Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men

Abstract:  Melatonin has previously been suggested to affect hemostatic function but studies on the issue are scant. We hypothesized that, in humans, oral administration of melatonin is associated with decreased plasma levels of procoagulant hemostatic measures compared with placebo medication and that plasma melatonin concentration shows an inverse association with procoagulant measures. Forty-six healthy men (mean age 25 ± 4 yr) were randomized, single-blinded, to either 3 mg of oral melatonin (n = 25) or placebo medication (n = 21). One hour thereafter, levels of melatonin, fibrinogen, and D-dimer as well as activities of coagulation factor VII (FVII:C) and VIII (FVIII:C) were measured in plasma. Multivariate analysis of covariance and regression analysis controlled for age, body mass index, mean arterial blood pressure, heart rate, and norepinephrine plasma level. Subjects on melatonin had significantly lower mean levels of FVIII:C (81%, 95% CI 71–92 versus 103%, 95% CI 90–119; P  = 0.018) and of fibrinogen (1.92 g/L, 95% CI 1.76–2.08 versus 2.26 g/L, 95% CI 2.09–2.43; P  = 0.007) than those on placebo explaining 14 and 17% of the respective variance. In all subjects, increased plasma melatonin concentration independently predicted lower levels of FVIII:C ( P  = 0.037) and fibrinogen ( P  = 0.022) explaining 9 and 11% of the respective variance. Melatonin medication and plasma concentration were not significantly associated with FVII:C and D-dimer levels. A single dose of oral melatonin was associated with lower plasma levels of procoagulant factors 60 min later. There might be a dose–response relationship between the plasma concentration of melatonin and coagulation activity.     

The role of stress hormones in the relationship between resting blood pressure and coagulation activity

BACKGROUND: Systemic hypertension confers a hypercoagulable state. We hypothesized that resting mean blood pressure (MBP) interacts with stress hormones in predicting coagulation activity at rest and with acute mental stress. METHODS: We measured plasma clotting factor VII activity (FVII:C), FVIII:C, fibrinogen, D-dimer, epinephrine and norepinephrine, and saliva cortisol in 42 otherwise healthy normotensive and hypertensive medication-free men (mean age 43 +/- 14 years) at rest, immediately after stress, and twice during 60 min of recovery from stress. RESULTS: At rest, the MBP-by-epinephrine interaction predicted FVII:C (beta = -0.33, P < 0.04) and D-dimer (beta = 0.26, P < 0.05), and the MBP-by-cortisol interaction predicted D-dimer (beta = 0.43, P = 0.001), all independent of age and body mass index (BMI). Resting norepinephrine predicted fibrinogen (beta = 0.42, P < 0.01) and D-dimer (beta = 0.37, P < 0.03), both independent of MBP. MBP predicted FVIII:C change from rest to immediately post-stress independent of epinephrine (beta = -0.37, P < 0.03) and norepinephrine (beta = -0.38, P < 0.02). Cortisol change predicted FVIII:C change (beta = -0.30, P < 0.05) independent of age, BMI and MBP. Integrated norepinephrine change from rest to recovery (area under the curve, AUC) predicted D-dimer AUC (beta = 0.34, P = 0.04) independent of MBP. The MBP-by-epinephrine AUC interaction predicted FVII:C AUC (beta = 0.28) and fibrinogen AUC (beta = -0.30), and the MBP-by-norepinephrine AUC interaction predicted FVIII:C AUC (beta = -0.28), all with borderline significance (Ps < 0.09) and independent of age and BMI. CONCLUSIONS: MBP significantly altered the association between stress hormones and coagulation activity at rest and, with borderline significance, across the entire stress and recovery interval. Independent of MBP, catecholamines were associated with procoagulant effects and cortisol reactivity dampened the acute procoagulant stress response.     

