8 Surgery in PWHs with inhibitors
1 Introduction
Surgery in persons with hemophilia and high-titer inhibitors is a clinical challenge and was for a long time considered as almost impossible.
Despite an increased risk of bleeding compared to non-inhibitor patients, surgical outcomes using bypassing agents have been generally good over the past 20-25 years [1]. While surgery remains a major challenge for patients with inhibitors, they should not be denied access to surgery.
All surgical procedures in patients should be conducted by a specialized surgeon in association with a hemophilia comprehensive care center.
Currently, there are no standardized laboratory tests to monitor the effectiveness and optimal dosage of bypassing products after surgery.
Preoperative evaluation of hemostatic response to bypassing agents using thrombin generation test (TGT) or thromboelastography has been shown to predict and optimize hemostatic outcomes during the peri- and postoperative phases [2,3].
1.1 RECOMMENDATION
All surgery in PWH should be planned and executed in close collaboration with an HTC.
2 aPCC and rFVIIa
The bypassing agents aPCC - factor eight inhibitor bypass activity (FEIBA®, Baxter AG, Vienna, Austria), and recombinant activated factor VII (rFVIIa) (NovoSeven®, NovoNordisk A/S, Bagsvaerd, Denmark) are the treatments of choice in patients with inhibitors if the inhibitor level exceeds 5 BU/mL.
The choice of bypassing agent depends on several factors, including the patient’s age, prior history of response, cost, and safety.
aPCC has been used for many years. It can be dosed every 8-12 hours, which is an advantage over rFVIIa that must be infused every 2-3 hours.
rFVIIa has the advantage of being less likely to be contaminated with infectious agents, even though that risk is now very low due to improved safety precautions.
Both products are effective in achieving hemostasis. If the first choice fails, switch to the other product.
Both aPCC and rFVIIa can cause side effects such as venous thrombotic events, disseminated intravascular coagulation (DIC), and myocardial infarction, but these risks are very low when used within the manufacturer’s recommended dosage range.
The main disadvantages of rFVIIa compared to aPCC are high cost and frequent infusions (see chapter Inhibitors).
2.1 Management of substitution therapy in the peri- and postoperative phase
- For patients with low-titer (<5 BU) or low-responding inhibitors, high-dose FVIII or FIX concentrates may be used initially to overcome the inhibitor. However, be prepared to switch to a bypassing agent at any time, as an anamnestic response may occur.
2.2 aPCC - FEIBA®
During the last 20 years more than 200 surgical procedures have been reported in case reports using aPCC as replacement therapy in patients with inhibitors.
Initial doses, frequency, and duration of aPCC treatment are variable, but continuous infusion has not been studied.
The hemostatic efficacy in these case series have been reported from 75-100% [4].
The Norwegian experience using aPCC for surgery counts 37 surgical procedures, 17 major and 20 minor [1–3,5].
APCC was delivered by short-time infusions (15-20 min) three times daily.
A preoperative loading dose of 100 IU/kg was given.
The following doses were adjusted to a total daily dose of 200 IU/kg/d.
Following the third postoperative day, the dose of aPCC was tapered to a daily dose 150 IU/kg and from the 7th postoperative day tapered gradually to 100 IU/kg.
50 IU/kg every second day was given as post-surgical prophylaxis and prior to physical therapy.
A good or excellent hemostatic outcome was observed for all minor procedures and in 15/17 (88%) of the major procedures.
A few consensus reports for using aPCC as replacement therapy in inhibitor patients undergoing surgery based on the present literature have been published [4,6].
Common in these recommendations are a preoperative bolus infusion of 50-100 IU/kg and then a dose of 75-100 IU/kg every 8-12 h with a maximum daily dose of 200 IU/kg and depending on the clinical condition and type of surgery the dose may be tapered until discharge (Table 1).
2.3 rFVIIa - NovoSeven®
Many small case series have reported successful hemostatic outcomes with rFVIIa for various surgical procedures in PWHs with inhibitors, but there is wide variation in doses and protocols, and only two small prospective randomized studies have been published on dosing and administration [7,8].
Shapiro and colleagues compared the effect of two doses of rFVIIa in 29 patients with inhibitors for minor and major operative procedures.
The patients were randomized to 35 mg/kg vs 90 mg/kg every 2 h for 2 days, then every 2-6 h for total 5 days.
Concerning major surgery, the effectiveness at day 5 was found to be 40% for the low dose whereas 83% for the high dose concluding that rFVIIa 90 mg/kg is an effective first-line option for major surgery in patients with inhibitors.
Concerning minor surgery, 70% and 100% of the procedures were found to be effective or partially effective for the low dose and high dose, respectively.
