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Essentials Retinal vein occlusion (RVO), characterized by blood hyperviscosity, has an unclear pathogenesis. We aimed to find out if hemorheological profile is altered by oxidative stress in RVO patients. Red blood cell (RBC) oxidative stress is associated to whole blood viscosity and RBC deformability. Reactive oxygen species alter RBC membrane rigidity, playing a key role in RVO pathogenesis.Background Retinal vein occlusion (RVO) is characterized by vision loss resulting from hypoperfusion and hypoxia of the retina. RVO pathogenesis is not yet fully understood, although blood hyperviscosity has been observed. Erythrocyte deformability plays a key role in determining blood viscosity, and it is critical to microvascular perfusion and oxygen delivery. It has been shown that oxidative stress-induced erythrocyte membrane fluidity alterations are linked to the progression of cardiovascular diseases. Objectives To determine whether erythrocytes from RVO patients show signs of oxidative stress, and whether this condition can modify the hemorheologic profile in these patients. Patients and Methods We analyzed the entire hemorheologic profile and erythrocyte oxidative stress - reactive oxygen species (ROS) production and membrane lipid peroxidation - in 128 RVO patients and 128 healthy subjects, matched for age and sex. Fluorescence anisotropy was used to evaluate the fluidity of erythrocyte membranes. Results In RVO patients, erythrocyte oxidative stress was present and positively correlated with whole blood viscosity and erythrocyte deformability. Multivariate linear regression analysis after adjustment for age, cardiovascular risk factors, medications, leukocyte number and mean corpuscular volume indicated that erythrocyte-derived ROS and erythrocyte lipid peroxidation were significantly and positively correlated with erythrocyte membrane viscosity and deformability. Moreover, in vitro experiments demonstrated that ROS have a key role in erythrocyte membrane fluidity. Conclusions Our findings indicate that erythrocyte oxidative stress plays a key role in the pathogenesis of RVO, and pave the way to new therapeutic interventions.

Introduction Sudden sensorineural hearing loss (SSNHL) involves an acute unexplained hearing loss, nearly always unilateral, that occurs over less than a 72-hour period. SSNHL pathogenesis is not yet fully understood. Cochlear vascular occlusion has been proposed as a potential mechanism of hearing damage and cochlear ischaemia has been related to alterations of cochlear microvessels. In addition, some researchers have focused their attention on the rheological alterations and blood hyperviscosity. Erythrocyte deformability plays a key role in determining blood viscosity, and it is critical to cochlear perfusion. It has been shown that oxidative stress-induced erythrocyte membrane fluidity alterations are linked to the progression of cardiovascular diseases. Methods To determine whether erythrocytes from SSNHL patients show signs of oxidative stress, and whether this condition can modify the haemorheologic profile in these patients, we analysed haemorheologic profile and erythrocyte oxidative stress in 35 SSNHL patients and 35 healthy subjects, matched for age and sex. Fluorescence anisotropy was used to evaluate the fluidity of erythrocyte membranes. Results Our results show a significant structural and functional involvement of erythrocyte membrane alterations in SSNHL, as well as elevated levels of membrane lipid peroxidation and intracellular reactive oxygen species (ROS) production. In addition, erythrocyte-derived ROS and erythrocyte lipid peroxidation positively correlated with whole blood viscosity and erythrocyte deformability. Moreover, in vitro experiments demonstrated that ROS display a key role in erythrocyte membrane fluidity. Conclusion These findings indicate that erythrocyte oxidative stress plays a key role in the pathogenesis of SSNHL and pave the way to new therapeutic interventions.