The paradoxical association between inherited factor VII deficiency and venous thrombosis

Summary.  Inherited factor VII (FVII) deficiency is considered to be a haemorrhagic disease. Nonetheless, some patients paradoxically present with venous thrombosis. We assessed whether there was a link between phenotype and genotype in seven patients with inherited FVII deficiency and thrombosis (eleven venous thrombotic events). For each patient (FVII:C < 50%), clinical data were collected, aetiological assessment of risk factors for thrombosis was investigated, and direct sequencing of the nine exons and promoter of the FVII gene ( F7 ) was performed. We present the second series ever published on FVII patients with thrombosis. In nine of the eleven thrombotic events, there was at least one classical triggering risk factor; clinical ( n  = 4), familial antecedent ( n  = 2), or biological, defined by phospholipid-binding antibodies or elevated FVIII:C levels ( n  = 7). In contrast to a previous series, only two events occurred after surgery, performed both with and without replacement therapy. The thrombotic event remained unexplained in one young patient, highlighting the lack of 'protection' against venous thrombosis by low FVII:C levels. Genetic mutations were found to be heterogeneous. Among the seven F7 sequence alterations identified in the present study, only two (p.Ala354Val and p.Arg364Gln) have previously been reported in FVII-deficient patients presenting with venous thrombosis. Our genetic analyses of the F7 mutations in these patients show the complexity of FVII deficiency associated with thrombosis. These data justify a holistic, clinical and biological approach for patients with these specific symptoms. This series also strongly suggest that mild FVII deficiency should not prevent physicians from using antithrombotic prophylaxis in FVII-deficient patients.     

Clinical efficacy and recovery levels of recombinant FVIIa (NovoSeven) in the treatment of intracranial haemorrhage in severe neonatal FVII deficiency

The use of replacement FVII is critical to the successful treatment of life-threatening bleeds in newborns and infants with severe FVII deficiency (<1%). However, the clinical efficacy, optimum dosage and pharmacologic recovery of rFVIIa in such children has not been studied systematically. This report is a case of an infant with severe FVII deficiency (FVII:C at 0%) and massive intracranial haemorrhage in which successful use of rFVIIa (NovoSeven) was carefully monitored. The drug was administered by intravenous bolus through a central line every 4 h at each of three dose levels: 15 microg kg-1, 22 microg kg-1 and 30 microg kg-1. FVII:C was >100% between 30 and 180 min after each infusion with mean trough levels above 25% for all three dose levels. There was no evidence of hyper-coagulation as indicated by measurements of the platelet count, D-dimer, plasma protamine paracoagulant and fibrinogen levels in spite of high FVII:C concentration. In this infant, rFVIIa was well-tolerated, maintained effective haemostasis with good clinical outcome, and produced consistent therapeutic mean trough levels above 25% FVII:C even at 15 microg kg-1 every 4 h.     

Urinary melatonin: a noninvasive method to follow human pineal function as studied in three experimental conditions

Abstract:  The aim of this study was to examine whether urinary melatonin, rather than urinary 6-sulfatoxymelatonin (aMT6s), can be used as an indicator of diurnally and seasonally changing melatonin secretion. The subjects (n = 15) spent three separate 24-hr periods in a climatic chamber during winter (n = 7) and summer (n = 8). Blood and urine samples were obtained during each period at 2- to 5-hr intervals. Serum melatonin and urinary melatonin and aMT6s were assayed by radioimmunoassay. The serum melatonin levels increased nearly 10-fold from low daytime to high nocturnal values. The mean nocturnal increase of urinary melatonin was 1.7-fold and that of urinary aMT6s was 4.6-fold. Both urinary melatonin and aMT6s correlated significantly with area under the curve melatonin in serum during the night, during the day and throughout the entire 24-hr observation period in all cases. The ratio between urinary melatonin and aMT6s excretion showed significant diurnal variation, being ninefold higher at 16:00 hr than at 07:00 or at 09:00 hr. The ninefold decrease in the urinary melatonin/aMT6s excretion ratio between the evening and the morning may reflect increased liver metabolism of melatonin during the night. Both urinary melatonin and aMT6s are good indicators of melatonin secretion, but the variation is significantly smaller for the former molecule.     

