Large-scale, high-throughput screening for coagulation and hematologic phenotypes in mice*

Peters, Luanne L.; Cheever, Eleanor M.; Ellis, Heather R.; Magnani, Phyllis A.; Svenson, Karen L.; Smith, R. V.; Bogue, Molly A.

doi:10.1152/physiolgenomics.00077.2002

Cited by 81 publications

(69 citation statements)

References 9 publications

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“…49 The normal phenotypic variation seen among the inbred strains for these and other hematologic values, including the MCV, is clear evidence for genetic determinants in mice as well, 50 and we have identified QTL for MCV in crosses between normal inbred strains (L.L.P and G.A.C., unpublished data, November 2003). Moreover, variation in hematologic parameters is known to affect disease severity.…”

Section: Discussionmentioning

confidence: 77%

Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency

Peters

Swearingen

Andersen

et al. 2004

Blood

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IntroductionHereditary spherocytosis (HS) is the most common inherited hemolytic anemia in people of Northern European descent, occurring with a frequency of approximately 1 in 2000. 1 HS is caused by defects in the red blood cell (RBC) membrane skeleton, a multiprotein structure located just beneath the lipid bilayer that imparts mechanical strength and elasticity to the RBC membrane. The major component of the membrane skeleton, spectrin, is present as tetramers of ␣-and ␤-subunits cross-linked into a 2-dimensional array by short actin filaments. [1][2][3] There are 2 major interactions between membrane skeleton components and integral membrane proteins that attach the spectrin array to the plasma membrane: (1) band 3-spectrin-ankyrin-protein 4.2 and (2) protein 4.1-p55-glycophorin C linkages. [4][5][6][7][8] The band 3-spectrin-ankyrin-protein 4.2 interactions are critical in the pathogenesis of HS. Defects in all of these proteins cause HS in humans and in mice. 1,9,10 Recent estimates are that approximately 50% of the mutations causing HS in European populations are in ankyrin, 20% in band 3, 20% in ␤-spectrin, 5% in protein 4.2, and less than 5% in ␣-spectrin. 1 Depending on the exact genetic defect, the hematologic phenotype varies from asymptomatic to life-threatening hemolysis requiring transfusion therapy and/or splenectomy. Secondary complications of HS include jaundice, gallstones, aplastic crises, and, more rarely, extramedullary hematopoietic masses and leg ulcers. 1 In the ankyrin-deficient nb mouse, progressive ataxia due to Purkinje cell degeneration occurs. 11 In other mouse models of HS, thrombosis and infarction are significant complicating factors. 12 Many specific molecular defects that cause HS in humans have been described. 1 Notably, as in other heritable syndromes, the clinical presentation varies significantly even among individuals with identical gene defects, illustrating the profound effects of genetic background on disease severity. 10 Identifying genetic modifiers by linkage analysis in humans is often difficult, if not impossible, due to environmental influences, genetic diversity, and small population (linkage group) size. Inbred mice, however, provide powerful tools for complex trait analysis. Moreover, as concordance between quantitative trait loci (QTL) in the mouse and human has been demonstrated for several diseases, complex trait analysis in the mouse has significant biomedical relevance. 13,14 Here, we describe a new spontaneous HS mutation in the mouse, wan, which arose on the C3H/HeJ (C3H) inbred strain, and identify QTL that modify the severity of the HS phenotype. Homozygous wan mice are severely anemic. A premature stop codon in the gene encoding erythroid band 3, Slc4a1 (solute carrier family 4 [anion exchanger], member 1; formerly Ae1, anion exchanger 1), results in complete deficiency of band 3 in homozygotes. In hybrid wan/wan newborns derived from F2 intercrosses between C3H wan/ϩ and Mus musculus castaneus (CAST/Ei), marked Reprints: Luanne L. Peters, The Jacks...