Takotsubo cardiomyopathy (TC) is characterized by transient hypokinesis of the left ventricular apex or midventricular segments with coronary arteries without significant stenosis. It is often associated with emotional or physical stress; however, its pathophysiology is still unclear. In the present study, we analyzed the alterations in blood viscosity and markers of endothelial damage induced by sympathetic stimulation in patients with previous TC. Seventeen women (mean age 71 years) with previous TC, included and investigated in the TC Tuscany Registry, were compared to a control group of 8 age- and risk factor-matched women with chest pain and coronary arteries free of stenosis. All subjects underwent the cold pressor test (CPT). Before and after the CPT, the hemorheologic parameters (whole blood viscosity at 0.512 s(-1) and 94.5 s(-1), plasma viscosity, erythrocyte deformability index, and erythrocyte aggregation), catecholamines, plasminogen activator inhibitor-1 (PAI-1), and von Willebrand factor levels were assessed. The patients with TC had significantly greater baseline PAI-1 levels (p

Peripheral arterial disease (PAD), is a common manifestation of systemic atherosclerosis. Advances on the development of such vascular disease have described with a number of novel risk factors. Hyperviscosity, due to alterations of blood cells and plasma components, may play a role on the pathogenesis of the disease. Aim of this study was to evaluate the possible association between hemorheological variables and PAD. The hemorheological variables [whole blood viscosity (WBV), erythrocyte deformability index (DI), plasma viscosity (PLV)] were analyzed in 90 patients and in 180 healthy subjects. WBV and PLV were measured by a Rotational Viscosimeter and DI by a filtrometer. DI and PLV were significantly different in patients as compared to controls. To investigate the possible association between these parameters and the disease we divided the study population into tertiles. At the univariate analysis, we found a significant association between the highest tertiles of PLV, of DI and the disease. A model adjusted for traditional risk factors showed an association between highest tertiles of PLV and PAD. After adjustment for confounding parameters highest tertiles of PLV remained to be significantly associated with the disease. Our data indicate that an alteration of plasma viscosity may modulate the predisposition to PAD.

Although pulmonary embolism (PE) and deep vein thrombosis (DVT) share many risk factors, it is uncertain whether thrombophilic abnormalities may impact differently on the development of these two clinical manifestations of venous thromboembolism (VTE). To give further insight into this issue, we estimated the association of PE with different types of thrombophilia and evaluated whether these abnormalities have a different prevalence in patients presenting with PE, alone or associated with DVT, as compared with those with isolated DVT. In this study 443 consecutive patients with a first episode of VTE and 304 matched healthy controls underwent laboratory screening for thrombophilia, including natural anticoagulants, factor V Leiden and prothrombin G20210A polymorphisms, antiphospholipid antibodies, homocysteine, factor VIII, and lipoprotein(a). Of the 443 patients, 224 patients had isolated DVT, 144 had combined DVT/PE, and 75 had isolated PE. At least one thrombophilic abnormality was detected in 72.8% of DVT, 66% of DVT/EP, and 60% of isolated PE patients. A high prevalence of hyperhomocysteinemia and elevated lipoprotein(a) levels was found in all patients with no significant differences among the three groups. The prevalence of prothrombin G20210A polymorphism and of elevated factor VIII levels was significantly higher in patients with DVT and DVT/PE than in controls, but not in those with isolated PE, whereas factor V Leiden polymorphism was associated with isolated DVT but not with DVT/PE or isolated PE. In conclusion, the thrombophilic burden seems different in isolated PE versus DVT with or without PE, suggesting that PE may encompass a different pathophysiological process of thrombosis to DVT.

A clot lysis time assay in which a tissue factor—induced fibrin clot is lysed by exogenously added tissue plasminogen activator has been recently reported. We evaluated the feasibility of clot lysis time in a routine hemostasis laboratory, and its correlation with thrombin activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 levels and changes with aging in 185 healthy participants. Clot lysis time was assessed by monitoring changes in turbidity during clot formation and subsequent lysis using a computerized kinetic spectrophotometric microtiter plate. After preliminary experiments, 100 and 160 ng/mL tissue plasminogen activator concentrations were chosen for the study. Clot lysis time was calculated by a new mathematical analysis of the lysis curve based on discrete derivative. Clot lysis time, thrombin activatable fibrinolysis inhibitor, and plasminogen activator inhibitor-1 plasma levels showed a normal distribution. For both concentrations of tissue plasminogen activator, clot lysis time progressively increased with increase in age (P < .0001) and was significantly correlated with thrombin activatable fibrinolysis inhibitor antigen, thrombin activatable fibrinolysis inhibitor activity, and plasminogen activator inhibitor-1 antigen (at least P < .01). During linear regression analysis, thrombin activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 antigen were found to significantly influence clot lysis time (at least P < .01). Clot lysis time determination has a good laboratory performance. Our new method of calculation is independent of the time of reading and allows a more accurate and consistent detection of both short and prolonged lysis times. Our data suggest the feasibility of the use of this test in the work of routine hemostasis laboratory.

