Preliminary experience with the use of recombinant factor VIIa to treat coagulation disturbances in pediatric patients. (Original Article).

Objective: This study evaluates the efficacy of recombinant factor VII (rVIIa) in the treatment of coagulation dysfunction in pediatric patients.

Methods: We retrospectively reviewed the records of pediatric patients who received rVIIa in the intensive care unit or operating room for treatment of coagulopathy. Case series in the literature were also reviewed.

Results: Ten patients, ranging in age from 3 months to 19 years, received 22 doses of rVIIa. Seven of the 10 patients had received fresh frozen plasma and cryoprecipitate before the administration of rVIIa without effect. All 10 patients had a fibrinogen level above 100 mg/dl and platelet count above 100,000/mm3 at the time of rVIIa administration. After rVIIa administration, there were significant decreases in prothrombin time, international normalized ratio, and partial thromboplastin time. No adverse effects were noted.

Conclusion: Recombinant factor VIIa can be used to effectively reverse coagulation disturbances in the pediatric patient even when treatment with fresh frozen plasma has failed. Given its therapeutic potential, prospective, randomized trials are warranted.

**********

Various etiologic factors may be responsible for coagulation disturbances in children, including congenital deficiencies; hepatic insufficiency; disseminated intravascular coagulation (DIC) from sepsis, shock, or closed head injury; dilution of coagulation factors after cardiopulmonary bypass or large-volume transfusions; and medications. Treatment includes reversal or elimination of the inciting event and when clinically significant bleeding occurs, correction of coagulation function with the administration of blood products, including cryoprecipitate, fresh frozen plasma (FFP), and platelet concentrates.

Despite its efficacy, problems exist with the use of FFP, including the potential for the transmission of infectious diseases, volume overload, anaphylactoid reactions, and alterations in serum ionized calcium level. In addition, the time required for thawing and administration may require 30 to 60 minutes, depending on the patient's cardiorespiratory status and ability to tolerate rapid fluid administration. Concerns regarding FFP are further magnified by the report of Cote et al (1) of cardiac arrest and severe hypotensive episodes with the administration of FFP. Such disturbances of cardiovascular function may be especially detrimental and poorly tolerated in the critically ill pediatric patient. In addition, in selected cases, despite the administration of significant volumes of FFP, coagulation disturbances may persist.

Recent advances in recombinant DNA technology have allowed the synthesis of various coagulation factors, including factor VII. In 1988, the first patient was treated with recombinant active factor VIIa (rVIIa). (2) To date, the majority of experience with rVIIa has been in the treatment of patients with hemophilia who have developed auto-antibodies against factor VIII, making infusions of factor VIII ineffective during bleeding episodes. (3) After there was evidence of its efficacy in the hemophiliac population, there has been an increasing body of clinical experience with rVIIa in other settings. We report the retrospective review of our experience with rVIIa to treat coagulopathy of various etiologies in pediatric patients.

Methods

This retrospective review was approved by the Institutional Review Board of the University of Missouri and included our initial 6-month experience with rVIIa (Novo-Seven; Novo Nordisk Pharmaceuticals, Inc., Princeton, NJ). The records from the blood bank were reviewed, and nonhemophiliac patients younger than 21 years of age who had received rVIIa were identified. Demographic information obtained included patient age, weight, sex, and underlying etiology for the coagulopathy. Additional information retrieved included blood product administration before the use of rVIIa, platelet count and fibrinogen level at the time of rVIIa administration, dose of rVIIa administered, and coagulation profile, including prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (PTT) before and after rVIIa doses. Adverse effects potentially related to rVIIa were also identified.

A paired, two-tailed t test was used to compare the PT, INR, and PTT before and after each dose of rVIIa. [chi square] test with the Yates correction was used to compare the number of PT, INR, and PTT values that returned to normal or less after each dose of rVIIa. All data are presented as mean [+ or -] SD.

