Blood Thinner Without Bleeding Risk

Written by Natalie Tran and Edited by Josephine Chan

Although a typical cut can be quite annoying, it is very rarely life-threatening. Excessive blood loss from a minor cut is seldom a concern, since blood has a unique mechanism to prevent life-threatening blood loss. When bleeding occurs, platelets, a type of cell, join together at the injury site to create a plug to prevent more blood from escaping. In a process known as coagulation, tiny particles travel to the platelet plug and assemble into fibrin, a gauze-like network designed to anchor the platelet plug into place [1]. Without coagulation of blood clots, every cut, regardless of severity, becomes life-threatening, but improper coagulation is also a cause for concern. For example, clots can form in a major vessel, such as the crucial vein in the leg, creating a “traffic jam” in the blood circulation and oxygenation process [2]. The heart would have to work harder to overcome the tension created by the blockage in order to transport the blood to its proper destination. 

To treat thrombosis, the formation of excessive clots in a blood vessel, physicians rely on blood thinners, specifically called anticoagulants. Although blood coagulation is reliant on both platelets and the formation of fibrin, anticoagulants are designed to target and suppress the particles—more commonly referred to as factors—which adhere to each other to form fibrin. Medications such as warfarin fall under the Vitamin K antagonists (VKA) class of anticoagulants and target the complex of Factors II, VII, IX, and X. [3]. Though there are blood thinners that target platelets, known as antiplatelet drugs, they are generally ineffective in treating thrombosis specifically. 

Like all medications, anticoagulants do come with side-effects, the most concerning being major bleeding risks. Anticoagulants are blunt tools, meaning they prevent clot formation regardless of location. Therefore, when a patient on anticoagulants does bleed, they may be unable to control their bleeding for a long period of time, if at all. Consequently, excessive blood loss from a small cut is a scary reality for those on anticoagulants. Patients on VKA, a common class of blood thinner used in anticoagulation therapy, are twice as likely to endure an excessive bleeding episode [4]. In the U.S. alone, upwards of 65,000 patients are rushed to emergency rooms due to warfarin-related blood loss every year [3]. 

A novel development in blood thinners may paradoxically curb the side effect of bleeding risks, where the theoretical backing of this new process is based on a pre-existing biological abnormality: the lack of Factor XII (FXII). Similar to Factors II, VII, IX, and X, FXII is a player in fibrin production and the coagulation, oddly enough, an absence of FXII does not lead to uncontrollable bleeding. In fact, most individuals who have an FXII deficiency are often unaware of this abnormality, as the disorder does not lead to symptoms [5]. However, there is an added benefit to being FXII deficient: those without FXII are less likely to develop thrombosis. Despite being artificially induced in a mouse study, thrombosis formation was delayed in FXII-deficient mice, proving that FXII plays a prominent role in blood vessel clots [6]. Thus, the combination of limiting thrombosis without the risk of abnormal bleeding unexpectedly makes FXII an ideal target for inhibition.Just as if the engine of a car is replaced by a motorcycle’s engine, the car will be unable to function normally. Similarly, a synthetic molecule, FXII900, is designed to replace FXII’s integral functional parts with an incorrect fragment, thus corrupting the whole complex. It has been found to be effective in delaying induced thrombosis in mice and other animal species [7]. However, clinical tests to prove whether or not induced FXII deficiency is a viable option for humans have yet to be tested.

References:

1. Palta, S., Saroa, R., Palta, A., (2014). Overview of coagulation system. Indian Journal of Anaesthesia, 58:515-523.
2. NHS. “Uses: Anticoagulant Medicines.” NHS Choices, NHS, 31 May 2018, www.nhs.uk/conditions/anticoagulants/uses/. 
3. Harter, K., Levine, M., Henderson, S.O., (2015). Anticoagulation Drug Therapy: A Review. West Journal of Emergency Medicine, 16:11-17. 
4. Shoeb, M., Fang, M.C., (2014). Assessing Bleeding Risk in Patients Taking Anticoagulants. Journal of Thrombosis and Thrombolysis, 35:312-319. 
5. National Organization for Rare Disorders. “Factor XII Deficiency.” NORD (National Organization for Rare Disorders), 2012, rarediseases.org/rare-diseases/factor-xii-deficiency/. 
6. Stavrou, E., Schmaier, A.H., (2010). Factor XII: WHat Does It Contribute To Our Understanding Of The Physiology and Pathophysiology of Hemostasis & Thrombosis. Thrombosis Research, 125:210-215. 
7. Wilbs, J., Kong, X., Middendorp, Simon, J.S., (2020). Cyclic peptide FXII inhibitor provides safe anticoagulation in a thrombosis model and in artificial lungs. Nature Communications, 11:3890.