Glanzmann's thrombasthenia overview
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Glanzmann's thrombasthenia |
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Differentiating Glanzmann's thrombasthenia from other Diseases |
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Diagnosis |
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Treatment |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]
Overview
In 1918, Eduard Glanzmann, a Swiss pediatrician, described Glanzmann's thrombasthenia for the first time. It was known formerly as “hereditary hemorrhagic thrombasthenia”, but Glanzmann proposed it was not abnormal platelet number but a disorder of clotting. Glanzmann's thrombasthenia is mainly divided into hereditary GT, variant GT, and acquired GT. Glanzmann's thrombasthenia is an autosomal recessive hematologic disorder . Megakaryocyte lineage is affected in this disease, and leads to dysfunctional platelet aggregation.The pathogenesis is related to a quantitative and/or qualitative defect in GpIIb/IIIa (αIIbβ3 integrin) construction. Glanzmann's thrombasthenia can be inherited in an autosomal recessive manner or acquired as an autoimmune disorder. In the hereditary type of Glanzmann's thrombasthenia GPIIb/IIIa (ITG αIIbβ3) is qualitative or quantitative disorder. The incidence/prevalence of Glanzmann's thrombasthenia is approximately one per 1,000,000 individuals worldwide. The highest reported prevalence in the world was in Iran, in 2004 the incidence of Glanzmann's thrombasthenia was approximately 2 per 100,000 individuals. The most potent risk factor in the heritable Glanzmann's thrombasthenia is consanguineous marriage. Autoantibodies production cause of acquired Glanzmann thrombasthenia. Common complications of include sever fatal bleeding following major surgeries , labor and delivery. 84% of patients with Glanzmann's thrombasthenia require at least once in their life red blood cell transfusion. The episodes of severe spontaneous hemorrhage is reduced with age. The treatment of bleeding episodes in patients with glanzmann's thrombasthenia includes local measures with or without anti-fibrinolytic therapy first, followed by platelet transfusion, and rFVIIa if bleeding persists. However, the majority of cases of glanzmann's thrombasthenia are self-limited and only require supportive care. Other options include desmopressin (DDAVP) which increases in plasma, the tissue plasminogen activator (TPA),FVIII and VWF, but it has no significant effect on platelet disorders, rFVIIa: Manages bleeding in most patients with glanzmann's thrombasthenia, rituximab, bevacizumab, hematopoietic stem cell transplantation and gene therapy. DDAVP prevents bleeding after dental extraction and minor surgery in patients with milder platelet defects. Glanzmann's thrombasthenia patients need regular dental visits and must maintain good oral hygiene because the recurrence of gingival bleeding is more in them. These patient should avoid contact sports. Estrogens, platelet transfusion, antifibrinolytic agents, and recombinant human factor VIIa are some other therapies used for treatment/prevention.
Historical Perspective
In 1918, Eduard Glanzmann, a Swiss pediatrician, described Glanzmann's thrombasthenia for the first time. It was known formerly as “hereditary hemorrhagic thrombasthenia”, but Glanzmann proposed it was not abnormal platelet number but a disorder of clotting. Later, it was defined as a heritable platelet disorder secondary to a dysfunction in GPIIb/IIIa complex. In 1956, Braunsteiner and Pakesch described Glanzmann's thrombasthenia as an inherited disorder with normal sized platelets that failed clot retraction. In 1965, Castaldi and Caen 7 showed that the platelet fibrinogen was either strongly diminished (in parallel with the impaired clot retraction) or borderline to the normal range. In 1966, Caen et al. explained 15 patients with Glanzmann's thrombasthenia, with decreased or nil platelet aggregation but the clot retraction was sometimes only mildly effected. The variant disease was first established in 1987 In the mid 1970’s, Nurden and Caen and Phillips et al. discovered a deficiency of both GPIIb/GPIIIa in thrombasthenic platelets. Today, it receives much recognition, as it was one of the first disorders to define GPIIb/IIIa as a platelet receptor for adhesive molecules (such as VWF and fibrinogen). Glanzmann's thrombasthenia served as a template for platelet aggregation process as well as targets for therapeutic measures.
