The International Prospective Glanzmann's Thrombasthenia Registry (GTR). Special Issues in Women.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2202-2202
Author(s):  
Roseline d'Oiron ◽  
Man-Chiu Poon ◽  
Rainer Zotz ◽  
Giovanni di Minno
Keyword(s):  
Surgical Procedures ◽  
Treatment Modalities ◽  
Female Group ◽  
Similar Distribution ◽  
Platelet Surface ◽  
Glanzmann’S Thrombasthenia ◽  
Antiplatelet Antibodies ◽  
Glanzmann's Thrombasthenia ◽  
Gynecological Surgical Procedures ◽  
Bleeding Episodes

Abstract Abstract 2202 Background. Glanzmann's thrombasthenia (GT) is a severe autosomal recessive bleeding disorder with defective platelet surface αIIb-β3 integrin. Specifities of women with GT are menorrhagia, gynecological surgeries, pregnancies and the consequences of antiplatelet allo-immunization (anti-HLA antibodies) or iso-immunization (anti-αIIb-β3integrin antibodies), especially regarding the risk of neonatal/fetal thrombocytopenia. Methods. The Glanzmann's Thrombasthenia Registry (GTR) is an international multicenter observational prospective registry, created to collect information on the effectiveness and safety of platelet transfusion (P), rFVIIa and other systemic hemostatic agents (mostly, antifibrinolytics [AF]) for the treatment of bleedings in GT patients. GTR offers a unique opportunity to collect data on gynecological issues in a large cohort of women with GT. In the following the terms “rFVIIa”, “P”, and “rFVIIa+P” may include use of AF. “AF” means AF only. Results. From 2004 to 2011, 218 GT patients from 45 sites in 15 countries from 4 continents were enrolled in the GTR. In the group of 127 females with a mean age of 22.4 years (y), 514 bleeding episodes and 114 surgical procedures were reported. The distribution according to age, type of GT, antiplatelet antibodies (AB) and platelet refractoriness (REF) was similar between females and males. However, the proportion of females with no AB and/or REF decreased with age especially after adolescence: 40/44 (91%) for patients <12 y, 12/15 (80%) for patients 12–17 y and 31/68 (45%) for patients ≥18 y. Among the 83 females older than 12 y, 40 (48%) had 90 episodes of menorrhagia collected in the GTR while only 4 pregnancies were reported during the period of study. Menorrhagia accounted for 17.5% of the bleeding episodes in the female group. Two thirds of menorrhagia were moderate episodes. Treatments used were rFVIIa in 15 patients, platelets (P) in 22 patients, rFVIIa+P in 6 patients and AF in 11 patients. rFVIIa was used more frequently in patients with a history of AB and/or REF while platelets and AF were nearly always used in non-immunized patients. Treatment with rFVIIa, P, rFVIIa+P and AF was successful in 79% (23 out of 29), 85% (22 out of 26), 43% (3 out 7) and 93% (26 out of 28) of instances respectively. The median cumulative doses of rFVIIa or P were higher in menorrhagia compared to those in all other types of bleedings. The 7 gynecological surgical procedures were 4 curettages (3 successfully treated with rFVIIa, 1 with P), and 3 caesarean sections successfully performed with P. The non-gynecological procedures were 77 dental, 7 gastrointestinal, 3 nasal, 3 orthopedic and 6 other surgeries. The rate of rebleedings was similar in admissions of females compared to all admissions. In conclusion, compared to their male counterparts, females with GT presented a similar distribution of bleedings and surgeries, immunization/refractoriness status, dosing, treatment modalities and efficacy. Menorrhagia was observed globally in half of the females with GT ≥12 y and represented one-fifth of the bleeding episodes reported in women included in GTR. Disclosures: d'Oiron: NovoNordisk: Honoraria. Off Label Use: rFVIIa (NovoSeven) in Glanzmann's thrombasthenia without antiplatelet antibodies or refractoriness to platelets. Poon:Novo Nordisk: Honoraria. Zotz:Novo Nordisk: Honoraria. di Minno:Novo Nordisk: Honoraria.