To evaluate the role of factor V Leiden, prothrombin G20210A polymorphism, plasminogen activator inhibitor type 1 (PAI-1) 4G/5G polymorphism, PAI-1, homocysteine, and lipoprotein (a) (Lp(a)) in the occurrence of major adverse cardiac events (MACE) in patients with acute coronary syndromes who underwent coronary stenting.520 patients (375 men and 145 women) with acute coronary syndromes and 520 age and sex matched controls were enrolled. MACE were recorded for 109 patients. Heterozygosity for factor V Leiden, prothrombin G20210A polymorphism, and 4G/5G polymorphism did not significantly differ between patients with and without MACE. A significantly higher percentage of patients with increased homocysteine (28% v 19%, p0.001) and PAI-1 concentrations (25% v 16%, p0.001) had MACE with respect to those who did not. In Kaplan-Meier survival analysis, the overall risk of MACE was significantly higher among patients with increased PAI-1 (p = 0.006) and homocysteine concentrations (p = 0.04). Cox regression analysis adjusted for age, sex, traditional cardiovascular risk factors, renal function, systolic left ventricular function, the number of stenosed vessels, and history of percutaneous coronary intervention or coronary artery bypass grafting showed that homocysteine (odds ratio 7.5, 95% confidence interval (CI) 1.1 to 57.7, p0.05) and PAI-1 concentrations (odds ratio 5.3, 95% CI 1.2 to 23.8, p0.05) within the fifth quintile (with respect to the first) were significant and independent risk factors for the future occurrence of MACE.Increased PAI-1 and homocysteine concentrations are independent risk factors for MACE after successful coronary stenting, whereas Lp(a) and thrombophilic polymorphisms are not predictive.

Background. No data are available about the optimal duration of oral anticoagulant therapy (OAT) after an episode of venous thromboembolism (VTE) occurring in renal transplant (RT) recipients. Our study was undertaken to evaluate the risk of VTE recurrence in patients developing a first episode of VTE after RT. Methods. Among 484 RT patients, 34 (7%) developed a first VTE: 28/34 VTE patients (Group 1) were prospectively studied, after stopping OAT. Group 1 was compared with a group of 84 patients without history of renal disease who had suffered from a first episode of VTE matched for age, sex and type of thrombotic event (Group 2) and with a matched group of 84 RT recipients with no history of VTE (Group 3). After OAT withdrawal, blood samples were obtained for thrombophilia and clotting activation markers (prothrombin fragment 1+2 (F1+2) and D-dimer plasma levels). Results. During follow-up, 14/28 patients of Group 1 and 8/84 patients of Group 2 experienced VTE recurrence (P

Recent reports have shown the importance of new risk factors for cardiovascular disease. We investigated the relationship between Lp(a), fibrinolytic parameters and anticardiolipin antibodies (aCL) and the occurrence of clinical recurrence owing to restenosis after elective balloon percutaneous transluminal coronary angioplasty (PTCA) without stenting. In 167 patients, undergoing PTCA, Lp(a) plasma levels, aCL, euglobulin lysis time (ELT), plasminogen activator inhibitor-1 (PAI-1) activity and tissue-type plasminogen activator (t-PA) plasma levels were evaluated before the procedure. During follow-up 29 patients underwent clinical recurrence due to restenosis. Lp(a) levels were significantly higher in patients with restenosis in comparison to those without (P0.05); an earlier restenosis was observed in patients with Lp(a) values450 mg/L. Kaplan-Meier survival estimate showed an earlier occurrence of restenosis in patients with base-line Lp(a)300 mg/l associated with aCL positivity. High Lp(a) plasma levels play a role in the occurrence of clinical recurrence due to restenosis after elective balloon PTCA without stenting; the association with aCL accelerates the development of restenosis.

