Jamie M Walker

Florida Hospital, بالم كوست، فلوريدا, Florida, United States

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Publications (3)9.75 Total impact

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    ABSTRACT: It is established that experimental metastasis requires platelet activity. CD154 expressed on and released from activated platelets induces an inflammatory response in endothelial cells and monocytes, including tissue factor production. CD154 has also been shown to activate platelets in vitro and promote thrombus stability in vivo. These CD154 effects may be mediated, at least in part, by CD40 signaling on platelets and vascular endothelial cells. We have previously demonstrated prolonged bleeding and PFA-100 closure times in mice deficient for Cd154 or its receptor Cd40. In the present study, we hypothesized that Cd40 and Cd154 promote lung tumor formation in experimental metastasis in mice. We created mice doubly deficient in Cd40 and Cd154 (Dbl KO) and found them to be both fertile and viable. Injected tumor cells seeded poorly in mice deficient in Cd40 or Cd154, as well as Dbl KO, compared to wild-type mice. We sought to determine whether blood-borne Cd40 versus endothelial Cd40 contribute differentially to reduced experimental lung metastasis, as observed in Cd40 deficient mice. By bone marrow transplantation, we created mice deficient for Cd40 either in the blood compartment but not in the endothelium, or vice versa. We found that mice deficient in blood compartment Cd40 had fewer lung nodules compared to wild-type mice and mice deficient in endothelial Cd40. Our findings suggest an important contribution of the Cd40-Cd154 pathway to experimental lung metastasis. Furthermore, the data points to a selective role for peripheral blood cell Cd40 in this process.
    No preview · Article · Oct 2009 · Clinical and Experimental Metastasis
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    ABSTRACT: Patients with heparin-platelet factor 4 (PF4) antibodies, particularly platelet-activating ones, are at risk for heparin-induced thrombocytopenia if administered heparin. We determined the heparin-PF4 antibody prevalence in emergency department (ED) patients presenting with chest pain or symptoms of thrombosis. Admission samples from 324 ED patients with chest pain or symptoms of thrombosis were tested for heparin-PF4 antibodies and, if positive, platelet-activating antibodies. Twenty-four (7.4%; 95% confidence interval, 4.8%-10.8%) patients had heparin-PF4 antibodies. Seropositivity occurred in 18 (9.2%) of 196 patients recently (< or =6 months) hospitalized vs 6 (4.7%) of 128 not recently hospitalized (P = .19), and in 16/231 (6.9%) patients with chest pain vs 8/93 (8.6%) with other thrombosis (P = .64). Of 22 seropositive patients retested, 8 (7 recently hospitalized) had platelet-activating antibodies. Heparin-PF4 antibody prevalence is 7.4% in ED patients with chest pain or thrombosis, with approximately 1 in 3 seropositive patients having platelet-activating antibodies. Alternative, nonheparin anticoagulation would be prudent in these at-risk patients.
    No preview · Article · Mar 2007 · American Journal of Emergency Medicine
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    ABSTRACT: Our initial finding that CD40- and CD40 ligand (CD40L)-deficient mice displayed prolonged tail bleeding and platelet function analyzer (PFA-100) closure times prompted us to further investigate the role of the CD40-CD40L dyad in primary hemostasis and platelet function. Recombinant human soluble CD40L (rhsCD40L), chemical cross-linking of which suggested a trimeric structure of the protein in solution, activated platelets in a CD40-dependent manner as evidenced by increased CD62P expression. CD40 monoclonal antibody (mAb) M3, which completely blocked rhsCD40L-induced platelet activation, also prolonged PFA-100 closure times of normal human blood. In contrast, CD40 mAb G28-5 showed less potential in blocking rhsCD40L-induced CD62P expression and did not affect PFA-100 closure times. However, when added to the platelets after rhsCD40L, G28-5 significantly enhanced the platelet response by causing clustering of, and signaling through, FcgammaRII. Similarly, higher order multimeric immune complexes formed at a 1/3 molar ratio of M90, a CD40L mAb, to rhsCD40L induced strong Fcgamma RII-mediated platelet activation when translocated to the platelet surface in a CD40-dependent manner, including the induction of morphological shape changes, fibrinogen binding, platelet aggregation, dense granule release, microparticle generation and monocyte-platelet-conjugate formation. The results suggest that CD40 may play a role in primary hemostasis and platelet biology by two independent mechanisms: First, by functioning as a primary signaling receptor for CD40L and, second, by serving as a docking molecule for CD40L immune complexes. The latter would also provide a potential mechanistic explanation for the unexpected high incidence of CD40L mAb-associated thrombotic events in recent human and animal studies.
    No preview · Article · Jul 2005 · Thrombosis and Haemostasis