Walking the Tightrope

By Sreeparna Vappala, PhD Student, Kizhakkedathu Lab

Imagine, you are walking on a tightrope. If you fall to one side of this narrow line, zombies are waiting to eat you up. On the other side, it is a fall into a crazy deep canyon. Terrifying, isn’t it? However, there is good news! By having the prefect concert of one’s movement, balance and coordination, tightrope can be mastered. Just like walking the tightrope; our bodies carefully coordinate blood cells and clotting molecules in the blood vessels to achieve a perfect balance between bleeding and clotting. However, disruption of this balance can lead to either excessive bleeding or undesirable clotting.

Efforts to decipher how blood orchestrates this balance between bleeding and clotting at a molecular level began in mid of 20th century. The early models of blood clotting were described by Davie, Ratnoff, and Macfarlane in 1964. They showed how the sequential cleavage of certain blood proteases, convert the liquid blood into a gel like clot. Although these models critically advanced our knowledge of the diseases caused by most clotting factor deficiencies, they were unable to explain several clinical and experimental observations. For example, these models couldn’t explain why people with FXI deficiency were prone to bleeding compared to people with FXII deficiency. Further research on these observations bridged the gaps in these models and has led to a better description of clot formation. Thus, the clot formation paradigm is no longer considered a linear sequence of proteolytic events that generate the final protease, thrombin, penultimate to clot production. The current understanding involves a complex interplay of cells in the vasculature and plasma clotting molecules. This interplay is regulated by multiple feedback mechanisms resulting in properly balanced clot formation.

Recently, a review article in the Journal of Transfusion and Apheresis Science was published by one of our CBR investigators, Dr. Edward Pryzdial. Together with his students and a clinical colleague, Dr. Pryzdial’s group set out to provide a high-level perspective of the latest advances in clotting system biochemistry and its relation to various bleeding disorders. He says, the aim of the article was to “provide guidance for graduate students and postdoctoral fellows who need a big-picture snapshot of hemostasis as a springboard for their own in-depth studies”. His aim was also, “to provide physicians with a streamlined resource for assistance in the clinic”. It is not only a useful resource for trainees and clinicians, but for anyone who is new to the field of coagulation or wants to dust-off their clotting concepts.

In this article, Dr. Pryzdial discusses tightrope walking strategy that blood uses to maintain the balance of hemostasis. He points out, how the default program of the vasculature is anti-clotting and any breach to the execution of this program switches it to clotting mode. Once a clot has done its job of sealing leaky vessels, it induces anti-clotting and clot dissolution to restore the normal flow of blood. Further, the review also illustrates the involvement of endothelial cells, platelets and RBCs in clot formation and lysis. Understanding the molecular principles of blood clotting is imperative in clinical settings. This encompassing overview of this convoluted clotting system is a great tool for clinicians to provide improved patient care and diagnosis.

Prior to publication of this review article, I took a graduate course taught by Dr. Pryzdial on the biochemistry of hemostasis. I can comment first hand that that the article is an excellent resource that I wish I had while immersed in the course!

  1. Pryzdial E.L.G., et al. (2018). Blood coagulation dissected. Transfusion and Apheresis Science,  57(4), pp. 449-457.