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\begin{document}

\title{Minimally invasive mitral valve repair and ablation of concomitant
atrial fibrillation in a patient with severe hemophilia A}



\author[1]{Alexander Bogachev-Prokophiev}%
\author[1]{Ravil Sharifulin}%
\author[1]{Anastasiia Karadzha}%
\author[1]{Natalya Larionova}%
\author[1]{Vladimir Shmyrev}%
\author[1]{Igor Kornilov}%
\author[2]{Andrey Mamaev}%
\author[1]{Alexander Afanasyev}%
\author[1]{Alexey Pivkin}%
\affil[1]{FSBI National Medical Research Center named after E N Meshalkin}%
\affil[2]{National Research Center for Hematology}%


\vspace{-1em}



  
  \date{June 13, 2024}


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\selectlanguage{english}
\begin{abstract}
Cardiac surgery in patients with hemophilia remains a serious problem
due to the risk of bleeding complications. Here, we report successful
treatment of mitral valve insufficiency and concomitant atrial
fibrillation in a patient with severe hemophilia A.%
\end{abstract}%



\sloppy


\textbf{Key clinical message}

Minimally invasive mitral valve repair and ablation of atrial
fibrillation, combined with FVIII level-controlled replacement therapy,
can be safely performed in patients with severe hemophilia.

\textbf{INTRODUCTION}

Hemophilia A is a rare X-linked bleeding disorder caused by mutations in
the gene that encodes factor VIII (FVIII) with a prevalence of 1/5000
live male births.\textsuperscript{1} Disease severity is based on FVIII
levels in the blood: the severe form is defined as a factor level
\textless{} 1\% of normal, the moderate form as a factor level of
1--5\%, and the mild form as a factor level between 5\% and
40\%.\textsuperscript{2} Cardiac surgery in patients with severe
hemophilia remains a serious problem due to the risk of large intra- and
postoperative blood loss, absence of evidence-based guidelines regarding
factor replacement therapy, and anticoagulation treatment after valve
intervention using cardiopulmonary bypass. Here, we report the
successful, minimally invasive treatment of mitral valve insufficiency
and concomitant atrial fibrillation (AF) in a patient with severe
hemophilia A.

\textbf{CLINICAL CASE}

A 50-year-old male (62 kg body weight) with a history of hemophilia A
entered our clinic with complaints of dyspnea during exercise,
palpitations, and weakness. The FVIII level was 0.7\% when hemophilia
was first diagnosed. The patient had mitral valve prolapse with moderate
regurgitation for over 12 years. A persistent form of AF was diagnosed a
year prior to presentation at our clinic for which he received
bisoprolol (2.5 mg/day).

Upon admission, the patient had deformation and limited mobility in the
elbow and knee joints (due to recurrent hemarthrosis), apex systolic
murmur, and an abnormal heart rhythm with a heart rate ranging from 55
to 160 beats per minute (bpm). An ECG revealed AF with a ventricular
rate of 110 bpm. Transthoracic echocardiography (TTE) showed both mitral
valve leaflets prolapse with severe regurgitation (vena contracta of 0.8
cm, effective regurgitant orifice area of 45 mm\textsuperscript{2}),
significant enlargement of the left atrium (volume of 270 mL), left
ventricular diastolic volume of 170 mL, and ejection fraction of 50\%.
The FVIII level was 8.7\% after replacement therapy with 1000 IU FVIII
(16 IU/kg) in 1 day. Inhibitory antibodies toward FVIII were not
detected. CHA2\selectlanguage{english}DS2-\selectlanguage{english}VASc Score was 1.

A perioperative coagulation management strategy for this patient was
developed. Thirty minutes preoperatively, he was administered 4000 IU
(65 IU/kg) of FVIII concentrate and reached a 109\% level of FVIII
activity. Surgery was performed using a right anterolateral
minithoracotomy (approximately 5 cm long) in the fifth intercostal space
with femoral artery and vein cannulation. Tranexamic acid (1 g/hour) was
infused, beginning with the skin incision to the completion of the
procedure. Prior to cannulation, a heparin bolus of 300 IU/kg was
administered and resulted in an activated clotting time [?] 400 s while on
cardiopulmonary bypass, during which FVIII replacement therapy was not
performed. Myocardial protection was performed using antegrade
cardioplegia (Custodiol, Dr. F K\selectlanguage{russian}ӧhler Chemie, Bensheim, Germany). The
mitral valve was repaired by quadrangular resection of the posterior
leaflet with sliding plasty and decalcification of the posterior
annulus, and implantation of a flexible band (40 mm, CardioMed, Penza,
Russia) (Figure 1).

