BACKGROUND

A sedentary lifestyle is a major risk factor for cardiovascular and thrombotic complications. While habitual endurance activity will reduce the risk of these adverse events, the influence of habitual resistance exercise is less clear. This study examined coagulation and fibrinolytic responses to an acute exhaustive resistance exercise test (AERET) in both resistance-trained (RT, min <em>2</em> yr, 5 men and 5 women) and untrained (UT, 5 men and 5 women) subjects.

METHODS

The AERET consisted of six sets of <em>1</em>0 repetitions of squats at 80% of <em>1</em>-repetition maximum. Venous blood was collected pre-exercise, immediate post exercise (IP), and +<em>1</em>5, +60, and +<em>1</em><em>2</em>0 minutes post exercise.

RESULTS

Compared to UT, RT exhibited a lower capacity to form a clot as seen by activated partial Thromboplastin time (aPTT) integrated area under the curve over time (iAUC) levels, lower pre-exercise and <em>1</em><em>2</em>0 min post-exercise plasminogen activator inhibitor -<em>1</em> (PAI-<em>1</em>) activity, and higher tissue plasminogen activator (tPA) activity immediately post-exercise. There were no significant differences between RT and UT for fibrinogen, <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> (PTF <em>1</em>+<em>2</em>), and thrombin-antithrombin complexes (TAT).

CONCLUSIONS

These results suggest that habitual resistance exercise training may provide an enhanced fibrinolytic state.

BACKGROUND

Whereas procoagulation abnormalities in acute stress are well established, little is known about the mechanism of hypercoagulation in chronic stress, such as post-traumatic stress disorder (PTSD). This is crucial, given the fact that chronic coagulation disturbances have been associated with increased morbidity and premature mortality due to thromboembolism and cardiovascular disorders, complications recently described in PTSD patients.

OBJECTIVE

To explore the mechanisms of hypercoagulation in chronic PTSD.

METHODS

Thirty patients diagnosed with chronic PTSD were enrolled and compared with a control group matched for age, gender and ethnicity. Hypercoagulation state was evaluated by levels of fibrinogen, D-dimer, <em>prothrombin</em> <em>fragment</em> F <em>1</em>+<em>2</em>, von Willebrand factor (vWF) antigen, factor VIII activity, activated protein C resistance, ProC Global assay, and tissue factor antigen. Psychiatric evaluation was performed using the Mini-International Neuropsychiatric Interview and Clinician Administered PTSD Scale (CAPS).

RESULTS

vWF antigen levels were significantly higher in patients with chronic PTSD compared with the controls (<em>1</em><em>2</em><em>1</em>.3 +/- 4<em>2</em> vs. 99.7 +/- <em>2</em>3, respectively, P = 0.034). Higher levels of vWF antigen and factor VIII activity were found in patients with severe chronic PTSD (CAPS>> 80), compared to controls and patients with chronic PTSD and less severe symptoms (CAPS < or = 80). However, no differences were observed in any other studied coagulation parameters between patients and controls.

CONCLUSIONS

Increased levels of vWF antigen and factor VIII activity were documented in severe chronic PTSD. These findings suggest that the higher risk of arterial and venous thromboembolic events in PTSD patients could be related to endothelial damage or endothelial activation.

OBJECTIVE

The hormonal components of combined oral contraceptives (COCs) have various metabolic and haemostatic effects. The objective of this study was to compare the metabolic and haemostatic effects of a novel COC comprising estradiol valerate/dienogest (E(<em>2</em>)V/DNG) with ethinylestradiol/levonorgestrel (EE/LNG).

METHODS

In a randomized, open-label study conducted in Germany over seven cycles, healthy women aged <em>1</em>8-50 years received E(<em>2</em>)V/DNG (E(<em>2</em>)V 3 mg on days <em>1</em>-<em>2</em>, E(<em>2</em>)V <em>2</em> mg/DNG <em>2</em> mg on days 3-7, E(<em>2</em>)V <em>2</em> mg/DNG 3 mg on days 8-<em>2</em>4, E(<em>2</em>)V <em>1</em> mg on days <em>2</em>5-<em>2</em>6, placebo on days <em>2</em>7-<em>2</em>8; n = 30) or EE/LNG (EE 0.03 mg/LNG 0.05 mg on days <em>1</em>-6, EE 0.04 mg/LNG 0.075 mg on days 7-<em>1</em><em>1</em>, EE 0.03 mg/LNG 0.<em>1</em><em>2</em>5 mg on days <em>1</em><em>2</em>-<em>2</em><em>1</em>, placebo on days <em>2</em><em>2</em>-<em>2</em>8; n = <em>2</em>8). The primary variables were the mean intraindividual relative changes from baseline to cycle 7 in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels. Changes in other lipid parameters, haemostatic parameters, sex hormone-binding globulin (SHBG), cortisol-binding globulin (CBG), carbohydrate metabolism parameters, blood pressure and body weight were also assessed.

RESULTS

Mean ± SD HDL cholesterol increased by 7.9% ± <em>2</em><em>1</em>.8% with E(<em>2</em>)V/DNG and decreased by <em>2</em>.3% ± <em>1</em>4.4% with EE/LNG. Mean ± SD LDL cholesterol decreased by 6.5% ± <em>1</em>5.9% with E(<em>2</em>)V/DNG and by 3.0% ± <em>1</em>7.4% with EE/LNG. Mean ± SD <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em> and D-dimer levels remained essentially unchanged in the E(<em>2</em>)V/DNG group (-0.6% ± 30.3% and -<em>2</em>.<em>1</em>% ± 43.5%, respectively), but increased in the EE/LNG group (by <em>1</em><em>1</em>7.3% ± 358.0% and 6<em>2</em>.9% ± 99.5%, respectively). Changes in other hepatic-induced parameters (SHBG, CBG) and carbohydrate metabolism were generally less pronounced with E(<em>2</em>)V/DNG versus EE/LNG. Body weight and blood pressure remained stable throughout the study in both treatment groups. Both formulations were well tolerated, with no serious adverse events reported.

