Comprehensive care of the patient with haemophilia and inhibitors ...

Haemophilia (2013), 19, 2–10 

DOI: 10.1111/j.1365-2516.2012.02922.x 

REVIEW ARTICLE 

Comprehensive care of the patient with haemophilia and 

inhibitors undergoing surgery: practical aspects 

R. KULKARNI 

Division of Pediatric and Adolescent Hematology/Oncology, Department of Pediatrics and Human Development, Michigan 

State University College of Human Medicine, East Lansing, MI, USA 

Summary. Congenital haemophilia is a rare and 

complex condition for which dedicated specialized 

and comprehensive care has produced measurable 

improvements in clinical outcomes and advances in 

patient management. Among these advances is the 

ability to safely perform surgery in patients with 

inhibitor antibodies to factors VIII and IX, in whom 

all but the most necessary of surgeries were once 

avoided due to the risk for uncontrollable bleeding 

due to ineffectiveness of replacement therapy. 

Nevertheless, surgery continues to pose a major 

challenge in this relatively rare group of patients 

because of significantly higher costs than in patients 

without inhibitors, as well as a high risk for bleeding 

and other complications. Because of the concentration 

of expertise and experience, it is recommended 

that any surgery in patients with haemophilia 

and inhibitors be planned in conjunction with a 

haemophilia treatment centre (HTC) and performed in 

a hospital that incorporates a HTC. Coordinated, 

standard pre-, intra- and postoperative assessments 

and planning are intended to optimize surgical 

outcome and utilization of resources, including costly 

factor concentrates and other haemostatic agents, 

while minimizing the risk for bleeding and other 

adverse consequences both during and after surgery. 

This article will review the special considerations 

for patients with inhibitors as they prepare for and 

move through surgery and recovery, with an emphasis 

on the roles and responsibilities of individual members 

of the multidisciplinary team in facilitating this 

process. 

Keywords: activated prothrombin complex concentrate, 

comprehensive health care, haemophilia, inhibitors, 

recombinant activated FVII, surgery 

Introduction 

Congenital haemophilia, a rare and complex condition, 

requires a lifetime of specialized care. A network 

of haemophilia treatment centres (HTCs) has been 

established in many developed countries to provide 

dedicated comprehensive, multidisciplinary care in a 

single setting [1]. In the United States, the provision of 

haemophilia care by these centres has led to an array 

of documented improved outcomes, including substantial 

reductions in hospital visits, health care costs, 

work and school absenteeism and even mortality [2,3]. 

Even in developing countries with limited haemostatic 

Correspondence: Roshni Kulkarni, MD, Department of Pediatrics 

and Human Development, Michigan State University Center 

for Bleeding and Clotting Disorders, Michigan State University, 

788 Service Road, B216 Clinical Center ‘B’ Wing, East Lansing, 

MI 48824, USA. 

Tel.: +517 355 5039; fax: +517 355 8312; 

e-mail: roshni.kulkarni@hc.msu.edu 

Accepted after revision 5 July 2012 

treatment options, the establishment of local expertise 

via such initiatives as ‘twinning’ programmes has 

resulted in improvements in patient care [1]. 

Approximately 20–30% and 1–6% of patients with 

severe haemophilia A and B, respectively [4], develop 

inhibitory antibodies that render replacement therapy 

ineffective, potentially leading to life-threatening bleeding 

events. Inhibitors are the most serious and costly 

complication of haemophilia, and they particularly 

pose a challenge when surgical intervention is necessary. 

In patients with low-titre inhibitors (

SURGERY IN PATIENTS WITH HAEMOPHILIA AND INHIBITORS 3 

in this population, to the detriment of affected patients 

[7,8]. Given the availability of effective bypassing 

agents, coupled with the increasing experience of HTCs 

in managing the surgical needs of patients with CHwI, 

even complex surgery is now feasible in this population 

[6,9–12]. However, the risk for uncontrollable bleeding 

remains a serious threat. Because of the specialized 

expertise required to ensure proper perioperative haemostasis, 

monitoring, and care of patients with inhibitors 

undergoing surgery, these procedures should 

ideally be performed in hospitals affiliated with HTCs, 

where there is a concentration of expert multidisciplinary 

resources [13]. 

The objective of this article is to summarize key 

practical aspects of the comprehensive care approach 

to surgery in CHwI, including important considerations 

before, during and after surgery. 

Methods 

A search of the PubMed database-indexed literature 

was undertaken, using a combination of the keywords 

‘hemophilia,’ ‘inhibitor’ and ‘surgery,’ to identify 

English-language articles describing general considerations 

for and anecdotal experience with surgery in 

patients with inhibitors published between January 

1990 and July 2012. Original articles, review articles 

and case reports and series were consulted for general 

principles and recommendations for perioperative 

assessment and management of patients with inhibitors. 

