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Scaling Issues in the Article Entitled “Cytokines in Blood From Septic Patients Interact With Surface-Immobilized Heparin”

Axelsson, Jonas; Adolfsson, Lars; Mccrea, Keith; Larm, Olle

doi: 10.1097/01.mat.0000386580.19736.e3
Letters to the Editor

Department of Renal Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden (Axelsson)

ExThera AB, Stockholm, Sweden (Adolfsson)

Robert Ward, Emergence LLC, Berkley, California (Mccrea)

ExThera AB, Stockholm, Sweden (Larm)

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In Response:

We thank the authors for their interest in our findings. It is well known that inflammatory disorders, regardless of the cause or degree of clinical activity, result, inter alia, in an enhanced expression of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1b, and IL-6. In addition, several clinical studies on the use of monoclonal antibodies against TNF-α for treating chronic and acute inflammatory disorders have shown a positive effect. Septic shock and inflammatory bowel diseases (IBDs) are among these.1,2

Based on these data, we and others—including Federspiel and coworkers3—believe that a technology could be developed for treating inflammatory disorders4 through affinity apheresis. Although TNF-α levels certainly reflect disease levels in many inflammatory conditions, we believe that an apheresis therapy should focus on reducing not only TNF but also the total inflammatory burden in these patients. Also, it remains to be elucidated whether ELISA-measured TNF levels reflect biological activity or also incorporates inactive forms. Thus, our work is focused on the goal of normalizing patient inflammatory activity after passage through an apheresis column.

The scientific rationale behind our technology is based on decades of studies by us and others on the use of devices with covalently linked heparin on blood-contacting surfaces, today often used in extracorporeal blood circuits,5,6 and recent findings concerning specific interactions between heparin/heparan sulfate and circulating cytokines.7 For example, during cardiopulmonary bypass (CPB) using standard oxygenators, patients exhibit a postoperative cytokine response that is not present when using a CPB device incorporating surfaces covered in covalently-linked heparin molecules.8 This finding may be explained by a study by Fujita et al.,9 who found that proinflammatory cytokines, especially TNF-α, adheres to the surface of heparin-coated fibers in oxygenators after CPB. They concluded that the heparin surface at least partly accounted for a reduction in the overall inflammatory response seen in their study.

Based on these and other findings, the data presented in our article were conceived as hypothesis generating, and we believe that they clearly demonstrate cytokine binding to an end-point heparinized surface. Future studies will have to be made to determine the putative benefit of this surface for various therapeutic uses.

In conclusion, we believe that it is very likely that clinical benefits will be derived from a device that can effectively remove cytokines and pathogens, and which presents a safe blood-contacting surface. At present, however, neither we nor Federspiel and coworkers have determined the optimal target concentrations of TNF-α, or other cytokines—not the best way to measure these—required for an effective therapy. We continue our work and we will publish our results as they become available.

Jonas Axelsson

Department of Renal Medicine

Karolinska Institutet

Karolinska University Hospital

Stockholm, Sweden

Lars Adolfsson

ExThera AB

Stockholm, Sweden

Keith Mccrea

Robert Ward

Emergence LLC

Berkley, California

Olle Larm

ExThera AB

Stockholm, Sweden

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References

1.Expert Reviews in Molecular Medicine: Accession information: Vol. 4; 24 February 2004.
2.Akobeng AK, Zachos M: Tumor necrosis factor-alpha antibody for induction of remission in Crohn's disease. Cochrane Database Syst Rev 1: CD003574, 2004.
3.DiLeo MV, Kellum J, Federspiel WJ: A simple mathematical model of cytokine capture using a hemoadsorption device. Ann Biomed Eng 37: 222–229, 2008.
4.Levi M, van der Poll T: Inflammation and coagulation. Crit Care Med 38: S26–S34, 2010.
5.Larm O, Larsson R, Olsson P: A new non-thrombogenic surface prepared by selective covalent binding of heparin via a modified reducing terminal residue. Biomater Med Devices Artif Organs 11: 161–173, 1983.
6.Bindslev L, Eklund J, Norlander O, et al: Treatment of acute respiratory failure by extracorporeal carbon dioxide elimination performed with a surface heparinized artificial lung. Anesthesiology 67: 117–120, 1987.
7.Hsu LC: Heparin-coated cardiopulmonary bypass circuits: Current status. Perfusion 16: 417–428, 2001.
8.Jessen ME: Heparin-coated circuits should be used for cardiopulmonary bypass. Anesth Analg 103: 1365–1369, 2006.
9.Fujita M, Ishihara M, Ono K, et al: Adsorption of inflammatory cytokines using a heparin-coated extracorporeal circuit. Artif Organs 26: 1020–1025, 2002.
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