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Glanzmann Thrombasthenia

Glanzmann thrombasthenia (GT) is a hereditary blood clotting disorder, which is typified by abnormal bleeding. This disease emerges from a genetic mutation that affects platelet aggregation.

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Presentation

GT manifests in periods of infancy or childhood. The clinical picture includes abnormal bleeding that is usually an exaggerated response to an injury [9]. Additionally, affected children experience epistaxis, which can be severe. Also, patients commonly have gingival bleeding, especially if their dental hygiene is poor [9]. Moreover, women frequently suffer from abnormal uterine bleeding that may warrant blood transfusions [9]. Very importantly, events such as childbirth, dental procedures, and surgery increase the risk for hemorrhagic complications. Further features such as gastrointestinal hemorrhage, hematuria, and joint bleeding may occur although they are rare.

Notable findings include purpura [5] [9] and ecchymoses.

Easy Bruising
  • Till the first visit to our hospital, he had not been diagnosed with GT despite a history of bleeding tendency, notably purpura in areas of easy bruising and prolonged bleeding time after abrasions and insect stings.[ncbi.nlm.nih.gov]
  • Easy bruising is often noticed early and the diagnosis is usually made by the age of five years. The commonest problems are easy bruising, nose bleeds, heavy periods and gum bleeding.[contact.org.uk]
  • But there is a small group of patients in whom repeated episodes of easy bruising, epistaxis and other bleeding episodes occur despite a normal platelet count and normal plasma coagulation factors.[nejm.org]
Ecchymosis
  • Patients typically present in early childhood with moderate to severe mucocutaneous bleeding, including menorrhagia, epistaxis, gingival bleeding, GI hemorrhage, and ecchymosis. Epistaxis can be severe, leading to iron deficiency anemia.[clinicaladvisor.com]
  • Upon physical exam in the clinic, mild effusion of the right knee was noted with no ecchymosis, and laxity tests and meniscal exams were negative. Range of motion was 2 degrees of extension and 110 degrees of flexion.[opnews.com]
  • ., bruising, purpura, ecchymosis, gum bleeding, epistaxis, gastrointestinal bleed and menorrhagia, are commonly seen.[jmgims.co.in]
Gagging
  • One was a C -- G substitution at the splice acceptor site (- 3) of exon 26 (CAG -- GAG) and the other was the insertion of an additional C at the region including six C bases between 2911 and 2916 in exon 28 (InsC).[ncbi.nlm.nih.gov]
Bleeding Gums
  • Symptoms may include any of the following: Heavy bleeding during and after surgery Bleeding gums Bruising easily Heavy menstrual bleeding Nosebleeds that do not stop easily Prolonged bleeding with minor injuries There is no specific treatment for this[medlineplus.gov]
  • Poor oral hygiene and local factors are the main etiological factors for bleeding gums.[jiaomr.in]
  • Signs and clinical symptoms associated with this disease can include easy bruising presence, epistaxis, bleeding gums, petechiae and bruising.[ivami.com]
  • Symptoms Symptoms may include any of the following: Heavy bleeding during and after surgery Bleeding gums Bruising easily Heavy menstrual bleeding Nosebleeds that do not stop easily Prolonged bleeding with minor injuries Exams and Tests The following[ufhealth.org]
Poor Oral Hygiene
  • Poor oral hygiene and local factors are the main etiological factors for bleeding gums.[jiaomr.in]
Purpura
  • Glanzmann thrombasthenia (GT) is a rare, autosomal recessive coagulopathy characterized by either qualitative or quantitative abnormalities of the membrane glycoprotein αIIbβ3 complex leading to bleeding tendencies, ranging from purpura to life-threatening[ncbi.nlm.nih.gov]
  • Review Topic QID: 101327 2 Thrombotic thrombocytopenic purpura 4 Idiopathic thrombocytopenic purpura 5 Glanzmann’s thrombasthenia M1 Select Answer to see Preferred Response PREFERRED RESPONSE 5 Sorry, this question is for PEAK Premium Subscribers only[medbullets.com]
Petechiae
  • History The clinical history of Glanzmann thrombasthenia may include the following: Excessive bleeding after dental extraction (this may often be the first sign of the disease) Petechiae and ecchymoses (although spontaneous petechiae are uncommon) Gingival[emedicine.medscape.com]
  • Symptoms include purpura, petechiae, bruising, gingival bleeding, epistaxis, and menorrhagia.[ncbi.nlm.nih.gov]
  • On physical exam, his extremities are spotted with petechiae and purpura. Suspicious of a congenital bleeding disorder, the pediatrician orders labs. A complete blood count comes back with normal platelet count but increased bleeding time.[medbullets.com]
Epistaxis
  • Key words: Epistaxis; Glanzmann's Thrombasthenia; Recurrent Epistaxis[scopemed.org]
  • Glanzmann thrombasthenia is a qualitative platelet function disorder manifested by skin bleeds, epistaxis, gingival bleeding, gastrointestinal hemorrhage, hematuria, hemarthrosis, intracranial hemorrhage and visceral hematomas.[ncbi.nlm.nih.gov]
  • A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Glanzmann thrombasthenia a hereditary platelet abnormality characterized by defective clot retraction, prolonged bleeding time, and related symptoms such as epistaxis and inappropriate bleeding.[web.archive.org]
Hematuria
  • 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.[ncbi.nlm.nih.gov]
  • […] the disease) Petechiae and ecchymoses (although spontaneous petechiae are uncommon) Gingival bleeding (which is worse with poor dental hygiene) Hemarthroses (rare) Family history of a bleeding disorder may or may not exist Gastrointestinal bleeding or hematuria[emedicine.medscape.com]

