7 Surgery in hemophilia
1 Introduction – preoperative planning
Surgical and invasive procedures can be performed safely in PWHs.
Due to the increased risk of bleeding complications during surgery, thorough planning is essential before surgery.
Coordinated standard pre-, intra-, and postoperative assessment and planning are essential for optimizing surgical outcomes, resource utilization, and minimizing the risk of bleeding and other adverse events during and after surgery.
Due to the concentration of expertise and experience at hemophilia treatment centers (HTC), it is recommended that all surgery in patients with hemophilia, and especially inhibitor patients, be planned and executed in conjunction with an HTC [1].
It is important to discuss the patient’s expectations for surgery and recovery before an orthopedic procedure. The hematologist should provide a written detailed treatment plan that outlines the duration and dosage of hemostatic therapies, as well as the rehabilitation phase.
The patient’s hemostatic function should be screened before surgery. Laboratory tests, including platelet count, APTT, prothrombin time, FVIII/FIX level, inhibitor test, fibrinogen, blood group including irregular antibodies, and recovery test, should be performed.
If an inhibitor test and in vivo response assessment for the factor concentrate that will be used during surgery have not been performed recently, they should be performed shortly before surgery to plan the factor replacement regimen during and after surgery.
It is important that an inhibitor test is performed recently before surgery and that an in vivo response assessment is performed to test the recovery of a standard dose of the factor concentrate selected for substitution during surgery. Data from these tests can be used to plan the substitution program during and after surgery.
Based on the in vivo response assessment results (recovery), a factor replacement regimen should be developed. This regimen should specify the exact number of units of coagulation factor to be used, the timing of concentrate infusions during surgery and the entire postoperative period, and whether bolus or continuous infusions are preferred.
The factor replacement regimen should also specify whether prophylactic treatment is needed during the rehabilitation training program, both in the hospital and at home.
Factor FVIII/FIX levels should be monitored closely in the immediate postoperative period and at least once daily during hospitalization to adjust the factor levels achieved [2].
If possible, surgery should be postponed during the first 20 exposure days to reduce the increased risk of inhibitor development.
Thromboprophylaxis should not be routinely administered to PWH. In patients with a previous venous thromboembolism (VTE) or severe risk factors, such as obesity and active cancer, thromboprophylaxis may be considered.
1.1 RECOMMENDATION
Surgical and invasive procedures can be performed safely in PWH.
1.2 RECOMMENDATION
All surgery in PWH, especially inhibitor patients, should be planned and executed in close collaboration with an HTC.
1.3 RECOMMENDATION
PWH undergoing surgery should have their factor levels monitored daily.
2 Substitution principles
- Two main approaches to factor replacement therapy are used in the clinical management of surgical episodes in PWH: bolus injections every 6-12 hours and continuous infusion via a pump delivery system [3].
2.1 Continuous infusion
Continuous infusion (CI) has been used in some hemophilia centers for many years.
One of the main advantages of continuous infusion is that it provides the patient with a safe and constant level of the coagulation factor by matching the rate of infusion with the rate of clearance.
A reasonably constant factor level may reduce or eliminate the risk of early and late re-bleeding, and continuous infusion may reduce factor concentrate spending compared to bolus injections by avoiding peaks in factor level.
Some concerns have been raised about continuous infusion (CI) practices, such as the theoretical risk of infection and/or factor concentrate degradation during storage at room temperature. However, extensive studies have shown that these risks are not significant within 72 hours of CI, as determined by laboratory testing of stability and sterility.
A common complication is battery failure or other malfunction of the delivery pump system.
Phlebitis at the infusion site was once common with CI but is now very rare after the addition of small amounts of heparin or low-molecular-weight heparin to the infusion bag.
Finally, suspicion has been raised that CI may be associated with development of inhibitors, especially in non-severe hemophilia, but there is no strong scientific evidence to support this claim.
2.2 Bolus injections
Bolus injections are pre-planned doses of factor concentrate given at regular intervals.
The response to bolus injections is dependent of the dose administered.
A sufficient factor level in blood is one that does not go below a predetermined trough level (immediately before the next dose) and that prevents excessive bleeding. This means that the trough level should be the lowest factor level that ensures adequate hemostasis in the clinical situation.
Because the hemostatic efficacy of bolus-administered factor concentrate depends on the trough level, a certain degree of spillage may be required to maintain that level.
While the trough level is a critical determinant of bleeding risk, the post-dose factor level can vary greatly.
A clear disadvantage of using bolus injection strategy is the requirements for frequent injections at 6–12-hour intervals.