heart disease and hypertriglyceridemia, and a good correlation was found between D-dimer and both

Background Thromboembolism occurs in 0.4% to 2% of the subjects undergoing radiofrequency ablation (RFA), but its mechanisms remain unclear. Our aim was to evaluate several parameters of the hemostatic system in relation to the electrophysiologic procedure. Methods Thirty consecutive patients were enrolled in the study. Fifteen underwent electrophysiologic study and 15 underwent radiofrequency ablation. Before the ablation procedure, all subjects were given an intravenous heparin bolus (2500 IU). Blood samples were drawn immediately before, at the end of, and 24 hours after the procedures. Spontaneous platelet aggregation in whole blood and in platelet-rich plasma, markers of clotting activation (prothrombin fragment 1+2 and the thrombin-antithrombin complex) and the fibrinolytic system (plasminogen activator inhibitor and D -dimer) levels were evaluated. Results At the end of the procedure, spontaneous platelet aggregation in whole blood, prothrombin fragment 1+2, thrombin-antithrombin complex, and D -dimer levels increased significantly in all patients. The hemostatic changes were more marked after RFA than after electrophysiology. Spontaneous aggregation in whole blood, prothrombin fragment 1+2, and thrombin-antithrombin complex levels at 24 hours after the procedure were similar to those observed before the procedure in both groups; D -dimer levels were still elevated with respect to preprocedure levels, with a trend toward higher levels in patients undergoing RFA rather than electrophysiology. A significantly more marked activation of coagulation (prothrombin fragment 1+2, P < .005) was found in patients in whom the mean duration of energy application was higher than 23.5 seconds. Conclusions Our data suggest that antithrombotic prevention with a prolonged administration of heparin and/or the association of antiplatelet agents should be considered in patients undergoing RFA. (Am Heart J 1999;138:128-32.)

Antiphospholipid antibodies (aPL) have been found to be associated with arterial and venous thrombosis. Percutaneous transluminal coronary angioplasty (PTCA) is an established therapy for ischaemic heart disease (IHD), which is still affected by restenosis at a rate of 20-30%. This study was aimed at investigating the possible role of aPL in restenosis after PTCA. In sixty consecutive IHD patients, aPL (lupus anticoagulant -LA- and anticardiolipin antibodies -aCL) and markers of haemostatic activation were investigated before PTCA, and patients were followed up for restenosis. No infections, autoimmune disease or treatment by drugs that may alter aPL levels occurred in any of the patients. aPL were found in 15/60 patients: aCL in 7/60, LA in 5/60 and aCL and LA in 3/60. No statistically significant difference was found between aPL negative and aPL positive patients in pre PTCA plasma levels of prothrombin activation fragment (F1+2) 1.4 nmol/l (0.3-5.71) vs 1.4 nmol/l (0.9-4.0), thrombin-antithrombin complex (TAT) 4.0 microg/l (1.1-34.2) vs 5.2 microg/l (2.1-60.0), D-dimer (DD) 25 ng/ml (2-515) vs 44 ng/ml (2-160) or plasminogen activator inhibitor activity (PAI) 4.8 IU/ml (2.5-36.4) vs 4.4 IU/ml (2.5-13.4). Restenosis was observed in 13/60 patients (7/45-15% - aPL negative and 6/15-40% - aPL positive patients) who underwent angiographic tests after PTCA because of recurring angina or positive exercise test. Restenosis occurred after 2.2 months (0.5-3) in aPL positive patients and after 3.5 months (1-12.8) in aPL negative. These results suggest that 1) restenosis with recurrent ischaemia occurs more frequently in aPL positive than in aPL negative patients, 2) in aPL positive patients restenosis occurs earlier, and 3) the presence of aPL is not associated with hypercoagulability.