Determinants of factor VIII plasma levels in carriers of haemophilia A and in control women

Summary.  Factor VIII (FVIII) levels show a considerable variability in female carriers of haemophilia A. Presently, the reasons for this are poorly understood. The aim of the study was to elucidate the influence of genetic and non-genetic parameters on FVIII plasma levels in carriers ( n  = 42). Results were compared with age-matched healthy women without carriership of haemophilia A ( n  = 42). Each carrier was tested for the family-specific mutation, ABO blood group, FVIII level, von Willebrand factor (VWF) antigen and activity and C-reactive protein (CRP). FVIII levels were lower in carriers compared to non-carriers [74% (51–103) vs. 142% (109–169), P  < 0.001]. No statistically significant differences were observed between the two groups with respect to VWF activity, prothrombin–time, hs-CRP, fibrinogen, body mass index (BMI), age and smoking status as well as the distribution of ABO blood groups. In non-carriers, FVIII was statistically significantly correlated with BMI, activated partial thromboplastin time (APTT), VWF antigen, hs-CRP and fibrinogen. In carriers, significant correlations between FVIII and APTT, VWF antigen and activity were found, whereas BMI, hs-CRP or fibrinogen did not correlate with FVIII. In non-carriers, the association of FVIII with ABO blood groups was statistically significant ( P  = 0.006), but not in carriers of haemophilia A ( P  = 0.234). The type of FVIII gene mutation did not influence FVIII levels. Carrier status is the major determinant of a carrier`s FVIII plasma level. Factors known to influence FVIII levels in the general population do not significantly affect FVIII activity in carriers, neither does the type of mutation influence FVIII levels.     

Evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders

Summary.  Desmopressin (DDAVP) affects haemostasis by the release of von Willebrand factor and coagulation factor VIII from endothelium. The aim of the study was to evaluate the results of DDAVP testing in paediatric patients with congenital bleeding disorders. Forty-one patients consisting of children with von Willebrand's disease (VWD, n  = 26) and platelet function defects (PFD, n  = 15) received DDAVP intravenously at a dosage of 0.3 μg/kg over 30 min. FVIII activity (FVIII), von Willebrand factor antigen (VWF:Ag), collagen-binding activity (VWF:CB) and PFA 100^® closure times (CT) were measured before, 60, 120 and 240 min after DDAVP. In VWD, the VWF:Ag increased threefold until 60 min and then it decreased continuously. Compared with baseline, VWF:Ag was significantly higher at 60 and 120 min but not at 240 min. In contrast, in PFD, the peak of VWF:Ag was reached after 120 min. Two hundred and forty minutes after DDAVP, the mean was still significantly elevated compared with baseline values. The course of VWF:CB corresponded to that of VWF:Ag. In patients with VWD and PFD, FVIII rose two- to threefold within 2 h after DDAVP. CT in patients with VWD shortened markedly within 120 min and then rose again. In all children with PFD, except one non-responder, the CT shortened within 240 min after DDAVP. Two non-responders with VWD were identified by the failed increase of VWF:Ag, VWF:CB and by prolonged CT. Haemostatic effects of DDAVP differ interindividually and dependent on the coagulation disorder. DDAVP was effective in most, but not in all patients. DDAVP testing is recommended to determine the individual haemostatic response.     