Classification
Glanzmann's thrombasthenia is mainly divided into hereditary GT, variant GT, and acquired GT. Glanzmann thrombasthenia (GT) is an autosomal recessive inherited qualitative platelet disordercharacterized by absence or reduction of platelet glycoprotein GPIIb or GPIIIa or CD61. Hereditary Glanzmann thrombasthenia is classified into three types The subtypes vary based on ethnicity. For example, Type I is more common in Arabs and Iraqi-Jews living in Israel, whilst type II is relatively frequent in the Japanese population. Variant type includes patients with platelets expression of αIIbβ3 more than 20% in which mainly the platelets are able to aggregate but they present the clinical phenotype of GT. The reason being that the stimulated platelets can not bind to soluble Fg or antibodies recognizing activation-dependent determinants on αIIbβ3. It is due to a single amino acid substitution. Acquired GT is defined by inhibition of platelet αIIbβ3 actual function due to the attack of autoantibodies. These antibodies can be produced in numerous disorders such as hematologic malignancy, transfusion, drugs and autoimmune diseases.
Pathophysiology
Glanzmann's thrombasthenia is an autosomal recessive hematologic disorder . Megakaryocyte lineage is affected in this disease, and leads to dysfunctional platelet aggregation.The pathogenesis is related to a quantitative and/or qualitative defect in GpIIb/IIIa (αIIbβ3 integrin) construction. This receptor mediates platelet aggregation and thrombus formation when the blood vessel is damaged. The GpIIb/IIIa is an adhesion receptor and is expressed in platelets. This receptor is activated when the platelet is stimulated by ADP, epinephrine, collagen and thrombin. The GpIIb/IIIa integrin is essential to the blood coagulation since it has the ability to bind fibrinogen, the von Willebrand factor, fibronectin and vitronectin. This enables the platelet to be activated by contact with the collagen-von Willebrand-complex that is exposed when the endothelial blood vessel lining is damaged and then aggregate with other thrombocytes via fibrinogen. Patients suffering from Glanzmann's thrombasthenia thus have platelets less able to adhere to each other and to the underlying tissue of damaged blood vessels. Integrin (ITG) αIIbβ3 has roll in platelet aggregation and adhesion, connection between cells, cell migration and thrombus formation.
Causes
Glanzmann's thrombasthenia can be inherited in an autosomal recessive manner or acquired as an autoimmune disorder. In the hereditary type of Glanzmann's thrombasthenia GPIIb/IIIa (ITG αIIbβ3) is qualitative or quantitative disorder. The autoantibodies production is the main cause of acquired Glanzmann's thrombasthenia It can be produced in the Acute lymphoblastic leukemia, Non-Hodgkin lymphoma, Multiple myeloma, Hairy cell leukemia, Myelodysplastic syndrome, Immune thrombocytopenic purpura (ITP), Pregnancy, Autoimmune diseases (eg, systemic lupus erythematosus, Immunethrombocytopenia),Anti-thrombotic drugs use , like abciximab, eptifibatide, and tirofiban which all antagonize αIIbβ3 and Platelet transfusions.
Differentiating Glanzmann's thrombasthenia overview from Other Diseases
Glanzman’s thrombasthenia must be differentiated from other diseases that cause severe hemorrhages , mucocutaneous bleeding , petechiae and ecchymosis, such as platelet disorders (like : Bernard-Soulier syndrome,platelet storage pool defects,platelet-type von Willebrand disease and gray platelet syndrome), Fibrinogen abnormalities ,(eg Afibrinogenemia), Von Willebrand Disease and Wiskott-Aldrich Syndrome.
Epidemiology and Demographics
The incidence/prevalence of Glanzmann's thrombasthenia is approximately one per 1,000,000 individuals worldwide. The highest reported prevalence in the world was in Iran, in 2004 the incidence of Glanzmann's thrombasthenia was approximately 2 per 100,000 individuals. Fatal bleeding can occur at any age in Glanzmann's thrombasthenia patients, however the prevalence of severe bleeding episodes are reduce with age. The case-fatality rate of Glanzmann's thrombasthenia is relatively low.
Risk Factors
The most potent risk factor in the heritable Glanzmann's thrombasthenia is consanguineous marriage. Autoantibodies production cause of acquired Glanzmann thrombasthenia.
Screening
According to the United States Preventive Services Task Force, screening for Glanzmann's thrombasthenia is not recommended.
Natural History, Complications, and Prognosis
Common complications of include sever fatal bleeding following major surgeries , labor and delivery. 84% of patients with Glanzmann's thrombasthenia require at least once in their life red blood cell transfusion. The episodes of severe spontaneous hemorrhage is reduced with age. Patients with Glanzmann's thrombasthenia, even the individuals of the same family and ethnicity manifest diverse bleeding frequency tendency and severity and even within the same family or ethnic group. In patients with Glanzmann's thrombasthenia, the quality of life of is influenced by several mucocutaneous hemorrhages and heavy bleeding in various conditions such as menstruation, trauma and surgery .A considerable complication of Glanzmann's thrombastheniais iron deficiency anemia. Prognosis is generally excellent with good supportive care and the mortality rate of patients with Glanzmann's thrombasthenia is relatively low.