Increased serum estradiol levels occurred during ovarian stimulation for assisted reproduction. Tissue factor pathway inhibitor (TFPI) plays a relevant role in regulating haemostatic equilibrium, and its decrease has been documented in conditions in which blood coagulation occurs. We investigated TFPI concentrations and coagulative pathway in healthy infertile women undergoing ovarian stimulation. We investigated 27 healthy infertile women, median age 37 (25-41) years, undergoing ovarian stimulation, observed during the mid-luteal phase of cycle (T0) and on day 5 (T1), and between day 7 and 9 (T2) of ovarian stimulation. Coagulative pathway was assessed by a global test [endogenous thrombin potential, (ETP)] and TFPI concentrations. TFPI values progressively and significantly decreased throughout the ovarian stimulation procedure (P = 0.03), contemporarily estradiol levels progressively and significantly increased from baseline to T2 (P

In Crohn's disease (CD) a condition of hypercoagulability with increased risk for thrombotic events has been reported. In this study we have investigated hemostatic parameters in thirty-one patients affected by CD before, 3 and 12 months after bowel operation, and in thirty healthy controls. Before surgery platelet number (PLT), fibrinogen (Fbg), prothrombin fragment F1 + 2 (F1 + 2), PAI and whole blood-spontaneous platelet aggregation (WB-SPA) were significantly higher (p at least0.0005) in patients than in controls, while factor XIII (F XIII) was significantly lower (p at least0.005). Three and twelve months after surgery PLT, FBG and WB-SPA significantly decreased in comparison to pre-surgery values (respectively p at least0.05 and p0.01), but PLT and Fbg were still significantly higher than in controls at 3 and 12 months (p0.01). At three and 12 months after operation F XIII was significantly higher in comparison with pre-surgery values (p at least0.05). The presence of antiphospholipid antibodies (aPL) was not different between CD patients and controls before surgery, whereas it significantly increased 12 months after surgery (p0.05). Our results suggest that in CD hemostatic changes are only in part influenced by local flogistic processes and that an inflammatory systemic condition may provoke both the bowel and extraintestinal manifestations of CD.

Hyperhomocysteinemia (HHcy) affects haemostasis and shifts its balance in favour of thrombosis. In vitro and in vivo studies suggested that HHcy may impair fibrinolysis either by influencing the plasma levels of fibrinolytic factors or by altering the fibrinogen structure. We investigated the influence of mild HHcy levels on plasma fibrinolytic potential by using clot lysis time (CLT) and fibrin susceptibility to plasmin-induced lysis in 94 patients with previous pulmonary embolism and no pulmonary hypertension. CLT was measured as lysis time of tissue factor induced clots exposed to exogenous tissue plasminogen activator (t-PA). The rate of in vitro plasmin-mediated cleavage of fibrin β-chain was assessed over a 6-h period on fibrin clots, which were obtained by exposition to thrombin of purified fibrinogen. Homocysteine plasma levels were measured by Abbott Imx immunoassay and we considered as altered the values above 15 μmol/L according to the literature. In 68 patients homocysteine levels were below 15 μmol/L (NHcy) and in 26 they were above (HHcy). Significant differences were observed between the two groups regarding plasma fibrinolytic potential (p = 0.016), TAFIact (expressed as clot lysis ratio) (p = 0.02), t-PA (0.008) and PLG (0.037), but not for the other assessed components. The HHcy-patients had a threefold higher risk to have an impaired fibrinolysis. Instead, a multivariate logistic regression analysis adjusted for significances of univariate showed that HHcy (OR 5.2 95% CI 1.7-15.9; p = 0.003) and BMI (OR 5.0 95% CI 1.6-15.9; p = 0.006) resulted independently associated with impaired fibrinolytic activity. HHcy affects TAFI-mediated hypofibrinolysis but not fibrin(ogen) structure or function as documented by fibrin degradation analysis.

Patients affected by inflammatory bowel disease (IBD) frequently suffer from thromboembolic events. Aims of this study were to investigate hemostatic system and the presence of antiphospholipid antibodies (aPL) in IBD patients. Forty-one patients affected by Crohn's disease (CD) and 19 by ulcerative colitis (UC) were studied, compared to 40 healthy control subjects. Platelet count (PLT), PT, aPTT, fibrinogen (Fib), prothrombin fragment F1+2, antithrombin (AT), protein C (PC), protein S (PS), factor XIII (FXIII), plasminogen (PLG), plasminogen activator inhibitor (PA1), spontaneous platelet aggregation in platelet-rich plasma (PRP-SPA) and in whole blood (WB-SPA), and antiphospholipid antibodies (aPL) were evaluated. PLT, Fib, F1+2 and WB-SPA were significantly increased in IBD patients (p at least0.05) both in active and inactive phases; aPL positivity was more frequent (p0.05) and FXIII was significantly decreased (p0.05) in comparison to control subjects. The thrombophilic state of IBD patients is not related to the degree of activity of the disease or to previous thrombotic events; aPL express the immunological alterations connected with IBD and are not the main cause of thrombotic events.

