Glanzmann's thrombasthenia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

Symptoms of Glanzmann’s thrombasthenia varies from a minor bruise to a life-threatening hemorrhage. 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. Common risk factors that increase autoantibodies production in acquired Glanzmann thrombasthenia include Acute lymphoblastic leukemia, Non-Hodgkin’s lymphoma, Multiple myeloma, Hairy cell leukemia and Myelodysplastic syndrome. 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.The diagnosis of Glanzmann thrombasthenia is confirmed through monoclonal antibody testing and flow cytometry. 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.

Symptoms of Glanzmann’s thrombasthenia varies from a minor bruise to a life-threatening hemorrhage. It may include any of the following manifestations:

• 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
• Bleeding into joints (rare)

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 thrombastheniaIt can be produced in the of following conditions:

• Acute lymphoblastic leukemia
• Non-Hodgkin lymphoma
• Multiple myeloma
• Hairy cell leukemia
• Myelodysplastic syndrome
• Immune thrombocytopenic purpura (ITP)
• Pregnancy
• Autoimmune diseases (eg, systemic lupus erythematosus, Immune thrombocytopenia)
• Drugs : Anti-thrombotic drugs use , like abciximab, eptifibatide, and tirofiban which all antagonize αIIbβ3
• Platelet transfusions

Common risk factors that increase autoantibodies production in acquired Glanzmann thrombasthenia include:

• Hematologic disorders and malignancies, such as :

1. Acute lymphoblastic leukemia
2. Non-Hodgkin’s lymphoma
3. Multiple myeloma
4. Hairy cell leukemia
5. Myelodysplastic syndrome
6. Immune thrombocytopenic purpura (ITP)

• Autoimmune diseases such as Lupus
• Drugs : Anti-thrombotic drugs use , like abciximab, eptifibatide, and tirofiban which all antagonize αIIbβ3
• Platelet transfusions.

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.The diagnosis of Glanzmann thrombasthenia is confirmed through monoclonal antibody testing and flow cytometry

Call for an appointment with your health care provider if you have a chronic disorder and you develop symptoms of Glanzmann thrombasthenia

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.

Call for an appointment with your health care provider if you have a chronic disorder and you develop symptoms of Glanzmann thrombasthenia

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.

Prognosis is generally excellent with good supportive care and the mortality rate of patients with Glanzmann’s thrombasthenia is relatively low

Common complications of include sever fatal bleeding following major surgeries , labor and delivery

https://www.wfh.org/en/sslpage.aspx?pid=658

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

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.

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.

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.

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.

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.

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.

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.

The most potent risk factor in the heritable Glanzmann’s thrombasthenia is consanguineous marriage. Autoantibodies production cause of acquired Glanzmann thrombasthenia.

According to the United States Preventive Services Task Force, screening for Glanzmann’s thrombasthenia is not recommended.

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.

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.

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).

Patients with Glanzmann’s thrombasthenia may be asymptomatic, or they could manifest mucosal bleeding, ecchymoses, petechiae and purpura or current bleeding on physical exam.

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.

There are no ECG findings associated with glanzmann’s thrombasthenia

There are no chest X-ray findings associated with glanzmann’s thrombasthenia

There are no echocardiography/ultrasound findings associated with glanzmann’s thrombasthenia

There are no CT findings associated with glanzmann’s thrombasthenia

There are no MRI findings associated with glanzmann’s thrombasthenia

There are no other imaging findings associated with glanzmann’s thrombasthenia

A bedside automated whole blood assay that measures platelet aggregation. It works on the principle of activated platelets binding to fibrinogen

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.

Surgical intervention is not recommended for the management of glanzmann’s thrombasthenia

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.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Niyousha Danesh, MD-MPH

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.

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^[1]. Later, it was defined as a heritable platelet disorder secondary to a dysfunction in GPIIb/IIIa complex.^[1]

In 1956, Braunsteiner and Pakesch described Glanzmann’s thrombasthenia as an inherited disorder with normal sized platelets that failed clot retraction.^[2]

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 the mid 1970’s, Nurden and Caen and Phillips et al. discovered a deficiency of both GPIIb/GPIIIa in thrombasthenic platelets.^[3]

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.^[2]The variant disease was first established in 1987.^[2]

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.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Niyousha Danesh, MD-MPH

Glanzmann’s thrombasthenia is mainly divided into hereditary GT, variant GT, and acquired GT. Glanzmann thrombasthenia (GT) is an autosomal recessive inherited qualitative platelet disorder characterized 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.

