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Tissue factor pathway inhibitor activity in severe sepsis
1Chiron Corporation, Emeryville, CA, USA.
Objective:
To review the preclinical and clinical evidence that provides the therapeutic rationale for recombinant human tissue factor pathway inhibitor (rTFPI) as a novel treatment for human sepsis.
Data Sources:
A summary of published English-language literature regarding preclinical studies and limited information published about three phase II clinical studies for the evaluation of rTFPI safety in sepsis patients.
Data Summary:
Tissue factor pathway inhibitor, the physiologic inhibitor of the tissue factor pathway, interrupts activation of coagulation at multiple steps, including tissue factor VIIa activity, Xa activity, prothrombinase complex, and thrombin generation. Recombinant human TFPI exhibits anticoagulant and anti-inflammatory activities in animal models and humans with sepsis. These activities appear to have an important therapeutic role in protecting the microvasculature from injury and preventing multiple organ failure in sepsis.
Conclusions:
Tissue factor pathway inhibitor is a potent inhibitor of clotting in the microvasculature, which is thought to protect organs from injury. Recombinant TFPI improved survival of septic animals in multiple models. Recent phase II results suggest that rTFPI is well tolerated, and they show a trend toward reduction in 28-day all-cause mortality in rTFPI-treated patients; in addition, rTFPI demonstrated significant reduction in thrombin generation. These results suggest that a powered study is indicated to further evaluate rTFPI utility for the adjunctive management of severe sepsis.
Insights
Recombinant human tissue factor pathway inhibitor (rTFPI) shows promise for treating sepsis by inhibiting clotting and reducing inflammation. Clinical trials suggest rTFPI is safe and may improve survival in sepsis patients.
Area of Science:
- Sepsis Pathophysiology
- Coagulation Cascade
- Pharmacology
Background:
- Sepsis involves dysregulated coagulation and inflammation, leading to microvascular injury and organ failure.
- Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant that regulates the extrinsic pathway of coagulation.
- Recombinant human TFPI (rTFPI) is being investigated as a therapeutic agent for sepsis.
Purpose of the Study:
- To review preclinical and clinical evidence supporting rTFPI as a sepsis treatment.
- To evaluate the therapeutic rationale for rTFPI in human sepsis.
Main Methods:
- Literature review of preclinical studies.
- Analysis of limited Phase II clinical trial data on rTFPI safety in sepsis patients.
Main Results:
- rTFPI demonstrated anticoagulant and anti-inflammatory effects in animal models and humans.
- Phase II trials indicated rTFPI is well-tolerated with a trend toward reduced mortality in sepsis patients.
- rTFPI significantly reduced thrombin generation in clinical studies.
Conclusions:
- rTFPI's inhibition of microvascular clotting may protect organs in sepsis.
- Preclinical and early clinical data support further investigation of rTFPI for severe sepsis management.
- A powered study is warranted to confirm rTFPI's efficacy in sepsis.