaryocytes in controls' bone marrow stem cells culture compared with normal serum. Conclusions We present the case of a patient with a progressive and severely perturbed platelet function associated with the presence of an IgM activating autoantibody directed against αIIb ß3 .

A unique phenotype of acquired Glanzmann thrombasthenia due to non-function-blocking anti-αIIbß3 autoantibodies.

Essentials Acquired Glanzmann thrombasthenia (aGT) is generally caused by function-blocking antibodies (Abs). We demonstrated a unique aGT case due to marked reduction of αIIbß3 with anti-αIIbß3 Abs. The anti-αIIbß3 Abs of the patient did not inhibit platelet function but reduced surface αIIbß3. Internalization of αIIbß3 induced by the Abs binding may be responsible for the phenotype. SUMMARY: Background Acquired Glanzmann thrombasthenia (aGT) is a bleeding disorder generally caused by function-blocking anti-αIIbß3 autoantibodies. Aim We characterize an unusual case of aGT caused by marked reduction of surface αIIbß3 with non-function-blocking anti-αIIbß3 antibodies (Abs). Methods A 72-year-old male suffering from immune thrombocytopenia since his 50s showed exacerbation of bleeding symptom despite mild thrombocytopenia. Platelet aggregation was absent with all agonists but ristocetin. Analysis of αIIbß3 expression and genetic analysis were performed. We also analyzed effects of anti-αIIbß3 Abs of the patient on platelet function and αIIbß3 expression. Results Surface αIIbß3 expression was markedly reduced to around 5% of normal, whereas his platelets contained αIIbß3 to the amount of 40-50% of normal. A substantial amount of fibrinogen was also detected in his platelets. There were no abnormalities in ITGA2B and ITGB3 cDNA. These results indicated that reduced surface αIIbß3 expression caused a GT phenotype, and active internalization of αIIbß3 was suggested. Anti-αIIbß3 IgG Abs were detected in platelet eluate and plasma. These Abs did not inhibit PAC-1 binding, indicating that the Abs were non-function-blocking. Surface αIIbß3 expression of a megakaryocytic cell line and cultured megakaryocytes tended to be impaired by incubation with the patient's Abs. After 2 years of aGT diagnosis, his bleeding symptom improved and surface αIIbß3 expression was recovered to 20% of normal with reduction of anti-αIIbß3 Abs. Conclusion We demonstrated a unique aGT phenotype due to marked reduction of surface αIIbß3. Internalization induced by anti-αIIbß3 Abs may be responsible in part for the phenotype.

Anti-αIIb ß3 immunization in Glanzmann thrombasthenia: review of literature and treatment recommendations.

Glanzmann thrombasthenia (GT) is caused by inherited defects of the αIIb ß3 platelet glycoprotein. This bleeding disorder can be treated with platelet transfusion therapy, but some patients will be immunized and begin to form anti-human leucocyte antigen (HLA) and/or anti-αIIb ß3 antibodies. These antibodies can bind and interfere with the function of the transfused platelets, rendering treatment ineffective. However, platelet transfusion refractoriness attributable to HLA antibodies may be managed by the selection of compatible donors, although they are not always readily available, particularly in an emergency. Thus, anti-αIIb ß3 antibodies represent one of the most severe complications in GT. Both genetic and environmental factors may contribute to the risk of anti-αIIb ß3 development, but the underlying pathogenic mechanisms are still unknown. This review will summarize the current knowledge of the risk factors for development of anti-αIIb ß3 antibodies in patients with GT and discuss how these findings may influence the clinical management of patients.

Immunisation against αIIbß3 and αvß3 in a type 1 variant of Glanzmann's thrombasthenia caused by a missense mutation Gly540Asp on ß3.

Treatment of bleeding in patients with Glanzmann's thrombasthenia (GT) can be hampered by iso-antibodies against the αIIbß3 integrin, which cause rapid clearance of transfused donor platelets. Type 1 GT patients with a total absence of αIIbß3 from the platelet surface are known to be susceptible to form such isoantibodies. In this study, we describe a type 1 GT patient with a missense mutation (Gly540Asn) located in the EGF3 domain of the ß3 integrin subunit. Cotransfection analysis in CHO cells demonstrates total absence of αIIbß3 from the surface, based on inappropriate αIIb maturation. The patient's serum was reactive with αIIbß3 and αvß3 integrins in a capture assay, when platelets and endothelial cells were used. Two specificities could be isolated from the patient's serum, anti-αIIbß3 and anti-αvß3 isoantibodies. Both specificities did not interfere with platelet aggregation. In contrast, isoantibodies against αvß3, but not against αIIbß3, were able to disturb endothelial cell adhesion onto vitronectin, triggered endothelial cell apoptosis and interfered with endothelial tube formation. This intriguing finding may explain more recently observed features of fetal/neonatal iso-immune thrombocytopenia in children from type 1 GT mothers with intracranial haemorrhage, which could be related to anti-endothelial activity of the maternal antibodies. In conclusion, we give evidence that two isoantibody entities exist in type 1 GT patients, which are unequivocally different, both in an immunological and functional sense. Further research on the clinical consequences of immunisation against αvß3 is required, predominantly in GT patients of childbearing age.

