Glanzmann’s thrombasthenia is an inherited blood pathology caused by dysfunction of the platelet hemostasis link and manifested by hemorrhagic syndrome. It is accompanied by the appearance of petechial rash, repeated and prolonged bleeding (from the nose, gums, the hole of the removed tooth, wounds, gastrointestinal tract, uterus). Possible hemorrhages in the retina, brain. Diagnosis is based on the study of blood test, coagulogram, platelet immunophenotyping, and molecular genetic test data. Symptomatic treatment: stopping bleeding with the help of hemostatic agents (sponge, antifibrinolytics), platelet transfusion, rFVII preparations.
D69.1 Qualitative defects of platelets. Glanzmann’s disease
“Congenital hemorrhagic thrombasthenia” was first described by a pediatrician from Switzerland, Edward Glanzmann, in 1918. However, the true cause of the disease became known only in the 1970s, and effective treatment was proposed at the beginning of this century. The prevalence of Glanzmann’s thrombasthenia in the population is 1:200 000-1:1 000000 of the population. The greatest incidence is recorded in closed populations, where closely related marriages are not uncommon (Pakistan, Iran, some provinces of Canada).
Congenital Glanzmann’s disease refers to hereditary thrombocytopathies with autosomal recessive transmission. The pathology is caused by a mutation of the ITGA2B and ITGB3 genes located at the 17q21.32 locus on the long arm of the 17th chromosome. The immediate cause is a quantitative decrease or dysfunction of the transmembrane protein ‒ integrin aIIbß3 on the platelet surface, which is an important link in the aggregation of blood plates. It is believed that up to 0.5% of the world’s population may be heterozygous carriers of mutations.
The acquired form of Glanzmann’s thrombasthenia is due to the presence of paraproteins or autoantibodies to platelets, which can disrupt the function of aIIbß3. This condition can occur with myeloma, lymphogranulomatosis, autoimmune thrombocytopenia.
Qualitative (dysfunction) or quantitative (deficiency) changes in proteins-integrins aIIbß3 (glycoproteins IIb and IIIa) lead to the development of Glanzmann’s thrombasthenia. These proteins are located on the platelet membrane and act as receptors that bind other glycoproteins (Willebrand factor, fibrinogen, fibronectin, vitronectin) into a special protein complex. Due to this, the formation of a blood clot normally occurs.
With a violation of the structure or insufficient content of GP IIb-IIIa, the platelet link of hemostasis suffers. Platelet adhesion becomes unstable, but platelet binding to fibrinogen and their aggregation – gluing with each other is more disrupted. There is a decrease in thrombin formation. There is no retraction of the blood clot. As a result, the forming platelet thrombus turns out to be loose, untenable and does not contribute to stopping bleeding. Morphology and the number of platelets in the blood with Glanzman thrombasthenia are usually normal or slightly reduced.
In clinical hematology, Glanzmann’s thrombasthenia is classified depending on the amount of glycoproteins IIb-IIIa on platelet membranes. There are 3 variants of pathology:
- Type I – the number of membrane proteins is <5% of the norm. This form accounts for about 75% of cases of Glanzmann’s thrombasthenia;
- Type II – the level of glycoproteins is 5-20%. It occurs in 15% of patients;
- Type III (variant) – the number of integrins is 20% or more of the norm, but there is a pronounced violation of their function.
In about half of patients, the onset of the disease occurs in the first year of life, in 85% of cases, manifestation occurs before the child reaches the age of 14. Episodes of hemorrhages occur both as a result of injuries and spontaneously. In children, nosebleeds (43%), petechial rash, ecchymoses and subcutaneous hematomas (30%), bleeding from the gums and oral mucosa (22%) that occur during teething and tooth replacement are most often noted.
In adults, typical manifestations are gastric and intestinal bleeding, prolonged bleeding from the wound with minor cuts. Women may experience menorrhagia, massive postpartum bleeding. The danger is represented by retinal hemorrhages, hemorrhagic stroke. Glanzmann’s thrombasthenia is characterized by blood loss associated with blood collection, tooth extraction, and surgical intervention.
An acutely developed hemorrhagic syndrome without timely help can be fatal. A case of death of a 10-year-old patient from hemorrhagic shock caused by bleeding from a small wound on the lip is described. Hemotransfusion due to severe blood loss is required at least once in a lifetime by 85% of patients with Glanzmann’s thrombasthenia. Carrying out any surgical interventions (even tooth extraction) without special training and hemostatic therapy, it is fraught with life-threatening bleeding.
