Glanzmann Thrombasthenia in Children: Experience From a Tertiary Care Center in Southern India.

BACKGROUND: Glanzmann thrombasthenia (GT) is a globally rare inherited disorder of hemostasis. OBJECTIVES: To describe the clinical profile of GT in a tertiary care center in Southern India. METHODS: A retrospective chart review of all children with GT was performed between January 2005 and August 2017 in the Department of Paediatrics. RESULTS: A total of 48 patients (representing 43 families) were included. Median age at diagnosis was 2.75 years (interquartile range: 1.5 to 6.75). Two thirds had an onset of bleeding within the first 2 years of life. Sixty-seven percent were born out of consanguineous marriage. The common symptoms were epistaxis, gingival bleeding, and ecchymoses. Neonatal onset of bleeding manifested as purpura, epistaxis, and intracranial hemorrhage. Postsurgical bleeding and menorrhagia were unique presentations in adolescence. About 25% had life-threatening hemorrhage while 50% had growth retardation due to chronic anemia. CONCLUSIONS: GT is relatively more common in areas of Southern India due to the higher prevalence of consanguinity. Chronic anemia can contribute to growth stunting in these patients.

Glanzmann Thrombasthenia: A Clinicopathological Profile.

OBJECTIVE: To describe the clinical presentation of patients with Glanzmann's thrombasthenia (GT) and evaluate their diagnostic, clinical, and laboratory parameters including platelet aggregometry. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Hematology and Blood Transfusion, The Children Hospital and Institute of Child Health, Lahore, from January 2006 to December 2013. METHODOLOGY: Patients presenting with mucocutaneous bleeding during study period and evaluated for diagnosis of inherited platelet function disorder, were included. Clinical data and family history were recorded. Laboratory investigations including complete blood count (CBC), peripheral blood smear (PBS), bleeding time (BT), activated partial thromboplastin time (APTT), prothrombin time (PT), and platelet aggregation studies were evaluated. RESULTS: Among 796 patients, 163 (20.4%) patients were diagnosed with Glanzmann's thrombasthenia. The male to female ratio was 1.2:1. Their mean age was 7 ±2.5 years ranging from 3 months to 35 years. Consanguinity was observed in 65% patients. Common presenting symptoms included easy bruisibility (76.6%), gum bleeding (56.4%), epistaxis (62.5%), and prolonged bleeding after injury (47.2%). Bleeding time was prolonged in 92%. Platelet aggregation studies showed decreased aggregation with ADP, Collagen and Epinephrine in 100% of these patients and 9.2% showed decreased aggregation with Ristocetin also. CONCLUSION: Glanzmann thrombasthenia was seen in a substantial number of patients (20.4%), possibly due to consanguineous marriages. GTpatients presented from early age to adulthood and raised awareness hoping to help in early diagnosis and more appropriate management. Extensive collaborated studies are needed to predict the true incidence of GTin Pakistan.

Stem Cell Transplant in Severe Glanzmann Thrombasthenia in an Adult Patient.

Glanzmann thrombasthenia is an inherited auto-somal recessive disorder characterized by normal platelet count but lack of platelet aggregation due to absence of platelet glycoprotein IIb/IIIa. The disease usually is associated with mild bleeding, but severe fatal hemorrhage may occur. Allogeneic stem cell transplant is the only curative method of treatment. A literature search showed 18 previously reported cases of Glanzmann thrombasthenia treated with allogeneic hematopoietic stem cell transplant. We report an 18-year-old woman with severe Glanzmann thrombasthenia who was treated with allogeneic hematopoietic stem cell transplant from her sister. After 24-month follow-up, the patient was well, had no bleeding tendency, and had mild chronic skin graft-versus-host disease.

Association of Factor V Secretion with Protein Kinase B Signaling in Platelets from Horses with Atypical Equine Thrombasthenia.