CONCLUSIONS

E(<em>2</em>)V/DNG had a minimal impact on metabolic and haemostatic parameters, and a more favourable effect than EE/LNG on lipid markers.

BACKGROUND

ClinicalTrials.gov Identifier: NCT00<em>1</em>85<em>2</em><em>2</em>4.

OBJECTIVE

Anxiety disorders have been shown to be correlated with an activation of coagulation and impairment of fibrinolysis. The aim of the study was to assess whether medication with a serotonergic antidepressant, which has been associated with abnormal bleeding, may modify this effect.

METHODS

Thirty-one anxiety patients, mostly with comorbid depression, and 3<em>1</em> healthy controls were included in the study. Group differences between anxiety patients medicated with a serotonergic antidepressant, patients without serotonergic antidepressant and controls were assessed for activated partial thromboplastin time, fibrinogen, factor VII, factor VIII, von Willebrand factor, von Willebrand ristocetin cofactor activity, <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em>, thrombin-antithrombin complex, d-dimer, α<em>2</em>-antiplasmin, plasmin-α<em>2</em>-antiplasmin complex (PAP), tissue plasminogen activator and plasminogen activator inhibitor. Intervening variables, such as age, sex, body mass index and smoking, were accounted for.

RESULTS

We found lower coagulation measures for fibrinogen (P = 0.03) and plasminogen activator inhibitor (P = 0.0<em>1</em>), and higher levels of PAP (P = 0.046) in patients with serotonergic antidepressant than in patients without serotonergic antidepressant. When controlling for smoking and body mass index, differences between the two groups were significant for PAP (P = 0.0<em>2</em>), von Willebrand ristocetin cofactor activity (P = 0.0<em>2</em>) and activated partial thromboplastin time (P = 0.046). Coagulation scores were similar in patients with serotonergic antidepressant to those of healthy controls.

CONCLUSIONS

Serotonergic antidepressants may counteract a procoagulant effect of anxiety and/or depression in anxiety patients.

OBJECTIVE

Sirtuin <em>1</em> influences gene expression and other cellular functions through deacetylation of histone and nonhistone proteins. We here sought to determine the effects of a small molecule sirtuin <em>1</em> activator, SRT2<em>1</em>04, on inflammation and coagulation induced by lipopolysaccharide in humans.

METHODS

A randomized, double-blind, placebo-controlled study.

METHODS

An academic hospital.

METHODS

Twenty-four healthy humans.

METHODS

All subjects received an intravenous injection with lipopolysaccharide. Subjects were randomized to one of three groups (n=8 per group): <em>1</em>) pretreatment with oral SRT2<em>1</em>04 for 7 days (2 g/d), 2) pretreatment with a single SRT2<em>1</em>04 dose (2 g), or 3) placebo.

RESULTS

SRT2<em>1</em>04 attenuated lipopolysaccharide-induced release of the cytokines interleukin-6 (mean peak levels of 58.8% [p<0.05] and 80.9% [p=0.078] after single and repeated SRT2<em>1</em>04 administration, respectively, relative to those measured after placebo treatment) and interleukin-8 (mean peak levels of 57.0% [p<0.05 vs placebo] and 77.<em>1</em>% [p<0.05 vs placebo] after single and repeated SRT2<em>1</em>04 ingestion, respectively, while not affecting tumor necrosis factor-α and interleukin-<em>1</em>0 release). SRT2<em>1</em>04 also reduced the lipopolysaccharide-induced acute phase protein response (C-reactive protein). SRT2<em>1</em>04 inhibited activation of coagulation, as reflected by lower plasma levels of the prothrombin fragment F<em>1</em>+2 (mean peak levels 57.9% [p<0.05] and 64.2% [p<0.05] after single and repeated SRT2<em>1</em>04 administration, respectively, relative to those measured after placebo treatment). Activation of the vascular endothelium (plasma von Willebrand levels) and the fibrinolytic system (plasma tissue-type plasminogen activator and plasminogen activator inhibitor type I) was not influenced by SRT2<em>1</em>04.

CONCLUSIONS

This is the first human study to demonstrate biological anti-inflammatory and anticoagulant responses consistent with the activation of sirtuin <em>1</em> by a small molecule.

Thrombocytin, a serine protease from Bothrops atrox venom, caused platelet aggregation and release of platelet constituents at a concentration of <em>1</em>0(-7) M and clot retraction at a concentration of <em>2</em> x <em>1</em>0(-9) M. Thrombocytin was slightly more active when tested on platelets in plasma than on washed platelets suspended in Tyrode--albumin solution. Thrombin was 5 times more active than thrombocytin when tested on platelets in plasma and 50 times more active when tested on washed platelets. The patterns or release induced by thrombocytin and thrombin were similar. Prostaglandin E<em>1</em> (<em>1</em>0(-5) M) produced complete inhibition of platelet release induced by thrombocytin and thrombin. Indomethacin (<em>1</em>0(-4) M) was without any effect. Antithrombin III, in the presence of heparin, inhibited the action of thrombocytin on platelets and on a synthetic peptide substrate (Tos-Gly-Pro-Arg-pNA.HCl). formation of an antithrombin III--thrombocytin complex was demonstrated on NaDodSO4--polyacrylamide gel electrophoresis. Hirudin and alpha <em>1</em>-antitrypsin did not inactivate thrombocytin. Thrombocytin had a low fibrinogen-clotting activity (less than 0.06% that of thrombin). Thrombocytin also caused progressive degradation of the alpha chain of human fibrinogen, and it cleaved <em>prothrombin</em>, releasing products similar to intermediate <em>1</em> and <em>fragment</em> <em>1</em> produced by thrombin. Thrombocytin activated factor XIII by limited proteolysis and increased the procoagulant activity of factor VIII in a manner analogous to that of thrombin.

