Transfusion of platelet concentrates remains the first-line therapy for Glanzmann thrombasthenia in case of bleeding or preparation for surgery. However, development of antibodies to platelet glycoprotein (Gp) IIb/IIIa complex or human leukocyte antigens (HLA) is frequent and the main cause of platelet refractoriness. Recombinant activated factor VII (rFVIIa) is a potent alternative for patients with Glanzmann thrombasthenia with anti-platelet antibodies. We describe a case of Glanzmann thrombasthenia with alloantibodies to platelet Gp IIb/IIIa complex who underwent a successful pyelolithotomy operation under the coverage of recombinant activated factor VIIa and platelet transfusions

Ayşegül Unüvar

Haluk Ander

Ilmay Bilge

Omer Devecioğlu

Orhan Ziylan

Sema Anak

The Turkish Journal of Pediatrics

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<---The Turkish Journal of Pediatrics 2003; 45: 64-66 CasePyelolithotomy in a patient with Glanzmann thrombasthenia andantiglycoprotein IIb/IIIa antibodies: the shortest possibleduration of treatment with recombinant activated factor VII andplatelet transfusionsÖmer Devecioðlu1, Ayþegül Ünüvar1, Sema Anak1, Ilmay Bilge2Haluk Ander3, Orhan Ziylan3Divisions of 1Hematology/Oncology, and 2Nephrology, Department of Pediatrics and 3Department of Urology, ÝstanbulUniversity Ýstanbul Faculty of Medicine, Ýstanbul, TurkeySUMMARY: Devecioðlu Ö, Ünüvar A, Anak S, Bilge Ý, Ander H, Ziylan O.Pyelolithotomy in a patient with Glanzmann thrombasthenia and antiglyloproteinIIb/IIIa antibodies: the shortest possible duration of treatment with recombinantactivated factor VII and platelet transfusions. Turk J Pediatr 2003; 45: 64-66.Transfusion of platelet concentrates remains the first-line therapy for Glanzmannthrombasthenia in case of bleeding or preparation for surgery. However,development of antibodies to platelet glycoprotein (Gp) IIb/IIIa complex orhuman leukocyte antigens (HLA) is frequent and the main cause of plateletrefractoriness. Recombinant activated factor VII (rFVIIa) is a potent alternativefor patients with Glanzmann thrombasthenia with anti-platelet antibodies.We describe a case of Glanzmann thrombasthenia with alloantibodies to plateletGp IIb/IIIa complex who underwent a successful pyelolithotomy operation underthe coverage of recombinant activated factor VIIa and platelet transfusions.Key words: Glanzmann thrombasthenia, alloimmunization, hematuria, rVIIa, platelet, surgery.Glanzmann thrombasthenia is a platelet functiondisorder due to the absence or abnormality ofthe platelet membrane glycoprotein (Gp) IIb/IIIacomplex. Transfusion of platelet concentrates isa first-line therapy. However, development ofalloantibodies to Gp IIb/IIIa complex is a majorproblem after repeated transfusions. In this case,different treatment modalities such asdesmopressin acetate (DDAVP), corticosteroids,etc. have been used with minimal success. Afterthe first successful use of recombinant activatedfactor VIIa [rFVIIa, NovoSeven® (Novo Nordisk,Bagsvaerd, Denmark)] by Tengborn and Petruson[1], it has been administered as a continuous ora bolus infusion for surgery in patients withGlanzmann thrombasthenia wo also hadantibodies to Gp IIb/IIIa complex or humanleukocyte antigens (HLA) or in patients withoutalloimmunization2-4.We report a patient with Glanzmann throm-basthenia wo also had alloantibodies to Gp IIb/IIIa complex who was successfully blocked withrFVIIa during pyelolithotomy operation, withony three days’ bolus infusion regimen, and alsoplatelet transfusions. Considering the shortestpossible time for a major surgery in patients withGlanzmann thrombasthenia, we gave plateletconcentrates two hours before pyelolithotonyand at the end of the operation.Case ReportThe patient was a nine-year-old boy diagnosed asGlanzmann thrombasthenia at five years of age.He was born to second-degree consanguineousparents with a family history of a brother whohad expired from hypovolemic shock due tohematuria. He was lost to follow-up for about twoyears. In February 1998, he was admitted to thehospital with hypovolemic shock due to severehematuria. He recovered by erythrocyte andplatelet transfusions, and macroscopic hematuriastopped. Evaluation of hematuria revealed a stonein the pelvis of his left kidney. After he wasdischarged, he was followed from the outpatient--->clinic. During this period, hematuria persisted, buthemoglobin levels were maintained with ironsupplementation. However, a gross hematuriaoccurred five months later and transfusion ofplatelet concentrates was given again.After this event, pyelolithotomy was planned, buttransfusion of platelet concentrates did notshorten