Continuous infusion factor replacement in haemophilia B during and after cardiac surgery: the better choice?

Abstract

A 57-year-old man with mild haemophilia B was admitted for coronary artery bypass graft surgery. His factor IX (FIX) activity was 15% on admission. Our goal was to maintain his FIX activity at 80%–100% for post-op days (PODs) 0–3, and at 60%–80% for PODs 4–14. Preoperatively, the patient was given recombinant FIX (rFIX) bolus using the formula:

Dosage needed=%(desired FIX level−current level of FIX)×weight (kg)×1.3.

This increased his activity to 100%. One IU of rFIX increased FIX activity by 0.8%; the half-life of rFIX is 18–24 hours. The rFIX infusion was started intraoperatively and continued after surgery to maintain target FIX activity. He was discharged on POD 9 on rFIX bolus dosing of 5000 IU every 12 hours for an additional 5 days. Using continuous factor infusion, we managed to decrease the amount rFIX used by >60% while maintaining steady state FIX activity level.

Background

Haemophilia B is an X-linked recessive disease with a deficiency in functional factor IX (FIX), affecting about 1:30 000 live male births.¹ The life expectancy of patients with haemophilia has improved over the recent decades, leading to increased prevalence of cardiovascular comorbidities requiring cardiovascular interventions and surgeries.² Managing factor replacement in patients undergoing cardiac surgery is challenging due to the complexity of the procedure, which involves heparinisation, surgical bleeding risk and postoperative antiplatelet treatment. Normal factor levels can be achieved by using repetitive bolus infusions or continuous infusion of FIX concentrate. Here, we discuss a case of haemophilia B undergoing cardiac surgery and receiving FIX replacement via continuous infusion.

Case presentation

A 57-year-old man with mild haemophilia B (endogenous FIX activity of 10%–12%) was admitted for a scheduled coronary artery bypass graft (CABG) surgery. He had undergone minor surgical procedures in the past, including colonoscopy and tooth extractions; haemostasis was achieved with bolus doses of recombinant FIX (rFIX) perioperatively. On admission, his blood work showed prothrombin time of 12.1 s, international normalised ratio 0.9, partial thromboplastin time 39.9 s and FIX activity of 15%. Preoperatively, he was challenged with rFIX (BeneFIX) to determine his response to treatment. The following formula was used to calculate the dose of the factor required to achieve target FIX level:

Dosage needed=%(desired FIX level−current level of FIX)×weight (kg)×1.3

The patient responded appropriately to the BeneFIX challenge of 3000 IU which raised his FIX activity to the desired level of 50%. The goal for surgery was to maintain his FIX activity level at 80%–100% for post-op days (PODs) 0–3, and at an activity level of 60%–80% for PODs 4–14. Using the replacement formula above, the required dose was calculated and adjusted at each step based on the FIX activity level obtained daily. All calculations were made under the premise that 1 IU of BeneFIX increased FIX activity by 0.8% and that the half-life of BeneFIX is 18–24 hours. The infusion rate was determined based on the expectation that FIX activity decreased by 3–4 IU/kg/hour.³ Therefore, to maintain FIX activity level via continuous infusion factor replacement (CIFR) at 80%–100%, the infusion rate was set at 272 IU/hour; to maintain the activity level at 60%–80%, the infusion rate was set at 200 IU/hour.

Treatment

Preoperatively, the patient was given a 7000 IU bolus of BeneFIX to raise his FIX activity level to 100%. BeneFIX infusion was started intraoperatively to maintain target FIX activity level. He was continued on the same BeneFIX infusion rate for the first 3 days postoperatively and his FIX levels remained above 100% (table 1). The epicardial wire and drain were removed on POD 3 and he was transitioned to bolus dosing that evening of 4000 IU of BeneFIX in anticipation of discharge on POD 4. However, his hospital course was complicated by the development of Dressler’s syndrome overnight, which led to a delay in his discharge and the resumption of the BeneFIX infusion on the morning of POD 4 with a target FIX activity of 60%–80% via CIFR until his discharge on POD 9 (figure 1).

Table 1.

Summary of the postoperative course until the day of discharge

	BeneFIX bolus dose (IU)	BeneFIX infusion rate (IU/hour)	Factor activity (%)	Goal factor level (%)	Number of vials (1000 IU) with CIFR	Hypothetical: number of vials (1000 IU) for bolus dosing
POD: −1	3000		15 to >50	80–100	40
POD: 0	7000	272	101			14
POD: 1*	3000	272	69 to >131			14
POD: 2		272	115			14
POD: 3	4000	272	92			14
POD: 4		200	97	60–80		10
POD: 5		200	100			10
POD: 6		200	90			10
POD: 7		200	92			10
POD: 8		200				10
POD: 9		200				10
Total number of vials used					40	116

POD: −1 is the day of admission.

POD: 9 is the day of discharge from the hospital.

*POD: 1—patient’s factor IX activity was 69% which corrected to 131% with a bolus dosing. 1000 IU=1 vial.

CIFR, continuous infusion factor replacement; POD, post-op day.

Figure 1.

Factor IX activity level during hospital admission.

