Researchers at the University of York have developed a new way to safely remove a blood-thinning drug used during surgery that can lead to harmful side-effects in recovering patients.
Heparin is a drug used during major surgery for blood-thinning, however, once surgery is complete, the heparin must be removed so clotting, and healing, can begin.
This is currently achieved using a medication called protamine, which binds to heparin and removes it from the bloodstream.
The protamine protein can, however, have adverse effects on patients and it must be used with caution.
Common side-effects from protamine include low blood pressure, slow heart rate, allergic reactions, as severe as anaphylaxis, and vomiting.
Researchers at the Universities of York, Trieste, Valencia, and the Universitat Jaume I, investigated whether a synthetic version of protamine could do the same job, reducing the potentially harmful side-effects.
Professor David Smith, from the University of York’s Department of Chemistry, said: “The problem in the past with creating a synthetic version of protamine is getting it to bind with heparin effectively and safely.
“Heparin is a very large molecule, so if you use small molecules to bind to it, they can struggle to do this effectively due to the mismatch in size.
However, you don’t necessarily want to use large synthetic molecules, because these can linger in the body and cause toxic side-effects.”
To side-step some of these issues, the team developed small synthetic molecules that assembled into a larger structure.
This combined the advantage of the larger molecules binding ability, but with the added benefit of being able to disassemble into small parts, thus reducing the likelihood of toxic side-effects.
They found, however, that once tested in human blood serum, the assembly of their initial molecules broke apart too quickly to usefully remove heparin molecules from the system.
Professor Smith said: “This was another hurdle to overcome.
How do we stop the assembly of small molecules breaking apart before the heparin is removed from the body?
“We decided to change the ‘molecular glue’ that stuck our assembly together.
This created a much more stable structure and enhanced the binding to heparin in the complex biological environment.
“Our goal now is to test this in model systems, and in the longer term move it towards clinical use, putting the right tools in the hands of teams responsible for surgery and making recovery for patients much safer and predictable.”
Protamine sulfate is a polycationic, highly positively charged protein derived from salmon sperm protein, with a molecular weight of approximately 4500 daltons.
Protamine has been used to neutralize anticoagulation due to unfractionated heparin administration (UFH) after cardiac bypass surgery in more than 2,000,000 patients yearly.
The mechanism of action involves binding to the negatively charged heparin molecules, forming a stable complex, and displacing ATIII from the heparin:ATIII complex.
Protamine is the only effective available antidote to excessive anticoagulation produced by UFH; it is not nearly as effective against the anticoagulant activity of LMWH or fondaparinux; coagulation tests such as PTT are not useful in monitoring its action against these agents.
Although it has not been established by controlled studies or supported by animal models, anecdotal evidence suggests that rFVIIa (50 to 120 µg/kg) may be effective in controlling massive bleeding associated with LMWH.
Protamine possesses additional intrinsic anticoagulant activities (including induction of platelet clumping with resultant thrombocytopenia, and interference with the formation of fibrin by thrombin), so that doses in excess of those calculated to neutralize UFH should be avoided.
Protamine administration may be associated with other adverse effects during bypass surgery, including hypotension, increased pulmonary artery pressure, pulmonary neutrophilsequestration, and anaphylaxis, which are mediated by complement activation, histamine release, thromboxane and nitric oxideproduction, and antibody production.
These have been compiled and reviewed by Park et al. (see Box 28.7).
Provided by University of York