The first case of surgical myocardial revascularization and endarterectomy of the right carotid artery in the same procedure in a patient with haemophilia A

Introduction. Haemophilia A is the most common hereditary coagulation disturbance occurring due to the lack of coagulation factor VIII. It is widely accepted that people with haemophilia have a reduced incidence of coronary artery disease, potentially because of the protective effect of the impaired coagulation against the pathogenic mechanisms of the acute coronary syndrome. Case report. A 53 - year - old man with mild haemophilia [FVIII 22% (mild form: more than 5% – 40% of normal)] was hospitalized because of frequent anginal pain at rest. Selective coronary angiography revealed a severe three - vessel coronary disease. A need for urgent surgical revascularization was indicated. The color duplex scan showed the existence of hemodynamically significant stenosis on the right internal carotid artery. After consulting a haematologist, a cardiac surgeon, and a vascular surgeon, it was concluded that due to high bleeding risk, the patient should undergo an endarterectomy of the right carotid artery and a triple aortocoronary bypass in the same procedure. Procedures were performed with a substitution of FVIII concentrate. The patient firstly underwent the endarterectomy of the right carotid artery. Then, the left mammary artery graft was implanted to the left anterior descending artery as well as the venous grafts to the first obtuse marginal artery and posterior descending branch. There were no complications. During the revasculariz ation , there was no need for blood transfusion, nor was there excessive bleeding in the postoperative period. The patient was discharged with antithrombotic therapy (aspirin, 50 mg). Conclusion . Patients with haemophilia are not protected against the development of atherosclerosis. Cardiac surgery in these patients presents a unique challenge for medical teams in securing haemostasis. Adequate substitution with factor VIII concentrate provides adequate haemostasis and the possibility for treatment with antiplatelet therapy.

were performed with a substitution of FVIII concentrate. The patient firstly underwent the endarterectomy of the right carotid artery. Then, the left mammary artery graft was implanted to the left anterior descending artery as well as the venous grafts to the first obtuse marginal artery and posterior descending branch. There were no complications. During the revascularization, there was no need for blood transfusion, nor was there excessive bleeding in the postoperative period. The patient was discharged with antithrombotic therapy (aspirin, 50 mg). Conclusion. Patients with haemophilia are not protected against the development of atherosclerosis. Cardiac surgery in these patients presents a unique challenge for medical teams in securing haemostasis. Adequate substitution with factor VIII concentrate provides adequate haemostasis and the possibility for treatment with antiplatelet therapy.

Introduction
Haemophilia A is the most common hereditary coagulation disorder occurring due to the lack of coagulation factor VIII (FVIII). The life expectancy of persons born with haemophilia, who have access to adequate treatment, should approach the average with the currently available treatment 1 .
It is widely accepted that people with haemophilia have a reduced incidence of coronary artery disease, potentially because of the protective effect of the impaired coagulation against the pathogenic mechanisms of acute coronary syndrome 2,3 . Also, data have demonstrated that mortality due to ischaemic heart disease is lower in haemophilia patients than in the general male population 4 . Advances in managing haemophilia increase the life expectancy and the development of age-related and lifestyle-associated disorders, such as atherosclerosis and ischaemic heart disease 2 .
Cardiac surgery in these patients presents a unique challenge to medical teams in securing haemostasis.

Case report
A 53-year-old male patient was hospitalized because of frequent chest pain at rest. The patient had a history of hypertension, hyperlipidemia, and long-term smoking experience. The personal history revealed haemophilia A with FVIII activity around 20%.
Laboratory examination verified decreased activity of factor FVIII [FVIII 22% (normal haemostasis requires at least a quarter (25%) of factor VIII activity)], normal activity of von Willebrand factor (vWF 112%), and prolonged activated partial thromboplastin time (aPTT) 37.5 s (reference range 29.1-41.9 s). He did not have FVIII inhibitors. The patient has been treated with cryoprecipitate in case of joint haemorrhages or dental interventions since childhood. Since 1980, the patients has been treated with FVIII concentrate from human plasma in preparation for tonsillectomy and cholecystectomy.
Following the advice of a haematologist, the patient received 3,000 IU of human FVIII concentrate prior to coronary angiography ( Figure 1). After substitution, the level of FVIII was 104%. Catheterization was performed via the right radial artery and revealed a severe threevessel coronary disease with high degree left main stenosis ( Figure 2). It indicated a need for urgent surgical revascularization. There were no haemorrhagic complications after the procedure.  In preparation for surgery, according to the existing guidelines and the history of transient ischemic attack less than six months prior to surgery, a color duplex scan of carotid arteries was performed 5 . It showed the existence of ulcerated plaque on the right internal carotid artery that gives haemodynamically significant stenosis of 85%. The computed tomography (CT) scan of carotid arteries and aorta was performed, and the ultrasound findings were confirmed. There were no significant plaques or calcifications in the ascending aorta. Endarterectomy was indicated due to the medical record of the transient ischaemic attack, the characteristic of the plaque, and the degree of stenosis 6 .
In patients with haemophilia, the surgical treatment raises costs due to the need for FVIII administration. A more complex perioperative period and a multidisciplinary approach are required, and there is also an increased bleeding risk. Because of that, simultaneous interventions are advisable when possible. In addition to this, it is known that haemophilic patients can develop anti-FVIII antibodies after 20-50 repeated FVIII administrations, which speaks in favour of a joint operation. After consulting a haematologist, cardiologist, cardiac surgeon, and vascular surgeon, it was concluded that the patient should undergo an endarterectomy and a triple aortocoronary bypass in the same procedure.
Due to an unsuitable radial artery diameter, the quality of preoperative ultrasound screening, and the fact that the patient was obese (higher risk of deep sternal wound infection is present if both mammary arteries were harvested), a surgeon decided to choose the left mammary artery in addition to the great saphenous vein as the grafts of choice for this procedure. The on-pump approach was selected over the off-pump after analyzing the coronary anatomy and the fact that there were no significant calcifications in the ascending aorta (with no significant risk of cross-clamp injury).
Before, during, and after surgery, the patient was constantly monitored by a haematologist. Every 30 min during surgery, the level of FVIII and aPTT were measured. FVIII was given according to given values. During the total heparinisation, activated clotting time was used to measure the heparinisation level. For the entire perioperative period, FVIII level was kept in a normal range.
Just before the surgery, the patient received a bolus of 3,500 IU of FVIII. After fifteen minutes, the level of FVIII was 101%, and after one hour, 90%. During that time, an endarterectomy was performed on the right carotid artery and the great saphenous vein from the right leg was harvested for the use as a venous graft. After that, a median sternotomy was done and the left mammary artery was harvested. Systemic heparin was given in 30,000 units and the extracorporeal circulation (ECC) was started. The anticoagulation activity of heparin was monitored by activated clotting time (ACT) and protamine sulphate was given twice to maintain ACT around 400 s. During the procedure, FVIII was added several times ( Figure 3). The patient underwent implantation of the left mammary artery to the left anterior descending artery (LAD) and two vein grafts to the first obtuse marginal (OM) artery and posterior descending (PD). There was no need for blood transfusion and antifibrinolytics were not prescribed. ECC lasted for 91 min, and the total revascularization time was 4 h. At the end of the procedure, the level of FVIII was 60%.
On the first postoperative day, aspirin in low-dose of 50 mg and low-molecular-weight heparin were introduced to the therapy. The level of FVIII was between 83% and 104% ( Figure 4).  From the second to the sixth postoperative day, 2 × 2,000 units of FVIII were prescribed. In the coming days, the dose was reduced (Figure 4). There was no excessive bleeding in the postoperative period.
At discharge, the level of FVIII was 55%. The patient was discharged with aspirin 50 mg, a statin, and a betablocker. The haematologist decided that the patient should not receive FVIII as long as its levels stay above 30%.
Fourteen months after the surgery, the level of FVII was 37% and during that period there were no haemorrhagic complications.