Glanzmann’s thrombasthenia is mainly divided into the following types:^[1][2][3]

Glanzmann thrombasthenia (GT) is an autosomal recessive inherited qualitative platelet disorder characterized by absence or reduction of platelet glycoprotein GPIIb or GPIIIa or CD61. Glanzmann thrombasthenia is classified into three types

• Patients with less than 5% of normal GPIIb/IIIa are classified as type I
• Type II variants have 5% to 20% normal GPIIb/IIIa
• ype III possess near-normal GPIIb/ IIIa levels but dysfunctional receptors

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.^[1]

This subset 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. ^[2]

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.^[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Niyousha Danesh, MD-MPH

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

• Integrin (ITG) αIIbβ3, formerly known as GPIIb/IIIa^[1] is a large heterodimeric cell transmembrane receptor consists of a larger αIIb and a smaller β3 subunit. These subunits are non-covalently linked, allowing for duplex signaling between the cell membrane and extracellular matrix, while instituting intracellular signaling pathways^[2]
• ITG αIIbβ3 has a 8×12 nm nodular head and two 18 nm stalks in electron microscope. These stalks have both transmembrane and cytoplasmic sides,which intracellular signaling proteins and molecules can attach to them, on the other hand the domain that binds to ligand is located in the head. ^[3]
• Hematopoietic stem cell generates Integrin αIIbβ3
• ITG αIIbβ3 consist of αIIb subunit and β3 subunit. Endoplasmic reticulum precursors accumulate these subunits and the Golgi apparatus process them.
• The αIIb subunit includes β-propeller area, which takes part in making a compound binding to calcium and platelet for platelet adhesion.
•  ITG αIIbβ3  is activated through the attachment with epidermal growth factor (EGF) site of the β3 subunit. β3 is connected to the vitronectin receptor (αvβ3). Transport process and platelet aggregation is through binding the receptor in head with vitronectin, VWF, fibronectin and fibrinogen.
• GPIIIa  on platelet is coded by ITGB3, a gene on chromosome 17q21. Whereas GPαIIb is coded by the gene ITGA2B, again on chromosome 17q21.
• ITGA2B mutations prevent β3 synthesis and lead to lack of αIIbβ3 and αvβ3 (vitronectin) receptors in individuals.
• The amount of GPIIb/IIIa receptor on platelet’s surface varies by two-fold between patients, therefore platelet consists of about 100,000 GPIIb/IIIa receptor copies. Platelet aggregates normally with only 50% gene-producing protein.
• GT manifestation and severity differ with homozygous or heterozygous mutations in gene.
• Mutations are capable of inhibiting intracellular trafficking, interfering with subunit production and complex formation. Remaining subunits of αIIb or β3 are diminished in complex formation abnormalities,
• Some mutation consequently defect fibrinogen receptor αIIbβ3 and platelet’s function. Most of these mutations occur in ITGA2B gene, because the number of exon in  ITGA2B(30) is greater than ITGB3 gene (15).
• Mutations could be either insertions, deletion,nonsense, frameshifts or missense.

• Missense mutations have different presentations it can block formation of subunits and maturation of integrin. By Leu196Pro β3 mutation clot retraction can take place partially, but when mutations in β3 Ser162Leu and Leu262Pro occur αIIbβ3 although platelets bind to fibrin and retract clot, they are not able to adhere to fibrinogen after stimulation .
• Mutations in  β-propeller domain of the αIIb subunit is observed in various types of GT, these mutations affect vastly αIIbβ3 expression and function other than interfering with calcium binding . Partial complex formation can be made despite some mutations in the αIIb subunit, even some individuals do not present GT symptoms contrary to mutations in αIIbβ3.^[4]
• Mutations could happen in subunit of αIIbβ3, or between αvβ3 and αIIbβ3. Hence αvβ3 tolerates mutations better than αIIbβ3. As an example there exist three kinds of mutations in αIIbβ3, in which αIIbβ3 complex is extremely activated and in the FAK of platelets tyrosine is phosphorylated when ITGA2B p.Phe993del, ITGB3 p.(Asp621_Glu660del) and ITGA2B p.Gly991Cysthat are mutated, though The mentioned mutations affect surface αIIbβ3 expression and change platelet morphology and count, but doesn’t manifest GT. ^{[5] [6] [7] [8] [2]}

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Niyousha Danesh, MD-MPH

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, Immune thrombocytopenia),Anti-thrombotic drugs use , like abciximab, eptifibatide, and tirofiban which all antagonize αIIbβ3 and Platelet transfusions.

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 of following conditions:^[1][2][3]

• Acute lymphoblastic leukemia
• Non-Hodgkin lymphoma
• Multiple myeloma
• Hairy cell leukemia
• Myelodysplastic syndrome
• Immune thrombocytopenic purpura (ITP)^[4]
• Pregnancy^[5]
• Autoimmune diseases (eg, systemic lupus erythematosus, Immune thrombocytopenia)^[6][7]
• Drugs : Anti-thrombotic drugs use , like abciximab, eptifibatide, and tirofiban which all antagonize αIIbβ3^[8]
• Platelet transfusions^[9]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Niyousha Danesh, MD-MPH

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.