Results

Twenty-two doses of rVIIa were administered to 10 patients, who ranged in age from 3 months to 19 years and in weight from 3.7 to 49 kg. Before administration of rVIIa, PT was greater than 15 seconds, the INR was greater than 1.5, and PTT was greater than 35 seconds in all 10 patients. Normal values at our institution are PT [less than or equal to] 13.5 seconds; INR, 0.8 to 1.2; and PTT [less than or equal to] 35 seconds. The etiologies of the coagulation disturbances are listed in Table 1. Seven of the 10 patients had received FFP (20-40 ml/kg) before the administration of rVIIa, while 4 of 10 had received cryoprecipitate to achieve a fibrinogen level greater than 100 mg/ml. Despite this therapy, the elevation of the INR and prolongation of the PT and PTT persisted. In all 10 patients, the platelet count was greater than 100,000/[mm.sup.3] at the time of administration of rVIIa. The dose of rVIIa varied from 50 to 100 [micro]g/kg. The means and standard deviations for the PT, INR, and PTT before and after th e 22 doses of rVIIa are listed in Table 2. After rVIIa administration, the PT decreased from a baseline of 20.1 [+ or -] 5.2 seconds to 12.5 [+ or -] 2.6 seconds (P < 0.0001), the INR decreased from 2.2 [+ or -] 0.3 to 0.9 [+ or -] 0.3 (P < 0.000 1), and the PTT decreased from 49.1 [+ or -] 18.1 seconds to 38.5 [+ or -] 7.4 seconds (P 0.0037). After administration of the 22 doses of rVIIa, the PT was [less than or equal to] 13.5 seconds in 19 cases, the INR was [less than or equal to] 1.2 in 20 cases, and the PTT was [less than or equal to] 35 seconds in 9 cases (P - 0.03 and P = 0.01 when comparing PTT to PT and INR, respectively). In the two cases in which the INR did not correct to 1.2, the INR values were 1.4 and 1.8. These two patients received doses of rVIIa on the lower end of the dosing range of 50 to 100 [micro]g/kg (one received 65 [micro]g/kg and one received 72 [micro]g/kg).

Seventeen doses of rVIIa were administered in the pediatric intensive care unit, while five doses were administered intraoperatively. Five patients received a single dose, and five patients received multiple doses. The indications for 17 of the 22 doses included active bleeding, while 5 doses were administered before a procedure. These five procedures included placement of an invasive device (intracranial pressure monitor in two patients and pericardial drainage catheter in one patient) and removal of an invasive device in two patients (intra-aortic balloon pump and transthoracic pulmonary artery catheter). No adverse effects related to the administration of rVIIa were identified.

Discussion

In our review, rVIIa administration effectively corrected coagulation function even when FFP had failed to do so. In addition to restoring coagulation function as evidenced by laboratory tests, clinically significant bleeding decreased. The efficacy of rVIIa administration is demonstrated by dramatic corrections of the INR from values as high as 6.8 down to 0.8 and from 5.3 down to 1.0; and the PT from 36.6 down to 10.8 and from 32.7 down to 13.4 in two of the patients. When evaluating the INR, 2 of the 22 doses did not normalize the INR to [less than or equal to]1.2 (1.5 and 1.8, respectively). As its primary effect is through the extrinsic pathway, our clinical experience demonstrates only partial correction of the PTT; however, clinically evident bleeding ceased in all instances.

The two doses of rVIIa that did not result in full correction of the INR were on the lower end of the dosing range (50-100 [micro]g/kg) of this retrospective review, suggesting that the currently recommended dose for hemophiliac patients with inhibitors (90 [micro]g/kg) should be used. The lower doses were based on our desire to try to limit cost by using the 1.2-mg vial instead of the 4.8-mg vial.

Outside the hemophiliac population, there are limited data regarding the use of rVIIa in pediatric patients. (4,6-8) Chuansumrit et al (4) used rVIIa in three children with hepatic failure and DIC, which was related to dengue fever in two patients and hepatic resection in a third. All three patients had active clinical bleeding. In the first two cases, rVIIa was used when clinical bleeding continued despite the administration of FFP and cryoprecipitate, while in the third case, only rVIIa was administered. The dosing regimen, which the authors noted was adopted from the recommendations regarding the use of rVIIa in patients with hemophilia and inhibitors, (5) included an initial bolus dose of 90 [micro]g/kg followed by a continuous infusion of 16.5 [micro]g/kg/h. The infusion was continued for 18 hours in one patient, 40 hours in another, and 72 hours in a third, resulting in control of clinical bleeding and correction of the coagulation profiles.

A second group studied by Chuansumrit et al (6) included a cohort of five children with coagulopathy and liver failure of various etiologies, including hepatitis, histiocytosis, biliary atresia, autoimmune processes, and hepatoblastoma. Each had an ongoing coagulation disturbance, despite the administration of FFP (40 ml/kg), and invasive procedures were indicated (upper endoscopy for hematemesis in three patients; liver biopsy in two patients). The administration of rVIIa in a dose of 40 [micro]g/kg resulted in normalization of the PT, and the procedures were performed without incident. One patient received 40 [micro]g/kg of rVIIa every 6 hours for 48 hours because of the recurrence of gastrointestinal bleeding.

