Summary

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether patients with haemophilia undergoing cardiac surgery have good surgical outcomes. Haemophilia A and haemophilia B are sex-linked recessive inherited diseases affecting males only, with females acting as carriers. The conditions result in various degrees of factor VIII or factor IX deficiency, respectively. The life expectancy of haemophilia patients is increasing and now approaches that of the general male population, and they are confronted with age-related co-morbidity, including ischaemic cardiovascular disease. Replacement of the deficient factor (VIII for haemophilia A and IX for haemophilia B) is the cornerstone of treatment; other therapeutic options include tranexamic acid, desmopressin and aprotinin. Recently, the advent of recombinant factor VIII and IX has eliminated the infective risk of using factor concentrates, such as prothrombin complex concentrate or fresh frozen plasma. A total of 84 papers were found using the reported search criteria, and out of this 25 papers, selected with reference to a more modern date range, provided the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results were tabulated. We conclude that there is lack of good-quality evidence and that, in all probability, these papers are subject to publication bias as poor outcomes are unlikely to have been reported. However, all the reported series showed that good outcomes are possible in this specific subgroup of patients given the correct approach. The data accrued from these studies (a total of 30 adults and three children) suggest that routine cardiac surgery can be performed safely in patients with haemophilia, with minimal morbidity and mortality. We identified the following key points to achieve this result: a team approach, a factor replacement protocol and perioperative monitoring of factor levels. Intraoperative plasma factor levels can be easily measured before heparin and after protamine sulphate administration, whereas during cardiopulmonary bypass this will require a chromogenic method. Exposure to factor concentrates early in the life might predispose a patient with severe haemophilia to the development of inhibitors. Moreover, the absence of inhibitors should be confirmed before any surgical procedure.

1. Introduction

A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [1].

2. Three-part question

Do [patients with haemophilia] undergoing [cardiac surgery] have good [clinical outcomes]?

3. Clinical scenario

You are in an multidisciplinary team (MDT) discussing a 66-year-old male with triple vessel disease. His symptoms are stable, but while an inpatient he was incidentally diagnosed with haemophilia B. You are in favour of surgery, but your routine risk assessment with EuroSCORE will not specifically address this subgroup of patients. You decide to search the literature for the best evidence available.

4. Search strategy

A Medline search 1950 to January 2011 was performed using the OVID interface

[exp Thoracic Surgery OR exp Coronary Artery Bypass] AND [cardiopulmonary bypass.mp] AND [exp Cardiopulmonary Bypass] AND [CABG.mp] AND [exp haemophilia A] AND [exp Haemophilia B] AND [exp Blood Coagulation disorders]

5. Search outcome

A total of 84 papers were found using the reported search methodology. From these, 25 papers were identified, with reference to a more modern date range, that provided the best evidence to answer the question. These are presented in Table 1 .

Table 1.

Best evidence papers

Author, date, journal Patient group Outcomes Key results Comments 
and country     
Study type     
(level of evidence)     
Tang et al., (2009), Six patients with Monitoring of the All patients were treated Small cohort 
Haemophilia, haemophilia A who coagulation status and with rfVIII  
Denmark, [2] underwent: AVR=1; adequate replacement  To attain comparable 
 AVR+CABG=2; therapy Patients with mild outcome to the 
Retrospective cohort CABG=2; resection of  haemophilia had an general cardiac 
study a ventricular  average total factor population adequate 
(level 2b) aneurysm+MVR=1  consumption of 43,250 IU (in terms of dose and 
   (range 42,500–94,500 IU) duration), factor 
   distributed over an 11–15- replacement and a 
   day treatment period multidisciplinary 
    approach are 
   The patient with moderate fundamental 
   haemophilia received a  
   total of 94,500 IU. The In valve cases, 
   total duration of the bioprostheses were 
   haemophilia substitution used 
   was 24 days  
    The use of tranexamic 
   The patient with severe acid is advocated for 
   haemophilia was all patients with 
   substituted with 50,000 IU haemophilia requiring 
   in total, given over 14 days major surgery 
     
   Patients were treated twice  
   daily, aiming to keep a  
   trough level of factor  
   VIIIc of approximately  
   0.5 IU ml.  
     
   All patients received  
   concomitant treatment  
   with tranexamic acid  
   during the first 6 –10  
   days postoperatively  
     
  Perioperative blood loss Haemophiliac patients  
  and transfusion experienced quite similar  
  requirement clinical outcomes when  
   compared with the general  
   population  
     
  Re-sternotomy for One patient (surgical  
  bleeding bleeding)  
     
  Mortality 0%  
     
  Postoperative 0%  
  development of   
  inhibitors   
     
MacKinlay et al., Five patients with Monitoring of the Patients with haemophilia Small cohort 
(2000), Haemophilia, haemophilia A undergoing: coagulation status and A received intermediate  
Australia, [3] CABG=2; AVR=1 adequate replacement purity factor VIII (CSL The presence of 
 (mechanical); therapy Antihaemophilic factor; haemophilia should in 
Retrospective case AVR+MVR=2  Commonwealth Serum no way compromise 
series (bioprosthesis); one patient  Laboratories Pty Ltd, the investigation and 
(level 4) with haemophilia B  Parkville, Victoria, management of 
 undergoing closure of ASD  Australia) with a potency cardiac disease 
 and drainage of pericardial  of 2±3 IU/mg when  
 effusion=1  reconstituted. The Standard 
   haemophilia B carrier heparinisation during 
   received a high purity FIX cardiac bypass and 
   product (Immu2nine, reversal with 
   Immuno, Austria). A bolus protamine sulphate 
   was administered appear to be safe 
   preoperatively, prior to  
   commencement of a Monitoring: factor 
   continuous infusion to assays in addition to 
   achieve a target factor routine coagulation 
   level (VIII or IX) of assays should be 
   100%. The initial infusion performed daily in the 
   rate was based on an postoperative period 
   initial clearance rate of 4.0  
   ml/kg/h [infusion rate No major bleeding 
   (IU/kg/h)=clearance× complications related 
   steady state concentration]. to warfarin therapy in 
    the patient (mild 
   During cardiac bypass, no haemophilia A) who 
   attempt was made to underwent 
   replace factor VIII (or IX) mechanical AVR 
   and overcome the (Medtronic Hall 
   dilutional effect of the valve) 
   pump circuit. A second  
   bolus was administered  
   when the patient came off  
   cardiac bypass, prior to  
   commencement of a  
   continuous infusion. A  
   target factor VIII (or IX)  
   level of 100% was  
   maintained in the immediate  
   postoperative period  
  Re-sternotomy for One patient returned to the  
  bleeding operating theatre  
   postoperatively for  
   management of surgical  
   bleeding  
  Mortality 0%  
Krakow et al., (2009), A 61-year-old man with Monitoring of the In total, the patient Coordination prior to 
Haemophilia, UK, [4] mild haemophilia B who coagulation status and required 4400 IU surgery between the 
 underwent AVR for severe adequate factor preoperatively and 2200 cardiac catheterisation 
Case report aortic stenosis with replacement IU top-up boluses on three team, cardiac surgery 
(level 4) bioprostheses  occasions prior to the team, transfusion 
   continuous infusion being medicine service and 
   set up at an initial rate of regional haemophilia 
   3.9 IU/kg/h for 4 h (1092 centre 
   IU), increasing to 8 IU/kg/h  
   for a further 60 h FIX level monitoring 
   (total units 33,600 IU) is complicated during 
   until a reduction to 6.3 IU/ CPB but can be easily 
   kg/h on POD 3 for 24 h done soon after 
   (total units 10,584 IU) protamine sulphate 
   until conversion to bolus administration and at 
   infusions on POD 4–10 arrival on the 
   (5500 units daily) in two intensive care unit 
   divided doses until POD 7,  
   when at discharge 4000 IU When continuous 
   were administered once infusion is used, the 
   daily at the local infusion rate should 
   community hospital. be recalculated and 
    adjusted at least daily 
   A total of 9 g tranexamic  
   acid was administered  
   perioperatively to promote  
   haemostasis  
  Routine Heparin 5000 U  
  thromboprophylaxis subcutaneously twice  
   daily starting on POD 1.  
   Aspirin from POD 5  
Rodriguez et al., (2010), A five-month-old infant Monitoring of the Preoperative bolus dose of Exposure to factor 
Pediatr Blood Cancer, with severe haemophilia A coagulation status and rfVIII (100 IU/kg) concentrates in severe 
USA, [5] undergoing cardiac surgery adequate replacement followed by continuous haemophilia early in 
 for correction of tetralogy  infusion of rfVIII life might predispose 
Case report of Fallot  intraoperatively. a patient to inhibitor 
(level 4)   At the end of the development 
   procedure, an additional Continuous infusion 
   bolus of rfVIII (100 of factor VIII (10 
   IU/kg) was given. IU/kg/h) to account 
   Postoperatively, for the haemodilution 
   continuous factor VIII encountered during 
   infusion was given – cardiac bypass and to 
   between 10 and 25 keep factor VIII 
   IU/kg/h to keep factor levels close to 100% 
   VIII levels between 55%  
   and 100% Heparin neutralisation 
    and chromogenic 
   Discharge was after a factor assay should be 
   week and the patient was planned during 
   treated twice daily with cardiac bypass when 
   rfVIII infusion (50 factor VIII levels will 
   IU/kg/dose) for seven days be monitored during 
    surgery 
  Postoperative Inhibitor development two  
  development of months after  
  inhibitors cardiothoracic surgery  
     
