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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.62 no.4 Campinas July/Aug. 2012
Erdem Nail DumanI; Sedat SaylanII; Bahanur CekicIII
IMD, Associate Professor, Karadeniz Technical University, Faculty of Medicine, Department of Anesthesiology, Turkey
IIMD, Anesthesiologist of the State Hospital, Turkey
IIIMD, Assistant Professor, Karadeniz Technical University, Faculty of Medicine, Department of Anesthesiology, Turkey
BACKGROUND AND OBJECTIVE: Glanzmann's thrombasthenia (GT) is an autosomal recessively inherited platelet disorder. There is not any specific treatment. Platelet transfusion is currently the standard treatment when bleeding does not respond to local measures and/or antifibrinolytic treatment, although it may result in alloimmunization. Recombinant activated factor VII (rFVIIa) might be used to avoid recurrent platelet transfusion.
CASE REPORT: We present early treatment with low-dose rFVIIa additional to platelet transfusion in a 5-year-old pediatric case with diagnosis of GT who developed prolonged bleeding under an elective adenoidectomy surgery. A total dose of 1,200 µg (60 µg.kg-1) rFVIIa could successfully stop bleeding, what can be accepted as low dose usage.
CONCLUSIONS: Such case reports may encourage the use of early treatment with low doses of rFVIIa in severe bleeds that did not stop despite of platelet transfusion, as well as in preventing bleeding in surgical procedures in patients with GT. Actually, additional studies are needed to define the minimal effective dose and attempts to determine the lowest effective dose may be encouraged by the result of this case, considering financial restrictions in the health care system.
Keywords: Anesthesia, General; Adenoidectomy; Factor VIIa/recombinant VIIa; Thrombasthenia.
Glanzmann's thrombasthenia (GT) is an autosomal recessively inherited platelet disorder that is caused by deficiency or abnormality of the platelet membrane glycoprotein (GP) IIb and/or IIIa1. It is rare in a global context but relatively more common in populations where consanguineous marriages are frequent1. The disorder was first described in 1918 by the Swiss pediatrician Eduard Glanzmann in a group of patients with normal platelet count but impaired clot retraction and prolonged bleeding time1.
Clinical manifestations include spontaneous epistaxis, gum bleeding, easy bruising, purpura, menorrhagia, gastrointestinal bleeding, hematuria, muscle hematoma, and traumatic or postoperative bleeding with a normal platelet count1,2. There is not specific treatment. When bleeding does not respond to local measures and/or antifibrinolytic drugs, platelet transfusion is currently the standard treatment. However, development of platelet refractoriness due to alloimmunization to GP IIb-IIIa and/or HLA may occur as a common problem after repeated platelet transfusions2. Blood products also carry other risks, including infections2. Recombinant activated factor VII (rFVIIa) might be used to avoid recurrent platelet transfusion, thereby reducing exposure to the associated risks, and to stop bleeding unresponsive to repeated platelet transfusion1,3,4. In a large international survey, rFVIIa treatment was found to be effective in 94% of evaluable surgical procedures and in 75% of evaluable bleeding episodes2. It is also recommended that treatment should be administered as early as possible: in the report of Almeida et al.5 good or excellent responses were observed in 71% of bleeds treated within 12 hours of onset, but in only 18% of bleeds treated after 12 hours.
We present an early low-dose rFVIIa use in addition to platelet transfusion in a pediatric case with GT who developed prolonged bleeding under an elective adenoidectomy surgery.
A 5 year-old boy of consanguineous parents with the diagnosis of GT was referred to "Ear, Nose and Throat Surgery Department" of our hospital with complaints of snoring, recurrent tonsillopharyngitis, sleeping apnea episodes and mouth breathing at sleeping, and because of these complaints tonsils and adenoids surgery was planned. The patient was diagnosed with GT two years ago, subsequent to the development of nose bleedings and bruisings. On the first admission, laboratory tests revealed that normal PT (16.3 sec) and aPTT (29.2 sec) and INR: 1.31. He had a prolonged bleeding time over 15 minutes, and normal platelet count (270x109.L-1). The diagnosis of GT was established by the absence of platelet aggregation in response to ADP, collagen, epinephrine and ristocetin.
Preoperative laboratory findings of the patient were as follows: a prolonged bleeding time (> 15 minutes) with a normal platelet count (282x109.L-1), normal PT (14.4 sec) and aPTT (28.5 sec) levels and INR 1.15. His hemoglobin level was 9.9 g.dL-1. He was taking iron supplementation treatment for his anemia for the last five months. Because of a problem in flow-cytometry analysis, it could not be checked whether the patient had alloantibodies to platelet Gp IIb/IIIa. He received platelet concentrate in a dose of 10 cc.kg-1 30 minutes before the surgery. Two 20G cannulae were placed in forearm veins. Induction of anesthesia was performed using thiopental, fentanyl and atracurium, followed by orotracheal intubation. Anesthesia was maintained with oxygen, nitrous oxide and sevoflurane. The bleeding of surgical site did not stop after adenoidectomy, so the tonsillectomy was abandoned. The bleeding could not be stopped within an hour with a platelet transfusion of 10 cc.kg-1 and red blood cell transfusion 7 mL.kg-1, the blood loss reached to 270 cc, hemoglobin level was 8.8 g.dL-1, platelet count was 256x109.L-1, PT 14.2 sec, aPTT 28.1 sec. The option of applying tranexamic acid and fresh frozen plasma was not available at that time. Only an option of rFVIIa (Novo Nordisk A/S, Bagsvaerd, Denmark) in a total dose of 1,200 µg (60 µg.kg-1) was available; therefore, this treatment was administered in three minutes. Bleeding stopped in ten minutes after giving rFVIIa; operation was ended and the patient was extubated. He was transferred to the post-anesthesia care unit and observed for three hours. His repeated blood counts were 8.4 g.dL-1 for hemoglobin and 292x109.L-1 for platelet count. Because of his anemia, red blood cell transfusion (5 cc.kg-1) was given. He was discharged on the third postoperative day from the hospital and had no further problems.