Additional anecdotal experience is available from case reports in the literature, which include one or two pediatric patients who received rVIIa (Table 3). (7-12) These reports lend further evidence for the efficacy of rVIIa administration, even when the coagulation defect fails to correct after the administration of FFP. There are now reports regarding the administration of rVIIa to approximately 22 nonhemophiliac pediatric patients with acquired coagulation disturbances.

In any clinically significant bleeding site, attempts should be made to exclude surgical causes of bleeding, to reverse, when possible, the etiologic factors contributing to the coagulopathy (eg, hypoperfusion, acidosis, hypothermia), and to correct coagulation function. Correction of coagulation function should focus on platelet count and function as well as on clotting factors, including fibrinogen concentration. In all of our patients, these factors were addressed, and coagulation disturbances persisted despite a platelet count greater than 100,000/[mm.sup.3], fibrinogen concentration greater than 100 mg/dl, and the administration of FFP to 7 of 10 of the patients in quantities varying from 20 to 40 ml/kg.

Given our experience and that reported in the literature, several settings may be present in which rVIIa should be considered. Administration of rVIIa may be indicated to control active bleeding or as prophylaxis to correct coagulation function before an invasive procedure (placement of an intracranial pressure monitor, central line or pericardial catheter), or removal of an invasive device (intra-aortic balloon pump or transthoracic pulmonary artery catheter). Administration of rVlla may also be considered when the coagulopathy does not respond to FFP, when there is not time to wait for the type and cross-match, thawing, and administration of FFP, or when an emergent procedure is needed. We found rVIIa administration to be effective in all of these clinical settings in our patients. When considering the use of FFP, additional issues to be considered include potential adverse hemodynamic effects, (13,14) the potential for volume overload, infectious disease transmission, and the previously mentioned time cons traints related to type and cross-match. Such problems are not seen with rVIIa administration, because it can be reconstituted quickly from powder with a small volume of saline (1-2 ml for the 1.2-mg vial) and can be administered intravenously for 2 to 3 minutes.

Although clinical experience is somewhat limited, no significant adverse effects have been noted in pediatric patients. Because synthetic factor VIIa requires tissue factor for activation, and because tissue factor is released only with vascular damage, the risk of excessive thrombogenesis should be limited. In pediatric cardiac surgery, however, there are no data regarding its use in patients with vascular anastomoses, such as system-to-pulmonary shunts, which may put the patient at high risk for thrombotic complications.

Dosing recommendations in pediatric patients are extrapolated in part from the literature on adult patients and supplemented by information from the pediatric hemophiliac population. Doses ranging from 40 to 100 [micro]g/kg have been administered in the nonhemophiliac pediatric population, including those in this report. To ensure efficacy in the majority of patients, doses of 90 [micro]g/kg may be required. In adults, Bernstein et al (15) reported a duration of effect that was dose-dependent, with normalization of the PT for 2 hours with 5 [micro]g/kg, 4 hours with 20 [micro]g/kg, and 12 hours with 90 [micro]g/kg. These data would coincide with our observations in the current cohort. In patients who had coagulation parameters checked in the hours after the dose of rVIIa, there was correction of the coagulation function for 8 to 12 hours. In addition to bolus dosing, one pediatric study reports the use of a continuous infusion of 16.5 to 33 [micro]g/kg/h. (5)

Given its potential therapeutic impact, rVIIa administration warrants further investigation in the pediatric population. In addition to its effects on coagulation function, preliminary data report augmentation of platelet function, suggesting a potential role of rVIIa in patients with bleeding and qualitative platelet disorders. (16, 17) Despite all of its potential benefits, cost remains a consideration. The cost of rVIIa is approximately 80 Cents/[micro]g, or $3,888 for the 4.8-mg vial and $972 for the 1.2-mg vial. Such information must be factored in when considering the cost of the agent itself versus potential benefits of decreased use of blood products, decreased intensive care unit stays, and the potential for decreased patient morbidity and mortality.