Workup

Patients presenting with abnormal bleeding warrant a thorough assessment consisting of personal and family history, a physical exam, and comprehensive testing.

Laboratory tests

The initial studies include a CBC and coagulation panel. Typical results include normal platelet count, iron deficiency anemia, normal activated partial thromboplastin time (aPTT), and normal prothrombin time (PT). However, bleeding time (BT) is prolonged [10].

One diagnostic tool analyzes platelet function with the light transmission aggregometry (LTA), which is very specific for GT. However, there is a disadvantage associated with this method since children and thrombocytopenic individuals may not be able to produce platelet-rich samples [11].

Another important diagnostic technique for GT patients, the platelet function analyzer (PFA), demonstrates the failure of platelets to plug the filters during the procedure [12]. Finally, flow cytometry and monoclonal antibodies will determine and confirm the deficiency of the GPIIb/IIIa unit.

Other

Genetic testing can reveal the DNA mutations that cause the disease.

Platelet Aggregation Abnormal
  • Desmopressin has been used with unequivocal success in patients with defective platelet adhesion, however, its role in platelet aggregation abnormalities is not established.[jnaccjournal.org]

Treatment

While there is no specific therapy or cure for GT, management of this disease is centered on supportive care, which is paramount for the prevention of complications and adverse outcomes.

Local treatment

In cases with a minor and local bleeding, the application of fibrin sealants can control the hemorrhage. With epistaxis and gingival bleeding, patients usually benefit from homeostatic measures such as nasal packing or the use of gel foam that contains thrombin.

Blood transfusion

Blood transfusions are commonly required [13] [14]. Special consideration should be applied in surgical patients with GT. Specifically, perioperative management should include prophylactic transfusions or readily available blood preparations.

Special consideration should be given to delivering mothers since childbirth poses a significant risk for hemorrhage. Therefore, platelet transfusions are given before delivery and possibly even a week postpartum [13].

Individuals who receive numerous transfusions may produce antibodies [9]. Therefore, platelet products should be screened and matched for HLA-compatibility to prevent anti-HLA alloimmunization. Note that high titers of antibodies render the patient refractory to future transfusions.

Novel therapy

Recombinant factor VIIa was approved for treatment of GT in 2014. This medication can be administered in actively bleeding patients and those who do not respond to platelet transfusions. Specifically, it is beneficial in GT individuals with antibodies [15]. It can be given in conjunction with anti-fibrinolytic drugs as recombinant factor VIIa plays a role in stabilizing new clots [16].

Other

Manifestations of GT should be managed accordingly. For example, menorrhagia is treated with additional doses of hormones like progesterone. Also, oral contraceptives should be given for maintenance therapy. Additionally, iron deficiency anemia should be addressed and treated with iron supplements. Finally, routine dental care is important to prevent gingival disease and reduce bleeding.

Prognosis

Patients who receive supportive care have a good prognosis. Adults are generally healthy as bleeding decreases with age. Also, mortality is rare.

Etiology

This condition was first described in 1918 by a Swiss physician known as Eduard Glanzmann when he discovered that GT occurred secondary to a dysfunction in the clotting process [1]. He also investigates the familial component. Later, it was discovered that mutations in genes on chromosome 17 are responsible for deficiency of GPIIb/IIIa receptor, which binds fibrinogen and von Willebrand factor (vWF).

Glanzmann thrombasthenia is an autosomal recessive disorder with mutations in gene(s) coding for the platelet GPIIb/IIIa (aIIbb3) integrin family receptor. The majority of defects occur in the ITGA2B (codes for αIIb) or ITGB3 (codes for β3) genes. There a myriad of abnormalities that have been identified for this disorder such as frameshifts, insertion, and missense mutations.