  Outcome Good  
     
Murugan et al., (2006), Two infants with Monitoring of the Infant 1: aim was for Close collaboration 
Ann Thorac Surg, UK, haemophilia A. The first coagulation status and factor VIII level >100 between 
[6] underwent repair of a total adequate replacement IU/dl before surgery. haematologist, 
 anomalous pulmonary therapy Throughout surgery, a laboratory, 
Case report venous connection. The  continuous infusion of cardiologist and 
(level 4) second had repair of a  Kogenate–Bayer factor cardiac surgeon is 
 ventricular septal defect  VIII concentrate was crucial 
 and total anomalous  maintained.  
 pulmonary venous  Postoperatively, factor The measurement of 
 connection  VIII levels were the plasma factor VIII 
   monitored twice daily, and concentration during 
   the infusion rate was bypass was performed 
   adjusted accordingly with using the 
   the aim of keeping blood chromogenic method 
   levels between 50 and 100  
   IU/dl. The infusion was  
   discontinued on POD 8  
   (139 IU/dl), and two  
   further boluses of 250  
   IU/dl factor VIII were  
   given on alternate days.  
   Infant 2: factor VIII  
   replacement intra- and  
   postoperatively using a  
   continuous infusion of  
   ReFacto (Wyeth  
   Laboratories) along  
   similar lines to patient 1.  
   The factor VIII infusion  
   was discontinued on POD 11  
     
  Outcome Good  
     
  Postoperative No inhibitor development  
  development of at 17 and 24 months after  
  inhibitors surgery, respectively  
     
Stine and Becton, A 63-year-old male with Monitoring of the 50 IU/kg of factor VIII 1 h Because of the normal 
(2006), Haemophilia, mild haemophilia A who coagulation status and preoperatively and then a physiological activity 
USA, [7] underwent successful mitral adequate replacement continuous infusion of of factor VIII, the 
 valve repair and CABG therapy factor VIII started at risk of thrombosis of 
Case report   4 IU/kg/h. This was the valve or coronary 
(level 4)   continued throughout the artery graft 
   surgery and discontinued necessitated the use of 
   on POD 3. After aspirin and warfarin 
   continuous infusion had  
   been discontinued, a daily  
   bolus of 25 IU/kg factor  
   VIII was given for seven  
   days  
     
  Thromboprophylaxis Aspirin and warfarin for  
   30 days, then stop  
     
  Outcome Good  
     
Thankachen et al., A 25-year-old man with Monitoring of the Preoperatively: 2 h prior The first published 
(2007), Asian haemophilia B who had an coagulation status and to surgery, 4000 IU of case report of a 
Cardiovasc Thorac AVR and MVR using a 2M adequate replacement factor IX concentrate were patient with 
Ann, India, [8] Starr Edwards valve in the therapy given as a bolus. haemophilia B 
 mitral position and a 22  After induction, another undergoing double 
Case report Medtronic valve in  bolus of 1500 IU factor IX mechanical valve 
(level 4) the aortic position. He had a  was given. replacement 
 previous history of an  Immediately after surgery,  
 intracerebral bleed three  a bolus of 3000 IU factor The surgical and 
 months earlier  IX and a continuous anaesthetic protocols 
   infusion of the same was were standard 
   started at a rate of 3  
   IU/kg/h, aiming for a The main problem was 
   factor IX level of 50%. An to decide on the amount 
   infusion of heparin was of anticoagulation, 
   started at a rate of 10 weighting the risk of 
   IU/kg/h after the thrombosis against 
   immediate postoperative the risk of 
   drainage was stopped. haemorrhage in a 
   On POD 3, 2500 IU patient with a 
   Dalteparin was injected previous cerebral 
   subcutaneously twice haemorrhage three 
   daily and was substituted months earlier. 
   for heparin. Heparin and 
   The patient was Dalteparin sodium 
   discharged on the 17th successfully were 
   day, and low-dose oral used to prevent valve 
   anticoagulation with thrombosis in the 
   acenocoumarol immediate 
   maintaining an INR postoperative period 
   between 1.5 and 2.0 was  
   started The patient was 
    discharged on the 
  Perioperative bleeding Total drainage from the 17th day without any 
   chest tubes was 670 ml in anticoagulation 
   the first 24 h  
     
  Re-sternotomy for On POD 4, cardiac  
  bleeding tamponade developed. A  
   subxiphoid  
   pericardiostomy was done,  
   and 300 ml blood was  
   drained  
     
  Other complications Acute renal failure, treated  
   by conservative  
   management without  
   dialysis  
     
  Outcome The patient was doing  
   well at nine months  
   follow-up  
     
Grandmougin et al., A 52-year-old patient with Monitoring of the Two hours prior to First report of the 
(2005), J Card Surg, diabetes mellitus, coagulation status and surgery: 6000 IU factor IX OPCAB experience 
France, [9] haemophilia B, chronic adequate replacement (BETAFACTR) → with severe 
 hepatitis C and impaired therapy 100%<factor IX <120%. haemophilia B 
Case report ventricular function  During operation: before The haematological 
(level 4) (LVEF: 29%). The patient  opening chest – 450 IU/h challenge consisted of 
 underwent a successful off-  factor IX (continuous finding a safe 
 pump myocardial  infusion) → 50% < factor balance between the 
 revascularisation  IX <60%. First risk of bleeding 
 (OPCAB×3)  postoperative week: complications and the 
   450 IU/h factor IX risk of 
   (continuous infusion) → hypercoagulability, 
   100% < factor IX <120%. mainly due to 
   Intravenous heparin if infusions of factor IX, 
   fibrinogen >3 g/l. Third and hence risk of 
   postoperative day: low myocardial 
   molecular weight heparin infarctions. In view of 
   (enoxaparin: 4000 IU/day) this, aspirin was not 
   +aspirin 160 mg/day. interrupted 
   Second postoperative  
   week+discharge: 4500 IU  
   factor IX/day (boluses) →  
   50% < factor IX <60%  
   +low molecular weight  
   heparin (enoxaparin: 4000  
   IU/day)+aspirin 160  
   mg/day  
     
