Xigris : how does it work, really?

Xigris, or "recombinant human activated Protein C," is an anticoagulant used to treat septic shock. How does Xigris work?

What does Protein C do?

Protein C is a key component of the body’s natural negative feedback loop for the coagulation cascade. The final steps in coagulation are the conversion of Prothrombin to Thrombin by Factor X and Factor V. Factor X is activated by Factor VIII.

Thrombin produces Fibrin, which is the building block of blood clots, but it also activates Protein C (PC) by converting it to activated Protein C (aPC). Activated Protein C (aPC) is an enzyme that breaks down Factor V and Factor VIII. By breaking down these factors, Factor X is inhibited and Factors X and V are inhibited from producing Thrombin. Hence the negative feedback loop: as Factors V and VIII increase the production of Thrombin, Thrombin increases the production of aPC, which then decreases the production of Factors V and VIII.

Figure: Coagulation cascade.

How does this apply to septic shock?

In inflammation, blood vessels are exposed to chemicals of inflammation like Interleukins (IL) and Tumor Necrosis Factor (TNF). Inflammation makes the blood vessels "leaky," which exposes the outside of the blood vessels to blood. (Normally, only the inside of the blood vessel is exposed to blood.)

When the cells on the outside of blood vessels are exposed to blood, they release a chemical called Tissue Factor. Also, the cells on the inside of blood vessels release Tissue Factor if they are damaged by inflammation. Tissue Factor starts the coagulation cascade.

Normally, the coagulation cascade started by Tissue Factor is kept in check by the Protein C negative feedback loop.

However, in sepsis, the inflammation response occurs systemically in the body. Because it is occurring everywhere at the same time, Protein C begins to get used up. When there is no Protein C left, the coagulation cascade's negative feedback loop stops. Without the negative feedback loop, coagulation occurs systemically in the body, since the inflammation is systemic.

Systemic coagulation causes micro-blood clots in the body's small blood vessels. These micro-clots can stop blood flow to some tissues, which causes systemic tissue damage and helps lead to multiple organ failure.

By giving activated Protein C (aPC), we can artificially maintain the coagulation cascade's negative feedback loop, which helps prevent tissue damage from systemic micro-clots.

Why don't we use warfarin to treat septic shock?

Since warfarin (Coumadin) is a relatively cheap anti-coagulant, it would seem logical to use it instead of activated Protein C. However, because of warfarin's specific pharmacodynamics, it actually decreases the body's Protein C before its anti-coagulant effect starts. In patients with A-Fib or other relatively harmless conditions, a temporary decrease in Protein C has no ill effects. However, it could be dangerous in patients with septic shock.

Why don't we use heparin to treat septic shock?

Since heparin is a relatively cheap anti-coagulant, it would seem logical to use it, too, instead of activated Protein C. However, think back to the coagulation cascade for a moment. Remember that there is an "extrinsic pathway" and an "intrinsic pathway" that lead to coagulation. What do these terms extrinsic and intrinsic mean?

Essentially, the intrinsic pathway is coagulation that is started due to conditions intrinsic to the body. Think of an MI. The blood clotting that leads to an MI is started by the body's response to the conditions of its blood vessels.

On the other hand, the extrinsic pathway is coagulation that is started due to conditions outside, foreign, or extrinsic to the body. Think of a cut. The blood clotting that is produced by a cut occurs when trauma damages blood vessels.

"Heparin" is actually a collection of different molecules that work on different parts of the coagulation cascade. Some heparin molecules work on the common pathway, but the others work on the intrinsic pathway, although coagulation that occurs due to septic shock is through the extrinsic pathway.

(In fact, research on whether heparin could help in sepsis is unclear. Because many patients are already receiving heparin for DVT prophylaxis, it is hard to create a robust trial of heparin for sepsis treatment. It does appear that it is safe to give Xigris and heparin together.)

Does activated Protein C do anything else?

Besides its role in the coagulation cascade's negative feedback loop, activated Protein C also inhibits some Interleukins, which helps to decrease the systemic inflammation occurring during shock. Both the body's natural aPC and Xigris have this property. And they both also inhibit the body's PAI-1, a chemical that helps to stop blood clots from breaking up. (That's an inhibitor of an inhibitor--i.e., aPC essentially increases the body's natural tPA.)

Does Xigris treat anything else besides septic shock?

Choi et al. (2007) tried to determine whether Xigris would be effective in a single-organ treatment. Citing research showing Xigris was especially effective in the treatment of sepsis occurring from pneumonia, they tried to determine whether Xigris would have a protective effect for the lung in treating ventilator-associated pneumonia. Taking samples from several human patients, they inoculated rats with P. aeruginosa and then treated them with either aPC, tPA, or heparin and had a control group treated with saline.

Interestingly, the results indicated that while Xigris had an anti-coagulant effect, it did not have the anti-inflammatory effect described above, as measured by neutrophil density in the lung tissue. As the authors indicate, this rat model of pneumonia cannot determine effects in people either for pneumonia or for sepsis. However, citing evidence that anti-inflammatories and anti-coagulants failed to improve mortality in sepsis, the authors imply the mechanisms by which Xigris actually works (as I have described above) may not actually explain its efficacy in improving outcomes.

How is Xigris made?

Mammalian cells are genetically modified to produce Protein C. They are then grown in lab cultures. The cells excrete the Protein C (PC) into the cultures, where the culture medium converts it to activated Protein C (aPC). The activated Protein C is then purified from the culture medium. Therefore the name "recombinant [i.e., genetic recombination] human activated Protein C," or rhAPC.

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  2. Medscape article on pathogenesis of septic shock. Retrieved February 23, 2009, from www.medscape.com/viewarticle/412839

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  5. Goda Choi, Jorrit-Jan H. Hofstra, Joris J. T. H. Roelofs, Sandrine Florquin, Paul Bresser, Marcel Levi, Tom van der Poll, Marcus J. Schultz (2007). Recombinant human activated protein C inhibits local and systemic activation of coagulation without influencing inflammation during Pseudomonas aeruginosa pneumonia in rats Critical Care Medicine, 35 (5), 1362-1368 DOI: 10.1097/01.CCM.0000261888.32654.6D

  6. M. Levi, M. Levy, M. D. Williams, I. Douglas, A. Artigas, M. Antonelli, D. Wyncoll, J. Janes, F. V. Booth, D. Wang, D. P. Sundin, W. L. Macias (2007). Prophylactic Heparin in Patients with Severe Sepsis Treated with Drotrecogin Alfa (Activated) American Journal of Respiratory and Critical Care Medicine, 176 (5), 483-490 DOI: 10.1164/rccm.200612-1803OC

  7. Fabián Jaimes, Gisela De La Rosa, Clara Arango, Fernando Fortich, Carlos Morales, Daniel Aguirre, Pablo Patiño (2006). A randomized clinical trial of unfractioned heparin for treatment of sepsis (the HETRASE study): design and rationale [NCT00100308] Trials, 7 (1) DOI: 10.1186/1745-6215-7-19

  8. Marcel Levi, Tom van der Poll (2004). Coagulation in sepsis: all bugs bite equally Critical Care, 8 (2) DOI: 10.1186/cc2816

  9. Warfarin necrosis. (2009). Wikipedia. Retrieved February 24, 2009, from http://en.wikipedia.org/wiki/Warfarin_necrosis

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