Predominately larger case series consisting of 

more than 10 cases and consensus protocols were referenced 

for perioperative haemostatic strategies; care 

was made to avoid inclusion of case series with potentially 

overlapping data. Smaller case series and case 

reports were primarily reviewed to identify any considerations 

for specific surgery types or novel approaches 

to surgery in CHwI overall. Supplemental literature 

searches were conducted around specific aspects of surgery 

(e.g. anaesthetic management, physiotherapy) as 

needed. Information from the literature was complemented 

by the author’s clinical experience in this area. 

Practical aspects of the surgical comprehensive 

care approach 

The comprehensive care approach ideally incorporates 

a number of specific pre-, intra-, and postoperative 

objectives for all patients with CHwI undergoing surgery, 

regardless of the procedure to be performed 

(Table 1). There may also be specific perioperative 

considerations for individual surgical procedures 

(Table 2). The primary goal of this coordinated, 

multidisciplinary approach is to optimize operative 

results and recovery, while limiting adverse outcomes. 

The most common types of surgeries that have been 

performed in patients with CHwI include central 

venous access device (CVAD) placement/removal and 

orthopaedic and dental procedures, although many 

other procedures have also been reported in this 

patient population [5,11]. 

General preoperative assessments and 

considerations 

Approximately 2–3 weeks prior to elective surgery, a 

member (or members) of the standard multidisciplinary 

core HTC team – consisting of a haematologist, 

nurse coordinator, social worker and physical therapist 

– will typically conduct an evaluation of whether 

or not the patient is an appropriate surgical candidate, 

based on a thorough familiarity with the nature and 

progression of the condition for which surgery is 

advocated, and will prepare the patient for surgery, 

including arranging any necessary preoperative assessments 

and referrals. Specifically, the haematologist 

provides a written detailed treatment plan including 

duration and dosage of haemostatic therapies, the 

HTC nurse communicates with the operating room 

and hospital nurses to ensure that the plan is carried 

out appropriately, and the physical therapist estimates 

when to initiate and how long to continue physical 

therapy in cases of orthopaedic surgery. Prior to surgery, 

several aspects of surgical readiness should be 

explored, including the patient’s history of adherence 

to prior treatment recommendations, patient expectations 

regarding surgical outcome and recovery and 

certain psychosocial elements, including current 

patient support systems. In cases in which they have 

not been previously assessed, these factors may be 

addressed during a formal preoperative visit, ideally 

several weeks before the scheduled surgery [14]. The 

preoperative visit also provides an opportunity to 

educate the patient and family about the surgical procedure 

itself and the expected course of recovery. 

In addition to a general health appraisal, the preoperative 

medical assessment should include a history, 

including history of prior surgery as well as response 

to bypassing agents, and an evaluation for comorbid 

conditions, such as hepatitis C or HIV infection or 

cardiopulmonary, renal, or liver disease, for the purposes 

of appropriate anaesthetic management and 

medication dosing. A comprehensive laboratory evaluation, 

including complete blood count; tests for liver 

and renal function; blood type; and haemostatic 

workup, including prothrombin time (PT), activated 

partial thromboplastin time (aPTT), fibrinogen, 

inhibitor assay, and for patients who have a low-titre 

inhibitor or who are undergoing immune tolerance 

therapy (ITT), a review of their pharmacokinetics 

study, which may be used to guide the dosing frequency 

of factor concentrates. A thrombophilia 

workup (factor V Leiden, prothrombin mutation, proteins 

C and S, and antithrombin levels), although not 

© 2012 Blackwell Publishing Ltd Haemophilia (2013), 19, 2–10

4 R. KULKARNI 

Table 1. 

Perioperative checklist for the patient with haemophilia and inhibitors undergoing surgery. 

Preoperative Intraoperative Postoperative 

Identify patient as a suitable surgical candidate 

with regard to: 

Expectations for surgical outcome 

Readiness for anticipated recovery programme 

Perform relevant laboratory testing, including: 

Haemostatic workup (PT, aPTT, fibrinogen, 

inhibitor titre, CBC, thrombophilic markers, 

if indicated) 

Tests of hepatic and renal function, if indicated 

Evaluate current and prior analgesic usage and 

any illicit drug use 

Request a dental evaluation (and treatment, 

if necessary) 

Refer to physical therapist to devise a plan 

for ‘prehabilitation’ and assess postsurgical 

rehabilitative needs 

Refer patient for nutritional assessment 

Plan perioperative i.v. access 

Notify blood bank to hold potentially needed 

blood products; devise a plan for 

intra- and postoperative haemostasis 

Administer preplanned haemostatic regimen and 

monitor response 

Apply surgical and anaesthetic 

practices and techniques that minimize the risk 

for bleeding both during and after surgery 

[including long term (e.g. avoid need for 

prolonged antithrombotic therapy)] 

aPTT, activated partial thromboplastin time; CBC, complete blood count; i.v., intravenous; PT, prothrombin time. 

