We describe a case of a 4-year-old girl with Burkitt’s lymphoma, who suffered from a massive gastrointestinal hemorrhage 3 days after chemotherapy. In spite of applying the common practice in correction of coagulopathy, thrombocytopenia persisted and bleeding became life-threatening. In the present case report, we report a successful control of bleeding with a single-dose administration of a biosimilar recombinant activated human factor VII (AryoSeven).
Recombinant activated human factor VII (rFVIIa) is a hemostatic agent principally licensed to treat bleeding episodes and perioperative management in hemophilia A or B adults and children with inhibitors and adults with acquired hemophilia, congenital factor VII (FVII) deficiency, and Glanzmann’s thrombasthenia. These indications may be presented only in a small population. rFVIIa has been widely used in off-label indications of managing bleeding episodes. The leading use of off-label indications includes managing patients suffering from coagulopathies, for example, massive, uncontrollable, or sometimes intractable hemorrhage in trauma patients [
rFVIIa has been found to enhance the thrombin generation on preactivated platelets. Therefore, it is assumed that the use of rFVIIa can be beneficial in providing hemostasis in other situations characterized by massive bleedings and impaired thrombin generation [
Notwithstanding the significant increase in pediatric case series, to date the bulk of literature on off-label use of rFVIIa has been confined to adult population. In the current study, we report a Burkitt’s lymphoma case suffering from a massive GI bleeding which was controlled with a single administration of AryoSeven following the unresponsive transfusion of appropriate blood products.
A 4-year-old girl was referred to our center with presentation of abdominal pain. Diagnostic sonography revealed an intussusception in this patient. Surgery was performed and a large mass was seen in ileocecal area. After the mass biopsy, Burkitt’s lymphoma stage IIb was diagnosed since other organs were not involved.
Chemotherapy was performed in accordance with the intermediate risk group protocol named LMB89. The first course started with one dose of COP (CPM 300 mg/m2 vincristine 1 mg/m2 and 60 mg/m2 prednisolone; prednisolone was continued for 7 days). One week later, the second course was administered with COPADM1 (CPM IV 250 mg/m2/dose, MTX 3000 mg/m2, doxorubicin 60 mg/m2, Vincristine 2 mg/m2, and 60 mg/m2 Prednisolone; prednisolone was continued for 5 days). Three days after the second chemotherapy course, the patient experienced febrile neutropenia. In spite of appropriate antibiotic therapy ceftazidime 800 mg IV, vancomycin 250 mg IV, and fluconazole 50 mg were administered with supportive therapy. The patient deteriorated and suffered from massive lower GI bleeding. Her blood test is described in Table
Provides lab data at time of bleeding.
Lab data | At the time of bleeding |
---|---|
WBC | 500 mm3 |
Hb | 8 g/dL |
Plt | 12000/mm3 |
PT | 15 seconds |
aPTT | 46 seconds |
FDP and D-Dimer |
Normal |
The patient received several units of pack cell, 0.25 unit/kg platelets, 15 cc/kg fresh frozen plasma, and some doses of cryoprecipitate for more than 3 days which is explained in Table
Different blood product injection and vital sings during 3 days of bleeding.
Blood product | Unit | Body temperature before injection | Blood pressure before injection | Pulse before injection | Breath before injection |
---|---|---|---|---|---|
PC | 1 U | 37 | 88 | 22 | |
Cryoprecipitate | — | — | — | — | — |
FFP | 170 mL | 37 | 88 | 22 | |
PC | 4 U | 38 | 126/48 | 124 | 25 |
FFP | 170 mL | 37.5 | 140/98 | 96 | 32 |
FFP | 170 mL | 37 | |||
PC | 4 U | 37 | 90/50 | 123 | 12 |
PC | 3 U | 37 | 110/60 | 110 | 24 |
FFP | 170 mL | — | — | — | — |
PC | 3 U | 37 | 90/50 | 122 | 12 |
PC | 3 U | 38 | 90/50 | 120 | 12 |
FFP | 170 mL | 37.3 | 90/50 | 108 | 30 |
PC | 3 U | 37 | 90/50 | 120 | 32 |
PC | 3 U | 37 | 90/50 | — | — |
FFP | 200 mL | 37 | 100/60 | 134 | 28 |
After 72 hours of refractory and sever bleeding, the patient was switched to 90
Coagulating factor evaluation during bleeding and treatment.
Date | PT patient | PT control | PT activity | INR | PTT |
---|---|---|---|---|---|
One day before bleeding | 12 | 12 | 100 | 1 | 31 |
First day of bleeding | 12 | 12 | 100 | 1 | 30 |
Second day of bleeding | 13.8 | 12 | — | 1.3 | 28 |
Third day of bleeding | 12 | 12 | — | 1 | 29 |
In order to identify the source of bleeding, the patient underwent endoscopy and colonoscopy after her general condition was stabilized. No specific finding, except for a severe mucosal fragility, was found. Her last lab data are presented in Table
Lab data 12 hours after administration of AryoSeven.
Lab data | 12 hours after AryoSeven |
---|---|
WBC | 3880/mm3 |
Hb | 11.7 g/dL |
Plt | 65000/mm3 |
PT | 12 seconds |
PTT | 34 seconds |
FDP and D-Dimer | Normal |
Patient’s chemotherapy was continued, her primary disease was at remission, and there was no sign of GI bleeding ever since. For other chemotherapy cycles, GCSF administration was performed to prevent febrile neutropenia. The levels of fibrinogen were not evaluated during the study because the required equipment was not available.
AryoSeven is activated coagulation recombinant factor VII which is produced by AryoGen Pharmed. The biosimilarity of AryoSeven with NovoSeven has been approved according to the randomized, multicenter, double-blind clinical trial [
The mechanism of rFVIIa is generation of thrombin and platelet, activation of factor X, and formation of haemostatic plug [
Lee et al. described 3 cases of pediatric oncology patients with severe GI bleeding with no sufficient response to blood transfusions, in which rFVIIa was administered with dose range of 88–102 mcg/kg/dose. They reported that the use of rFVIIa resulted in a reduction in blood product support requirement and administration of rFVIIa was effective in 2 out of 3 patients in stopping the bleeding [
In conclusion, if there is no response to supportive therapy and administration of octreotide in controlling bleeding, use of recombinant factor VIIa can be lifesaving.
According to wide range of off-label indications of recombinant factor VIIa, we can say that it could be a wise option at refractory bleedings as the second-line therapy. The important problem is dose modification at off-label situations because there are some reports of thromboembolic events in off-label indications which were not fatal and not life-threatening.
A randomized clinical trial for off-label indication of recombinant FVIIa in pediatric hemorrhage could be helpful in assessing the safety and efficacy of this medication.
The authors declared that there are no competing interests.