Glanzmann's thrombasthenia overview
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Glanzmann's thrombasthenia |
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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], Niyousha Danesh, MD-MPH
Overview
Glanzmann's thrombasthenia is an extremely rare autosomal recessive bleeding syndrome affecting the megakaryocyte lineage, in which the platelets lack glycoprotein IIb/IIIa (ITG αIIbβ3), [1] either qualitative or quantitative. Hence, no fibrinogen bridging can occur, which results in faulty platelet aggregation and diminished clot retraction. Spontaneous mucocutaneous bleeding is common and can lead to fatal bleeding episodes.
GT is associated with clinical variability: some patients have only minimal bruising while others have frequent, severe and potentially fatal hemorrhages. The site of bleeding in GT is clearly defined: purpura, epistaxis, gingival bleeding, and menorrhagia are nearly constant features; gastrointestinal bleeding and hematuria are less common. In most cases, bleeding symptoms manifest rapidly after birth, even if GT is occasionally only diagnosed in later life. Diagnosis should be suspected in patients with mucocutaneous bleeding with absent platelet aggregation in response to all physiologic stimuli, and a normal platelet count and morphology. [2] Bleeding time is also significantly prolonged in this disease.
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
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. The of the bleeding episodes in 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 .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 Criteria
History and Symptoms
Physical Examination
Laboratory Findings
Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Prevention
References
- ↑ Solh T, Botsford A, Solh M (2015). "Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options". J Blood Med. 6: 219–27. doi:10.2147/JBM.S71319. PMC 4501245. PMID 26185478.
- ↑ Nurden AT (2006). "Glanzmann thrombasthenia". Orphanet J Rare Dis. 1: 10. doi:10.1186/1750-1172-1-10. PMC 1475837. PMID 16722529.