# The role of contact pathway factors in mechanical circulation

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $562,539

## Abstract

SUMMARY
Extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB) are associated with a
devastating but poorly understood thromboinflammatory state. Standard anticoagulation strategies result in
significant bleeding risk, yet are inadequate as life-threatening thromboses remain common. There are no
effective strategies to mitigate the inflammatory storm initiated within minutes of starting mechanical circulatory
support. Data from the PIs lab suggests that factor XII (FXII) promotes both thrombosis and inflammatory
mediated organ damage during ECMO. There is significant interest in FXII as a target in mechanical circulation,
but the mechanisms coupling FXII to mechanical circulation associated thromboinflammation are under-
studied. FXII is a multifunctional protease that bridges the hemostatic and inflammatory systems. FXII activates
factor XI (FXI), leading to thrombin generation. The importance of FXII-mediated FXI activation in the setting
of mechanical circulation has never been evaluated. Data from the PIs lab suggests mechanical circulation
components can promote thrombin-mediated FXI activation, significantly limiting the relevance of FXII in some
contexts. Moreover, targeting FXII appears inadequate during CPB with open heart operations where
sternotomy and cardiac manipulation increase circulating tissue factor levels. FXII also activates prekallikrein
(PKK) to the active protease kallikrein (Kal). Kal is linked to multiple inflammatory pathways, including
complement activation and bradykinin generation. Kal has also been proposed to promote thrombosis
independently of FXI. FXII-mediated PKK activation has been proposed to drive inflammatory events during
ECMO, but there are no studies directly evaluating the role of PKK in mechanical circulation associated
thromboinflammation. Data from the PIs lab suggests that targeting PKK significantly limits thrombosis and
organ damage in ECMO. The proposed studies will use novel gene-targeted rats developed specifically for this
proposal, and cutting-edge pharmacological agents to test the following hypotheses: 1) FXII promotes ECMO
and CPB related thromboinflammatory pathologies by independent mechanisms related to activation of FXI
and PKK. 2) FXI is a superior antithrombotic target in mechanical circulation contexts with relatively high
circulating TF levels, such as exist during CPB. 3) FXII-mediated PKK activation promotes key inflammatory
events that lead to organ damage during ECMO/CPB, as well as thromboembolic complications. 4) Combined
strategies targeting FXI and FXII, or FXI and PKK, provide better protection from thrombosis and inflammatory
organ damage than targeting one of these factors alone, without incurring a major bleeding risk. The proposed
studies will provide needed insights into the mechanisms coupling FXII to mechanical circulation associated
thromboinflammatory pathologies. The knowledge gained will critically inform future clinical trials of available
...

## Key facts

- **NIH application ID:** 10518491
- **Project number:** 1R01HL160582-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** David L Morales
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $562,539
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518491

## Citation

> US National Institutes of Health, RePORTER application 10518491, The role of contact pathway factors in mechanical circulation (1R01HL160582-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10518491. Licensed CC0.

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