Platelet and leukocyte activation has been demonstrated in polycythemia vera (PV) and essential thrombocythemia (ET), but such information is limited in primary myelofibrosis (PMF). Platelet, leukocyte, endothelial, and coagulation activation status was assessed in <em>2</em>6 PMF patients and compared with data from <em>2</em><em>2</em> age- and sex-matched healthy individuals. Study included flow cytometry assessment of platelet P-selectin expression [at baseline and after adenosine diphosphate (ADP), thrombin and arachidonic acid stimulation], platelet-neutrophil and platelet-monocyte complexes, and CD<em>1</em><em>1</em>b expression in neutrophils and monocytes. Additionally, soluble P-selectin, sCD40L, tissue factor, thrombomodulin, <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em> (F<em>1</em> + <em>2</em>), and D-dimer were measured by enzyme-linked immunosorbent assays. The above parameters were correlated with the patients' clinical data and presence of the JAK<em>2</em> V6<em>1</em>7F mutation. Compared with controls, PMF patients had increased baseline platelet activation, as shown by significantly higher levels of soluble and platelet P-selectin expression, and also higher percentages of platelet-monocyte complexes. Neutrophil and monocyte CD<em>1</em><em>1</em>b expression was significantly higher in patients with the JAK<em>2</em> mutation than in those with wild-type allele or the controls. Endothelial and coagulation activation, as demonstrated by increased plasma levels of thrombomodulin and F<em>1</em> + <em>2</em>, was also found in PMF, with patients with the JAK<em>2</em> mutation showing significantly higher values of F<em>1</em> + <em>2</em> than those with wild-type allele. In conclusion, PMF patients have platelet, leukocyte, endothelial, and coagulation activation similar to that in PV and ET. CD<em>1</em><em>1</em>b overexpression and F<em>1</em> + <em>2</em> are correlated with the presence of the JAK<em>2</em> mutation.

During ovarian gonadotrophin stimulation for ovulation induction or in vitro fertilization, a clinical severe ovarian hyperstimulation syndrome (OHSS) may occur. Only few studies have investigated the mechanism responsible for the alterations of the haemostatic system in women affected by severe OHSS. The aim of the present study was to investigate the correlation between the magnitude of ovarian stimulation and the increase in fibrin formation and degradation in severe OHSS. Twenty-five patients (age range <em>2</em>3-43 years) who were hospitalized for severe OHSS, <em>2</em>5 women undergoing in vitro fertilization who did not develop OHSS (case-control group) and <em>2</em>5 healthy age-matched women (healthy control group) were investigated. On the day of admission a number of haemostatic markers, including D-dimer, thrombin-antithrombin complexes (TAT), <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em> (F<em>1</em> + <em>2</em>), plasmin-antiplasmin complexes (PAP), tissue factor (TF), tissue factor pathway inhibitor (TFPI) and von Willebrand factor antigen (vWF), were examined. In patients with severe OHSS, TF, D-dimer, TAT, F<em>1</em> + <em>2</em>, PAP and vWF antigen plasma levels were significantly higher than those observed both in the case-control group and in healthy controls, whereas TFPI levels were significantly lower (P < 0.005) with respect to both case-controls and healthy controls. D-Dimer levels were related with serum oestradiol levels and oocyte number recovered (r = 0.45, P < 0.00<em>1</em> and r = 0.47, P < 0.00<em>1</em>, respectively). D-Dimer and TAT levels were significantly (P < 0.05 and P < 0.005, respectively) higher in OHSS patients with unsuccessful pregnancy outcome (D-dimer, <em>2</em><em>2</em>6.5, 56-<em>1</em>449 ng/ml; TAT, <em>1</em>9.8, 3.<em>1</em>-8<em>2</em>.6 microg/l) with respect to those with successful outcome of pregnancy (D-dimer, <em>1</em>45, <em>2</em>9-330 ng/ml; TAT, 5.0, <em>1</em>.0-<em>1</em>9.6 microg/l). Our data indicate that a marked hypercoagulability with alterations of TF and TFPI levels is detectable in patients with severe OHSS and that it is related to the clinical outcome.

Patients with end-stage renal disease (ESRD) exhibit features of a hypercoagulable state, which may contribute to atherosclerosis. Kynurenines are the metabolites of tryptophan degradation in mammals. We examined the relationship between coagulation activation and kynurenines in 9<em>2</em> patients with ESRD on maintenance haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) and <em>2</em>0 healthy controls. We measured the plasma levels of: tissue factor (TF), its pathway inhibitor (TFPI), the marker of coagulation activation - <em>prothrombin</em> <em>fragments</em> <em>1</em>+<em>2</em> (F(<em>1</em>+<em>2</em>)), kynurenine (KYN) and its metabolites: kynurenic (KYNA), anthranilic (AA) and quinolinic (QA) acids. The ratio of KYNA to KYN (kyna/kyn), AA to KYN (aa/kyn) and QA to KYN (qa/kyn), reflecting intensified activity of enzymes which converted KYN to its metabolites, were also determined. Measured coagulation parameters and kynurenines were significantly elevated in ESRD patients compared to controls. TF, TFPI and F(<em>1</em>+<em>2</em>) were significantly associated with AA, aa/kyn, QA and qa/kyn ratio. Multiple regression analysis showed that fibrinogen (p<0.0<em>1</em>) and above mentioned KYN metabolites (all p<0.05) were the independent variables significantly associated with increased F(<em>1</em>+<em>2</em>) levels, reflecting hypercoagulability in ESRD patients. In conclusion, this study represents the first to investigate both the coagulation system and KYN pathway in ESRD patients. The coagulation was enhanced in dialysed uraemic patients compared with the healthy controls demonstrated by increased TF, TFPI and F(<em>1</em>+<em>2</em>) levels. These changes were correlated with activation of the KYN pathway. Finally, fibrinogen and KYN metabolites are independently and significantly associated with the hypercoagulable state in uraemic patients on CAPD and HD treatment.

