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Abstract

  1. Top of page
  2. Abstract
  3. Case Reports
  4. Discussion
  5. Acknowledgments
  6. Conflict of Interest
  7. References

Background

Patients with congenital Factor XIII (FXIII) deficiency have impaired fibrin stabilization and are at high risk for surgical bleeding. Data regarding the use of FXIII concentrates before and during surgery are lacking. The objective of this study was to report the use of plasma-derived FXIII concentrate (Corifact in the United States; Fibrogammin P in other countries) in patients with congenital FXIII deficiency undergoing surgical procedures.

Study Design and Methods

FXIII concentrate at preoperative doses ranging from 25 to 40 U/kg was administered to six patients with congenital FXIII deficiency undergoing major or minor surgeries.

Results

FXIII concentrate was administered immediately before surgery for five surgical cases; three of these patients achieved excellent hemostasis during and after surgery, while two had intraoperative bleeding. In one surgical case, a regular prophylactic dose of FXIII concentrate was administered to the patient 1 week before minor surgery. FXIII concentrate provided rapid replacement of FXIII activity. In all but one of the patients given a dose of FXIII designed to increase FXIII levels more than 50%, there was satisfactory intraoperative and postoperative hemostasis. One patient undergoing aortic valve replacement on cardiopulmonary bypass (CPB) was the exception. Intraoperative bleeding in this patient was associated with lower-than-expected blood levels of FXIII.

Conclusion

Preoperative plasma-derived FXIII concentrate allowed for sufficient hemostasis in most patients with FXIII deficiencies. Additional doses were necessary to achieve hemostasis in one patient who underwent a CPB procedure.

Abbreviation
CPB

cardiopulmonary bypass

Factor XIII (FXIII) deficiency is a rare autosomal recessive congenital bleeding disorder resulting from defects in genes encoding the “A”-chain or “B”-chain subunits of the FXIII coagulation protein.[1] FXIII is capable of cross-linking a variety of proteins, but its function in cross-linking fibrin is crucial for clot stabilization and the prevention of bleeding. The incidence of severe FXIII deficiency (<1% FXIII) is estimated to be one in 5 million people,[2] but the true incidence of FXIII deficiency is unknown, as heterozygous patients will have higher baseline FXIII levels and may not exhibit overt symptoms.[1] Patients with severe FXIII deficiencies usually present with umbilical cord bleeding, mucosal bleeding, poor wound healing, primary intracranial hemorrhage, or spontaneous miscarriage. Patients with less severe FXIII deficiency (with levels from 2%-50% activity) are rarely symptomatic, and may only be diagnosed after an invasive procedure or other hemostatic challenge. Traditionally, FXIII deficiency has been assessed qualitatively by plasma clot solubility in concentrated urea, acetic acid, or monochloroacetic acid.[3] However, since clot solubility assays detect only low levels of FXIII activity (<3.0%), moderate deficiencies were frequently missed.[4] More recently, quantitative assays have been developed that allow for more precise measurement of FXIII levels and may be used to confirm the diagnosis when FXIII deficiency is suspected.

Although low levels of FXIII are associated with a high risk for intraoperative bleeding,[5-7] threshold FXIII levels needed to achieve hemostasis during and after various invasive procedures are unknown. Traditional therapy for patients with congenital FXIII deficiency undergoing surgery involved the use of cryoprecipitates to raise the patient's FXIII levels. However, cryoprecipitate has the disadvantage of containing unknown quantities of FXIII, making replacement unpredictable and difficult in surgical situations.

Plasma-derived FXIII concentrate that provides high, quantifiable levels of FXIII, with low risk for virus transmission due to pasteurization, viral inactivation, and nanofiltration steps in the manufacturing process, is now available in many countries.[8, 9] FXIII concentrate (human) is approved in parts of Europe and other regions of the world as Fibrogammin P (CSL Behring, Marburg, Germany) and, as of 2011, is available in the United States as Corifact.[10] Although not licensed in Canada, Fibrogammin P has been widely used under the Special Access Programme of Health Canada. In 2013, the US Food and Drug Administration approved the addition of a surgical indication for Corifact to include the prophylactic treatment and perioperative management of surgical bleeding in adult and pediatric patients with congenital FXIII deficiency. Clinical studies demonstrated that spontaneous bleeds and bleeding from mild trauma were significantly reduced with the prophylactic use of FXIII concentrate in patients with severe FXIII deficiency.[11-13] The approved dose for prophylaxis is 40 U/kg, which is estimated to increase plasma FXIII levels up to 90%. It is recommended that this dose should be given every 4 weeks to maintain trough levels of more than 5%. In 2012, the first recombinant FXIII concentrate (Subunit A) was licensed in Canada (Tretten, Novo Nordisk, Mississauga, Ontario, Canada).[14]

Although FXIII concentrates appear to offer an advantage over cryoprecipitate in the prevention of bleeding in patients with FXIII deficiency who are undergoing surgery, there are few data available on dosing perioperatively. This report presents summaries of six patients who received FXIII concentrate for correction of FXIII levels perioperatively for the prevention and treatment of surgical bleeding.