Stimulated Glanzmann’s Thrombasthenia Platelets Produce Microvesicles

1995 ◽  
Vol 74 (06) ◽  
pp. 1533-1540 ◽  
Author(s):  
Pål André Holme ◽  
Nils Olav Solum ◽  
Frank Brosstad ◽  
Nils Egberg ◽  
Tomas L Lindahl
Keyword(s):  
Complement System ◽  
Shape Change ◽  
Annexin V ◽  
Platelet Surface ◽  
Glanzmann’S Thrombasthenia ◽  
Large Numbers ◽  
Glanzmann's Thrombasthenia ◽  
Series Of Experiments ◽  
The Complement System ◽  
Number Of Particles

SummaryThe mechanism of formation of platelet-derived microvesicles remains controversial.The aim of the present work was to study the formation of microvesicles in view of a possible involvement of the GPIIb-IIIa complex, and of exposure of negatively charged phospholipids as procoagulant material on the platelet surface. This was studied in blood from three Glanzmann’s thrombasthenia patients lacking GPIIb-IIIa and healthy blood donors. MAb FN52 against CD9 which activates the complement system and produces microvesicles due to a membrane permeabilization, ADP (9.37 μM), and the thrombin receptor agonist peptide SFLLRN (100 μM) that activates platelets via G-proteins were used as inducers. In a series of experiments platelets were also preincubated with PGE1 (20 μM). The number of liberated microvesicles, as per cent of the total number of particles (including platelets), was measured using flow cytometry with FITC conjugated antibodies against GPIIIa or GPIb. Activation of GPIIb-IIIa was detected as binding of PAC-1, and exposure of aminophospholipids as binding of annexin V. With normal donors, activation of the complement system induced a reversible PAC-1 binding during shape change. A massive binding of annexin V was seen during shape change as an irreversible process, as well as formation of large numbers of microvesicles (60.6 ±2.7%) which continued after reversal of the PAC-1 binding. Preincubation with PGE1 did not prevent binding of annexin V, nor formation of microvesicles (49.5 ± 2.7%), but abolished shape change and PAC-1 binding after complement activation. Thrombasthenic platelets behaved like normal platelets after activation of complement except for lack of PAC-1 binding (also with regard to the effect of PGE1 and microvesicle formation). Stimulation of normal platelets with 100 μM SFLLRN gave 16.3 ± 1.2% microvesicles, and strong PAC-1 and annexin V binding. After preincubation with PGE1 neither PAC-1 nor annexin V binding, nor any significant amount of microvesicles could be detected. SFLLRN activation of the thrombasthenic platelets produced a small but significant number of microvesicles (6.4 ± 0.8%). Incubation of thrombasthenic platelets with SFLLRN after preincubation with PGE1, gave results identical to those of normal platelets. ADP activation of normal platelets gave PAC-1 binding, but no significant annexin V labelling, nor production of microvesicles. Thus, different inducers of the shedding of microvesicles seem to act by different mechanisms. For all inducers there was a strong correlation between the exposure of procoagulant surface and formation of microvesicles, suggesting that the mechanism of microvesicle formation is linked to the exposure of aminophospholipids. The results also show that the GPIIb-IIIa complex is not required for formation of microvesicles after activation of the complement system, but seems to be of importance, but not absolutely required, after stimulation with SFLLRN.

Pregnancy in a Patient of Glanzmann's Thrombasthenia with Antiplatelet Antibodies

1997 ◽  
Vol 23 (3) ◽  
pp. 247-250 ◽  
Author(s):  
Rajesh Kashyap ◽  
Alka Kriplani ◽  
Renu Saxena ◽  
D. Takkar ◽  
V. P. Choudhry
Keyword(s):  
Glanzmann’S Thrombasthenia ◽  
Antiplatelet Antibodies ◽  
Glanzmann's Thrombasthenia

Additional Glycoprotein Defects In Glanzmann’s Thrombasthenia Platelets

1981 ◽  
Author(s):  
J L McGregor ◽  
K J Clemetson ◽  
E James ◽  
A Capitanio ◽  
M Dechavanne ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Gel Electrophoresis ◽  
Lens Culinaris ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Platelet Surface ◽  
Glanzmann’S Thrombasthenia ◽  
Healthy Donors ◽  
Glanzmann's Thrombasthenia ◽  
Dimensional Electrophoresis