We hypothesized that infusion of recombinant human antithrombin without concomitant heparin would have dose-dependent anticoagulant properties and potentially decrease endotoxin (lipopolysaccharide [LPS])-induced cytokine production. This was a randomized, double-blind, placebo-controlled study in parallel groups enrolling 30 healthy male volunteers. The active treatment groups received infusions of recombinant human antithrombin to increase antithrombin levels to <em>2</em>00% and 500% before infusion of <em>2</em> ng/kg endotoxin (LPS). Infusion of antithrombin dose-dependently decreased coagulation (P < .0<em>1</em> by repeated-measures ANOVA): peak levels of <em>prothrombin</em> <em>fragment</em> (<em>1</em>.8 nmol/L [95% confidence interval (CI), <em>1</em>.3-<em>2</em>.3 nmol/L] in the 500% antithrombin group and 4.4 nmol/L [95% CI, <em>2</em>.7-6.<em>2</em> nmol/L] in the placebo group at 4 hours), thrombin antithrombin complexes (<em>1</em><em>2</em> microg/L [95% CI, 8-<em>1</em>6 microg/L] in the 500% antithrombin group and 34 microg/L [95% CI, <em>2</em>0-48 microg/L] in the placebo group at 4 hours), and D-dimer (0.<em>2</em> microg/L [95% CI, 0.<em>1</em>-0.<em>2</em> microg/L] in the 500% antithrombin group and 0.5 microg/L [95% CI, 0.4-0.7 microg/L] in the placebo group). Recombinant human antithrombin decreased peak interleukin-6 levels by 40% (<em>2</em><em>2</em><em>2</em> pg/mL [95% CI, <em>1</em>48-<em>2</em>95 pg/mL] and <em>2</em><em>1</em>6 pg/mL [95% CI, <em>1</em><em>1</em><em>2</em>-3<em>2</em>0 pg/mL] in the 500% and <em>2</em>00% antithrombin groups, respectively, versus 357 pg/mL [95% CI, <em>2</em>4<em>1</em>-474 pg/mL] in the placebo group; P < .00<em>1</em> by ANOVA). Finally, infusion of recombinant human antithrombin rapidly and transiently decreased neutrophil counts (by <em>1</em>9% [95% CI, 8%-30%] in the 500% antithrombin group versus 6% [95% CI, <em>1</em>%-<em>1</em>0%] in the placebo group, P = .00<em>2</em> by Kruskal-Wallis ANOVA) and monocyte counts (by 30% [95% CI, <em>1</em>6%-44%] in the 500% antithrombin group and <em>1</em>8% [95% CI, 9%-<em>2</em>8%] in the <em>2</em>00% antithrombin group versus 8% [95% CI, 5%-<em>2</em>0%] in the placebo group, P = .04) before LPS challenge, indicating that recombinant human antithrombin directly interacts with these leukocyte subsets. In summary, recombinant human antithrombin dose-dependently inhibited tissue factor-triggered coagulation. Effects on leukocytes and inhibition of interleukin-6 release seem to represent specific pharmacodynamic properties of recombinant human antithrombin.

Semen contains enzymes and inhibitors of the haemostatic system as well as the high molecular weight seminal vesicle (HMW-SV) proteins. The former may have roles in seminal clotting and in liquefaction through "fibrinolytic" activity, which may ultimately affect fertility. Although a limited number of studies have addressed the subject, the role of clotting and fibrinolytic factors in semen remains poorly understood. The liquefaction time and the distribution of components vary across split ejaculates. This may have an important bearing on the way clotting/fibrinolytic factors in semen are assessed. Semen contains tissue factor (TF, Thromboplastin, CD<em>1</em>4<em>2</em>), which originates from the prostate and is associated with prostasomes. The function of TF (and prostasomes) in semen is still a matter for speculation. Recently the presence of minute amounts of factor VII in semen has been demonstrated but its importance is uncertain. Semen also contains a thrombin-like enzyme, <em>prothrombin</em> <em>fragments</em> <em>1</em> and <em>2</em> (F<em>1</em>+<em>2</em>), D-dimer (DD) and thrombin-antithrombin (TAT) complexes. The presence of several fibrinolytic factors has been demonstrated in semen but few questions about their potential impact on semen quality have been raised. Factors found include tissue plasminogen activator (t-PA), urinary plasminogen activator (u-PA) and plasmin. There are also traces of fibrinogen, plasminogen, plasminogen activator inhibitor-<em>1</em> (PAI-<em>1</em>), factor VIII coagulant activity (VIII:c) and fibrin monomers. The co-ordinate expression of both TF and PAI-<em>1</em> by decidual cells of the endometrium is believed to be important in maintaining haemostasis during endovascular trophoblast invasion. Kallikrein-like serine protease inhibitors including prostate specific antigen (PSA) are known to be present in semen at high concentrations. In semen PSA is also found in a complex form with protein C inhibitor (PCI) with mutually inhibitory consequences. A better understanding of the spectrum of coagulating and liquefaction agents in semen to include classical haemostatic processes and the pathogenesis resulting from any imbalances between or within either system may provide the basis for the development of more selective and efficient agents affecting global fertility. Here we review aspects of male reproductive physiology in the light of recent findings concerning conventional clotting/fibrinolytic systems in human semen with a view to stimulating further research.

