Platelet size and density affect shear-induced thrombus formation in tortuous arterioles

Chesnutt, Jennifer K.W.; Han, Hugang

doi:10.1088/1478-3975/10/5/056003

Cited by 31 publications

(32 citation statements)

References 82 publications

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“…53 Analysis of the effect of MPV on thrombus formation using computational modeling showed that a higher MPV is favorable to thrombus formation 54 ; accordingly, we do not expect that the lower MPV observed in Pf4-Lox tg/tg platelets accounts for the propensity of thrombus formation in this model. The decrease in MPV cannot be attributed to changes in megakaryocyte ploidy levels because LOX did not affect ploidy in the current model.…”

Section: Org Frommentioning

confidence: 86%

Lysyl oxidase is associated with increased thrombosis and platelet reactivity

Matsuura¹,

Mi²,

Koupenova³

et al. 2016

Blood

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• 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

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Section: Org Frommentioning

confidence: 86%

Lysyl oxidase is associated with increased thrombosis and platelet reactivity

Matsuura¹,

Mi²,

Koupenova³

et al. 2016

Blood

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“…4 Moreover, diabetic patients display tortuous micro-vessels and large platelets; the extent of tortuosity is an important factor in shear-induced thrombosis in micro-vessels. 5 Thrombosis accounts for 80% of deaths in patients with diabetes mellitus who have an increased risk of developing sepsis and infection, particularly in intensive care units. 5,6 Diabetes mellitus and septic shock increase the production of reactive oxygen species (ROS) and pro-inflammatory cytokines, involving particularly the kallikrein-kinin system.…”

mentioning

confidence: 99%

“…5 Thrombosis accounts for 80% of deaths in patients with diabetes mellitus who have an increased risk of developing sepsis and infection, particularly in intensive care units. 5,6 Diabetes mellitus and septic shock increase the production of reactive oxygen species (ROS) and pro-inflammatory cytokines, involving particularly the kallikrein-kinin system. 7 Kinin B1 receptor (B1R), an important component of this system, is upregulated by endotoxins and may represent a therapeutic target in sepsis, yet its contribution in the acute phase of lipopolysaccharide (LPS)-induced endotoxin shock remains controversial.…”

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confidence: 99%

A primary role for kinin B1 receptor in inflammation, organ damage, and lethal thrombosis in a rat model of septic shock in diabetes

et al. 2015

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Diabetes mellitus and septic shock increase the incidence of mortality by thrombosis. Although kinin B1 receptor (B1R) is involved in both pathologies, its role in platelet function and thrombosis remains unknown. This study investigates the expression, the inflammatory, and pro-thrombotic effects of B1R in a model of septic shock in diabetic rats. SpragueDawley rats were made diabetic with streptozotocin (STZ) (65 mg/kg, i.p.). Four days later, control and STZ-diabetic rats were injected with lipopolysaccharide (LPS) (2 mg/kg, i.p.) or the vehicle. B1R antagonist (SSR240612, 10 mg/kg by gavage) was given either acutely (12 and 24 h prior to endpoint analysis) or daily for up to 7 days. Moreover, a 7-day treatment was given either with cyclooxygenase (COX)-2 inhibitor (niflumic acid, 5 mg/kg, i.p.), non-selective COX-1 and COX-2 inhibitor (indomethacin, 10 mg/kg, i.p.), non-selective nitric oxide synthase (NOS) inhibitor (L-NAME, 50 mg/kg by gavage), iNOS inhibitor (1400W, 5 mg/kg, i.p.), or heparin (100 IU/kg, s.c.). The following endpoints were measured: edema and vascular permeability (Evans blue dye), B1R expression (qRT-PCR, western blot, flow cytometry), aggregation in platelet-rich plasma (optical aggregometry), and organ damage (histology). Rats treated with STZ, LPS, and STZ plus LPS showed significant increases in edema and vascular permeability (heart, kidney, lung, and liver) and increased expression of B1R in heart and kidney (mRNA) and platelets (protein). Lethal septic shock induced by LPS was enhanced in STZ-diabetic rats and was associated with lung and kidney damage, including platelet micro-aggregate formation. SSR240612 prevented all these abnormalities as well as STZ-induced hyperglycemia and LPS-induced hyperthermia. Similarly to SSR240612, blockade of iNOS and COX-2 improved survival. Data provide the first evidence that kinin B1R plays a primary role in lethal thrombosis in a rat model of septic shock in diabetes. Pharmacological rescue was made possible with B1R antagonism or by inhibition of iNOS and COX-2, which may act as downstream mechanisms.

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“…Our previous work (Chesnutt and Han, 2013) showed that our activation model was either in quantitative or qualitative agreement with a shear-induced platelet activation model that accounted for magnitude of and exposure time to shear stress (Alemu and Bluestein, 2007), depending on the parameters chosen for the model of Alemu and Bluestein.…”

Section: Discussionmentioning

confidence: 52%

Effect of Red Blood Cells on Platelet Activation and Thrombus Formation in Tortuous Arterioles

Chesnutt

Han

2013

Front. Bioeng. Biotechnol.

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Thrombosis is a major contributor to cardiovascular disease, which can lead to myocardial infarction and stroke. Thrombosis may form in tortuous microvessels, which are often seen throughout the human body, but the microscale mechanisms and processes are not well understood. In straight vessels, the presence of red blood cells (RBCs) is known to push platelets toward walls, which may affect platelet aggregation and thrombus formation. However in tortuous vessels, the effects of RBC interactions with platelets in thrombosis are largely unknown. Accordingly, the objective of this work was to determine the physical effects of RBCs, platelet size, and vessel tortuosity on platelet activation and thrombus formation in tortuous arterioles. A discrete element computational model was used to simulate the transport, collision, adhesion, aggregation, and shear-induced platelet activation of hundreds of individual platelets and RBCs in thrombus formation in tortuous arterioles. Results showed that high shear stress near the inner sides of curved arteriole walls activated platelets to initiate thrombosis. RBCs initially promoted platelet activation, but then collisions of RBCs with mural thrombi reduced the amount of mural thrombus and the size of emboli. In the absence of RBCs, mural thrombus mass was smaller in a highly tortuous arteriole compared to a less tortuous arteriole. In the presence of RBCs however, mural thrombus mass was larger in the highly tortuous arteriole compared to the less tortuous arteriole. As well, smaller platelet size yielded less mural thrombus mass and smaller emboli, either with or without RBCs. This study shed light on microscopic interactions of RBCs and platelets in tortuous microvessels, which have implications in various pathologies associated with thrombosis and bleeding.

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Platelet size and density affect shear-induced thrombus formation in tortuous arterioles

Cited by 31 publications

References 82 publications

Lysyl oxidase is associated with increased thrombosis and platelet reactivity

Lysyl oxidase is associated with increased thrombosis and platelet reactivity

A primary role for kinin B1 receptor in inflammation, organ damage, and lethal thrombosis in a rat model of septic shock in diabetes

Effect of Red Blood Cells on Platelet Activation and Thrombus Formation in Tortuous Arterioles

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