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Section: Discussionmentioning

confidence: 77%

Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency

Peters

Swearingen

Andersen

et al. 2004

Blood

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“…Coagulation assays were performed on the BCS-XP coagulation analyzer (Siemens) using reagents from the manufacturer and adapted procedures for mouse coagulation testing. 25 Mouse fibrinogen concentrations were measured by the functional Clauss method, using diluted thrombin reagent, calibrated with standard human plasma. Activated partial thromboplastin time and prothrombin time were measured by addition of CaCl 2 /contact activator (Actin FS) mixture or thromboplastin (Innovin), respectively.…”

Section: In Vivo Study: Mouse Thromboembolism Modelmentioning

confidence: 99%

Evaluation of the profibrinolytic properties of an anti-TAFI monoclonal antibody in a mouse thromboembolism model

Vercauteren¹,

Emmerechts

Peeters³

et al. 2011

Blood

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The enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. Activated thrombin activatable fibrinolysis inhibitor (TAFIa) attenuates fibrinolysis and is an attractive target to develop profibrinolytic drugs. TAFI can be activated by thrombin, thrombin/thrombomodulin, or plasmin, but the in vivo physiologic TAFI activator(s) are unknown. Here, we generated and characterized MA-TCK26D6, a monoclonal antibody raised against human TAFI, and examined its profibrinolytic properties in vitro and in vivo. In vitro, MA-TCK26D6 showed a strong profibrinolytic effect caused by inhibition of the plasmin-mediated TAFI activation. In vivo, MA-TCK26D6 significantly decreased fibrin deposition in the lungs of thromboembolism-induced mice. Moreover, in the presence of MA-TCK26D6, plasmin-␣ 2 -antiplasmin complexes in plasma of thromboembolism-induced mice were significantly increased compared with a control antibody, indicative of an acceleration of fibrinolysis through MA-TCK26D6. In this study, we show that plasmin is an important TAFI activator that hampers in vitro clot lysis. Furthermore, this is the first report on an anti-TAFI monoclonal antibody that demonstrates a strong profibrinolytic effect in a mouse thromboembolism model. (Blood. 2011;117(17): 4615-4622)

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“…In the absence of estradiol in acyclicity, female platelets are again more susceptible to thrombosis (Wong et al , 2008 ;Bailey et al , 2009 ). Platelets are indeed found to express ER β , which is hypothesized to have a direct effect on platelet function (Peters et al , 2002 ;Jayachandran and Miller , 2003 ;Bailey et al , 2009 ). Thus, it becomes clear that there are not only sex-based differences in coagulation processes but also age-based differences; as in a hypoestrogenic state, females not only have higher coagulation factors but also higher maximal platelet aggregation capabilities than males, rendering them more prone to thrombosis in an acyclic state.…”

Section: Neuroprotectionmentioning

confidence: 98%

“…It has been noted that both megakaryocytes and platelets express the estrogen receptor beta (ER β ) as well as the androgen receptor (Jayachandran and Miller , 2003 ;Bailey et al , 2009 ); thus, it is almost certain that the sex hormones have an effect on thrombosis. Estrogen is hypothesized to have a direct effect on platelet function, whereas androgen seems to regulate megakaryocyte biology and platelet production (Peters et al , 2002 ;Bailey et al , 2009 ).…”

Section: Thrombosismentioning

confidence: 99%

Interrelation between inflammation, thrombosis, and neuroprotection in cerebral ischemia

Spuy¹,

Pretorius²

2012

Reviews in the Neurosciences

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Stroke by mechanism of thrombotic cerebral ischemia is one of the leading causes of death and/or disability worldwide. Current research is under consensus that there are sex-based differences in both the prevalence and presentation of stroke and thrombosis. Here we discuss the interrelation between thrombosis and infl ammation and call attention to points in the cerebral ischemic cascade where estrogen may be involved in neuroprotection. Cerebral ischemia triggers a series of events including infl ammation, which is deeply interrelated with thrombosis; infl ammation not only produces local thrombosis, but thrombosis can also amplify infl ammation especially through the synergism of leukocyte and platelet activity. Research involving experimental animal models of cerebral ischemia has shown that sex hormones, especially estrogen, offer a degree of neuroprotection. Mechanisms of this neuroprotection may be linked to certain anti-infl ammatory properties of estrogen, as well as estrogen ' s regulation of thrombosis through the lowering of coagulation factors, among others. It is also understood that sex hormones alter the function and morphology of platelets and fi brin networks, and changes in platelet and fi brin network morphology offer one of the earliest confi rmations of infl ammation. Sex hormone levels, infl ammatory processes, and thrombotic mechanisms are profoundly interconnected in predicting the outcome of cerebral ischemia.

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Large-scale, high-throughput screening for coagulation and hematologic phenotypes in mice*

Cited by 81 publications

References 9 publications

Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency

Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency

Evaluation of the profibrinolytic properties of an anti-TAFI monoclonal antibody in a mouse thromboembolism model

Interrelation between inflammation, thrombosis, and neuroprotection in cerebral ischemia

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