Comparison of animal and human blood for in vitro dynamic thrombogenicity testing of biomaterials

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Abstract

Background

To determine suitable alternatives to human blood for in vitro dynamic thrombogenicity testing of biomaterials, four different animal blood sources (ovine, bovine, and porcine blood from live donors, and abattoir porcine blood) were compared to fresh human blood.

Methods

To account for blood coagulability differences between individual donors and species, each blood pool was heparinized to a donor‐specific concentration immediately before testing in a dynamic flow loop system. The target heparin level was established using a static thrombosis pre‐test. For dynamic testing, whole blood was recirculated at room temperature for 1 h at 200 ml/min through a flow loop containing a single test material. Four materials with varying thrombotic potentials were investigated: latex (positive control), polytetrafluoroethylene (PTFE) (negative control), silicone (intermediate thrombotic potential), and high‐density polyethylene (HDPE) (historically thromboresistant). Thrombus weight and surface area coverage on the test materials were quantified, along with platelet count reduction in the blood.

Results

While donor‐specific heparin levels varied substantially from 0.6 U/ml to 7.0 U/ml among the different blood sources, each source was able to differentiate between the thrombogenic latex and the thromboresistant PTFE and HDPE materials ( p < 0.05). However, only donor ovine and bovine blood were sensitive enough to differentiate an increased response for the intermediate thrombotic silicone material compared to PTFE and HDPE.

Conclusions

These results demonstrated that multiple animal blood sources (particularly donor ovine and bovine blood) may be suitable alternatives to fresh human blood for dynamic thrombogenicity testing when appropriate control materials and donor‐specific anticoagulation levels are used.

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Most cited references 39

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Peter Quehenberger, Bernd Jilma, Jolanta Siller-Matula … (2008)

Many animals are used in research on blood coagulation and fibrinolysis, but the relevance of animal models to human health is often questioned because of differences between species. The objective was to find an appropriate animal species, which mimics the coagulation profile in humans most adequately. Species differences in the coagulation profile with and without thrombin stimulation in vitro were assessed in whole blood by Rotation Thromboelastometry (ROTEM). Endogenous thrombin generation was measured in platelet-poor plasma. Measurements were performed in blood from five different species: humans, rats, pigs, sheep and rabbits. In humans and sheep, the clotting time (ROTEM) was in the same range with or without thrombin stimulation and a 100-fold lower dose of thrombin (0.002 IU) was required to cause a shortening in the clotting time as compared to rats, pigs and rabbits (0.2 IU) (p<0.05). Similarly, the endogenous thrombin potential (ETP) was in the same range in humans and sheep. The maximum clot firmness with or without thrombin stimulation was similar in rabbits and humans. The maximum lysis with or without thrombin stimulation was similar in humans and pigs. Significant species differences exist in the coagulation profile with or without thrombin stimulation. Most importantly, sheep had a clotting time most similar to humans and could thus be a suitable species for translational coagulation studies. Moreover, our findings confirm the potential usefulness of pigs as an experimental species to study fibrinolytic pathway and support the usefulness of rabbits as a species for examining platelets.

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Sheep, pig, and human platelet-material interactions with model cardiovascular biomaterials.

Melody Goodman (1999)

The relationship between cardiovascular device performance in animals and humans is not straightforward. As the principal formed element in a thrombus, platelets play a major role in determining the hemocompatibility of mechanical heart valves and other high-shear-rate cardiovascular devices. Since larger animals are required to test many such devices, sheep and porcine platelet responses were compared to humans. Adhesion, spreading, and the formation of thrombilike structures were examined in vitro on pyrolytic carbon mechanical heart valve leaflets, National Institutes of Health-reference polyethylene and silicone rubber, and Formvar. Principal findings were that platelet responses are strongly dependent upon the biomaterial and the species: Porcine and human platelets spread extensively on pyrolytic carbon, formed thrombuslike structures on Formvar, and were least active on silicone rubber. Human and porcine platelets responded differently to polyethylene: Human platelets spread extensively, while porcine platelets remained pseudopodial. In contrast, sheep platelets attached much less, never reached fully spread shapes, and were far less active overall. Since porcine responses were generally similar to humans, pigs may be a useful predictor of in vivo platelet-biomaterial interaction in humans. Conversely, as ovine platelets were much less active, this must be accounted for in the evaluation of cardiovascular devices tested in sheep. Copyright 1999 John Wiley & Sons, Inc.