Glanzmann Thrombasthenia

Article Author:
Katherine Krause
Article Editor:
Brendan Graham
Updated:
6/4/2019 7:08:48 PM
PubMed Link:
Glanzmann Thrombasthenia

Introduction

Glanzmann thrombasthenia (GT), first described in 1918, is a congenital bleeding disorder caused by a defect and/or deficiency of a platelet integrin, alpha IIb beta3.[1][2] The integrin is the platelet fibrinogen receptor and essential to platelet aggregation and hemostasis.[3] Patients with this disorder have lifelong bleeding episodes that often involve the mucocutaneous membranes [2]

Etiology

GT is an autosomal recessive disorder with mutations involving chromosome 17q21, specifically the ITGA2B or ITGB3 genes.[2][4][5] Mutations of either gene can cause GT, and hundreds of mutations have been reported. GT results when a patient is homozygous for the same mutation or is a compound heterozygote for different mutations.[3] The various genetic alterations can lead to different levels of function and expression of the alpha IIb beta3 integrin.[2] The Manouche mutation has no alpha IIb beta3 integrin expression. [6]

Acquired GT is due to an autoantibody against the platelet fibrinogen receptor. Many hematologic conditions can lead to antibody formation, such as multiple myeloma. [7] One case report describes an anti-alpha IIb beta3 antibody in a patient with systemic lupus erythematosus. [8] These cases are rare, and GT mostly commonly refers to the inherited form, which is otherwise described in this article.

Epidemiology

The prevalence of GT is estimated to be about 1:1,000,000 in the general population.[2] In certain areas, such as those with high consanguinity, the prevalence is roughly 1:200,000 or higher.[3][6] Pakistan and the Canadian province Newfoundland and Labrador are some of the areas with a high prevalence.[9][6] Some patients may have mild symptoms and are never identified as having GT, so the actual prevalence may be higher than reported.[6] Studies show that females are slightly more frequently affected than males. GT is commonly encountered in children and young adults but can affect any age.[2]

Pathophysiology

The alpha IIb beta3 integrin, formerly known as GPIIb-IIIa, is the platelet’s fibrinogen receptor. When platelets are activated, the αIIbβ3 integrin shifts into its active configuration to allow fibrinogen binding. As platelets bind the fibrinogen, they aggregate and provide primary hemostasis. Without functioning fibrinogen receptors, or without enough of them, bleeding can be spontaneous or occur with an injury.[2][7] Additionally, platelets in GT are not as efficient at generating thrombin, an essential part of converting fibrinogen to fibrin.[3] Secondary hemostasis occurs when cross-linked fibrin stabilizes the platelet plug, and is thus also affected by GT.[6]

Histopathology

GT is a platelet disorder, and platelets are identified on blood smears. In general, the platelets of a patient with GT appear normal, but rare mutations can result in platelets that are of unequal size.[4][5] Isolated families with GT have been identified as having large and relatively few platelets, a condition known as macrothrombocytopenia.[3]

History and Physical

When evaluating a patient for potential Glanzmann Thrombasthenia, his or her bleeding and bruising history is a common starting point. Additionally, a family history of bleeding can be an important aid in diagnosis. Epistaxis is particularly prevalent in children,[3] and other common manifestations are menorrhagia and gingival bleeds [2] Gastrointestinal bleeding is less frequently reported, and some cases of GT are undiagnosed until an invasive procedure.[4][10] Most patients with GT are diagnosed at an early age, with symptoms often appearing within the first year of life. Bleeding can occur after circumcision and can even require transfusion,[2], but some patients will have improvement in their symptoms by adulthood. Use of a bleeding assessment tool may be beneficial to help identify abnormalities.[11] 

A voluntary Glanzmann Thrombasthenia Registry enrolled patients with GT, and their data indicates that the first symptoms occurred at a median age of 1one year and a mean of 5.6 years. Of the enrollees, 85% were diagnosed with GT by 14 years of age.[3]