Use of recombinant activated factor VII in patients with Glanzmann's thrombasthenia: a review of the literature.

Glanzmann's thrombasthenia (GT) is a rare bleeding disorder characterized by a quantitative or qualitative defect of glycoprotein IIb/IIIa on the platelet membrane. Managing bleeding episodes is often difficult, and a variety of modalities have been used, including platelet transfusions, recombinant factor VIIa (rFVIIa), and other supportive care. The aim of this review was to present the clinical experience with rFVIIa bolus infusion (rFVIIa BI) for treatment of bleeding episodes and prevention of bleeding during surgical procedures in patients with GT. A literature search was performed to identify rFVIIa-treated patients with GT. Overall, one international survey, one open-label study, and 40 case reports identified 172 bleeding episodes treated with rFVIIa and 62 procedures covered with rFVIIa. In the international survey, rFVIIa BI was used for 96 bleeding episodes in 59 patients. Recombinant FVIIa was effective in 76 bleeding episodes (79%). Of 34 surgical procedures, 25 procedures received rFVIIa BI with 92% bleeding-prevention efficacy. The open-label study reported 28 patients with 28 rFVIIa BI-treated bleeds, and 26 (93%) bleeding episodes responded to rFVIIa. Published case reports revealed that 25 (69%) of 36 bleeds and 27 (96%) of 28 surgeries responded to rFVIIa BI treatment. Overall, 26 adverse events were reported in 19 patients, including five thromboembolic events in two patients where a possible relationship with rFVIIa could not be excluded. Two large studies and 40 case reports provide a literature base to support the efficacy and safety of rFVIIa BI in patients with GT.

Multicolor flow cytometry for evaluation of platelet surface antigens and activation markers.

INTRODUCTION: Flow cytometry allows the analysis of multiple antigens in a single tube at a single cell level. We present a rapid and sensitive two tube flow cytometric protocol for the detection of multiple platelet antigens and activation markers gated on a pure platelet population. MATERIALS AND METHODS: The presence of platelet specific antigens was analyzed in citrated whole blood of normal platelets and from patients diagnosed with platelet abnormalities. Quiescent platelets as well as stimulated platelets were analyzed using a gating strategy based on ubiquitously expressed platelet membrane markers. A ubiquitously expressed platelet marker was combined with antibodies against the activated alpha2b-beta3 (PAC-1), Lysosomal Activated Membrane Protein (CD63) and P-selectin (CD62P). RESULTS: We were able to detect the platelet antigens CD36, CD41, CD42a, CD42b and CD61 in one single tube. Our approach allowed the single tube determination of PAC-1, CD63 and CD62P after activation of platelets by thrombin, collagen, ADP and PAR-1, and determination of platelet abnormalities. CONCLUSIONS: Our two tube multi-parameter screening protocol is suited for the analysis of platelet antigens expressed on quiescent and activated platelets and allows the detection of aberrancies as found in blood of patients with thrombocytopathy such as Glanzmann Thrombasthenia, storage pool disease with diminished granule content and patients treated with clopidogrel and acetylsalicylic acid.

Natural history of platelet antibody formation against αIIbß3 in a French cohort of Glanzmann thrombasthenia patients.

Treatment of the bleeding syndrome in Glanzmann thrombasthenia (GT) is often complicated by naturally occurring isoantibodies directed against the αIIbß3 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-αIIbß3 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 αIIbß3 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 αIIbß3 and (ii) 8 patients carrying other defects of ITGA2B or ITGB3 with different expression levels of αIIbß3. Our results confirm that patients with premature termination mutations resulting in platelets lacking αIIbß3 are the most susceptible to form isoantibodies, a finding that may be useful in deciding the choice of therapy between platelet transfusion and the use of recombinant factor VIIa (FVIIa).

Allogeneic hematopoietic stem cell transplantation in Glanzmann thrombasthenia complicated by platelet alloimmunization.

