Bone microstructure and volumetric bone mineral density in patients with hyperuricemia with and without psoriasis.

We analyzed volumetric bone mineral density (vBMD) and bone microstructure using HR-pQCT in subjects with normouricemia (NU) and subjects with hyperuricemia (HU) with and without psoriasis (PSO). HU was associated with higher cortical vBMD and thickness. Differences in average and trabecular vBMD were found between patients with PSO + HU and NU. INTRODUCTION: Hyperuricemia (HU) and gout are co-conditions of psoriasis and psoriatic arthritis. Current data suggest a positive association between HU and areal bone mineral density (BMD) and a negative influence of psoriasis on local bone, even in the absence of arthritis. However, the influence of the combination of HU and psoriasis on bone is still unclear. The aim of this study was to assess the impact of HU with and without psoriasis on bone microstructure and volumetric BMD (vBMD). METHODS: Healthy individuals with uric acid levels within the normal range (NU), with hyperuricemia (HU), patients with hyperuricemia and psoriasis (PSO + HU), and patients with uric acid within the normal range and psoriasis (PSO + NU) were included in our study. Psoriasis patients had no current or past symptoms of arthritis. Average, trabecular, and cortical vBMD (mgHA/cm3); trabecular number (Tb.N, 1/mm) and thickness (Tb.Th, mm); inhomogeneity of the network (1/N.SD, mm); and cortical thickness (Ct.Th., mm) were carried out at the ultradistal radius using high-resolution peripheral quantitative computed tomography. In addition, bone turnover markers such as DKK-1, sclerostin, and P1NP were analyzed. RESULTS: In total, 130 individuals were included (44 NU participants (34% female), 50 HU (24%), 16 PSO + HU (6%), 20 PSO + NU (60%)). Subjects were aged: NU 54.5 (42.8, 62.1), HU 57.5 (18.6, 65.1), PSO + HU 52.0 (42.3, 57.8), and PSO + NU 42.5 (34.8, 56.8), respectively. After adjusting for age, sex, BMI, and diabetes, patients in the HU group revealed significantly higher values of cortical vBMD (p < 0.001) as well as cortical thickness (p = 0.04) compared to the NU group. PSO + NU showed no differences to NU, but PSO + HU demonstrated both lower average (p = 0.03) and trabecular vBMD (p = 0.02). P1NP was associated with average, cortical, and trabecular vBMD as well as cortical thickness while sclerostin levels were related to trabecular vBMD. CONCLUSION: Hyperuricemia in otherwise healthy subjects was associated with a better cortical vBMD and higher cortical thickness. However, patients with both psoriasis and hyperuricemia revealed a lower vBMD.

Angiotensin inhibition stimulates PPARgamma and the release of visfatin.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) exhibit beneficial antidiabetic effects in patients with type 2 diabetes independent of their blood pressure-lowering effects. Some antidiabetic properties of ARB and ACE-I might by exerted by activation of peroxisome proliferator-activated receptor gamma (PPARgamma). However, it is not clear whether this action is drug specific. MATERIALS AND METHODS: The binding affinity of telmisartan, valsartan, lisinopril, rosiglitazone and angiotensin II to PPARgamma was assessed in a cell-free assay system. PPARgamma signalling was studied in isolated skeletal muscle cells using Western blot analysis of phosphorylated protein kinase B (pAKT) and phosphorylated insulin like growth factor-1 receptor (pILGF-1R). Further, the ability of the drugs under study to stimulate the release of the adipocytokine visfatin was investigated in isolated human adipocytes, skeletal muscle cells, and umbilical vein endothelial cells (HUVEC). RESULTS: The binding affinity to PPARgamma was highest for telmisartan with a half-maximal effective concentration of 463 nM, followed by lisinopril (2.9 microM) and valsartan (6.2 microM). In skeletal muscle cells phosphorylation of ILGF-1R was 2-fold increased after incubation with telmisartan or valsartan and 1.7-fold with lisinopril. pAKT expression was enhanced after incubation with telmisartan, valsartan and with lisinopril. The release of visfatin from adipocytes was 1.6-fold increased after treatment with lisinopril and about 2.0-fold increased with telmisartan and valsartan. Similar results were obtained in skeletal muscle cells and HUVEC. CONCLUSIONS: Our data confirm agonism of telmisartan, valsartan and lisinopril on PPARgamma. Pharmacokinetic differences may explain different potencies of PPARgamma stimulation by drugs acting on the renin-angiotensin system in clinical settings.