Haemostatic and fibrinolytic changes in obese subjects undergoing bariatric surgery: the effect of different surgical procedures

BackgroundLittle is known about effects of different bariatric surgery procedures on haemostatic and fibrinolytic parameters.ResultsA total of 77 GBP and 79 SG subjects completed the study. At baseline no difference in coagulation parameters was found between the two groups. After both GBP and SG, subjects showed significant changes in haemostatic and fibrinolytic variables and in natural anticoagulant levels. The Δ% changes in FVII, FVIII, FIX, vWF, fibrinogen, D-dimer, protein C and protein S levels were significantly higher in subjects who underwent GBP than in those who underwent SG. Multivariate analysis confirmed that GBP was a predictor of higher Δ% changes in FVII (β=0.268, p=0.010), protein C (β=0.274, p=0.003) and protein S (β=0.297, p<0.001), but not in all the other variables. Following coagulation factor reduction, 31 subjects (25.9% of GBP and 13.9% of SG; p=0.044) showed overt FVII deficiency; protein C deficiency was reported by 34 subjects (32.5% of GBP vs 11.4% of SG, p=0.033) and protein S deficiency by 39 (37.6% of GBP vs 12.6% of SG, p=0.009). Multivariate analyses showed that GBP was associated with an increased risk of deficiency of FVII (OR: 3.64; 95% CI: 1.73–7.64, p=0.001), protein C (OR: 4.319; 95% CI: 1.33–13.9, p=0.015) and protein S (OR: 5.50; 95% CI: 1.71–17.7, p=0.004).DiscussionGBP is associated with an increased risk of post-operative deficiency in some vitamin K-dependent coagulation factors. Whereas such deficiency is too weak to cause bleeding, it is significant enough to increase the risk of thrombosis.     

Melatonin attenuates lipopolysaccharide-induced acute lung inflammation in sleep-deprived mice

Abstract:  Sleep disorders are great problems in modern society. Even minimal changes of sleep can affect health. Especially, patients with pulmonary diseases complain of sleep problems such as sleep disturbance and insomnia. Recent studies have shown an association between sleep deprivation (SD) and inflammation, however, the underlying mechanisms remain unclear. In the present study, we investigated whether melatonin protects against acute lung inflammation in SD. Male ICR mice were deprived sleep using modified multiplatform water bath for 3 days. Acute lung inflammation was induced by lipopolysaccharide (LPS; 5 mg/kg). Melatonin (5 mg/kg) and LPS was administered in SD mice at day 2. Mice were divided into five groups as control, SD, LPS, LPS + SD, and LPS + SD + melatonin (each group, n = 11). Mice were killed on day 3 after treatment of melatonin and LPS for 24 hr. Lung tissues were collected for histological examination and protein analysis. The malondialdehyde (MDA) level was determined for the effect of oxidative stress. Melatonin restored weight loss in LPS + SD. Histological findings revealed alveolar damages with inflammatory cell infiltration in LPS + SD. Melatonin remarkably attenuated the alveolar damages. In western blot analysis, LPS reduced the levels of Bcl-XL and procaspase-3 in SD mice. After treatment with melatonin, the levels of Bcl-XL and procaspase-3 increased when compared with LPS + SD. LPS treatment showed an increase of TUNEL-positive cells, whereas melatonin prevented the increase of cell death in LPS + SD animals. In lipid peroxidation assay, melatonin significantly reduced the elevated MDA level in LPS + SD. Our results suggest that melatonin attenuates acute lung inflammation during SD via anti-apoptotic and anti-oxidative actions.     

Factor VIII concentrate infusion in patients with haemophilia results in decreased von Willebrand factor and ADAMTS‐13 activity

