Ann Thorac Surg 2007;83:1547-1549
© 2007 The Society of Thoracic Surgeons
Case Reports
Postoperative Coagulopathy in a Pediatric Patient After Exposure to Bovine Topical Thrombin
Sheri S. Crow, MDa,
Vita V. Sullivan, MDd,
Agnes E. Aysola, MDb,
Nigel S. Key, MB, FRCPc,
Paul Harker-Murray, MD, PhDa,
John E. Foker, MD, PhDd,
Marie E. Steiner, MD, MSa,*
a Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
b Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
c Department of Medicine, University of Minnesota, Minneapolis, Minnesota
d Department of Surgery, University of Minnesota, Minneapolis, Minnesota
Accepted for publication October 30, 2006.
* Address correspondence to Dr Steiner, Pediatric Hematology/Oncology and Pediatric Pulmonary/Critical Care, MMC 484, University of Minnesota, Minneapolis, MN 55455 (Email: stein083{at}umn.edu).
 |
Abstract
|
|---|
Severe postoperative coagulopathy developed in a child with congenital heart disease due to a factor V inhibitor from repetitive exposure to bovine topical thrombin. This case report alerts pediatric providers to consider these inhibitors when postoperative coagulopathy occurs. Potential treatment options are reviewed.
|
Introduction
|
|---|
Many children with congenital cardiac disease undergo multiple surgical procedures, each with its own technical variables, including the use of bovine topical thrombin to aid in local hemostatic control. The frequent association between bovine topical thrombin and acquired factor V inhibitor development is well described in adults. However the medical literature contains only one case report involving a pediatric patient [1]. A pediatric case of factor V inhibitor resulting from repetitive bovine topical thrombin exposure was recently diagnosed. The details of this case and subsequent management follow.
A 16-month-old girl with pulmonary atresia and intact ventricular septum presented for her third cardiac operation. Previous coagulation studies had been normal. Prior to this procedure, coagulation studies were remarkable only for an international normalized ratio slightly prolonged at 1.22 (normal, 0.9 to 1.1) and factor VII levels low at 41% (normal, 60% to 140%); intravenous Vitamin K was given.
The patient underwent pulmonary angioplasty, right ventricular outflow tract augmentation with a new right ventricular-to-pulmonary artery homograft and upsizing of the central shunt. The patient’s intraoperative bleeding was managed with transfusion and local application of 5,000 units of bovine topical thrombin. Attempts to separate from bypass were unsuccessful, so the patient was placed on extracorporeal membrane circulation. Hemostatic control could not be achieved and the mediastinum was re-explored. Bleeding sites were identified and controlled and an additional 5,000 units of bovine topical thrombin was applied for local hemostasis. A mediastinal washout was done on postoperative day 2 and another 5,000 units of bovine topical thrombin were applied during the procedure. Decannulation from extracorporeal membrane circulation was achieved on postoperative day 5. A mediastinal washout and closure were performed on postoperative day 12 and an additional 5,000 units of bovine tropical thrombin was applied again.
Throughout the postoperative period the patient demonstrated a worsening refractory coagulopathy. A comprehensive coagulation analysis was undertaken.
|
Factor V Activity Assay Method
|
|---|
Measurement of factor V activity level was performed by a one-stage clotting assay using the Stago Sta-r (Stago, Parsippany, NJ) instrument. Forty µL factor V deficient plasma (Stago) were mixed with 40 µL patient plasma that were prediluted tenfold with Hepes NaCl diluent. Eighty µL thromboplastin/CaCl2 reagent (Dade Behring, Deerfield, IL) was added to the mixture. After 1 minute incubation at 37°C, clotting times were recorded. Factor V levels were measured at 1/10, 1/20, 1/40, and 1/80 dilutions.
|
Factor V Inhibitor Screening Method
|
|---|
A plasma mixing study was performed to detect a neutralizing antibody to factor V. Factor V activity level was measured in the patient plasma, in normal reference plasma, and in an aliquot of both plasmas mixed together in equal proportions. Factor V level was assayed both immediately after mixing and after 1 hour incubation at 37°C. Presence of a neutralizing inhibitor was identified if the factor V level in the mixed sample at either time was 15% or more below the expected value.
Review of factor levels identified a precipitous drop in factor V levels postoperatively (Fig 1). Mixing studies revealed a factor V inhibitor consistent with a history of re-exposure to bovine topical thrombin (Table 1).
