Glanzmann's thrombasthenia is a rare disease characterized by the absence or severely decreased platelet aggregation due to a quantitative or qualitative deficit of GPIIB / IIIA complexes at the platelet surface membrane. [1]
This condition is characterized by an haemorrhagic mucocutaneous diathesis due to prolonged bleeding time.
Laboratory parameters include normal platelet counts, morphology, prothrombin time (PT), and activated thromboplastin times (aPTT). In contrast, PFA-100 test shows prolonged closure times. [3, 4]. Flow cytometry, evaluating platelet structure and function, provides the definitive diagnosis. [5]
Epistaxis, easy bruising, purpura, gingival bleeding and menorrhagia are the most common clinical symptoms. [6] Epistaxis is often a cause of severe bleeding in childhood. Menorrhagia may be critical, resulting in anaemia, and it is usually associated with excessive bleeding at the menarche. [7] Other common clinical features include bleeding from the urinary and gastrointestinal tracts, surgical procedures
and traumatic events. [8]
Depending on laboratory parameters, Glanzmann's thrombasthenia is classified into the following variants: type 1 variants (< 5% GPIIb-IIIa expression) which is related to severe bleeding, type 2 (5–20% expression of GPIIb-IIIa) and qualitative GT variants in which the bleeding phenotype may be less severe. [6] Haemostatic management is associated with the severity of clinical manifestations. Currently, the main treatment remains supportive.
Local bleeding can be managed using various methods, including compression, use of tranexamic acid or topical thrombin applied to superficial wounds. Epistaxis is managed by cauterization or nasal packing, while menorrhagia may be managed with tranexamic acid and hormone therapy. [7] When local measures and antifibrinolytics fail to control bleeding, the first line of treatment for severe haemorrhage is platelet transfusion. [9] Platelet transfusions are usually effective in controlling haemorrhages, but there is a risk of alloimmunisation by HLA antigens or the specific missing GPs leading to transfusion refractoriness. Approximately 15–30% of individuals become refractory to transfusion and a significant percentage develops antibodies against GP IIb-IIIa or HLA. [10, 11] In Glanzmann patients who are refractory to platelet transfusions recombinant FVIIa is licensed for use. [9, 12] In the near future bone marrow transplant and gene therapy technology may guarantee an effective option to cure this otherwise lifelong disease. [13, 14]
Pregnancy and delivery should be managed in collaboration between haemophilia, anesthesia, neonatology and obstetric units. Glanzmann's thrombasthenia is characterized by an increased percentage of primary and secondary post-partum hemorrages. [15, 16]
The risk of significant antenatal bleeding is low. Conversely, intra-partum and postpartum bleeding are common and frequently severe justifying measures such as active management of the third stage of labour with uterotonics drugs, as emphasized in current guidelines. [9, 12] Concerning vaginal delivery, recent guidelines support the use of rFVIIa combined with tranexamic acid. This practice avoids the use of platelets transfusions and the related risk of developing maternal antiplatelet antibodies that may cross the placenta, resulting in neonatal alloimmune thrombocytopenia and subsequent severe bleeding. Consequently, it is currently recommended monitoring maternal alloantibody titre during pregnancy as a routine screening, in order to prevent and minimize adverse foetal outcomes. [12]
The administration of rFVIIa in patients suffering from Glanzmann thrombasthenia was described as a successful treatment in several cases [17, 18] and there are case reports confirming the efficacy of recombinant factor VIIa in the treatment of massive postpartum haemorrhage refractory to other treatments. [19]
There are no clear data related to dosing schedules, but 90 lg/kg infused as close to delivery as possible, followed by further 2- hourly infusions for a maximum of three to four doses or until haemostasis is clinically secure, is a reasonable approach. [9] If bleeding occurs despite this treatment, HLA-selected platelets should be infused. [12] HLA- matched platelets transfusion is suggested as an alternative to rFVIIa for vaginal delivery and as first-line prophylaxis against PPH after caesarean section. [9, 12] According to individual variations in platelet recovery, an algorithm for correction of hemostasis during delivery in Glanzmann's thrombasthenia is available. [20]
Postpartum haemorrhage is unpredictable and may occur within 1–2 weeks after delivery; the median time to secondary PPH is 10 days after delivery, irrespective of whether prophylaxis is given at the time of delivery. This confirms that each patient requires individual assessment, planning and close observation after delivery; therefore, anti-fibrinolytic therapy should be administered for at least 2 weeks, even after apparently uncomplicated deliveries without signs of bleeding manifestations.
Currently, the mode of delivery is not related to maternal bleeding risk. [15] In case of increased risk of neonatal bleeding, due to inherited alloimmune thrombocytopenia, ventouse extraction and forceps deliveries are contraindicated. [9, 12]
Regional anaesthesia in patients with platelet dysfunction should be avoided because haemostasis cannot be maneged. If there is comorbidity that makes the risk of general anaesthesia high, a management plan should be settled in advance between the haematologist and anaesthetist in case a caesarean section becomes necessary. Caesarean section may reduce the risk of PPH, providing an improved uterine evacuation, but late PPH remains a possible complication. [9, 12]