Discussion
As the haemophilia population is getting older, studies have established that cardiovascular mortality is three times more common as a cause of death 7 , but that mortality is 60% lower than in the general population [8][9][10][11] . Several potential reasons may explain the low incidence of coronary artery disease in patients with haemophilia. These patients have hypocoagulable status and are significantly less likely to form a thrombotic mass. They also have a less established atheroma in blood vessels 12 . However, the patients with haemophilia might not be protected from atherosclerosis, as demonstrated by clinical studies 13 and autopsy reports on haemophiliacs with fatal myocardial infarction showing extensive atherosclerotic lesions and only rarely fresh thrombi 14 .
Patients with haemophilia have an increased tendency to bleed, and, therefore, any invasive procedure is associated with an increased risk of hemorrhagic complications. Artery incision is confined with a high risk of local complications, but it can be effectively reduced by substituting a coagulation factor or by choosing access via radial artery for catheterization 15 , as was the case with our patient. Considering that different complications are possible during invasive procedures, and sometimes urgent surgery is necessary, it was decided that higher doses of FVIII be given.
However, applying the missing coagulation growth factor may increase the risk of acute thrombosis in patients with unstable atherosclerotic plaques. Girolami et al. 15 studied 36 cases of acute coronary syndrome in patients with haemophilia A. In most cases, the event occurred during or after the infusion of recombinant FVIII, desmopressin, and prothrombin complex concentrates 14 .
In addition, one of the treatment-related complications occurring mainly in haemophilia A patients is the development of an inhibitor, usually an IgG antibody, which is directed against the specific deficient factor and may occur shortly after the replacement therapy has been initiated 16 .
Cardiac surgery constitutes a major haemostatic challenge because of sternotomy, the need for total heparinization, ECC, mild hypothermia, and cardiac arrest. However, there is no uniform protocol for the substitution of FVIII that can be applied in a bolus or an infusion 17 . According to the World Federation of Haemophilia recommendations, patients with haemophilia A undergoing major surgery should be supplemented with FVIII before the procedure to achieve the level of 80%-100% of FVIII activity 1 .
Procedures using cardiopulmonary bypass incorporated standard heparinization protocols in many patients with haemophilia described in the literature, after 100% correction of factor levels by a bolus or continuous administration of factor concentrates 25-31 . During surgery, the level of FVIII was monitored and the concentrate was added according to values gathered. On heparin induction, the level of FVIII decreased to 10% and after that to 1%. Then, the patient received protaminesulphate and 500 IU more of FVIII. After that, the level of FVIII increased to 60%. The level of FVIII increased due to the substitution and neutralization of heparin with protaminesulphate.
Antiplatelet therapies are important for preventing thrombosis after cardiac surgery 30 . Haemophilia is not associated with abnormalities of platelet number or platelet function. However, antiplatelet therapy can increase the haemorrhagic tendency 19 . To minimize these risks, the clotting factor deficiency has to be corrected. As coronary artery bypass grafting and patients with coronary disease are required to be on single or dual antiplatelet therapy, for haemophilic patients, the use of aspirin in 50 mg dosage is recommended as long as FVIII is above 30% with regular measurements of FVIII level. Dual antiplatelet therapy is discouraged in these patients 31 .

Conclusion
Patients with haemophilia are not protected from the development of atherosclerosis. Cardiac surgery in these patients presents a unique challenge to medical teams in securing haemostasis. Adequate substitution with FVIII concentrate provides adequate haemostasis and the possibility for treatment with antiplatelet therapy.