The Clotting Cascade and Haemophilia A

Have you ever wondered how our body creates scabs? What about when it all goes wrong? If so, the clotting cascade is your answer! The clotting cascade is a sequence of proteins that activate one another to stop us from bleeding out and, eventually, they help us form a clot. However, when we lack certain proteins within this cascade, it can cause us to bleed out or produce unwanted clots. A prime example of a clotting disease is Haemophilia A which is a deficiency in factor VIII (8).

The clotting cascade

Simplified diagram of the clotting cascade, Kshiraja Dighe

For some context, there are 3 pathways within the clotting cascade. The intrinsic, extrinsic and common pathway. The intrinsic and extrinsic pathways are activated in different instances. For example, when blood is exposed to collagen due to endothelial cell damage (the cells in the inner portion of a blood vessel), that’s when the intrinsic pathway is activated. However, when tissue factor is released from the endothelial cells, the extrinsic pathway is activated. Both pathways lead to the common pathway which eventually causes a fibrin clot to form. This clot, when stabilised with factor XIII (13), stops the bleeding.

Factor VIII

Factor VIII (8) is a well-known factor within the intrinsic pathway which brings activated factor IX (9) and factor X (10) together to activate factor X and therefore, activate the common pathway. A decrease in this factor means the common pathway cannot be activated. This results in a fibrin clot that can’t be formed and so a patient will keep bleeding.

Symptoms

Common symptoms of haemophilia A is internal bleeding, excessive bleeding post surgery, bruising, joint pain and many more upsetting symptoms.

Diagnostic test

In the lab, we test for factor VIII by centrifuging the blood sample (spinning the sample at a high speed to separate the contents). We take the plasma out and run a factor VIII assay on the plasma. This assay typically measures the optical density of factor VIII by using a reagent that contains all factors but factor VIII. In this way, no other factor deficiencies can affect the test result. The optical density of the plasma is measured and using a standard curve, the approximate amount of factor VIII in the sample is calculated.

Treatment

One of the treatments for Haemophilia A includes Emicizumab which is a monoclonal antibody (lab-made antibodies that act like real antibodies in the body). This replaces the function of factor VIII by bringing activated factor IX and factor X together to mimic the natural reaction and induce activation of the common pathway. In this way, the clotting cascade is continued and patients don’t bleed out!

Conclusion

Haemophilia bleeding, HTI centers

Luckily, there is a lot of promising research being published for people with blood disorders and many new treatments who could help patients. In conclusion, without the clotting cascade, our body would not be able to fix wounds for us. So next time your body patches up a wound, remember to say thank you to it!

Bibliography

Biorender (2024). BioRender. [online] www.biorender.com. Available at:

https://www.biorender.com/.

Chaudhry, R. and Babiker, H.M. (2019). Physiology, Coagulation Pathways. [online] Nih.gov. Available at:

https://www.ncbi.nlm.nih.gov/books/NBK482253/.go.drugbank.com. (n.d.)

Emicizumab. [online] Available at:

https://go.drugbank.com/drugs/DB13923.

GOSH Hospital site. (2024). Haemophilia A. [online] Available at:

https://www.gosh.nhs.uk/conditions-and-treatments/conditions-we-treat/haemophilia-0/.