Thrombin-independent contribution of tissue factor to inflammation and cardiac hypertrophy in a mouse model of sickle cell disease

Sparkenbaugh, Erica; Chantrathammachart, Pichika; Chandarajoti, Kasemsiri; Mackman, Nigel; Key, Nigel S.; Pawliński, Rafał

doi:10.1182/blood-2015-11-681114

Cited by 20 publications

(26 citation statements)

References 24 publications

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“…Interestingly, in sickle mice, EC‐specific TF deletion attenuated IL‐6 expression, but had no effect on thrombin generation . Similar results were observed in sickle mice expressing very low levels of TF in all non‐hematopoietic cells (including EC and all perivascular sources) . TF is known to induce intracellular signaling via activation of protease‐activated receptor 2 (PAR‐2) by the ternary TF, factor VIIa (FVIIa), and FXa complex .…”

Section: Role Of Tissue Factor (Tf) In Scdmentioning

confidence: 64%

“…Taken together, these data suggest that endothelial cell TF contributes to signaling rather than activation of coagulation in a mouse model of SCD . As a consequence of reduced IL‐6 expression, sickle mice deficient in endothelial cell TF or expressing low levels of TF in all non‐hematopoietic cells demonstrate attenuation of hypertrophic heart remodeling .…”

Section: Role Of Tissue Factor (Tf) In Scdmentioning

confidence: 79%

“…Furthermore, in sickle mice the interaction of TFpositive neutrophils with endothelial cells initiates thrombus formation in cremaster arterioles in a laser injury model [59]. Together with the absence of reduced thrombin generation observed in sickle mice deficient in endothelial cell TF, leukocyte TF is the most likely source of TF that contributes to the activation of coagulation in SCD [27,52].…”

Section: Leukocyte Tfmentioning

confidence: 99%

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Prothrombotic aspects of sickle cell disease

Sparkenbaugh

Pawliński

2017

Journal of Thrombosis and Haemostasis

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Summary Sickle cell disease (SCD) is a hematologic disorder caused by a well‐characterized point mutation in the β‐globin gene. Abnormal polymerization of hemoglobin tetramers results in the formation of sickle red blood cells that leads to vascular occlusions, hemolytic anemia, vascular inflammation and cumulative, multiple organ damage. Ongoing activation of coagulation is another hallmark of SCD. Recent studies strongly suggested that hypercoagulation in SCD is not just a secondary event but contributes directly to the disease pathophysiology. In this article we summarize mechanisms leading to the activation of coagulation, review data indicating direct contribution of coagulation to the pathology of SCD and, we discuss the anticoagulation as a possible treatment strategy to attenuate the disease progression

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Section: Role Of Tissue Factor (Tf) In Scdmentioning

confidence: 64%

Section: Role Of Tissue Factor (Tf) In Scdmentioning

confidence: 79%

Section: Leukocyte Tfmentioning

confidence: 99%

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Prothrombotic aspects of sickle cell disease

Sparkenbaugh

Pawliński

2017

Journal of Thrombosis and Haemostasis

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“…Because HK deficiency attenuated plasma TAT and IL-6 levels in a short-term experiment, we hypothesized that long-term attenuation of coagulation and inflammation might reduce organ dysfunction and early mortality, as previously shown. 8,10 To test this hypothesis, we generated SS/WT and SS/HK −/− chimeras and tracked survival for 8 months. SS/HK −/− showed significantly improved survival compared with SS/WT mice ( Figure 3A).…”

Section: Kininogen Contributes To Early Mortality Of Sickle Micementioning

confidence: 99%

“…We and others have observed tissue factor (TF)-dependent activation of coagulation in sickle cell patients and mouse models, [3][4][5][6][7] and reported that this pathway contributes to inflammation and end-organ damage in sickle mice. 3,[8][9][10][11][12][13] High molecular weight kininogen (HK) circulates in complex with factor XI (FXI) or prekallikrein (PK) and serves as a non-enzymatic cofactor for activation of both proteins by factor XIIa (FXIIa). HK is a 120-kD α-globulin comprised of six domains.…”

Section: Introductionmentioning

confidence: 99%

High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease

Sparkenbaugh

Kasztan

Ellsworth

et al. 2020

Journal of Thrombosis and Haemostasis

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Background Sickle cell disease (SCD) is characterized by chronic hemolytic anemia, vaso‐occlusive crises, chronic inflammation, and activation of coagulation. The clinical complications such as painful crisis, stroke, pulmonary hypertension, nephropathy and venous thromboembolism lead to cumulative organ damage and premature death. High molecular weight kininogen (HK) is a central cofactor for the kallikrein‐kinin and intrinsic coagulation pathways, which contributes to both coagulation and inflammation. Objective We hypothesize that HK contributes to the hypercoagulable and pro‐inflammatory state that causes end‐organ damage and early mortality in sickle mice. Methods We evaluated the role of HK in the Townes mouse model of SCD. Results/Conclusions We found elevated plasma levels of cleaved HK in sickle patients compared to healthy controls, suggesting ongoing HK activation in SCD. We used bone marrow transplantation to generate wild type and sickle cell mice on a HK‐deficient background. We found that short‐term HK deficiency attenuated thrombin generation and inflammation in sickle mice at steady state, which was independent of bradykinin signaling. Moreover, long‐term HK deficiency attenuates kidney injury, reduces chronic inflammation, and ultimately improves survival of sickle mice.

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The thrombin–inflammation axis in cancer progression

Cantrell

Palumbo

2020

Thrombosis Research

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Thrombin-independent contribution of tissue factor to inflammation and cardiac hypertrophy in a mouse model of sickle cell disease

Cited by 20 publications

References 24 publications

Prothrombotic aspects of sickle cell disease

Prothrombotic aspects of sickle cell disease

High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease

The thrombin–inflammation axis in cancer progression

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