Spontaneous haemothorax: an uncommon presentation of Glanzmann thrombasthenia

Glanzmann thrombasthenia is a rare hereditary qualitative platelet disorder characterized by a lifelong bleeding tendency due to quantitative and qualitative abnormalities of the platelet integrin alpha(IIb)beta3. Common clinical manifestations include purpuric type skin bleeding, prolonged bleeding from minor cuts, epistaxis, gingival bleeding and menorrhagia. Less frequently, gastrointestinal system bleeding may occur. Haemarthrosis, haematuria, intracranial and visceral haemorrhage are very rare symptoms. This study reports a 3-y-old girl with Glanzmann thrombasthenia who presented with life-threatening haemothorax. There was no history of recent trauma or drug usage and no vascular or parenchymal abnormalities to explain the development of haemothorax. Conclusion: To the authors' knowledge this is the first case of Glanzmann thrombasthenia complicated by spontaneous haemothorax.     

Homozygous point mutations in platelet glycoprotein ITGA2B gene as cause of Glanzmann thrombasthenia in 2 families

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex. Physiologically, the integrin GPIIb/IIIa binds Von Willebrand factor and fibrinogen on activated platelets. GT is caused by genetic alterations in ITGA2B or ITGB3 (genes encoding GPIIb and GPIIIa).This study describes 2 siblings diagnosed with GT type I associated with homozygous point mutations in ITGA2B. All patients presented with typical bleeding disorder including moderate hematomas, petechiae, and mucocutaneous bleedings.Both siblings showed severely reduced platelet aggregation especially after stimulation with collagen and adenosine diphosphate. Absence of platelet GPIIb/GPIIIa complex was determined using flow cytometry. Molecular genetic analysis revealed 2 distinct homozygous point mutations in exon 18 of ITGA2B. Family 1 was identified with c.1878G>C and family 2 with c.1787T>C substitution. While the c.1787T>C mutation causes a single amino acid substitution p.I565T, the c.1878G>C mutation (p.Q595H) is predicted to induce a mRNA splicing anomaly.These mutations were identified as cause of GT type I in the described patients. Patients with GT should be documented in a prospective register to verify the correlation between the severity of bleeding symptoms and the pathogenic mutation. This can have effects on therapeutic decisions.     

Successful Use of Recombinant Factor VIIa (NovoSeven) During Cardiac Surgery in a Pediatric Patient with Glanzmann Thrombasthenia

Glanzmann thrombasthenia is a rare, hereditary, congenital disorder of platelet function characterized by inappropriate bleeding that is difficult to control. Recombinant activated factor VII (rFVIIa) is a new treatment that is used to stop bleeding and provide surgical support for these patients. This report describes the use of rFVIIa to prevent serious bleeding during and after open-heart surgery in a child with Glanzmann thrombasthenia.     

Use of rFVIIa in 4 children with Glanzmann thrombasthenia

Inherited deficiencies of platelet surface glycoproteins, such as Glanzmann thrombasthenia (GT), occasionally result in severe bleeding episodes. Platelet transfusion is considered standard therapy for securing hemostasis in subjects with GT when local measures and antifibrinolytic agents are inadequate. We describe 4 case studies which suggest that recombinant activated factor VII may be an effective alternative to platelet transfusion in preventing or controlling bleeding, including surgical bleeding, in patients with GT.     

Allogeneic stem cell transplantation for Glanzmann thrombasthenia

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by normal platelet count, but lack of platelet aggregation. The molecular basis is linked to quantitative and/or qualitative abnormalities of the membrane glycoprotein IIb/IIIa complexes. Usually it is associated with mild bleeding but may lead to severe and potentially fatal hemorrhages. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment. However, because of the risks associated with HSCT, it is generally not recommended unless there are life threatening hemorrhages, or the patient has developed refractoriness to platelet transfusion due to antibody formation. Herein, we report an 11‐year‐old female from United Arab Emirates (UAE) with severe GT and anti platelet alloimmunization successfully treated with HSCT from her HLA‐identical sibling. Pediatr Blood Cancer 2009;52:682–683. © 2008 Wiley‐Liss, Inc.     