  Perioperative bleeding Overall bleeding was 530 ml  
     
  Thromboprophylaxis Intraoperative bolus of  
   aspirin 250 mg followed  
   by a daily dose of 160 mg  
     
  Outcome Doing well at eight  
   months’ follow-up  
     
Sheth et al., (2001), A 14-year-old African- Monitoring of the Factor VIII was used as a Successful cardiac 
Haemophilia, USA, American male, with coagulation status and bolus (preoperatively) and transplantation of a 
[10] severe factor VIII adequate replacement as continuous infusion child with 
 deficiency and a high titre therapy (intra- and haemophilia and a 
Case report of inhibitor who underwent  postoperatively). high titre of inhibitor. 
(level 4) cardiac transplantation for  CPB was primed with 1 l Excellent haemostasis 
 dilated cardiomyopathy. He  fresh frozen plasma was provided using a 
 was HIV seronegative but  instead of normal saline, combination of factor 
 infected with hepatitis C  to preclude haemodilution VIII and rfVIIa and 
   of the plasma factor VIII resulted in no 
   concentration additional morbidity 
    associated with the 
   Once anamnesis patient's 
   developed on POD 6, coagulopathy 
   rfVIIa therapy was  
   initiated. On day 15, This is the first report 
   rfVIIa was replaced with of the use of rfVIIa 
   alternate-day infusions of for major cardiac 
   PCCs surgery 
     
  Perioperative bleeding On POD 7, the patient  
   developed transient  
   bleeding from the chest  
   tube and knee  
   haemarthrosis controlled  
   with ε-aminocaproic acid  
   (2.5–5 g every 6–8 h) for 48 h  
     
  Other complications Seizure activity on POD 2  
   led to an MRI diagnosis of  
   a cerebral watershed  
   injury. The patient made a  
   full neurological recovery  
   On POD 6, the patient also  
   developed Enterococcus  
   faecalis bacteraemia  
     
  Outcome The patient was  
   discharged on POD 21. He  
   is doing well at 24  
   months’ follow-up  
     
Mannucci and Mauser- Case series (three cases), Monitoring of the Complete clotting factor All anticoagulant and 
Bunschoten, (2010), with one patient with mild coagulation status and correction attained before antiplatelet treatments 
Haemophilia, Italy, [11] haemophilia A who adequate replacement surgery. Clotting factor should be tailored to 
 underwent mechanical therapy correction was continued the individual patient 
Case series/report AVR for aortic stenosis  for 10 days after surgery. profile and should 
(level 4)   Low molecular weight take into account the 
   heparin (5000–7500 U severity of 
   twice daily) was given for haemophilia and of 
   10 days. After this time, cardiovascular 
   coumarin derivatives were disease, as well as the 
   administered, aiming for patient's age, 
   an INR of 2.5–3.5 inhibitor status and 
    renal function 
  Outcome No complications  
     
Pesaro et al., (2009), A 37-year-old man with Monitoring of the Factor IX infusion: 6500 After PCI on the 
Clinics (Sao Paolo), severe haemophilia B and coagulation status and IU presurgery and 2000 native vessel for graft 
Brazil, [12] HIV seropositive adequate replacement IU postsurgery with occlusion, clopidogrel 
 undergoing OPCAB×2 therapy continuous infusion in was administered for 
Case report   order to keep the plasma 30 days, and 
(level 4)   concentration at 40% for acetylsalicylic acid 
   the first two days, at 30% was prescribed 
   for POD 3–6, and at 20% permanently 
   until POD 12  
     
  Thromboprophylaxis After surgery, the patient  
   was not treated with  
   antiplatelet drugs  
     
  Complications Six months later, there  
   was obstruction of the  
   saphenous vein graft,  
   treated with percutaneous  
   angioplasty (PCI) of the  
   circumflex coronary artery  
   with a bare metal stent  
   and used factor IX during  
   the procedure  
     
  Outcome Well and asymptomatic at  
   six months’ follow-up  
     
Kumano et al., (2006), A 34-year-old man with Monitoring of the None. Diagnosed with Article in Japanese. 
Kyobu Geka, Japan, [13] Marfan syndrome and coagulation status and mild haemophilia A only First report of cardiac 
 aortic regurgitation due to adequate replacement before discharge operations in Marfan 
Case report annuloaortic ectasia who therapy  syndrome with 
(level 4) underwent aortic root   haemophilia A 
 replacement with a Complications Excessive intraoperative Anamnesis was 
 composite valve graft  bleeding due to negative for bleeding 
   coagulopathy after the episodes, and 
   termination of CPB, and haemophilia A was 
   the patient needed a large missed during the 
   volume of transfusions to preoperative work-up 
   obtain haemostasis  
     
  Outcome Good  
     
Eren et al., (2006), Patient with haemophilia A Monitoring of the Level of factor VIII kept The patient was 
Thorac Cardiovasc who underwent CABG× coagulation status and at 100% during the discharged on POD 14 
Surg, Germany, [14]  adequate replacement operation and the first  
  therapy postoperative week.  
Case report   Correcting factor (B-  
(level 4)   domain-deleted rfVIII)  
   was administered as bolus  
   therapy  
     
  Complications No bleeding complication  
     
De Bels et al., (2004), A 53-year-old male with Monitoring of the Two hours prior to A second bolus of 33 
Eur J Anaesthesiol, haemophilia A undergoing coagulation status and surgery, a bolus of 50 IU IU kg/l factor VIIIc 
Belgium, [15] CABG×3+MVR adequate replacement kg-1 factor VIIIc was was administered to 
 (mechanical) therapy given, obtaining a factor control severe 
Case report   VIIIc concentration of bleeding before 
(level 4)   129% of normal. This was wound closure 
   followed by a continuous  
   infusion of 3 IU kg/h/l Cell-saver blood 
   until POD 3. Tranexamic acid returned to the patient 
   1 g was given before incision might account for the 
    haemodilution of 
  Perioperative bleeding The total drainage volume clotting factors 
   was 1590 ml. The  
   transfusion requirement  
   was high: six packed red  
   cell, four units of fresh  
   frozen plasma and six  
   units of pooled platelets  
     
  Outcome Discharged on POD 9 on  
   warfarin. Well at six  
   weeks’ follow-up  
     
Kaminishi et al., (2003), A 53-year-old man with Monitoring of the Simple bolus infusions of Routine operative and 
Jpn J Thorac mild haemophilia A who coagulation status and factor VIII concentrate CPB techniques 
Cardiovasc Surg, Japan, underwent a modified adequate replacement were given before and No late bleeding 
[16] Bentall operation for aortic therapy after CPB to achieve complications despite 
 annuloectasia  100% blood levels, and warfarin therapy 
Case report   were then given  
(level 4)   postoperatively every 12 h  
   for seven days to maintain  
   50% levels  
     
  Perioperative bleeding Good haemostasis.  
   Transfused with 10 units  
   of platelet concentrate  
     