BACKGROUND

Aging and hypertension are well-known risk factors for cerebral white matter lesions. Prothrombotic status has been shown to be a risk factor for cardiovascular disease. In this study, we investigated the relationships among prothrombotic status, ambulatory blood pressure (ABP), and white matter hyperintensity (WMH) in elderly hypertensives.

METHODS

Measurement of <em>prothrombin</em> <em>fragments</em> <em>1</em>+<em>2</em> (F<em>1</em>+<em>2</em>), von Willebrand Factor (vWF) and plasminogen activator inhibitor-<em>1</em> (PAI-<em>1</em>), ABP monitoring (ABPM), and brain magnetic resonance imaging (MRI) were performed in 5<em>1</em>4 Japanese elderly hypertensives (7<em>2</em>.3 years old, male 37%). WMH cases were further divided into deep subcortical white matter lesion (DWML) or periventricular hyperintensity (PVH).

RESULTS

Deep WMH (DWMH) had significant positive correlations with age, use of antiplatelet agents, log F<em>1</em>+<em>2</em>, log vWF, log PAI-<em>1</em>, and <em>2</em>4-h systolic BP (SBP). PVH had significant positive correlations with age, male gender, smoking, use of antiplatelet agents, white coat hypertension (WCH), log vWF, and <em>2</em>4-h SBP. Severe PVH had significant positive correlations with age, use of antiplatelet agents, WCH, and <em>2</em>4-h SBP, and that was marginally correlated with log F<em>1</em>+<em>2</em>. In the logistic linear regression analysis, log F<em>1</em>+<em>2</em> was significantly associated with DWMH (P < 0.0<em>1</em>) and severe PVH (P < 0.05) adjusted for age and <em>2</em>4-h SBP. Log PAI-<em>1</em> was significantly associated with DWMH (P < 0.05) adjusted for age and <em>2</em>4-h SBP.

CONCLUSIONS

In the present study, F<em>1</em>+<em>2</em> and PAI-<em>1</em> were positively associated with WMH after adjustment for <em>2</em>4-h SBP in elderly hypertensives. In addition to the conventional risk factors, prothrombotic status might serve as a significant determinant for WMH.

BACKGROUND

Although some authors have already evaluated the predictive value of various parameters regarding the duration of chronic spontaneous urticaria (CSU), it remains uncertain which ones have importance in clinical practice as prognostic factors that indeed enable prediction. Similarly, some authors have investigated parameters that might be related to severe cases of CSU. However, the results of studies evaluating several parameters as markers of disease severity are fragmented. Thus, we performed a systematic review to summarize the findings of studies investigating the parameters associated with CSU duration and severity.

METHODS

Two authors independently searched PubMed until June <em>2</em>0<em>1</em><em>2</em> for observational retrospective or prospective studies addressing clinical or laboratory parameters associated with disease duration or severity in CSU patients.

RESULTS

We found <em>1</em>,<em>1</em>36 potentially relevant published papers related to the subject, 34 of which were included in the systematic review. A total of <em>1</em>6, 6 and <em>1</em><em>2</em> articles evaluated CSU parameters on severity, duration or both, respectively.

CONCLUSIONS

Our findings suggest that disease severity might predict CSU duration. Similarly, evidence suggests that plasma levels of <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em>, D-dimer and C-reactive protein may function as markers of CSU severity.

We studied exercise-induced changes in coagulation and fibrinolytic factors and activation products in different age categories. Thirty-eight sedentary males, divided in three age categories (cats I-III; <em>2</em>0-30, 35-45 and 50-60 y) were subjected to a standardized exercise test. Pre-exercise levels (cats I-III resp) of FVII:c (<em>1</em>05 +/- 5, <em>1</em><em>2</em><em>1</em> +/- 6 and <em>1</em><em>2</em>3 +/- 7% NP), fibrinogen (<em>2</em>.35 +/- 0.<em>1</em><em>2</em>, <em>2</em>.55 +/- 0.<em>1</em>0 and <em>2</em>.66 +/- 0.09 mg/ml), <em>prothrombin</em> activation <em>fragment</em> F<em>1</em> + <em>2</em> (0.80 +/- 0.<em>1</em>0, 0.80 +/- 0.<em>1</em><em>1</em> and <em>1</em>.<em>2</em><em>2</em> +/- 0.<em>1</em>6 nM), t-PA (5.<em>2</em> +/- 0.6, 9.<em>2</em> +/- <em>1</em>.0, 8.6 +/- <em>1</em>.<em>2</em> ng/ml) and PAI-I (4<em>2</em>.8 +/- 7.5, 67.6 +/- 7.6, 6<em>2</em>.<em>2</em> +/- <em>1</em>0.9 ng/ml) showed differences that seemed related to age. Regression analysis revealed associations with anthropometry (FVII:c, fibrinogen, F<em>1</em>+<em>2</em>, t-PA, PAI-<em>1</em>) rather than with age. Exercise-induced changes in coagulation (increase in von Willebrand factor and FVIII:c and a shortening of APTT) and fibrinolytic potential (increase in t-PA and u-PA) were of comparable magnitude for the three age categories. Hardly any change in F<em>1</em> + <em>2</em> (6%) was observed, while thrombin-antithrombin complexes (93%), plasmin-antiplasmin complexes (79%) and D-dimer (77%) almost doubled during maximal exercise. We conclude that anthropometric differences play a more significant role than age on constitutive levels of haemostatic factors in participants up to 60 years of age. The magnitude of exercise-induced changes is comparable in the age categories under study, and simply super-imposed on constitutive (pre-exercise) levels. Clear evidence for <em>prothrombin</em> activation is lacking, but plasmin formation is enhanced during exercise.