BACKGROUND: Two congenital bleeding diatheses have been identified in Thoroughbred horses: Glanzmann thrombasthenia (GT) and a second, novel diathesis associated with abnormal platelet function in response to collagen and thrombin stimulation. HYPOTHESIS/OBJECTIVES: Platelet dysfunction in horses with this second thrombasthenia results from a secretory defect. ANIMALS: Two affected and 6 clinically normal horses. METHODS: Ex vivo study. Washed platelets were examined for (1) expression of the αIIb-ß3 integrin; (2) fibrinogen binding capacity in response to ADP and thrombin; (3) secretion of dense and α-granules; (4) activation of the mammalian target of rapamycin (mTOR)-protein kinase B (AKT) signaling pathway; and (5) cellular distribution of phosphatidylinositol-4-phosphate-3-kinase, class 2B (PIK3C2B) and SH2 containing inositol-5'-phosphatase 1 (SHIP1). RESULTS: Platelets from affected horses expressed normal amounts of αIIb-ß3 integrin and bound fibrinogen normally in response to ADP, but bound 80% less fibrinogen in response to thrombin. α-granules only released 50% as much Factor V as control platelets, but dense granules released their contents normally. Protein kinase B (AKT) phosphorylation was reduced after thrombin activation, but mTOR Complex 2 (mTORC2) and phosphoinositide-dependent kinase 1 (PDK1) signaling were normal. SH2-containing inositol-5'-phosphatase 1 (SHIP1) did not localize to the cytoskeleton of affected platelets and was decreased overall consistent with reduced AKT phosphorylation. CONCLUSIONS AND CLINICAL SIGNIFICANCE: Defects in fibrinogen binding, granule secretion, and signal transduction are unique to this thrombasthenia, which we designate as atypical equine thrombasthenia.

Coincidence of Glanzmann's thrombasthenia with hereditary haemorrhagic telengiectasia in a man with gastrointestinal bleeding.

Here we report a case of a 57-year-old man referred to our hospital with weakness, lethargy, melena, and rectorrhalgia. His physical examination and past medical history showed gingival bleeding, several episodes of epistaxis and post-surgery bleeding. Primary laboratory evaluation revealed only anaemia. Gastrointestinal findings including upper endoscopy and colonoscopy documented normal status, but balloon endoscopy illustrated telengiectasia-like lesions in the mid-jejunum. The case was suspected to be haemophilia due to the past medical history, although complete haemostatic evaluation demonstrated Glanzmann's thrombasthenia. The diagnosis of co-occurrence of hereditary haemorrhagic telengiectasia and Glanzmann's thrombasthenia was confirmed. This case revealed the coincidence of two bleeding tendencies, which, although rare, is a possible phenomenon. We recommend carrying out both primary and secondary haemostatic profiles for every patient with bleeding diathesis.

Two types of procoagulant platelets are formed upon physiological activation and are controlled by integrin α(IIb)ß(3).

OBJECTIVE: Phosphatidylserine (PS) externalization by platelets upon activation is a key event in hemostasis and thrombosis. It is currently believed that strong stimulation of platelets forms 2 subpopulations, only 1 of which expresses PS. METHODS AND RESULTS: Here, we demonstrate that physiological stimulation leads to the formation of not 1 but 2 types of PS-expressing activated platelets, with dramatically different properties. One subpopulation sustained increased calcium level after activation, whereas another returned to the basal low-calcium state. High-calcium PS-positive platelets had smaller size, high surface density of fibrin(ogen), no active integrin α(IIb)ß(3), depolarized mitochondrial membranes, gradually lost cytoplasmic membrane integrity, and were poorly aggregated. In contrast, the low-calcium PS-positive platelets had normal size, retained mitochondrial membrane potential and cytoplasmic membrane integrity, and combined retention of fibrin(ogen) with active α(IIb)ß(3) and high proaggregatory function. Formation of low-calcium PS-positive platelets was promoted by platelet concentration increase or shaking and was decreased by integrin α(IIb)ß(3) antagonists, platelet dilution, or in platelets from kindlin-3-deficient and Glanzmann thrombasthenia patients. CONCLUSIONS: Identification of a novel PS-expressing platelet subpopulation with low calcium regulated by integrin α(IIb)ß(3) can be important for understanding the mechanisms of PS exposure and thrombus formation.

Acute epidural hematoma in a patient with Glanzmann's thrombasthenia: case report.