the bleeding time because ofalloimmunization just before the surgery.Antibodies to Gp IIb/IIIa complex were detectedfor the first time using flow-cytometry analysis.Recombinant FVIIa was not commerciallyavailable in Turkey, and the surgery wascancelled. The patient was followed very closelyfor hydronephrosis. In October 1999, the size ofthe kidney stone became bigger and grade IIhydronephrosis was detected. Antibodies to GpIIb/IIIa were assessed again, and they werestrongly positive. Surgery was planned withrFVIIa as it was available. Prior to initiation oftreatment with rFVIIa, the patient and hisparents were fully informed about the durg, andhis father and mother signed an informedconsent form. Recombinant FVIIa was given ina dose of 100 µg/kg (totally 2.4 mg)intravenously. Bleeding time performed twohours later was more than 15 minutes. A seconddose of rFVIIa and 8 units of plateletconcentrates were administered at the sametime, although we had experienced refractorinessto previous applications. The next bleeding time,performed two hour later, was 5 minutes. Aftergiving the third dose of rFVIIa, the operationbegan. During surgery, there was no significantbleeding. However, at the end of the operation,because of mild oozing from the operation site,8 units of platelet concentrates were given, again.Recombinant FVIIa therapy was continued at thesame dose for a total of 12 doses on the firstpost-operative day. On the second day, rFVIIaTable I. Some Hematological Parameters of the Case (Pre- and Post-Operatively)Operation-1 (Day 0) 1 2 3 4 5 6 7Hb (g/dl) 11.0 10.2 10.4 11.0 10.8 10.8 10.9 10.2 10.1WBC (/mm3) 5000 9400 6100 5700 – – 3500 3300 3400PLT (/mm3) 320.000 403.000 416.000 430.000 – – 340.000 284.000 267.000BT (minutes) >15 2 2 2 2 2 2.5 2.5 >15PT (seconds) 14 7.4 7.6 8.0 13.4 17.2 14.4 – 12.9aPTT (seconds) 33.1 31.1 28.4 27.6 32 30.9 31.4 – 24BT : bleeding time.PT : prothrombin time.aPTT : activated partial thromboplastin time.was given every 3 hours, and on the third dayevery 4 hours. After a total of doses, rFVIIa wasstopped. At the post-op 40th hour, macroscopichematuria ceased, and on the sixth day,microscopic hematuria also disappeared. Theduration of macroscopic and microscopichematuria after the pyelolithotomy was similarin patients without hemostatic defect. Thepatient was followed closely by hematologicalparameters that are given in Table I. Theshortening of prothrombin time (PT) wasobserved on the first day of the operation(Day 0), and the other tests remainedunchanged during the post-op period except fora mild increase in platelet count. PT returned tonormal level after the third day. Bleeding timewas normal by the seventh day, four days afterthe cessation of rFVIIa.DiscussionRefractoriness due to alloimmunization is acommon problem after repeated administrationof platelet concentrates. Patients withGlanzmann thrombasthenia and antibodies toGp IIb/IIIa complex have had problem duringserious bleeding episodes or surgery. For a longtime, they had been treated with alternativemeasures such as intravenous immunoglobulin(IVIG), DDAVP, steroids, etc. RecombinantFVIIa has been successfully used forhemophiliac patients with inhibitors to factorVIII or IX5,6. As in the case of use of rFVIIa,hemostasis is started by the formation of acomplex between tissue factor and activatedfactor VII following trauma or injury. It hasbeen shown that rFVIIa can induce hemostasisin the absence of FVIII and FIX. In addition,in vitro studies have shown that rFVIIa canbind to the activated platelet surface with lowaffinity and induce the thrombin burst forVolume 45 • Number 1 Pyelolithotomy in Glanzmann Thrombasthenia 65<---hemostasis7. Tengborn and Petruson1 firstreported the successful use of rFVIIa for severeepistaxis in a patient with Glanzmannthrombasthenia. After this report, rFVIIa wasused by other investigators for bleeding episodesor surgery in patients with Glanzmannthrombasthenia with or without alloantibodiesto platelet Gp IIb/IIIa complex or HLA2-4,8. Ithas also been used for patients with othercongenital or acquired functional plateletdisorders including Bernard-Soulier syndrome,platelet type (pseudo) von Willebrand disease,and thrombocytopathies due to uremia ormyelodysplastic syndrome9-12.Recombinant FVIIa has been used as acontinuous infusion for surgery in patients withGlanzman thrombasthenia who also hadalloantibodies to platelet Gp IIb/IIIa complex orHLA for four procedures and as a bolus injectionduring bilateral herniorrhaphy in children withGlanzmann thrombasthenia without antibodies2-4.Three of them were minor procedures such asbilateral herniorrhaphy, central line removal andintestinal