Background-A recent study showed that clopidogrel reduces thrombo-occlusive complications in patients with symptomatic atherosclerosis more effectively than aspirin. Methods and Results-The effects of clopidogrel and aspirin have been compared, singly and in combination, for measurements of 111 In-labeled platelets and 125 I-labeled fibrin deposition in baboon models of arterial thrombosis and related to platelet aggregation and expression of activation epitopes induced by ADP, collagen, and thrombin receptor agonist peptide (TRAP) and to template bleeding times (BTs). Low-dose oral clopidogrel (0.2 mg ⅐ kgIn-platelet and 125 I-fibrin deposition for segments of prosthetic vascular graft, deployed endovascular metallic stents, and endarterectomized aorta (PϽ0.009 in all cases); (2) elimination of ADP-induced platelet aggregation (PϽ0.001); (3) modest inhibition of collagen-induced platelet aggregation (PϽ0.01); (4) no reduction in TRAP-induced platelet aggregation; and (5) minimal prolongation of BTs (Pϭ0.03). High-dose oral clopidogrel (Ն2 mg/kg) produced the same effects within 3 hours. The effects of clopidogrel dissipated over 5 to 6 days. Aspirin 10 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 alone did not decrease 111 In-platelet and 125 I-fibrin deposition on segments of vascular graft but detectably decreased 111 In-platelet and 125 I-fibrin accumulation on stents (PϽ0.01), minimally inhibited ADP-and collagen-induced platelet aggregation (PϽ0.05 in both cases), and minimally prolonged BTs (Pϭ0.004). Within 3 hours of aspirin administration, the antithrombotic effects of acute high-dose or chronic low-dose clopidogrel were substantially enhanced, and BTs were modestly prolonged without inhibiting platelet aggregation induced by TRAP (PϽ0.001 in all cases compared with clopidogrel alone). Conclusions-Clopidogrel produces irreversible, dose-dependent, intermediate reduction in thrombosis that is substantially enhanced by the addition of aspirin. The effects of combining aspirin and clopidogrel need to be evaluated in patients at risk of vascular thrombosis. (Circulation. 1998;98:2461-2469.)

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Problem CD300a is an immunomodulatory molecule of the immunoglobulin receptor superfamily expressed in the leukocytes of myeloid and lymphoid lineages. However, its biological function on CD8+ T lymphocytes remains largely unknown. This study was conducted to assess the biological significance of CD300a expression in T lymphocytes and to determine whether its expression in peripheral T lymphocytes changes in pregnant women presenting with anti-fetal rejection. Methods of Study Microarray analysis was performed using total RNA isolated from peripheral CD300a+ and CD300a− T lymphocytes. Flow cytometric analysis of the peripheral blood samples of pregnant women and pathologic examination of the placentas were conducted. Results A large number of genes (N = 1,245) were differentially expressed between CD300a− and CD300a+ subsets of CD8+ T lymphocytes, which included CCR7, CD244, CX3CR1, GLNY, GZMB, GZMK, IL15, ITGB1, KLRG1, PRF1, and SLAMF7. Gene Ontology analysis of differentially expressed genes demonstrated enrichment of biological processes such as immune response, cell death, and signal transduction. CD300a expression in CD8+ T lymphocytes was coupled to a more cytotoxic molecular signature. Of note, the proportion of CD300a+CD8+ T lymphocytes increased in pregnant women with chronic chorioamnionitis (anti-fetal rejection of the chorioamniotic membranes; P < 0.05). Conclusion The findings of this study strongly suggest an increase of systemic T lymphocyte-mediated cytotoxicity in pregnant women with chronic chorioamnionitis as a manifestation of maternal anti-fetal rejection.

Thrombocytopenia has been characterized in six patients infected with human immunodeficiency virus (HIV) with respect to the delivery of viable platelets into the peripheral circulation (peripheral platelet mass turnover), marrow megakaryocyte mass (product of megakaryocyte number and volume), megakaryocyte progenitor cells, circulating levels of endogenous thrombopoietin (TPO) and platelet TPO receptor number, and serum antiplatelet glycoprotein (GP) IIIa49-66 antibody (GPIIIa49-66Ab), an antibody associated with thrombocytopenia in HIV-infected patients. Peripheral platelet counts in these patients averaged 46 ± 43 × 103/μL (P = .0001 compared to normal controls of 250 ± 40×  103/μL), and the mean platelet volume (MPV) was 10.5 ± 2.0 fL (P > 0.3 compared with normal control of 9.5 ± 1.7 fL). The mean life span of autologous111In-platelets was 87 ± 39 hours (P = .0001 compared with 232 ± 38 hours in 20 normal controls), and immediate mean recovery of 111In-platelets injected into the systemic circulation was 33% ± 16% (P = .0001 compared with 65% ± 5% in 20 normal controls). The resultant mean peripheral platelet mass turnover was 3.8 ± 1.5 × 105 fL/μL/d versus 3.8 ± 0.4 × 105 fL/μL/d in 20 normal controls (P > .5). The mean endogenous TPO level was 596 ± 471 pg/mL (P = .0001 compared with 95 ± 6 pg/mL in 98 normal control subjects), and mean platelet TPO receptor number was 461 ± 259 receptors/platelet (P = .05 compared with 207 ± 99 receptors/platelet in nine normal controls). Antiplatelet GPIIIa49-66Ab levels in sera were uniformly increased in HIV thrombocytopenic patients (P < .001). In this cohort of thrombocytopenic HIV patients, marrow megakaryocyte number was increased to 30 ± 15 × 106/kg (P = .02 compared with 11 ± 2.1 × 106/kg in 20 normal controls), and marrow megakaryocyte volume was 32 ± 0.9 × 103 fL (P = .05 compared with 28 ± 4.5 × 103 fL in normal controls). Marrow megakaryocyte mass was expanded to 93 ± 47 × 1010 fL/kg (P = .007 compared with normal control of 31 ± 5.3 × 1010 fL/kg). Marrow megakaryocyte progenitor cells averaged 3.3 (range, 0.4 to 7.3) CFU-Meg/1,000 CD34+ cells compared with 27 (range, 0.1 to 84) CFU-Meg/1,000 CD34+ cells in seven normal subjects (P = .02). Thus, thrombocytopenia in these HIV patients was caused by a combination of shortening of platelet life span by two thirds and doubling of splenic platelet sequestration, coupled with ineffective delivery of viable platelets to the peripheral blood, despite a threefold TPO-driven expansion in marrow megakaryocyte mass. We postulate that this disparity between circulating platelet product and marrow platelet substrate results from direct impairment in platelet formation by HIV-infected marrow megakaryocytes.