Use of Recombinant Factor VIIa for Bleeding in Children with Glanzmann Thrombasthenia

Glanzmann thrombasthenia is a very rare inherited platelet function disorder in which bleeding may be extremely difficult to stop. Recombinant factor VIIa is one of the alternative treatments for bleeding. The authors report here their experience with the use of factor VIIa, which may be useful for arresting bleeding in Glazmann thrombasthenia.     

Successful Use of Recombinant Factor VIIa (NovoSeven) During Cardiac Surgery in a Pediatric Patient with Glanzmann Thrombasthenia

Glanzmann thrombasthenia is a rare, hereditary, congenital disorder of platelet function characterized by inappropriate bleeding that is difficult to control. Recombinant activated factor VII (rFVIIa) is a new treatment that is used to stop bleeding and provide surgical support for these patients. This report describes the use of rFVIIa to prevent serious bleeding during and after open-heart surgery in a child with Glanzmann thrombasthenia.     

Allogeneic stem cell transplantation for Glanzmann thrombasthenia

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by normal platelet count, but lack of platelet aggregation. The molecular basis is linked to quantitative and/or qualitative abnormalities of the membrane glycoprotein IIb/IIIa complexes. Usually it is associated with mild bleeding but may lead to severe and potentially fatal hemorrhages. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment. However, because of the risks associated with HSCT, it is generally not recommended unless there are life threatening hemorrhages, or the patient has developed refractoriness to platelet transfusion due to antibody formation. Herein, we report an 11‐year‐old female from United Arab Emirates (UAE) with severe GT and anti platelet alloimmunization successfully treated with HSCT from her HLA‐identical sibling. Pediatr Blood Cancer 2009;52:682–683. © 2008 Wiley‐Liss, Inc.     

Spontaneous haemothorax: an uncommon presentation of Glanzmann thrombasthenia

Glanzmann thrombasthenia is a rare hereditary qualitative platelet disorder characterized by a lifelong bleeding tendency due to quantitative and qualitative abnormalities of the platelet integrin alpha(IIb)beta3. Common clinical manifestations include purpuric type skin bleeding, prolonged bleeding from minor cuts, epistaxis, gingival bleeding and menorrhagia. Less frequently, gastrointestinal system bleeding may occur. Haemarthrosis, haematuria, intracranial and visceral haemorrhage are very rare symptoms. This study reports a 3-y-old girl with Glanzmann thrombasthenia who presented with life-threatening haemothorax. There was no history of recent trauma or drug usage and no vascular or parenchymal abnormalities to explain the development of haemothorax. Conclusion: To the authors' knowledge this is the first case of Glanzmann thrombasthenia complicated by spontaneous haemothorax.     

Use of rFVIIa in 4 children with Glanzmann thrombasthenia

Inherited deficiencies of platelet surface glycoproteins, such as Glanzmann thrombasthenia (GT), occasionally result in severe bleeding episodes. Platelet transfusion is considered standard therapy for securing hemostasis in subjects with GT when local measures and antifibrinolytic agents are inadequate. We describe 4 case studies which suggest that recombinant activated factor VII may be an effective alternative to platelet transfusion in preventing or controlling bleeding, including surgical bleeding, in patients with GT.     

Bleeding and surgery in children with Glanzmann thrombasthenia with and without the use of recombinant factor VII a