Rapid achievement of PML-RAR alpha polymerase chain reaction (PCR)-negativity by combined treatment with all-trans-retinoic acid and chemotherapy in acute promyelocytic leukemia: a pilot study.

The reverse transcriptase-polymerase chain reaction (RT-PCR) for the fusion transcript of PML-RAR alpha can be used to detect minimal residual disease (MRD) in acute promyelocytic leukemia (APL). We have applied a semi-quantitative two-step PCR assay (sensitivity: step 1 = 1 in 10(3) cells; step 2 = 1 in 10(6) cells) to monitor the dynamics of MRD after combined therapy with all-trans-retinoic acid (ATRA) and chemotherapy (CT) in 5 patients in whom complete clinical remission (CR) was achieved. The patients received an induction treatment with ATRA for 47, 40, 38, 14 or 10 days. In three patients ATRA was followed by CT. Two patients with hyperleukocytosis at diagnosis or after ATRA received an overlapping CT starting from day 3 or 7. Four of the five patients became two-step PCR-negative in their bone marrow within 43 to 82 days after onset of therapy. Two-step PCR-negatively was achieved with ATRA plus one course of CT in these four patients who are still in continuous complete remission after 19, 18, 7 and 5 months. One of these patients did not even receive consolidation CT because of congestive heart failure. The fifth patient remained second-step PCR-positive and relapsed after 5 months. Our results indicate that the combined regimen can rapidly reduce MRD below a detection limit of 1 in 10(6) cells within 1-3 months and that these results can even by achieved by a short course of ATRA together with only one cycle of CT.

Semicarbazide-sensitive amine oxidase catalyzes endothelial cell-mediated low density lipoprotein oxidation.

OBJECTIVE: Deamination products of semicarbazide-sensitive amine oxidases (SSAO), i.e. aldehydes, superoxide and ammonia have been shown to initiate vascular damage. SSAOs are copper-enzymes, present in endothelial (EC), smooth muscle cells (SMC) and in blood. Transition metals ions (Cu, Fe) mediate the oxidative (atherogenic) modification of LDL by SMC and EC. The physiological source of the active metal ions is still under debate. We hypothesize that SSAOs may catalyze LDL oxidation by endothelial cells via enzyme-complexed Cu++. METHODS: EC isolated from human umbilical veins and cultured in 35 mm wells in RPMI-1640 medium were used as LDL oxidation system. RESULTS: Diamine oxidase (DAO), a SSAO which activity is elevated in tissues and sera of diabetic patients, catalyzes the oxidation of LDL by EC. In the presence of purified DAO (0.07 to 70 U/l) LDL oxidation was increased up to 10-fold as measured by thiobarbituric acid reactive substance (TBARS) formation as well as apoprotein modification of LDL. Chemical blockage of the SSAO substrate binding site did not inhibit the catalytic effect of DAO on LDL oxidation. Denaturation of the enzyme did not destroy the ability of the preparation to facilitate LDL oxidation by EC. The potential of the enzyme to catalyze LDL oxidation was not suppressed in the presence of serum. However, selective removing of enzyme-copper completely abolished the ability of the enzyme to trigger cell-mediated LDL oxidation. CONCLUSION: DAO, beside generating angiopathic deamination products, has the potential to act as a pathophysiological catalyst of LDL atherogenic modification by vascular cells.