Glanzmann’s thrombasthenia can be suspected if the patient has increased bleeding (subcutaneous hemorrhages, spontaneous bleeding, hemorrhages after invasive manipulations). The initial diagnosis is usually carried out by therapists and pediatricians, followed by mandatory consultation with a hematologist, genetics. The necessary examinations include:
- Investigation of platelet count and morphology. The cell count shows that the platelet count is within the normal range and slightly reduced. Thrombocytopenia and posthemorrhagic anemia are registered only after episodes of massive blood loss. The structure and size of the blood plates are also not significantly changed.
- Optical aggregometry. Allows you to determine the functional characteristics of platelets. A characteristic feature of Glanzmann’s thrombasthenia is a sharp decrease / absence of platelet aggregation with the addition of collagen, ADP, thrombin (in reaction with ristocetin, aggregation is preserved).
- Hemostasiogram. Examination of the coagulation system reveals an elongation of bleeding time and thrombin time. Other clotting factors (Willebrand factor, APTT, prothrombin, fibrinogen) are normal. A thromboelastogram indicates a violation of the platelet chain of hemostasis with an unchanged plasma component.
- Immunophenotyping of platelets. It is carried out using flow cytometry using monoclonal antibodies. A decrease in CD41 and CD61 expression is detected.
- Genetic analysis. At the consultation of the geneticist, a family history is found out, the presence of hemorrhagic syndrome in the next of kin. The method of confirming diagnosis is a molecular genetic analysis that detects mutations in the ITGA2B and ITGB3 genes.
Glanzmann’s thrombasthenia is differentiated from other hemorrhagic syndromes ‒ Bernard-Soulier thrombocytodystrophy and Willebrand’s disease.
To date, the disease is incurable, but the developed therapeutic algorithms make it possible to prevent or quickly stop the bleeding that occurs. A diet with an increased content of vitamins A, C, P K, phospholipids is recommended. To stop small local hemorrhages, hemostatic wipes, hemostatic sponge, fibrin glue are used. Nosebleeds are stopped with the help of an anterior tamponade. Ascorutin, dicinone, and ATP injections are prescribed.
With the development of bleeding, intravenous administration of tranexamic and aminocaproic acid, recombinant coagulation factor VIIa, transfusion of thromboconcentrate is indicated. Patients with Glanzmann’s thrombasthenia who need frequent blood transfusions need an individual selection of donors compatible with HLA-system antigens (prevention of alloimmunization). Allogeneic bone marrow transplantation is a radical remedy for Glanzmann’s thrombasthenia gravis.
Prognosis and prevention
Patients with Glanzmann’s thrombasthenia should be monitored by a hematologist. They need to observe a protective regime for life, avoid injury. It is required to exclude canned foods containing vinegar and salicylates from the diet. It is forbidden to take drugs that reduce platelet aggregation: disaggregants, NSAIDs, anticoagulants. Any invasive manipulations should be carried out under the guise of hemostatic therapy. With strict adherence to the recommendations, it is possible to avoid frequent hemorrhagic episodes and severe bleeding.
- Description and Clinical Management of Patients With Glanzmann’s Thrombasthenia in a University Hospital, a Referral Center Specialized in Hemostasis, in Bogotá, Colombia. Solano MH, Chaves K, Casas CP. Cureus. 2022 Jun 4;14(6):e25657. link
- Analysis of Integrin αIIb Subunit Dynamics Reveals Long-Range Effects of Missense Mutations on Calf Domains. Anies S, Jallu V, Diharce J. Int J Mol Sci. 2022 Jan 13;23(2):858. link
- Glanzmann Thrombasthenia: Use of the Soft Splint with Tranexamic Acid Paste to Reduce Spontaneous Oral Bleeding. Bhavyaa R, Vignesh KC Int J Clin Pediatr Dent. 2021 Jul-Aug;14(4):580-585. link
- Characterization of the Role of Integrin α5β1 in Platelet Function, Hemostasis, and Experimental Thrombosis. Janus-Bell E, Yakusheva A, Scandola C, Receveur N, Ahmed UM, Mouriaux Thromb Haemost. 2022 May;122(5):767-776. link