Focusing on the difficulties and based on practice, Professor Sun Jing and Feng Xiaoqin broke the forbidden area of hemophilia heart surgery and played the voice of China

Recently, the Southern Hospital team of Southern Medical University issued a "Chinese voice" at the International Society for Thrombosis and Hemostasis (ISTH), publishing a speech entitled "Prevention of perioperative hemorrhage during open cardiac surgery in children with high titer inhibitor by Emicizumab combined with.

Hemophilia A (HA) is an X-linked occult bleeding disorder with congenital factor VIII (FVIII) deficiency, and patients' surgery, especially cardiac surgery, has attracted clinical attention

Lin Pei-shuang² et al.

Factor replacement therapy plays a leading role

Disease management is complicated by the formation of FVIII inhibitors, which are formed in 20% to 30% of patients with severe HA and in 5% to 10% of patients with moderate and mild HA

Long-term hemostasis and anticoagulation or antithrombosis after valve surgery or coronary artery bypass grafting in HA patients are also a major dilemma

Ferraris et ^al.

Despite the difficulties of HA surgery or heart surgery, as more and more medical practitioners explore surgery, using detailed factor alternatives and close monitoring of factor levels and multidisciplinary collaboration, there are more and more successful reports of
HA surgery.

Surgery is no longer a contraindication and can become a beacon of hope for the treatment of diseases in patients
.

The case report published by the team of Southern Hospital of Southern Medical University aims to explore the treatment strategy
of major surgery for children with hemophilia A with high titer inhibitors prophylaxis treated with amissizumab.

The case information is as follows:

• Basic information: 2-year-old boy weighing 13 kg, diagnosed with severe hemophilia A with ventricular septal defect and severe pulmonary hypertension, inhibitor titer 27-35BU/ml
  .
  
  

• Diagnosis and treatment process: 4 prophylactic subcutaneous injections of emelizumab (30 mg/week)
  in children before surgery.
  
  After systemic heparinization, extracorporeal circulation undergoes ventricular septal repair and mitral valvuloplasty
  .
  
  The intraoperative artery blockade time is 69 minutes
  .
  
  RhFVII 1-2 mg/dose, q2h-q12h, is used in perioperative phases and amedalizumab 30 mg/week
  for 2 weeks after surgery.
  
  

• Results: After three uses of Amelizumab, the equivalent FVIII level reached 9.
  8%-15.
  7%,
  respectively.
  
  The amount of intraoperative bleeding is about 60 ml
  .
  
  Intravenous rhFVII 2 mg/dose is given initially after surgery, and red blood cell transfusion and fresh frozen plasma are given to support therapy, after which rFVII is gradually reduced
  .
  
  1 week after surgery, the inhibitor titer is 14.
  3BU/ml
  .
  
  The drainage tube was removed on the 5th day after surgery and the patient recovered well
  .
  
  The patient's postoperative cold agglutination test (CAT) is shown in Figure
  1.
  
  

Figure 1: Postoperative CAT levels

This case shows that in children with hemophilia A with high titer inhibitors, it is safe to undergo heart surgery
after a multidisciplinary team has developed a perioperative management plan.

The success of the Southern Hospital team is expected to provide some guidance for the clinical surgical treatment of patients with hemophilia
.

Looking at the world, the authoritative research on emmysizumab has also been actively explored
in this field.

Recently, the journal Blood Advances published surgical outcomes for hemophilia A patients who used emelizumab prophylaxis in the HAVEN 1-4 study^, and the results showed that a total of 233 surgeries (215 minor surgeries; Major surgery 18 cases), preoperative median exposure time of lemesizumab was 278 (177-431) days
.

Of the 141/215 (65.
6%) minor surgeries performed without additional coagulation factor supplementation, 121 (85.
8%) were not associated
with postoperative bleeding.

Fifteen in 18 patients (83.
3%) required additional coagulation factor drug therapy
for major surgery.

Enrolled patients who underwent both major and minor surgeries had no deaths, thrombosis, thrombotic microangiopathy, or the development of new FVIII inhibitors, and the safety was good
.

Table 1 HAVEN 1-4 studies patients undergoing major and minor surgeries

The study shows that patients with hemophilia who receive prophylaxis with emelizumab can safely undergo minor surgeries and major surgeries, which also provides some experience
for patients with nonfactorial hemophilia.

In view of the above case reports and related clinical research progress, Professor Sun Jing and Professor Feng Xiaoqin of the Southern Hospital team made wonderful comments from different angles
.

The patient is a child with congenital heart disease, the ventricular septal defect has a large flow of components, and has formed severe pulmonary hypertension, mitral valve moderate to severe insufficiency, severe condition resulting in cardiac abnormalities nearly 2 times larger than the same age, and combined with severe hemophilia A, accompanied by high titer FVIII inhibitors
.

For such patients, the difficulty of stopping bleeding during surgery increases sharply, and the risk of postoperative bleeding is extremely high
.

At present, the experience of hemophilia surgery in China is still relatively scarce, and there is no precedent
for similar surgery.

When the child is treated, heart surgery is urgent, and we need to quickly formulate a rigorous perioperative treatment plan to maintain the stability of the function of the coagulation system, reduce the risk of perioperative bleeding, and ensure the safety of
cardiac surgery.

The child cannot wait for immune tolerance induction therapy to remove the inhibitors before starting surgery, nor is it suitable for rhFVII alone, because rhFVII will be consumed to varying degrees in cardiac surgery, and the hemostasis efficiency is difficult to grasp
.