Analgesic regimen taking prior analgesic use 

into account 

Use mechanical techniques for 

thromboprophylaxis; consider pharmacological 

prophylaxis in patients with underlying 

thrombophilia only 

Observe patient for infection and maintain 

strict aseptic care 

Monitor wound healing; continue haemostatic 

therapy through beginning of healing 

Avoid premature mobilization and physical 

therapy; pretreat with bypassing agent 

prior to therapy sessions, once initiated 

Table 2. Specific considerations for individual surgical procedures in patients with haemophilia and inhibitors.* 

Cardiac valve replacement 

Bioprosthetic valve recommended in lieu of mechanical valve, which requires long-term anticoagulation [55] 

LMWH recommended for immediate postoperative thromboprophylaxis in patients with haemophilia, in conjunction with CFC [55] † 

Cardiac surgery requiring ECCS 

Consider FFP vs. saline prime of bypass circuit to avoid dilution of coagulation factors [12] ‡ 

Standard heparinization generally employed after CFC in patients with haemophilia without inhibitors [56] § 

To maintain factor levels after surgery, consider reinfusing entire pump volume instead of just the RBC fraction (may require additional protamine to 

reverse heparin in perfusionate) [12] 

Hepatic procedures and surgeries 

Maintenance of a low CVP may be considered to minimize hepatic venous bleeding [57] 

Transjugular biopsy has been described in a patient with haemophilia A and high-titre inhibitor; may reduce the risk for bleeding compared with 

percutaneous biopsy [58] 

In addition to haemostatic treatments targeting the inhibitor, FFP may be necessary in patients with pre-existing hepatic dysfunction to replace other 

deficient coagulation factors (FII, FVII, or FX) [59] 

Synovectomy 

Radiosynovectomy is first-line treatment, particularly in patients with inhibitors [60] 

Should proceed to arthroscopic synovectomy if radiosynovectomy is unsuccessful after three consecutive attempts [60] 

Osteotomy 

Internal fixation is preferred for stabilization of osteotomy site because external fixators may be associated with soft tissue bleeding and infection along 

the pin tracks [8] 

Bony pseudotumour excision 

Surgical excision is treatment of choice for proximal pseudotumors, but may be associated with profuse bleeding and infection [60] 

Consider embolization or radiotherapy in lieu of surgical removal in patients with inhibitors [60] 

CFC, clotting factor correction; CVP, central venous pressure; ECCS, extracorporeal circulatory support; FFP, fresh frozen plasma; FII, factor II; FVII, 

factor VII; FX, factor X; LMWH, low-molecular weight heparin; RBC, red blood cell. 

*In most cases, in the absence of evidence specifically in patients with CHwI, individual considerations are based on theoretical principles aimed at minimizing 

bleeding risk in any patient or in patients with an increased risk for bleeding. Recommendations or considerations that apply specifically to 

patients without inhibitors (but may be extrapolated to patients with inhibitors) are denoted. 

† Recommendations are specifically for patients with haemophilia without inhibitors; no corresponding recommendations exist for patients with inhibitors 

at present. 

‡ Applies primarily to patients with inhibitors receiving factor replacement for haemostatic coverage. 

§ Cases in patients with inhibitors are limited and describe primarily patients with low-titre inhibitors. In all cases, high-dose factor replacement was used 

intraoperatively; heparinization protocols were not described. 

routinely performed, can be undertaken in those with 

a prior history or family history of thrombosis. 

In conjunction with the pain management team, a 

preoperative assessment of pain and current and prior 

use of prescribed opioids, illicit drugs or recreational 

substances should be performed. Dental evaluation 

and treatment may be warranted, particularly if 

implantation of a prosthetic device or CVAD is 

expected. A physical therapy evaluation may also be 

warranted for patients undergoing elective orthopaedic 

surgery (EOS). During the initial preoperative visit, 

the therapist will typically evaluate the patient’s 

baseline musculoskeletal and functional status and 

bleeding patterns in preparation for planning a post- 

Haemophilia (2013), 19, 2–10 

© 2012 Blackwell Publishing Ltd


operative rehabilitative regimen and initiate a plan for 

preoperative therapy, or ‘prehabilitation,’ as needed 

[8]. In addition, the therapist can determine the necessity 

for mobility aids or adaptations to the home environment 

that may facilitate mobility and prevent 

injury after discharge. 

