Keeping the Blood Flowing
The saliva of Vampire bats (Desmodus rotundus) prevents blood clotting to ensure a good feed.
The blood in our vessels and arteries brings nutrients and oxygen to the parts of the body where it is needed. It removes waste to ensure our tissues and organs can function effectively.
Blood clots are created to plug a hole if a vessel is damaged. A blood clot where it’s not needed or wanted can be fatal if it travels to a major organ - blocking the flow of blood to the heart can cause a heart attack (myocardial infarction). Blockage of an artery in the lungs can cause a pulmonary embolism, and a sudden blockage or loss of blood flow to the brain causes an acute ischemic stroke. Deep vein thrombosis occurs when a blood clot forms in a deep vein, usually in the leg. If this clot dislodges and travels elsewhere in the circulation, it can block the flow of blood to the brain, to the lungs, or to the heart.
Since blood is so fundamental to the life of a mammal, it is perhaps not surprising to learn that lots of different animals have evolved venom to mess with it. For some that feed on blood, their venom keeps the blood flowing - it stops the clotting cascade that fixes the wound. For others, a bite that prevents clotting can cause such major blood loss that the prey is left immobilised, an easy target.
I remember learning about blood clotting in science lessons at school. There was something so tactile about the mechanism - we could easily imagine the fibrin molecules forming a net across the wound, catching platelets to form a plug to stop more blood escaping. My friend Alison drew a cartoon of what was happening in her finger when she got a papercut in French class. Describing it in the French language clearly didn’t have the same appeal.
A number of therapies - blood thinners - have been developed from venom that can be used to dissolve life-threatening clots, keep the blood moving during surgery, and help to prevent heart attacks. Anti-platelet medications Eptifibatide (brand name Integrilin) from the venom of the Pigmy rattlesnake (Sistrurus miliarius barbouri), and Tirofiban (brand name Aggrastat), modified from the Saw-tailed viper (Echis carinatus), are used to stop platelets clumping together to form blood clots.
Net-forming fibrin is liberated to cover the wound from its precursor fibrinogen by a molecule called thrombin. Batroxobin from the Brazilian lancehead snakes, Bothrops moojeni and B. atrox, is similar to thrombin. However, instead of producing fibrin that forms blood clots, the fibrin it makes doesn’t cross-link and remains as single molecules that are easily destroyed. In this way, Batroxobin is able to get rid of the body’s stores of fibrinogen, stopping blood clots from forming.
The medicinal leech, Hirudo medicinalis, has long been used to treat blood disorders, so much so that it is now endangered in many parts of the world. This leech feeds on the blood of mammals, and to ensure the blood keeps flowing, they secrete a blood thinner in their saliva called hirudin. Hirudin blocks the action of thrombin by binding to both its active site and the part of thrombin that recognises fibrinogen, thus preventing the formation of fibrin blood clots. Bivalirudin (brand name Angiomax) is based on Hirudin that has been approved for the prevention of blood clots during surgery.
While thrombin works to encourage fibrin to form blot clots, another molecule, plasmin, works to break down blood clots. Plasmin is liberated by the action of tissue plasminogen activator (tPA for short) on the plasmin precursor molecule called plasminogen.
Like the medicinal leech, vampire bats (Desmodus rotundus) feed on the blood of mammals. Rather than using hirudin, however, vampire bats have their own molecule in their saliva to prevent blood clotting and ensure a good feed. This molecule, called Desmoteplase, was being developed as a blood thinner by pharmaceutical company Lundbeck.
Desmoteplase is similar to Alteplase (brand name Activase), a synthetic form of human tPA, first approved by the FDA in 1987 for managing diseases involving blood clots, including heart attacks. Both Alteplase and Desmoteplase require the presence of fibrin to liberate plasmin from plasminogen.
Alteplase is broken down quickly by the body - it has a half-life of about 5 minutes. This means that it has a limited therapeutic window of 6 hours after the onset of the stroke. In many situations it might not be possible to get the patient to a hospital for treatment within this time. Desmoteplase has a much longer half-life, lengthening the possible therapeutic window. It also binds more specifically to fibrin, triggering fewer unwanted side effects. Rather than causing damage to the brain and nervous system, it is a protective molecule.
It’s been ten years since Lundbeck stopped developing Desmoteplase [1], and what I find interesting are the threads of information that have been left behind. Lundbeck reportedly owns the global rights, yet the name of the therapeutic doesn’t appear anywhere on their website - understandably, since it’s not part of their current development pipeline.
Desmoteplase showed promise in some clinical trials, performing better than the standard Alteplase. But in another trial little difference was seen, and in another there were reports of symptomatic intracranial hemorrhage - a brain bleed - something that can happen when treating acute ischemic stroke. This can be fatal, and in this case, it was.
Reference
Sagonowsky, E. (2014) Lundbeck discontinues further development of desmoteplase; 2014 profit guidance range narrowed. Fierce Biotech. Accessed: December 3, 2024.
Further Reading
Bordon, K. C. F., Cologna, C. T., Fornari-Baldo, E. C. et al. (2020) From Animal Poisons and Venoms to Medicines: Achievements, Challenges and Perspectives in Drug Discovery Front. Pharmacol. 11:1132.
Piechowski-Jozwiak, B., Abidi, E., El Nekidy, W.S. et al. (2022) Clinical Pharmacokinetics and Pharmacodynamics of Desmoteplase Eur. J. Drug Metab. Pharmacokinet. 47:165–176.
About the Illustration
A vampire bat (Desmodus rotundus) flies through caves - which are H&E stained blood vessels. Watercolour, coloured charcoal pencil and biro on cartridge paper, A3.