In addition, the child's perioperative recovery takes a long time, in order to be able to recover smoothly, it is necessary to ensure good hemostasis
during the period.

After many discussions, it was decided to use emesizumab once a week, and after 1 month of treatment, after the patient's level of emescilizumab was stable, cardiac surgery
with extracorporeal circulation was carried out with the support of rhFVII.

Happily, the patient's postoperative recovery was very good and he was successfully discharged after
more than a month of treatment.

In the absence of amyclizumab, surgery could only be performed with the support of rhFVII or prothrombin complexes for patients with low titer inhibitors, and surgery for patients with high and low inhibitors was almost forbidden
.

However, the hemostatic efficiency of rhFVII or prothrombin complex is not 100%, and ultra-long perioperative rhFVII requires repeated use, the price is expensive, and the risk of thrombosis of prothrombin complex is large, so it is also very prudent
to perform surgery for patients with low titer inhibitors.

In addition to the latest findings from HAVEN 1-4, STASEY ^study7 published during ASH 2021 showed that 37 patients with hemophilia A with suppressors underwent 56 minor surgeries and 22 major surgeries
.

57.
1% of minor surgeries and 18.
2% of major surgeries were performed
without additional use of preventive therapeutic drugs.

81.
8% of major surgeries were performed with additional prophylactic drugs, and although 66.
7% of these patients experienced postoperative bleeding, only half were bleeding that required
treatment.

This also reaffirms that most patients with hemophilia A and inhibitors who receive emelizumab can safely perform minor surgeries without additional prophylactic drugs, and that additional prophylactic drugs can safely perform major surgeries
.

At the same time, it is hoped that the successful implementation of this case operation in our center will enhance the confidence
of doctors in relevant fields in China to perform surgical treatment for patients with hemophilia and suppressors.

In short, some progress has been made in the surgical treatment of patients with hemophilia, but it is still difficult
.

It is expected that practitioners from all walks of life will continue to carry out relevant explorations, accumulate more experience, clear obstacles as soon as possible, and bring tangible benefits
to patients with hemophilia.

Professor Jing Sun

• Professor of Hematology, Southern Hospital, Southern Medical University, Chief Physician

• Member of the Expert Committee of the Chinese Hematopoietic Stem Cell Transplantation Bank

• Member of the Transplantation and Cell Therapy Group of the Hematology and Tumor Branch of the Chinese Anti-Cancer Association

• Member of the Hemostasis Group of the Hematology Branch of the Chinese Medical Association

• Deputy Chairman of the Hematology Branch of Guangdong Medical Doctor Association /Leader of the Coagulation Team

• Chairman of the Rare Disease Committee of Guangdong Pharmaceutical Association

• Vice Chairman of rare disease branch of Guangdong Medical Association

• Member of the Standing Committee of the Hematology Branch of guangdong Medical Association / Leader of the Coagulation Team

• Chairman of the Hematology and Tumor Branch of Guangzhou Anti-Cancer Association

• Editor-in-chief of the Handbook of Care for Hemophilia Care

• Editorial Board member of "Consensus on diagnosis and treatment of hemophilia in China"

• Member of the editorial board of hemophilia Chinese edition and editorial board member of the Journal of Hemostasis

Professor Feng Xiaoqin

• Director of the Department of Pediatric Hematology and Oncology, Southern Hospital, Southern Medical University

• Member of the Oncology Group of the Science Branch of the Chinese Medical Association

• Member of the Standing Committee of the Children's Critical Care Branch of the Guangdong Medical Association, and the leader of the Hematology Critical Care Group

• Deputy leader of Guangdong Hemophilia Expert Group

• Member of the editorial board of Haemophilia Chinese edition

• Vice Chairman of pediatrics branch of Guangdong Women Physicians Association

• He is a visiting scholar at the University of Hong Kong School of Medicine, and has studied at Stjude Children's Research Hospital and Presbyterian Hospital in the United States

• His main research direction is pediatric blood diseases and hematopoietic stem cell transplantation, and he is good at the diagnosis and treatment of childhood leukemia, thalassemia, coagulation diseases, and comprehensive care for hemophilia

References:

1.
X.
Feng, et,al.
ISTH 2022 Congress, PO0033

2.
Lin, Pei-Shuang, and Yun-Tai Yao.
“Perioperative Management of Hemophilia A Patients Undergoing Cardiac Surgery: A Literature Review of Published Cases.
” Journal of cardiothoracic and vascular anesthesia vol.
35,5 (2021): 1341-1350.

3.
Ma HP, Xu WF, Yu J, et al.
Heparin sensitivity and postoperative blood loss in patients undergoing cardiac surgery with cardiopulmonary bypass[J].
Eur J Anaesthesiol.
2020 Mar; 37(3):162-169.

4.
Jiménez-Yuste V, Rodríguez-Merchán EC, Matsushita T, Holme PA.
Concomitant use of bypassing agents with emicizumab for people with haemophilia A and inhibitors undergoing surgery.
Haemophilia.
2021 Jul; 27(4):519-530.

5.
Ferraris VA, Boral LI, Cohen AJ, et al.
Consensus review of the treatment of cardiovascular disease in people with hemophilia A and B.
Cardiol Rev 2015; 23:536

6.
Kruse-Jarres, Rebecca et al.
“Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies.
” Blood advances, bloodadvances.
2022007458.
8 Aug.
2022.

7.
Giancarlo Castaman, et al.
ASH 2021 No.
344.

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