Nat Commun: An alternative to aspirin? Scientists have developed synthetic blood anticoagulants that do not increase the risk of bleeding!

Patients with diseases caused by thrombosis, such as pulmonary embolism, ischemic stroke, and myocardial infarction, usually take "blood thinner" drugs such as aspirin and clopidogret to prevent the formation or growth of blood clots, help blood flow smoothly, and prevent further development of the disease.
however, almost all of the anticoagulants available can cause serious or even life-threatening bleeding side effects after injury.
urgent need to develop safe anticoagulants that reduce or do not have the risk of bleeding.
Recently, researchers from the University of Bern and the Federal Institute of Technology in Lausanne, Switzerland, designed a highly active and stable FXII cyclopeptide inhibitor (FXII900) that reduces experimental thrombosis caused by iron chloride in mice and inhibits blood clotting in rabbits' inositive membrane oxygenation (ECMO) environments without increasing the risk of bleeding and is a promising candidate for safe thrombosis protection in acute medical conditions.
the results of the study were published recently in Nature Communications.
Coagulation factor FXII is a proteinase involved in coagulation pathways in the body, and previous studies have found that genetically modified mice lacking FXII had significantly reduced thrombosis in injury-induced arteries and venous thrombosis in mouse models with no bleeding side effects.
who naturally lack FXII and FXII knockout mice also have normal hemorrhage and do not bleed abnormally.
therefore, drugs targeted at this protease may have anti-thrombosis effects without impairing clotting function.
based on this, the researchers continued to replace some of the amino acids of the previously developed FXII inhibitor FXII618 with synthetic amino acids, evaluated and tested their stability and Ki values, and resulted in a new FXII inhibitor FXII900 that was more effective and highly specific than any prey, stable in human plasma, with a half-life of at least 128 hours and a length of about 25 times longer than FXII618.
the researchers assessed the ability of FXII900 to block FXII-driven plasma clotting, measured the active part of the blood clotting enzyme time (aPTT) and coagulation enzyme time (PT, reaction coagulation factor activity) in the blood after incubating FXII900, and found that FXII900 extended the aPTT in human plasma, 4.3 times longer than FXII 618, and had no effect on the maximum test concentration.
addition, the inhibitor can also extend aPTT in the plasma of mice, rabbits and pigs, and has no extended effect on PT.
this shows that FXII900 can effectively inhibit the intrinsic clotting pathway of the off-body.
evaluated the pharmacogenic dynamics of FXII900 in mice, rabbits and pigs and found that effective plasma concentrations were achieved in animals and maintained at 12-40min without any toxicity or other adverse effects observed.
FXII900's inhibition effect on FXIIa in different species, the researchers then evaluated the effect of FXII900's thrombosis protection effect in feclide-induced thrombosis mouse models.
monitored blood flow in mice injected with 7.5% FeCl3 solution in two groups of FXII900 and control treatment. The
study found that blood clots appeared rapidly in seven of the eight control group mice, five had blood clots, five had completely blocked blood vessels, and only three of the mice treated with FXII900 had blood clotting 10 minutes later than the control group, and no complete blood vessel closure had been observed.
showed that FXII900 inhibited thrombosis in iron chloride-induced mice.
the FXII900 and PBS controlled mice's bleeding tendencies were evaluated using the tail cross-cutting model and found that FXII900 had no effect on their normal hemorrhage ability.
FXII-driven blood clotting is a major challenge in in vitro circulation surgery, artificial lung systems are often used for long periods of time to support the lives of severe patients.
Therefore, the researchers used artificial lung rabbit models to test the clinical potential of FXII900 to inhibit FXII-driven clotting in ECMO, and found that FXII900 treatment extended aPTT, active clotting time (ACT) by about 10 times, and treated rabbits showed perfectly normal bleeding time.
's analysis of the artificial lungs found that the blood clot volume of the rabbit treated with the inhibitor was significantly smaller than that of the control group, which showed that FXII900 inhibited blood clotting in the rabbit's inositive membrane oxygenation (ECMO) environment without increasing the risk of bleeding.
the only problem is that the inhibitor is relatively short in the body, it is too small and the kidneys filter it out," said the authors of the paper.
in the case of artificial lungs, this will mean continuous infusions, as it takes longer cycle times to suppress blood clotting in days, weeks or months.
solve this problem, we are currently designing FXII inhibitors with longer retention times.
"