Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenecity of human platelets

Abstract

Tissue factor (TF) is an essential cofactor for the activation of blood coagulation in vivo. We now report that quiescent human platelets express TF pre-mRNA and, in response to activation, splice this intronic-rich message into mature mRNA. Splicing of TF pre-mRNA is associated with increased TF protein expression, procoagulant activity, and accelerated formation of clots. Pre-mRNA splicing is controlled by Cdc2-like kinase (Clk)1, and interruption of Clk1 signaling prevents TF from accumulating in activated platelets. Elevated intravascular TF has been reported in a variety of prothrombotic diseases, but there is debate as to whether anucleate platelets—the key cellular effector of thrombosis—express TF. Our studies demonstrate that human platelets use Clk1-dependent splicing pathways to generate TF protein in response to cellular activation. We propose that platelet-derived TF contributes to the propagation and stabilization of a thrombus.

The pleiotropic role of the fibrinogen γ′ chain in hemostasis

“…Alternatively, it could be that platelets only contain or activate the splicing machinery that produces ␥A fibrinogen, similar to the type of tissue-specific regulatory control described for interleukin-1␤ 53 and tissue factor. 54 …”

No evidence for tissue factor on platelets

“…[2][3][4] Identification of these disease-causing mutations in patients can help in genetic testing to confirm or rule out a suspected syndrome or help determine a person's chance of developing or passing on a genetic disorder. Presently, more than 2796 mutations have been identified in BCPs.…”

PAF-acetylhydrolase expressed during megakaryocyte differentiation inactivates PAF-like lipids

“…Cells at culture day 7 are referred to as megakaryocyte precursors. Cells at culture day 13, which lacked CD34 but expressed ␣ IIb integrins and other critical platelet biomarkers, [25][26][27] are referred to as megakaryocytes.…”