Beth talks blood: Part 5

We all know that I’m a platelet girl at heart but we mustn’t forget the blood coagulation cascade, it is a vital part of haemostasis. Platelets and coagulation factors work together to prevent bleeding in incidences such as vascular injury. So one can’t be without the other and like most systems in the body, it involves a lot of things happening at the same time so when we study it, it can be quite overwhelming!

Blood coagulation is a dynamic process and is called a cascade due to its similarity to a waterfall. The principle is a cascade of pro-enzymes (inactive enzymes), leading to activation of downstream enzymes. In the coagulation cascade, activated enzymes are denoted by the addition of an ‘a’ [1-4].

The numbering system of the enzymes involved in blood coagulation are in Roman numerals and like most things, are named in order of discovery. The aim of the coagulation cascade is haemostasis, which is the arrest of bleeding! Haemostasis is maintained by complicated interactions between coagulation, the fibrinolytic system, platelets and the vessel wall [1-3].

Coagulation is split into two pathways (intrinsic and extrinsic) that leads to a common pathway, ultimately leading to clot formation. Normal coagulation represents a tight balance between pro-coagulant and anti-coagulant mechanisms, to ensure normal working order. Any imbalance in the coagulation system can cause issues such as thrombosis (hypercoagulation) or bleeding, imbalances like this can occur during the preoperative period and critical illness [1-4].

Extrinsic pathway [1-3]:

  • First step in plasma mediated haemostasis 
  • Activated by Tissue Factor (TF) which is exposed during injury
  • TF binds with Factor VIIa and calcium to promote conversation of Factor X to Factor Xa 

Intrinsic pathway [1-3]:

  • Parallel pathway for thrombin activation by factor XII*
  • Begins with Factor XII, HK, Pre-kallekrein and Factor XI resulting in activation of Factor XI 
  • Factor XIa further activates, Factor IX which then acts with is cofactor (Factor VIII) to form the ‘tenase’ complex on a phospholipid surface to active Factor X

*Interestingly, a deficiency in FXII does not cause bleeding making the intrinsic pathway an attractive target for potential anti-thrombosis drugs

Common pathway [1-3]:

  • Activated Factor X, along with its cofactor (Factor V), tissue phospholipids, platelet phospholipids and calcium from the ‘prothrombinase’ complex, coverts pro-thrombin into Thrombin (AKA Factor IIa)
  • Thrombin cleaves circulating fibrinogen to insoluble fibrin and actives factor XIII forming covalent cross linked Fibrin polymers incorporated in the primary platelet plug
  • The fibrin network stabilises the clot and forms a definitive secondary haemostatic plug to allow the cessation of bleeding and to start the process of wound healing 

Blood clots [5]:

Without blood clots during injury, we would bleed out from even the smallest of injuries. Blood clots can also form inside the body at sites of injury within a blood vessel. When the clot’s job is done there are processes that cause the clot to dissolve (fibrinolysis) but sometimes this doesn’t occur, and it’s these kinds of clots that can have serious consequences. These unwanted clots have the potential to block blood supply to the heart, the brain or veins of the legs. They can also move, travelling through the bloodstream to different parts of the body. Unwanted blood clots can arise from plaque rupture and can be dangerous, leading to serious life-threatening conditions such as stroke or heart attack.

Fibrinolysis [1, 3, 6]:

Fibrinolysis is the enzymatic breakdown of the soluble fibrin in blood clots after clots are formed. Plasmin cuts the fibrin meshwork in various places leading to the production of circulating fragments. These fragments are then cleared by other proteases in the blood. There are two fibrinolytic processes; primary fibrinolysis is a normal body process whereas secondary fibrinolysis is the breakdown of blood clots due to medication or disorder. 

Anti-coagulants [6, 7]:

Anti-coagulant drugs are usually prescribed after a cardiovascular event or as a preventative measure. There are many different anti-coagulant drugs out there that target different parts of blood coagulation, including clotting factors, platelets or fibrinolysis (more on this in a future post). The aim of anti-coagulants are to prevent the formation of unwanted blood clots, a common side effect of this however, is bleeding. Anti-coagulants have to be tightly controlled to make sure that those that are on anti-coagulants are not at too high a risk of bleeding or clotting. Development of new anti-coagulants aim to prevent blood clots without risk of bleeding by targeting clotting factors such as FXII (no bleeding risk) or FXI (minimal bleeding risk).

Fun fact, I used to work on the blood coagulation cascade before moving to the platelet field. I think it’s definitely helped me having a background in blood coagulation prior to working with platelets, all of these processes are happening at the same time but they’re usually studied separately. 

For extra fun, let me know in the comments if you have any punny coagulation/clotting jokes. A personal fave of mine is:

“So I heard you two tied the clot”

-“We sure did”

“Coagulations!”

I’m aware that joke is terrible but you’ve got to love a good pun joke, right?

Thank you for reading, I hope you enjoyed this post.

See you in the next one,

Beth x

References:

[1] Palta, S., Saroa, R. and Palta, A., 2014. Overview of the coagulation system. Indian Journal of Anaesthesia, 58(5), p.515.

[2] Chaudhry R, Usama SM, Babiker HM. Physiology, Coagulation Pathways. [Updated 2020 Sep 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482253/

[3] Pilli, V., 2018. Understanding the Clotting Cascade, Regulators, and Clinical Modulators of Coagulation. Hematology – Latest Research and Clinical Advances,.

[4] Labtestsonline.org.uk. 2020. Coagulation Cascade. [online] Available at: <https://labtestsonline.org.uk/tests/coagulation-cascade&gt;.

[5] Strokecenter.org. 2020. Thrombus Formation III–Activation Of Coagulation Cascade | Internet Stroke Center. [online] Available at: <http://www.strokecenter.org/professionals/brain-anatomy/atherosclerosis-and-thrombus-formation/thrombus-formation-iiiactivation-of-coagulation-cascade/&gt;.

[6] Publishing, H., 2020. Blood Clots: The Good, The Bad, And The Deadly – Harvard Health. [online] Harvard Health. Available at: <https://www.health.harvard.edu/heart-health/blood-clots-the-good-the-bad-and-the-deadly&gt;.

[7] Weitz, J. and Fredenburgh, J., 2017. Factors XI and XII as Targets for New Anticoagulants. Frontiers in Medicine, 4.

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