Additional preoperative considerations may include 

devising a plan for perioperative intravenous access. 

For long-term postoperative access, placement of a 

CVAD or a peripherally inserted central catheter 

(PICC) may be considered in lieu of peripheral access 

[14]. However, given that the presence of inhibitors is 

an independent risk factor for infection after total 

knee replacement (TKR) [15], the potential benefits of 

CVAD placement must be weighed against the risk for 

infection in patients with inhibitors. Patients should 

be advised to discontinue any non-steroidal antiinflammatory 

drugs or antiplatelet agents a week prior 

to surgery [13]. Referral should be made to a dietician 

to evaluate nutritional status, since obesity or 

malnourishment as determined by body mass index is 

an important predictor of postoperative complications 

[16,17]. Finally, as part of the holistic approach to 

preparing a patient with inhibitors for surgery, the 

HTC social worker should conduct a full psychosocial 

assessment, including identification of potential 

barriers to and requirements for optimal recovery. 

The consulting surgeon should have experience 

operating on patients with CHwI in addition to performing 

the specific indicated surgery. Solimeno et al. 

[15] reported that the experience and expertise of the 

operating surgeon was an independent predictor of 

infection risk following TKR in patients with haemophilia, 

with and without inhibitors. The preoperative 

surgical evaluation provides the surgeon with an 

opportunity to examine the patient and review or 

obtain relevant studies, and discuss the surgical procedure 

and expected outcome and recovery with the 

patient as part of the informed consent process. The 

surgeon should be made aware of the patient’s HIV 

and hepatitis C status, as affected patients are more 

susceptible to postoperative infections. In addition, to 

reduce the risk for transmission of these blood-borne 

pathogens to the surgical team, personal protective 

equipment and appropriate disposal of contaminated 

materials is warranted [8]. If use of ethanol lock to 

prevent CVAD infections [18] is intended, the surgeon, 

in consultation with the HTC staff, should 

determine catheter compatibility with ethanol [19]. 

To ensure access to relevant laboratory studies and 

specialists, elective procedures should be scheduled for 

early in the week and as early in the day as possible 

[13,20]. For maximal effectiveness, the time between 

administration of haemostatic treatments and surgery 

should be minimized. This is possible if the haematology 

team is informed of the precise time (within 1–2 h)at 

which surgery will occur [20]. A haematologist should 

also be readily available for consultation during at least 

the first few days after surgery [13]. Often, in cases of 

orthopaedic procedures, the surgeon may consider performing 

multiple surgeries during a single operative 

session; patients with CHwI frequently require multiple 

such surgeries [8,14]. However, patients must be 

informed in advance of the compounded duration and 

rigour of recovery following multiple procedures under 

a single anaesthetic administration [13]. 

The coordination of urgent or emergent procedures 

in patients with CHwI poses a particular challenge, 

given the need for rapid mobilization of resources and 

multidisciplinary collaboration in such cases. Sufficient 

supplies of haemostatic agents must be readily accessible, 

along with laboratory, blood bank and pharmacy 

support. When possible (e.g. for pending organ transplantation), 

advance planning should be undertaken 

to ensure prompt availability of these resources at the 

time of surgery [12]. 

For elective procedures, the initial plan for perioperative 

haemostasis is devised by the haematologist 

before surgery, based on such factors as the patient’s 

inhibitor titre and prior responses to specific haemostatic 

agents, as well as the expected magnitude and 

risk for bleeding based on whether the surgery is major 

or minor [10]. Preoperative planning should incorporate 

a determination of the specific haemostatic therapies 

to be used during and after surgery, including 

dosing regimens and whether continuous or bolus 

treatment will be used. It is often helpful for a member 

of the HTC team to be present in the operating room 

(OR) to assist in communication between the OR staff 

and the patient/family and to provide on-site guidance 

regarding haemostatic management, if needed. 

The use of high-dose FVIII or FIX concentrates to 

overcome inhibitors in CHwI undergoing surgery, 

although ideal and measurable [8,21], is often 

restricted to those with low-titre or low-responding 

inhibitors or those who have successfully achieved 

tolerance. Both bolus and continuous administration 

of replacement factor have been effectively used in this 

setting, although in patients with haemophilia B and 

inhibitors, the use of high doses of FIX may increase 

the risk for anaphylaxis [10]. In patients with haemophilia 

A receiving FVIII replacement for surgery, an 

anamnestic increase in inhibitor titre may occur, 

necessitating a switch to bypassing therapy [22]. 