The left and right atrial ablation was performed according to the Cox
maze IV pattern\textsuperscript{3} using the nitrous oxide-based CryoICE
Probe (AtriCure Inc., Mason, OH, USA). The left atrial appendage was
excluded using a double-layer 3/0 polypropylene suture. After weaning
the patient from bypass, protamine was administered to inactivate
heparin. The cardiopulmonary bypass and cross-clamping times were 110
and 90 min, respectively. After inactivating heparin, 2000 IU (32 IU/kg)
of FVIII was injected (Figure 2).

The patient was extubated 10 hours after being transferred to the
intensive care unit (ICU). The early postoperative period was
complicated by moderate heart failure; therefore, the patient received
inotropic therapy during the first day. An episode of supraventricular
tachycardia was noted in the ICU and cured by amiodarone infusion. The
total drainage losses were 700 mL (first day), and 400 mL (second day).
The patient received 500 mL of fresh frozen plasma on postoperative day
1. The minimum hemoglobin level was 89 g/L and blood transfusions were
not required. The patient was transferred from the ICU to the general
ward on postoperative day 3.~Postoperatively, no anticoagulant or
antiplatelet therapy was prescribed.

Postoperative replacement therapy was maintained as follows. A bolus of
3000 IU (48 IU/kg) FVIII was administered 12 hours after the first
injection, then 3000 IU of FVIII was continued every 12 hours on days
1--3, 2000 IU (32 IU/kg) every 12 hours on days 4--7, and 3000 IU (48
IU/kg) once per day on days 8--14. Beginning on postoperative day 15,
1000 IU FVIII (16 IU/kg) was administered every other day. The FVIII
levels were measured twice a day during the first 3 days post-surgery
and once every day until discharge.

TTE at the time of discharge revealed trivial mitral regurgitation. A 24
h Holter monitoring device confirmed a sinus rhythm with an average
daily heart rate of 72 bpm and freedom from AF. The patient was
discharged 15 days after surgery. The hemoglobin level at discharge was
119 g/L. Bisoprolol and amiodarone (2.5 and 200 mg/day, respectively)
were prescribed for 3 months.

Two years post-surgery, the patient was classified with New York Heart
Association class I heart failure, had sinus rhythm without AF
paroxysms, and had no bleeding or thrombotic complications. TTE revealed
trivial mitral insufficiency and a left ventricle ejection fraction of
60\%.

\textbf{DISCUSSION}

Heart valve surgery in patients with severe hemophilia remains a
significant challenge due to severe changes in the hemostatic system and
increased risk of bleeding complications. There are no guidelines for
the perioperative management of hemophiliacs undergoing cardiac surgery.
Current practice is based on expert opinions, case reports, or small
case series. In most cases, biological prostheses are used for valve
replacement in hemophiliacs. Since life expectancy of patients with
hemophilia has increased, the possibility of degeneration of biological
prostheses and need for further surgery may carry an even greater risk
to the patient. In the case of mitral insufficiency in young patients,
valve repair is preferable to valve replacement as it potentially avoids
the need for short\selectlanguage{english}-term anticoagulation treatment. The literature
presents a few cases of mitral valve reconstruction in hemophilia A
patients.\textsuperscript{4-7} Only one describes a minimally invasive
mitral valve repair with concomitant atrium
ablation.\textsuperscript{8}Minimally invasive approach for mitral valve
surgery has advantages over standard sternotomy, which may be especially
important in patients with bleeding disorders. It reduces intra- and
postoperative bleeding resulting in a decreased need for transfusion.
Furthermore, ventilation time and ICU or hospital stays are
shortened.\textsuperscript{9,10}

Factor replacement therapy is crucial for successful surgical treatment
of hemophiliac patients. Patients with a pre-planned coagulation
management strategy can successfully undergo complex cardiac surgery as
patients without hemostatic disturbances. According to the
recommendations of the World Hemophilia
Federation,\textsuperscript{11}the following FVIII activity levels
should be achieved in patients undergoing major surgical procedures:
before surgery, 80--100\%; postoperative days 1--3, 60--80\%;
postoperative days 4--6, 40--60\%; and postoperative days 7--14,
30--50\%. Other recommendations for patients undergoing coronary artery
bypass grafting suggest that FVIII levels should be 80--100\% until
postoperative day 5 and above 50\% after that.\textsuperscript{12} In
our case, we maintained FVIII levels above 80-100\% during the first 3
days post-surgery and 50-100\% until postoperative day 7. This strategy
allowed us to prevent hemorrhagic complications in the postoperative
period.