  Outcome Good recovery.  
   Discharged on warfarin  
     
Ghosh et al., (2003), A 27-year-old male with Monitoring of the None The author relied on 
Clin Lab Haematol, unrevealed haemophilia A coagulation status and  D-dimer tests to find 
India, [17] who underwent surgery for adequate replacement  evidence of systemic 
 MVR (mechanical) therapy  fibrin generation, and 
Case report    testing positive 
(level 4)  Thromboprophylaxis Low-dose warfarin at 1 starting postoperative 
   mg/day, aiming for an warfarin therapy 
   INR between 1.5 and 2  
    Postoperative 
  Complications Severe postoperative development of 
   bleeding and a protracted inhibitors at follow-up 
   postoperative recovery  
     
  Outcome Patient survived but at a  
   huge cost in terms of  
   morbidity  
     
Donahue et al., (1999), An 80-year-old man with Monitoring of the Dose of rfIX was chosen Despite the patient's 
J Cardiothorac Vasc haemophilia B who coagulation status and to increase the level to unfortunate outcome, 
Anesth, USA, [18] underwent CABG×3 adequate replacement 100% of normal. bleeding was not 
  therapy Replacement therapy with clinically a problem, 
Case report   factor IX concentrate 7000 even though the 
(level 4)   U bolus 2 h before patient faced two 
   surgery, with a 4000–5000 consecutive 
   U bolus each day after operations, the second 
   surgery for one week. carried out as an 
   Antifibrinolytic therapy emergency with deep 
   with ε-aminocaproic acid hypothermic 
   as a 10 g bolus followed circulatory arrest 
   by a 1 g/h infusion  
     
  Complications Acute type A aortic  
   dissection on POD 2  
     
  Outcome Died on POD 1 after type A  
   dissection repair  
   because of severe right  
   ventricular failure  
     
Nahas et al., (1996), A 57-year-old man with Monitoring of the The evening before the Replacement therapy 
Cardiovasc Surg, USA, mild haemophilia A coagulation status and procedure, the patient can result in the 
[19] undergoing CABG×2 adequate replacement received 4000 U factor appearance of 
  therapy VIIIc, which was repeated inhibitors to factor 
Case report   just before surgery. On the VIII. Their absence 
(level 4)   day of surgery, the patient should be confirmed 
   received 2000 U factor before each elective 
   VIII every 8 h. On POD 1, surgical procedure 
   he received 1000 U every 8  
   h, and then 1000 U twice  
   a day up to POD 11  
     
  Outcome Good recovery.  
   Discharged on POD 11  
     
Bukowski et al., (1996), A 64-year-old patient with Monitoring of the Infusion of factor IX Article in French 
Ann Fr Anesth Reanim, haemophilia B who coagulation status and concentrates from one day  
France, [20] underwent CABG×4 adequate replacement before surgery until POD  
  therapy 19  
Case report     
(level 4)  Outcome Good with no  
   haemorrhagic  
   complications  
     
Palanzo and Sadr, A 71-year-old male with Monitoring of the Monoclonal antibody- First report of a 
(1995), Perfusion, non-insulin-dependent coagulation status and purified factor IX patient with 
USA, [21] diabetes mellitus and adequate replacement concentrate (5000 U) haemophilia B who 
 haemophilia B who therapy Infused daily until underwent CABG with 
Case report underwent CABG×6  discharge the aid of aprotinin 
(level 4)    and monoclonal 
  Outcome Good. Discharged on POD 6 antibody-purified 
    factor IX concentrate 
     
Dimitrova et al., (1995), A patient with moderate Monitoring of the Substitution therapy was Article in Bulgarian 
Khirurgiia (Sofia), haemophilia B, undergoing coagulation status and realised with factor IX  
Bulgary, [22] CABG adequate replacement concentrate (Bebulin-  
  therapy TIM4-IMMUNO)  
Case report     
(level 4)  Outcome Good  
     
Scharfman et al., A 52-year-old male with Monitoring of the 7500 U of factor IX Factor IX concentrate 
(1993), J Thorac haemophilia B who coagulation status and concentrate given 2 h is also known as 
Cardiovasc Surg, underwent CABG×4 adequate replacement before surgery to achieve PCC; this contains 
USA, [23]  therapy 100% levels, and factors VII, II, X and 
   subsequently 3750 U IX. Heparin was 
Case report   every 24 h for seven days added to the replace- 
(level 4)   to maintain factor IX ment solution 
   levels at 50% to decrease the risk of 
  Outcome The patient was treated thrombotic 
   without complications complications 
    associated with use of 
    PCC: Risk of infective 
    complications 
     
Wilson et al., (1991), A 74-year-old white man Monitoring of the The patient was given 60 Intraoperative 
J Cardiothorac Vasc with haemophilia B who coagulation status and U/kg factor IX as heat- determination of 
Anesth, USA, [24] underwent CABG×3 adequate replacement treated human factor IX factor IX levels. The 
  therapy complex (Konyne, 5200 level remained stable 
Case report   U; Cutter Biological, West during hypothermia, 
(level 4)   Haven, CT, USA) 8 h CPB and rewarming. 
   preoperatively to attain a The expected 30% 
   level of 60% factor IXc decrease in factor IX 
   activity. Postoperatively, level associated with 
   he was to be given the haemodilution of 
   10 U/kg of the factor IX CPB was not 
   complex every 12 h for six observed 
   days postoperatively  
     
  Outcome The perioperative course  
   went smoothly without  
   any significant bleeding  
   complications  
     
Mazzucco et al., (1986), A child with severe factor Monitoring of the The factor IX level was Risk of infective 
Ann Thorac Surg, Italy, IX deficiency who coagulation status and normalised immediately complications and 
[25] underwent repair of adequate replacement before operation and at the development of 
 ventricular septal defect therapy end of CPB by infusing inhibitors 
Case report and aortic regurgitation  PCC and fresh frozen  
(level 4)   plasma. The partial  
   thromboplastin time and  
   factor IX serum levels  
   were monitored for 20  
   days postoperatively and  
   showed factor IX activity  
   higher than 50%  
     
  Outcome Uneventful  
Author, date, journal Patient group Outcomes Key results Comments 
and country     
Study type     
(level of evidence)     
Tang et al., (2009), Six patients with Monitoring of the All patients were treated Small cohort 
Haemophilia, haemophilia A who coagulation status and with rfVIII  
Denmark, [2] underwent: AVR=1; adequate replacement  To attain comparable 
 AVR+CABG=2; therapy Patients with mild outcome to the 
Retrospective cohort CABG=2; resection of  haemophilia had an general cardiac 
study a ventricular  average total factor population adequate 
(level 2b) aneurysm+MVR=1  consumption of 43,250 IU (in terms of dose and 
   (range 42,500–94,500 IU) duration), factor 
   distributed over an 11–15- replacement and a 
   day treatment period multidisciplinary 
    approach are 
   The patient with moderate fundamental 
   haemophilia received a  
   total of 94,500 IU. The In valve cases, 
   total duration of the bioprostheses were 
   haemophilia substitution used 
   was 24 days  
    The use of tranexamic 
   The patient with severe acid is advocated for 
   haemophilia was all patients with 
   substituted with 50,000 IU haemophilia requiring 
   in total, given over 14 days major surgery 
     
   Patients were treated twice  
   daily, aiming to keep a  
   trough level of factor  
   VIIIc of approximately  
   0.5 IU ml.  
     