Although preoperative attempts to reduce the inhibitor 

titre using rituximab [9] and ITT [6] have been 

described, these treatments have limitations, most 

notably the time required for such regimens to take 

effect and, with immunosuppressive eliminative 

agents, the potential for susceptibility to infections. 

Bypassing agents are the haemostatic products of 

choice for patients with high-titre or high-responding 

inhibitors or those with haemophilia B and inhibitors. 

Each of the commercially available bypassing agents – 


6 R. KULKARNI 

recombinant activated FVII (rFVIIa; NovoSeven ® RT; 

Novo Nordisk A/S, Bagsvaerd, Denmark) and activated 

prothrombin complex concentrate (aPCC; 

FEIBA ® , Factor Eight Inhibitor Bypassing Agent); 

Baxter Healthcare Corporation (Westlake Village, CA, 

USA) – have been successfully used for haemostatic 

coverage for surgery in both children and adults with 

CHwI, with comparable efficacy and safety. However, 

there are no evidence-based guidelines for the use of 

either agent in this setting. Recombinant FVIIa has a 

relatively short half-life of 2.7 h in adults and 1.3 h in 

children [23]. Optimal dosing remains uncertain. 

The choice of product for those with high-titre 

inhibitors is dependent on the age of the patient, prior 

exposure to plasma products, type of bleeding episode, 

volume-of-reconstitution cost, efficacy and safety. At 

most institutions, for patients who are plasma-naïve 

or for those with haemophilia B and inhibitors, rFVIIa 

is used to achieve rapid haemostasis (recombinant porcine 

FVIII may likewise be used for the same purpose 

in patients with haemophilia A and inhibitors who are 

plasma-naïve, when it becomes available). However, 

for patients with haemophilia A who have been previously 

exposed to plasma products, either aPCC or 

rFVIIa may be used [24]. The accompanying algorithm 

provides some guidance regarding haemostatic 

therapy (Fig. 1), although therapy is often highly 

individualized. In particular, the limited availability of 

bypassing agents or even factor concentrates in certain 

parts of the world may necessitate an individualized 

approach to management and adaptations in haemostatic 

regimens, such as the intra- and postoperative 

use of low-dose aPCC, cryoprecipitate, or adjunctive 

therapies like antifibrinolytics and fibrin glue [25,26]. 

The use of rFVIIa for haemostatic coverage in major 

and minor emergency and (mostly) elective surgeries 

in paediatric and adult patients with CHwI has been 

described in several retrospective series [6,27–31], a 

recent literature review [32], and a more recent analysis 

by Valentino et al. of data from two prospective 

studies, the Hemophilia and Thrombosis Research 

Society registry and the literature [5]. Dosing varied 

substantially across these sources. In most cases, initial 

rFVIIa doses of 90–120 µg kg 1 were used, with a 

tendency towards higher initial doses for major surgeries 

[27–29]. Subsequent intra- and postoperative 

rFVIIa dosing varied and incorporated both bolus and 

continuous administration of rFVIIa. In some of the 

centres represented in retrospective case series, standardized 

regimens were described [6,27]. Overall, 

rFVIIa was reported as effective in the vast majority 

of cases encompassed by the aforementioned sources. 

In the analysis by Valentino et al. [5], which incorporated 

a small number of medical procedures (n = 45) 

in addition to surgical and dental procedures, rFVIIa 

was deemed effective in 333 (84%) of the 395 cases 

represented. Thromboembolic complications attributable 

to rFVIIa were reported in 0.025% of procedures 

included in that analysis. 

Consensus recommendations for rFVIIa dosing for 

minor and intermediate or major surgical procedures 

in both adult and paediatric patients with CHwI have 

been published (Table 3) [33]. Subsequently, a consensus 

protocol [13] for rFVIIa dosing was devised specifically 

for EOS based on published data and expert 

opinion, incorporating recommendations for concomitant 

tranexamic acid dosing (Table 4), provided there 

are no contraindications. Satisfactory intraoperative 

haemostasis was achieved utilizing the higher initial 

rFVIIa dosing endorsed by this protocol in 13 procedures 

performed in five comprehensive haemophilia 

care centres in the United Kingdom and Ireland [13]. 

More recently, Caviglia et al. [34] recommended the 

following for optimal perioperative dosing of rFVIIa 

and aPCC: for rFVIIa, 120–180 µg kg 1 preoperatively 

followed by 90 µg kg 1 every 2 h postoperatively, 

and for aPCC, 100 U kg 1 preoperatively 

followed by 75–100 U kg 1 postoperatively, to a 

maximum of 200 U kg 1 . 