We investigated the effects of ethinylestradiol dose (50, 30 and <em>2</em>0 microg) and progestogen type [desogestrel (DSG), gestodene (GSD), levonorgestrel (LNG) and norgestimate (NGM)] in oral contraceptives on <em>2</em>4 hemostatic variables. In a multicenter, randomized, comparative study, 707 healthy, nonsmoking, nulliparous women were treated for six cycles with one of the seven monophasic oral contraceptives tested. Significantly greater increases in <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> and factor VII (activity and antigen), were found in the DSG, NGM and GSD groups compared to the LNG group. Similarly, significantly lower levels of protein S (free and total) and increased APC-sr (endogenous thrombin potential based) were found in the same groups compared with the LNG group. In addition, the estradiol dose (50 vs. 30 microg) significantly influenced these parameters. All changes were within the normal range and have not been associated with an increased risk of venous thromboembolic event (VTE). However, raised levels of these variables are associated with prothrombotic states such as pregnancy. The significance of the haemostatic changes found in this study in relation to VTE risk remains to be determined, but results of this study probably cannot explain the differences in risk of VTE between OCs containing different progestogens.

BACKGROUND

Inflammation-induced procoagulant changes and alterations in platelet activity appear to play an important role in thromboembolic complications of infective endocarditis (IE).

OBJECTIVE

The aim of this study was to investigate systemic coagulation activity, fibrinolytic capacity, and platelet activation in patients with IE with and without embolic events by measuring the plasma levels of <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> (PF<em>1</em>+<em>2</em>), thrombin-antithrombin III complex (TAT), plasminogen activator inhibitor-<em>1</em> (PAI-<em>1</em>), beta-thromboglobulin (beta-TG), and platelet factor 4 (PF4), respectively.

METHODS

The study included 76 consecutive patients (female = 55, male = <em>2</em><em>1</em>, mean age <em>2</em>6 years, range 8-64 years) with definite IE according to the Duke criteria; of these, <em>1</em>3 (<em>1</em>7.<em>1</em>%) had embolic events.

RESULTS

Plasma concentrations of PF<em>1</em>+<em>2</em> (3.<em>2</em> +/- <em>1</em>.3 vs. <em>1</em>.7 +/- 0.7 and <em>1</em>.4 +/- 0.7 nmol/l, p < 0.00<em>1</em>, respectively) and TAT (7.3 +/- <em>1</em>.5 vs. <em>2</em>.9 +/- <em>1</em>.<em>2</em> and <em>2</em>.<em>2</em> +/- <em>1</em>.<em>1</em> ng/ml, p < 0.00<em>1</em>, respectively) were elevated in patients with embolic events compared with patients without embolic events and control subjects. Similarly, patients with embolic events had increased plasma levels of beta-TG (63.3 +/- <em>1</em>0.9 vs. 33.<em>1</em> +/- <em>1</em><em>1</em>.6 and <em>1</em>9.<em>1</em> +/- <em>1</em>0.6 ng/ml, p < 0.00<em>1</em>, respectively) and PF4 (<em>1</em>06.0 +/- <em>2</em>8.7 vs. 50.3 +/- <em>1</em>6.7 and 43.0 +/- <em>1</em>5.8 ng/ml, p < 0.00<em>1</em>, respectively) compared with those without embolic events and the control group. Embolic patients also had higher PAI-<em>1</em> levels than nonembolic patients and healthy subjects (<em>1</em>4.4 +/- 6.4 vs. 8.6 +/- 5.9 and 5.4 +/- 4.3 ng/ml, p = 0.00<em>2</em>, respectively).

CONCLUSIONS

Patients with IE and with subsequent thromboembolism have increased systemic coagulation activation, enhanced platelet activity/damage, and impaired fibrinolysis. The resulting imbalance produces a sustained hypercoagulable state, which contributes to the increased risk of thromboembolic events in this particular group.

Recent studies have demonstrated that even a low-intensity resistance exercise can effectively induce muscle hypertrophy and strength increase when combined with moderate blood flow restriction (BFR) into the exercising muscle. Although serious side effects of low-intensity resistance exercise with BFR have not been reported, a concern of thrombosis has been suggested, because this type of exercise is performed with restricted venous blood flow and pooling of blood in extremities. Thus, the purpose of this study was to investigate the effects of low-intensity resistance exercise with BFR on coagulation system in healthy subjects. Ten healthy men (<em>2</em>5.<em>1</em> +/- <em>2</em>.8 year) performed four sets of leg press exercises with and without BFR (<em>1</em>50-<em>1</em>60 mmHg) at an intensity of 30% of one-repetition maximum (<em>1</em>RM). In each exercise session, one set with 30 repetitions was followed by three sets with <em>1</em>5 repetitions. Blood samples were taken before, and <em>1</em>0 min, <em>1</em>, 4 and <em>2</em>4 h after the exercise. <em>Prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em> (PTF) and thrombin-antithrombin III complex (TAT) were measured as markers of thrombin generation, whereas D-dimer and fibrin degradation product (FDP) were measured as markers of intravascular clot formation. Changes in plasma volume (PV) were calculated from haemoglobin and hematocrit values. PV reduction was significantly greater after the exercise with BFR than without (P<0.05). However, neither markers of thrombin generation nor intravascular clot formation increased after the exercises. These results suggest that low-intensity resistance exercise with BFR does not activate coagulation system in healthy subjects.

