Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm

Lamrani, Lamia; Lacout, Catherine; Ollivier, Véronique; Denis, Cécile V.; Gardiner, Elizabeth E.; Noe, Benoit Ho Tin; Vainchenker, William; Villeval, Jean‐Luc; Jandrot‐Perrus, Martine

doi:10.1182/blood-2013-10-530832

Cited by 51 publications

(41 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Elevated hematocrit in animal models of polycythemia vera or erythropoietin‐induced erythrocytosis did not correlate with thrombosis. Moreover, enhanced FeCl 3 ‐induced thrombosis in polycythemia vera mice was associated with an increased tail bleeding time, perhaps as a result of simultaneous deficiency of GPVI and impaired multimerization of von Willebrand factor . The same bleeding tendency was revealed in mice with extremely high hematocrit (85%), whereas animals with a lower hematocrit were indistinguishable from controls in a thrombosis model, suggesting that the prothrombotic effects of RBCs may be compensated for by other mechanisms .…”

Section: Quantitative and Qualitative Changes In Rbcs Related To Bleementioning

confidence: 85%

Red blood cells: the forgotten player in hemostasis and thrombosis

Weisel

Litvinov

2019

Journal of Thrombosis and Haemostasis

294

272

View full text Add to dashboard Cite

Summary New evidence has stirred up a long‐standing but undeservedly forgotten interest in the role of erythrocytes, or red blood cells (RBCs), in blood clotting and its disorders. This review summarizes the most recent research that describes the involvement of RBCs in hemostasis and thrombosis. There are both quantitative and qualitative changes in RBCs that affect bleeding and thrombosis, as well as interactions of RBCs with cellular and molecular components of the hemostatic system. The changes in RBCs that affect hemostasis and thrombosis include RBC counts or hematocrit (modulating blood rheology through viscosity) and qualitative changes, such as deformability, aggregation, expression of adhesive proteins and phosphatidylserine, release of extracellular microvesicles, and hemolysis. The pathogenic mechanisms implicated in thrombotic and hemorrhagic risk include variable adherence of RBCs to the vessel wall, which depends on the functional state of RBCs and/or endothelium, modulation of platelet reactivity and platelet margination, alterations of fibrin structure and reduced susceptibility to fibrinolysis, modulation of nitric oxide availability, and the levels of von Willebrand factor and factor VIII in blood related to the ABO blood group system. RBCs are involved in platelet‐driven contraction of clots and thrombi that results in formation of a tightly packed array of polyhedral erythrocytes, or polyhedrocytes, which comprises a nearly impermeable barrier that is important for hemostasis and wound healing. The revisited notion of the importance of RBCs is largely based on clinical and experimental associations between RBCs and thrombosis or bleeding, implying that RBCs are a prospective therapeutic target in hemostatic and thrombotic disorders.

show abstract

Section: Quantitative and Qualitative Changes In Rbcs Related To Bleementioning

confidence: 85%

Red blood cells: the forgotten player in hemostasis and thrombosis

Weisel

Litvinov

2019

Journal of Thrombosis and Haemostasis

294

272

View full text Add to dashboard Cite

show abstract

“…Previous studies in animal models have examined the pathophysiologic effects of elevated hematocrit in JAK 2 V617F -induced polycythemia vera (PV) or erythrocytosis mediated by endogenous overproduction of erythropoietin. [25][26][27][28] Findings from these studies expose complex, and sometimes discordant, effects of hematocrit on coagulation and failed to reveal a clear relationship between hematocrit and thrombosis. For example, a mouse model of JAK 2 V617F -induced PV exhibits a prothrombotic phenotype following FeCl 3 injury to mesenteric vessels, but an apparent paradoxical increase in bleeding following tail transection.…”

Section: Introductionmentioning

confidence: 99%

“…For example, a mouse model of JAK 2 V617F -induced PV exhibits a prothrombotic phenotype following FeCl 3 injury to mesenteric vessels, but an apparent paradoxical increase in bleeding following tail transection. 27 However, these mice are deficient in platelet glycoprotein VI and have reduced plasma von Willebrand factor multimers, 27 making it difficult to assess the contribution of elevated hematocrit to thrombosis. Mice genetically engineered to overexpress human erythropoietin also show increased bleeding in a tail bleeding model.…”