Immunoglobulin E response to human proteins in atopic patients.

The demonstration that human IgE recognizes both exogenous allergens and structurally related human proteins has led to the hypothesis that IgE autoreactivity may be a pathogenic factor in atopic diseases. To determine the frequency of occurrence as well as the disease specificity of this phenomenon, we tested sera from patients with atopic diseases and, for control purposes, from persons with immunologically mediated disorders for serum IgE reactivity with nitrocellulose-blotted human proteins. We found that 12 of 20 sera from atopic patients with pronounced skin lesions contained Western blot-detectable IgE antibodies. Patients suffering predominantly from allergic rhinoconjunctivitis as well as control individuals failed to display serum IgE autoreactivity, but occasionally exhibited elevated serum IgE levels. The molecular weights of the IgE-defined autoantigens ranged predominantly from 10 to 100 kDa. Whereas some of these were expressed in only certain cell types, others were detected in histogenetically different cells. Our results suggest that IgE autoimmunity occurs frequently in atopic dermatitis patients and may be of pathogenic relevance for the chronicity of skin manifestations typical of this disease.

Hemodynamic effects of parathyroid hormone-related peptide-(1-34) in humans.

It has been suggested that PTH-related peptide-(1-34) (PTHrP) is a regulator or modulator of regional or systemic cardiovascular function with varying vasodilating actions in different species. We have studied the cardiovascular pharmacodynamic profile of PTHrP in healthy humans. In a double blind, placebo-controlled, cross-over study design, eight healthy subjects were assigned to stepwise increased i.v. doses of PTHrP. In addition, a dose-response curve to PTHrP was constructed in a dorsal hand vein in eight subjects. PTHrP dose-dependently increased pulse rate and renal plasma flow by more than 50% (P < 0.0001 for both parameters, by ANOVA), but only a small venodilating response was seen in hand vein experiments, and no effect was noted on mean arterial blood pressure or cardiac inotropic performance. Although it is unlikely that PTHrP regulates systemic hemodynamics, its chronotropic effect and its potent action on renal plasma flow may represent the primary cardiovascular physiological targets of action.

Glucocorticoids dose-dependently increase plasma levels of granulocyte colony stimulating factor in man.

Glucocorticoids increase neutrophil counts by decreasing the margination of neutrophils and mobilizing neutrophils from the bone marrow pool. The mechanisms for these effects however are not fully elucidated, but it has been demonstrated that dexamethasone enhances release of colony stimulating factor (G-CSF) in-vitro. We therefore hypothesized, that dexamethasone may increase plasma levels of G-CSF. A double blind, randomized, placebo-controlled, three-way cross-over trial was conducted in nine healthy men. Every subject received four identical infusions of saline, 0.04 mg/kg or 1.0 mg/kg dexamethasone during three observation periods of 48 hours each. The low dose of dexamethasone increased G-CSF levels from a baseline of 15.5 ng/L (CI: 10.6-20.4) by 240% (CI: 115-366%) at 24 hours. The high dexamethasone dose increased G-CSF levels from a baseline of 12.3 ng/L (CI: 9.7-14.9) by 871% (CI: 592-1149%) at 24 hours (p=0.008 for all comparisons). No further increase was observed at 48 hours but the effect was less pronounced (p<0.008 and p=0.08 for the high and the low dose of dexamethasone, respectively). Granulocyte-macrophage-CSF (GM-CSF) levels were below the assay's detection limit of 0.36 ng/L in all subjects. In conclusion, dexamethasone dose dependently increases G-CSF levels in healthy men, an effect which may account for some of its effects on neutrophils.

Effects of estradiol on circulating P-selectin.