   All patients received  
   concomitant treatment  
   with tranexamic acid  
   during the first 6 –10  
   days postoperatively  
     
  Perioperative blood loss Haemophiliac patients  
  and transfusion experienced quite similar  
  requirement clinical outcomes when  
   compared with the general  
   population  
     
  Re-sternotomy for One patient (surgical  
  bleeding bleeding)  
     
  Mortality 0%  
     
  Postoperative 0%  
  development of   
  inhibitors   
     
MacKinlay et al., Five patients with Monitoring of the Patients with haemophilia Small cohort 
(2000), Haemophilia, haemophilia A undergoing: coagulation status and A received intermediate  
Australia, [3] CABG=2; AVR=1 adequate replacement purity factor VIII (CSL The presence of 
 (mechanical); therapy Antihaemophilic factor; haemophilia should in 
Retrospective case AVR+MVR=2  Commonwealth Serum no way compromise 
series (bioprosthesis); one patient  Laboratories Pty Ltd, the investigation and 
(level 4) with haemophilia B  Parkville, Victoria, management of 
 undergoing closure of ASD  Australia) with a potency cardiac disease 
 and drainage of pericardial  of 2±3 IU/mg when  
 effusion=1  reconstituted. The Standard 
   haemophilia B carrier heparinisation during 
   received a high purity FIX cardiac bypass and 
   product (Immu2nine, reversal with 
   Immuno, Austria). A bolus protamine sulphate 
   was administered appear to be safe 
   preoperatively, prior to  
   commencement of a Monitoring: factor 
   continuous infusion to assays in addition to 
   achieve a target factor routine coagulation 
   level (VIII or IX) of assays should be 
   100%. The initial infusion performed daily in the 
   rate was based on an postoperative period 
   initial clearance rate of 4.0  
   ml/kg/h [infusion rate No major bleeding 
   (IU/kg/h)=clearance× complications related 
   steady state concentration]. to warfarin therapy in 
    the patient (mild 
   During cardiac bypass, no haemophilia A) who 
   attempt was made to underwent 
   replace factor VIII (or IX) mechanical AVR 
   and overcome the (Medtronic Hall 
   dilutional effect of the valve) 
   pump circuit. A second  
   bolus was administered  
   when the patient came off  
   cardiac bypass, prior to  
   commencement of a  
   continuous infusion. A  
   target factor VIII (or IX)  
   level of 100% was  
   maintained in the immediate  
   postoperative period  
  Re-sternotomy for One patient returned to the  
  bleeding operating theatre  
   postoperatively for  
   management of surgical  
   bleeding  
  Mortality 0%  
Krakow et al., (2009), A 61-year-old man with Monitoring of the In total, the patient Coordination prior to 
Haemophilia, UK, [4] mild haemophilia B who coagulation status and required 4400 IU surgery between the 
 underwent AVR for severe adequate factor preoperatively and 2200 cardiac catheterisation 
Case report aortic stenosis with replacement IU top-up boluses on three team, cardiac surgery 
(level 4) bioprostheses  occasions prior to the team, transfusion 
   continuous infusion being medicine service and 
   set up at an initial rate of regional haemophilia 
   3.9 IU/kg/h for 4 h (1092 centre 
   IU), increasing to 8 IU/kg/h  
   for a further 60 h FIX level monitoring 
   (total units 33,600 IU) is complicated during 
   until a reduction to 6.3 IU/ CPB but can be easily 
   kg/h on POD 3 for 24 h done soon after 
   (total units 10,584 IU) protamine sulphate 
   until conversion to bolus administration and at 
   infusions on POD 4–10 arrival on the 
   (5500 units daily) in two intensive care unit 
   divided doses until POD 7,  
   when at discharge 4000 IU When continuous 
   were administered once infusion is used, the 
   daily at the local infusion rate should 
   community hospital. be recalculated and 
    adjusted at least daily 
   A total of 9 g tranexamic  
   acid was administered  
   perioperatively to promote  
   haemostasis  
  Routine Heparin 5000 U  
  thromboprophylaxis subcutaneously twice  
   daily starting on POD 1.  
   Aspirin from POD 5  
Rodriguez et al., (2010), A five-month-old infant Monitoring of the Preoperative bolus dose of Exposure to factor 
Pediatr Blood Cancer, with severe haemophilia A coagulation status and rfVIII (100 IU/kg) concentrates in severe 
USA, [5] undergoing cardiac surgery adequate replacement followed by continuous haemophilia early in 
 for correction of tetralogy  infusion of rfVIII life might predispose 
Case report of Fallot  intraoperatively. a patient to inhibitor 
(level 4)   At the end of the development 
   procedure, an additional Continuous infusion 
   bolus of rfVIII (100 of factor VIII (10 
   IU/kg) was given. IU/kg/h) to account 
   Postoperatively, for the haemodilution 
   continuous factor VIII encountered during 
   infusion was given – cardiac bypass and to 
   between 10 and 25 keep factor VIII 
   IU/kg/h to keep factor levels close to 100% 
   VIII levels between 55%  
   and 100% Heparin neutralisation 
    and chromogenic 
   Discharge was after a factor assay should be 
   week and the patient was planned during 
   treated twice daily with cardiac bypass when 
   rfVIII infusion (50 factor VIII levels will 
   IU/kg/dose) for seven days be monitored during 
    surgery 
  Postoperative Inhibitor development two  
  development of months after  
  inhibitors cardiothoracic surgery  
     
  Outcome Good  
     
Murugan et al., (2006), Two infants with Monitoring of the Infant 1: aim was for Close collaboration 
Ann Thorac Surg, UK, haemophilia A. The first coagulation status and factor VIII level >100 between 
[6] underwent repair of a total adequate replacement IU/dl before surgery. haematologist, 
 anomalous pulmonary therapy Throughout surgery, a laboratory, 
Case report venous connection. The  continuous infusion of cardiologist and 
(level 4) second had repair of a  Kogenate–Bayer factor cardiac surgeon is 
 ventricular septal defect  VIII concentrate was crucial 
 and total anomalous  maintained.  
 pulmonary venous  Postoperatively, factor The measurement of 
 connection  VIII levels were the plasma factor VIII 
   monitored twice daily, and concentration during 
   the infusion rate was bypass was performed 
   adjusted accordingly with using the 
   the aim of keeping blood chromogenic method 
   levels between 50 and 100  
   IU/dl. The infusion was  
   discontinued on POD 8  
   (139 IU/dl), and two  
   further boluses of 250  
   IU/dl factor VIII were  
   given on alternate days.  
   Infant 2: factor VIII  
   replacement intra- and  
   postoperatively using a  
   continuous infusion of  
   ReFacto (Wyeth  
   Laboratories) along  
   similar lines to patient 1.  
   The factor VIII infusion  
   was discontinued on POD 11  
     
  Outcome Good  
     
  Postoperative No inhibitor development  
  development of at 17 and 24 months after  
  inhibitors surgery, respectively  
     
Stine and Becton, A 63-year-old male with Monitoring of the 50 IU/kg of factor VIII 1 h Because of the normal 
(2006), Haemophilia, mild haemophilia A who coagulation status and preoperatively and then a physiological activity 
USA, [7] underwent successful mitral adequate replacement continuous infusion of of factor VIII, the 
 valve repair and CABG therapy factor VIII started at risk of thrombosis of 
Case report   4 IU/kg/h. This was the valve or coronary 
(level 4)   continued throughout the artery graft 
   surgery and discontinued necessitated the use of 
   on POD 3. After aspirin and warfarin 
   continuous infusion had  
   been discontinued, a daily  
   bolus of 25 IU/kg factor  
   VIII was given for seven  
   days  
     