There is a very rare acquired form of GT that results from antibodies to the GPIIb/IIIa complex. This infrequent type was observed in a patient with non-Hodgkin lymphoma [2] [3]. Another variant, transient GT, may emerge in patients receiving antithrombotic medications [4].

Epidemiology

The prevalence of GT is estimated to be 1 in a population of 1 million [5]. With regards to the patient demographics, some studies have demonstrated a slight preference for females [6]. Furthermore, this disease is more predominant in specific ethnic groups in which consanguinity is prevalent. Specifically, a higher incidence is found in populations such as Palestinians, Jordanian tribes, Iraqi Jews, and certain French Gypsy communities [7].

Sex distribution
Age distribution

Pathophysiology

The GPIIb/IIIa is heterodimeric membrane receptor that is composed of two subunits: αIIb and β3. In the event of an injury, this receptor promotes the adherence of platelets to the endothelium, platelet aggregation, and thrombus formation. This complex is also involved in other cellular mechanisms such as cell migration and cell-to-cell communication.

Injured endothelium secretes fibrinogen and adhesive proteins that attach to platelets and form a plug at the damaged site. Activated platelets prompt conformational changes in the GPIIb/IIIa unit, thereby allowing the receptor to bind fibrinogen [8]. The bound fibrinogen bridges platelets to each other and signals for further aggregation. The overall process generates homeostasis. Hence, a dysfunction in the GPIIb/IIIa receptor leads to prolonged bleeding.

Prevention

As a hereditary disorder, GT cannot be prevented. However, genetic counseling is available for patients and their family members to provide them with information about the disease, its mode of inheritance, expectations, and other important details. Prenatal testing can be done if the genetic defect in the family is identified.

Education

Additionally, there are precautions for patients and their parents:

  • Patients should wear a medical bracelet or possess proper documentation in case of emergencies or trauma
  • They should understand when to seek emergency care
  • They should be informed thoroughly about the disease

Medications to avoid

Any drug that reduces the function of platelets or affects coagulation is contraindicated in patients with GT. The list of drugs includes aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, heparin, clopidogrel, ticlopidine, GP IIb/IIIa inhibitors, tissue plasminogen activator (tPA), streptokinase, urokinase, certain volume expanders, and dipyridamole.

Summary

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by the failure of platelet aggregation. Mutations in genes coding for GPIIb/IIIa integrin family receptor will lead to an abnormality or deficiency of this receptor, which is essential in platelet aggregation. Since platelets are integral to homeostasis, disruption in their function will lead to impairment of the coagulation process.

The clinical picture manifests in infants or young children. The main features include exaggerated bleeding responses, epistaxis, and gingival bleeding. Additionally, women will often experience heavy menstrual bleeding and possibly complications with childbirth. Patients undergoing surgery or teeth extractions may also have difficulty with hemorrhage control.

Infants and children with excessive and/or prolonged bleeding should be evaluated with a personal and family history, a physical exam, and laboratory tests. The latter includes complete blood cell (CBC), coagulation studies, and diagnostic techniques that assess for platelet aggregation function, flow cytometry and monoclonal antibodies. The above tools will reveal findings that are characteristic of GT.

With regards to therapy and management, patients will often receive supportive care with platelet transfusions, especially for those undergoing surgical procedures, childbirth, trauma, etc. Additionally, local fibrin sealants are used for smaller wounds. A new agent, recombinant factor VIIa, can be administered for patients actively bleeding or those who are refractory to transfusions.

Individuals who are appropriately treated will lead healthy lives. Affected children and their parents should be educated thoroughly about GT and establish care with the healthcare provider. Additionally, genetic counseling is available to patients and their family members.

Patient Information

What is Glanzmann thrombasthenia?

Glanzmann thrombasthenia (GT) is an inherited blood clotting disorder. In this rare condition, there is a dysfunction of the platelets. Therefore, blood clotting does not work properly and these patients experience abnormal bleeding. This disease can be life-threatening if not treated appropriately.

What are the causes?

This disease develops from mutations in genes that are responsible for producing glycoprotein IIb/IIIa, which are found on chromosome 17.

GT is inherited in an autosomal recessive pattern. This means that the affected individual has two bad copies of the gene in order to have the disease. In other words, the patient inherits a bad copy from each parent.

What are the signs and symptoms?

This disease presents in infants or early years of childhood. The main features are as follows:

How is it diagnosed?

Patients with abnormal bleeding should be evaluated with a personal and family history, a physical exam, and laboratory tests such as:

  • Complete blood count will show normal number of platelets
  • Coagulation studies will show prolonged bleeding time
  • Platelet aggregation studies will be abnormal
  • Flow cytometry and monoclonal antibodies will reveal a deficiency in GPIIb/GPIIIa receptor
  • Genetic testing to determine the mutation

How is it treated?

