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Criteria for distinguishing among etiologies of thrombocytosis are limited in their capacity to delineate clonal (essential thrombocythemia [ET]) from nonclonal (reactive thrombocytosis [RT]) etiologies.We studied platelet transcript profiles of 126 subjects (48 controls, 38 RT, 40 ET [24 contained the JAK2V 617 F mutation]) to identify transcript subsets that segregated phenotypes. Cross-platform consistency was validated using quantitative real-time polymerase chain reaction (RT-PCR). Class prediction algorithms were developed to assign phenotypic class between the thrombocytosis cohorts, and by JAK2 genotype. Sex differences were rare in normal and ET cohorts (< 1% of genes) but were male-skewed for approximately 3% of RT genes. An 11-biomarker gene subset using the microarray data discriminated among the 3 cohorts with 86.3% accuracy, with 93.6% accuracy in 2-way class prediction (ET vs RT). Subsequent quantitative RT-PCR analysis established that these biomarkers were 87.1% accurate in prospective classification of a new cohort. A 4-biomarker gene subset predicted JAK2 wild-type ET in more than 85% patient samples using either microarray or RT-PCR profiling, with lower predictive capacity in JAK2V 617 F mutant ET patients. These results establish that distinct genetic biomarker subsets can predict thrombocytosis class using routine phlebotomy. (Blood. 2010;115:7-14) IntroductionPlatelets mediate the initial first step in hemostasis while simultaneously providing the negatively charged phospholipid surface required for contact phase-mediated propagation of the coagulation cascade. Despite these key functions, molecular defects causally implicated in platelet-associated bleeding or thrombotic risk are largely unknown, best characterized by loss of glycoproteins (GP) IIb/IIIa (␣ IIb ␤ 3 ; Glanzmann thrombasthenia) or the GPIb-IX-V complex (Bernard-Soulier syndrome). 1 Similarly, protein overexpression may favor platelet activation and thrombus formation, providing conceptual support for the presence of biomarkers that may confer enhanced thrombosis susceptibility risk. Thus, polymorphisms within the ITGA2 gene encoding the ␣2 polypeptide of the heterodimeric ␣ 2 ␤ 1 collagen receptor increase receptor surface density and are associated with an increased risk of ischemic heart disease in homozygotes (especially smokers), 2,3 although confirmatory results using meta-analyses for a distinct subset of hemostatic proteins have been somewhat disappointing. 4,5 Similarly, platelet membrane polymorphisms have been linked to stroke in small studies, but the evidence is not strong. [6][7][8][9] Such studies highlight the relevance of identifying additional gene/protein biomarkers that may be causally linked to clinically relevant platelet phenotypes.Platelets retain megakaryocyte-derived mRNA, although the platelet transcriptome is less complex than that of nucleated cells. 10,11 Furthermore, platelets have evolved unique adaptive molecular signals for maintenance of genetic and protein diversity. 12 Quiescent platelets...

The prevalence of immunologic and coagulation disorders in 75 schizophrenic patients treated with chlorpromazine or other antipsychotic drugs was evaluated. Four groups were studied: Group A, chlorpromazine treatment for more than 2 1/2 years; Group B, chlorpromazine and other antipsychotic drug treatment for more than 2 1/2 years; Group C, chlorpromazine treatment for less than 2 1/2 years; Group D, no chlorpromazine, but other antipsychotic drug treatment. Significant elevation of serum IgM and prolongation of partial thromboplastin time were noted in patients who had long-term chlorpromazine treatment. The latter was caused by a circulating inhibitor resembling that seen with systemic lupus erythematosus. There was a significant correlation between the IgM level versus chlorpromazine dose or duration of treatment and the partial thromboplastin time versus chlorpromazine dose or duration of treatment. In Groups A and B, 63% had a positive antinuclear antibody test (greater than or equal to 1:80), 40% had antibodies to native DNA, and 58% had antibodies to nucleoprotein. These antibodies were negative in the other groups. The percentages of T lymphocytes were below normal in 13 of 41 patients treated with chlopromazine. Twenty of 42 patients in Groups A and B, and none of 28 in Groups C and D had splenomegaly. This study indicates that most patients on long-term chlorpromazine treatment develop one or more immunologic abnormalities.

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