The membrane protein P-selectin tethers leukocytes to endothelial cells (EC) and on activated platelets, and may play a role in atherosclerosis. Lower plasma levels of a soluble (c) P-selectin have recently been observed in premenopausal women compared to those in men. Given the antiatherogenic-cardioprotective effect of 17 beta-estradiol (E2), we hypothesized that E2 may down-regulate the expression of P-selectin and subsequently decrease cP-selectin levels. The effects of E2 on levels of plasma cP-selectin were evaluated during the menstrual cycle in healthy women (n = 18) and by measuring the effect of a single im injection of 10 mg E2 valerate (n = 9) or placebo (n = 10) on cP-selectin levels in healthy male volunteers. In women, the cyclic increase in serum E2 concentrations was accompanied by a decrease in cP-selectin levels from 110 ng/mL [95% confidence interval (CI), 100-137 ng/mL] in the follicular phase. The decrease reached a maximum of 13% (95% CI, 2-19%, P = 0.014) in the luteal phase. In men, cP-selectin decreased from a median of 139 ng/mL (95% CI, 113-165) to 125 ng/mL (95% CI, 97-152; P = 0.038) 4 days after E2 injection. The median baseline value of cP-selectin in the 19 male volunteers was 133 ng/mL (95% CI, 115-143 ng/mL) and was approximately 30% higher than those in the female volunteers during the midcycle (P = 0.024) and luteal (P = 0.012) phases, but was not different from that during the follicular phase. In sum, our study suggests that E2 lowers cP-selectin levels. An E2-induced decrease in cP-selectin reflects either decreased activation or damage of platelets and/or endothelial cells in vivo. Thus, our study may point to an additional mechanism for the residual antiatherogenic-cardioprotective effect of E2 that cannot be explained by its lipid-lowering effects.

Acetaminophen has greater antipyretic efficacy than aspirin in endotoxemia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the antipyretic efficacy of aspirin and acetaminophen (INN, paracetamol) in 30 male volunteers with the use of endotoxin (lipopolysaccharide) to elicit a standardized febrile response. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in parallel groups. Subjects received an intravenous endotoxin bolus of 4 ng/kg after premedication with either placebo, 1000 mg aspirin, or 1000 mg acetaminophen by mouth. RESULTS: Peak body temperatures were 38.5 degrees C +/- 0.2 degrees C in the placebo group, 37.6 degrees C +/- 0.2 degrees C in the acetaminophen group (P = .001 versus placebo), and 38.6 degrees C +/- 0.2 degrees C in the subjects treated with aspirin (P = .001 versus acetaminophen; P = .570 versus placebo) at 4 hours after lipopolysaccharide infusion. Subjective symptom scores for chills and perception of fever were higher in the placebo group than in the acetaminophen group (chills, 2.5 +/- 0.3 versus 1.0 +/- 0.2, P = .009 and fever, 2.5 +/- 0.2 versus 2.0 +/- 0.2, P = .021). Tumor necrosis factor-alpha, interleukin-6, and interleukin-8 levels rose by several orders of magnitude (P < .001 versus baseline in all groups), without significant intergroup differences. CONCLUSIONS: Acetaminophen was the superior antipyretic drug in endotoxemia compared with aspirin. Treatment with acetaminophen ameliorates subjective symptoms induced by endotoxemia without compromising the humoral response of a subject to endotoxin. This observation has clinical interest and may also help to improve the lipopolysaccharide model, which can be used to test anti-inflammatory and anticoagulatory drugs.

Tyrosine: an inhibitor of LDL oxidation and endothelial cell cytotoxicity initiated by superoxide/nitric oxide radicals.

Tyrosyl radicals can catalyze LDL oxidation. In addition to their LDL oxidizing ability, superoxide (O2.-)/nitric oxide (NO.) generate phenoxyl radicals when reacting with tyrosine. Therefore we tested if tyrosine can act as a pro-oxidant in O2.-/NO.-initiated LDL oxidation. When LDL was exposed to O2.-/NO., tyrosine exerted a strong inhibitory effect on O2.-/ NO.-initiated LDL oxidation as measured by TBARS formation and alteration in electrophoretic mobility of LDL. Tyrosine was also able to protect human endothelial cells from the cytotoxic effect of O2.-/NO.. Because O2.-/NO. can occur in vivo, the results may indicate that serum-free tyrosine could act as an efficacious physiological antioxidant in case of O2.-/NO.-initiated LDL oxidation and endothelial cell cytotoxicity.

