This essay ties in with my video entry for the Biochemical Society Science Communication Prize and goes into a lot more detail about the fascinating molecular biochemistry involved in blood clotting and hypercoagulation.
For a brief overview of this essay, please see the animated video: Blood Clotting: The Good, The Bad & The Sticky
When Blood is Much Thicker than Water:
Hypercoagulation in Alzheimer’s, Thrombosis & COVID-19
As a daring child who played rough and knew no fear, my elbows and knees were always covered with scrapes. Observing how they scabbed over in just a matter of minutes, as morbidly fascinating as it was predictable, always distracted me from the pain these little injuries brought. Little did I know that I was witnessing the first stages of haemostasis which seals off any breach in a blood vessel.
Cell fragments, known as platelets, and important proteins such as tissue factors and fibrinogen, work together to form blood clots. The very instant a blood vessel is cut, glycoproteins known as von Williebrand factors (vWF) quickly rush and bind to the collagen in the surrounding tissue. The collagen, which gives our skin its elasticity, only encounters vWF when a blood vessel is cut. The vWF proteins act as molecular first responders, constantly patrolling the blood stream in an inactive globular structure, until shear stress exerted by blood flow propels them into action. Conformational changes allow vWF to stretch out and bind to passing platelets. Many of these platelets bind together to create a thrombus (a rudimentary platelet plug).
Like a camping tent in a windstorm, this plug can be carried away by the fast-flowing bloodstream unless it is strongly anchored down. This is where the coagulation cascade comes in. Platelet proteins and tissue factors, released by the ruptured blood vessel, activate a series of coagulation factors and enzymes to convert the abundant yet inactive fibrinogen into the polymerising protein fibrin. This flurry of protein activity produces the fibrin network that stabilises the thrombus – stemming the flow of blood.
In the prime of our health, haemostasis is very easy to take for granted, but defects in coagulation underpin a shocking range of ailments. Whilst I experienced the positive effects of haemostasis, my grandfather faced its sinister side. He suffered from a neurodegenerative condition rooted in errant blood clotting: Alzheimer’s disease.
Neurodegeneration & Nervous System Disorders
Alzheimer’s disease is characterised not only by the formation of plaques in synaptic gaps between neurons, but also by decreased cerebral blood flow. The dual nature of this disease gives rise to two unique theories regarding its development: the vascular hypothesis and the amyloid hypothesis.
Just as fibrin bridges adjacent platelets in a thrombus, it might also bridge the vascular and amyloid hypotheses. Fibrin is usually separated from neurons by a wall of cellular ‘bouncers’ which form the blood-brain barrier. In patients with Alzheimer’s disease, prior inflammation in the brain causes fibrin to build up at the barrier. Excess fibrin weakens the barrier by eroding endothelial tight junction proteins between each of the cellular ‘bouncers’. Fibrin molecules can now squeeze past with disastrous consequences.
Once inside the brain, fibrin binds to the short amyloid beta peptides which naturally reside in healthy brains. Fibrin enhances amyloid beta aggregation, creating a network of amyloid fibrils which form the notorious plaques. Amyloid beta also has an influence on fibrin, making it stickier so that any thrombus formed is more resistant to dissolving and hence more likely to block blood vessels in the brain. Since a sudden stop in blood supply to the brain causes stroke, the ‘fibrin hypothesis’ also explains the increased risk of stroke in Alzheimer’s disease patients. The good news is that drugs which inhibit fibrin from binding to amyloid beta could be an effective therapy for halting the progression of dementia.
Fibrinogen is also complicit in many nervous system diseases by inhibiting the essential process of remyelination. Just like electrical wires are insulated with plastic to prevent shock, neurons are coated with an insulating myelin sheath, which prevents distortion of signals in the brain and increases their transmission speeds. In multiple sclerosis and spinal cord injuries, neurons not only lose their protective coat of myelin but also the ability to repair and remyelinate. Myelination is produced by oligodendrocyte cells that are formed from adult stem cells when needed; rogue fibrinogen activates the BMP signalling pathway which inhibits stem cells from differentiating into oligodendrocytes. Without these oligodendrocytes, remyelination is impossible. By administering drugs which remove fibrinogen, researchers have successfully enhanced remyelination in vitro – hinting at the possibility of new therapies for spinal cord injuries.
Tale of Two Thromboses
Haemostasis complications can arise even without infiltrating the blood-brain barrier, especially when blood clots form without any blood vessels breaking. Thrombosis, in which large blood clots form and hinder blood flow, is responsible for the vast majority of stroke cases and cardiovascular diseases.
In arterial thrombosis, a plaque of fat, stuck to the arterial wall, ruptures and spews out its contents, triggering coagulation. Platelets and vWF huddle around, attracted by tissue factors released by the plaque, to initiate the formation of a thrombus as if the artery were actually ruptured. However, since the vessel is already narrowed by the plaque, the thrombus could block blood flow entirely – resulting in serious consequences.