First-line use of aPCC for major and minor emergency 

and (again mostly) elective surgeries in paediatric 

and adult patients with CHwI has been described 

in several retrospective series comprising 11 or more 

surgeries [6,22,27,35–39]. In general, initial doses of 

50–100 U kg 1 were given prior to surgery, either as 

a single dose or as multiple doses in the days or hours 

preceding surgery. Subsequent aPCC doses totalling 

up to 200 U kg 1 day 1 were administered beginning 

6–8 h after surgery at 6- to 12-h intervals for variable 

durations of time. Consensus recommendations for 

aPCC dosing for both major and minor surgeries have 

been developed (Table 3) [33]. Criteria for satisfactory 

haemostasis were met in 80% or more of cases in 

each of the aforementioned series. There was a single 

thromboembolic event reported across more than 170 

surgeries in the combined series. 

The sequential or combined use of rFVIIa and aPCC 

for haemostatic coverage during surgery and the early 

postoperative period has also been described in 

patients with CHwI [35,40]; in some cases, this strategy 

was adopted due to prior clinical response to one 

or both bypassing agents or bleeding complications 

relative to the current surgery [35,40], while in others, 

patients were switched to aPCC after initial coverage 

with rFVIIa because of cost [35]. With combined therapies, 

one should be cautious about the occurrence of 

thromboembolic events [40], although none have been 

reported in patients with CHwI undergoing surgery. 

Although not available at all institutions, preoperative 

evaluation of haemostatic response to bypassing 

agents using thrombin generation testing (TGT) or 

thromboelastography (TEG) has been proposed as a 

means to optimize the haemostatic management of 

individual patients with inhibitors for surgery [13,41]. 

Haemophilia (2013), 19, 2–10 



Haemophilia with inhibitors undergoing surgery 

Fig. 1. Proposed algorithm for the selection of a 

haemostatic agent for patients with CHwI 

undergoing surgery, as utilized at the author’s 

institution and derived from the literature 

[4,35,54]. The selection of agent is dependent on 

the type of haemophilia (A vs. B), and in patients 

with haemophilia A, whether the patient is 

plasma-naïve or -experienced. aPCC, activated 

prothrombin complex concentrate; CHwI, 

congenital haemophilia with inhibitors; CI, 

continuous infusion; FVIII, factor VIII; rFVIIa, 

recombinant-activated factor VII. 

Low titre/ 

low responder 

Haemophilia A 

High titre 

Haemophilia B 

FVIII 100 U kg –1 

loading dose 

followed by 50– 

100 U kg –1 q8–12 h 

OR CI 10 U kg –1 h –1 Plasma-naïve 

rFVIIa bolus 90–120 µg kg –1 q2 h 

for 48 h (single 270 µg kg –1 dose 

Plasma-experienced 

has been used), then increase 

interval; CI may also be used 

(see Table 3) 

If no response: may increase 

rFVIIa dose or switch to aPCC 

May alternate rFVIIa and aPCC 

Minor surgery: treat for 3 days 

rFVIIa (see 

dosages under 

haemophilia A) 

Major surgery: aPCC 200 U kg –1 

(max). Doses of 50–100 U kg –1 

q8–24 h for 2–4 days then taper 

over complete treatment course 

If no response, switch to rFVIIa 

May alternate rFVIIa and aPCC 

Minor surgery: aPCC 100–150 

U kg –1 for 3 days 

Table 3. Consensus recommendations for rFVIIa and aPCC dosing for surgery in patients with haemophilia and inhibitors [33]. 

Postoperative dosing 

Preoperative dosing 

Days 1–5 Days 6–14 

rFVIIa 

Minor surgery 90–120 µg kg 1 q2 h* 90–120 µg kg 1 q2 h up to four times then q3–6 h for 24 h 

Intermediate/major surgery 120 µg kg 1 q2 h † 90–120 µg kg 1 q2 h Day 1, then q3 h Day 2, then q4 h Days 3–5 90–120 µg kg 1 q6 h 

Continuous infusion 15–50 µg kg 1 h 1 15–50 µg kg 1 h 1 15–50 µg kg 1 h 1 

aPCC 

Minor surgery 50–75 U kg 1 50–75 U kg 1 q12–24 h one to two times 

Intermediate/major surgery 75–100 U kg 1 75–100 U kg 1 q8–12 h 75–100 U kg 1 q12 h 

aPCC, activated prothrombin complex concentrate; rFVIIa, recombinant-activated factor VII. 

*Recommended initial preoperative paediatric dose is 120–150 µg kg 1 q2 h. 

† Recommended initial preoperative paediatric dose is 150 µg kg 1 q2 h. 