Table 1

Etiology of the coagulation disturbance in patients receiving
recombinant factor VIIa

                                No. of
Etiology                       patients

Dilutional (n = 4)
 Large-volume transfusion         3
 Status postcardiopulmonary       1
  bypass
Disseminated intravascular
 coagulation (n = 4)
 Head trauma                      2
 Status post-cardiac arrest       1
 Sepsis and shock                 1
Hepatic insufficiency (n = 2)
 Cystic fibrosis                  1
 Cholestasis from prolonged       1
  parenteral nutrition

Table 2

Coagulation test values before and after administration of recombinant
factor VIIa (a)

                     Normal values at                Patient
Parameter            our institution         baseline ([+ or -] SD)

PT (seconds)   [less than or equal to] 13.5     20.1 [+ or -] 5.2
INR                      0.8-1.2                2.2 [+ or -] 0.3
PTT (seconds)   [less than or equal to] 35     49.1 [+ or -] 18.1

                       After rVIIa
Parameter      administration ([+ or -] SD)     P

PT (seconds)        12.5 [+ or -] 2.6        <0.0001
INR                  0.9 [+ or -] 0.3        <0.0001
PTT (seconds)       38.5 [+ or -] 7.4         0.0037

(a) rVIIa, recombinant factor VIIa

PT, prothrombin time

INR, international normalized ratio

PTT, partial thromboplastin time

Table 3

Anecdotal reports of recombinant factor VIIa use in infants and children
(a)

Case report (ref. no.)      No. of patients (age)

Kalicinski et al, 1999 (7)    2 (2.5 yr, 6 yr)











Al Douri et al, 2000 (8)      1 (2.5 yr)






Kenet, 2001 (9)               1 (6 yr)






Tobias, 2002 (10)             2 (8 yr, 13 yr)










Tobias Ct al, 2002 (11)       1 (19 yr)










Tobias et al, 2003 (12)       1 (4 mo)








Case report (ref. no.)         Clinical setting

Kalicinski et al, 1999 (7)  Hepatic transplantation











Al Douri et al, 2000 (8)    Cardiac surgery






Kenet, 2001 (9)             Thoracic surgery






Tobias, 2002 (10)           Posterior spinal fusion










Tobias Ct al, 2002 (11)     Cardiac arrest










Tobias et al, 2003 (12)     Cardiac surgery








Case report (ref. no.)                 Outcome

Kalicinski et al, 1999 (7)  Perioperative coagulopathy despite
                             administration of FFP and
                             cryoprecipitate, with INRs of 5.7
                             and 6.9. Patient 1 received 100
                             [micro]g/kg of rVIIa before
                             incision and again 2 hours later,
                             resulting in INRs of 0.7 to 1.1
                             during the surgery. Patient 2,
                             received one dose of rVIIa
                             preoperatively, and INR was 1.1
                             to 2.4 intraoperatively.

Al Douri et al, 2000 (8)    Significant postoperative bleeding
                             with blood loss through chest
                             tubes. Administration of rVIIa (30
                             [micro]g/kg) resulted in cessation
                             of bleeding and correction of
                             coagulation function.

Kenet, 2001 (9)             Intraoperative arrest and
                             coagulopathy. Administration of
                             rVIIa (90 [micro]g/kg) led to
                             correction of coagulation function
                             and cessation of clinical
                             bleeding.

Tobias, 2002 (10)           Intraoperative blood loss and
                             coagulopathy. No response
                             following administration or 20-30
                             ml/kg of FFP. Administration of
                             rVIIa (90 [micro]g/kg) corrected
                             coagulation function. PTs
                             decreased from 16.8 to 10.6 and
                             16.9 to 12.6 while INRs decreased
                             form 1.7 to 0.8 and 1.5 to 0.9 in
                             the 2 patients, respectively.

Tobias Ct al, 2002 (11)     Removal of intra-aortic balloon
                             pump after stabilization of
                             cardiovascular function.
                             Coagulation dysfunction despite
                             administration of 5 units of FFP.
                             Following rVIIa administration (70
                             [micro]g/kg), PT decreased from
                             19.8 to 12.5, and INR decreased
                             from 2.2 to 0.9. IABP removed
                             without clinical bleeding.

Tobias et al, 2003 (12)     Excessive postoperative bleeding.
                             Concerns regarding potential
                             hemodynamic effects of FFP.
                             Administration of rVIIa (90
                             [micro]g/kg) resulted in a
                             decrease of PT from 36.6 to 10.8
                             and decrease in INR from 6.8 to
                             0.8.

(a) FFP, fresh frozen plasma; rVIIa, recombinant factor VIIa; INR,
international normalized ratio; PT, prothrombin time; IABP, intraaortic
balloon pump.

Accepted June 17, 2002.

References

(1.) Cote CJ, Drop LJ, Hoaglin DC, Daniels AL, Young ET. Ionized hypocalcemia after fresh frozen plasma administration to thermally injured children: Effects of infusion rate, duration, and treatment with calcium chloride. Anesth Analg 1988;67:152-160.

(2.) Hedner U, Glazer S, Pingel K, et al. Successful use of recombinant factor VIIa in patient with severe haemophilia A during synovectomy. Lancet 1988;2:1193 (letter).