Pruthi and colleagues [8] studied the efficacy and safety of administering rFVIIa after an initial bolus dose of 90 mg/kg and then randomization to either repetitive bolus infusion (BI) (90 mg/kg) every two hours or continuous infusion (CI) 50 mg/kg/h for 5 days in 22 major surgical procedures in hemophilia A or B patients with inhibitors.
They found comparable hemostatic efficacy and safety of BI and CI, however the treatment was considered as ineffective in three subjects in each arm.
Valentino and colleagues reported from the Haemophilia and Thrombosis research registry and literature, which also incorporated a small number of medical procedures (n=45), in addition to surgical and dental procedures, and found rFVIIa to be effective in 333 (84%) of the 395 cases represented [9].
Thromboembolic complications attributable to rFVIIa were reported in 0.025% of these procedures.
Based on the present literature a few general expert recommendations have been given for using rFVIIa to cover surgical procedures [6,10] Table 1 .
The initial bolus dose should at least be 90 mg/kg given immediately preoperatively and then every 2 h for at least 48 h.
However, due to observed bleeding complications in a minority of procedures an even higher initial bolus dose of 120-180 mg/kg have been proposed. After 2 days the dosage interval may be increased to 3, 4 the 6 h on days 3, 5, and 8 respectively, and continued until discharge.
Pretreatment with 90 mg/kg is recommended before each physical therapy session.
In case of unexpected peri- or postoperative bleeding episodes using bypassing agents, one should increase the dose of already initiated treatment agent to maximum dose for rFVIIa (up to 270 mg/kg) or aPCC (200 IU/kg/d).
If hemostasis is not achieved, rapidly implement an alternative bypassing agent, as in unresponsive severe bleeding episodes.
If monotherapy with either bypassing agent at maximum doses is ineffective, sequential or concomitant treatment with both bypassing agents may be considered for salvage treatment.
2.4 RECOMMENDATION
APCC and recombinant activated factor VII (rFVIIa, NovoSeven®) are the treatment of choice in patients where the inhibitor level exceeds 5 BU/mL. For dosage see Table 1 .
3 Emicizumab, Hemlibra®
Emicizumab is a humanized monoclonal antibody that bridges activated factor IX (FIXa) and FX and replaces the function of activated FVIII [11].
Emicizumab was approved by the United States Food and Drug Administration in 2017 and the European Medicines Agency in 2018, for prophylaxis in PWH with or without FVIII inhibitors.
Although emicizumab prophylaxis has been shown to be highly efficient in preventing spontaneous bleeds [12], patients may require additional administration of bypassing agents (BPAs) or clotting factors to control bleeding and during surgery.
The scarcity of published reports of surgery in patients treated with emicizumab and the occurrence of thrombotic events following cumulative doses of aPCC in the HAVEN 1 emicizumab trial (thrombotic microangiopathy and thrombosis reported in two participants each who had received multiple infusions of aPCC for breakthrough bleeding) (>100IU/kg/24 h) [12] have led to recommendations from the United Kingdom Haemophilia Centres Doctors’ Organisation (UKHCDO) [13].
However, recommendations how to mitigate risks are given, like those present in a recent review of the literature by an international expert group with practical recommendations [14]. This review lists experiences from 10 major surgeries all of which were arthroplasties, as well as from 25 minor surgeries including 15 central venous catheter device insertion/replacement/removal, 4 circumcisions and 6 dental procedures.
Since then, additional reports have been published, such as a single center American report describing results from 20 minor and 5 major surgeries performed in 17 and 5 patients, respectively [15]. In all major and in 15 minor surgeries additional coagulation factor therapy was given and there were no major bleeds, thrombotic events, or deaths.
In addition, a report published in 2021 describes the results from a questionnaire sent to 144 hemophilia treatment centers (HTC) in 21 European countries. In this study, results from a total of 52 inhibitor positive patients underwent surgery (17 major and 45 minor) while on emicizumab.
Major surgeries were mainly covered with rFVIIa by 93.3% of HTCs (n = 14), while 6.7% (n = 1) preferably managed them with emicizumab alone.
Minor surgeries were primarily treated with tranexamic acid (57.1%; n = 12), followed by treatment with emicizumab alone (23.8%; n = 5) and treatment with rFVIIa (19.0%; n = 4).
Nineteen HTCs answered questions on efficacy of emicizumab during surgery: hemostasis was unsatisfactory in 1 out of 16 (6.3%) major procedures and in 4 out of 43 (9.3%) minor procedures [16].
Therefore, since all reported data is observational, evidence-based guidelines cannot be given on the use of emicizumab treated patients during surgery, but for simplicity we refer to the practical guidelines given by Jiménez-Yuste et al [14].
For major surgery, it is recommended that emicizumab should be dosed as per the prescribed maintenance regimen throughout the pre-, peri- and post-operative period but that caution regarding emicizumab administration should be taken when more than one-third of whole blood volume is lost during surgery, because the distribution of emicizumab into the third extracellular compartment has not been described in detail.
