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Hypercoagulability of the blood might partially explain the increased cardiovascular disease risk in posttraumatic stress disorder (PTSD) and is also triggered by anticipatory stress. We hypothesized exaggerated procoagulant reactivity in patients with PTSD in response to a trauma-specific interview that would be moderated by momentary stress levels. We examined 23 patients with interviewer-diagnosed PTSD caused by myocardial infarction (MI) and 21 post-MI patients without PTSD. A second diagnostic (i.e., trauma-specific) interview to assess posttraumatic stress severity was performed after a median follow-up of 26 months (range 12-36). Before that interview patients rated levels of momentary stress (Likert scale 0-10) and had blood collected before and after the interview. The interaction between PTSD diagnostic status at study entry and level of momentary stress before the follow-up interview predicted reactivity of fibrinogen (P=0.036) and d-dimer (P=0.002) to the PTSD interview. Among patients with high momentary stress levels, PTSD patients had greater fibrinogen (P=0.023) and d-dimer (P=0.035) reactivity than non-PTSD patients. Among patients with low momentary stress levels, PTSD patients had less d-dimer reactivity than non-PTSD patients (P=0.024); fibrinogen reactivity did not significantly differ between groups. Momentary stress levels, but not severity of posttraumatic stress, correlated with d-dimer reactivity in PTSD patients (r=0.46, P=0.029). We conclude that momentary stress levels moderated the relationship between PTSD and procoagulant reactivity to a trauma-specific interview. Procoagulant reactivity in post-MI patients with PTSD confronted with their traumatically experienced MI was observed if patients perceived high levels of momentary stress before the interview.

Acute psychosocial stress accelerates blood coagulation and elicits hemoconcentration which mechanisms are implicated in acute coronary thrombotic events. We investigated the extent to which the change in prothrombotic measures with acute stress reflects hemoconcentration and genuine activation of coagulation.Twenty-one middle-aged healthy men underwent three sessions of a combined speech and mental arithmetic task with one-week intervals. Coagulation and plasma volume were assessed at baseline, immediately post-stress, and 45 min post-stress at sessions one and three. Measures of both visits were aggregated to enhance robustness of individual biological stress responses. Changes in eight coagulation measures with and without adjustment for simultaneous plasma volume shift were compared.From baseline to immediately post-stress, unadjusted levels of fibrinogen (p=0.028), clotting factor VII activity (FVII:C) (p=0.001), FVIII:C (p0.001), FXII:C (p0.001), and von Willebrand factor (VWF) (p=0.008) all increased. Taking into account hemoconcentration, fibrinogen (p=0.020) and FVII:C levels (p=0.001) decreased, activated partial prothrombin time (APPT) shortened (p0.001) and prothrombin time (PT) was prolonged (p0.001). Between baseline and 45 min post-stress, unadjusted (p=0.050) and adjusted (p=0.001) FVIII:C levels increased, adjusted APTT was prolonged (p=0.017), and adjusted PT was shortened (p=0.033). D-dimer levels did not significantly change over time.Adjustment for stress-hemoconcentration altered the course of unadjusted levels of several prothrombotic factors. After adjustment for hemoconcentration, APPT was shortened immediately post-stress, whereas 45 min post-stress, FVIII:C was increased and PT was shortened. Procoagulant changes to acute stress may reflect both hemoconcentration and genuine activation of coagulation molecules and pathways.

Psychosocial stress might increase the risk of atherothrombotic events by setting off an elevation in circulating levels of the proinflammatory cytokine interleukin (IL)-6. We investigated the effect of aspirin and propranolol on the responsiveness of plasma IL-6 levels to acute psychosocial stress. For 5 days, 64 healthy subjects were randomized, double-blind, to daily oral aspirin 100mg plus long-acting propranolol 80 mg, aspirin 100mg plus placebo, long-acting propranolol 80 mg plus placebo, or placebo plus placebo. Thereafter, all subjects underwent the 13-min Trier Social Stress Test, which combines a preparation phase, a job interview, and a mental arithmetic task. Plasma IL-6 levels were measured in blood samples collected immediately pre- and post-stress, and 45 min and 105 min thereafter. The change in IL-6 from pre-stress to 105 min post-stress differed between subjects with aspirin medication and those without (p =0.033; eta p2=0.059). IL-6 levels increased less from pre-stress to 105 min post-stress (p

