We have previously shown functional differences in fibrinogen from hyperhomocysteinemic rabbits compared to that in control rabbits. This acquired dysfibrinogenemia is characterized by fibrin clots that are composed of abnormally thin, tightly packed fibers with increased resistance to fibrinolysis. Homocysteine thiolactone is a metabolite of homocysteine (Hcys) that can react with primary amines. Recent evidence suggests that Hcys thiolactone-lysine adducts form in vivo. We now demonstrate that the reaction of Hcys thiolactone with purified fibrinogen in vitro produces fibrinogen (Hcys fibrinogen) with functional properties that are strikingly similar to those we have observed in homocysteinemic rabbits. Fibrinogen purified from homocysteinemic rabbits and Hcys fibrinogen are similar in that (1) they both form clots composed of thinner, more tightly packed fibers than their respective control rabbit and human fibrinogens; (2) the clot structure could be made to be more like the control fibrinogens by increased calcium; and (3) they both form clots that are more resistant to fibrinolysis than those formed by the control fibrinogens. Further characterization of human fibrinogens showed that Hcys fibrin had similar plasminogen binding to that of the control and an increased capacity for binding tPA. However, tPA activation of plasminogen on Hcys fibrin was slower than that of the control. Mass spectrometric analysis of Hcys fibrinogen revealed twelve lysines that were homocysteinylated. Several of these are close to tPA and plasminogen binding sites. Lysines are major binding sites for fibrinolytic enzymes and are also sites of plasmin cleavage. Thus, modification of lysines in fibrinogen could plausibly lead to impaired fibrinolysis. We hypothesize that the modification of lysine by Hcys thiolactone might occur in vivo, lead to abnormal resistance of clots to lysis, and thereby contribute to the prothrombotic state associated with homocysteinemia.

Objective A recent investigation at Barnes-Jewish Hospital located in St. Louis, Missouri, found that an estimated 22% of adults presenting for inpatient surgery screened as high risk for obstructive sleep apnea (OSA). Surgical patients with OSA have multiple comorbidities and are at increased risk for perioperative complications. Our objective was to determine whether a prior diagnosis of OSA, or a positive screen for OSA is associated with increased risk for 30 days and one year mortality. Methods B-J APNEAS (Barnes-Jewish Apnea Prevalence in Every Admission Study) was a prospective cohort study. Unselected adult surgical patients at Barnes Jewish Hospital were prospectively enrolled between February 2006 and April 2010. All patients completed preoperative OSA screening and those who were at risk for OSA according to a combination of the Berlin and Flemons screening tools received targeted postoperative interventions. STOP and STOP-BANG scores were also obtained. Results Overall, the sample included 14,962 patients, of whom 1,939 (12.9%) reported a history of OSA. All four screening tools identified a high prevalence of undiagnosed patients at risk for OSA (9.5% to 41.6%), but agreement among screens was not strong with Kappa ranging from 0.225 to 0.611. There was no significant difference in 30 day postoperative mortality between patients with possible OSA (based on their history or on a positive OSA screen with any of the four instruments) and the rest of the surgical population. Significant differences in one-year mortality were noted between the low and high-risk groups as identified by the Flemons’ (4.96% versus 6.91%; p <0.0001), STOP (5.28% versus 7.57%; p <0.0001) and STOP-BANG (4.13% versus 7.45%; p <0.0001) screens. After adjusting for risk factors, none of the OSA screening tools independently predicted mortality rate up to one year postoperatively. Conclusion Neither a prior diagnosis of OSA, or a positive screen for OSA risk was associated with increased 30 day or one year postoperative mortality. It is possible that incorporating OSA screening and patient safety measures into routine care mitigated the early postoperative complications in this patient cohort. The results of this study highlight uncertainties and research priorities for the medical community.