Salicylate promotes myeloperoxidase-initiated LDL oxidation: antagonization by its metabolite gentisic acid.

The oxidative modification of low density lipoprotein (LDL) may play a significant role in atherogenesis. Tyrosyl radicals generated by myeloperoxidase (MPO) can act as prooxidants of LDL oxidation. Taking into consideration, that monophenolic compounds are able to form phenoxyl radicals in presence of peroxidases, we have tested salicylate, in its ability to act as a prooxidant in the MPO system. Measurement of conjugated dienes and lipid hydroperoxides were taken as indicators of lipid oxidation. Exposure of LDL preparations to MPO in presence of salicylate revealed that the drug could act as a catalyst of lipid oxidation in LDL. The radical scavenger ascorbic acid as well as heme poisons (cyanide, azide) and catalase were inhibitory. The main metabolite of salicylic acid, gentisic acid, showed inhibitory action in the MPO system. Even when lipid oxidation was maximally stimulated by salicylate the LDL oxidation was efficaciously counteracted in presence of gentisic acid at salicylate/gentisic acid ratios that could be reached in plasma of patients receiving aspirin medication. Gentisic acid was also able to impair the tyrosyl radical catalyzed LDL peroxidation. The results suggest that salicylate could act like tyrosine via a phenoxyl radical as a catalyst of LDL oxidative modification by MPO. But the prooxidant activity of this radical species is effectively counteracted by the salicylate metabolite gentisic acid.

Salicylate inhibits LDL oxidation initiated by superoxide/nitric oxide radicals.

Simultaneously produced superoxide/nitric oxide radicals (O2*-/NO*) could form peroxynitrite (OONO-) which has been found to cause atherogenic, i.e. oxidative modification of LDL. Aromatic hydroxylation and nitration of the aspirin metabolite salicylate by OONO- has been reported. Therefore we tested if salicylate may be able to protect LDL from oxidation by O2*-/NO* by scavenging the OONO reactive decomposition products. When LDL was exposed to simultaneously produced O2*-/NO* using the sydnonimine SIN-1, salicylate exerted an inhibitory effect on LDL oxidation as measured by TBARS and lipid hydroperoxide formation and alteration in electrophoretic mobility of LDL. The cytotoxic effect of SIN-1 pre-oxidised LDL to endothelial cells was also diminished when salicylate was present during SIN-1 treatment of LDL. Spectrophotometric analysis revealed that salicylate was converted to dihydroxybenzoic acid (DHBA) derivatives in the presence of SIN-1. 2,3- and 2,5-DHBA were even more effective to protect LDL from oxidation by O2*-/NO*. Because O2*-/NO* can occur in vivo, the results may indicate that salicylate could act as an efficacious inhibitor of O2*-/NO* initiated atherogenic LDL modification, thus further supporting the rationale of aspirin medication regarding cardiovascular diseases.

Homocysteine promotes the LDL oxidase activity of ceruloplasmin.

Ceruloplasmin (CP) oxidises low density lipoprotein (LDL). The oxidising potential depends on the formation of Cu(+)-CP which is redox-cycled during oxidation. Homocysteine (HCY) reduces free Cu(2+), potentiating its cell-damaging property. We show that HCY enhanced LDL oxidation by CP, but did not activate the LDL oxidising potential of Cu(2+)-diamine oxidase. Selective removal of the redox-active Cu(2+) abolished the LDL oxidase activity of CP. However, HCY partially restored the LDL oxidase activity of redox-copper depleted CP, indicating that the remaining six copper atoms in CP may also be involved in the process. Spectroscopic and oxidation inhibition studies using the Cu(+)-reagent bathocuproine revealed that HCY induced Cu(+)-CP formation, thus promoting its LDL oxidase activity.

p-Hydroxyphenylacetaldehyde, the major product of tyrosine oxidation by the activated myeloperoxidase system can act as an antioxidant in LDL.

