Page 51 - Haematologica April 2020

Clinical and molecular aspects of GT
treatment any time of day, and also benefit from being pro- vided directly with medical alerts, and emergency medical contact and treatment information to present when seek- ing urgent care from clinicians who are not familiar with their case history. Education on avoidance of over-the- counter medications that increase bleeding risk such as non-steroidal anti-inflammatories and aspirin products should be provided. Prescription medications that can affect hemostasis should be carefully monitored.29
Hemostatic management
The treatment of bleeding in patients with GT includes management of acute or chronic bleeding and prevention of hemorrhagic complications around the time of proce- dures. The choice of treatment depends on the severity of bleeding (Table 1), availability of products, and prior responses to therapy, and is similar in some aspects to the management of patients with other severe bleeding disor- ders. Note that desmopressin (DDAVP), commonly used in von Willebrand Disease and other milder disorders of platelet function, is of limited clinical utility in the treat- ment of GT (Table 1).
Recombinant activated factor VII (rFVIIa) is approved by the European Medicines Agency (EMA) and the FDA for the treatment of patients with GT. The approval of this drug has changed the landscape of treatment of GT and has allowed for better hemostatic outcomes in all patients, especially those who do not respond to platelet transfusions. Optimal dosing and interval of doses vary by center and clinical situation. Typical doses for acute bleeding are 90 mcg/kg intravenous (IV) every 2-6 hours until hemostasis is achieved (at least 3 doses). Perioperative dosing is 90 mcg/kg immediately before surgery and every two hours during the procedure, with doses every 2-6 hours postoperatively to prevent post- surgical bleeding.30 Effectiveness of this drug in the treat- ment of acute bleeding is high31 when started early in the course of bleeding and used in combination with other hemostatic treatment. It is also useful for perioperative management.32 Although cases of thromboembolism dur- ing rFVIIa therapy in GT patients have occurred, it remains a safe medication in this population, with low rates of adverse reactions.
Transfusion
Patients with GT have a high risk of development of isoantibodies, with up to 30% of patients developing anti- GPIIb/IIIa or anti-HLA antibodies after platelet transfusion.33 Patients with pathogenic variants causing premature stop codons and leading to absent GPIIb/IIIa are at the highest risk of anti GPIIb/IIIa alloimmunization compared to those with other types of variants (81% vs. 25%).34 Once these antibodies develop, the patient may no longer respond to platelet transfusion. For this reason, platelet transfusions should be reserved for only major sur- geries, life-threatening bleeding, and significant bleeding that does not respond to the above measure. Transfusions in women of reproductive age should ideally be avoided as the antibodies can cross the placenta and affect the fetus.35
Bone marrow transplant
Allogeneic stem cell transplantation has been success- fully performed in selected patients with severe recurrent bleeding using reduced intensity conditioning with good clinical outcomes.36,37 The presence in the recipient of antiplatelet antibodies affecting the graft remains a chal- lenge in this patient population.38
Pregnancy
Pregnant women with GT have a high rate of compli- cations and are best managed in a specialized center with a multidisciplinary team. While most complications relate to bleeding and occur at the time of delivery, manage- ment of the pregnant GT patients should start in the pre- natal period. Counseling of the pregnancy-associated risks and screening of the father in consanguineous fami- lies to identify at-risk fetuses is important. Identification of HLA or GPIIb/IIIa antibodies during pregnancy, which are present in up to 70% of patients, is key for planning delivery. In general, regional anesthesia is contraindicated and support with rFVIIa and antifibrinolytics is given for vaginal deliveries with the option of adding platelet trans- fusion for cesarian sections.39 Primary post-partum hem- orrhage is common, and a large proportion of women will require red cell transfusion. Clinicians should be aware that, given the phenotypic variability of this disorder, around half the women with GT who are pregnant may not be aware of the diagnosis.35
Future directions
Gene therapy is highly promising in providing a cure for patients with GT, with significant progress made using different techniques, vectors and model organ- isms.40-42 However, further advances that allow safe trans- gene delivery and stable expression in human models are still required.33
Ongoing challenges
Despite advances in the understanding of the patho- physiology, the relative ease of access to clinical laborato- ry techniques, and recent improvements in treatment options (such as rFVIIa), many challenges remain in the care of patients with this rare disorder. Access to clini- cians and laboratories with the required expertise and resources to diagnose and treat GT is difficult, especially in areas of the world with limited resources. Large-scale data analysis and clinical research are problematic given the limited numbers of patients available and the highly constrained funding for rare disorders. Initiatives through the World Federation of Hemophilia for clinical care and multinational collaborations including the Glanzmann Thrombasthenia Registry for analysis of clinical out- comes, and sharing of molecular data through creation of publicly accessible databases have taken important steps in bridging the gaps. However, more investment is need- ed to guarantee timely access to quality care, until a true cure for the disease is developed.
haematologica | 2020; 105(4)
893