Innovative use of recombinant activated factor VII during physical rehabilitation in an Italian child with Glanzmann's thromboasthenia.

Abstract

In 1918 Eduard Glanzmann described a series of patients with normal platelet count but prolonged bleeding time and modified clot retraction. This rare, recessively inherited platelet disorder was named Glanzmann’s thromboasthenia (GT). It has a high expression in certain ethnic groups, such as Iraqi Jews, Iranians, Arabs, French Gypsies and Indians, in which consanguineous marriages are common. The disease is due to the absence or decrease in the expression of the platelet glycoprotein (GP) IIb/IIIa membrane complex1,2. GPIIb and GPIIIa are present in the platelet membrane as heterodimeric molecules and the GPIIb/IIIa or αIIbβ3 complex represents a member of the ubiquitous integrin family of cell surface receptors. GT is usually considered the most frequent inherited integrin disorder3. Bleeding manifestations in this autosomal recessive disorder occur in patients who are homozygous or compound heterozygous for GPIIb/IIIa mutations. GPIIb/IIIa complex is involved in platelet aggregation, resulting from the binding of fibrinogen to this glycoprotein complex on activated platelets2–4. The diagnostic features of GT consist of absent platelet aggregation in response to all physiological stimuli and abnormal clot retraction, in presence of normal ristocetin-induced agglutination, platelet count and morphology. Platelet αIIbβ3 deficiency should always be confirmed in newly diagnosed patients by monoclonal antibodies and flow cytometry analysis3. Clinical manifestations seen in childhood include easy bruising, epistaxis, gingival bleeding, menorrhagia and less frequently gastrointestinal bleeding, haematuria, haemarthrosis, muscle haematoma and nervous system haemorrhages2. Bleeding complications are also frequent after dental extraction, surgery and giving birth. The bleeding tendency in GT patients is highly variable: some patients remain asymptomatic, whereas others experience severe bleeding episodes. Treatment measures for mild bleeding are local pressure through nasal packing with gelatine sponge for epistaxis, local haemostatics such as fibrin glue and topical thrombin, as well as the use of anti-fibrinolytic agents. The standard therapy for severe bleeding is platelet transfusion. However, repeated transfusions may result in the development of antibodies against GPIIb/IIIa and/or human leucocyte antigens (HLA), resulting in refractoriness to further platelet transfusions. Moreover, transfusions are not always readily available and the use of blood products is associated with the risk of infections and allergic reactions. An alternative effective agent is, therefore, needed for the management of GT patients, particularly those who are refractory to platelet transfusion5,6. Recombinant human activated factor VIIa (rFVIIa) is structurally similar to the coagulation factor VIIa derived from human plasma. It is produced by expressing the cloned gene for human factor VII in baby hamster kidney cells without the use of human serum or other human proteins7. Factor VIIa exerts its haemostatic effect only after interaction with the tissue factor, usually at the site of injury. In the presence of platelet disorders, a tissue factor-dependent mechanism operates to generate thrombin for initial platelet activation with exposure of coagulant surfaces. However, the impaired platelet activation hampers the amplification phase and thrombin generation is not sufficient for fibrin formation. High doses of rFVIIa activate platelets and mediate increased thrombin generation, which is important for further activation, adhesion and aggregation of platelets as well as the formation of fibrin to improve the haemostatic process. The use of rFVIIa (Novoseven®, Bagsvaerd, Denmark) has been approved in many countries including North America, Europe, Australia and Japan for the treatment of bleeding in patients with haemophilia A or B with inhibitor antibodies, as well as acquired haemophilia. The efficacy of rFVIIa has also been documented in patients with GT and its use has been approved by the European Medical Evaluation Agency (EMEA) for the management of bleeding in GT patients with anti-platelet antibodies and a history of platelet refractoriness, as well as in patients with FVII deficiency8. Haemarthrosis is extremely rare in GT patients. The clinical and pathophysiological features of joint bleeding have been extensively investigated in haemophilic patients. Recurrent haemorrhages can result in synovial hypertrophy, followed by haemosiderin deposition, which increase the risk of synovitis. The inflamed synovium is even more prone to haemorrhage. Cartilage and subchondral bone destruction is thought to be either a consequence of the catabolic activity of the inflamed synovium and/or to be caused by the direct toxic effects of blood breakdown products themselves. The latter mechanism results in loss of joint space, subchondral bone irregularity, erosions, and subchondral cyst formation. These changes ultimately lead to severe functional impairment (haemophilic arthropathy)9. Here we report the case of an Italian 11-year old male GT patient with traumatic ankle haemarthrosis who was treated with a novel regimen of rFVIIa, in order to prevent joint damage.