(3.) Hedner U. Recombinant coagulation factor VIIa: From the concept to clinical application in hemophilia treatment in 2000. Semin Thromb Hemost 2000;26:363-366.

(4.) Chuansumrit A, Chantarojanasiri T, Isarangkura P, et al. Recombinant activated factor VII in children with acute bleeding resulting from liver failure and disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2000;l1(Suppl l):S10l-S105.

(5.) Schulman S, Bech Jensen M, Varon D, et al. Feasibility of using recombinant factor VIIa in continuous infusion. Thromb Haemost 1996;75:432-436.

(6.) Chuansumrit A, Treepongkamna S, Phuapradit P. Combined fresh frozen plasma with recombinant factor VIIa in restoring hemostasis for invasive procedures in children with liver diseases. Thromb Haemost 2001;85:748-749 (letter).

(7.) Kalicinski P, Kaminski A, Drewniak T, et al. Quick correction of hemostasis in two patients with fulminant liver failure undergoing liver transplantation by recombinant activated factor VII. Transplant Proc 1999;31:378-379.

(8.) Al Douri M, Shafi T, Al Khudairi D, et at. Effect of the administration of recombinant activated factor VII (rFVIIa; NovaSeven) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery. Blood Coagul Fibrinolysis 2000;11(Suppl 1):S121-S127.

(9.) Kenet G. rFVIIa for profuse bleeding in surgical patients. Bloodline Rev 2001;1:12-13. Available at: http://www.privatelectureseries.com/stories/storyReader$45. Accessed: November 19, 2002.

(10.) Tobias JD. Synthetic factor VIIa to treat dilutional coagulopathy during posterior spinal fusion in two children, Anesthesiology 2002;96:1522- 1525.

(11.) Tobias JD, Berkenbosch JW, Muruve NA, Schmaltz RA. Correction of a coagulopathy using recombinant factor VII before removal of an intra-aortic balloon pump. J Cardiothorac Vasc Anesth 2002;16:612-614.

(12.) Tobias JD, Berkenbosch JW, Russo P. Recombinant factor VIIa to treat bleeding following cardiac surgery in an infant. Pediatr Crit Care Med 2003;4:49-51.

(13.) Cote CJ, Drop LJ, Hoaglin DC, Daniels AL, Young ET. Ionized hypocalcemia after fresh frozen plasma administration to thermally injured children. Anesth Anaig 1988;67:152-160.

(14.) Hashim SW, Kay HR, Hammond GL, Kopf GS, Geha AS. Noncardiogenie pulmonary edema after cardiopulmonary bypass: An anaphylactoid reaction to fresh frozen plasma. Am J Surg 1984;147:560-564.

(15.) Bernstein DE, Jeffers L, Erhardtsen E, et al. Recombinant factor VIIa corrects prothrombin time in cirrhotic patients: A preliminary study. Gastroenterology 1997;l13:1930-1937.

(16.) Poon MC, Demers C, Jobin F, Wu JWY. Recombinant factor VIIa is effective for bleeding and surgery in patients with Glanzmann thrombasthenia. Blood 1999;94:3951-3953.

(17.) Kristensen J, Killander A, Hippe E, et at. Clinical experience with recombinant factor VIIa in patients with thrombocytopenia. Haemostasis 1996;26(Suppl 1):159-164.

RELATED ARTICLE: Key Points

* Various etiologic factors may be responsible for coagulation disturbances in children, including congenital deficiencies, hepatic insufficiency, disseminated intravascular coagulation, dilution of coagulation factors from large-volume transfusions, and medications.

* Potential problems with administration of fresh frozen plasma include the transmission of infectious diseases, volume overload, anaphylactoid reactions, and alterations in serum ionized calcium level, as well as the time required for the type and cross-match to be completed, thawing, and administration.

* In our patient cohort, administration of recombinant factor VIIa corrected coagulation function even when administration of fresh frozen plasma in doses ranging from 20 to 40 ml/kg was ineffective.

* Administration of recombinant factor VIIa should be considered when coagulation disturbances persist despite the administration of fresh frozen plasma or if time constraints limit the availability of fresh frozen plasma.

From the Departments of Anesthesiology and Pediatrics and the Division of Pediatric Anesthesiology/Pediatric Critical Care, University of Missouri, Columbia, MO.

Reprint requests to Joseph D. Tobias, MD, Department of Anesthesiology, Pediatric Critical Care/Pediatric Anesthesiology, University of Missouri, 3W40H, One Hospital Drive, Columbia, MO 65212. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9601-0012