Biorheology of Platelet Activation in the Bloodstream Distal to Thrombus Formation

Zilberman‐Rudenko, Jevgenia; Itakura, Asako; Maddala, Jeevan; Baker‐Groberg, Sandra M.; Vetter, R. L.; Tucker, Erik I.; Gruber, András; Gerdes, Christoph

doi:10.1007/s12195-016-0448-5

Cited by 6 publications

(5 citation statements)

References 24 publications

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“…Single platelet consumption (reduction of the single platelet population in the bloodstream as quantitated on a forward vs side-scatter FACS plot), platelet activation (CD62P expression), and platelet microaggregate formation in solution (CD41a/CD31 high positive) was quantified using flow cytometry as described previously. 9,10…”

Section: Resultsmentioning

confidence: 99%

“…Platelet CD62P expression levels and single platelet consumption were determined as described previously. 9,10 Microaggregate formation was determined by the upshift in fluorescence intensity in CD31/CD41a double-positive events.…”

Section: Methodsmentioning

confidence: 99%

“…8 Specifically, FXI activation by FXIIa has been shown to promote thrombin generation and contribute to local platelet activation and consumption of platelets in the bloodstream distal to sites of thrombus formation under shear flow ex vivo and in vivo . 9,10 Conversely, inhibition of FXI activation by FXIIa has been shown to attenuate coagulopathy development and promote survival in mice with polymicrobial sepsis 11 as well as prevent collagen-coated vascular graft occlusion in a primate model of thrombosis. 12 It is unclear whether bacterial components such as long-chain polyP are capable of promoting systemic thrombin generation in the circulating blood.…”

Section: Introductionmentioning

confidence: 99%

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Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo

Zilberman‐Rudenko

Reitsma

Puy

et al. 2018

ATVB

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Objective Terminal complications of bacterial sepsis include development of disseminated intravascular consumptive coagulopathy. Bacterial constituents, including long-chain polyphosphates (polyP), have been shown to activate the contact pathway of coagulation in plasma. Recent work shows that activation of the contact pathway in flowing whole blood promotes thrombin generation and platelet activation and consumption distal to thrombus formation ex vivo and in vivo. Here, we sought to determine whether presence of long-chain polyP or bacteria in the bloodstream promotes platelet activation and consumption in a coagulation factor (F)XII-dependent manner. Approach and Results Long-chain polyP promoted platelet P-selectin expression, microaggregate formation and platelet consumption in flowing whole blood in a contact activation pathway-dependent manner. Moreover, long-chain polyP promoted local fibrin formation on collagen under shear flow in a FXI-dependent manner. Distal to the site of thrombus formation, platelet consumption was dramatically enhanced in the presence of long-chain polyP in the blood flow in a FXI- and FXII-dependent manner. In a murine model, long-chain polyP promoted platelet deposition and fibrin generation in lungs in a FXII-dependent manner. Lastly, in a non-human primate model of bacterial sepsis, pretreatment of animals with an antibody blocking FXI activation by FXIIa reduced LD100 S. aureus-induced platelet and fibrinogen consumption. Conclusions This study demonstrates that bacterial-type long-chain polyP promotes platelet activation in a FXII-dependent manner in flowing blood, which may contribute to sepsis-associated thrombotic processes, consumptive coagulopathy and thrombocytopenia.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo

Zilberman‐Rudenko

Reitsma

Puy

et al. 2018

ATVB

Self Cite

View full text Add to dashboard Cite

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“…It has been shown that acute coronary syndrome patients did not benefit when given systemic direct antithrombins in a safe dose, implying that local thrombin-induced platelet activation is prevalent and less sensitive to thrombin inhibition 40 . Similarly, inhibition of the coagulation factors X, XI or thrombin dramatically reduce the degree of platelet activation and microaggregate formation in the bloodstream without affecting the degree of local platelet deposition and aggregation on the surface of immobilized collagen 41 . These and other data support the notion that endogenous thrombin generated at the site of thrombosis is a more potent platelet activator for a number of reasons, including resistance to antithrombins.…”