GT is a rare disorder and its clinical manifestations are similar to other platelet function disorders. Platelet transfusion is the standard treatment for severe bleeding and surgical support in these patients. However, repeated platelet transfusions can result in alloimmunization, which makes subsequent transfusions ineffective1. Hemostasis is started by the formation of a complex between tissue factor and activated factor VII following trauma or injury. It has been shown that rFVIIa can induce hemostasis via binding to the surface of activated platelets to directly activate factors IX and X independent of tissue factor and thus enhance thrombin generation in the absence of FVIII and FIX.
In the literature, it has been demonstrated that rFVIIa is an alternative treatment for bleeding and surgical support with less adverse effect1-4. The first reported use of rFVIIa occurred in 1988 in a hemophilia patient. In a retrospective surgical case series reported by O'Connell et al.6, a wide range of 15-180 mg.kg-1 rFVIIa is used for massive bleeding. In 1996, Tengborn and Petruson first reported the successful use of rFVIIa for treating severe epistaxis in a 2-year-old boy with GT who had not responded to conservative treatment7. After this report, rFVIIa was used by other investigators for bleeding episodes or surgery in patients with GT with or without alloantibodies to platelet Gp IIb/IIIa complex or HLA1,3,4,8,9. We also used rFVIIa for treating this pediatric GT patient under adenoidectomy surgery for the first time in the literature. In a large international survey, rFVIIa treatment was found to be effective in 94% of evaluable surgical procedures and in 75% of evaluable bleeding episodes2. It is also recommended that treatment should be administered as early as possible: in the report of Almeida et al.5 good or excellent responses were observed in 71% of bleeds treated within 12 hours of onset, but in only 18% of bleeds treated after 12 hours.
The optimal dose and interval have not yet been determined for rFVIIa use in GT patients. The reported treatment protocols are quite heterogeneous with respect to doses, duration and modalities of administration and associated treatments9. At present, the relationship between the doses of rFVIIa, the thrombin burst crucial for stable clot formation, and the actual measurable blood FVII levels are still unknown. Even though the minimum rFVIIa level that is necessary to maintain hemostasis is unknown, the standard recommended dose is 90 µg.kg-1 (range 80-120 µg) at intervals of two hours (at least 3 doses)10. However, use of low doses such as 67 µg.kg-1 was reported in a review related with the intraoperative use of recombinant activated factor VII11. In a report of rFVIIa use in trauma patients, doses of 60-100 µg/kg were used12.
In a study done by Almeida et al.5, a single dose of 100 µg.kg-1 was given in bleeding episodes of two children with GT, and because of an excellent response, they required no maintenance dose5. We also achieved to maintain the adequate homeostasis with early use of a single low-dose rFVIIa such as 60 µg.kg-1 additional to preoperative platelet transfusion in our GT patient. Use of rFVIIa in a single dose of 70 µg.kg-1 in the treatment of uncontrolled postsurgical hemorrhage in a patient with deep venous thrombosis was also found effective13. Moreover, in total hepatectomy case with a life threatening bleeding unresponsive to platelet transfusion, single bolus dose of 90 µg.kg-1 rFVIIa was successfully used14. Several analyses have suggested that early treatment with rFVIIa is particularly beneficial, resulting in improved success rates with lower doses5,15.
As mentioned by Poon et al.4 many of the bleeding episodes did not bleed again in the absence of maintenance doses. It is possible that in patients with normal plasma coagulation systems, once a primary platelet plug has formed to stop bleeding, a permanent clot is readily formed by the fibrin deposition and stabilization. However, maintenance doses may be needed for severe, posttraumatic and gastrointestinal bleeding.
In summary, although this unique case report is not enough to make a precise decision about the use of rFVIIa in GT patients while bleeding and it is hard to perform randomized clinical trials in a rare condition like GT, such case reports may encourage the use of early treatment with low doses of rFVIIa in severe bleeds that did not stop despite of platelet transfusion, and in preventing bleeding in surgical procedures in such patients. In addition, it may help to reduce exposure to the risks after repeated platelet infusions. Actually, additional studies are needed to define the minimal effective dose; therefore, attempts to determine the lowest effective dose of such an expensive compound may be encouraged by the result of this case in the presence of financial restrictions in the health care system.
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