Glanzmann’s thrombasthenia (G.T.) platelets are deficient in 2 major membrane GP (IIb and IIIa). In order to investigate if these are the only defects in this disorder, platelets from G.T. patients and from healthy donors were isolated, washed and surface-labelled by techniques specific for protein or for sugars (sialic acid or penultimate galactose/N-acetylgalactosamine residues). Labelled or unlabelled platelets were solubilized in sodium dodecyl sulphate (SDS) and separated by 2-dimensional polyacrylamide gel electrophoresis, first according to isoelectric point and then according to molecular weight. Glycoproteins from unlabelled platelets separated by 2-dimensional electrophoresis were identified by binding of 125I-labelled Lens culinaris lectin (mannose, glucose specific) GPIIbA1 and IIIaA1 were absent in one G.T. patient while in others lower amounts of 2 GP were found in positions similar to these GP. Major membrane GP (IbA1, IbA2, IbB1 and IIIbA1) had more intensely labelled terminal sialic acid moieties in G.T. platelets than in normals. A major membrane GP designated Ic had an altered pi and its penultimate galactose/N-acetyl galactosamine residues labelled more intensely in G.T. platelets than in controls. One high M.Wt. GP and a number of lower M.Wt. GP (IVa, IVb and VII) normally found in platelets of healthy donors were absent in G.T. platelets. These results indicate strongly that there is a major perturbation of the platelet surface in G.T.

The International Prospective Glanzmann's Thrombasthenia Registry (GTR) Special Issues in Children

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3341-3341
Author(s):  
Rainer Zotz ◽  
Giovanni di Minno ◽  
Roseline d'Oiron ◽  
Man-Chiu Poon
Keyword(s):  
Surgical Procedures ◽  
Treatment Options ◽  
Combined Treatment ◽  
Gastrointestinal Surgery ◽  
Severe Bleeding ◽  
Separate Analysis ◽  
Median Dose ◽  
Glanzmann’S Thrombasthenia ◽  
Dental Procedures ◽  
Glanzmann's Thrombasthenia

Abstract Abstract 3341 Background. Glanzmann's thrombasthenia (GT) is a severe inherited bleeding disorder with defective platelet membrane αIIbβ3. Until now there have been only limited data regarding treatment of GT with platelets (P), NovoSeven (rFVIIa), and antifibrinolytics (AF) in children. Methods. The GTR is an international prospective multicenter registry on the efficacy and safety of rFVIIa as well as platelets and AF for non-surgical and surgical bleedings in GT patients. From 2004 to 2011, 218 GT patients from 45 sites in 15 countries from 4 continents were enrolled in the GTR, including 106 children. In the following the terms “rFVIIa”, “P”, and “rFVIIa+P” may include use of AF. “AF” means AF only. Results for surgical bleedings. Of the 96 patients with surgical procedures (n=204), 27 (28%) were children (21 < 12 yrs, 6 adolescents 12–17 yrs) with 42 procedures (21%). Dental procedures were the most frequent intervention (n=26, 62%), followed by nasal procedures (n=4, 10%), and gastrointestinal surgery and excision (each n=3, 7%). The majority of surgeries were treated equally often with rFVIIa (n= 14, 33%) and P (n=12, 29%), followed by rFVIIa+P (n=9, 21%) and AF (n=7, 17%). In major surgical procedures (n=8, 19%), children were mostly treated with rFVIIa (n=3, 38%) or with rFVIIa+P (n=3, 38%), while P (n=1, 13%) or AF (n=1, 13%) was used less often. In minor procedures (n=34), P or rFVIIa were administered about twice as often as rFVIIa+P, or AF, respectively (P: n=11, 26%, rFVIIa: n=11, rFVIIa+P: n=6, 14%, AF: n=6). rFVIIa (7/26, 27%), P (8/26, 31%) and AF (7/26, 27%) were used equally often in dental procedures (rFVIIa+P 4/26, 15%). When children were treated with AF in surgery, it was always in dental procedures (7/7). The median dose was 93μg/kg. Regarding the efficacy of the different treatments, rFVIIa was 100% successful (14/14), as well as P (12/12). The efficacy of rFVIIa+P was 56% (5/9), that of AF 43% (3/7). There were no rebleedings. The numbers of minor and major procedures stratified according to the presence of antibodies and/or refractoriness are too low to allow for a separate analysis. Results for non-surgical bleedings. Out of 184 GT patients with non-surgical bleeding, 105 were < 18 years old. No history of antibodies (AB) and/or refractoriness (REF) was present in 86 of these patients (82%). AB were documented in 11 (10.5%); REF in 3 (2.9%); and REF + AB in 5 (4.8%). Bleeding (n=628) was moderate in 483 (77%) and severe in 145 (23%) episodes. Among moderate bleedings, 286/483 (59%) were spontaneous; among severe bleedings, 130/145 (90%) were spontaneous. In moderate bleedings, rFVIIa was used in 175 (36%) episodes; P in 153 (32%); AF in 130 (27%); and rFVIIa+P in 25 (5.2%). In severe bleedings, rFVIIa was used in 22 (15%) episodes; P in 62 (43%); rFVIIa+P in 22 (15%); and AF in 39 (27%). The median dose of rFVIIa was 90μg/kg. The proportion of successful treatments (bleeding stopped within 6 h of starting treatment) for rFVIIa was 78% for spontaneous and 87% for traumatic bleeding. These figures were 74% and 79%, respectively, with P; 71% and 43%, respectively, with rFVIIa+P; and 82% and 89%, respectively, with AF only. The numbers were too low to allow for a stratification for presence of AB and/or REF. Treatment failure was documented in only 13 episodes (2% of 628), 8 having received only AF. Out of 628 bleedings, 37 re-bleedings (bleedings re-starting within 6–24 h after having stopped) were registered: 6/197 after treatment with rFVIIa (3%), 20/215 with P (9.3%), 8/47 with rFVIIa+P (17%) and 3/169 with AF (1.8%). Thromboembolic events were not reported. Allergic reactions were reported following treatment with P (3/215, 1.4%). Conclusions. The GTR results for children show that the efficacy of rFVIIa was as good as that of P. rFVIIa was safe. In non-surgical bleedings, P were preferred in all cases but traumatic moderate bleeding (preference for rFVIIa); surgical bleedings were treated equally often with rFVIIa and P. Overall, the efficacy was high for all treatment options. The re-bleeding rate was higher after P only than after rFVIIa only in non-surgical bleedings. The merit of the combined use of rFVIIa and platelets could not be assessed in this non-randomized study since the combined treatment is usually applicated in cases of severe bleeding with insufficient success of single treatment options. Disclosures: Zotz: Novo Nordisk: Honoraria. Off Label Use: Recombinant actived FVII. di Minno:Novo Nordisk: Honoraria. d'Oiron:NovoNordisk: Honoraria. Poon:Novo Nordisk: Honoraria.

