Hemostatic Agents in Trauma: The Life-saving Potential of Bioadhesives in the Brain

Biologics

surgery

Hemostatic agents could prove to be invaluable for preventing excessive bleeding during surgical procedures. Image Source: Flickr User Army Medicine

 

When it comes to major surgical procedures, techniques and technologies have advanced substantially; however, bleeding can still arise as a significant complication. Mortality rates in surgery are currently ~0.1%; however, they increase substantially to 5-8% for elective vascular surgery and 20% for surgeries with severe bleeding.1 The source of this bleeding may be caused by either technical issues or pre-existing conditions the patient has. The body’s natural clotting mechanisms may be sufficient for papercuts, but they fall short in severe trauma and in surgery. A catch-all needs to be implemented either prophylactically or during a procedure to prevent excessive bleeding.

Active Hemostatic Agents: Where Mechanical Options Fail

The FDA approved an active hemostatic agent called Raplixa for use in surgery in April 2015. Hemostatic agents may be considered either mechanical or active. Mechanical agents prevent bleeding by forming a mechanical barrier, whereas active hemostats contain active biological materials. Most tissue bioadhesives rely on clotting proteins that are already present in blood plasma, such as thrombin and fibrinogen. With modern lab software, researchers have been able to more overcome innovation barriers to produce many thrombin-based products, both as a stand-alone and in combination with a gelatin matrix. Fibrin glues tend to include both thrombin and fibrinogen. Raplixa is a tissue sealant that has been shown to be more effective at stopping bleeding both on its own and in conjunction with an absorbable gelatin sponge, as compared to an absorbable sponge alone. Once the medication is dissolved, a reaction between the fibrinogen and thrombin creating a blood clot with relatively few side effects.2

Active hemostatic agents open doors to a number of untapped therapeutic targets; they can stop bleeding when mechanical means are not an option, such as during intracranial hemorrhage (ICH). In primary spontaneous intracerebral hemorrhage, bleeding may continue for 24 hours, which is referred to as hematoma expansion. Hematoma expansion is often associated with injury and death due to increased intracranial pressure, brain herniation and physical disruption in the brain.3

As such, hematoma expansion is associated with a poor prognosis and may be a good therapeutic target for future therapies. Through the aid of comprehensive lab software, efficiency barriers may be overcome to better design active, biologic hemostatic agents for hematoma expansion.

Disruptions of the Blood Brain Barrier

To date, a system to safely and reliably deliver an active hemostatic agent into the brain has not yet been developed. There are a number of factors at play, a couple of which are the ability to target specific areas within the brain and to cross the blood brain barrier (BBB). Under normal pathophysiological conditions, the BBB is very “picky” as to what it allows through. Therapeutic delivery to the brain is a persistent issue that both physicians and researchers face as the selective permeable BBB does not permit the passage of many therapeutics. In recent years, a number of systems have been designed to allow transport across these tight junctions, including peptides and antibodies.

Through the integration of modern lab software, antibodies can be manufactured to function with a lower affinity to widely deliver therapeutics. Watts, a researcher investigating the use of low-affinity antibodies, compares this to a ski lift where “the high-affinity antibodies never get off the ski lift [and] the low-affinity antibodies get off and are widely distributed.”4 By tossing aside a few of the rules that have been learned through the use of monoclonal antibodies, low-affinity, multispecific antibody therapies could be developed to target multiple epitopes throughout the brain to assist with the delivery of active hemostatic agents in the event of ICH. This is still a hotly debated approach and using the latest lab software to track and design these antibodies, from discovery to manufacturing, will allow researchers to continue to explore this realm and quash disputes.

In cases of ischemic stroke secondary brain damage, such as BBB dysfunction, may occur after the initial bleed. Delayed BBB hyperpermeability is associated with brain edema formation and an influx of leukocytes in the brain, further increasing the mortality and morbidity in ICH. Brain therapeutic delivery systems, such as those described above, could deliver hemostatic to dampen the initial bleed, reduce the effects and duration of hematoma expansion and potentially prevent the basement membrane degradation that leads to BBB hyperpermeability. Additionally, bioadhesives may be used to assist in the repair of the BBB, preventing further neuronal injury and cell death that often occurs within the days and weeks that follow ischemic stroke.

Designing and production of low-affinity antibodies can be made easier through the use of technology platforms that allows researchers to process and understand a high volume of antibody sequence data. BIOVIA Biologics enables scientists to be more productive by supporting research from discovery to manufacturing. One of the platform’s key capabilities is its “Discovery and Analysis” feature, a unified informatics tools that simplifies the analysis of biological data, such as antibody activity data correlation and developability predictions. Please contact us today to learn more about how our software options can support the efforts of your lab.

  1. “Pathophysiology of bleeding in surgery.” April 2006, http://www.sciencedirect.com/science/article/pii/S0041134506000480
  2.  “FDA approves Raplixa to help control bleeding during surgery”, April 30, 2015, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm445247.htm
  3.  “Vascular disruption and blood–brain barrier dysfunction in intracerebral hemorrhage,” July 15, 2014, http://fluidsbarrierscns.biomedcentral.com/articles/10.1186/2045-8118-11-18
  4. “Boosting Brain Uptake of a Therapeutic Antibody by Reducing Its Affinity for a Transcytosis Target,” May 25, 2011, http://stm.sciencemag.org/content/3/84/84ra44.long