BACKGROUND: An inherited deficiency of platelet glycoprotein II b/III a (GP II b/III a), Glanzmann thrombasthenia, can lead to excessive bleeding and require platelet transfusion to secure hemostasis. Antibodies to GP II b/III a or HLA may platelet transfusion render ineffective to stop bleeding or to cover surgery. Recombinant factor VII a has been introduced as therapeutic alternative and has been suggested to be effective. PATIENTS AND AIMS OF THE STUDY: In a retrospective evaluation, bleeding episodes and surgery in six patients treated with antifibrinolytics and with and without the additional use of rFVII a were analysed to achieve informations for treatment indication and efficacy. RESULTS: Nineteen mucosal and subcutaneous bleeding episodes, two dental surgeries and seven joint bleeds occurred. In 11 mild to moderate mucocutaneous bleeds treated without rFVII a, seven stopped within 48 hours, three stopped until the fourth day; one showed recurrence. Three bleeds were treated with rFVII a and responded within 24 hours. One severe bleed treated without rFVII a did not stop until the 8 (th) day after cautery. In 4 severe bleeds treated with rFVII a, one stopped within 24 hours, one showed recurrence, one was treated with platelet transfusion concurrently and one did not respond to rFVII a. Clinical signs persisted in one conservatively treated elbow joint bleed, whereas in two episodes treated with rFVII a, the bleeding responded within 5 and 7 days and in four episodes in at least 4 days. Two dental surgeries showed no recurrence after rFVII a over 18 or 36 hours. CONCLUSIONS: In severe mucocutaneous bleeding episodes or joint bleeding rFVII a is of some benefit whereas in surgeries like teeth extraction, prophylactically administered rFVII a seems effective to avoid bleeding. In mild to moderate mucocutaneous bleeding events, antifibrinolytics and local measures were sufficient in most cases and the additional use of rFVII a does not seem to be necessary. Further information is needed to elaborate clear indications for the rational use of rFVII a in bleeding episodes in patients with Glanzmann thrombasthenia compared to standardized baseline treatment. This information may generate a prospective multicenter study to provide clear advice with respect to bleeding site, severity and duration.     

Sustained engraftment post bone marrow transplant despite anti-platelet antibodies in Glanzmann thrombasthenia

BACKGROUND: Patients with Glanzmann thrombasthenia (GT) have normal platelet counts but abnormal platelet aggregation and carry the risk of life-threatening bleeding. We report three patients who received bone marrow transplantation (BMT) for type I GT and discuss the risk and management of anti-platelet antibodies. PATIENTS AND RESULTS: Diagnosis of GT was made through abnormal platelet aggregation studies or the absence of GPIIb/IIIa by flow cytometry. All patients had severe bleeding requiring multiple red blood cell transfusions. One patient received an unrelated donor transplant and two received matched sibling donor transplants following conditioning therapy with busulfan, cyclophosphamide, and fludarabine. Two patients developed an anti-platelet antibody, treated in one with intravenous immune globulin (IVIG). Engraftment of white blood cells and platelets was achieved on day +13 to +14 and +17 to +25, respectively. Complete donor chimerism and GPIIb/IIIa+ platelets are sustained at +22 to +30 months post transplant. CONCLUSIONS: In summary, patients with GT and history of severe hemorrhage can be cured with BMT, but the presence of anti-platelet antibodies should be sought and platelet transfusions minimized prior to transplant. IVIG may be helpful in cases of refractory immune thrombocytopenia related to anti-platelet antibodies. Improvement in transplant-related complications with current transplant regimens allows consideration of BMT for life-threatening non-malignant disorders such as GT.     

Novel and recurrent mutations of ITGA2B and ITGB3 genes in Korean patients with Glanzmann thrombasthenia

Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder caused by defective glycoprotein, αIIb and β3, encoded by ITGA2B and ITGB3 genes, respectively. We herein describe four unrelated Korean patients with genetically confirmed GT. Two patients were homozygous for c.1913+5G>T (IVS11+5G>T) mutation of ITGB3 with a signature of founder effect. The other two patients were compound heterozygous for two mutations of ITGA2B: c.[2333A>C];[2975delA] (p.[Q778P];[E992Gfs*30]) and c.[1750C>T];[2333A>C] (p.[R584X];[Q778P]). The c.2975delA mutation was a novel frameshift mutation of ITGA2B. Although from a limited number of patients, these results suggests c.1913+5G>T of ITGB3 is a recurrent mutation in Korean patients with GT.     

Single-center experience: use of recombinant factor VIIa for acute life-threatening bleeding in children without congenital hemorrhagic disorder