Table 4. Consensus protocol for rFVIIa dosing in EOS in patients with haemophilia and inhibitors [13]. 

rFVIIa dosing 

Adjunctive haemostatic therapies 

Preoperative 120–180 µg kg 1 TXA: 25 µg kg 1 PO q6–8 h evening before surgery 

Intraoperative 

Postoperative* 

90 µg kg 1 q2 h; final intraoperative bolus before final 

reduction in hip arthroplasty and before release of 

tourniquet (if used) in knee arthroplasty 

90 µg kg 1 q2 h for first 48 h, then 

q3 h 9 48 h, then 

q4 h 9 72 h, then 

q6 h through discharge † 

Consider topical application of a fibrin sealant or vasoconstrictor 

(e.g. epinephrine) to minimize capillary oozing 

Continue TXA 25 µg kg 1 PO q6–8 h until discharge 

90 µg kg 1 bolus 10 min prior to removal of drains or sutures 

EOS, elective orthopaedic surgery; PO, per os (by mouth); rFVIIa, recombinant activated factor VII; TXA, tranexamic acid. 

*Downward titration of rFVIIa dosing should only occur if there is good haemostasis. 

† Discharge should occur in ∼ 10–12 days after surgery in uncomplicated cases. 

In a small prospective study of 10 surgeries in patients 

with inhibitors, in vitro and ex vivo TGT were used 

to assess the dose-dependent haemostatic response to 

each bypassing agent preoperatively; TGT was then 

used intra- and postoperatively to monitor the 

response to haemostatic therapy, which was selected 

based on the preoperative TGT results [41]. Thrombin 

generation correlated with clinical haemostasis in this 

study, and preoperative TGT results were generally 

predictive of perioperative haemostatic response. 

Thromboelastography was similarly used to guide 

rFVIIa therapy in a patient with CHwI undergoing 

urgent evacuation of a spinal cord haematoma [42]. 

Although these preliminary findings suggest the potential 

utility of these techniques for optimizing haemostatic 

therapy in individual patients with CHwI 


8 R. KULKARNI 

undergoing surgery, further study and validation are 

needed before they can be more widely adopted for 

this purpose [13,41]. 

Intraoperative considerations 

Preoperative planning of haemostatic coverage for 

surgery should incorporate a strategy for monitoring 

haemostatic response during surgery. However, this 

poses a challenge in CHwI as the major drawbacks of 

rFVIIa and aPCC are their unpredictable haemostatic 

effect, lack of laboratory assays to monitor efficacy 

and dosing frequency, as well as the potential risk of 

thrombosis. The utility of plasma-based coagulation 

assays such as PT and aPTT is limited, as these assays 

do not assess clot stability, the effect of platelets in 

haemostasis, or thrombin generation on the surface of 

platelets, which is thought to be a key component of 

the haemostatic mechanism of rFVIIa [43]. As 

previously mentioned, the use of TGT and TEG in this 

setting is still investigational. 

The team must be prepared to manage any excessive 

breakthrough bleeding that may occur during surgery. 

In addition to adjustments in the primary haemostatic 

therapy in use, adjunctive haemostatic agents may be 

used. Despite concerns about potential thrombogenic 

risks and a lack of consensus related to the concomitant 

use of antifibrinolytic agents with bypassing 

agents to augment surgical haemostasis, this practice 

has been extensively employed in patients with CHwI 

[9,13,27,28,31,35,44]. To optimize haemostasis and 

prevent postoperative bleeding, the surgeon should 

attempt to minimize soft tissue dissection and should 

pay meticulous attention to primary haemostasis at 

the conclusion of surgery [30]. When feasible and 

especially for abdominal surgeries [45], a less invasive 

(e.g. laparoscopic) overall approach is preferable to 

open surgery; however, the potential risks of a less 

invasive approach, including limited access to the surgical 

field in the event of accidental vascular injury, 

must be weighed against potential benefits such as 

reduced postoperative pain and hastened recovery 

with a smaller incision [45]. Topical haemostatic 

agents, such as fibrin glue or topical thrombin, may 

be used as needed to augment systemic haemostatic 

treatments [13,27,28,30,36]. The potential for 

impaired wound healing in patients with haemophilia 

should also be considered in the technical approach to 

surgery [17]. Additional procedure-specific considerations 

of which the surgeon and OR team should have 

prior knowledge are outlined in Table 2. 