Case Reports

  1. Top of page
  2. Abstract
  3. Case Reports
  4. Discussion
  5. Acknowledgments
  6. Conflict of Interest
  7. References

Patient 1 (total knee arthroplasty)

Patient 1 is a 60-year-old male who presented at age 11 with bleeding of the knee and was diagnosed with congenital FXIII deficiency. FXIII levels were reported as undetectable at the time of diagnosis, although the diagnostic assay used is unknown.

The patient had a history of long-term prophylactic therapy, using 2 units of fresh-frozen plasma (FFP) monthly starting at the age of 18 and switching to at-home monthly administration of FXIII concentrate in 2011. Previous surgeries included fusion laminectomy of L1, L2, L3, and L4 in March 1984 and, under coverage with FFP (2 units of FFP before surgery and an additional 2 units of FFP the day after surgery in each case), partial meniscectomy (March 2008), and hemorrhoidectomy (November 2008), each with excellent outcomes. At the time of the currently reported surgery, he was leading an active lifestyle as a scuba diver and had been a professional welder. Other medical conditions included obesity (body mass index, 32), hypertension, epistaxis, and hepatitis C, which was successfully treated with interferon and ribavirin in 2005.

Patient 1 underwent right total knee arthroplasty in February 2012. His preoperative FXIII level was less than 2% (Fig. 1A), and he received a preoperative dose of 40 U/kg FXIII concentrate (Table 1). He was treated with warfarin for 3 weeks for postoperative thromboprophylaxis as recommended by his orthopedic surgeon.

figure

Figure 1. FXIII activity levels. FXIII activity levels during and after surgery in two patients (A, B) with congenital FXIII deficiency treated preoperatively with FXIII concentrate. Patient 4 underwent a FXIII pharmacokinetic analysis 1 month before his surgery (B). Arrows indicate time at which a dose of FXIII concentrate was administered. *Administered for test infusion (●) and immediately before surgery (○). †Infusion administered 8 hours after the preoperative dose. 0 hr = beginning of surgery.

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Table 1. Patient surgeries and FXIII concentrate dosing
PatientSurgery or procedureFXIII concentrate, preop (U/kg)FXIII concentrate, intra- and postop (U/kg)Perioperative bleedingComments
  1. * 8 hours after initial dose.

1Total knee arthroplasty4040 (2 days postop)No 
2Herniated disk repair30 No 
3Port placement40 No 
4Aortic valve replacement4040 (intraop*)Intraoperative bleedingFXIII levels were lower than expected on CPB (40%)
5Wisdom teeth extraction40 (7 days before surgery)20 (6 hr postop)Early postoperative bleedingFXIII level 40% at the time of bleeding
6Partial hepatectomy and cholecystectomy25 Intraoperative bleeding due to venous tearResolved with vascular repair

The patient achieved excellent hemostasis during surgery with no excess bleeding. His FXIII level was 84% in the afternoon after surgery (Fig. 1A). After surgery, FXIII levels in the early morning on Postoperative Days 2 and 3 were 75 and 59%, respectively. The patient received an additional 40-U/kg dose of FXIII concentrate on Postoperative Day 2. He remained in the hospital for 4 days. Long-term follow-up indicated that the patient had an excellent recovery, with a full range of motion and an active lifestyle. He was placed on his usual long-term prophylactic treatment with monthly 40 U/kg FXIII concentrate 2 weeks after surgery.

Patient 2 (herniated disk repair)

Patient 2 is a 33-year-old male who was diagnosed with FXIII deficiency when he was 5 years old. He was receiving 35 U/kg FXIII concentrate every 28 days as bleeding prophylaxis and had stable preinfusion FXIII levels (13%-19%). A short FXIII pharmacokinetic analysis was conducted 2 months before his surgery. His preinfusion FXIII level at that time was 13%. After an infusion with 35 U/kg FXIII concentrate, his FXIII levels 30 and 60 minutes postinfusion were 139 and 94%, respectively.