Pregnancy is sometimes related to thromboembolic complications (1) and alterations in different hemostatic parameters have been reported in pregnancy (2–4). In particular, a progressive increase in fibrinogen and D-dimer levels occurs during normal pregnancy (5–9). D-dimer levels may be predictive for some complications such as preeclampsia (10) and they have been also reported to be useful for diagnosis of abruptio placentae (6). However, it remains to be established if common ELISA for D-dimer are able to discriminate pathologic samples in conditions such as intrauterine growth retardation (IUGR) or gestational hypertension (GH). Aim of the present study has been to evaluate the behavior of D-dimer in pregnant women with IUGR and GH.

The measurement of fibrinogen (Fg) plasma levels is one of the more frequently performed tests in clinical practice, usually by clotting assay. However, for the diagnosis of dysfibrinogenemia the use of an immunological assay is necessary to compare total and clottable protein. Little information is available on the range of the ratio clottable (C) Fg/immunological (I) Fg levels in normal population. This study aimed at evaluating the CFg/IFg ratio in 70 control subjects (age range 17-74 years – group A), in 57 acute patients (age range 17-79 years – group B) and in 14 pregnant women (age range 27-41 years, pregnancy weeks 30-40 – group C), as a physiologic model of hyperfibrinogenemia. CFg was assayed on citrated plasma by the Clauss clotting method and IFg was assayed by radial immunodiffusion technique. In the three groups, CFg/IFg ratios were not significantly different (respectively group A 0.98 ± 0.17, group B 1.02 ± 0.18 and group C 1.01 ± 0.11), whereas both CFg (310 ± 45 mg/dl) and IFg (326 ± 70mg/dl) levels were lower (p < 0.001) in control subjects than in patients (CFg 556 ± 92 mg/dl; IFg 561 ± 121 mg/dl) and in pregnant women (CFg 530 ± 65 mg/dl; IFg 530 ± 77 mg/dl). The analysis of the relationship between CFg and IFg in the three groups (group A: y = 11.53 + 1.01x, r = 0.64, p < 0.001; group B: y = 68.72 + 0.88x, r = 0.67, p < 0.001; group C: y = 71.59 + 0.87x, r = 0.73, p < 0.01) indicates that a good correlation exists (p < 0.001) for values of fibrinogenemia ranging from 180 to over 700 mg/dl. A reference range of CFg/IFg (mean ± 2 SD in group A) was 0.64-1.32. These data could be of practical importance for a rapid screening of dysfibrinogenemias.

Renal transplant recipients (RTRs) are at increased risk of cardiovascular complications. An altered hemorheological profile may determine both cardiovascular complications and progression of renal failure in RTRs. We performed this study to evaluate the rheologic status in 239 RTRs at least 12 months after transplantation with stable and normal renal function compared with 90 control subjects. In RTRs, a significantly higher hematocrit-adjusted, but not native, whole blood viscosity was found (P < .0001). Moreover, plasma viscosity and red blood cell deformability were significantly higher in patients than in control subjects (P < .0001), whereas no difference in erythrocyte aggregation between patients and control subjects was observed (P = .5). Fibrinogen, but not hematocrit, significantly increased in RTRs (P = .001). This preliminary study provides evidence of an altered hemorheologic profile in RTRs.

We investigated the hemorheologic profile in 110 women undergoing controlled ovarian stimulation and provide evidence that smokers and women with body mass index >25 kg/m 2 exhibit alterations of rheologic profile. A progressive increase of whole-blood viscosity throughout the ovarian stimulation cycle was observed; deformability and aggregation of erythrocytes decreased from baseline to the beginning of recombinant FSH administration, then remained unchanged throughout the next days; hematocrit mildly decreased during the last days of recombinant FSH administration; and fibrinogen and cholesterol levels decreased and increased, respectively, throughout the stimulation cycle.