BACKGROUND: For Thrombasthenia Glanzmann (GT) patients presenting with a severe clinical phenotype due to complete lack of thrombocyte function or increased titres of anti-platelet antibodies hematopoietic stem cell transplantation (SCT) is the only curative therapy. CASE REPORT: We report the case of a 13-month-old boy, presenting with a severe course of GT, who was successfully treated with an HLA-identical sibling bone marrow transplant. SCT was complicated by anti-platelet alloimmunization after platelet transfusion successfully treated with high dosage immunoglobulins (2 g/kg) and partial plasma exchange. CONCLUSION: SCT may be a viable option for selected patients with GT. However, SCT in GT carries its own significant risks, resulting from the development of anti-platelet antibodies. A critical risk-benefit analysis is mandatory prior to SCT.

Molecular analysis of a patient with type I Glanzmann thrombasthenia and clinical impact of the presence of anti-αIIbß3 alloantibodies.

The occurrence of transfusion-related alloimmunization against αIIbß3 is a major concern in patients with Glanzmann thrombasthenia (GT). However, few data are available about molecular defects of GT patients with anti-αIIbß3 alloantibodies as well as clinical impact of these antibodies on platelet transfusion. Here, we report a case of type I GT with anti-HLA and anti-αIIbß3 alloantibodies, who underwent laparoscopic total gastrectomy due to gastric cancer. We found a novel ß3 nonsense mutation, 892C > T (Arg272X), and the patient was homozygous for the mutation. Laparoscopic gastrectomy was successfully performed with continuous infusion of HLA-matched platelet concentrates and bolus injection of recombinant factor VIIa at 2 h intervals. Total bleeding was 370 mL and no red-cell transfusion was necessary. Flow cytometric analysis employing anti-αIIbß3 monoclonal antibody revealed that the transfused platelet count was maintained around 20-30 × 109/L during the operation and 10 × 109/L on the following day. Flow cytometric analysis also showed that transfused platelets retained normal reactivity to ADP stimulation. These results indicate that flow cytometry is useful to assess survival and function of transfused platelets in GT patients with anti-αIIbß3 antibodies.

Prevalence of allo-immunization anti-HLA and anti-integrin alphaIIbbeta3 in Glanzmann Thromboasthenia patients.

SUMMARY: Platelet transfusions, main therapy of Glanzmann Thromboasthenia (GT), can induce an allo-immunization against human leucocyte antigen and integrin alphaIIbbeta3. We have investigated in our GT patients the rate of allo-immunization and of refractoriness to platelet transfusions. From 1975 until December 2005, we have followed 17 GT patients: 14 type 1, 3 variant type; nine females, eight males; median age at diagnosis 9.8 years (range 1-44.5); median age at the time of the study 35.5 years (range 23.6-68.5). In our patients, 121 bleeding episodes occurred (24 severe, 37 moderate, and 60 mild). Ten major and 22 minor surgical procedures have been performed. Two spontaneous deliveries and three caesarian sections with five live births were performed; moreover, one late foetal loss occurred, and one voluntary abortion was performed. Sixteen of 17 patients have been transfused at least once in life with platelets and/or red blood cells (RBC). All transfused patients have been investigated for the presence of anti-HLA and anti-integrin alphaIIbbeta3 allo-antibodies. The positiveness of allo-antibodies has been demonstrated in 4/16 transfused patients (25%): isolated for anti-HLA in two; isolated for anti-integrin alphaIIbbeta3 in one; and combined in one. In spite of the presence of allo-antibodies, platelet transfusions have always been effective and the haemostasis was not compromised.

Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcgammaRIIa and the integrin beta3 cytoplasmic domain.

Thrombocytopenia and thrombosis following treatment with the integrin alphaIIbbeta3 antagonist eptifibatide are rare complications caused by patient antibodies specific for ligand-occupied alphaIIbbeta3. Whether such antibodies induce platelet clearance by simple opsonization, by inducing mild platelet activation, or both is poorly understood. To gain insight into the mechanism by which eptifibatide-dependent antibodies initiate platelet clearance, we incubated normal human platelets with patient serum containing an alphaIIbbeta3-specific, eptifibatide-dependent antibody. We observed that in the presence of eptifibatide, patient IgG induced platelet secretion and aggregation as well as tyrosine phosphorylation of the integrin beta3 cytoplasmic domain, the platelet FcgammaRIIa Fc receptor, the protein-tyrosine kinase Syk, and phospholipase Cgamma2. Each activation event was inhibited by preincubation of the platelets with Fab fragments of the FcgammaRIIa-specific mAb IV.3 or with the Src family kinase inhibitor PP2. Patient serum plus eptifibatide did not, however, activate platelets from a patient with a variant form of Glanzmann thrombasthenia that expressed normal levels of FcgammaRIIa and the alphaIIbbeta3 complex but lacked most of the beta3 cytoplasmic domain. Taken together, these data suggest a novel mechanism whereby eptifibatide-dependent antibodies engage the integrin beta3 subunit such that FcgammaRIIa and its downstream signaling components become activated, resulting in thrombocytopenia and a predisposition to thrombosis.

