COAGULATION disturbances and excessive surgical bleeding are major risks associated with any surgical procedure in which blood loss is common. In pediatric-aged patients, one of the more common surgical procedures associated with significant blood loss is posterior spinal fusion. During such procedures, blood loss may equal or exceed a blood volume. 1When blood component therapy, including packed red blood cells, are used to replace blood loss, a dilutional coagulopathy can occur related either to thrombocytopenia or the dilution of coagulation factors. When abnormal coagulation function is demonstrated by prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT), treatment generally includes the administration of fresh frozen plasma (FFP) and cryoprecipitate if the fibrinogen level is low. Although this therapy is generally effective, repeated doses of FFP may be required, and occasionally, coagulation disturbances persist. The author presents two children who developed dilutional coagulopathy during posterior spinal fusion for neuromuscular scoliosis. When FFP failed to correct the coagulopathy, synthetic factor VIIa (NovoSeven®, Novo Nordisk Pharmaceutials, Princeton, NJ) was successfully used. The current status of synthetic factor VIIa and its potential role in the treatment of dilutional coagulopathy are discussed.
An 8-yr-old, 26-kg girl with neuromuscular scoliosis presented for posterior spinal fusion. Anesthetic care included controlled hypotension with remifentanil–isoflurane to maintain a mean arterial pres-sure of 55–65 mmHg. Aprotinin was administered in a dose of 30,000 units·kg−1·h−1. The coagulation parameters and treatments are listed in table 1. The normal ranges are: prothrombin time (PT) 12.0–15.2 s, International Normalized Ratio (INR) 0.8–1.2, partial thromboplastin time (PTT) 23.2–36.0 s, and fibrinogen 187–419 mg/dl. Throughout the hospital course, the patient's platelet count remained above 100,000/mm3. Eighteen hours postoperatively, when the coagulation function was abnormal again and failed to correct with a unit of FFP (280 ml), the decision was made to use synthetic factor VII, since the patient's hematocrit had decreased from 30% to 23% and there was 590 ml of output into the surgical drain. After the infusion of synthetic factor VII, there was less than 50 ml of sanguinous drainage from the wound and the drain was removed the next morning. Coagulation studies 24 h later remained within normal limits.
A 13-yr-old, 38-kg boy with neuromuscular scoliosis presented for posterior spinal fusion. Anesthetic care included controlled hypotension with remifentanil–isoflurane–labetolol to maintain a mean arterial pressure of 55–65 mmHg. Aprotinin was administered in a dose of 30,000 units·kg−1·h−1. The coagulation profiles and treatments are listed in table 2. Postoperatively, the patient's platelet count remained above 100,000/mm3. Eighteen hours postoperatively, when the coagulation function was abnormal again, based on the previous inability of FFP to correct the abnormal coagulation function, the decision was made to use synthetic factor VIIa. Output over the 12 h from the surgical drains was 692 ml. After the infusion of synthetic factor VII, there was less than 50 ml of sanguinous drainage from the wound and the drain was removed the next morning. Coagulation studies 24 h later remained within normal limits.
Normal coagulation requires the interaction and normal function of various components of the coagulation cascade including platelets, vascular endothelium, and plasma glycoproteins (clotting factors). The clotting cascade has been divided into intrinsic and extrinsic pathways. The extrinsic pathway is initiated by damage to blood vessels and the subsequent release of a transmembrane protein known as tissue factor (TF). TF interacts with and activates factor VII, resulting in the formation of active factor X. Activated factor X with activated factor V results in the conversion of prothrombin to thrombin, which subsequently converts fibrinogen to fibrin (common pathway). 2
Before the availability of isolated synthetic factors, FFP and cryoprecipitate were used to treat patients with congenital or acquired coagulation defects. Although generally effective, the obvious health hazards of infectious disease transmission, including the hepatitis and acquired immune deficiency viruses, make this a less than optimal approach to such problems. This problem was alleviated by the production of synthetic factor VIII and IX via recombinant DNA technology. However, 15–25% of patients with factor VIII deficiency (hemophilia A) develop antibodies against factor VIII, making future infusions of factor VIII ineffective during bleeding episodes. 3Although activated vitamin K dependent factor concentrates can be used in these patients, their efficacy is low and they are associated with thromboembolic effects. 4,5Since factor VIIa must interact with TF to become active, it was postulated that it would be the perfect alternative in hemophiliacs with inhibitors because it would bypass the extrinsic system (factors VIII and IX), activating the extrinsic pathway, and would not be associated with thromboembolic risks. In 1988, the first patient was treated with synthetic factor VIIa at the Karolinska Hospital in Stockholm, Sweden. Factor VIIa was successfully used as the sole hemostatic agent during synovectomy in a patient with hemophilia and inhibitors. 6