Coagulopathy is an important cause of mortality in critically ill children. Traditional therapies to correct coagulopathy lead to great time delays and cause fluid overload in patients. The authors report the effectiveness and safety of the activated recombinant factor VII (rFVIIa) administration in a series of 13 nonhemophiliac children with acute, life-threatening bleeding. In this retrospective study, the records of the patients who were not diagnosed with congenital hemorrhagic disorder and were administered rFVIIa due to any other reason in Ege University Faculty of Medicine, Department of Pediatrics, between February 2002 and February 2007 were reviewed retrospectively. Thirteen nonhemophiliac patients with acute life-threatening bleeding and ages ranging from 2 days to 15 years received rFVIIa over a 5-year period. Three patients were diagnosed with hemaphagocytic lymphohistiocytosis, 4 with prematurity, sepsis, and disseminated intravascular coagulation (DIC), 5 with sepsis, multiple organ dysfunction syndrome, and DIC, and 1 with acute liver failure. Severe bleeding resulted from pulmonary (n = 3), lower gastrointestinal system (n = 2), esophagus varices (n = 1), pulmonary and gastrointestinal system (n = 4), pulmonary, gastrointestinal system, and intracranial hemorrhage (n = 1), and gastrointestinal system and intracranial hemorrhage (n = 2). Median frequency of rFVIIa administration was 3 per patient (range 2-15) and median dose of rFVIIa was 90 microg/kg, ranging from 60 to 135 microg/kg each administration. All of the patients were given fresh frozen plasma and if necessary platelet transfusion (n = 10) or fibrinogen concentrate (n = 3) before administration of rFVIIa. In 6 patients, lack of success to control bleeding by conventional methods was the only cause to start rFVIIa. In 7 patients, the need for volume restriction was also a significant contributing factor in deciding to start rFVIIa. Median PT was 32.9 s (range: 19-65) before rFVIIa administration and it was decreased to 11.6 s (range: 10.7-12.8), 2-3 h after rFVIIa infusion. Bleeding was stopped completely in 10 patients at least for 24 h and decreased in 3 patients 30-45 min after rFVIIa administration. Two patients had thrombotic complications attributed to rFVIIa administration. No other complication was observed in the other patients. In this retrospective study, rFVIIa was found to be effective at controlling severe hemorrhagic symptoms of different etiologies in children without congenital hemorrhagic disorder. In addition to the rapid control of bleeding, administration of this agent improved fluid balance and led to a reduction in blood product requirements in critically ill children. However, survival was still poor (23%), and 2/13 (15.4%) patients developed venous and arterial thrombosis within 3 h of treatment. The authors emphasize that in acquired, acute life-threatening bleeding, simultaneous administration of rFVIIa with conventional treatment may contribute to patient survival. However, the risk of thromboembolism should be considered before this treatment is given.     

Use of recombinant factor VIIa (rFVIIa) to control intraoperative bleeding in pediatric brain tumor patients

Surgical bleeding during the resection of brain tumors in children may be related to tumor vascularity, pathology, and location. Despite improvements in neurosurgical technique, neuroanesthesia, and blood product replacement, bleeding can be life-threatening in these surgeries. We report eight pediatric patients in whom recombinant factor VIIa (rFVIIa) was used to control intraoperative bleeding during surgical resection of pediatric brain tumors. rFVIIa should be considered as a method to control intraoperative bleeding that is unresponsive to conventional interventions. Additional studies are needed to determine optimal patient selection and drug dosing, efficacy and safety.     

The use of recombinant coagulation factor VIIa in uncontrolled postoperative bleeding in children undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVE: To assess the hemostatic efficacy of recombinant coagulation factor VIIa (rFVIIa) in the management of uncontrolled bleeding in postcardiac surgery with cardiopulmonary bypass in children. DESIGN: An open-label study. SETTING: A postoperative intensive care unit. PATIENTS: Eight consecutive pediatric patients with excessive bleeding after cardiac surgery with cardiopulmonary bypass that met the criteria for reexploration and did not respond to optimal transfusions of platelets and fresh frozen plasma. INTERVENTIONS: rFVIIa 30 microg/kg was given as a bolus injection. A higher dose of 60 microg/kg was used if a patient had preoperative coagulopathy, preoperative multiple-organ failure, or indications that required an emergency operation. The same dose was repeated 15 mins after the previous injection if the bleeding had not decreased. If the bleeding had decreased but still exceeded 10 mL/hr for body weight 5 kg, the same dose was repeated 2 hrs after the previous injection. A maximum of four doses could be given before rFVIIa was considered ineffective and a reexploration was needed. MEASUREMENTS AND MAIN RESULTS: Postoperative blood loss was estimated from the volume of chest tube drainage. rFVIIa successfully controlled bleeding and prevented reexploration in all seven patients who received treatment according to the protocol. One patient who received only one dose of rFVIIa required reexploration because a second dose was not available. No adverse events related to rFVIIa were seen. CONCLUSIONS: rFVIIa may be useful in preventing reexploration in uncontrolled postoperative bleeding in children undergoing cardiac surgery with cardiopulmonary bypass. Randomized, placebo-controlled studies are needed to confirm the safety and efficacy of rFVIIa in this clinical setting.     