In April 2010, Patient 2 received a preoperative dose of 30 U/kg FXIII concentrate on the day of surgery for repair of a herniated disc. This dose was 4 days earlier than his usually scheduled dose. The patient's regular treatment schedule was reset and commenced again from the day of surgery. The surgery was uneventful, with no postoperative bleeding, and no additional hemostatic intervention was required. Patient 2 continued regular monthly prophylactic treatments with FXIII concentrate. His preinfusion FXIII activity level 1 month after surgery was 10%.

Patient 3 (port placement)

Patient 3 is a 14-year-old female who was diagnosed with congenital FXIII deficiency at 1 year of age using the chromogenic ammonia release assay. She was receiving 40 U/kg FXIII concentrate every 28 days as prophylaxis and had preinfusion FXIII levels ranging from 10% to 23%.

She received a preoperative dose of 40 U/kg FXIII concentrate on the day of surgery for placement of a port. This dose was one of her regularly scheduled treatments, which continued every 28 days. Her preinfusion FXIII level was 23%. The surgery was uneventful. No postoperative bleeding occurred, and no additional hemostatic interventions were required. The patient resumed monthly treatments with FXIII concentrate, maintained therapeutic FXIII activity levels, and did not experience any bleeding.

Patient 4 (aortic valve replacement)

Patient 4 is a 53-year-old male who was first diagnosed with FXIII deficiency 1 year earlier when he presented with significant, protracted bleeding that began 2 weeks after defibrillator implantation and required prolonged hospitalization. At that time, his baseline FXIII level was 20%; a FXIII inhibitor assay was performed to rule out an acquired FXIII deficiency and was negative. He had no history of spontaneous bleeding and had a history of several earlier surgeries without bleeding. His medical history was significant for end-stage renal disease on hemodialysis, hypertension, hyperlipidemia, nonischemic cardiomyopathy, and aortic stenosis.

In preparation for aortic valve replacement surgery, a FXIII pharmacokinetic analysis was conducted 1 month before surgery. The patient's preinfusion FXIII activity level at that time was 17%. After infusion with 40 U/kg FXIII concentrate, his FXIII activity levels 30 minutes, 60 minutes, 4 hours, 24 hours, 48 hours, and 9 days postinfusion were 80, 96, 115, 95, 75, and 52%, respectively (Fig. 1B). On the day of surgery, Patient 4 was given 40 U/kg FXIII concentrate immediately before intubation, with the goal of at least 100% FXIII correction (Fig. 1B). Early in surgery, the patient became hypotensive and did not respond well to vasopressors; therefore, his chest was opened urgently, internal cardiopulmonary resuscitation was performed, and the patient was placed on cardiopulmonary bypass (CPB).

FXIII activity levels were checked intraoperatively at 3 and 7 hours after administration of the preoperative FXIII dose and were 40 and 43%, respectively (Fig. 1B), despite the 100% preoperative FXIII dose. These levels were considerably lower than expected based on his prior pharmacokinetic study. An additional dose of 40 U/kg FXIII concentrate was administered 8 hours after the initial preoperative dose. Before receiving this additional dose of FXIII, Patient 4 experienced excessive bleeding during surgery and received 9 units of red blood cells (RBCs), 3 units of platelets, 7 units of FFP, and a single dose of recombinant coagulation FVIIa (90 μg/kg). Hemostasis was obtained, the surgery was completed, and the patient was transferred to the surgical intensive care unit 6 hours after the surgery was initiated.

The patient's FXIII level 13 hours after the second FXIII concentrate dose (21 hr after the preoperative dose) was 143%. He was maintained on vasopressors and balloon pump support for 2 days postoperatively, and no further bleeding was noted. On Postoperative Day 4, his FXIII level was 88%. He received a 50% correction dose of FXIII concentrate (20 U/kg) on Postoperative Day 8 and was discharged.

Six days after discharge (Postoperative Day 14), he was readmitted for fever and abdominal pain and was found to have ischemic colitis. During this time, he noted bright red blood per rectum. His hemoglobin levels dropped from 10 to 7.5 g/dL and his FXIII level was 42%. He was transfused with 6 units of RBCs and 4 units of FFP. He was also given an additional 50% correction dose (20 U/kg) of FXIII concentrate on Postoperative Day 22. He experienced no further episodes of bleeding and recovered uneventfully. Patient 4 did not receive any additional doses of FXIII. There were no bleeding episodes during long-term follow-up.