Sustained engraftment post bone marrow transplant despite anti-platelet antibodies in Glanzmann thrombasthenia

BACKGROUND: Patients with Glanzmann thrombasthenia (GT) have normal platelet counts but abnormal platelet aggregation and carry the risk of life-threatening bleeding. We report three patients who received bone marrow transplantation (BMT) for type I GT and discuss the risk and management of anti-platelet antibodies. PATIENTS AND RESULTS: Diagnosis of GT was made through abnormal platelet aggregation studies or the absence of GPIIb/IIIa by flow cytometry. All patients had severe bleeding requiring multiple red blood cell transfusions. One patient received an unrelated donor transplant and two received matched sibling donor transplants following conditioning therapy with busulfan, cyclophosphamide, and fludarabine. Two patients developed an anti-platelet antibody, treated in one with intravenous immune globulin (IVIG). Engraftment of white blood cells and platelets was achieved on day +13 to +14 and +17 to +25, respectively. Complete donor chimerism and GPIIb/IIIa+ platelets are sustained at +22 to +30 months post transplant. CONCLUSIONS: In summary, patients with GT and history of severe hemorrhage can be cured with BMT, but the presence of anti-platelet antibodies should be sought and platelet transfusions minimized prior to transplant. IVIG may be helpful in cases of refractory immune thrombocytopenia related to anti-platelet antibodies. Improvement in transplant-related complications with current transplant regimens allows consideration of BMT for life-threatening non-malignant disorders such as GT.     

Use of Recombinant Factor VIIa for Bleeding in Children with Glanzmann Thrombasthenia

Glanzmann thrombasthenia is a very rare inherited platelet function disorder in which bleeding may be extremely difficult to stop. Recombinant factor VIIa is one of the alternative treatments for bleeding. The authors report here their experience with the use of factor VIIa, which may be useful for arresting bleeding in Glazmann thrombasthenia.     

Use of recombinant factor VIIa for bleeding in children with Glanzmann thrombasthenia

Glanzmann thrombasthenia is a very rare inherited platelet function disorder in which bleeding may be extremely difficult to stop. Recombinant factor VIIa is one of the alternative treatments for bleeding. The authors report here their experience with the use of factor VIIa, which may be useful for arresting bleeding in Glazmann thrombasthenia.     

Platelet function and immune response

Altered platelet function may cause abnormal bleeding tendency or thrombosis. The goal of this article is to provide insights for understanding how platelet functions are related to immune response. Autoantibodies and drug-induced platelet antibodies have been demonstrated to downregulate or enhance platelet function. Drug-induced immune thrombocytopenia is an important adverse effect of glycoprotein IIb/IIIa antagonists. Platelets respond to binding of glycoprotein IIb/IIIa by partial platelet activation. This includes conformational changes of glycoprotein IIb/IIIa. Membrane changes may expose immunogenic neoantigens capable of abnormally altering immune responses. The presence of drug-dependent antibodies in an unexpectedly high frequency compared with the frequency of overt thrombocytopenia has opened a model for further studies. These may include monitoring of antiplatelet immune responses when new platelet antagonists are developed and comparisons of specific immune responses in other acute thrombocytopenias, such as those induced by quinidine or heparin and that associated with gold therapy or in acute profound thrombocytopenia, which may follow vaccination with live attenuated viruses.     

Glanzmann thrombasthenia in a neonate

Glanzmann thrombasthenia is a qualitative platelet function disorder manifested by skin bleeds, epistaxis, gingival bleeding, gastrointestinal hemorrhage, hematuria, hemarthrosis, intracranial hemorrhage and visceral hematomas. We report a six day old newborn presenting with hematuria following suprapubic aspiration, who was diagnosed as Glanzmann thrombasthenia. We believe it to be the youngest case reported in the literature.     

Acquired Glanzmann's thrombasthenia associated with acute lymphoblastic leukemia

Acquired Glanzmann's thrombasthenia is an uncommon event in association with leukemia. The authors describe a patient with acute lymphoblastic leukemia (ALL) who presented with severe hemorrhagic syndrome, without disseminated intravascular coagulation. The patient's course was complicated by the occurrence of severe hemorrhagic episodes, with a thrombasthenia-like profile, requiring multiple transfusions with packed red cells, platelets, and fresh-frozen plasma. Biological explorations detected anti-GPIIb/IIIa complex antibodies. The patient finally died with refractory disease and persistent bleeding. This case is the first reported of autoantibodies to GPIIb/IIIa in ALL. Such paraneoplastic syndrome is potentially responsible for severe life-threatening hemorrhage.     