The use of recombinant factor VIIa in a patient with Noonan syndrome and life-threatening bleeding.

OBJECTIVE: To present a case report of a patient with Noonan syndrome who developed life-threatening gastrointestinal bleeding shortly after cardiac surgery that was successfully treated with recombinant factor VIIa. DESIGN: Case report. SETTING: Pediatric intensive care unit of a children's hospital. PATIENT: Ten-month-old with Noonan syndrome and massive gastrointestinal bleeding resulting in severe hypovolemic shock. INTERVENTIONS: Recombinant factor VIIa was used in this patient's severe bleeding associated with Noonan syndrome after no other supportive measures were successful. MEASUREMENTS AND MAIN RESULTS: Recombinant Factor VIIa significantly decreased the patient's bleeding and allowed his hypovolemic shock to improve. Ultimately, the patient made a complete recovery. CONCLUSIONS: Noonan syndrome has a constellation of both cardiac and noncardiac malformations including an increased risk of bleeding, and recombinant factor VIIa is an important agent in the treatment of significant bleeding.     

Use of recombinant factor VIIa for refractory hemorrhage during extracorporeal membrane oxygenation.

OBJECTIVE: To describe the outcome and treatment of two patients with recombinant factor VIIa (rFVIIa) for severe hemorrhage associated with extracorporeal membrane oxygenation (ECMO). DESIGN: Case report. SETTING: A 38-bed pediatric intensive care unit and 20-bed pediatric cardiac intensive care unit at a tertiary care children's hospital. Patient: Two patients with life-threatening hemorrhagic complications associated with ECMO requiring massive transfusion of blood products. INTERVENTIONS: Administration of repeated doses of rFVIIa at 90 microg/kg/dose. MEASUREMENT AND MAIN RESULTS: Patient 1 was an 11-yr-old male with a dilated cardiomyopathy who had undergone an orthotopic heart transplant treated with venoarterial ECMO postoperatively for right ventricular dysfunction. Patient 2 was a 13-yr-old male treated with venoarterial ECMO for cardiopulmonary failure from necrotizing staphylococcal pneumonia. Both patients had severe hemorrhage from the cannulation sites and thoracostomy tubes requiring massive transfusion to maintain intravascular blood volume and replace clotting factors. Both patients were treated with rFVIIa every 2-4 hrs and attained hemostasis. Patient 1 was administered three doses and Patient 2 was administered ten doses. No evidence of abnormal thrombus formation was noted in their respective ECMO circuits. CONCLUSIONS: The efficacy of rFVIIa in reducing intractable bleeding postcardiac surgery and in other coagulopathic states is being investigated. Despite theoretical concerns of thrombosis, these cases illustrate that there may be a role for the cautious use of rFVIIa in treating severe and intractable hemorrhage associated with ECMO.     

Spontaneous liver hemorrhage during laparotomy for necrotizing enterocolitis: a potential role for recombinant factor VIIa

Necrotizing enterocolitis remains a serious condition in very low birth weight infants, particularly in those infants who require surgery. Perioperative hemorrhage is a potentially fatal complication in this population. We describe our experience in 4 premature infants with necrotizing enterocolitis who received recombinant factor VIIa to manage life-threatening intraoperative hemorrhage.     

Use of recombinant factor VIIa prior to lumbar puncture in pediatric patients with acute leukemia

The persistence of abnormal coagulation test results after standard treatment with fresh frozen plasma (FFP) poses significant problems in children with acute leukemia requiring a diagnostic lumbar puncture and intrathecal chemotherapy. We report the prophylactic use of a single dose of 90 microg/kg recombinant activated factor VII (rFVIIa) in three children and the rapid correction of abnormal coagulation test results previously not corrected by FFP. Administration of rFVIIa was useful in avoiding a delay of diagnostic lumbar punctures and intrathecal chemotherapy. Hemorrhagic complications and adverse effects of rFVIIa were not observed. Prospective evaluation of this indication and dose appears warranted. (c) 2005 Wiley-Liss, Inc.     

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

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.