Blood Coagulation and Alternative Pre-mRNA Splicing: An Overview

Vladimir   Y.   Bogdanov

Abstract

Throughout the 20th century, great advances were made in understanding of how blood coagulation occurs, what physiological and biochemical mechanisms are responsible for its regulation, and what genes and their protein products comprise the essential components of the hemostatic network. Recently, complete sequencing of the human genome revealed that the structural diversity of higher eukaryotes cannot be solely attributed to the number of protein-encoding genes, whereas tools of molecular biology helped establish that pre-mRNAs produced by most protein-encoding genes undergo alternative splicing, a mechanism that enables production of multiple protein isoforms by a single gene. Research in the field of thrombosis and hemostasis revealed that the genes encoding several critical proteins at various junctures of the coagulation cascade produce alternatively spliced protein isoforms with distinct structural and biochemical characteristics, revealing a principally novel dimension in the regulation of blood clotting and, possibly, a few novel therapeutic approaches to treatment of abnormal hemostasis. This review summarizes recently published data pertaining to biosynthesis of the alternatively spliced isoforms of tissue factor (TF, or coagulation factor III), tissue factor pathway inhibitor (TFPI), and coagulation factor XI (FXI), and discusses future directions of this continuously evolving area of biomedical research, with an emphasis on molecular mechanics responsible for regulation of constitutive as well as alternative pre-mRNA splicing.

Keywords: von Willebrand factor, activated protein C (APC), pro-coagulant activity (PCA), tissue factor pathway inhibitor, coagulation factor

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