A 7-year-old girl with Glanzmann's thrombasthenia (GT) fell and hit her head against a table. Within 2 hours she began to vomit and became drowsy. On admission to our hospital her Glasgow Coma Scale score was 13. Computed tomography (CT) on admission showed acute epidural hematoma in the left posterior fossa. We administered platelets, performed emergent lateral suboccipital craniotomy, and totally removed the epidural hematoma. Postoperative CT showed no evidence of hematoma or re-bleeding. She was discharged without neurological deficits 14 days after the operation. GT is a platelet aggregation disorder due to a functional loss of platelet membrane glycoprotein IIb/IIIa. The present patient with GT underwent successful emergency craniotomy after platelet transfusion.

Glanzmann's thrombasthenia: report of a case and review of the literature.

Glanzmann's thrombasthenia is a rare congenital bleeding disorder. Patients usually present with mucocutaneous bleeding and excessive bleeding associated with trauma and/or surgery. Patients have an increased bleeding time and a normal platelet count with abnormal platelet function assays. Genetically, Glanzmann's thrombasthenia is associated with mutations in the genes which encode for glycoproteins, GPIIb or GPIIIa. Defects in these genes lead to a lack of or highly reduced expression of the glycoprotein complex (GPIIb/GPIIIa), resulting in platelet dysfunction. Bleeding is managed by platelet transfusions. Bone marrow transplants have been used successfully in rare cases. With proper supportive care Glanzmann's thrombasthenia has a very good prognosis.

The use of recombinant FVIIa in a patient with Glanzmann thrombasthenia with uncontrolled bleeding after tonsillectomy.

Glanzmann's thrombasthenia is an inherited platelet function disorder caused by quantitative or qualitative defects of the platelet membrane glycoprotein IIb/IIIa complex. Activated recombinant factor VII (rFVIIa) has recently been used in the treatment of patients with Glanzmann's thrombasthenia. We report herein a 16-year-old boy with Glanzmann's thrombasthenia who did not respond to conservative treatment for excessive bleeding and hyperfibrinolysis after tonsillectomy and who was successfully treated with rFVIIa. We suggest that rFVIIa at repeated doses of 80-100 microg/kg may be used effectively in patients with Glanzmann's thrombasthenia having excessive bleeding associated with hyperfibrinolysis after tonsillectomy in addition to tranexamic acid treatment.

Analysis of adenoviral attachment to human platelets.

BACKGROUND: Systemic adenoviral (Ad) vector administration is associated with thrombocytopenia. Recently, Ad interaction with mouse platelets emerged as a key player determining liver uptake and platelet clearance. However, whether Ad can activate platelets is controversial. Thus, in vitro analysis of Ad attachment to platelets is of interest. METHODS: We developed a direct flow cytometry assay to specifically detect Ad particles adherent to human platelets. The method was pre-validated in nucleated cells. Blocking assays were employed to specifically inhibit Ad attachment to platelets. Platelet activation was analyzed using annexin v flow cytometry. RESULTS: We found in vitro that Ad binding to human platelets is synergistically enhanced by the combination of platelet activation by thrombin and MnCl2 supplementation. Of note, Ad binding could activate human platelets. Platelets bound Ad displaying an RGD ligand in the fiber knob more efficiently than unmodified Ad. In contrast to a previous report, CAR expression was not detected on human platelets. Integrins appear to mediate Ad binding to platelets, at least partially. Finally, alphaIIbbeta3-deficient platelets from a patient with Glanzmann thrombasthenia could bind Ad 5-fold more efficiently than normal platelets. CONCLUSION: The flow cytometry methodology developed herein allows the quantitative measurement of Ad attachment to platelets and may provide a useful in vitro approach to investigate Ad interaction with platelets.

Modulation of clinical phenotype of Glanzmann's thrombasthenia by thrombogenic mutations.