Another disadvantage of bolus injection methods is related to the substitution program and its costs. The peak value of factor in blood probably represents an overshoot of factor needed, and thus a relative risk of overuse of factor concentrates.
2.3 RECOMMENDATION
Factor replacement for PWH undergoing surgery can be given as either repeated bolus infusions or continuous infusions.
3 Major surgery including orthopedic surgery
FVIII/IX level 7-100 IU/dL immediately before a surgical procedure and replacement therapy for 7-10 days after major surgery are to be targeted.
Prophylaxis should then be continued.
Tranexamic acid (25 mg/kg p.o / 10 mg/kg i.v.) should be combined with factor replacement 3-4 times daily for 7-10 days.
For the bolus infusion: A bolus dose of approximately 50 IU/kg (FVIII) should be administered just before anesthesia.
The dose for giving a steady state level is calculated for the next 24 h according to the formula (clearance (CL) x BW x 24) where default values of 3 and 4 can be used as CL for FVIII and FIX respectively.
Two hours after the bolus dose (see above) it is recommended to give another 2.000 IU to an adult patient and the total dose for the next 24 h according to the formula is then given in 6-hour intervals for FVIII and 8-hour intervals for FIX.
3.1 Continuous infusion
Recovery calculation to determine the initial bolus dose:
\[ Recovery = \frac{Increase \ in \ factor \ level \ (\%) \ x \ BW}{Test \ dose \ IU} \]
\[ Bolus \ dose = \frac{Desired \ increase \ in \ factor \ level \ (\%) \ x \ BW}{Recovery} \]
\[ {Infusion \ rate = Clearance \ x \ desired \ factor \ level \ (IU/kg)} \]
\[ {Daily \ dose = Infusion \ rate \ x \ BW \ x \ 24 \ h} \]
\[ Clearance = \frac{Infusion \ concentration \ kIU/L \ x \ infusion \ rate \ mL/24 \ h}{Measured \ factor \ level \ kIU/L} \]
Clearance(mL/h/kg) is often measured. It varies between individuals and products, especially for FIX:
Hemophilia A: Adult: 3, Children: 5
Hemophilia B: Adult: 6
Desired FVIII/IX levels in the patients for continuous infusion and trough levels for the bolus injection group:
Day 1-3: 70 IU/dL
Day 4-6: 0.50 IU/dL
Day 7-9: 0.30 IU/dL
Then tapering off - bolus infusions before physiotherapy [3].
4 Minor surgery
- In general, a factor level of 50 IU/dL is recommended before the surgical procedure and replacement therapy for 1-5 days depending on the procedure.
5 Specific surgery
5.1 Dental extraction
- For invasive surgical intervention it is recommended to increase the factor level 50 IU/dL before surgery and use an oral antifibrinolytic agent (tranexamic acid) agent before and after surgery in combination with local therapy [4].
5.2 Circumcision
A general recommendation for circumcision is a factor level of 70-100 IU/dL at the start of surgery and a level >50 IU/dL maintained for at least 2-3 days (some recommend 7-10 days) together with antifibrinolytics.
When performing circumcision in patients with mild hemophilia A, desmopressin (DDAVP) 0.3 µg/kg intravenously before the initiation of surgery and an additional dose on the second day can be considered in DDAVP responding patients [5].
5.3 Liver biopsy
In patients undergoing liver biopsy, the preoperative factor level should be as for major surgery 70-100 IU/dL and replacement therapy should be continued for at least 3 days with concomitant use of tranexamic acid as described below [6].
Bed rest for 8-12 h after the biopsy is recommended.
5.4 Tonsillectomy/adenectomy
5.5 Prostatectomy
- Prostatectomy should be considered as major surgery. However, substitution therapy should be continued for at least 2 weeks due to the increased risk of late bleeding complications [6].
5.6 Mild hemophilia
Surgery in persons with mild hemophilia A can be performed using desmopressin (DDAVP) when FVIII can be raised to an appropriate therapeutic level.
Administration of desmopressin (DDAVP) can raise FVIII level adequately (three to six times baseline levels) in patients with mild, and possibly moderate, hemophilia A.
Testing for DDAVP response prior to surgery should be performed after one and four hours.
Desmopressin does not affect FIX levels and is of no value in hemophilia B.
Dose:
– 0.3 mg/kg i.v. or s.c.
– 300 mg i.n. (spray) (150 mg if BW <30 kg)
Intravenously (i.v.): slow injection of DDAVP (diluted in 10 mL saline) for 15 minutes or infusion (diluted in 50-100 mL saline) for 30 minutes diluted in 50-100 mL saline. Peak FVIII/VWF levels are observed at 60 minutes.
Subcutaneously (s.c.): Peak FVIII/VWF levels are reached after about 120 minutes.