  Thromboprophylaxis Aspirin and warfarin for  
   30 days, then stop  
     
  Outcome Good  
     
Thankachen et al., A 25-year-old man with Monitoring of the Preoperatively: 2 h prior The first published 
(2007), Asian haemophilia B who had an coagulation status and to surgery, 4000 IU of case report of a 
Cardiovasc Thorac AVR and MVR using a 2M adequate replacement factor IX concentrate were patient with 
Ann, India, [8] Starr Edwards valve in the therapy given as a bolus. haemophilia B 
 mitral position and a 22  After induction, another undergoing double 
Case report Medtronic valve in  bolus of 1500 IU factor IX mechanical valve 
(level 4) the aortic position. He had a  was given. replacement 
 previous history of an  Immediately after surgery,  
 intracerebral bleed three  a bolus of 3000 IU factor The surgical and 
 months earlier  IX and a continuous anaesthetic protocols 
   infusion of the same was were standard 
   started at a rate of 3  
   IU/kg/h, aiming for a The main problem was 
   factor IX level of 50%. An to decide on the amount 
   infusion of heparin was of anticoagulation, 
   started at a rate of 10 weighting the risk of 
   IU/kg/h after the thrombosis against 
   immediate postoperative the risk of 
   drainage was stopped. haemorrhage in a 
   On POD 3, 2500 IU patient with a 
   Dalteparin was injected previous cerebral 
   subcutaneously twice haemorrhage three 
   daily and was substituted months earlier. 
   for heparin. Heparin and 
   The patient was Dalteparin sodium 
   discharged on the 17th successfully were 
   day, and low-dose oral used to prevent valve 
   anticoagulation with thrombosis in the 
   acenocoumarol immediate 
   maintaining an INR postoperative period 
   between 1.5 and 2.0 was  
   started The patient was 
    discharged on the 
  Perioperative bleeding Total drainage from the 17th day without any 
   chest tubes was 670 ml in anticoagulation 
   the first 24 h  
     
  Re-sternotomy for On POD 4, cardiac  
  bleeding tamponade developed. A  
   subxiphoid  
   pericardiostomy was done,  
   and 300 ml blood was  
   drained  
     
  Other complications Acute renal failure, treated  
   by conservative  
   management without  
   dialysis  
     
  Outcome The patient was doing  
   well at nine months  
   follow-up  
     
Grandmougin et al., A 52-year-old patient with Monitoring of the Two hours prior to First report of the 
(2005), J Card Surg, diabetes mellitus, coagulation status and surgery: 6000 IU factor IX OPCAB experience 
France, [9] haemophilia B, chronic adequate replacement (BETAFACTR) → with severe 
 hepatitis C and impaired therapy 100%<factor IX <120%. haemophilia B 
Case report ventricular function  During operation: before The haematological 
(level 4) (LVEF: 29%). The patient  opening chest – 450 IU/h challenge consisted of 
 underwent a successful off-  factor IX (continuous finding a safe 
 pump myocardial  infusion) → 50% < factor balance between the 
 revascularisation  IX <60%. First risk of bleeding 
 (OPCAB×3)  postoperative week: complications and the 
   450 IU/h factor IX risk of 
   (continuous infusion) → hypercoagulability, 
   100% < factor IX <120%. mainly due to 
   Intravenous heparin if infusions of factor IX, 
   fibrinogen >3 g/l. Third and hence risk of 
   postoperative day: low myocardial 
   molecular weight heparin infarctions. In view of 
   (enoxaparin: 4000 IU/day) this, aspirin was not 
   +aspirin 160 mg/day. interrupted 
   Second postoperative  
   week+discharge: 4500 IU  
   factor IX/day (boluses) →  
   50% < factor IX <60%  
   +low molecular weight  
   heparin (enoxaparin: 4000  
   IU/day)+aspirin 160  
   mg/day  
     
  Perioperative bleeding Overall bleeding was 530 ml  
     
  Thromboprophylaxis Intraoperative bolus of  
   aspirin 250 mg followed  
   by a daily dose of 160 mg  
     
  Outcome Doing well at eight  
   months’ follow-up  
     
Sheth et al., (2001), A 14-year-old African- Monitoring of the Factor VIII was used as a Successful cardiac 
Haemophilia, USA, American male, with coagulation status and bolus (preoperatively) and transplantation of a 
[10] severe factor VIII adequate replacement as continuous infusion child with 
 deficiency and a high titre therapy (intra- and haemophilia and a 
Case report of inhibitor who underwent  postoperatively). high titre of inhibitor. 
(level 4) cardiac transplantation for  CPB was primed with 1 l Excellent haemostasis 
 dilated cardiomyopathy. He  fresh frozen plasma was provided using a 
 was HIV seronegative but  instead of normal saline, combination of factor 
 infected with hepatitis C  to preclude haemodilution VIII and rfVIIa and 
   of the plasma factor VIII resulted in no 
   concentration additional morbidity 
    associated with the 
   Once anamnesis patient's 
   developed on POD 6, coagulopathy 
   rfVIIa therapy was  
   initiated. On day 15, This is the first report 
   rfVIIa was replaced with of the use of rfVIIa 
   alternate-day infusions of for major cardiac 
   PCCs surgery 
     
  Perioperative bleeding On POD 7, the patient  
   developed transient  
   bleeding from the chest  
   tube and knee  
   haemarthrosis controlled  
   with ε-aminocaproic acid  
   (2.5–5 g every 6–8 h) for 48 h  
     
  Other complications Seizure activity on POD 2  
   led to an MRI diagnosis of  
   a cerebral watershed  
   injury. The patient made a  
   full neurological recovery  
   On POD 6, the patient also  
   developed Enterococcus  
   faecalis bacteraemia  
     
  Outcome The patient was  
   discharged on POD 21. He  
   is doing well at 24  
   months’ follow-up  
     
Mannucci and Mauser- Case series (three cases), Monitoring of the Complete clotting factor All anticoagulant and 
Bunschoten, (2010), with one patient with mild coagulation status and correction attained before antiplatelet treatments 
Haemophilia, Italy, [11] haemophilia A who adequate replacement surgery. Clotting factor should be tailored to 
 underwent mechanical therapy correction was continued the individual patient 
Case series/report AVR for aortic stenosis  for 10 days after surgery. profile and should 
(level 4)   Low molecular weight take into account the 
   heparin (5000–7500 U severity of 
   twice daily) was given for haemophilia and of 
   10 days. After this time, cardiovascular 
   coumarin derivatives were disease, as well as the 
   administered, aiming for patient's age, 
   an INR of 2.5–3.5 inhibitor status and 
    renal function 
  Outcome No complications  
     
Pesaro et al., (2009), A 37-year-old man with Monitoring of the Factor IX infusion: 6500 After PCI on the 
Clinics (Sao Paolo), severe haemophilia B and coagulation status and IU presurgery and 2000 native vessel for graft 
Brazil, [12] HIV seropositive adequate replacement IU postsurgery with occlusion, clopidogrel 
 undergoing OPCAB×2 therapy continuous infusion in was administered for 
Case report   order to keep the plasma 30 days, and 
(level 4)   concentration at 40% for acetylsalicylic acid 
   the first two days, at 30% was prescribed 
   for POD 3–6, and at 20% permanently 
   until POD 12  
     
  Thromboprophylaxis After surgery, the patient  
   was not treated with  
   antiplatelet drugs  
     
  Complications Six months later, there  
   was obstruction of the  
   saphenous vein graft,  
   treated with percutaneous  
   angioplasty (PCI) of the  
   circumflex coronary artery  
   with a bare metal stent  
   and used factor IX during  
   the procedure  
     