Alloimmunization in Congenital Deficiencies of Platelet Surface Glycoproteins: Focus on Glanzmann's Thrombasthenia and Bernard–Soulier's Syndrome

2018 ◽  
Vol 44 (06) ◽  
pp. 604-614 ◽  
Author(s):  
Roseline d'Oiron ◽  
Man-Chiu Poon
Keyword(s):  
Platelet Transfusion ◽  
Clinical Laboratory ◽  
Human Leukocyte ◽  
Factor Vii ◽  
Platelet Glycoprotein ◽  
Recombinant Activated Factor Vii ◽  
Platelet Surface ◽  
Glanzmann’S Thrombasthenia ◽  
Platelet Antibodies ◽  
Glanzmann's Thrombasthenia

AbstractGlanzmann's thrombasthenia (GT) and Bernard–Soulier's syndrome (BSS) are well-understood congenital bleeding disorders, showing defect/deficiency of platelet glycoprotein (GP) IIb/IIIa (integrin αIIbβ3) and GPIb-IX-V complexes respectively, with relevant clinical, laboratory, biochemical, and genetic features. Following platelet transfusion, affected patients may develop antiplatelet antibodies (to human leukocyte antigen [HLA], and/or αIIbβ3 in GT or GPIb-IX in BSS), which may render future platelet transfusion ineffective. Anti-αIIbβ3 and anti-GPIb-IX may also cross the placenta during pregnancy to cause thrombocytopenia and bleeding in the fetus/neonate. This review will focus particularly on the better studied GT to illustrate the natural history and complications of platelet alloimmunization. BSS will be more briefly discussed. Platelet transfusion, if unavoidable, should be given judiciously with good indications. Patients following platelet transfusion, and women during and after pregnancy, should be monitored for the development of platelet antibodies. There is now a collection of data suggesting the safety and effectiveness of recombinant activated factor VII in the management of affected patients with platelet antibodies.

