Pediatric Cardiology and Pulmonology

Annexin A2: Probing the Connection Between Cardiopulmonary Bypass and Acute Postoperative Respiratory Dysfunction in Children

    Is annexin A2 altered following cardiopulmonary bypass and does the loss of annexin A2 lead to organ dysfunction in children? This is the question that Deyin D. Hsing, MD, a pediatric cardiac intensivist in the Division of Pediatric Critical Care Medicine at NewYork-Presbyterian/Weill Cornell Medicine and NewYork-Presbyterian Komansky Children’s Hospital, is seeking to answer with her current and ongoing research.

    Dr. Hsing specializes in the care of pediatric cardiac patients with a particular emphasis on those undergoing open heart surgery with cardiopulmonary bypass. Dr. Hsing’s early research initially focused on acute respiratory failure and, in 2016, she was introduced to Katherine A. Hajjar, MD, Vice Chair for Research in the Department of Pediatrics and the Brine Family Professor of Cell and Developmental Biology at Weill Cornell Medicine, whose lab had recently made important discoveries related to annexin A2 and respiratory conditions.

    As a plasma membrane protein, annexin A2 (A2) has been rigorously studied in experimental models for the dominant role it plays in a number of disease processes such as cancer, blood disorders, and vascular syndromes. In fact, Dr. Hajjar is credited with the discovery of annexin A2 and demonstrating its importance in vascular homeostasis and angiogenesis.

    A Common Ground for A2 Research

    “Just before I joined Dr. Hajjar’s lab, they had found that genetically engineered mice without annexin A2 tend to have more pulmonary edema when they are placed in a hypoxemic environment compared to normal wild type mice with annexin A2, and that A2 functions to maintain vascular integrity in the face of alveolar hypoxia,” notes Dr. Hsing. “This was very interesting to me because the beginning of acute respiratory distress syndrome and acute lung injury at a molecular level starts with pulmonary edema formation, hypoxemia, and interruption of blood flow to the lungs by disruption of the alveolar cell barrier. A2 is also one of the most abundantly expressed plasma membrane proteins in the lung endothelium. So, I was introduced to Dr. Hajjar, whose life’s work involves annexin A2, to further explore the connection to more acute respiratory failure.” In the years since, Dr. Hajjar has continued as Dr. Hsing’s mentor and colleague in the study of annexin A2.

    “Having taken care of a variety of pediatric cardiac patients after their open heart surgery, I realized that even though they all develop significant inflammation, some patients do better than others,” says Dr. Hsing. “Major efforts are ongoing to try to identify which group of patients are more susceptible to the systemic inflammatory response induced by bypass and, therefore, perhaps do not do as well as similar patients who have a more favorable response. Dr. Hajjar’s lab was already doing a separate experiment in a group of adult patients with sepsis looking at inflammation in general and how it impacts annexin A2. In both sepsis and cardiopulmonary bypass, inflammation involves the phenomenon called systemic inflammatory response syndrome. Whereas sepsis is triggered by an inciting event that’s usually infectious in nature, the systemic inflammatory response that we see with bypass patients is a sterile insult and not infectious, which is the prevalent hypothesis in the literature under study today.”

    When considering systemic inflammatory response syndrome (SIRS) in pediatric patients who go on bypass, Dr. Hajjar and Dr. Hsing knew that they all uniformly experience SIRS response. “Compared to the adult sepsis patients, who generally first present in the ER without us knowing the exact timing of the initial insult, pediatric patients who go on bypass for a heart repair, we know that the insult occurs during the bypass,” explains Dr. Hsing. “Suspecting that A2 may be impacted in this population, in whom we can, in essence, control the insult time, we thought it would be a good population to look at to determine whether A2 plays a role in the development of organ dysfunction, especially since this had never been studied in animals or humans.”

    Substantiating Their Thesis

    Dr. Hajjar, Dr. Hsing, and their NewYork-Presbyterian colleagues, including Patrick Flynn, MD, and Sheila Carroll, MD, Interim Co-Chiefs of the Division of Pediatric Cardiology at NewYork-Presbyterian/Weill Cornell Medicine, embarked on a novel study to determine whether A2 is impacted in pediatric patients after bypass and, if so, does it correlate to a clinically significant finding to potentially predict their postoperative course. They proposed that “compromised pulmonary function after cardiopulmonary bypass may result from loss of A2 and compromised vascular integrity in the lung."

    “While we had a hypothesis, we didn’t know what we would find, so we designed this as a small pilot study to start the investigation,” says Dr. Hsing.

    Their prospective observational study, which was published in Critical Care Explorations, took place over a one-year period in 22 children, ages one month to 18 years old, undergoing cardiac surgery requiring cardiopulmonary bypass. The researchers analyzed A2 expression in peripheral blood mononuclear cells at different time points and assessed the relationship of A2 expression with organ function at each time point in the early postoperative period. The study’s findings confirmed the clinical significance of their hypothesis:

    • Proteolysis of A2 was a universal finding among all subjects in the study cohort
    • The degree of A2 depletion immediately after bypass in one month to 23-month-olds correlated strongly with the extent of organ dysfunction
    • A2 depletion immediately after bypass also correlated with more protracted requirement for both respiratory support and invasive ventilation in this age group

    “These were results that nobody had seen before,” says Dr. Hsing. “What was particularly noteworthy is that we actually found the change in A2 impacted the youngest patients with regard to their postoperative respiratory status, especially in those under two years of age.

    There was definitely a clear differential between the younger and the older age group, and the correlation was surprisingly very strong for the younger group, which is an exciting finding. This is understandable in that surgeries in those so young are more complex and require a longer time on bypass. In our study, the level of A2 in these younger patients was inversely proportional to the intensity of needed respiratory support. This could be due to increased pulmonary vascular leak or damage to type II alveolar cells, thereby reducing pulmonary surfactant production, to which A2 has been linked in previous studies.”

    A Framework for Future Research

    The study has since expanded with a goal to involve multiple centers with a target enrollment of 200 patients, and a separate sub-study that focuses on those patients under two years old. “We are still very much in the earlier investigative stages, confirming the clinical significance, focusing more on the younger group of patients, and trying to develop a pathway that makes sense and that will eventually influence the development of therapeutic options for those who are at higher risk of long-term injury after cardiopulmonary bypass,” adds Dr. Hsing. “And while the results in the older population did not have a statistically significant correlation, likely due to the limited sample size, it was approaching statistical significance. This is why our expanded study is not limited to just those children under two. Our ultimate objective is to determine if preserving A2 can mitigate acute respiratory distress caused by cardiopulmonary bypass.”

      Learn More

      Hsing DD, Stock AC, Greenwald BM, et al. Annexin A2 Loss After Cardiopulmonary Bypass and Development of Acute Postoperative Respiratory Dysfunction in Children. Critical Care Explorations. 2023;5(2):e0862-e0862. doi:10.1097/cce.0000000000000862

      ‌Luo M, Flood EC, Almeida D, et al. Annexin A2 supports pulmonary microvascular integrity by linking vascular endothelial cadherin and protein tyrosine phosphatases. Journal of Experimental Medicine. 2017;214(9):2535-2545. doi:10.1084/jem.20160652

      For more information

      Dr. Deyin D. Hsing
      Dr. Deyin D. Hsing
      [email protected]