The major hypothesis of this clinical investigation is that low levels of free protein S, a natural anticoagulant protei in plasma, are associated with an increased incidence of myocardial infarction in middle aged men. Free protein S (that portion of plasma protein S which is not in complex with C4b binding protein) is a cofactor for the anticoagulant effect of activated protein C. Patients presenting with acute myocardial infarction have significantly reduced levels of free protein S. This investigation will determine in a blinded, prospective fashion, if low levels of free protein S are associated with an increased incidence of myocardial infarction. Plasma samples will be obtained yearly for 5 years from 2,350 men aged 50-59 years who will be participants in the Second Northwick Park Heart Study sponsored by the British Medical Research Council Epidemiology and Medical Care Unit. Clinical endpoints for the study will be documented fatal and non-fatal myocardial infarction. To prevent potential bias, this laboratory will be blinded to the clinical endpoints until all samples have been collected and all causes of death in the study population have been adjudicated. ln addition to free protein S, total protein S and C4b binding protein will be measured. The study design will permit the assessment of the temporal relationship between the development of low free protein S levels and the occurrence of myocardial infarction and the presence or absence of a biologic gradient (dose-response) between levels of free protein S and the frequency of infarction. These two analyses are important in assessing whether the observed association is causal or whether low protein S occurs as a consequence of myocardial infarction. Three levels of free protein S have been defined prior to initiating the study to determine if the frequency of myocardial infarction does follow a biologic gradient. The measurement of other potential markers of risk by other laboratories, such as prothrombin fragment Fl+2 and factor X activation peptide, will permit a comprehensive evaluation of hemostatic risk factors in myocardial infarction. If the major hypothesis proves correct, patients at high risk of myocardial infarction can be identified and can be targeted for future studies to examine specific intervention therapy. A second study will be conducted in women to examine protein S as a risk factor for myocardial infarction.
| D'Angelo, A; Vigano-D'Angelo, S; Esmon, C T et al. (1988) Acquired deficiencies of protein S. Protein S activity during oral anticoagulation, in liver disease, and in disseminated intravascular coagulation. J Clin Invest 81:1445-54 |
| Esmon, N L; D'Angelo, A; Vigano-D'Angelo, S et al. (1987) Analysis of protein C and protein S in disease states. Dev Biol Stand 67:75-82 |
| Comp, P C; Thurnau, G R; Welsh, J et al. (1986) Functional and immunologic protein S levels are decreased during pregnancy. Blood 68:881-5 |
| Vigano D'Angelo, S; Comp, P C; Esmon, C T et al. (1986) Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states. J Clin Invest 77:416-25 |