Physical examination is focused on identifying bleeding and its sequelae, such as ecchymoses.[11] As epistaxis is a common manifestation of GT, the nasal cavity should be carefully inspected.[4][7]

Evaluation

The Subcommittee on Platelet Physiology, part of the International Society on Thrombosis and Haemostasis (ISTH), has offered guidance on the diagnosis of GT and other inherited platelet function disorders (IPFD). According to their algorithm, if the patient has clear clinical bleeding abnormalities, preliminary laboratory tests may include a complete blood count (CBC), activated partial thromboplastin time (PTT), prothrombin time, and assessments for von Willebrand disease such as von Willebrand Factor (vWF) antigen, ristocetin cofactor activity, and factor VIII coagulant activity. These tests help rule out more common causes of bleeding, and they are generally normal in GT and other IPFD. Further evaluation consists of platelet function studies or next-generation sequencing. Screening may include a blood smear, light transmission aggregometry (LTA), platelet granule release assessment, and flow cytometry to analyze platelet surface glycoproteins.

LTA, the gold standard test, reveals altered platelet aggregation with agonists other than ristocetin.[7] Flow cytometry typically shows defective expression of alpha IIb beta 3 integrin, although some cases with defective integrins may demonstrate normal expression.[11] The integrin components are identified as CD41 (alpha IIb) and CD61 (beta 3). CD42b, a glycoprotein important in binding vWF, should be normally expressed.[2] Of note, the platelet function analyzer (PFA) test was not recommended by the ISTH. The PFA test simulates damaged endothelium and measures the platelet plug formation time, which is prolonged in GT.[7]

Secondary tests may include clot retraction, which is impaired in GT. Molecular genetic tests are included in the ISTH guidance for cases that remain undiagnosed after other laboratory studies. Gene mutations in ITGA2B or ITGB3 are identified in GT.[11]

Treatment / Management

As with many bleeding disorders, a tiered management system exists for GT. For mild bleeding episodes, initial treatment may include local pressure, cauterization, sutures, or ice therapy.[3][9][6] Some providers also use antifibrinolytic agents, such as tranexamic acid, which can be used as a mouthwash for gingival bleeding.[9][6] After the failure of synthetic nasal packing and conventional therapies, successful treatment with salt pork packing and concomitant antibiotics has been reported.[4]

If the bleeding is unresponsive or incompletely responds to local measures, or if the patient is undergoing surgery, platelets and/or recombinant activated clotting factor VII (rFVIIa) may be required.[3] Platelet transfusion as surgical prophylaxis and as the treatment for moderate to severe bleeding is standard for GT.[6] Recombinant FVIIa binds to activated platelets and creates a thrombin burst, helping fibrinogen conversion to fibrin and subsequent hemostasis. Recombinant FVIIa is approved in the United States for GT patients with platelet refractoriness. In Europe, rFVIIa is additionally approved for GT patients with platelet antibodies. For the treatment of surgical bleeds, rFVIIa alone can be highly effective. Its efficacy has led to its frequent off-label use for surgical procedures and bleeding.[3] Data from the Glanzmann Thrombasthenia Registry suggest that treatment with rFVIIa with or without antifibrinolytics is as effective as or more effective than treatment with platelets with or without antifibrinolytics.[6] Dosing is adjusted for operative vs. non-operative procedures, and children may require more rFVIIa than adults.[3] In select patients, however, rFVIIa may be ineffective.[7]

Female patients may require menorrhagia management and should be screened for iron deficiency. Antifibrinolytics are the initial treatment for menorrhagia, although continuous hormone supplementation is a common preventative management technique.[7] Menarche may require a blood transfusion, and in those cases, immediate treatment with high-dose estrogen followed by continuous oral contraceptives could be considered.[5] Surgical management with endometrial ablation or hysterectomy can be performed for women not interested in preserving fertility. For pregnant GT patients planning to deliver vaginally, guidelines recommend some form of prophylaxis, such as an anti-fibrinolytic or rFVIIa. Operative guidelines also recommend rFVIIa as prophylaxis for Cesarean sections.[7]