The oxidative modification of low density lipoprotein (LDL) may play a significant role in atherogenesis. HOCl generated by the myeloperoxidase/H2O2/Cl- system of activated neutrophils may be operative in vivo making LDL atherogenic. Tyrosine has been found to be oxidized by HOCl to p-hydroxyphenylacetaldehyde (p-HA) capable of modifying phospholipid amino groups in LDL. As an amphiphatic phenolic compound, p-HA may have the potential to act as an antioxidant in the lipid phase of LDL. The present results show that (a) tyrosine exerts a protective effect on LDL modification by HOCl, (b) p-HA could act as antioxidant associated with the lipoprotein preventing cell- and transition metal ion-mediated LDL oxidation and (c) p-HA was able to scavenge free radicals.

The salicylate metabolite gentisic acid, but not the parent drug, inhibits glucose autoxidation-mediated atherogenic modification of low density lipoprotein.

Oxidation of low density lipoprotein (LDL) by glucose-derived radicals may play a role in the aetiology of atherosclerosis in diabetes. Salicylate was shown to scavenge certain radicals. In the present study, aspirin, salicylate and its metabolites 2,5- and 2, 3-dihydroxybenzoic acid (DHBA) were tested for their ability to impair LDL oxidation by glucose. Only the DHBA derivatives, when present during LDL modification, inhibited LDL oxidation and the increase in endothelial tissue factor synthesis induced by glucose oxidised LDL. The LDL glycation reaction was not affected by DHBA. The antioxidative action of DHBA may be attributed to free radical scavenging and/or chelation of transition metal ions catalysing glucose autoxidation.

The immune system and the effects of non-volatile anesthetics on neutrophil transmigration through endothelial cell monolayers.

Inflammation represents the consequence of capillary dilation with accumulation of fluid and transmigration of leukocytes into the surrounding tissue. Leukocytes play a major role in the defense system of the body against invading microorganisms. This defense system has a non-specific branch consisting of granulocytes and macrophages and a specific branch of lymphocytes. Granulocytes release cytotoxic compounds from their intracellular granules into their local environment when encountering microorganisms. This random destruction happens rapidly, but it may also harm healthy tissue of the body. Leukocytes patrol the body by circulating through the blood and lymphatic system ensuring a continuous surveillance which is a prerequisite for an efficient defense. Upon tissue damage and inflammation, leukocytes are recruited from the blood to sites of injury, and this trafficking displays exquisite specificity. In the late 1890 s, Metchnikoff noted the power of certain blood cells to move towards microorganisms and ingest them. In fact, leukocytes adhere to the endothelium of the blood vessels, and subsequently leave the circulation by transmigration through the intercellular junctions of the endothelial cell monolayer. Transmigration is driven by chemoattractants, a process known as diapedesis. Reversible adherence of leukocytes to the endothelium, basement membranes, and other surfaces is an essential event in the establishment of inflammation, whose molecular basis is beginning to be understood. Inflammation may become chronic in many pathophysiologic processes and disease states. In long-term mechanically ventilated critically ill patients, non-volatile anesthetics are needed over a prolonged time period. Perioperative infections are a major cause of morbidity and mortality in critically ill patients. Therefore, the influence of non-volatile anesthetics and opioid agents on the immune system is of high interest. After presentation of the different effectors of the immune system and their fluxes through the body, the aim of this review is to propose a general model of leukocyte transmigration through endothelial cell monolayers. It emphasizes in which way different non-volatile anesthetic drugs may affect the non-specific branch of the immune system, i.e. the leukocyte transmigration through endothelial cell monolayers.