Experience using factor VIIa outside of the hemophilia population is somewhat limited. White et al. reported the successful use of factor VIIa in two surgical patients who developed coagulopathy and bleeding after massive transfusion. 7Despite correction of coagulation function as demonstrated by normalization of the PT–PTT and platelet counts, the patients continued to have bleeding. Bleeding stopped after factor VIIa infusion and the authors suggest that factor VIIa has the potential to act as a universal hemostatic agent, and its use should be considered where there is intractable intraabdominal hemorrhage that has failed to respond to conventional therapy. Bernstein et al. demonstrated that synthetic factor VIIa was effective in normalizing the PT in nonbleeding adults with hepatic cirrhosis (Child's B or C). 8The duration of the effect was dose-dependent with normalization of the PT for 2 h with 5 μg/kg, 4 h with 20 μg/kg, and 12 h with 90 μg/kg. Erhardtsen et al. demonstrated normalization of the PT after synthetic factor VIIa administration to adult volunteers treated with vitamin K antagonists. 9
To date, there have been no major adverse effects associated with the administration of synthetic factor VIIa in pediatric-aged patients. As it must interact with TF, which is released at the site of tissue injury, there should be limited risk of thromboembolic events. Of note is the fact that although the coagulation profile (PT and PTT) will correct, synthetic factor VIIa will not increase other factor levels that are decreased related to either dilutional or consumptive effects. As such, once the factor VII levels have declined, unless there is replacement (exogenous administration or endogenous production) of these factor levels, the coagulation defect will recur. Based on the data of Bernstein et al. , 8the duration of effect of a 90 μg/kg dose is 12 h and repeat monitoring of coagulation function is suggested.
Correction of the coagulation disturbance was not achieved in the 2 children reported herein after the administration of routine doses of FFP (20–30 ml/kg). Although it is possible that the coagulation defect could have been corrected with additional FFP; in addition to rapidly correcting the coagulation defect, there are other potential advantages of synthetic factor VIIa when compared with FFP. These include no infectious disease risk; a much smaller volume, thereby allowing rapid administration without concerns of volume overload; and an easy to use preparation that is quickly diluted and administered, whereas FFP has to be thawed, necessitating a 30–45 preparation time. The more rapid administration and correction of the coagulation defect could theoretically lead to a reduction in blood loss, improved surgical visualization, and perhaps decreased surgical time. In addition, preliminary data suggests that synthetic factor VIIa improves platelet function, adding a secondary beneficial effect on coagulation function during the perioperative period. The significant effect of factor VIIa on platelet function is demonstrated by preliminary data, suggesting that it may be an effective agent to control bleeding in patients with qualitative and quantitative platelet disorders. 10,11Adverse effects have been limited, including rare reports of anaphylactoid reactions. As synthetic factor VIIa is not proteolytically active, but rather must react with TF to become active, there is a limited risk of excessive thrombogenesis, and to date no increased incidence of thromboembolic complications has been noted.
Although synthetic factor VIIa was effective, the obvious shortcomings of a case report must be recognized. The findings reported are observational without a control group to demonstrate the advantages of this therapy over the administration of additional doses of FFP. Although there was correction of coagulation parameters, which should theoretically lead to a reduction of intraoperative blood loss, there was no control group to demonstrate any intraoperative benefit with regard to blood loss. This case report should not be taken as a suggestion to use synthetic factor VIIa whenever a coagulation disturbance cannot be corrected with FFP. Such therapy should be regarded as investigational rather than standard. I chose to use factor VII given the high-risk population involved (neuromuscular scoliosis) and their known predisposition to intraoperative bleeding, dilutional coagulopathy with a blood loss of more than one blood volume, a normal fibrinogen level and normal platelet count, no readily reversible etiology of the coagulopathy (heparin or warfarin therapy), and failure of standard therapy (FFP). Given the potential use of this agent, randomized investigations appear warranted to fully delineate the role of this agent in the treatment of perioperative coagulopathies in specific high-risk populations, and clinical scenarios. These trials should focus on the attainment of evidence-based medicine with evaluation of cost issues as well as the potential impact of the various therapies on intraoperative blood loss, blood product exposure, and postoperative morbidity.