Patient 5 (wisdom teeth extraction)

Patient 5 is a 29-year-old male who was diagnosed using the chromogenic ammonia release assay with congenital FXIII deficiency when he was less than 2 months old. He had been receiving 40 U/kg FXIII concentrate every 28 days as prophylaxis. He had a history of easy bruising, electrocution, right orbital floor fracture, and double vision. His surgical history was positive for splenectomy and impacted wisdom teeth.

The patient received routine prophylactic treatment with 40 U/kg FXIII concentrate 7 days before surgical removal of four wisdom teeth. Before this infusion, his FXIII level was 11%. After surgery, the patient received 3 g of aminocaproic acid four times daily for 5 days. The patient experienced moderate bleeding at home for more than 4 hours after surgery and was instructed to visit the clinic for a 50% correction dose of 20 U/kg FXIII concentrate that day (6 hr after surgery). Of note, although the patient was concerned about the bleeding, he did not experience a decrease in hematocrit, and the oral surgeon felt that this level of bleeding was within the normal range. Before this treatment, his FXIII level was 40%, consistent with having received a dose of 40 U/kg 7 days before. The patient noted that bleeding began subsiding on the day after surgery and resolved completely 5 days after the additional infusion with FXIII concentrate. The patient resumed regular monthly treatment with FXIII concentrate and did not experience any spontaneous bleeding.

Patient 6 (partial hepatectomy and cholecystectomy)

Patient 6 is a 69-year-old female who was diagnosed at age 49 with congenital FXIII deficiency when she presented with excessive bleeding following laparotomy for salpingitis and peritonitis. She had a significant history of prior hemorrhagic complications, including umbilical cord hemorrhage at birth, prolonged hospital admission for bleeding and infected hematoma after appendectomy during her youth, excessive bleeding after dental extraction, and extensive bruising after minor trauma. She had responded in the past to treatment with cryoprecipitate. She started receiving regular prophylaxis with 6 U/kg FXIII concentrate every 3 weeks in 1999 and experienced a dramatic decrease in bruising. Although her initial diagnosis was based on a qualitative clot solubility test, numerous subsequent quantitative measurements with the chromogenic ammonia release assay showed trough levels of FXIII of 4% to 5% while on prophylaxis. Other prior medical history included hypertension, obesity, osteoarthritis, and carcinoma in situ of the breast in 2005. In 2011, a biopsy was performed following the discovery of a single 7.7-cm suspicious mass in the left lobe of the liver. The biopsy was performed immediately after her regular prophylactic dose of 6 U/kg FXIII concentrate. The procedure was uncomplicated and the biopsy was positive for carcinoma.

In January 2012, Patient 6 received 25 U/kg FXIII concentrate, but her surgery of exploratory laparotomy, biopsy of the right lobe of the liver, left hepatectomy, and cholecystectomy was postponed. Fifteen days later, the surgery proceeded as previously planned. She was given 25 U/kg FXIII concentrate immediately before surgery. There was no excessive bleeding initially; however, transfusion of 4 units of RBCs intraoperatively was required after brisk bleeding from an accidental tear to a large hepatic vein. Bleeding stopped with vascular repair, and there was no sign of coagulopathy. Thrombin (FloSeal, Baxter, Deerfield, IL) was applied topically. No delayed or postoperative bleeding occurred, and no other hemostatic treatment or transfusion was required. The patient was discharged on Postoperative Day 8. The final histologic diagnosis was cholangiocarcinoma. She then resumed her usual prophylactic dose of 6 U/kg FXIII concentrate every 3 weeks. Her cancer remained in remission as of August 2012.

Discussion

  1. Top of page
  2. Abstract
  3. Case Reports
  4. Discussion
  5. Acknowledgments
  6. Conflict of Interest
  7. References

We present six cases detailing the use of FXIII concentrate in patients with congenital FXIII deficiency undergoing surgery. Hemostatic levels of FXIII for patients undergoing surgery are not well established. Each of the patients reported here received FXIII concentrate in doses from 25 to 40 U/kg preoperatively, which is expected to increase FXIII levels to 60% to 100%, which is similar to a normal reference range of 50% to 150% for healthy individuals. Pharmacokinetic studies of FXIII concentrate in subjects with congenital FXIII deficiency demonstrated a maximum plasma concentration (Cmax) of 0.9 ± 0.20 U/mL (mean ± SD, equivalent to 90 ± 20%) and a half-life of 6.6 ± 2.29 days (mean ± SD) after a dose of 40 U/kg.[10] In the two patients reported here who underwent preoperative pharmacokinetic testing, FXIII kinetics were consistent with published data. No thrombotic events or problematic wound healing were reported after treatment with FXIII concentrate.

