Dysfunctional platelet membrane receptors: From humans to mice

The Room Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Hemostasis and Thrombosis, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
Thrombosis and Haemostasis (Impact Factor: 4.98). 10/2004; 92(3):478-85. DOI: 10.1267/THRO04090478
Source: PubMed


Insights into hemostasis and thrombosis have historically benefited from the astute diagnosis of human bleeding and thrombotic disorders followed by decades of careful biochemical characterization. This work has set the stage for the development of a number of mouse models of hemostasis and thrombosis generated by gene targeting strategies in the mouse genome. The utility of these models is the in depth analysis that can be performed on the precise molecular interactions that support hemostasis and thrombosis along with efficacy testing of various therapeutic strategies. Already the mouse has proven to be an excellent model of the processes that support hemostasis and thrombosis in the human vasculature. A brief summary of the salient phenotypes from knockout mice missing key platelet receptors is presented, including the glycoprotein (GP) Ib-IX-V and GP IIb/IIIa (alphaIIb/beta3) receptors; the collagen receptors, GP VI and alpha2/beta1; the protease activated receptors (PARs); and the purinergic receptors, P2Y(1) and P2Y(12). A few differences exist between mouse and human platelets and where appropriate those will be highlighted in this review. Concluding remarks focus on the importance of understanding the power and limitations of various in vitro, ex vivo and in vivo models currently being used and the impact of the mouse strain on the described platelet phenotype.

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    • "The potential important advantage of using a rabbit aneurysmal SAH model to investigate microthrombosis formation postaneurysmal SAH is the fact that the rabbit coagulation system is very similar to that in humans [21, 22]. Human-resemblance of larger animals makes them an attractive tool to provide new insights into the study of microvascular thrombosis [23, 24]. "
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    ABSTRACT: Background. Microvascular dysfunction and microthrombi formation are believed to contribute to development of early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (SAH). Objective. This study aimed to determine (i) extent of microthrombus formation and neuronal apoptosis in the brain parenchyma using a blood shunt SAH model in rabbits; (ii) correlation of structural changes in microvessels with EBI characteristics. Methods. Acute SAH was induced using a rabbit shunt cisterna magna model. Extent of microthrombosis was detected 24 h post-SAH (n = 8) by fibrinogen immunostaining, compared to controls (n = 4). We assessed apoptosis by terminal deoxynucleotidyl transferase nick end labeling (TUNEL) in cortex and hippocampus. Results. Our results showed significantly more TUNEL-positive cells (SAH: 115 ± 13; controls: 58 ± 10; P = 0.016) and fibrinogen-positive microthromboemboli (SAH: 9 ± 2; controls: 2 ± 1; P = 0.03) in the hippocampus after aneurysmal SAH. Conclusions. We found clear evidence of early microclot formation in a rabbit model of acute SAH. The extent of microthrombosis did not correlate with early apoptosis or CPP depletion after SAH; however, the total number of TUNEL positive cells in the cortex and the hippocampus significantly correlated with mean CPP reduction during the phase of maximum depletion after SAH induction. Both microthrombosis and neuronal apoptosis may contribute to EBI and subsequent DCI.
    Full-text · Article · Jul 2014 · BioMed Research International
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    • "We are aware of the limitation of our model system which includes a significant interspecies difference in structure and/or isoforms of proteins expressed on mPLTs versus hPLTs that could affect hPLT adhesion and aggregation [29] in a mouse model. Ultrastructurally, the similarities are much greater than the differences [30]. Most hPLT agonists, such as arachidonate, thrombin, collagen and ADP, can be used to activate mPLTs [31], [32]. "
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    ABSTRACT: We previously reported that ultraviolet light B (UVB)-treated human platelets (hPLTs) can cause acute lung injury (ALI) in a two-event SCID mouse model in which the predisposing event was Lipopolysaccharide (LPS) injection and the second event was infusion of UVB-treated hPLTs. To delineate contributions of host mouse platelets (mPLTs) and neutrophils in the pathogenesis of ALI in this mouse model, we depleted mPLTs or neutrophils and measured hPLT accumulation in the lung. We also assessed lung injury by protein content in bronchoalveolar lavage fluid (BALF). LPS injection followed by infusion of UVB-treated hPLTs resulted in sequestration of both mPLTs and hPLTs in the lungs of SCID mice, although the numbers of neutrophils in the lung were not significantly different from the control group. Depletion of mouse neutrophils caused only a mild reduction in UVB-hPLTs accumulation in the lungs and a mild reduction in protein content in BALF. In comparison, depletion of mPLTs almost completely abolished hPLTs accumulation in the lung and significantly reduced protein content in BALF. UVB-treated hPLTs bound to host mPLTs, but did not bind to neutrophils in the lung. Aspirin treatment of hPLTs in vitro abolished hPLT accumulation in the lung and protected mice from lung injury. Our data indicate that host mPLTs accumulated in the lungs in response to an inflammatory challenge and subsequently mediated the attachment of transfused UVB-hPLTs. Neutrophils also recruited a small percentage of platelets to the lung. These findings may help develop therapeutic strategies for ALI which could potentially result from transfusion of UV illuminated platelets.
    Full-text · Article · Sep 2012 · PLoS ONE
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    • "We and others, by using large animal models of thrombosis, have supported the hypothesis that vessel wall-derived TF is a primary contributor to arterial thrombus formation and propagation, yet, blood-borne TF may also contribute depending on the triggering lesion and the shear rate [23] [24]. Besides all this, an accurate in-depth determination of the mouse haemostatic system (i.e., coagulation and fibrinolytic systems, platelet structure, and platelet receptor/enzyme system) is still lacking, as nicely reviewed by Tsakiris et al, [25] and Ware [26], and species-related differences between rodents and humans should also be considered before interpreting the data. For instance, platelet counts in mice on average are four times those of humans and platelets are only approximately one half the volume of human platelets. "
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    ABSTRACT: Atherosclerosis and its thrombotic complications are responsible for remarkably high numbers of deaths. The combination of in vitro, ex vivo, and in vivo experimental approaches has largely contributed to a better understanding of the mechanisms underlying the atherothrombotic process. Indeed, different animal models have been implemented in atherosclerosis and thrombosis research in order to provide new insights into the mechanisms that have already been outlined in isolated cells and protein studies. Yet, although no model completely mimics the human pathology, large animal models have demonstrated better suitability for translation to humans. Indeed, direct translation from mice to humans should be taken with caution because of the well-reported species-related differences. This paper provides an overview of the available atherothrombotic-like animal models, with a particular focus on large animal models of thrombosis and atherosclerosis, and examines their applicability for translational research purposes as well as highlights species-related differences with humans.
    Full-text · Article · Jan 2011 · BioMed Research International
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