Glanzmann’s thrombasthenia (defective platelet integrin αIIb-β3): proposals for management between evidence and open issues

2009 ◽  
Vol 102 (12) ◽  
pp. 1157-1164 ◽  
Author(s):  
Giovanni Di Minno ◽  
Matteo Di Minno ◽  
Man-Chiu Poon ◽  
Antonio Coppola
Keyword(s):  
Clinical Management ◽  
Factor Vii ◽  
Major Surgery ◽  
Clinical Settings ◽  
Minor Bleeding ◽  
Antifibrinolytic Agents ◽  
Recombinant Activated Factor Vii ◽  
Platelet Surface ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia

SummaryGlanzmann’s Thrombasthenia (GT) is a rare autosomal recessive bleeding disorder, characterized by a quantitative or qualitative defect of platelet surface αIIb-β3 integrin. Presently, no specific guideline/algorithm for clinical management for GT is available. Due to the rarity and heterogeneity of inherited platelet abnormalities, recommendations and guidelines are based on reports from opinions and clinical experience of panel of experts, and refer to the general management of platelet disorders. Based on the limited evidence in the area and on the strategies in clinical settings of inherited/acquired platelet defects, proposals for management of minor bleeding; moderate/major bleeding unresponsive to conservative management; major surgery; minor surgery and dental procedures for GT patients without, or with anti-platelet isoantibodies are reported. In addition to life-style advices and continuous patient education programs, when and how to employ/combine local measures, antifibrinolytic agents, hormone treatment, platelet transfusions and recombinant activated Factor VII is described. The prospective collection of treatments in GT patients recently established (Glanzmann’s Thrombasthenia Registry, GTR), based on a careful definition of clinical settings and outcomes, is likely to provide newer insight for optimising clinical management in GT.

Mutation Analysis and Clinical Sprectrum Of Patients With Glanzmann’s Thrombasthenia and Bernard Soulier Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4751-4751
Author(s):  
Huseyin Tokgoz ◽  
Umran Caliskan ◽  
Akar Nejat ◽  
Erdem Ak
Keyword(s):  
Gastrointestinal Bleeding ◽  
Mutational Analysis ◽  
Conflicts Of Interest ◽  
Platelet Surface ◽  
Genetic Characteristics ◽  
Mediastinal Hematoma ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia ◽  
Life Threatening ◽  
Bernard Soulier Syndrome

Introduction and Aim Glanzmann’s thrombasthenia (GT) is an inherited disorder of platelet aggregation, resulting from defective glycoprotein IIb/IIIa on platelet surface. Bernard Soulier Syndrome (BSS) is also an inherited disorder of platelet adhesion and associated with defective glycoprotein Ib-V-IX on platelet surface. Both of these disorders usually present with mucocutaneous bleedings. We aimed to evaluate the clinical and genetic characteristics of the patients diagnosed as BSS and GT in department of pediatric hematology of Meram Faculty of Medicine, retrospectively. Method Seven patients diagnosed with BSS and 20 patients diagnosed with GT were enrolled to the study. Medical records of patients were reviewed retrospectively. Glycoprotein IIb gen rearrangement was investigated in genetic department of Ankara University Medical School, Turkey. Mutational analysis for BSS was performed in Medicina Interna ed Oncologia Medica, Italy. The correlation between clinical outcome and genotyping was investigated. Results Of 20 patients of GT, 8 were male and 12 were female. Of 7 patients of BSS, all of them were female. Glycoprotein IIB gene rearrangement was detected in 7 patient of GT. 5 of 7 were newly described mutations in published literature. Mutations in GpIBB and GpIBA gene were detected in 7 patients with BSS. No correlation was observed among the clinical and genotype characteristics of patients both with GT and BSS. The most common patterns of bleeding were epistaxis and gum bleeding. Life threatening bleeding was seen in 5 of GT patients (4 gastrointestinal bleeding, 1 mediastinal hematoma) and 2 of BSS patients (1 splenic rupture and 1 gastrointestinal bleeding). No patients had died due to major bleedings. One patient with GT experienced spontaneous duodenal intramural bleeding resulting duodenal obstruction. One patient with BSS experienced spontaneous mediastinal hematoma. Although the BSS, it is interesting that the patient was able to control of mediastinal hematoma. Further investigations revealed the patient has prothrombotic mutation (heterozygous FV Leiden). Conclusion The most common bleeding pattern in patients with thrombocyte dysfunction is mucocutaneous bleeding. Some patients may suffer from life-threatening bleedings. Our study contributes to the literature because of five newly described mutations in GT patients. It may be hypothesed that the presence of prothrombotic mutation in patients with thrombocyte dysfunction may reduce the severity of bleedings. Disclosures: No relevant conflicts of interest to declare.