General postoperative care 

Pain management is a primary concern in the immediate 

postoperative period. Knowledge of the patient’s 

prior analgesic regimen may be critical for anticipating 

postoperative analgesic requirements, since patients 

receiving opioids before surgery may require higherthan-usual 

initial doses. Non-steroidal anti-inflammatory 

drugs should be avoided because they may induce 

platelet dysfunction and cause gastrointestinal bleeding 

[46]. Although highly effective and shown to be 

safe in patients with haemophilia without inhibitors 

after sufficient factor replacement [47,48], regional 

and neuraxial anaesthetic and analgesic techniques are 

contraindicated because of the risk for bleeding and a 

lack of evidence supporting their safety in these 

patients [8]. Given the limited options for delivering 

analgesia in patients with CHwI, consultation with 

the anaesthesiology or pain service may be especially 

helpful in this patient population. 

Although bleeding is the primary complication of 

surgery in CHwI, thrombosis is also a concern, given 

postoperative immobility and exposure to potentially 

thrombogenic haemostatic treatments. This risk may 

be particularly increased in older patients and in the 

setting of overcorrected FVIII levels [49,50]. Whereas 

postoperative anticoagulation (e.g. low-molecularweight 

heparin) has been advocated in specific groups 

of patients with haemophilia without inhibitors, 

namely older patients who have undergone major 

orthopaedic surgery [49] and patients with normal or 

near-normal trough factor levels following factor 

replacement [50], this practice is not generally recommended 

in patients with inhibitors [49,50]. Instead, 

non-pharmacological measures, such as intermittent 

pneumatic or graded compression methods, may be 

used [49]; however, pharmacological thromboprophylaxis 

may be considered in patients with underlying 

thrombophilia [46]. 

Infection may be especially catastrophic after joint 

replacement, potentially prompting prosthetic 

removal. Patients with haemophilia are at increased 

risk for delayed infection in particular [14]. The most 

likely source of delayed infection in this population is 

bacteraemia from a CVAD or during a dental 

procedure. Therefore, patients with CVADs or joint 

hardware should receive antimicrobial prophylaxis 

before any dental procedure. In addition, patients or 

their carers should be educated regarding the importance 

of using strict aseptic technique when caring for 

and accessing CVADs or PICCs or when attempting 

self-infusion. 

Bleeding is perhaps the most serious concern after 

surgery in CHwI. Bleeding into the operative site after 

arthroplasty may lead to infection and loss of the 

prosthesis [51]. Therefore, in contrast to the traditional 

postsurgical approach, early mobilization of 

patients with inhibitors after arthroplasty is often discouraged 

because of the possibility of bleeding, even 

at the risk of compromising ultimate range of motion 

[51]. Once physical therapy is instituted, pretreatment 

with a bypassing agent is recommended before each 

Haemophilia (2013), 19, 2–10 



therapy session for 2–4 weeks after surgery [52,53]. 

For most major surgeries reported in the literature, 

haemostatic therapy was continued for ca 10–14 days, 

with longer durations in cases complicated by 

postoperative bleeding. When unexpected postoperative 

bleeding occurs, several strategies may apply, 

including adjustment of dosing or replacement of the 

current haemostatic agent, cessation of rehabilitative 

measures, or platelet transfusion if there is thrombocytopenia 

or evidence of platelet dysfunction [13]. 

Consultation with the haematology team in the event 

of excessive postoperative bleeding is critical. 

Discharge planning for home, rehabilitative, or 

other facilities should be an integral part of preoperative 

assessment and should include an evaluation of 

the home environment and psychosocial support system 

by the HTC. To optimize outcomes, after 

discharge, ongoing communication with the HTC 

regarding home infusion therapy, physical therapy and 

coordination of care is crucial. 

Conclusions 

Comprehensive care and advances in haemostatic 

treatments have made it possible to safely perform a 

wide array of surgical procedures, specifically in 

patients with inhibitors, although restricted access to 

haemostatic treatments and comprehensive care in the 

developing world poses additional challenges in the 

surgical management of patients with CHwI. A coordinated 

series of peri- and intraoperative events carried 

out by the multidisciplinary HTC team will 

ensure optimal outcome in patients with CHwI undergoing 

surgery. 

Acknowledgements 

Dr. Kulkarni contributed to the conceptualization, content and composition 

of this manuscript. Writing assistance was provided by Lara Primak, 

MD, of ETHOS Health Communications in Newtown, Pennsylvania, 

USA, with financial support from Novo Nordisk Inc, in compliance with 

international Good Publication Practice guidelines. Dr. Kulkarni received 

no remuneration of any kind for the development of this manuscript. 

Disclosures 

Roshni Kulkarni is a consultant for Novo Nordisk, Baxter, Bayer, Octapharma 

and CSL Behring; is on the speakers’ bureau for Novo Nordisk 

and CSL Behring; and participates in clinical research protocols for Novo 

Nordisk, Baxter and Biogen Idec. 

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