Dr. Hajjar is Vice Chair for Research in the Department of Pediatrics and the Brine Family Professor of Cell and Developmental Biology.  She also serves as Chair of the Graduate Program in Physician Assistant Studies and Co-Chair fo the Graduate Program in Cell and Developmental Biology. Dr. Hajjar's Lab focuses on the intersection of hemostasis and angiogenesis. Hemostasis is the process by which bleeding is curtailed following blood vessel injury. It is initiated by an enzymatic cascade, which culminates in the activation of thrombin, the enzyme that converts soluble plasma fibrinogen into insoluble fibrin. The fibrinolytic system regulates hemostasis by activating the serine protease plasmin, which cleaves cross-linked fibrin to generate biologically active polypeptides. Scientists in Dr. Hajjar's lab identified the annexin A2 system as a key component of the fibrinolytic system. Expressed on endothelial cells, annexin A2 (A2) is a calcium-regulated, phospholipid-binding protein that forms a heterotetrameric complex with protein p11 (S100A10). The Hajjar Lab discovered that the A2 complex binds two major components of the fibrinolytic system, plasminogen and tissue plasminogen activator, and accelerates the generation of plasmin at cell surfaces.

Understanding the in vivo function of the A2 system is a major goal of the Hajjar Lab. Their development of the A2-deficient mouse uncovered two important findings – first, the knockouts displayed the predicted accumulation of fibrin within blood vessels, and, second, the mice exhibited defects in new blood vessel formation (angiogenesis) – leading to the hypothesis that fibrinolysis and angiogenesis are functionally linked. This postulate has been strengthened by the observation that metabolic blockade of A2 function by the amino acid homocysteine also leads to fibrin accumulation and defective angiogenesis. Evidence that A2 regulates hemostasis in humans derives from studies in patients with acute promyelocytic leukemia in which overexpression of A2 correlates with severe, sometimes life-threatening hemorrhage. Individuals with antiphospholipid syndrome, moreover, often have thrombosis in association with high-titer anti-A2 antibodies that inhibit A2 function or activate endothelial cells. High titer anti-A2 antibodies have also been reported in a cohort of patients with cerebral vein thrombosis.

The Hajjar Lab discovered that synthesis of A2, like many key angiogenesis factors, is regulated by ischemia, through the action of the hypoxia-inducible factor-1 transcription factor, which binds directly to a hypoxia responsive element within the A2 gene promoter. This mechanism for stimulating A2 expression underlies ischemic retinal vascular disease in a mouse model that mimics two human diseases, retinopathy of prematurity and diabetic retinopathy. In the mouse model retinal vascular proliferation requires A2-mediated remodeling of fibrin. Further work has revealed that A2 and p11 co-regulate each other; while endothelial cell A2 stabilizes protein p11 and prevents its ubiquitination and proteasomal degradation, p11 supports the src kinase-stimulated, nonclassical secretion of A2 from the cytoplasm to the cell surface. In addition, the lab has uncovered a novel feedback mechanism whereby plasmin, generated by the A2 system, interacts with toll-like receptor-4 to activate intracellular protein kinase C (PKC). PKC subsequently phosphorylates A2 on N-terminal domain serine residues, thereby disrupting the complex with p11 and restricting further translocation to the cell surface. The lab's most recent studies highlight the contributions of A2-mediated membrane repair mechanisms in regulating the innate immune system through preservation of lysosomal integrity. The lab cntones to build upon hese emerging pathways to develop strategies that target the A2 system in specific disease settings.