Preventative management and symptomatic treatment work well for many patients. In select GT patients with an extremely poor quality of life, curative treatment by way of hematopoietic stem cell transplant has been effective.[6] Transplant comes with its risks, and careful assessment of the clinical scenario with its potential risks and benefits is essential.[3][5]

Differential Diagnosis

GT patients with bleeding initially have a broad differential, including thrombocytopenia and acquired platelet dysfunction (such as NSAID use). Hermansky-Pudlak syndrome, von Willebrand disease, and Bernard-Soulier syndrome should also be considered.[6] Other platelet function disorders, such as gray platelet syndrome, Medich platelet syndrome, and Scott syndrome, are possible but less likely.[11]

Pertinent Studies and Ongoing Trials

Gene editing and gene transfer for GT are in experimental stages. [3][6]

Toxicity and Side Effect Management

Treatment of GT patients with platelets can result in anti-HLA antibodies as well as antibodies against integrin alpha IIb beta 3. Treatment with HLA-compatible platelets can be beneficial, and immunoadsorption techniques for anti-alpha IIb beta 3 are available. GT patients can experience the same reactions (i.e., anaphylaxis or transfusion-related acute lung injury) as other patients receiving blood products and need to be treated accordingly.[3]

Treatment with rFVIIa can result in thromboembolic complications, although this is rare in patients with inherited bleeding disorders.[6]

Prognosis

GT is a severe bleeding disorder, and life-threatening or fatal bleeding can occur spontaneously or with invasive procedures, severe trauma, or as a consequence of childbirth.[3][6] The broad mutational causes of GT yield many clinical presentations that range in severity. Patients can do well with healthcare team preparation and coordination, such as the 52-year-old man with GT who had a successful open aortic valve replacement.[10] In general, GT bleeding episodes are not as life-threatening as those associated with inherited coagulation disorders.[2]

Complications

Patients with GT and chronic mild bleeding may develop iron deficiency anemia, but the majority of GT complications are related to its treatment rather than the disease itself.[6]

Approximately 17% of GT patients who receive leukocyte-reduced platelets develop anti-HLA antibodies, and that percentage increases significantly if the platelets are not leukocyte-reduced. Of the patients who develop anti-HLA antibodies, roughly half are refractory to future platelet transfusions. Patients with certain mutations may develop antibodies to the surface antigens of the alpha IIb beta 3 integrin.[3][6] Patients with GT can also develop anti-platelet antibodies. Anti-platelet antibodies can cross the placenta, and studies of pregnant women with GT and anti-platelet antibodies have demonstrated a spectrum of fetal effects ranging from thrombocytopenia to neonatal death secondary to intracranial hemorrhage.[7][12]

Deterrence and Patient Education

Patients with GT should be educated on how to recognize abnormal bleeding. Additionally, they should be instructed to avoid unnecessary trauma and not to take medications that interfere with platelet function. The importance of dental hygiene should be stressed as well. Some patient subgroups require special attention, i.e., young female patients may need instructions for heavy menstrual bleeding. Family planning discussions including the risk of childbirth and affected children are important for some patients as well.[6]

Pearls and Other Issues

GT is classified into three types based on the function and expression (compared to non-GT platelets) of the alpha IIb beta 3 integrin. Less than 5% expression of the integrin corresponds to Type I GT, 5% to 20% expression corresponds to type II GT, and greater than 20% expression with dysfunction corresponds to variant-type GT. Variant-type GT is rare.[7]

Enhancing Healthcare Team Outcomes

Most clinicians do not have extensive experience in the management of GT, but medical literature suggests certain approaches that can be beneficial. All of the following approaches have evidence levels of V.

When possible, HLA-matched, single donor, leukocyte-reduced platelets should be used for patients with GT to reduce the development of anti-HLA antibodies. Patients receiving platelets should also be assessed for antibodies periodically. For girls and reproductive age women, platelet transfusion should be avoided if possible to prevent the formation of antibodies.