The effects of coagulation factor concentrate infusion on restoring secondary haemostasis in patients with haemophilia are obvious. It is not known whether coagulation factor concentrate infusion affects primary haemostasis or induces an acute inflammatory response. In this study, the influence of a factor VIII (FVIII) concentrate bolus infusion on platelet activation and responsiveness, endothelial activation, and inflammation in adult patients with severe haemophilia A was assessed. VWF showed a mild, but significant decrease 15 min after FVIII infusion (85.02 IU dL^?1) vs. before infusion (92.04 IU dL^?1; P = 0.017), while ADAMTS‐13 levels also show a mild but significant decrease from 66.1 ng mL^?1 before infusion, to 53.9 ng mL^?1 (P = 0.012) 15 min after and 50.8 ng mL^?1 (P = 0.050) 60 min after infusion. Platelet P‐selectin expression decreased 15 min (33.3 AU) and 60 min (38.7 AU) after infusion compared to before infusion (41.3 AU; P = 0.018 and 0.036). In conclusion, a single infusion of a high dose FVIII concentrate in haemophilia A patients may influence primary haemostasis by decreasing VWF, ADAMTS‐13 and the number of circulating activated platelets. These effects possibly occur as a consequence of binding of the infused FVIII to VWF, influencing its processing. When treating severe haemophilia A patients with coagulation concentrate infusion, one should realize this does not merely correct FVIII levels but also may influence primary haemostasis.     

Effect of beta2-adrenergic receptor functioning and increased norepinephrine on the hypercoagulable state with mental stress

Background Procoagulant stress responses may contribute to atherosclerosis development and acute coronary thrombosis. In the present study, we examined the role of β₂-adrenergic receptor function and plasma catecholamines in the stress-induced increase in the 2 hypercoagulability markers thrombin-antithrombin III (TAT) complex and fibrin D-dimer (DD). Methods Lymphocyte β₂-adrenoreceptor sensitivity and density were assessed at rest, and plasma levels of TAT, DD, epinephrine, and norepinephrine were measured at rest and in response to a standardized mental stress task in 19 normotensive and mildly hypertensive nonmedicated subjects (mean age 38 years, age range 29 to 48 years). Results The stressor elicited a significant increase in TAT (P = .024), DD (P = .026), and norepinephrine (P = .005). Resting β₂-adrenoreceptor sensitivity (isoproterenol-stimulated cyclic adenosine monophosphate production) plus the norepinephrine change scores (stress minus rest) accounted for 59% of the variance in the absolute TAT increase in response to stress (P = .001). Hypertension status and demographic variables such as sex did not influence the results. Conclusions Acute mental stress may trigger a hypercoagulable state evidenced by increased thrombin activity and increased fibrin turnover. β₂-Adrenergic receptor sensitivity and plasma catecholamine activity may mediate the procoagulant response to acute stressors. These mechanisms may help explain the adverse impact of mental stress on the cardiovascular system. (Am Heart J 2002;144:68-72.)     

Wilate use in 47 children with von Willebrand disease: the North London paediatric haemophilia network experience

Children with von Willebrand disease (VWD) in whom DDAVP is ineffective or contraindicated require treatment with a coagulation factor concentrate containing von Willebrand factor (VWF) and factor VIII (FVIII). The aim of this study was to monitor the safety, efficacy and tolerability of Wilate^® (a VWF:FVIII concentrate with a 1:1 ratio) used across the North London Paediatric Haemophilia Network since May 2010. In total, 47 children (aged 0.0–17.0 years) with type 1 (n = 28), type 2 (n = 7), type 3 (n = 10) and acquired VWS (n = 2) have been treated for bleeds, surgery and/or prophylaxis using 260 000 IU Wilate^®. Analysis of dose and frequency of treatment show expected responses to treatment with mean doses of 55, 50 and 50 IU kg^?1 for bleeds, surgery and prophylaxis respectively. Most bleeds responded to a single treatment. Surgical procedures were covered with clinician approved dosing schedules with 95% (39/41) reported as having excellent or good efficacy. There was no accumulation of FVIII or VWF and no thromboembolic events. This case series confirms the efficacy, safety and tolerability of Wilate^® in neonates, children and adolescents when used on‐demand, prophylactically and in the surgical setting.     