BACKGROUND: Glanzmann's thrombasthenia (GT) is an autosomal recessive bleeding disorder which is due to a defect in platelet aggregation in response to multiple physiological agonists. It has been demonstrated that the clinical phenotype of various diseases inherited in a classic Mendelian fashion can be modulated by a series of factors, inherited as well as acquired. METHODS: A total of 45 GT patients were screened for the thrombogenic polymorphisms, i.e., FV Leiden (R506Q), Prothrombin G20210A, MTHFR C677T and HPA-1 by PCR/RFLP. RESULTS: MTHFR C677T heterozygous was seen in 6 patients, FV Leiden heterozygous in one and Prothrombin G20210A gene variant in none. HPA-1 was seen in 3 patients of whom 1 was homozygous and 2 were heterozygous. CONCLUSION: Thus the coinheritance of heterozygous FV Leiden alone or homozygous HPA 1b alone or the combined heterozygosity of MTHFR and HPA-1 were predicted to alter the clinical phenotype. Whereas the inheritance of heterozygous MTHFR alone or heterozygous HPA-1 alone did not altered the clinical phenotype significantly. Hence FV Leiden, MTHFR C677T polymorphism along with PLA-1 and homozygous HPA-1 were the probable ameliorating factor in GT mild phenotype.

Glanzmann's thrombasthenia: an overview.

Glanzmann's thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder due to a defect in platelet function. The hallmark of this disease is severely reduced/absent platelet aggregation in response to multiple physiological agonists. Bleeding signs in GT include epistaxis, bruising, gingival hemorrhage, gastrointestinal hemorrhage, hematuria, menorrhagia, and hemarthrosis. Homozygous or compound heterozygous mutations in the genes of GPIIb and GPIIIa lead to GT. A patient with GT, with no possible causative mutations in GPIIb and GPIIIa genes, may harbor defects in a regulatory element affecting the transcription of these 2 genes. GT occurs in high frequency in certain ethnic populations with an increased incidence of consanguinity such as in Indians, Iranians, Iraqi Jews, Palestinian and Jordanian Arabs, and French Gypsies. Carrier detection in GT is important to control the disorder in family members. Carrier detection can be done both by protein analysis and direct gene analysis.

Diagnostic tool for Glanzmann's thrombasthenia clinicopathologic spectrum.

OBJECTIVE: To platelet aggregometry and describe the clinical spectrum of Glanzmann's thrombasthenia diagnosed by platelet aggregometry. STUDY DESIGN: A case-series. PLACE AND DURATION OF STUDY: This study was carried out at the clinical laboratories at the Aga Khan University Hospital, Karachi from January 2003 to January 2006. PATIENTS AND METHODS: All patients irrespective of age and gender presenting with bleeding symptoms and having normal platelet count were evaluated. Demographic details, relevant clinical history along with results of complete blood count, bleeding time and platelet aggregation studies were retrieved through computerized data base and evaluated for the diagnosis of Glanzmann's thrombasthenia. RESULTS: During the study period, 50 out of 2317 patients (2.2%) were diagnosed as Glanzmann's thrombasthenia by platelet aggregometry with male to female ratio of 0.85:1 and median age of 10.2 years (ranging from 3 months to 27 years). Common symptoms were epistaxis, oral and gingival bleed, bleeding from minor cuts and trauma that were observed in 46% of the patients; while 18%, 8% and 10% of them also complained of bruising, hematuria and bleeding per rectum respectively. Majority i.e. 86% had a bleeding time greater than 10 minutes. All patients had received blood or blood products for their bleeding episodes. CONCLUSION: Platelet aggregometry is a useful diagnostic modality for the assessment of Glanzmann's thrombasthenia. The disorder presents with muco-cutaneous bleeding and was found to be a common cause of bleeding in our setup.

Platelet function defects.

Inherited defects of platelet function are a heterogeneous group of disorders that can result in bleeding symptoms ranging from mild bruising to severe mucocutaneous haemorrhage. These defects may be classified according to their effect on the various steps of platelet microthrombi formation including initiation, extension and cohesion, or based on their particular structural or functional deficiency. Platelet membrane receptor deficiencies result in the rare, but well-characterized syndromes of defective clot initiation, such as Bernard-Soulier Syndrome. Platelet storage pool defects are the most common disorders affecting the extension phase of clot formation. Glanzmann thrombasthenia, with absent or dysfunctional alpha IIb beta 3 receptor is the prototypical defect of the cohesion/aggregation phase of microthrombi formation. Many of these disorders share common treatments although some therapies will have greater efficacy for one patient than another and should be individualized so as to provide optimal control of symptoms. Currently much effort is being put into methods to more rapidly and accurately diagnose patients with platelet disorders and to initiate appropriate therapy and prevent life threatening bleeding.