This article evaluates the prevalence of cardiovascular and thrombophilic risk factors in patients with retinal artery occlusion. Forty-one patients with a first episode of a retinal artery occlusion underwent complete ophthalmic examination, routine blood testing and specific laboratory tests for thrombophilia, such as fasting and postmethionine homocysteine, lipoprotein(a), plasminogen activator inhibitor-1, factor VIII, factor V Leiden, factor II G20210A polymorphism, lupus anticoagulant and anticardiolipin antibodies. The control population consisted of 100 healthy individuals comparable as regards age and sex. At univariate analysis, hypertension, smoking, dyslipidaemia (both high cholesterol and triglyceride levels), antiphospholipid antibodies, hyperhomocysteinaemia, elevated factor VIII and lipoprotein(a) levels were significantly associated with retinal artery occlusion; at multivariate analysis, adjusted for age, sex, traditional and thrombophilic risk factors, smoking, hypercholesterolaemia, elevated homocysteine and lipoprotein(a) levels confirmed their independent role as risk factors for retinal artery occlusion. In conclusion, the results of the present pilot study demonstrate that the prevalence of hypercholesterolaemia and smoking and the 'thrombophilic burden' are increased in patients with retinal artery occlusion. Our findings may have implications for the management of these patients, suggesting the need for an intensive and tailored secondary prevention and new therapeutic approaches.

A progressive increase in D-dimer plasma levels together with an increase in fibrinogen has been previously reported during normal pregnancy. However, significantly different D-dimer levels have been observed in different assays, due to different specificity of the antibodies employed. The aim of this study was to verify the increase in fibrin degradation product levels during normal pregnancy, using a recently introduced specific D-dimer ELISA. We determined D-dimer (ELISA) and fibrinogen (clotting method) plasma levels in 63 normal pregnant women, during three different periods of pregnancy (A, 7-20 weeks; B, 21-30 weeks; C, > 30 weeks). During period A, D-dimer plasma levels (range 2-103 ng/ml) showed an insignificant increase compared with a control group of non-pregnant women (range 2-73 ng/ml). During periods B and C, we observed an increase in D-dimer level (P < 0.0001) compared with period A, with a significant correlation between D-dimer levels and gestational age (P < 0.0001). Period A fibrinogen levels (range 3.24-6.43 g/l) were significantly higher (P < 0.0001) than in controls (range 2.31-4.71 g/l), with a further increase in periods B and C. In conclusion, we confirmed a progressive increase in plasma concentrations of fibrin degradation product during normal pregnancy, but D-dimer levels were significantly lower than those reported in the literature for other ELISAs.

Background and Purpose— In patients with atrial fibrillation (AF), oral anticoagulant therapy (OAT) is effective in reducing stroke and embolism. However, despite OAT, ischemic events do occur in some patients. Studies specifically addressing the identification of risk factors for ischemic events during well-conducted OAT are not available. In this study, we prospectively investigated the role of classic risk factors and homocysteine levels in the occurrence of ischemic complications in 364 AF patients on OAT. Methods— The quality of anticoagulation levels and the occurrence of bleeding and thrombotic events were recorded. Results— During follow-up (859 patient years) 21 patients had ischemic complications (rate 2.4×100 patient-years). Homocysteine plasma levels were higher in these patients than in patients without ischemic complications during OAT ( P P =0.001). Conclusion— In conclusion, our results indicate that AF patients with multiple risk factors may not be sufficiently protected by OAT, even when this is well conducted.