Diagnosis
Diagnostic Study of Choice
There is no single diagnostic study of choice for the diagnosis of Glanzmann's thrombasthenia, but it can be diagnosed based on Platelet aggregation assays which is panel of assays measuring platelet aggregation and activation in vitro. using like ADP, arachidonic acid, collagen, epinephrine, thrombin, and ristocetin.
History and Symptoms
Glanzmann's thrombasthenia is diagnosed at the neonatal age or early childhood, commonly before the age of 5 and the early manifestations are mostly easily bruising, mucocutaneous bleeding, epistaxisdue to digital manipulation or a sever hemorrhage after a surgery, such as circumcision. The severity of the presenting symptoms has no known relation to the affected gene. However, mutations in the ITGB3 gene manifest bleeding more than the other gene. Symptoms of Glanzmann's thrombasthenia varies from a minor bruise to a life-threatening hemorrhage. It may include easily bruising (76.6%), nosebleeds that do not stop easily (62.5%), bleeding gums (56.4%), prolonged bleeding with minor injuries (47.2%), heavy menstrual bleeding, postpartum bleeding, gastrointestinal bleeding, heavy bleeding during and after surgery and bleeding into joints (rare).
Physical Examination
Patients with Glanzmann's thrombasthenia may be asymptomatic, or they could manifest mucosal bleeding, ecchymoses, petechiae and purpura or current bleeding on physical exam.
Laboratory Findings
Initial evaluation of a patient for a suspected functional platelet disorder should include a complete blood count and examination of the peripheral blood smear. The red blood cell count is usually normal. Some patients with Glanzmann's thrombasthenia may have reduced count of red blood cell, because of coexisting iron deficiency or bleeding. The platelet count in Glanzmann's thrombasthenia is mostly on the lower end of normal. The activated partial thromboplastin time (PTT) and prothrombin time (PT) are in this disease commonly normal. Platelet aggregation assays which is panel of assays measuring platelet aggregation and activation in vitro using like ADP, arachidonic acid, collagen, epinephrine, thrombin, and ristocetin. There are several newer technologies in current clinical use measuring various aspects of platelet function. The most widely tested is the PFA-100 device. It is used to distinguish between an aspirin-induced defect and more severe platelet dysfunction. Platelet aggregation failure in LTA with all agonists except ristocetin is diagnostic of Glanzmann's thrombasthenia. Laboratory findings consistent with the diagnosis of Glanzmann's thrombasthenia include prolonged bleeding time (BT) and failure of platelets plugging to the collagen-based filter in the PFA-100 test.
Electrocardiogram
There are no ECG findings associated with glanzmann's thrombasthenia
Chest x ray
There are no chest X-ray findings associated with glanzmann's thrombasthenia
Echocardiography and ultrasound
There are no echocardiography/ultrasound findings associated with glanzmann's thrombasthenia
CT scan
There are no CT findings associated with glanzmann's thrombasthenia
MRI
There are no MRI findings associated with glanzmann's thrombasthenia
Other Imaging Findings
There are no other imaging findings associated with glanzmann's thrombasthenia
Other Diagnostic Studies
A bedside automated whole blood assay that measures platelet aggregation. It works on the principle of activated platelets binding to fibrinogen
Treatment
Medical Therapy
The treatment of bleeding episodes in patients with glanzmann's thrombasthenia includes local measures with or without anti-fibrinolytic therapy first, followed by platelet transfusion, and rFVIIa if bleeding persists. However, the majority of cases of glanzmann's thrombasthenia are self-limited and only require supportive care. Other options include desmopressin (DDAVP) which increases in plasma, the tissue plasminogen activator (TPA),FVIII and VWF, but it has no significant effect on platelet disorders, rFVIIa: Manages bleeding in most patients with glanzmann's thrombasthenia, rituximab, bevacizumab, hematopoietic stem cell transplantation and gene therapy.
Surgery
Surgical intervention is not recommended for the management of glanzmann's thrombasthenia
Prevention
DDAVP prevents bleeding after dental extraction and minor surgery in patients with milder platelet defects. Glanzmann's thrombasthenia patients need regular dental visits and must maintain good oral hygiene because the recurrence of gingival bleeding is more in them. These patient should avoid contact sports. Estrogens, platelet transfusion, antifibrinolytic agents, and recombinant human factor VIIa are some other therapies used for treatment/prevention.