The perioperative use of rFVIIa is both safe and effective.[13][14]

Antifibrinolytic agents should not be used in GT patients with bleeding in the urinary tract due to potential clots.[7]

A multidisciplinary approach involving specialized nursing, social workers, and physical therapy can promote recognition of abnormal bleeding and teach techniques for self-management. Appropriate athletic activities, vocational training, and other psychosocial issues can also be addressed.[6] Multidisciplinary discussions are essential to operative planning as well. Surgeons, anesthesiologists, and transfusion medicine physicians can help optimize perioperative management.[10]


References

[1] Doherty D,Singleton E,Byrne M,Ryan K,O'Connell NM,O'Donnell JS,Lavin M, Missed at first Glanz: Glanzmann thrombasthenia initially misdiagnosed as Von Willebrand Disease. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2018 Dec 5;     [PubMed PMID: 30551951]
[2] Iqbal I,Farhan S,Ahmed N, Glanzmann Thrombasthenia: A Clinicopathological Profile. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2016 Aug;     [PubMed PMID: 27539755]
[3] Poon MC,Di Minno G,d'Oiron R,Zotz R, New Insights Into the Treatment of Glanzmann Thrombasthenia. Transfusion medicine reviews. 2016 Apr;     [PubMed PMID: 26968829]
[4] Humphreys I,Saraiya S,Belenky W,Dworkin J, Nasal packing with strips of cured pork as treatment for uncontrollable epistaxis in a patient with Glanzmann thrombasthenia. The Annals of otology, rhinology, and laryngology. 2011 Nov;     [PubMed PMID: 22224315]
[5] Nurden AT,Freson K,Seligsohn U, Inherited platelet disorders. Haemophilia : the official journal of the World Federation of Hemophilia. 2012 Jul;     [PubMed PMID: 22726100]
[6] Lee A,Poon MC, Inherited platelet functional disorders: General principles and practical aspects of management. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2018 Aug;     [PubMed PMID: 30031712]
[7] Solh T,Botsford A,Solh M, Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options. Journal of blood medicine. 2015;     [PubMed PMID: 26185478]
[8] Nurden AT,Fiore M,Nurden P,Pillois X, Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models. Blood. 2011 Dec 1;     [PubMed PMID: 21917754]
[9] Borhany M,Fatima H,Naz A,Patel H,Shamsi T, Pattern of bleeding and response to therapy in Glanzmann thrombasthenia. Haemophilia : the official journal of the World Federation of Hemophilia. 2012 Nov;     [PubMed PMID: 22970800]
[10] Sheikh AY,Hill CC,Goodnough LT,Leung LL,Fischbein MP, Open aortic valve replacement in a patient with Glanzmann's thrombasthenia: a multidisciplinary strategy to minimize perioperative bleeding. Transfusion. 2014 Feb;     [PubMed PMID: 23710629]
[11] Gresele P, Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. Journal of thrombosis and haemostasis : JTH. 2015 Feb;     [PubMed PMID: 25403439]
[12] Barg AA,Hauschner H,Luboshitz J,Livnat T,Straus T,Levy-Mendelovich S,Lubetsky A,Rosenberg N,Kenet G, From thrombasthenia to next generation thrombocytopenia: Neonatal alloimmune thrombocytopenia induced by maternal Glanzmann thrombasthenia. Pediatric blood     [PubMed PMID: 30216638]
[13] Rajpurkar M,Chitlur M,Recht M,Cooper DL, Use of recombinant activated factor VII in patients with Glanzmann's thrombasthenia: a review of the literature. Haemophilia : the official journal of the World Federation of Hemophilia. 2014 Jul;     [PubMed PMID: 24948404]
[14] Di Minno MND,Ambrosino P,Myasoedova V,Amato M,Ventre I,Tremoli E,Minno AD, Recombinant Activated Factor VII (Eptacog Alfa Activated, NovoSeven®) in Patients with Rare Congenital Bleeding Disorders. A Systematic Review on its Use in Surgical Procedures. Current pharmaceutical design. 2017;     [PubMed PMID: 28034354]