In five surgery cases, FXIII concentrate was administered immediately before surgery; three of these patients achieved excellent hemostasis during and after surgery, while two had intraoperative bleeding. In one case, intraoperative bleeding was related to an arterial tear that was corrected surgically with subsequent hemostasis. The other case of intraoperative bleeding occurred in a patient undergoing aortic valve replacement on CPB. Intraoperative bleeding in this patient (who had previously had a FXIII concentrate pharmacokinetic study in preparation for surgery) was associated with blood levels of FXIII after the FXIII concentrate infusion that were significantly lower than levels predicted by his earlier pharmacokinetic study. His intraoperative FXIII level, drawn 3 hours after administration of a 100% correction dose of FXIII concentrate, was only 40%. Previous studies of hemostatically normal patients on CPB have shown that native FXIII levels decrease by approximately 34% to 42%, which is presumed to be due to increased consumption while on CPB.[15, 16] A second dose of 40 U/kg FXIII concentrate given at the completion of surgery after the patient was removed from the CPB pump showed the expected recovery of FXIII, with no additional postoperative bleeding. These findings suggest that patients with congenital FXIII deficiency who require CPB should have their FXIII levels carefully monitored due to enhanced loss or consumption of FXIII during the CPB procedure; these patients may require additional doses intraoperatively to maintain hemostasis.

In one case, the patient's regular prophylactic dose of FXIII concentrate was administered 1 week before extraction of four wisdom teeth; the patient continued to bleed for several hours after the procedure, despite a documented FXIII level of 40% at the time of bleeding. Bleeding improved after the administration of FXIII concentrate and compression of the wound.

Previous authors have suggested that a dose of 10 to 20 U/kg FXIII concentrate or target FXIII levels as low as 5% may be sufficient for surgery in FXIII-deficient patients.[17, 18] However, our experience demonstrates that some patients with FXIII levels as high as 40% are at risk for perioperative hemorrhage. This experience suggests that FXIII should be administered immediately before major surgery to achieve FXIII levels of at least 50%; in patients undergoing prolonged or complicated surgeries, target levels of 100% should be considered. Additional dosing requirements during surgery and postoperatively will be mandated by the patient's clinical condition and laboratory results of FXIII levels whenever possible. The ability to perform timely laboratory monitoring of FXIII levels is ideal in complex surgeries in patients with congenital FXIII deficiency.

Pharmacokinetic studies before surgery are helpful for determining the optimal individual dosage for achieving a desired target level. This is also helpful in cases where FXIII levels cannot be obtained rapidly during the perioperative course so that the treating physician has confidence in achieving the preoperative therapeutic goal for an individual patient.

In conclusion, FXIII concentrate provided rapid replacement of FXIII in patients undergoing invasive procedures. In all but one of the patients given a dose of FXIII designed to increase FXIII levels to more than 50%, there was satisfactory intraoperative and postoperative hemostasis consistent with the known half-life of FXIII. An exception was noted in the one patient who was placed on CPB and whose FXIII levels were lower than expected, reflecting increased utilization or consumption of FXIII due to the CPB procedure. Future studies looking at the pharmacokinetics of FXIII during invasive procedures will help to enhance our knowledge and inform our clinical practice in these patients.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Case Reports
  4. Discussion
  5. Acknowledgments
  6. Conflict of Interest
  7. References

The authors thank Amanda Sheldon, PhD, Erin P. Scott, PhD, and Roderick H. Sayce, BSc, at Complete Publication Solutions, LLC, for editorial assistance and CSL Behring for funding this editorial support.

Conflict of Interest

  1. Top of page
  2. Abstract
  3. Case Reports
  4. Discussion
  5. Acknowledgments
  6. Conflict of Interest
  7. References

JSL receives research funding from CSL Behring. CAL and DJN report receiving advisory board fees and research funding from CSL Behring. JSP receives research funding from CSL Behring, Biogen, Bayer, Baxter, Novo Nordisk, Octapharma, and AskBio. VBF is an employee of CSL Behring. MJ has disclosed no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Case Reports
  4. Discussion
  5. Acknowledgments
  6. Conflict of Interest
  7. References