Section: Discussionmentioning

confidence: 99%

Activated Monocytes Enhance Platelet-Driven Contraction of Blood Clots via Tissue Factor Expression

Peshkova

Minh

Tutwiler

et al. 2017

Sci Rep

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Platelet-driven reduction in blood clot volume (clot contraction or retraction) has been implicated to play a role in hemostasis and thrombosis. Although these processes are often linked with inflammation, the role of inflammatory cells in contraction of blood clots and thrombi has not been investigated. The aim of this work was to study the influence of activated monocytes on clot contraction. The effects of monocytes were evaluated using a quantitative optical tracking methodology to follow volume changes in a blood clot formed in vitro. When a physiologically relevant number of isolated human monocytes pre-activated with phorbol-12-myristate-13-acetate (PMA) were added back into whole blood, the extent and rate of clot contraction were increased compared to addition of non-activated cells. Inhibition of tissue factor expression or its inactivation on the surface of PMA-treated monocytes reduced the extent and rate of clot contraction back to control levels with non-activated monocytes. On the contrary, addition of tissue factor enhanced clot contraction, mimicking the effects of tissue factor expressed on the activated monocytes. These data suggest that the inflammatory cells through their expression of tissue factor can directly affect hemostasis and thrombosis by modulating the size and density of intra- and extravascular clots and thrombi.

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“…Platelet activation (%) was determined as the ratio of CD62P positive population of CD31/CD41 double-positive events as described previously. [19, 20] Percent microaggregate formation was determined by the upshift in fluorescence intensity in CD31/CD41 double-positive events. To measure platelet GPIbα levels, platelets were incubated with 1:50 dilution of mouse anti-human monoclonal AK2 primary antibody for 30 minutes at RT followed by 30 minutes incubation with 1:50 final dilution of anti-CD41-PE and anti-CD31-eFluor450 and 1:1000 final dilution of anti-mouse IgG-AF640 secondary antibody.…”

Section: Methodsmentioning

confidence: 99%

Effect of Pneumatic Tubing System Transport on Platelet Apheresis Units

Zilberman‐Rudenko

Zhao

Reitsma

et al. 2018

Cardiovasc Eng Tech

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Platelet apheresis units are transfused into patients to mitigate or prevent bleeding. In a hospital, platelet apheresis units are transported from the transfusion service to the healthcare teams via two methods: a pneumatic tubing system (PTS) or ambulatory transport. Whether PTS transport affects the activity and utility of platelet apheresis units is unclear. We quantified the gravitational forces and transport time associated with PTS and ambulatory transport within our hospital. Washed platelets and supernatants were prepared from platelet apheresis units prior to transport as well as following ambulatory or PTS transport. For each group, we compared resting and agonist-induced platelet activity and platelet aggregate formation on collagen or von Willebrand factor (VWF) under shear, platelet VWF-receptor expression and VWF multimer levels. Subjection of platelet apheresis units to rapid acceleration/deceleration forces during PTS transport did not pre-activate platelets or their ability to activate in response to platelet agonists as compared to ambulatory transport. Platelets within platelet apheresis units transported via PTS retained their ability to adhere to surfaces of VWF and collagen under shear, although platelet aggregation on collagen and VWF was diminished as compared to ambulatory transport. VWF multimer levels and platelet GPIb receptor expression was unaffected by PTS transport as compared to ambulatory transport. Subjection of platelet apheresis units to PTS transport did not significantly affect the baseline or agonist-induced levels of platelet activation as compared to ambulatory transport. Our case study suggests that PTS transport may not significantly affect the hemostatic potential of platelets within platelet apheresis units.

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Biorheology of Platelet Activation in the Bloodstream Distal to Thrombus Formation

Cited by 6 publications

References 24 publications

Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo

Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo

Activated Monocytes Enhance Platelet-Driven Contraction of Blood Clots via Tissue Factor Expression

Effect of Pneumatic Tubing System Transport on Platelet Apheresis Units

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