• Platelet Disorders (like : Bernard-Soulier syndrome,platelet storage pool defects,platelet-type von Willebrand disease and gray platelet syndrome)^[1]Bernard-Soulier Syndrome^[2]

• Von Willebrand Disease
• Wiskott-Aldrich Syndrome
• Fibrinogen abnormalities(eg Afibrinogenemia)

Diseases	Laboratory Findings					Physical Examination				History and Symptoms						Treatment
	Bleeding Time (BT)	PT	aPTT	Platelet count	vWF	Petechiae & Purpura	Ecchymosis	Mucocutaneous hemorrhage	Severe fatal bleeding	Epistaxis	Oral bleeding	Menorrhagia & Postpartum hemorrhage	Infection	Hemarthrosis	Additional information
Glanzmann Thrombasthenia[3]	↑	Normal (Nl)	Nl	lower level of Normal	Nl	+	+	+	+	+	+	+	_	_	Autosomal recessive (AR) GpIIb/IIIa receptor defect ITGA2B and ITGB3 gene Platelet aggregation responds to ristocetin but not (ADP), epinephrine, and collagen.	Local hemostatic procedures Anti-fibrinolytic drugs rFVIIa, IVIG, plasmapheresis, corticosteroids, rituximab HSCT[4]
Von Willebrand disease (vWD)	Nl	Nl	↑	Nl	↓	+	+	+	+	+	+	+	_	_	Autosomal dominant (AD) and autosomal recessive, AR (rare)	vWF DDAVP factor VIII concentrates[1]
Bernard-Soulier Syndrome[2]	↑	↓	Nl	↓ giant platelets	↑	+	+	+	+	+	+	+	_	_	AR ↓GPIb/IX/V platelets platelets do not aggregate in response to ristocetin but responds to ADP, epinephrine, and collagen	DDAVP antifibrinolytic rFVIIa[5]
Wiskott-Aldrich Syndrome[6]	Nl	Nl	Nl	↓ microthrombocytopenia	Nl	+	+	↓	+ (specially GI bleeding)	+	↓	↓	+	_	X-linked defect in The WASp gene +Severe eczema	antibiotics, antivirals, antifungals, chemotherapy immunoglobulins corticosteroids
Inherited Abnormalities of Fibrinogen[7]	↑	↑	↑	Nl	↓	Inherited Abnormalities of Fibrinogen	+	+	+	+	+	+	_	+	Fibrinogen defect 3gene:FGA, FGB, and FGG	Fibrinogen concentrates cryoprecipitate[8]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Niyousha Danesh, MD-MPH

Glanzmann’s thrombasthenia has incidence/prevalence of 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.

• Glanzmann’s thrombasthenia has incidence/prevalence of approximately one per 1,000,000 individuals worldwide ^[1]

• 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.^[2]
• 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.

• • The incidence of Glanzmann’s thrombasthenia decreases with age; the median age at diagnosis is 8 years.^[2]
  • Glanzmann’s thrombasthenia commonly manifests in individuals younger than 5 years of age.

• • Glanzmann’s thrombasthenia usually affects individuals of the Arabs,Southern Indians,Hindus,Jordanians, Iranians,Palestinian, Iraqi Jews and French Gypsies races. individuals of the other parts of the world are less likely to develop Glanzmann’s thrombasthenia ^[3][4]
  • In Israel, 12 males and 10 females fulfilled the ‘Criteria for establishing the diagnosis of Glanzmann’s thrombasthenia ^[5]
  • The majority of Glanzmann’s thrombasthenia cases are reported in middle east including individuals of Palestinian, Israel Iran, Iraq, Saudi Arabia,India, Jordan and France. while in these ethnic groups consanguineous marriages is more prevalent ^[6]

• • Women are slightly more affected by Glanzmann’s thrombasthenia than men. The female to male ratio is approximately 1.38 to 1.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

The most potent risk factor in the heritable Glanzmann’s thrombasthenia is consanguineous marriage. Autoantibodies production cause of acquired Glanzmann thrombasthenia.

Common risk factors that increase autoantibodies production in acquired Glanzmann thrombasthenia include:

• Hematologic disorders and malignancies, such as :^[1]

1. Acute lymphoblastic leukemia
2. Non-Hodgkin’s lymphoma
3. Multiple myeloma
4. Hairy cell leukemia
5. Myelodysplastic syndrome
6. Immune thrombocytopenic purpura (ITP)

• Autoimmune diseases such as Lupus ^[2]
• Drugs : Anti-thrombotic drugs use , like abciximab, eptifibatide, and tirofiban which all antagonize αIIbβ3
• Platelet transfusions. ^[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

According to the United States Preventive Services Task Force, screening for Glanzmann’s thrombasthenia is not recommended.

According to the United States Preventive Services Task Force, screening for Glanzmann’s thrombasthenia is not recommended.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

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 thrombasthenia is iron deficiency anemia. Prognosis is generally excellent with good supportive care and the mortality rate of patients with Glanzmann’s thrombasthenia is relatively low.

Natural history, Complications and Prognosis comprises: ^[1][2][3][4]

• Common complications of include sever fatal bleeding following major surgeries , labor and delivery^[1]
• 84% of patients with Glanzmann’s thrombasthenia require at least once in their life red blood cell transfusion^[2]
• The episodes of severe  spontaneous hemorrhage is reduced with age^[2]
• Bleeding episodes can vary greatly among affected individuals, even in the same family
• 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^[3]
• A considerable complication of Glanzmann’s thrombasthenia is iron deficiency anemia.

• Prognosis is generally excellent with good supportive care and the mortality rate of patients with Glanzmann’s thrombasthenia is relatively low^[2]