There is no specific treatment for this disease, however, patients may require blood platelet transfusions especially if they undergo:

  • Surgery
  • Dental procedures
  • Childbirth
  • Trauma

There is a new medication called NovoSeven RT, a recombinant factor VIIa, which can be beneficial. Also, fibrin sealants can be used for local wounds.

Can it be prevented?

Since this disease is inherited, it cannot be prevented. However, genetic counseling is offered to patients and their family members to provide education regarding what the disease is, how it is inherited, and other important details.

Patients with GT should avoid medications such as:

Additionally, there are precautions:

  • Patients and parents should learn about the disease
  • Patients and parents of young patients should be aware of the condition and when to seek emergency care
  • Patients should wear medical emergency bracelets or have proper identification in case of emergency or trauma

What is the prognosis?

The prognosis is usually excellent as adults are usually healthy. Also, the bleeding decreases as the patient gets older.

References

Article

  1. Nurden AT, Pillois X, Wilcox DA. Glanzmann thrombasthenia: state of the art and future directions. Semin Thromb Hemost. 2013; 39(6):642–655.
  2. Malik U, Dutcher JP, Oleksowicz L. Acquired Glanzmann's thrombasthenia associated with Hodgkin's lymphoma: a case report and review of the literature. Cancer. 1998; 82(9):1764-8.
  3. Tholouli E, Hay CR, O'Gorman P, et al. Acquired Glanzmann's thrombasthenia without thrombocytopenia: a severe acquired autoimmune bleeding disorder. Br J Haematol. 2004; 127(2):209-13
  4. Albrecht C, McVey JH, Elliott JI, et al. A novel missense mutation in ABCA1 results in altered protein trafficking and reduced phosphatidylserine translocation in a patient with Scott syndrome. Blood. 2005; 106:542–549.
  5. Rosas RR, Kurth MH, Sidman J. Treatment and outcomes for epistaxis in children with Glanzmann’s thrombasthenia. Laryngoscope. 2010; 120(12):2374–2377.
  6. Nurden AT, Ruan J, Pasquet KM, et al. A novel 196Leu to Pro substitution in the beta3 subunit of the alphaIIbbeta3 integrin in a patient with a variant form of Glanzmann thrombasthenia. Platelets. 2002; 13(2):101–111.
  7. Stevens RF, Meyer S. Fanconi and Glanzmann: the men and their works. Br J Hematol. 2002; 119(4):901–904.
  8. Fullard JF. The role of the platelet glycoprotein IIb/IIIa in thrombosis and haemostasis. Curr Pharm Des. 2004;10(14):1567-76.
  9. George JN, Caen JP, Nurden AT. Glanzmann's thrombasthenia: the spectrum of clinical disease. Blood. 1990; 75(7):1383–95.
  10. Arai M, Yamamoto N, Moroi M, et al. Platelets with 10% of the normal amount of glycoprotein VI have an impaired response to collagen that results in a mild bleeding tendency. Br J Haematol. 1995; 89(1):124– 130.
  11. Bettache N. Impaired redistribution of aminophospholipids with distinctive cell shape change during Ca2+ - induced activation of platelets from a patient with Scott syndrome. Br J Haematol. 1998;101(1):50–58.
  12. Bolton - Maggs PH. Definition of the bleeding tendency in factor XI - deficient kindreds – a clinical and laboratory study.Thromb Haemost . 1995;73(2):194–202.
  13. Nurden AT, George JN. Inherited abnormalities of the platelet membrane: Glanzmann thrombasthenia, Bernard-Soulier syndrome, and other disorders. "Hemostasis and Thrombosis, Basic Principles and Clinical Practice" VI edition. Colman RW, Marder VJ, Clowes AW, et al, eds. Lippincott, Williams & Wilkins, Philadelphia; 2005:987-1010.
  14. Bellucci S, Caen J. Molecular basis of Glanzmann's thrombasthenia and current strategies in treatment. Blood Rev. 2002; 16(3):193-202.
  15. Poon MC, D'Oiron R, Von Depka M, et al. International Data Collection on Recombinant Factor VIIa and Congenital Platelet Disorders Study Group: Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann's thrombasthenia: results of an international survey. J Thromb Haemost. 2004; 2(7):1096-1103.
  16. He S, Jacobsson Ekman G, Hedner U. The effect of platelets on fibrin gel structure formed in the presence of recombinant factor VIIa in hemophilia plasma and in plasma from a patient with Glanzmann thrombasthenia. J Thromb Haemost. 2005; 3(2):272-279.

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Last updated: 2019-07-11 20:39