In contrast, venous thrombosis is not caused by a plaque clinging to the blood vessel but rather by a change in blood chemistry. In a healthy individual, after a clot has successfully plugged the leak in a vessel, it needs to stop growing. Excess fibrin and platelets must now be cleared away. TFPI protein sequesters excess tissue factor to limit platelet recruitment and antithrombin molecules bind irreversibly to thrombin, the enzyme that makes fibrin, so fibrin production also stops.
An increase in coagulation enzymes and tissue factors, coupled with a decrease in TFPI and antithrombin, is a recipe for thrombosis. These changes in blood chemistry can be caused by cancer, obesity and surgery, or inherited in DNA. In fact, around 5% of Caucasians inherit a mutation in the gene coding for coagulation factor V which makes it resistant to inhibition by anticoagulant Protein C. People with this mutation have ‘stickier’ blood which clots more easily- giving them a higher risk of venous thrombosis.
An Aspirin A Day Keeps the Platelets Away
Just as the development of thrombosis depends on its location – artery or vein – so does the treatment. Coagulation factors control the formation of blood clots in veins, hence anticoagulants, which inhibit the activity of coagulation factors, are used to treat venous thrombosis. Warfarin, treasured by humans and feared by rats, is a vitamin K antagonist with humble beginnings as a pesticide. This drug inhibits vitamin K epoxide reductase, an enzyme needed to form many coagulation factors, therefore preventing excess coagulation in veins and, at lethally high doses in rats, causing unstoppable internal bleeding.
Platelets are the key players in arterial thrombosis. To prevent hypercoagulation in arteries, drugs which inhibit platelet activation are administered. The most renowned antiplatelet drug, aspirin, belongs to the cyclooxygenase inhibitor drug class. Cyclooxygenase (COX-1) is needed to synthesise thromboxane-A2, a potent chemical messenger which activates platelets; its inhibition keeps platelet activation in check.
Interestingly, aspirin also inhibits a different cyclooxygenase (COX-2) which is used to produce prostaglandins, the chemical messengers involved in pain and inflammation.
But the relationship between coagulation and the inflammation runs far deeper…
The Clot Before the Storm
Our coagulation and immune systems communicate with each other through small signalling molecules called cytokines. Pro-inflammatory cytokines activate the coagulation cascade and are becoming infamous for their role in the coronavirus disease we are currently struggling with.
When the coronavirus first invades the body, coagulation is activated which kickstarts inflammation and overproduces cytokines. These cytokines, in turn, fuel coagulation in a disastrous positive feedback loop which ravages the body: a cytokine storm.
In an ideal immune response, fibrin slightly weakens the walls of the pulmonary blood vessel to let immune cells pass through and burrow into infected lung tissue, where they are needed. In a cytokine storm, however, fibrin overreacts and weakens the blood vessels too much – making them so leaky that the lungs fill with fluid. Since hypercoagulation has gone haywire, fibrin is laid down at a rapid rate, scarring over healthy lung tissue and forming clots that choke the blood flow – resulting in permanent lung damage.
But there is a sliver of hope. Now that we know that cytokines and coagulation conspire to worsen the disease, we can approach the issue of COVID-19 lung damage from a new angle, using anticoagulants. Research into hypercoagulation and the cytokine storm has already reached hospitals – benefitting patients, giving them a greater chance of survival and opening the door to exciting new therapies.
References:
Jose, R. J., & Manuel, A. (2020). COVID-19 cytokine storm: the interplay between inflammation and coagulation. The Lancet Respiratory Medicine. doi:10.1016/s2213-2600(20)30216-2
Mackman, N. (2008). Triggers, targets and treatments for thrombosis. Nature, 451(7181), 914–918. doi:10.1038/nature06797
Dahlbäck, B. (2000). Blood coagulation. The Lancet, 355(9215), 1627–1632. doi:10.1016/s0140-6736(00)02225-x
Cortes-Canteli, M., Zamolodchikov, D., Ahn, H. J., Strickland, S., & Norris, E. H. (2012). Fibrinogen and Altered Hemostasis in Alzheimer’s Disease. Journal of Alzheimer’s Disease, 32(3), 599–608. doi:10.3233/jad-2012-120820
Giannis, D., Ziogas, I. A., & Gianni, P. (2020). Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. Journal of Clinical Virology, 104362. doi:10.1016/j.jcv.2020.104362
Markiewski, M. M., Nilsson, B., Nilsson Ekdahl, K., Mollnes, T. E., & Lambris, J. D. (2007). Complement and coagulation: strangers or partners in crime? Trends in Immunology, 28(4), 184–192. doi:10.1016/j.it.2007.02.006
http://www.biocompare.com. (2017). Blood Clot Protein Fibrinogen Inhibits Brain Regeneration. [online] Available at: https://www.biocompare.com/Life-Science-News/344042-Blood-Clot-Protein-Fibrinogen-Inhibits-Brain-Regeneration/
Poll, T. van der, Jonge, E. de and An, H. ten C. (2013). Cytokines as Regulators of Coagulation. [online] Landes Bioscience. Available at: https://www.ncbi.nlm.nih.gov/books/NBK6207
Curiosity Killed The Cation 