Effects of mobile phone electromagnetic fields at nonthermal SAR values on melatonin and body weight of Djungarian hamsters (Phodopus sungorus)

Abstract:  In three experiments, adult male Djungarian hamsters ( Phodopus sungorus ) were exposed 24 hr/day for 60 days to radio frequency electromagnetic fields (RF-EMF) at 383, 900, and 1800 MHz, modulated according to the TETRA (383 MHz) and GSM standards (900 and 1800 MHz), respectively. A radial waveguide system ensured a well defined and uniform exposure at whole-body averaged specific absorption rates of 80 mW/kg, which is equal to the upper limit of whole-body exposure of the general population in Germany and other countries. For each experiment, using two identical waveguides, hamsters were exposed (n = 120) and sham-exposed (n = 120) in a blind fashion. In all experiments, pineal and serum melatonin levels as well as the weights of testes, brain, kidneys, and liver were not affected. At 383 MHz, exposure resulted in a significant transient increase in body weight up to 4%, while at 900 MHz this body weight increase was more pronounced (up to 6%) and not transient. At 1800 MHz, no effect on body weight was seen. The results corroborate earlier findings which have shown no effects of RF-EMF on melatonin levels in vivo and in vitro. The data are in accordance with the hypothesis that absorbed RF energy may result in metabolic changes which eventually cause body weight increases in exposed animals. The data support the notion that metabolic effects of RF-EMFs need to be investigated in more detail in future studies.     

Elevated fibrinogen levels and subsequent subclinical atherosclerosis: the CARDIA Study

ObjectiveTo determine whether elevated levels of hemostatic factors are associated with the subsequent development of subclinical cardiovascular disease.MethodsFibrinogen, factors VII (FVII) and VIII (FVIII), and von Willebrand factor (vWF) were measured in 1396 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Coronary artery calcification (CAC) and carotid intimal/medial thickness (CIMT) were determined 13 years later. The adjusted prevalence of CAC and mean CIMT across the quartiles of each hemostatic factor was computed for the total sample and for each race and gender group.ResultsThe age-, race-, and gender-adjusted prevalences of CAC with increasing quartiles of fibrinogen were 14.4%, 15.2%, 20.0%, and 29.1% (p < 0.001 for trend). This trend persisted after further adjustment for body mass index (BMI), smoking, educational level, center, systolic blood pressure (BP), diabetes, antihypertensive medication use, total and high-density lipoprotein (HDL) cholesterol, and CRP. A similar trend was observed for CIMT (age-, race- and gender-adjusted, p < 0.001; multivariable-adjusted, p = 0.014). Further analyses of race and gender subgroups showed that increasing quartiles of fibrinogen were associated with CAC and CIMT in all subgroups except black men. The prevalence of CAC was not associated with increasing quartiles of FVII, FVIII, or vWF, suggesting they may be less involved in plaque progression.ConclusionAn elevated fibrinogen concentration in persons aged 25–37 is independently associated with subclinical cardiovascular disease in the subsequent decade.     

Correlation between endogenous VWF:Ag and PK parameters and bleeding frequency in severe haemophilia A subjects during three‐times‐weekly prophylaxis with rFVIII‐FS