Bleeding and surgery in children with Glanzmann thrombasthenia with and without the use of recombinant factor VII a

BACKGROUND: An inherited deficiency of platelet glycoprotein II b/III a (GP II b/III a), Glanzmann thrombasthenia, can lead to excessive bleeding and require platelet transfusion to secure hemostasis. Antibodies to GP II b/III a or HLA may platelet transfusion render ineffective to stop bleeding or to cover surgery. Recombinant factor VII a has been introduced as therapeutic alternative and has been suggested to be effective. PATIENTS AND AIMS OF THE STUDY: In a retrospective evaluation, bleeding episodes and surgery in six patients treated with antifibrinolytics and with and without the additional use of rFVII a were analysed to achieve informations for treatment indication and efficacy. RESULTS: Nineteen mucosal and subcutaneous bleeding episodes, two dental surgeries and seven joint bleeds occurred. In 11 mild to moderate mucocutaneous bleeds treated without rFVII a, seven stopped within 48 hours, three stopped until the fourth day; one showed recurrence. Three bleeds were treated with rFVII a and responded within 24 hours. One severe bleed treated without rFVII a did not stop until the 8 (th) day after cautery. In 4 severe bleeds treated with rFVII a, one stopped within 24 hours, one showed recurrence, one was treated with platelet transfusion concurrently and one did not respond to rFVII a. Clinical signs persisted in one conservatively treated elbow joint bleed, whereas in two episodes treated with rFVII a, the bleeding responded within 5 and 7 days and in four episodes in at least 4 days. Two dental surgeries showed no recurrence after rFVII a over 18 or 36 hours. CONCLUSIONS: In severe mucocutaneous bleeding episodes or joint bleeding rFVII a is of some benefit whereas in surgeries like teeth extraction, prophylactically administered rFVII a seems effective to avoid bleeding. In mild to moderate mucocutaneous bleeding events, antifibrinolytics and local measures were sufficient in most cases and the additional use of rFVII a does not seem to be necessary. Further information is needed to elaborate clear indications for the rational use of rFVII a in bleeding episodes in patients with Glanzmann thrombasthenia compared to standardized baseline treatment. This information may generate a prospective multicenter study to provide clear advice with respect to bleeding site, severity and duration.     

Life threatening menorrhagia in thrombasthenia. (Glanzmann-Naegeli) thrombasthenia]

Glanzmann's Thrombasthenia is a rare inherited disorder of platelet aggregation with normal platelet count and humoral coagulation. It is caused by the deficiency or functional disorder of platelet membrane glycoproteins IIb und IIIa. This complex is considered to be a receptor for fibrinogen. Menorrhagia often occurs as a clinical manifestation of affected females. We report a case of severe menorrhagia in a 13-year-old girl during her third menstrual cycle. She needed several red blood cell transfusions. The bleeding could only be stopped by administration of Lynestrenol.     

Recombinant Activated Factor VII Usage in Life Threatening Hemorrhage: A Pediatric Experience

Objective  

To determine the safety and efficacy of off label usage of Recombinant activated factor VII (rFVIIa) in children with severe bleeding in non-hemophiliac children with diverse etiologies like leukemia, post hematopoietic stem cell transplantation, dengue shock syndrome and Glanzmann thrombasthenia.     

小儿血小板无力症45例临床及实验室资料分析

目的　分析总结血小板无力症(GT)患儿的临床特征和实验室资料。方法　对 1990~2002年中国医学科学院中国协和医科大学血液学研究所血液病医院收治的 45例GT患儿的临床表现、实验室资料、治疗措施进行回顾分析。结果　45例血小板无力症患儿的血小板对多种诱导聚集剂(ADP、AA、COLADR等 )反应低下或(和)缺如;瑞斯托霉素诱导的血小板聚集正常。结论　多种诱导聚集剂诱导的血小板聚集试验是诊断GT的关键。     

Novel and recurrent mutations of ITGA2B and ITGB3 genes in Korean patients with Glanzmann thrombasthenia

Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder caused by defective glycoprotein, αIIb and β3, encoded by ITGA2B and ITGB3 genes, respectively. We herein describe four unrelated Korean patients with genetically confirmed GT. Two patients were homozygous for c.1913+5G>T (IVS11+5G>T) mutation of ITGB3 with a signature of founder effect. The other two patients were compound heterozygous for two mutations of ITGA2B: c.[2333A>C];[2975delA] (p.[Q778P];[E992Gfs*30]) and c.[1750C>T];[2333A>C] (p.[R584X];[Q778P]). The c.2975delA mutation was a novel frameshift mutation of ITGA2B. Although from a limited number of patients, these results suggests c.1913+5G>T of ITGB3 is a recurrent mutation in Korean patients with GT.     

