ecallantide and Blood-Coagulation-Disorders

Cardiovascular disease, including stroke, myocardial infarction, and venous thromboembolism, is one of the leading causes of morbidity and mortality worldwide. Excessive coagulation may cause vascular occlusion in arteries and veins eventually leading to thrombotic diseases. Studies in recent years suggest that coagulation factors are involved in these pathological mechanisms. Factors XIa (FXIa), XIIa (FXIIa), and plasma kallikrein (PKa) of the contact system of coagulation appear to contribute to thrombosis while playing a limited role in hemostasis. Contact activation is initiated upon autoactivation of FXII on negatively charged surfaces. FXIIa activates plasma prekallikrein (PK) to PKa, which in turn activates FXII and initiates the kallikrein-kinin pathway. FXI is also activated by FXIIa, leading to activation of FIX and finally to thrombin formation, which in turn activates FXI in an amplification loop. Animal studies have shown that arterial and venous thrombosis can be reduced by the inhibition of FXI(a) or PKa. Furthermore, data from human studies suggest that these enzymes may be valuable targets to reduce thrombosis risk. In this review, we discuss the structure and function of FXI(a) and PK(a), their involvement in the development of venous and arterial thrombosis in animal models and human studies, and current therapeutic strategies.

Topics: Animals; Arterial Occlusive Diseases; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Disease Models, Animal; Enzyme Activation; Factor Xa Inhibitors; Factor XI Deficiency; Factor XIa; Humans; Mice; Mice, Knockout; Plasma Kallikrein; Prekallikrein; Protein Processing, Post-Translational; Species Specificity; Thrombophilia; Thrombosis; Venous Thrombosis

The contact activation system (CAS) and kallikrein/kinin system (KKS) are older recognized biochemical pathways that include several proteins that skirt the fringes of the blood coagulation, fibrinolytic, complement and renin-angiotensin fields. These proteins initially were proposed as part of the hemostatic pathways because their deficiencies are associated with prolonged clinical assays. However, the absence of bleeding states with deficiencies of factor XII (FXII), prekallikrein (PK) and high-molecular-weight kininogen indicates that the CAS and KKS do not contribute to hemostasis. Since the discovery of the Hageman factor 60 years ago much has been learned about the biochemistry, cell biology and animal physiology of these proteins. The CAS is a pathophysiologic surface defense mechanism against foreign proteins, organisms and artificial materials. The KKS is an inflammatory response mechanism. Targeting their activation through FXIIa or plasma kallikrein inhibition when blood interacts with the artificial surfaces of modern interventional medicine or in acute attacks of hereditary angioedema restores vascular homeostasis. FXII/FXIIa and products that arise with PK deficiency also offer novel ways to reduce arterial and venous thrombosis without an effect on hemostasis. In summary, there is revived interest in the CAS and KKS due to better understanding of their activities. The new appreciation of these systems will lead to several new therapies for a variety of medical disorders.

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Bradykinin; Factor XII; Factor XIIa; Hemostasis; Homeostasis; Humans; Inflammation; Kallikrein-Kinin System; Kininogen, High-Molecular-Weight; Mice; Plasma Kallikrein; Prekallikrein; Receptors, Bradykinin; Thrombosis

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Factor XI Deficiency; Factor XIa; Factor XIIa; Feedback, Physiological; Genotype; Humans; Kininogen, High-Molecular-Weight; Phenotype; Plasma Kallikrein; Prekallikrein