polypectomy and biopsy2,3. The othertwo were major procedures, one of themintestinal resection and the other Bilroth-2gastrectomy3,4. Recombinant FVIIa was given for1, 3, and 7 days in minor procedures, for 5 daysin Bilroth-II gastrectomy, and for 15 days inintestinal resection. However, bilateral deepvenous thrombosis and pulmonary embolismdeveloped six days later after the cessation ofrFVIIa in the last patient. In our patient, rFVIIawas used only for three days in conjunction withtwo platelet transfusions, one just before surgeryand one immediately after. This is the shortesttime reported for a major surgery in patients withGlanzmann thrombasthenia. The other differencewas the use of rFVIIa as a bolus infusion insteadof a continuous one for a major surgery.Our experience supports that rFVIIa is effectiveand safe for patients with Glanzmannthnrombasthenia and alloantibodies to Gp IIb/IIIacomplex. Bolus infusion can be given instead ofcontinuous infusion with careful monitoring ofbleeding. Combined rFVIIa treatment and limitedplatelet transfusion for three days may be sufficientinstead of a long duration treatment. It is possiblethat the platelets bound all antibodies, and someresidual platelets provide hemostasis.In conclusion, the experience with rFVIIa forpatients with Glanzmann thrombasthenia isstill very limited due to the number of patients,bleeding episodes and surgical interventions.Accumulation of enough data will allow us tounderstand the role of rFVIIa in Glanzmannthrombasthenia. Better programs for theapplication of rFVIIa could be considered forthe future.AcknowledgementWe thank Man-Chiu Poon, MD (Canada),Jeanne M. Lusher, MD (USA) and Anton Sutor,MD (Germany) for their critical support.Recombinant activated factor VII (NovoSeven)was supplied at no cost to our patient by NovoNordisk Turkey Inc.REFERENCES1. Tengborn L, Petruson B. A patient with Glanzmannthrombasthenia and epistaxis successfully treated withrecombinant factor VIIa (Letter). Thromb Haemost1996; 75: 981.2. Poon M-C, d’Orion R and the International Registry onRecombinant Factor VIIa and Congenital Platelet DisordersGroup. Recombinant activated factor VII (NovoSeven®)treatment of platelet-related bleeding disorders. BloodCoagul Fibrinolysis 2000; 11 (Suppl): 55-68.3. d’Orion R, Menart C, Trzeciak MC, et al. Use ofrecombinant factor VIIa in 3 patients with inherited type1 Glanzmann’s thrombasthenia undergoing invasiveprocedures. Thromb Haemost 2000; 83: 644-647.4. Wielenga JJ, Siebel Y, van Buuren HR, et al. Use ofrecombinant factor VIIa and HLA matched plateletsto prevent bleeding during and after major surgery ina patient with Glanzmann’s thrombasthenia (Abstract).Haemophilia 1998; 4: 299.5. Lusher J, Ingerslev J, Roberts H, Hedner U. Clinicalexperience with recombinant factor VIIa. Blood CoagulFibrinolysis 1998; 9 (Suppl): 119-128.6. Kessler CM. New products for managing inhibitors tocoagulation factors: a focus on recombinant factor VIIaconcentrate. Curr Opin Hematol 2000; 7: 408-413.7. Hedner U. NovoSeen as a universal haemostatic agent.Blood Coagul Fibrinolysis 2000; 11 (Suppl): 107-111.8. Poon M-C, Demers C, Jobin F, Wu JW. Recombinant factorVIIa is effective for bleeding and surgery in patients withGlanzmann thrombasthenia. Blood 1999; 94: 3951-3953.9. Peters M, Heijboer H. Treatment of a patient withBernard-Soulier syndrome and recurrent nosebleedswith recombinant factor VIIa (Letter). ThrombHaemost 1998; 80: 352.10. Fressinaud E, Sigaud-Fix M, Le Boterff C, Piot B. Use ofrecombinant factor VIIa (NovoSeven®) for dental extractionin a patient affected by platelet-type (pseudo-) vonWillebrand disease (Abstract). Haemophilia 1998; 4: 299.11. Révész T, Arets B, Bierings M, van den Bos C, DuvalE. Recombinant factor VIIa in severe uremic bleeding(Letter). Thromb Haemost 1998; 80: 353.12. Meijer K, Sieders E, Slooff MJ, de WolfJTh, van derMeer J. Effective treatment of severe bleeding due toacquired thrombocytopathia by single dose administrationof activated recombinant factor VII (Letter). ThrombHaemost 1998; 80: 204.66 Devecioðlu Ö, et al The Turkish Journal of Pediatrics • January - March 2003

Pyelolithotomy in a patient with Glanzmann thrombasthenia and antiglycoprotein IIb/IIIa antibodies: the shortest possible duration of treatment with recombinant activated factor VII and platelet transfusions

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Pyelolithotomy in a patient with Glanzmann thrombasthenia and antiglycoprotein IIb/IIIa antibodies: the shortest possible duration of treatment with recombinant activated factor VII and platelet transfusions

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