Immunisation against αIIbβ3 and αvβ3 in a type 1 variant of Glanzmann’s thrombasthenia caused by a missense mutation Gly540Asp on β3

2016 ◽  
Vol 116 (08) ◽  
pp. 262-271 ◽  
Author(s):  
Hevi Wihadmadyatami ◽  
Lida Röder ◽  
Heike Berghöfer ◽  
Gregor Bein ◽  
Kathrin Heidinger ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Missense Mutation ◽  
Tube Formation ◽  
Integrin Subunit ◽  
Childbearing Age ◽  
Platelet Surface ◽  
Glanzmann’S Thrombasthenia ◽  
Total Absence ◽  
Glanzmann's Thrombasthenia

SummaryTreatment of bleeding in patients with Glanzmann’s thrombasthenia (GT) can be hampered by iso-antibodies against the αIIbβ3 integrin, which cause rapid clearance of transfused donor platelets. Type 1 GT patients with a total absence of αIIbβ3 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 β3 integrin subunit. Cotransfection analysis in CHO cells demonstrates total absence of αIIbβ3 from the surface, based on inappropriate αIIb maturation. The patient’s serum was reactive with αIIbβ3 and αvβ3 integrins in a capture assay, when platelets and endothelial cells were used. Two specificities could be isolated from the patient’s serum, anti-αIIbβ3 and anti-αvβ3 isoantibodies. Both specificities did not interfere with platelet aggregation. In contrast, isoantibodies against αvβ3, but not against αIIbβ3, 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 αvβ3 is required, predominantly in GT patients of childbearing age.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals A Cys374Tyr homozygous mutation of platelet glycoprotein IIIa (beta 3) in a Chinese patient with Glanzmann's thrombasthenia

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1666-1675 ◽  
Author(s):  
CM Grimaldi ◽  
F Chen ◽  
LE Scudder ◽  
BS Coller ◽  
DL French
Keyword(s):  
Platelet Aggregation ◽  
Receptor Expression ◽  
Hunan Province ◽  
Initial Slope ◽  
Platelet Glycoprotein ◽  
Homozygous Mutation ◽  
Binding Studies ◽  
Platelet Surface ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia

A 20-year-old woman from a consanguineous family in the Hunan Province of the People's Republic of China was diagnosed as having Glanzmann's thrombasthenia based on (1) nearly a lifelong history of epistaxis, gum bleeding, petechiae, and purpura; (2) severe menorrhagia resulting in anemia and need for whole-blood transfusion; (3) normal coagulation assays; (4) prolonged bleeding time; (5) absent clot retraction; (6) decreased glass bead retention; (7) absent platelet aggregation in response to adenine diphosphate, epinephrine, and collagen; and (8) normal initial slope of platelet aggregation in response to ristocetin, but with a diminished maximal extent. The patient's platelets had a decreased level of platelet fibrinogen, but the deficiency was not as severe as in other Glanzmann's thrombasthenia patients. As judged by monoclonal antibody binding studies, surface glycoprotein (GP) IIb/IIIa (alpha IIb beta 3) expression was less than 15% of normal and alpha v beta 3 vitronectin receptor expression was 15% to 19% of normal, suggesting that the defect was in GPIIIa (beta 3). Immunoblotting of platelet lysates demonstrated decreased levels of GPIIb (approximately 30% to 35% of normal) and GPIIIa (approximately 10% of normal), and the GPIIb had undergone normal maturational processing into GPIIb heavy and light chains. Sequence analysis of the patient's GPIIIa RNA identified a G to A mutation at nucleotide 1219, predicting a Cys to Tyr substitution at residue 374. The patient's parents, who are first cousins, are asymptomatic and have only minor reductions in platelet aggregation. Direct sequencing of polymerase chain reaction-amplified cDNA and GPIIIa exon VIII indicated that the patient is homozygous and her parents are heterozygous for the mutation. Transient transfection studies in Chinese hamster ovary cells indicated that the mutation results in an 85% to 90% reduction in GPIIb/IIIa surface expression, but these cells retain the ability to mediate adhesion to immobilized fibrinogen. The relative preservation of platelet fibrinogen despite the very low level of platelet surface GPIIb/IIIa expression in this patient raises some interesting questions regarding the mechanism of fibrinogen uptake and the pathophysiology of Glanzmann's thrombasthenia.

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