  Outcome Well and asymptomatic at  
   six months’ follow-up  
     
Kumano et al., (2006), A 34-year-old man with Monitoring of the None. Diagnosed with Article in Japanese. 
Kyobu Geka, Japan, [13] Marfan syndrome and coagulation status and mild haemophilia A only First report of cardiac 
 aortic regurgitation due to adequate replacement before discharge operations in Marfan 
Case report annuloaortic ectasia who therapy  syndrome with 
(level 4) underwent aortic root   haemophilia A 
 replacement with a Complications Excessive intraoperative Anamnesis was 
 composite valve graft  bleeding due to negative for bleeding 
   coagulopathy after the episodes, and 
   termination of CPB, and haemophilia A was 
   the patient needed a large missed during the 
   volume of transfusions to preoperative work-up 
   obtain haemostasis  
     
  Outcome Good  
     
Eren et al., (2006), Patient with haemophilia A Monitoring of the Level of factor VIII kept The patient was 
Thorac Cardiovasc who underwent CABG× coagulation status and at 100% during the discharged on POD 14 
Surg, Germany, [14]  adequate replacement operation and the first  
  therapy postoperative week.  
Case report   Correcting factor (B-  
(level 4)   domain-deleted rfVIII)  
   was administered as bolus  
   therapy  
     
  Complications No bleeding complication  
     
De Bels et al., (2004), A 53-year-old male with Monitoring of the Two hours prior to A second bolus of 33 
Eur J Anaesthesiol, haemophilia A undergoing coagulation status and surgery, a bolus of 50 IU IU kg/l factor VIIIc 
Belgium, [15] CABG×3+MVR adequate replacement kg-1 factor VIIIc was was administered to 
 (mechanical) therapy given, obtaining a factor control severe 
Case report   VIIIc concentration of bleeding before 
(level 4)   129% of normal. This was wound closure 
   followed by a continuous  
   infusion of 3 IU kg/h/l Cell-saver blood 
   until POD 3. Tranexamic acid returned to the patient 
   1 g was given before incision might account for the 
    haemodilution of 
  Perioperative bleeding The total drainage volume clotting factors 
   was 1590 ml. The  
   transfusion requirement  
   was high: six packed red  
   cell, four units of fresh  
   frozen plasma and six  
   units of pooled platelets  
     
  Outcome Discharged on POD 9 on  
   warfarin. Well at six  
   weeks’ follow-up  
     
Kaminishi et al., (2003), A 53-year-old man with Monitoring of the Simple bolus infusions of Routine operative and 
Jpn J Thorac mild haemophilia A who coagulation status and factor VIII concentrate CPB techniques 
Cardiovasc Surg, Japan, underwent a modified adequate replacement were given before and No late bleeding 
[16] Bentall operation for aortic therapy after CPB to achieve complications despite 
 annuloectasia  100% blood levels, and warfarin therapy 
Case report   were then given  
(level 4)   postoperatively every 12 h  
   for seven days to maintain  
   50% levels  
     
  Perioperative bleeding Good haemostasis.  
   Transfused with 10 units  
   of platelet concentrate  
     
  Outcome Good recovery.  
   Discharged on warfarin  
     
Ghosh et al., (2003), A 27-year-old male with Monitoring of the None The author relied on 
Clin Lab Haematol, unrevealed haemophilia A coagulation status and  D-dimer tests to find 
India, [17] who underwent surgery for adequate replacement  evidence of systemic 
 MVR (mechanical) therapy  fibrin generation, and 
Case report    testing positive 
(level 4)  Thromboprophylaxis Low-dose warfarin at 1 starting postoperative 
   mg/day, aiming for an warfarin therapy 
   INR between 1.5 and 2  
    Postoperative 
  Complications Severe postoperative development of 
   bleeding and a protracted inhibitors at follow-up 
   postoperative recovery  
     
  Outcome Patient survived but at a  
   huge cost in terms of  
   morbidity  
     
Donahue et al., (1999), An 80-year-old man with Monitoring of the Dose of rfIX was chosen Despite the patient's 
J Cardiothorac Vasc haemophilia B who coagulation status and to increase the level to unfortunate outcome, 
Anesth, USA, [18] underwent CABG×3 adequate replacement 100% of normal. bleeding was not 
  therapy Replacement therapy with clinically a problem, 
Case report   factor IX concentrate 7000 even though the 
(level 4)   U bolus 2 h before patient faced two 
   surgery, with a 4000–5000 consecutive 
   U bolus each day after operations, the second 
   surgery for one week. carried out as an 
   Antifibrinolytic therapy emergency with deep 
   with ε-aminocaproic acid hypothermic 
   as a 10 g bolus followed circulatory arrest 
   by a 1 g/h infusion  
     
  Complications Acute type A aortic  
   dissection on POD 2  
     
  Outcome Died on POD 1 after type A  
   dissection repair  
   because of severe right  
   ventricular failure  
     
Nahas et al., (1996), A 57-year-old man with Monitoring of the The evening before the Replacement therapy 
Cardiovasc Surg, USA, mild haemophilia A coagulation status and procedure, the patient can result in the 
[19] undergoing CABG×2 adequate replacement received 4000 U factor appearance of 
  therapy VIIIc, which was repeated inhibitors to factor 
Case report   just before surgery. On the VIII. Their absence 
(level 4)   day of surgery, the patient should be confirmed 
   received 2000 U factor before each elective 
   VIII every 8 h. On POD 1, surgical procedure 
   he received 1000 U every 8  
   h, and then 1000 U twice  
   a day up to POD 11  
     
  Outcome Good recovery.  
   Discharged on POD 11  
     
Bukowski et al., (1996), A 64-year-old patient with Monitoring of the Infusion of factor IX Article in French 
Ann Fr Anesth Reanim, haemophilia B who coagulation status and concentrates from one day  
France, [20] underwent CABG×4 adequate replacement before surgery until POD  
  therapy 19  
Case report     
(level 4)  Outcome Good with no  
   haemorrhagic  
   complications  
     
Palanzo and Sadr, A 71-year-old male with Monitoring of the Monoclonal antibody- First report of a 
(1995), Perfusion, non-insulin-dependent coagulation status and purified factor IX patient with 
USA, [21] diabetes mellitus and adequate replacement concentrate (5000 U) haemophilia B who 
 haemophilia B who therapy Infused daily until underwent CABG with 
Case report underwent CABG×6  discharge the aid of aprotinin 
(level 4)    and monoclonal 
  Outcome Good. Discharged on POD 6 antibody-purified 
    factor IX concentrate 
     
Dimitrova et al., (1995), A patient with moderate Monitoring of the Substitution therapy was Article in Bulgarian 
Khirurgiia (Sofia), haemophilia B, undergoing coagulation status and realised with factor IX  
Bulgary, [22] CABG adequate replacement concentrate (Bebulin-  
  therapy TIM4-IMMUNO)  
Case report     
(level 4)  Outcome Good  
     
Scharfman et al., A 52-year-old male with Monitoring of the 7500 U of factor IX Factor IX concentrate 
(1993), J Thorac haemophilia B who coagulation status and concentrate given 2 h is also known as 
Cardiovasc Surg, underwent CABG×4 adequate replacement before surgery to achieve PCC; this contains 
USA, [23]  therapy 100% levels, and factors VII, II, X and 
   subsequently 3750 U IX. Heparin was 
Case report   every 24 h for seven days added to the replace- 
(level 4)   to maintain factor IX ment solution 
   levels at 50% to decrease the risk of 
  Outcome The patient was treated thrombotic 
   without complications complications 
    associated with use of 
    PCC: Risk of infective 
    complications 
     