A Toll-like receptor 2-integrin beta3 complex senses bacterial lipopeptides via vitronectin.

Toll-like receptor 2 (TLR2) initiates inflammation in response to bacterial lipopeptide (BLP). However, the molecular mechanisms enabling the detection of BLP by TLR2 are unknown. Here we investigated the interaction of BLP with human serum proteins and identified vitronectin as a BLP-recognition molecule. Vitronectin and its receptor, integrin beta(3), were required for BLP-induced TLR2-mediated activation of human monocytes. Furthermore, monocytes from patients with Glanzmann thrombasthenia, which lack integrin beta(3), were completely unresponsive to BLP. In addition, integrin beta(3) formed a complex with TLR2 and this complex dissociated after BLP stimulation. Notably, vitronectin and integrin beta(3) coordinated responses to other TLR2 agonists such as lipoteichoic acid and zymosan. Our findings show that vitronectin and integrin beta(3) contribute to the initiation of TLR2 responses.

A new case of acquired Glanzmann's thrombasthenia: diagnostic value of flow cytometry.

BACKGROUND: Acquired Glanzmann's thrombasthenia (aGT) is a rare hemorrhagic disorder caused by autoantibodies, alloantibodies, or paraproteins directed against platelet GPIIb/IIIa. Its diagnosis requires several laboratory assays and mixing tests, which are complex and time consuming. We describe here a new case of aGT and compare different tests for the detection of GPIIb/IIIa-blocking autoantibodies. METHODS: A previously healthy 27-year-old male developed severe mucocutaneous bleeding, despite a normal platelet count, associated with non Hodgkin lymphoma. RESULTS: Blood clotting tests were normal. Bleeding time and PFA-100 were unmeasurable. Platelet aggregation was absent in response to all agonists except ristocetin. Platelet adhesion to collagen at high shear was impaired. Platelet granular content and release was normal. Flow cytometry showed normal binding of some anti-GPIIb/IIIa antibodies (SZ21 and SAP), and decreased binding of others (P2, SZ22, A2A 9/6). Binding of PAC-1, against activated GPIIb/IIIa, and of fibrinogen, was absent. In mixing tests, patient's serum inhibited aggregation, adhesion, and PAC-1 and A2A9/6 binding to control platelets. The patient's antibody, purified by affinity chromatography, recognized purified GPIIb by western blotting. Isolated patient's IgG inhibited platelet aggregation and A2A 9/6 binding by flow cytometry. CONCLUSIONS: Flow cytometry is especially useful for the diagnosis of aGT, being the only test able to characterize both the functional effect and the molecular target of the patient's autoantibody.

Acquired Glanzmann's thrombasthenia caused by glycoprotein IIb/IIIa autoantibodies of the immunoglobulin G1 (IgG1), IgG2 or IgG4 subclass: a study in six cases.

BACKGROUND: Acquired Glanzmann's thrombasthenia (GT) is an uncommon bleeding disorder caused by glycoprotein (GP) IIb/IIIa-specific autoantibodies. Covering of the fibrinogen binding site of GPIIb/IIIa results in a moderate-to-severe bleeding tendency. MATERIALS AND METHODS: We performed a diagnostic evaluation and evaluated the underlying risk factors in six patients with a bleeding tendency caused by acquired GT. RESULTS: One patient, with GPIIb/IIIa autoantibodies of the immunoglobulin G2 (IgG2) subclass, used diclophenac and recovered after discontinuation of this drug. A second patient was primarily diagnosed with multiple angiodysplastic lesions. In this patient, the acquired GT was caused by GPIIb/IIIa autoantibodies of the IgG4 subclass that was treated with DDAVP and platelet transfusions. A third patient with Hodgkin's lymphoma and anti-GPIIb/IIIa of the IgG2 subclass was treated for haemorrhagic diathesis with corticosteroids and azathioprin. A fourth patient, with IgG2 anti-GPIIb/IIIa autoantibodies, diagnosed with mantle cell lymphoma, responded well to treatment of an axillary mass with local radiotherapy. The fifth and sixth patients, with IgG1 anti-GPIIb/IIIa autoantibodies, appeared to have GT after splenectomy because of autoimmune thrombocytopenia. They were treated with corticosteroids, intravenous immunoglobulin and Rituximab. CONCLUSION: Although it might be a rare event, one should be aware of acquired GT as a cause of an unexpected primary disorder of haemostasis in patients with lymphoma or autoimmune disease. The lack of platelet destruction in these cases of acquired GT can be explained, either by the subclass of the autoantibodies (i.e. IgG2 or IgG4) or by the arrested platelet destruction by IgG1 (or IgG3) autoantibodies after splenectomy.