Octostim® solution (15 mg/mL) is the most suitable for s.c. administration, due to its high concentration. Often a single 15 mg dose s.c. will suffice in adults.
An additional dose of DDAVP is infused on the second day (12/24h).
DDAVP may cause fluid retention, which deserves special attention in the youngest children (<4 years) in whom FVIII concentrate should be considered. A fluid restriction of 1-1.5 L is recommended.
5.7 Tranexamic acid
Tranexamic acid is an antifibrinolytic agent.
Administration can be oral, intravenous, or topical (e.g., as mouthwash).
It can be used in combination with DDAVP, FVIII/FIX and rFVIIa.
To increase its effectiveness, tranexamic acid should be given prior to elective procedures and in repeated doses to ensure adequate tissue concentrations.
Dose:
– Orally 25 mg/kg 3-4 times daily for 7-10 days.
– Intravenously 10 mg/kg 3-4 times daily for 7-10 days.
– Mouthwash 10 mL of a 5% solution 4 times daily, which can be swallowed.
5.7.1 Limitations
Contraindicated in the management of upper urinary tract bleeds.
Dose reduction is necessary in patients with renal insufficiency.
Should be avoided, or its usage minimized, in patients with a recent thromboembolism and/or a previous personal or family history of thromboembolic disease.
No data are available on the use of tranexamic acid in newborns.
5.7.2 Adverse effects
- Nausea, vomiting, diarrhea, and abdominal pain.
5.8 RECOMMENDATION
Major surgery: FVIII/IX level 70-100 IU/dL immediately before a surgical procedure and replacement therapy for 7-10 days.
5.9 RECOMMENDATION
Tranexamic acid (25 mg/kg p.o / 10 mg/kg i.v.) should be combined with factor replacement 3-4 times daily for 7-10 days.
6 Postoperative management
Adequate pain control is essential for successful postoperative management and rehabilitation.
However, neuraxial anesthetic and analgesic techniques (such as epidural anesthesia) are generally contraindicated postoperatively due to the risk of bleeding. Nerve blocks may be used in this patient population with caution and under replacement coverage.
Acetylsalicylic acid and Cyclooxygenase-1 (COX-1) inhibitors should also be avoided since they induce platelet dysfunction and thereby contribute to impaired hemostasis.
COX-2 inhibitors are suitable with proton pump inhibitors unless there is renal insufficiency.
Patients undergoing elective orthopedic surgery should be assessed for pre- and post-operative rehabilitation by a physical therapist experienced in the management of hemophilia. The physical therapist should communicate frequently with the other members of the hemophilia treatment team.
7 Orthopedic aspects
Orthopedic surgery in PWH is a team effort, involving the surgeon and the comprehensive hemophilia center team to address important considerations.
The optimal timing of orthopedic surgery in hemophilic patients is uncertain, but young people’s demanding social and professional lives often favor early correction of joint disease.
This has led to a trend towards earlier orthopedic intervention, with a shift in focus from pain relief to restoring functional ability.
Recommended plasma factor levels before and after surgery:
| Hemophilia A and B | ||
|---|---|---|
| Desired level kIU/L | Duration (days) | |
| Major surgery | ||
| Pre-op | 0.7-1.0 | |
| Post-op | 0.6-0.8 | 1-3 |
| 0.4-0.6 | 4-6 | |
| 0.3-0.4 | 7-9 | |
| Minor surgery | ||
| Pre-op | >0.5 | |
| Post-op | 1-5 depending on procedure |
8 EHL products and surgery
- Prophylaxis during and after surgical procedures using an extended half-life product (EHL) should follow the same principles as when using a standard half-life (SHL) product for both hemophilia B and A.
9 Non-factor replacement therapy and surgery in non-inhibitor patients
- Minor and major surgeries with ongoing emicizumab treatment with or without substitution of SHL-FVIII products have been successfully reported. All surgical or invasive procedures on prophylaxis must be managed by the HTC.
9.1 Minor surgery
Prophylaxis with FVIII concentrate is not strictly necessary for minor surgery or invasive procedures (such as central venous catheter insertion, endoscopy with biopsy, or dental/oral procedures).
Tranexamic acid administered as mouthwash is particularly useful for dental/oral procedures. However, FVIII concentrate should be promptly available in adequate doses to be administered if bleeding complications occur.
9.2 Major surgery
For surgery or invasive procedures at high risk of bleeding, replacement treatment with FVIII concentrate is advised, aiming at maintaining FVIII levels >50 IU/dL.
To this purpose, plasma FVIII daily monitoring by using a chromogenic assay with bovine reagents should be carried out [7].