Patients with severe haemophilia A experience frequent and spontaneous bleeding, causing debilitating damage to joints and decreasing quality of life. Prophylaxis with factor VIII (FVIII) reduces joint damage if initiated early. Circulating FVIII levels may be influenced by endogenous von Willebrand factor (VWF), a chaperone protein that binds and stabilizes FVIII. The aim of this study was to determine whether endogenous VWF antigen (VWF:Ag) levels are correlated with FVIII pharmacokinetic (PK) parameters and clinical outcomes in patients with severe haemophilia A. Previously treated, non‐inhibitor patients in a multinational, randomized, double‐blind, Ph II study received prophylaxis with once‐weekly BAY 79‐4980 (35 IU kg^?1) or thrice‐weekly recombinant sucrose‐formulated FVIII (rFVIII‐FS; 25 IU kg^?1). PK parameters were evaluated at weeks 1 and 26. The number of bleeds per patient during the study was captured as part of the core efficacy endpoint. Spearman rank correlations assessed relationships of VWF:Ag levels with patient age, PK and annualized bleeding rate. Of 131 study patients (aged 13?64 years; BAY 79‐4980, n = 63; rFVIII‐FS, n = 68), 27 (21%; n = 15 and 12 respectively) were evaluable for PK assessment. Baseline VWF:Ag levels correlated with patient age (P < 0.0001). There was no significant difference in PK results between treatments; thus, PK parameters and VWF levels of all patients were analysed together. AUC_norm and T_1/2 significantly increased with increased VWF:Ag (P < 0.001); clearance significantly decreased with increased VWF:Ag (P = 0.002). Annualized bleeding rate in patients treated with 3× per week rFVIII‐FS significantly correlated with VWF:Ag and age (P = 0.038 and 0.021 respectively). PK parameters as well as the clinical outcome significantly correlated with endogenous VWF:Ag. The improved clinical outcome in subjects with high VWF:Ag levels may be explained by VWF:Ag influence on FVIII PK.     

Effects of high-dose methylprednisolone therapy on coagulation factors in patients with acute immune thrombocytopenic purpura.

Autoimmune thrombocytopenic purpura (ITP) is a disease that presents with skin and mucous membrane bleeding due to thrombocytopenia. In the literature, there are a few studies about the effect of high-dose steroid therapy on coagulation tests in different diseases, but their results are still controversial. In this study, coagulation parameters were investigated that might have a role in hemostatic compensation in childhood acute ITP before and after high-dose methylprednisolone (HDMP) treatment. The study includes 21 children age 1.5 to 14 years with acute ITP and 21 healthy age-matched control subjects. All patients with acute ITP received HDMP for 7 days. Before and after HDMP treatment (0 and 8 days) prothrombin time, partial thromboplastin time, fibrinogen, Protein C, Protein S, antithrombin III, and the levels of factor II (FII), FV, FVII, FVIII, FIX, FX, FXI, and FXII were studied in all subjects. The results were compared with those of the control group. Pre-treatment Protein C and Protein S levels in the patient group were significantly lower than those in the control groups (p<0.05). Protein S and Protein C levels were significantly improved after HDMP treatment in patient group. There were lower FV, FVII, FX values in the patient group compared to the control groups on admission. There was no difference in AT III and fibrinogen levels before and after treatment. As a result, some changes in the coagulation system associated with thrombocytopenia were observed in patients with acute ITP. These changes may be accepted as compensatory mechanisms to maintain hemostasis.     

The Effect of Carbon Dioxide Insufflation Applied at Different Pressures and Periods on Thrombotic Factors

The aim of this experimantal study which is applied on rats, is to determine the differences on the clotting factors over the application of low and high intraabdominal pressure (IAP) values in different periods of time in carbon dioxide (CO₂) pneumoperitoneum. Thirty rats were randomized into five groups (n = 6): a control group (Group K) and 1 h and 6 mm Hg IAP (Group A), 2 h and 6 mm Hg IAP (Group B), 1 h and 12 mm Hg IAP (Group C) and 2 h and 12 mm Hg IAP were created with CO₂ pneumoperitoneum (Group D). At the end of the experiment, plasma samples taken from subjects and fibrinogen, FII (prothrombin), FV, FVII, FVIII, FIX, FX, FXI, FXII, von willebrand’s factor (vWF), ristocetin cofactor, protein C, protein S, antithrombin III (AT III) levels are studied. There were statistically significant differences in the mean levels of FII, FV, FVII, FVIII, FIX, FX, FXI, FXII, and protein S between the groups. A hypercoagulable state occurred with the following: increase in the coagulation parameters compared to the control group; increase in FVII in the group only Group C; decrease in AT III in all groups compared to the control group; decrease in protein C in the group only XII Group D compared to control group; decrease in protein S in all groups except group D compared to control group. CO₂ insufflation predisposes to thromboembolic events both by inducing coagulation factors and by suppressing the fibrinolytic system contrary to the controversies in the literature.     