Partial inhibition of nitric oxide synthase primes the stimulated pathway of vWF-secretion in man.

Increased release of von Willebrand factor (vWF) has been linked to the pathogenesis of atherosclerosis. For this complex disease, impairment of endothelium-derived, nitric oxide production and impaired vascular relaxation has also been reported. Since endothelially produced nitric oxide (NO) is known to inhibit secretion of the Weibel-Palade bodies in animals, we hypothesized that NO could mitigate vWF secretion. In a randomized, placebo controlled cross-over trial, eight male volunteers received N-monomethyl-L-arginine (LNMMA) to block endothelial NO production or placebo, and vWF release was stimulated by infusing desmopressin in three cumulative doses (0.05, 0.15, 0.4 microg/kg) in both periods. At a threshold dose of 0.l5 microg/kg desmopressin, concomitant partial blockade of NO production resulted in 20% higher levels of vWF (P<0.04). However, maximal vWF release after 0.4 microg/kg desmopressin was unaffected by L-NMMA (Delta7% between periods, P=0.88). These data show the dampening effect of NO production on vWF release in response to threshold concentrations of secretagogues. This may in part explain the higher vWF levels in cardiovascular diseases associated with impaired endothelial NO generation.

Increased levels of activated factor VII and decreased plasma protein S activity and circulating thrombomodulin during use of oral contraceptives.

In the present study the effect of oral contraceptive (OC) treatment on selected factors involved in the activation, i.e. circulating activated factor VII (cFVIIa), and in the inhibition of blood coagulation, i.e. plasma protein S activity and circulating thrombomodulin (cTM), were for the first time measured in OC users in a prospective study. Beside other coagulation variables, these parameters were measured during treatment with three low estrogen formulations containing different gestagen components (norgestimate, gestodene). During OC treatment increases in the activation markers prothrombin fragment F1 + 2 and D-Dimer were found, suggesting an increased activation of blood coagulation and fibrinolysis. Along with elevated plasma levels of FVII antigen, cFVIIa was also found increased in all three treatment groups, while inhibitory components of blood coagulation, plasma protein S activity and cTM, significantly and similarly decreased during treatment in all three treatment groups. We conclude that low dose estrogen pills induce similar changes in the plasma levels of main regulatory components of blood coagulation, despite differences in their gestagen components. Increased levels of activators and decreased activities of inhibitors may contribute to arterial and venous thrombotic complications seen in predisposed OC users.

PIP: The effect of oral contraceptive (OC) treatment on selected factors involved in the activation and inhibition of blood coagulation was measured in a prospectively randomized parallel-group centralized-center study. These were circulating activated factor VII (cFVIIa) as well as plasma protein S activity and circulating thrombomodulin (cTM). In addition to other coagulation variables these parameters were measured during treatment with 3 low-estrogen formulations containing different gestagen components (norgestimate, gestodene). 60 healthy women 19-37 years old were included. The women in Group I used Cileste tablets containing 35 mcg ethinyl estradiol (EE) and 250 mcg norgestimate (NG). Group II women used the 3-phase preparation Tri-Cileste containing EE and different doses of NG; and Group II women used the 3-phase preparation Triodena containing different doses of EE and gestodene (GS). 21 days on treatment were followed by 7 days off of treatment before the next cycle was started. Participants were treated for 6 cycles. Blood samples were obtained during the luteal phase before treatment and on days 18-22 of the 3rd and 6th treatment cycle. The plasma levels of various coagulation parameters, such as fibrinogen (Cileste, Tri-Cileste p 0.05; Triodena p 0.0005); fibrin-split product D-Dimer (Cileste p 0.05; Tri-Cileste, Triodena p 0.005), prothrombin fragment F1+2 (Cileste p 0.0005); Tri-Cileste, Triodena p 0.05); Factor VII antigen (Cileste, Triodena p 0.0005; Tri-Cileste p 0.005); FVII clotting activity (Cileste p 0.0005; Tri-Cileste p 0.05; Triodena p 0.005), and activated factor VII (Cileste p 0.0005; Tri-Cileste p 0.05; Triodena p 0.005) were significantly higher during the 3rd treatment cycle compared with the pretreatment values. A significant decrease was also found in the plasma levels of total and free protein S antigen (total protein S: Cileste p 0.05; Tri-Cileste, Triodena p 0.005; free protein S: Cileste, Tri-Cileste p 0.0005; Triodena p 0.05) and circulating thrombomodulin (Cileste p 0.05; Tri-Cileste p 0.0005; Triodena p 0.005).