Antiphospholipid antibodies (aPLs) are associated with thrombosis, but the mechanisms of this thrombotic tendency are unknown. We studied 56 patients 6<em>1</em><em>2</em> with systemic lupus erythematosus [SLE] and aPLs and previous thrombosis, <em>1</em><em>2</em> with SLE and aPLs but no thrombosis, <em>1</em>5 with SLE without aPLs or thrombosis, <em>1</em><em>1</em> with primary antiphospholipid syndrome with thrombosis, and 6 asymptomatic subjects with aPLs) to investigate the ability of aPLs to induce tissue factor (TF) expression on human normal monocytes. A double direct immunofluorescence technique (anti-CD<em>1</em>4 and anti-TF) was used, and procoagulant activity in viable and disrupted cells was measured after plasma incubation for 6 hours at 37 degrees C with normal mononuclear cells. Hemostasis regulatory proteins, <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em>, and thrombin-antithrombin III complex levels were determined. Increased TF expression and procoagulant activity were observed using plasma samples from SLE patients with aPLs and thrombosis (P < .0<em>1</em>) and from primary antiphospholipid syndrome patients (P < .0<em>1</em>) but not from patients with SLE and aPLs but no thrombosis, patients with SLE without aPLs, or asymptomatic patients with aPLs. Purified aPL immunoglobulins from one primary antiphospholipid syndrome and two SLE patients added to normal plasma showed a significant increase in both TF expression and procoagulant activity (P < .05) compared with purified aPL from two SLE patients without thrombosis. The addition of nonspecific IgG from three SLE patients without aPLs and from three control subjects did not increase TF expression. Low free protein S was seen in eight patients. Increased TF expression and low free protein S correlated with thrombosis (P < .0<em>1</em>) and with higher <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em> and thrombin-antithrombin III values (P < .0<em>1</em>). These observations may contribute to a further understanding of the thrombotic risk in aPL patients.

OBJECTIVE

The aim of study was to assess whether activation of blood coagulation and platelets is enhanced in aortic stenosis (AS) and if so, to determine factors that might modulate these processes.

METHODS

Seventy-five patients with AS (48 males, <em>2</em>7 females, aged 65+/-<em>1</em>0 years) were enrolled in the study. A control group comprised 75 age- and sex-matched subjects. We determined markers of thrombin generation (thrombin-antithrombin complex [TAT], <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> [F<em>1</em>+<em>2</em>]), platelet activation (soluble CD40 ligand [sCD40L], beta-thromboglobulin [beta-TG], P-selectin) in peripheral blood plasma. The extent of atherosclerosis in the carotid and coronary arteries was assessed as a potential confounding factor.

RESULTS

Mean concentrations of thrombin and platelet markers were higher approximately two-fold in the AS group than in controls (p<0.005 for all comparisons). Maximal gradient was positively associated with TAT (r=0.6<em>1</em>, p<0.00<em>1</em>), F<em>1</em>+<em>2</em> (r=0.60, p<0.00<em>1</em>), sCD40L (r=0.5<em>2</em>, p<0.0<em>1</em>) and beta-TG (r=0.70, p<0.00<em>1</em>). Aortic valve area (AVA) negatively associated only with one platelet marker, beta-TG (r=-0.30, p<0.05). The presence of concomitant atherosclerotic plaque in the carotid (in 65% of patients) or coronary arteries (in 43% of patients) did not influence thrombin generation and platelet activation in patients with AS.

CONCLUSIONS

AS predisposes to prothrombotic state. Maximal gradient as an index of turbulent flow associated with activation of coagulation and platelets. In contrast, the small aortic valve area was not closely related to these parameters.

We have shown that the contact (kallikrein-kinin) system is involved in the pathogenesis of experimental enterocolitis. We now investigate activation of the contact and coagulation pathways, platelets, and neutrophils in active and inactive ulcerative colitis patients as compared to normal controls. In active ulcerative colitis patients, a significant decrease of plasma prekallikrein, high molecular weight kininogen, and C<em>1</em> inhibitor levels was observed as compared with controls, as well as prekallikrein activation on western blots. Significant elevation of <em>prothrombin</em> <em>fragment</em> (F<em>1</em> + <em>2</em>), which indicates thrombin generation, and elastase-alpha <em>1</em>-antitrypsin complexes, reflecting neutrophil activation, were found in patients with active disease. Plasma beta-thromboglobulin, a marker of platelet activation, was elevated in both active and inactive disease and appears to be a feature of ulcerative colitis. Activation of contact and coagulation pathways, as well as neutrophils, may mediate inflammation in the active phase of ulcerative colitis.

OBJECTIVE

The influence hemostatitc parameters on the morphological extent and severity of coronary artery disease were studied in patients with and without DM type <em>2</em>.

BACKGROUND

It is known that patients with diabetes (DM) have abnormal metabolic and hemostatic parameters

METHODS

Of <em>1</em>50 consecutive patients with angiographically proven coronary artery disease <em>2</em>9 presented with DM. Additionally to parameters of lipid-metabolism fibrinogen, tissue-plasminogenactivator (t-PA), plasminogen-activator-inhibitor (PAI), plasmin-a-antiplasmin (PAP), <em>prothrombin</em>-<em>fragment</em> <em>1</em>+<em>2</em> (F<em>1</em>+<em>2</em>), thrombin-antithrombin (TAT), von-willebrand-factor (vWF), platelet factor 4 (PF4), glykomembranproteine <em>1</em>40 (GMP<em>1</em>40) and the rheologic parameters plasma viscosity and red blood cell aggregation were evaluated. The extent and severity of CAD was evaluated according to the criteria of the American Heart Association.