Wilson et al., (1991), A 74-year-old white man Monitoring of the The patient was given 60 Intraoperative 
J Cardiothorac Vasc with haemophilia B who coagulation status and U/kg factor IX as heat- determination of 
Anesth, USA, [24] underwent CABG×3 adequate replacement treated human factor IX factor IX levels. The 
  therapy complex (Konyne, 5200 level remained stable 
Case report   U; Cutter Biological, West during hypothermia, 
(level 4)   Haven, CT, USA) 8 h CPB and rewarming. 
   preoperatively to attain a The expected 30% 
   level of 60% factor IXc decrease in factor IX 
   activity. Postoperatively, level associated with 
   he was to be given the haemodilution of 
   10 U/kg of the factor IX CPB was not 
   complex every 12 h for six observed 
   days postoperatively  
     
  Outcome The perioperative course  
   went smoothly without  
   any significant bleeding  
   complications  
     
Mazzucco et al., (1986), A child with severe factor Monitoring of the The factor IX level was Risk of infective 
Ann Thorac Surg, Italy, IX deficiency who coagulation status and normalised immediately complications and 
[25] underwent repair of adequate replacement before operation and at the development of 
 ventricular septal defect therapy end of CPB by infusing inhibitors 
Case report and aortic regurgitation  PCC and fresh frozen  
(level 4)   plasma. The partial  
   thromboplastin time and  
   factor IX serum levels  
   were monitored for 20  
   days postoperatively and  
   showed factor IX activity  
   higher than 50%  
     
  Outcome Uneventful  

ASD, atrial septal defect; AVR, atrial valve replacement; CABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; FIX, Factor IX; HIV, human immu-nodeficiency virus; INR, International Normalized Ratio; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; MVR, mitral valve replace -ment; OPCAB, off-pump coronary artery bypass; PCC, prothrombin complex concentrate; PCI, percutaneous coronary intervention; POD, postoperative day; rf, recombinant factor.

6. Results

Tang et al. [2] presented a retrospective cohort study of six patients with haemophilia A undergoing the following: coronary artery bypass grafting (CABG; n=2); aortic valve replacement (AVR; n=1); CABG+AVR (n=2); or ventricular resection+mitral valve repair (n=1). The key point identified was the management protocol for factor replacement therapy. All patients received tranexamic acid during the first 6–10 postoperative days (PODs). The authors reported no deaths. One patient needed re-sternotomy for bleeding.

MacKinlay et al. [3] showed similar results in a case series of six patients. Five of these had haemophilia A and were undergoing CABG (n=2), AVR (n=1) or AVR+MVR (n=2); one, with haemophilia B, was undergoing atrial septal defect closure. Factor concentrate (VIII or IX) was given by bolus administrations preoperatively to achieve target levels of 100%, and was continued over the seven to 14 days after surgery to avoid late bleeding complications.

Krakow et al. [4] reported an uncomplicated AVR in a 61-year-old man with mild haemophilia B, with factor IX replacement.

Rodriguez et al. [5] described the case of a five-month-old infant with severe haemophilia A who underwent correction of tetralogy of Fallot. Recombinant factor (rf) VIII infusion was continued up to POD 14. The patient developed inhibitors two months later.

Murugan et al. [6] reported two infants with haemophilia A who successfully underwent repair of a total anomalous pulmonary venous connection (case 1) and repair of a ventricular septal defect and total anomalous pulmonary venous connection (case 2). The rfVIII was similarly given up to POD 7–14. Measurement of plasma factor VIII concentration during cardiopulmonary bypass (CPB) was performed using a chromogenic method.

Stine and Becton [7] reported a successful mitral valve repair and CABG using rfVIII in a patient with mild haemophilia A.

Thankachen et al. [8] presented a 25-year-old man with haemophilia B who underwent successful mechanical mitral valve replacement (MVR)+AVR under cover of factor IX concentrate. On POD 4, the patient developed cardiac tamponade requiring surgical drainage.

Grandmougin et al. [9] administered an intraoperative bolus of aspirin 250 mg to prevent graft thrombosis, as well as infusions of rfIX, in off-pump myocardial revascularisation [off-pump coronary artery bypass (OPCAB)] of a patient with haemophilia B.

Sheth et al. [10] presented the case of a 14-year-old male patient with severe haemophilia A and a high titre of inhibitor who successfully underwent cardiac transplantation. High-dose factor VIII bolus therapy followed by a continuous infusion provided haemostasis. On POD 2, he was diagnosed with a cerebral watershed injury. Once anamnesis developed on POD 6, rfVIIa therapy was initiated.

Like others, Mannucci and Mauser-Bunschoten [11] conducted successful mechanical AVR in a 45-year-old male with mild haemophilia A using rfVIII that was continued until POD 10.

Pesaro et al. [12] reported OPCAB in a patient with severe haemophilia B using factor IX replacement. No antiplatelet agent was used, and six months later the patient was diagnosed with vein graft occlusion at angiography.

Kumano et al. [13] reported on a 34-year-old man with unrevealed mild haemophilia A and Marfan syndrome who underwent aortic root replacement with a composite valve graft. A large volume of blood products was required to achieve postoperative haemostasis.

Eren et al. [14] reported a patient with haemophilia A who underwent uncomplicated CABG with the adequate replacement therapy of rfVIII. Similarly, De Bels et al. [15] performed successful CABG and MVR (mechanical) on a 53-year-old male with haemophilia A using factor VIII concentrate infusion.

Kaminishi et al. [16] described a successful modified Bentall operation in a patient with mild haemophilia A, under factor VIII concentrate cover.

Ghosh et al. [17] described a 27-year-old male with unrevealed haemophilia A who underwent MVR (mechanical) without any correcting factor replacement therapy. He developed severe postoperative bleeding. The patient survived but had a protracted postoperative recovery.

Donahue et al. [18] performed CABG, with subsequent emergency reoperation on POD 2 for acute type A aortic dissection, on a 80-year-old man with haemophilia B using rfIX. The patient's eventual death resulted from complications of aortic dissection rather than coagulopathy. In fact, the authors were able to achieve good haemostasis in both operations, the latter performed under hypothermia.

Nahas et al. [19] reported a 57-year-oId man with mild haemophilia A who underwent uncomplicated CABG with factor VIII concentrate infusion.

Likewise, Bukowski et al. [20] performed CABG on a patient with haemophilia B using factor IX concentrate. Palanzo and Sadr [21] first reported uncomplicated CABG in haemophilia B using aprotinin and monoclonal antibody-purified factor IX concentrate. Dimitrova et al. [22] had an analogous experience with a patient with moderate haemophilia B, undergoing CABG, using factor IX concentrate.

Scharfman et al. [23] added heparin into the replacement solution in patient with haemophilia B undergoing CABG to decrease the risk of thrombotic complications associated with prothrombin complex concentrate (PCC).

Wilson et al. [24] measured factor IX activity levels around CPB, showing them to be stable during haemodilution, hypothermia and CPB in a patient undergoing CABG with mild haemophilia B using supplemental factor IX therapy.

Mazzucco et al. [25], likewise, reported successful repair of a ventricular septal defect and aortic regurgitation in a child with severe haemophilia B using PCC and fresh frozen plasma.

7. Clinical bottom line

There is lack of good quality evidence, although we concede the difficulty of performing randomised controlled trials in this patient population, and in all probability these papers are subject to publication bias as poor outcomes are unlikely to have been reported. However, there are compelling data showing that good surgical outcomes are possible for patients with haemophilia undergoing cardiac surgery. The key points we identified to achieve these results are a team approach, a factor replacement protocol advocating continuous infusion, and monitoring of factor levels perioperatively. Intraoperative plasma factor levels can be easily measured before heparin and after protamine sulphate administration, whereas during CPB this will require a chromogenic method. Exposure to factor concentrates early in life might predispose a patient with severe haemophilia to develop inhibitors. Moreover, their absence should be confirmed before any surgical procedure.

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