View larger version (16K):
[in this window]
[in a new window]
|
Fig 1. Postoperative coagulation results. Factors II, V and IX (% activity) and partial thromboplastin time (PTT) (seconds) are plotted by day of hospitalization. Factor V activity is markedly lower than the other factors, suggesting an inhibitor.
|
|
The patient underwent a double-volume exchange transfusion followed by intravenous immunoglobulin (400 mg/kg/day) for 2 days. Subsequent blood products were withheld unless the patient had active bleeding and interventional procedures were avoided. The coagulopathy slowly resolved and factor V levels increased (Fig 1). No serious bleeding complications occurred.
|
Comment
|
|---|
Thousands of patients are annually exposed to bovine topical thrombin, primarily during cardiac, neurosurgical, or orthopedic procedures. All primarily thrombin compounds available in the United States are bovine derived to avoid the risk of human viral transmission [2]. Bovine preparations contain bovine prothrombin, thrombin, and a small amount of factor V. Bovine topical thrombin exposure often results in the development of anti-bovine and anti-human antibodies to any of these components [3–5] because there is approximately 70% homology between bovine and human coagulation factors [2]. Bovine topical thrombin exposure is currently the most common cause of acquired factor V inhibitor [6]. One prospective study demonstrated that 94.3% of exposed patients developed antibodies to one or more bovine coagulation proteins, and 51% of patients developed antibodies to human coagulation factors, mainly directed against human factor V and thrombin. Cross-reactivity with human factors occurred independent of thrombin dose or prior surgical procedure. The maximum antibody levels against human and bovine proteins tended to peak at approximately 4 to 8 weeks postoperatively, but may persist 10 years after exposure [3].
Although the development of factor V inhibitors is well recognized, there is very little consensus on management. In their review, Streiff and Ness [6] concluded therapy should be dictated by the clinical features of each individual patient. Patients with asymptomatic elevation of their coagulation studies may be carefully monitored for signs of bleeding. Patients with mild to moderate bleeding may be initially managed with steroids and supportive transfusions. Should these interventions fail to provide hemostasis, plasma manipulation may be warranted. In those patients whose underlying condition warrants anticoagulation, the risk for thrombosis must be weighed cautiously against the risk of bleeding.
Our patient was believed to be at significant risk for bleeding complications. Therefore she underwent double-volume exchange transfusion to acutely correct her coagulopathy and to presumably reduce her antibody titer. She also received IVIgG to enhance factor V survival. Steroids were not used to treat her factor V antibody because of her potential for fungal infection.
In conclusion, we present one pediatric patient with profound, new coagulopathy and an acquired factor V inhibitor after repeated bovine topical thrombin exposure. The incidence of these inhibitors in pediatric patients undergoing repetitive cardiac operations is unknown. The differential diagnosis of a new postoperative coagulopathy should include factor V and/or thrombin inhibitors. Optimal management of these inhibitors is still not well defined, but may include a variety of immunomodulatory manipulations. Clinical trials investigating these questions could potentially identify risk factors for bleeding and limit unnecessary blood product exposure.
|
References
|
|---|
- Tarantino MD, Ross MP, Daniels TM, et al. Modulation of an acquired coagulation factor V inhibitor with intravenous immune globulin J Pediatr Hematol Oncol 1997;19:226-231.[Medline]
- Schoenecker JG, Johnson RK, Fields RC, et al. Relative purity of thrombin-based hemostatic agents used in surgery J Am Col Surg 2003;197:580-590.
- Ortel TL, Mercer MC, Thames EH, et al. Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin Ann Surg 2001;233:88-96.[Medline]
- Caroll JF, Moskowitz KA, Edwards NM, et al. Immunologic assessment of patients treated with bovine fibrin as a hemostatic agent Thromb Haemost 1996;76:925-931.[Medline]
- Banninger H, Hardegger T, Tobler A, et al. Fibrin glue in surgery: frequent development of inhibitors of bovine thrombin and human factor V Br J Haematol 1993;85:528-532.[Medline]
- Streiff MB, Ness PM. Acquired FV inhibitors: a needless iatrogenic complication of bovine thrombin exposure Transfusion 2002;42:18-26.[Medline]
Top
Abstract
Introduction