Objective: The study was conducted to determine activation of coagulation in patients undergoing open and endovascular infrarenal abdominal aortic aneurysm repair (EVAR).Methods: In a prospective, comparative study, 30 consecutive patients undergoing open repair (n = 15) or EVAR (n = 15) were investigated. Blood samples to determine fibrinopeptide A, fibrin monomer, thrombin-antithrombin complex, and D-dimer were taken up to 5 days postoperatively. Routine hematologic and hematochemical parameters as well as clinical data were collected.Results: Both groups showed comparable demographic variables. Operating time was longer in open repair (249 +/- 77 minutes vs 186 +/- 69 minutes, P < .05). Perioperatively elevated markers of coagulation were measured in both groups. Fibrinopeptide A levels did not differ significantly between the groups (P = .55). The levels of fibrin monomer and thrombin-antithrombin complex were significantly higher in patients undergoing EVAR (P < .0001), reflecting increased thrombin activity and thrombin formation compared with open surgery. The D-dimer level did not differ significantly between the groups. These results were also valid after correction for hemodilution.Conclusion: These data suggest increased procoagulant activity in EVAR compared with open surgery. A procoagulant state may favor possible morbidity derived from micro- and macrovascular thrombosis, such as in myocardial infarction, multiple organ dysfunction, venous thrombosis and thromboembolism, or disseminated intravascular coagulation.

Background In unstable angina, the clinical efficacy of heparin is limited in time, and recurrence of adverse events has been reported after discontinuation of the anticoagulant. Methods In 21 episodes of unstable angina, we used the plasma level of fibrinopeptide A (FPA) and of thrombin-antithrombin complex (TAT) to evaluate the pattern of thrombin inhibition by heparin and the effect of stopping heparin and initiating aspirin. Results At admission, the plasma level of FPA was increased: median value 3.7 ng/mL compared with 5.5 ng/mL in a control group of 20 patients with early myocardial infarction (not significant). The following findings were observed during a 4-day course of intravenous heparin infusion: (1) FPA decreased significantly 6 hours after the start of therapy; (2) FPA was lower when activated partial thromboplastic time (aPTT) was >1.5 times baseline; (3) there was a significant negative correlation between aPTT and FPA. Twenty-four hours after heparin was discontinued and aspirin initiated, a significant increase in TAT and FPA in plasma was observed. Conclusions The results confirm ongoing fibrin formation in the active phase of unstable angina, indicate incomplete and variable inhibition of thrombin by heparin during continuous infusion, and suggest a risk of re-emergence of thrombosis (in spite of initiating aspirin) 24 hours after withdrawal of heparin. Data demonstrate a better control of thrombin activity when heparin is infused at rates that maintain aPTT at >1.5 times baseline, as currently recommended in unstable angina. (Am Heart J 1998;136:1106-13.)

