# Mechanisms of coagulation-dependent pathologies in sickle cell disease

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $388,750

## Abstract

Abstract
Sickle cell disease (SCD) is a hematologic disorder caused by a point mutation in the globin
gene. A chronic hypercoagulable state is one of the hallmarks of SCD. Clinical studies
demonstrate that SCD patients are at an increased risk of venous thromboembolism, which is
associated with increased mortality. Recent studies from our group and others have
demonstrated that the hypercoagulable state contributes to chronic vascular inflammation and
end-organ damage in mouse models of SCD. These studies strongly suggest that the
hypercoagulable state in SCD contributes to disease pathology, rather than being a secondary
event. A growing body of evidence indicates that targeting the intrinsic pathway reduces
thrombotic risk without affecting hemostasis. Our preliminary results demonstrate that FXII
deficiency/inhibition reduces the prothrombotic state in sickle cell mice during both steady state
and vaso-occlusive crises. FXIIa-dependent activation of FXI was required only for the
increased thrombin generation observed during vaso-occlusive crisis. In contrast, thrombin
generation during steady state did not require FXI and instead was mediated by high molecular
weight kininogen, Mac-1 integrin and tissue factor. Using mouse models, in vitro experiments
and clinical samples, we propose to further investigate the mechanism of FXIIa-dependent
thrombin generation in SCD and evaluate the long-term effects of FXII deficiency/inhibition on
the prothrombotic state, vascular inflammation and end-organ damage in sickle mice. A better
understanding of FXIIa contribution to the pathology of SCD may lead to the development of
new, anticoagulant-based therapy that would not increase bleeding risk and could be a part of
multimodal approach to prevent cumulative organ damage in patients with SCD.

## Key facts

- **NIH application ID:** 10178080
- **Project number:** 5R01HL142604-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** RAFAL L PAWLINSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10178080

## Citation

> US National Institutes of Health, RePORTER application 10178080, Mechanisms of coagulation-dependent pathologies in sickle cell disease (5R01HL142604-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10178080. Licensed CC0.

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