Section: Introductionmentioning

confidence: 99%

“…26 Erythropoietin-infused mice with less dramatically elevated hematocrit (60% 6 5.5%) do not differ from controls in a FeCl 3 -induced mesentery thrombosis model. 27 However, because erythropoietin has downstream effects on multiple cell types, [29][30][31][32] it is also difficult to assess specific effects of elevated hematocrit with this approach.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Elevated hematocrit enhances platelet accumulation following vascular injury

Walton

Lehmann

Skorczewski

et al. 2017

Blood

View full text Add to dashboard Cite

Red blood cells (RBCs) demonstrate procoagulant properties in vitro, and elevated hematocrit is associated with reduced bleeding and increased thrombosis risk in humans. These observations suggest RBCs contribute to thrombus formation. However, effects of RBCs on thrombosis are difficult to assess because humans and mice with elevated hematocrit typically have coexisting pathologies. Using an experimental model of elevated hematocrit in healthy mice, we measured effects of hematocrit in 2 in vivo clot formation models. We also assessed thrombin generation, platelet-thrombus interactions, and platelet accumulation in thrombi ex vivo, in vitro and in silico. Compared with controls, mice with elevated hematocrit (RBC) formed thrombi at a faster rate and had a shortened vessel occlusion time. Thrombi in control and RBC mice did not differ in size or fibrin content, and there was no difference in levels of circulating thrombin-antithrombin complexes. In vitro, increasing the hematocrit increased thrombin generation in the absence of platelets; however, this effect was reduced in the presence of platelets. In silico, direct numerical simulations of whole blood predicted elevated hematocrit increases the frequency and duration of interactions between platelets and a thrombus. When human whole blood was perfused over collagen at arterial shear rates, elevating the hematocrit increased the rate of platelet deposition and thrombus growth. These data suggest RBCs promote arterial thrombosis by enhancing platelet accumulation at the site of vessel injury. Maintaining a normal hematocrit may reduce arterial thrombosis risk in humans.

show abstract

“…57 In another model transplanted with JAK2V617F knock-in cells, time to occlusion after FeCl 3 treatment was decreased as compared with controls, but formed thrombi were unstable, which was attributed to reduced levels of GPVI. 58 Analysis of thrombosis in vivo in the GATA-1 low mouse model is precluded by the extreme thrombocytopenia observed in those animals. 59 One interesting prospect of future studies will be to analyze the contribution of LOX to the thrombotic phenotype observed in JAK2V617F mouse models.…”

Section: Org Frommentioning

confidence: 99%

Lysyl oxidase is associated with increased thrombosis and platelet reactivity

Matsuura¹,

Mi²,

Koupenova³

et al. 2016

Blood

View full text Add to dashboard Cite

• Mice overexpressing LOX in platelets have more severe thrombosis than normal animals.• LOX expression influences platelet adhesion to collagen. ) were generated. Pf4-Lox tg/tg mice had a normal number of platelets; however, time to vessel occlusion after endothelial injury was significantly shorter in Pf4-Lox tg/tg mice, indicating a higher propensity for thrombus formation in vivo.Exploring underlying mechanisms, we found that Pf4-Lox tg/tg platelets adhere better to collagen and have greater aggregation response to lower doses of collagen compared with controls. Platelet activation in response to the ligand for collagen receptor glycoprotein VI (cross-linked collagen-related peptide) was unaffected. However, the higher affinity of Pf4-Lox tg/tg platelets to the collagen sequence GFOGER implies that the collagen receptor integrin a 2 b 1 is affected by LOX. Taken together, our findings demonstrate that LOX enhances platelet activation and thrombosis. (Blood. 2016;127(11):1493-1501

show abstract

Hemostatic disorders in a JAK2V617F-driven mouse model of myeloproliferative neoplasm

Abstract: Key Points Mice constitutively developing a JAK2V617F-induced PV exhibit a bleeding tendency combined with the accelerated formation of unstable clots. Hemostatic defects are not concomitant with JAK2V617F expression, suggesting they are not directly caused by the mutation.

Cited by 51 publications

References 52 publications

Red blood cells: the forgotten player in hemostasis and thrombosis

Red blood cells: the forgotten player in hemostasis and thrombosis

Elevated hematocrit enhances platelet accumulation following vascular injury

Lysyl oxidase is associated with increased thrombosis and platelet reactivity

Contact Info

Product

Resources

About