The increased risk of venous thromboembolic disease after journeys of long duration, particularly after air flights [1,2], is believed to be the consequence of a combination of multiple factors [3,4]. Among these, venous stasis in the legs induced by the seated position is considered a main causal element in thrombus formation [5,6]. In a previous study we simulated immobilization during a long trip by keeping healthy subjects in a seated position for 6 h. There was no activation of the coagulation system, but we observed a significant decrease of prothrombin fragment 1+2 (F1+2) consistent with reduced thrombin formation [7]. More recently, Hodkinson et al. again observed a significant reduction of coagulation activation markers after 3 h of immobile sitting in a control group of healthy subjects [8]. The aim of the present study was to investigate in a different and, to our knowledge, original model whether artificially provoked venous stasis induces an activation of the coagulation system in vivo. Ten healthy male volunteers (mean age 34 years, range 26– 47 years) without risk factors for thromboembolism were included after having signed informed consent. The study was approved by the local ethics committee. After a 15-min rest, venous blood stasis was induced in both legs by applying a pressure cuff around the thigh inflated to 50 mmHg for 30 min. Blood was collected in CTADPPACK anticoagulant from an antecubital vein prior to cuff inflation (08.00 h, baseline), and after 15 and 30 min of stasis. The blood samples were put on ice, immediately centrifuged and stored at )80 C until measurement of F1+2, a marker of thrombin generation (Enzygnost F1+2; Behring, Marburg, Germany) and fibrinopeptide A (FPA), a marker of ongoing fibrin formation (radioimmunoassay reagents supplied by Imco, Stockholm, Sweden). Statistical probability was assessed by ANOVA on ranks, and single time-points were compared by Wilcoxon signed rank test. A two-tailed P < 0.05 was considered significant. The results are summarized in Table 1. All values were within the normal range. Over a period of 30 min a significant decrease in the plasma level of F1+2 (from a median of 0.46 to 0.43 nmol L, P 1⁄4 0.027) was observed, whereas FPA levels did not change. We found good intrapersonal correlation of F1+2 between the three time points (r between 0.62 and 0.79, P < 0.01). There was no artefactually elevated value for FPA. Taken together, the data indicate that the markers were reflecting true basal coagulation activity of each individual at the single time points. With a different and original experimental model of venous stasis we were able to replicate the results of our previous study [7], which indicated decreased thrombin generation during prolonged sitting. The design of the present study renders improbable any influence of circadian fluctuation or stress factors on the coagulation system, pointing to venous stasis as the causal factor for decreased F1+2 concentration. On extrapolation, these results suggest that the F1+2 decrease we previously observed during sitting was mostly the consequence of venous stasis. The decline in thrombin generation after venous stasis is at variance with common concepts and is difficult to interpret. It is known, however, that thrombin has anticoagulant activities in an intact vascular bed by its role in the protein C pathway, one of the important regulatory mechanisms of blood coagulation in vivo [9]. Downregulation of thrombin generation could therefore lead to a decrease in activated protein C, and thus to a disequilibrium between proand anticoagulant factors. Furthermore, thrombin by itself or together with thrombomodulin plays a role in the fibrinolytic system by activating the thrombin activatable fibrinolysis inhibitor (TAFI) [10]. Nevertheless, it is difficult to assess the influence of variations in thrombin concentration within its normal range on TAFI activation due to the lack of data in literature from studies in vivo. At least, it remains hypothetical whether and to what extent the decreased thrombin generation associated with prolonged sitting or with artificially induced venous stasis represents a prothrombotic state, and can thus be of relevance in the pathogenesis of travel-associated thrombosis. Correspondence: Hans Stricker, Servizio di Angiologia, Reparto di Medicina Interna, Ospedale Regionale di Locarno, CH-6600 Locarno, Switzerland. Tel.: +41 9 1811 4549; fax: +41 9 1811 4783; e-mail: hans.stricker@ eoc.ch

We have studied in vitro the effects of altered physicochemical properties of thyroglobulin molecules in solution and of the solution itself on iodination kinetics and hormone synthesis. Any change in hydrodynamic properties had a far greater effect in compartmentalized systems, obtained by coating the test tubes with peroxidase, than in conventional homogeneously mixed systems. Increasing thyroglobulin concentration in a range still far below that existing in vivo greatly retarded iodination and hormone synthesis. In contrast, a number of physiological and non-physiological changes of thyroglobulin structure, such as desialylation, preiodination, oxidation and denaturation, strikingly accelerated iodination. The highly variable physical-chemical state of thyroglobulin molecules appears to be a main determinant of protein diffusion within the colloid and, thereby, of iodination kinetics and rate of hormone synthesis. Moreover, alterations of the physicochemical state of thyroglobulin molecules may explain some hitherto ill-understood diffusion phenomena in live follicles.

The density of in vitro iodinated thyroglobulin (Tgb) molecules, measured by isopycnic centrifugation, increases linearly with their iodine content. In contrast, the iodine to density (I:D) regression for differently iodinated native rat Tgbs is not constant but varies, depending on experimental conditions: For LID-fed rats the slope of the individual I:D regression line of each Tgb decreases linearly with the decreasing mean degree of iodination of the sample (r = 0.9104, P less than 0.01). On the other hand, in Tgb samples synthesized by propylthiouracil-blocked glands, the I:D regression is no longer linear. Rather, a bimodal pattern is obtained revealing a preexisting highly iodinated Tgb pool together with newly synthesized, non-iodinated protein. The results indicate: (a) the mean degree of iodination of a native Tgb cannot be estimated accurately if only its mean density is known, and (b) the degree of heterogeneity of iodination is identical for any in vivo produced Tgb sample with the same iodine content.