Correlation between hypothalamic catecholamine synthesis and ether stress-induced ACTH secretion.

The rates of synthesis of norepinephrine (NE) and dopamine (DA) in several regions of the hypothalamus have been estimated after exposure of rats to stresses that increase ACTH secretion. The rate of 3H-NE and 3H-DA accumulation from 3H-tyrosine in vitro was used as an index of catecholamine synthesis rates. Exposure to ether vapor, 30 min of cold environment, or laparotomy increased ACTH secretion significantly, as indicated by plasma corticosterone levels. However, only the ether stress affected hypothalamic catecholamines; both NE and DA synthesis rates were increased in the arcuate nucleus are (ANA), but not in the median eminence (ME) or the residual hypothalamus (RH). Dexamethasone treatment blocked the stress-induced ACTH secretion, but had no affect on basal or stress-induced rates of amine synthesis. It is concluded that catecholamines in the ANA participate in mediating ether stress-induced ACTH secretion.     

Study of coagulation function in thawed apheresis plasma for photochemical treatment by amotosalen and UVA

Background and Objectives  Photochemical treatment (PCT) based on amotosalen and ultraviolet A light (UVA) demonstrated a wide range of pathogen inactivation. However, coagulation proteins are affected by this treatment. The aim of this study was to evaluate the coagulation parameters in apheresis plasma units after thawing and processing by PCT.
Materials and Methods  Thirty apheresis plasma units were rapidly frozen at ≤ –30°C after collection. Plasma units were thawed after 7 days for PCT with amotosalen and UVA light. Treated apheresis units were refrozen and stored at ≤ –30°C for 1 month. Samples were collected for each plasma units at several times of process. Coagulation times (prothrombin time, activated partial thromboplastin time), coagulation factors (fibrinogen, Factor [F] II, FV, FVII, FVIII, FIX, FX, FXI), prothrombin fragments 1 and 2, antithrombotic proteins (protein C, protein S, antithrombin) and total protein content were measured. Functionality of ADAMTS-13 was also tested.
Results  After thawing, coagulation times were slightly increased and a decrease of FV, FVIII and protein C activity was found. The mean recovery for all proteins, except one, ranged from 81% to 97% of the baseline activity in plasma units after thawing and PCT. FVIII was more affected with a mean recovery of 69 ± 8%. ADAMTS-13 function was also preserved after the whole process. The effect of an additional 1-month frozen storage on coagulation parameters was minimum.
Conclusion  Coagulation protein levels after thawing and processing of plasma by PCT with amotosalen and UVA were preserved well in the physiological ranges.     

Age-dependent increase of FVIII:C in mild haemophilia A

Summary.  Variability of FVIII:C levels in healthy individuals and age-dependent increase are a known phenomenon. In haemophilia, increasing FVIII:C levels with age have not been described yet. In our study, we evaluated this issue retrospectively in a cohort older than 45 years of 29 patients with mild haemophilia and 14 patients with moderate or severe haemophilia at last visit at the haemophilia centre Frankfurt. The median duration of observation evaluated in this study was 17 years (range 5–28). Results show a significant correlation of increasing FVIII:C levels with age in mild haemophilia ( P  = 0.000041) and a non-significant tendency to a higher increase in higher age ( P  = 0.085652). The median difference of FVIII:C level between the first and last measurement was 8% of normal plasma concentration (range −3% to +35%). Median FVIII:C level increase of patients younger than 62 years was 7.5% (range −3 to 22), median increase in older patients was 12% (range 0–35). This tendency could not be correlated to decreased number of bleedings, but FVIII substitution dosage should be adapted to changing plasma levels at higher age to prevent overdosing or thrombotic risks. Possible causes and contributing factors for increasing FVIII:C levels are discussed. Statistical significance remains to be confirmed in larger prospective studies also including younger patients.