RESULTS

Patients with DM presented with a higher number of conventional risk factors as compared to non-diabetic patients. Additionally there were significant differences for F<em>1</em>+<em>2</em>, red blood cell aggregation and PAI. Diabetic patients showed a more severe extent of coronary arteriosclerosis, which also could be found more distally. A significant relationship between blood-glucose, thrombocyte-activation (vWF), endogenous fibrinolysis (PAI) and the severity of CAD and a more distal location of stenoses could be found (r = 0.6, p < 0.00<em>1</em>).

CONCLUSIONS

Patients with coronary artery disease and DM type <em>2</em> showed marked alterations of metabolic, hemostatic, fibrinolytic and rheologic parameters, which can produce a prothrombogenic state. A direct association of thrombogenic factors on coronary morphology could be shown. This can be the pathophysiologic mechanism of more severe and distal pronounced coronary atherosclerosis in these patients.

To determine the influence of aging on the activity of the hemostatic system, we measured the plasma concentration of <em>prothrombin</em> <em>fragments</em> <em>1</em>+<em>2</em> (F <em>1</em>+<em>2</em>), thrombin-antithrombin III complexes (TAT) and fibrin degradation <em>fragments</em> D-dimers (D-D) in 80 healthy subjects with age ranging between <em>2</em>0 and 94 years. All subjects were free of acute or chronic diseases. The three markers (semi-log scale) were positively correlated with age (r greater than 0.7, p less than 0.0<em>1</em>). Mean plasma levels of F <em>1</em>+<em>2</em>, TAT and D-D were two- to five-fold higher in subjects with age greater than or equal to 60 as compared to those less than 60 years (n = 40 in both groups). In these two groups, normal values for F <em>1</em>+<em>2</em>, TAT and D-D ranged from 0.3-<em>1</em>.<em>2</em> vs 0.7-<em>2</em>.4 nmol/l, <em>1</em>.4-<em>2</em>.6 vs <em>1</em>.9-6.4 micrograms/l and 33-433 vs 3<em>1</em><em>2</em>-<em>1</em><em>1</em>80 micrograms/l, respectively. Sex did not influence the results. We conclude that the activity of the hemostatic system is markedly age-dependent, and that elderly subjects display a biological picture of "prethrombotic" state. In addition, for a right clinical use of these three markers, age should be taken into account when normal range is to be established.

A staphylocoagulase-binding region in human <em>prothrombin</em> was studied by utilizing several <em>fragments</em> prepared from <em>prothrombin</em> by limited proteolysis. Bovine <em>prothrombin</em>, prethrombin <em>1</em>, prethrombin <em>2</em>, and human diisopropylphosphorylated alpha-thrombin strongly inhibited formation of the complex ("staphylothrombin") between human <em>prothrombin</em> and staphylocoagulase, but bovine <em>prothrombin</em> <em>fragment</em> <em>1</em> and <em>fragment</em> <em>2</em> had no effect on the complex formation, indicating that the binding region of human <em>prothrombin</em> for staphylocoagulase is located in the prethrombin <em>2</em> molecule. To identify further the staphylocoagulase-binding region, human alpha-thrombin was cleaved into the NH<em>2</em>-terminal large <em>fragment</em> (Mr = <em>2</em>6,000) and the COOH-terminal <em>fragment</em> (Mr = <em>1</em>6,000) by porcine pancreatic elastase. Of these <em>fragments</em>, the COOH-terminal <em>fragment</em>, which includes Asn-<em>2</em>00 to the COOH-terminal end of the alpha-thrombin molecule, partially inhibited the complex formation between staphylocoagulase and human <em>prothrombin</em>. In contrast, the NH<em>2</em>-terminal large <em>fragment</em> did not show any inhibitory effect on the staphylothrombin formation. These results suggest that the staphylocoagulase interacts with human <em>prothrombin</em> through the COOH-terminal region of alpha-thrombin B chain. Other plasma proteins, factor X, factor IX, protein C, protein S, protein Z, all of which are structurally similar to <em>prothrombin</em>, did not inhibit the staphylothrombin formation at all, indicating that a specific interaction site with staphylocoagulase is contained only in the <em>prothrombin</em> molecule.

The purpose of this study was to evaluate whether or not, using sensitive analytical methods for the measurement of coagulation and fibrinolysis enzyme activity, there was a hypercoagulable state in patients with melanoma, and whether differences existed between those with or without metastases. Seventy-one patients were studied, 45 with localized tumors (stages Ia and Ib) and <em>2</em>6 with metastases (stages II-IV). Plasma level of activated factor VII, <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em>, thrombin-antithrombin complex, fibrinopeptide A, plasmin-antiplasmin complex and D-dimer were much higher in the whole group of 7<em>1</em> patients than in 45 controls with benign nevi. However, when melanoma patients with or without metastases were compared, there were smaller differences, with only thrombin-antithrombin complex, plasmin-antiplasmin and D-dimer significantly higher in metastatic melanoma. These results indicate that in patients carrying a tumor endowed with high procoagulant activity in vitro, there is a laboratory picture of hypercoagulability with secondary hyperfibrinolysis in vivo. However, differences between patients with localized and metastatic tumors for markers of hypercoagulability are not striking, in spite of the fact that metastatic cells support greater coagulant activity than primary cells in vitro.