For major surgery in patients with high titer inhibitors (>5 Bethesda Units [BU]), concomitant hemostatic treatment with rFVIIa should be given (for dosing see Table 2).
APCC should only be given to patients not responsive to rFVIIa and in reduced doses (Table 2).
If inhibitor titre is low (<5 Bethesda Units [BU]), high doses of FVIII could be used to achieve hemostasis.
For minor surgery administration of BPAs should be considered on an individual basis, and in some cases, no BPAs may be required.
If a BPA is indicated, rFVIIa should be used (for dosing, see Table 2) and aPCC only to patients not responsive to rFVIIa and in reduced doses.
4 Alternative treatments
4.1 Recombinant porcine FVIII
Recombinant porcine FVIII (r-pFVIII, Obizur®) has been approved by the EMA for treatment of acquired hemophilia A but has also been used for patients with congenital hemophilia A with inhibitors.
In a small phase II study, eight or fewer injections of r-pFVIII successfully controlled all 25 bleeding episodes in nine patients without anti-pFVIII antibodies. r-pFVIII was well tolerated, with no serious adverse events reported [17].
The use of r-pFVIII in a surgical procedure has only been described in one case report where a 5-year-old male, refractory to ITI, was operated because of a progressively symptomatic aortic coarctation [18].
r-p FVIII was preferred over aPCC or rFVIIa because of the ability to assay FVIII levels throughout the procedure.
Haemostasis with r-pFVIII was excellent but because of declining peak and trough levels of FVIII suggesting a rising porcine inhibitor titre, he was switched to aPCC after the procedure.
The cost of r-p VIII is substantially higher than that of the other bypassing agents and cannot be recommended to be used in patients with congenital HA with inhibitors until more data on its efficacy is available.
4.2 Bypassing agents and antifibrinolytics
The antifibrinolytic agent tranexamic acid (TXA) increases clot stability and is used concomitantly with coagulation factor replacement to improve hemostasis in PWHs without inhibitors.
It is not contraindicated to combine rFVIIa with TXA to improve hemostasis although it is not systematically studied.
In contrast to rFVIIa, aPCC has not been recommended to be given together with TXA unless a time lag of 6 h between administrations of the two drugs.
The reason for this caution is safety concerns with an estimated increased risk of thrombotic events and disseminated intravascular coagulation (DIC). However, strong evidence supporting this precaution is lacking.
At least whenever possible applied locally either as mouth rinse or moistened dressings the combination of TXA and aPCC is considered as safe.
The dose of tranexamic acid commonly used is 10 mg/kg intravenously or 25 mg/kg orally 3-4 times daily for 7-10 days.
4.3 Bypassing agents and thromboprophylaxis
Although thrombosis might be a concern using bypassing agents, postoperative anticoagulation (e.g., low-molecular-weight heparin) is not recommended in patients with inhibitors.
For most of the patients the use of graduated compression stockings and early mobilization are sufficient to prevent venous thromboembolism.
According to current knowledge, the presence of emicizumab does not affect the efficacy or safety of tranexamic acid.
5 Tables
| Preoperative dose | Postoperative management | |
|---|---|---|
| rFVIIa | ||
| Minor surgery | 90 µg/kg | 90 µg/kg every 2 h up to four times, then every 3-6 h until discharge. |
| Major Surgery | 90-120 µg/kg | 90 µg/kg every 2 h the first 48 h, then 90 µg/kg every 3, 4 the 6 h on days 3, 5, and 8 respectively until discharge. CI*: 50 µg/kg/h. |
| aPCC | ||
| Minor surgery | 50-100 IU/kg | 50-75 IU/kg every 8-12 h until discharge. |
| Major surgery | 75-100 IU/kg | 70 IU/kg every 8 h for at least 3 days with a maximum daily dose of 200 IU/kg. Dose may be tapered from day 4 to 50-75 IU/kg every 8 h. |
*CI: Continuous infusion
| Preoperative dose | Postoperative management | |
|---|---|---|
| rFVIIa | ||
| Minor surgery | 90 µg/kg | 90 µg/kg rFVIIa (single dose) and/or tranexamic acid 10 mg/kg i.v. (x4 doses). In the event of excessive post-operative bleeding, an additional 90 µg/kg rFVIIa may be considered. |
| Major Surgery | 90-120 µg/kg Tranexamic acid 10 mg/kg i.v. |
Perioperatively:
Post-operative dosing recommendations:
|
| aPCC | Only patients not responsive to rFVIIa | |
| Minor surgery | < 50 IU/kg | Individualized low doses (<50 IU/kg per dose) every 8–12 h until bleeding is resolved. |
| Major Surgery | < 50 IU/kg | Individualised low doses (<50 IU/kg per dose) every 8–12h until bleeding is controlled. |