A variant form of thrombasthenia

We encountered two siblings with abnormal bruising since infancy. Studies revealed functional platelet defects characterized by a lack of platelet aggregation and adenosine triphosphate release on exposure to adenosine diphosphate and collagen as well as variable responses with ristocetin (at concentrations of less than or equal to 1.25 g/L) and arachidonic acid. In addition, little or no platelet aggregation was observed after exposure to hexadimethrine bromide (Polybrene), the calcium ionophore A23187, and the thromboxane/endoperoxide analogue U46619. The membrane proteins IIIa and Ib were present, as determined with monoclonal antibody testing, and no platelet-associated IgG was found. Platelet analysis with routine electron microscopy and ultrastructural cytochemistry revealed normal morphologic features and no deficiencies in the number of alpha granules dense bodies and other organelles. The platelet abnormality may represent a new variant of thrombasthenia.     

Successful unrelated donor cord blood transplantation for Glanzmann’s thrombasthenia

Kitko CL, Levine JE, Matthews DC, Carpenter PA. Successful unrelated donor cord blood transplantation for Glanzmann’s thrombasthenia.
Pediatr Transplantation 2011: 15: e42–e46. © 2009 John Wiley & Sons A/S. Abstract: GT, a rare disorder of platelet function, can lead to life‐threatening bleeding, particularly following the development of antiplatelet antibodies. Curative therapy includes HCT but previous reports are limited predominantly to matched siblings and have excluded CBT. Delayed or non‐engraftment of platelets because of antiplatelet antibodies might be particularly concerning after CBT for GT. Here, we report two successful unrelated cord blood transplants for GT. Recurrent life‐threatening bleeding was the primary indication for HCT, with one patient developing antiplatelet antibodies pre‐HCT. Bleeding risks associated with delivery of the conditioning regimen and the toxicity that follows should be carefully considered, including tunneled central venous line catheter placement, inclusion of B cell‐specific therapy to potentially decrease antiplatelet antibody production, and targeted busulfan dosing. This is the first report of successful unrelated cord blood HCT for GT and indicates that modifications to supportive care can improve the safety of this potentially curative therapy for patients with severe, life‐threatening disease manifestations.     

Glanzmann’s Thrombasthenia

Glanzmann’s thrombasthenia (GT) is an uncommon cause of bleeding in children. We diagnosed two siblings as having GT on the basis of flow cytometric studies. Both had cutaneous bleedings and epistaxis since early childhood. Hematological investigations revealed prolonged bleeding time and a normal platelet count. Both the patients had absence of aggregation of platelets with the agonist adenosine diphosphate. Absence of the GPIIb/ IIIa receptor was confirmed by flow cytometry. A short review of the disorder is presented.     

Autoantibodies and CD5+ B cells in childhood onset immune thrombocytopenic purpura

We evaluated platelet associated immunoglobulin (PaIg) G, PaIgM, platelet associated autoantibodies to platelet glycoprotein IIb/IIIa (Pa-GPIIb/IIIa), the percentage of CD5⁺ B cells and the amount of platelet-bound anti-GPIIb/IIIa monoclonal antibody (mAb) in the peripheral blood of 29 patients with childhood onset chronic immune thrombocytopenic purpura (c-ITP). The percentage of CD5⁺ B cells ranged from 2 to 8% (4.7 ± 2.0) in control patients and 1 to 18% (6.2 ± 4.2) in the ITP patients. There was no overall significant difference between the two groups, but the percentage of CD5⁺ B cells in six of the ITP patients was higher than the mean + 2 s.d. of the controls. There was a significant correlation between the percentage of CD5⁺ B cells and PaIgM (y = 1.73x + 13.4, r = 0.40, P < 0.05). This finding is the basis for the speculation that CD5⁺ B cells may play an important role in the production of PaIgM in vivo. There was no correlation between the amounts of PaIgG and Pa-GPIIb/IIIa. This suggests that the amount of PaIgG does not accurately reflect of the amount of Pa-GPIIb/IIIa. Furthermore, we have demonstrated that autoantibodies to GPIIb/IIIa are directed to more than one epitope.