Outcome and follow-up

The patient was discharged home on aspirin and BeneFIX bolus dosing of 5000 IU (five vials) every 12 hours administered by a visiting home nurse for an additional 5 days (until POD 14). He was doing well at the 2-week follow-up visit, as well as the subsequent 3-month follow-up.

Discussion

Haemophilia B in an X-linked recessive blood coagulation disorder caused by mutations in the FIX gene located on the long arm of X chromosome that leads to a quantitative deficiency in functional FIX.¹ It is classified based on FIX activity into mild (5%–40%), moderate (1%–5%) and severe disease (<1%). When compared with haemophilia A, this disease has less severe phenotype with less severe/frequent bleeding events and better long-term outcomes.⁴ In general, the average life expectancy of a patient with severe haemophilia (A or B) is 66 years, and for those with moderate/mild haemophilia (A or B), it is 77 years, which is a dramatic improvement when compared with the life expectancy of 12 years in the 1960s.^{2 5} With this increase in life expectancy, patients have to now confront age-related comorbidities, including coronary artery disease. The exact incidence of cardiovascular disease in patients with haemophilia is not known; however, some studies show a reduced mortality rate from ischaemic heart disease in patients with haemophilia when compared with their age-matched population.⁶ Indications for CABG surgery in haemophilia patients are the same as those for non-hemophilic patients and typically include three-vessel coronary artery disease and left main coronary artery stenosis.⁷

Treatment of haemophilia B relies on replacing FIX when bleeding episodes occur, and prophylactic factor infusion to prevent these episodes.⁸ There are multiple options for factor replacement, including plasma-derived FIX, rFIX, rFIX-Fc fusion protein and glycopegylated FIX.⁹ Major challenges with factor replacement lie in the short half-life of the factor, requiring frequent infusions and the development of antibodies/inhibitors to the factor replacement. Inhibitors are reported to develop in 3%–5% of patients receiving FIX replacement, compared with 25%–30% with factor VIII replacement.^{10 11} Managing patients with haemophilia (both A and B) also comes at great financial cost. In 2013, the mean annual cost per patient for patients with haemophilia A and B was $206 027 and $179 747, respectively.¹² The treatment cost is even higher for patients with inhibitors, with annual costs exceeding $400 000.¹³ Ninety-two per cent of the total direct medical costs and 80% of the overall costs are usually attributable to factor replacement therapy alone.

Factor replacement during surgery is a complex procedure involving multidisciplinary teamwork and is highly expensive given the cost of the FIX concentrate.^{14 15} Case reports of successful factor replacement and management in patients undergoing cardiac surgery using both bolus dosing and CIFR methods are present in the literature.¹⁶ Studies have also demonstrated the stability and sterility of BeneFIX when reconstituted and stored at room temperature for up to 7 days.¹⁷ The World Federation of Hemophilia recommends that patients with haemophilia B undergoing major surgery reach preoperative FIX activity of 60%–80%, with gradual tapering to an activity of 50% until wound healing is achieved, usually over a period of 10–14 days.⁸ Guidelines from the Japanese Society on Thrombosis and Hemostasis and the World Federation of Hemophilia describe the details of bolus and continuous infusions; both highlight several advantages of CIFR over the bolus infusion as it is a safer, practical and more convenient method of factor replacement. Continuous infusion maintains a steadier state of factor level in the blood compared with bolus infusion, which can cause peaks and troughs, potentially predisposing the patient to bleeding if FIX levels fall below 40%, or thrombosis if FIX levels rise higher than 200%. CIFR is also more cost-effective, since the the amount of factor used via this method is significantly less compared with bolus infusion.^{8 18} Moreover, CIFR perioperatively has not been reported to increase the development of factor inhibitors.¹⁹ Disadvantages associated with CIFR include the complexity of this method and challenges associated with learning and performing the dosing calculations. It requires effective and timely lab monitoring to efficiently monitor factor levels and an experienced pharmacist to reconstitute the medication. As for concerns regarding the sterility of the reconstituted factor products, there have been no clinical reports of higher incidences of infectious complications with the CIFR method. However, due to the theoretical risk of bacterial contamination, reconstitution of the factor should be performed under aseptic conditions and caution should be exercised in all patients, especially those with central lines.²⁰

Medical management of the age-related cardiovascular diseases with anti-coagulants and anti-platelets agents in patients with haemophilia can be challenging due to their increased propensity to bleed. Evidence-based guidelines are limited and management is largely based on expert opinion, involving a risk versus benefit assessment in every case.²¹ With cardiovascular surgery, intraoperative anti-thrombotic therapy can be used as long as factor levels are corrected and maintained at 80% or greater. Postoperative use of aspirin should be initiated at a low dose and continued indefinitely thereafter, unless significant contraindications arise; in patients with severe haemophilia (factor level <1%), aspirin should be avoided unless given with prophylactic factor replacement.⁷

Learning points.

• Our case highlights the feasibility, safety and cost-effectiveness of continuous infusion factor replacement (CIFR) therapy compared with repetitive bolus infusions.

• It leads to 65.5% less factor concentrate use during the hospitalisation.

• With CIFR being more predictable and favourable, steady state of the factor level was achieved, avoiding peaks and troughs that have the potential increased risk of bleeding (if factor IX (FIX) level falls below 40%) and thrombosis (if FIX levels are greater than 200%).