Plasma levels of activated factor VII decrease during the menstrual cycle.

Men have an increased cardiovascular risk as compared to women, which is largely ascribed to the cardioprotective effects of female sex steroids. We hypothesised that this may be reflected by differences in the activation status of the coagulation system. Hence the aim of this study was to compare plasma levels of activated factor VII (FVIIa) in men and women, and to study the influence of the menstrual cycle on FVIIa levels. In a prospective study we investigated 20 healthy young women and 20 men. Men had significantly higher levels of activated factor VII (60 mU/ml, CI: 52 to 67) than women during all phases of the menstrual cycle. In women FVIIa was higher during the follicular phase (41 mU/ml, CI: 33 to 50) than during midcycle (34 mU/ml, CI: 24 to 45; p = 0.022 vs. follicular phase) and during the luteal phase (33 mU/ml, CI: 24 to 42; p = 0.006 vs. follicular phase). Prothrombin fragment (F1 + 2) levels decreased from 0.86 nmol/l (CI: 0.51-1.21) by -23% (-39% to -8%; p = 0.011) during midcycle and by -25% (CI: -51% to 1%; p = 0.023) during the luteal phase. These data support the contention that plasma levels of FVIIa, a key enzyme of the coagulation cascade, may be down-regulated by endogenously produced female sex hormones during the menstrual cycle. This may at least partially explain the marked gender differences found in FVIIa.

D-dimer and TAT measurement in patients with deep venous thrombosis: utility in diagnosis and judgement of anticoagulant treatment effectiveness.

The plasma levels of thrombin-antithrombin III-complexes (TAT) and the fibrin split product D-Dimer were measured in 39 patients with phlebographically proven acute DVT: 34 patients had proximal DVT, 5 had calf DVT. The sensitivity of D-Dimer and TAT measurements in the diagnosis of proximal DVT was found to be dependent on the duration of symptoms: 0 to 7 days (n = 27): elevated D-Dimer levels (greater than 120 ng/ml) = 1, D-Dimer Latex test positive (greater than 500 ng/ml) = 1, elevated TAT levels (greater than 6 ng/ml) = 0.88. Eight to 14 days (n = 7): elevated D-Dimer levels = 1, D-Dimer Latex test positive = 0.33, elevated TAT levels = 0.66; specificity: elevated D-Dimer: 0.48, D-Dimer Latex test: 1, elevated TAT: 0.76. Calf DVT patients (n = 5) had elevated D-Dimer levels, negative Latex tests and 3 of them had normal TAT values. Hemostatic and fibrinolytic parameters were also determined in 13 patients during heparin treatment of proximal DVT. Elevated D-Dimer and TAT levels rapidly decreased after initiation of anticoagulant therapy. In 2 of 13 patients a marked increase in D-Dimer and TAT levels was observed in periods of ineffective heparinization, documented by normal or only slightly prolonged thrombin clotting times. We conclude from our results that 1) D-Dimer EIA measurement, in contrast to TAT measurement, shows a very high sensitivity in the diagnosis of DVT, 2) due to low specificity this test can only be used to exclude thrombosis in patients with suspected DVT, and 3) the determination of the plasma levels of D-Dimer and TAT may be useful for judging the effect of anticoagulant treatment on thrombotic processes.