Although patients with hemophilia are relatively protected from
thrombosis, there is still a risk of thromboembolism, especially in the
presence of concomitant AF. According to frequently cited antithrombotic
treatment algorithms for hemophiliacs with nonvalvular AF,
antithrombotic regimens are based on baseline FVIII levels and risk of
thromboembolic complications.\textsuperscript{13} Low-dose aspirin
therapy is indicated in patients with high stroke risk (CHA\selectlanguage{english}2DS2-\selectlanguage{english}VASc
Score [?]2) with baseline FVIII levels of 1--10\% and patients with
baseline FVII of 10--30\%. Long-term anticoagulation treatment with
vitamin K antagonists is indicated when factor levels are above 30\%. In
the presence of AF in hemophiliacs undergoing cardiac surgery,
antithrombotic treatment remains unclear. Concomitant ablation and left
atrial appendage closure should be considered to restore the sinus
rhythm, reduce thromboembolic risk, and decrease dosages or not
prescribe anticoagulants and antiplatelets in patients with low stroke
risk.

\textbf{CONCLUSION}

This case demonstrates that minimally invasive mitral valve repair can
be safely performed in patients with hemophilia. Using a comprehensive
approach, including a FVIII level-controlled replacement therapy, a
minimally invasive valve repair, and sinus rhythm restoration, allows to
minimize the risk of complications in the perioperative and
postoperative periods in patients with severe hemophilia A.

\textbf{ACKNOWLEDGMENTS}

None

\textbf{CONFLICT OF INTEREST}

None declared

\textbf{AUTHOR CONTRIBUTIONS}

ABP: approved the final manuscript; RS: wrote the manuscript; AK: wrote
the manuscript; NL: wrote the manuscript; VS: reviewed the manuscript;
IK: reviewed the manuscript; AM: reviewed the manuscript; AA: wrote the
manuscript; AP: wrote the manuscript and prepared figures.

\textbf{REFERENCES}

1. Berntorp E, Shapiro AD. Modern haemophilia care. \emph{Lancet} .
2012;379(9824):1447-1456.

2. Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia:
communication from the SSC of the ISTH. \emph{J Thromb Haemost} .
2014;12(11):1935-1939.

3. Bogachev-Prokophiev AV, Afanasyev AV, Pivkin AN, et al. A left atrial
versus a biatrial lesion set for persistent atrial fibrillation ablation
during open heart surgery. \emph{Eur J Cardiothorac Surg} .
2018;54(4):738-744.

4. Xu H, Henry D, Li C, Zhao H, Yang Y. Peri-cardiac surgery coagulation
management in a severe hemophilia A patient: A case
report.\emph{Medicine (Baltimore)} . 2019;98(24):e15897.

5. Zatorska K, Orlowska-Baranowska E, Abramczuk E, et al. Short and
long-term management of haemophilia A patient requiring heart valve
surgery. \emph{Haemophilia} . 2012;18(4):e352-e354.

6. Bhave P, McGiffin D, Shaw J, et al. Guide to performing cardiac
surgery in patients with hereditary bleeding disorders. \emph{J Card
Surg} . 2015;30(1):61-69.

7. Miller VM, Vardas PN, Davies JE, Lewis CT. Robotic mitral valve
repair in a

type B hemophiliac. \emph{J Card Surg} . 2020;35(5):1129-1131.

8. Tran DQ, Moss E, Murphy DA, Kempton CL. Mitral valve repair in a
Jehovah's witness with haemophilia A with high-titre
inhibitor.\emph{Haemophilia} . 2015;21(6):e523-e525.

9. Lange R, Voss B, Kehl V, Mazzitelli D, Tassani-Prell P, G\selectlanguage{ngerman}ünther T.
Right minithoracotomy versus full sternotomy for mitral valve repair: A
propensity matched comparison. \emph{Ann Thorac Surg} .
2017;103(2):573-579.

10. Mihos CG, Santana O, Pineda AM, Lamas GA, Lamelas J. Right anterior
minithoracotomy versus median sternotomy surgery for native mitral valve
infective endocarditis. J \emph{Heart Valve Dis} . 2014;23(3):343-349.

11. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for
the management of hemophilia. \emph{Haemophilia} . 2013;19(1):e1-e47.

12. Kanellopoulou T, Nomikou E. Replacement therapy for coronary artery
bypass surgery in patients with hemophilia A and B. \emph{J Card Surg} .
2018;33(2):76-82.

13. Aguilar C. Antithrombotic therapy in a patient with mild haemophilia
A and

atrial fibrillation: case report and brief review of the
literature.\emph{Blood Coagul Fibrinolysis} . 2015;26(3):346-349.

\textbf{Legends}

Figure 1. Intraoperative photographs. A. Transesophageal
echocardiography, severe mitral regurgitation. B. Quadrangular resection
of the posterior leaflet with sliding plasty. C. Flexible band in the
mitral valve position. D. Final transesophageal echocardiography
revealed trivial mitral regurgitation.

Figure 2. Dynamics of FVIII (\%), hemoglobin levels
(g\textbackslash{}L), and FVIII concentrate doses (IU\textbackslash{}kg)\selectlanguage{english}
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