Introduction Hypofibrinolysis, at least in part due to high levels of plasminogen activator inhibitor-1 (PAI-1), has been reported to occur frequently in patients with coronary artery disease (CAD). A recently described carboxypeptidase, thrombin-activatable fibrinolysis inhibitor (TAFI), is involved in the regulation of the balance between coagulation and fibrinolysis. High TAFI plasma levels may therefore contribute to a hypofibrinolytic state and to an increased risk for thrombotic disorders. There are contradictory results regarding TAFI levels in CAD patients, possibly because the characteristics of patients investigated and the time of blood sampling were different among different studies. Materials and methods Fibrinolytic inhibitors (TAFI activity, TAFI antigen and PAI-1 activity plasma levels) were measured in 44 consecutive patients admitted to the Coronary Care Unit of the University of Florence and in a group of 44 healthy controls, matched for age and sex, to detect a possible association of their levels with acute CAD. Results No differences were found in TAFI levels, either activity or antigen, between patients and controls. PAI-1 activity was significant different between patients and controls ( p = 0.0001). The frequencies of TAFI activity and antigen over cut-off levels were similar in patients and controls. Instead, higher PAI-1 levels were more frequent ( p = 0.04) in patients respect to controls. The univariate analysis confirmed the association of increased PAI-1 levels with acute CAD [OR = 3.3; p = 0.04]. Among the patients, TAFI and PAI-1 levels were not different according to clinical presentation of symptoms or indication to immediate percutaneous revascularization. Conclusion Our study suggests that in acute phase of CAD no increased levels of TAFI are detectable in plasma.

Sudden sensorineural hearing loss is a frequent disease whose aetiology is still unknown in about 80% of patients. Aim of this study was to evaluate if haemorheological changes and some indexes of hypercoagulability and hypofibrinolysis are associated with idiopathic sudden sensorineural hearing loss (ISSHL).We studied 63 patients with ISSHL and 67 healthy control subjects, matched for age, sex and traditional cardiovascular risk factors. Haemorheological studies were performed by assessing whole blood viscosity (WBV) at 0.512 s(-1) and 94.5 s(-1), plasma viscosity (PLV) and erythrocyte deformability index (DI). To assess whole blood coagulation Sonoclot analysis was performed. Sonoclot variables studied were Sonoclot activated clotting time (SonACT), clot rate and time to peak. Fibrinogen, PAI-1 antigen (ag) and factor VIII:C plasma levels were also measured.WBV, PLV, SonACT, clot rate, time to peak, PAI-1ag and factor VIII:C were significantly altered in patients in comparison with controls (p0.05). A multivariate analysis (adjusted for traditional cardiovascular risk factors, hematocrit, fibrinogen, haemostatic and haemorheological variables) indicated that WBV at 94.5 s(-1), DI, SonACT, clot rate, PAI-1ag plasma levels and factor VIII:C activity were independently associated with ISSHL (p0.05).The observed changes in viscosity, blood clotting and fibrinolysis may contribute, at least in part, to the pathophysiological mechanism of ISSHL.

Summary. Background: In recent years there has been a significant increase in the diagnosis of sudden sensorineural hearing loss (SSHL) in western, countries with an incidence of 20 of 100 000 people affected every year. No clear causes for this disease have been found thus far, but cochlear ischemia has been hypothesized in patients in whom an infectious episode or acoustic neurinoma have been excluded. Objectives: The aim of this case–control study was to investigate a number of acquired and inherited thrombophilic risk factors [antithrombin, protein C and S; factor V (FV) Leiden, FII polymorphism; lupus anticoagulant (LA); anticardiolipin (aCL) antibodies; fasting homocysteine (Hcy); lipoprotein(a) (Lp(a)); plasminogen activator inhibitor-1 (PAI-1)] in addition to cardiovascular risk factors in patients with idiopathic SSHL (ISSHL). Patients and methods: We investigated 155 patients (67 male/88 female; age: 55 (range 19–79 years) with a diagnosis of ISSHL within 30 days from the onset of symptoms, and 155 controls (67 male/88 female; age 54 (range 19–78 years). Fasting Hcy levels were significantly higher in patients than in controls [11.6 (6.7–60) μmol/L vs. 8.7 (5.0–24) μmol/L] as well as PAI-1 levels [19 (2–95) mg/dL vs. 14.5 (4.0–87) mg/dL]. Lupus anticoagulant was present in 13 of 155 (8.4%) patients; 20 patients (12.9%) had positivity of aCL (four IgM and 16 IgG). In no patient was a deficiency of physiological clotting inhibitors antithrombin, protein C and protein S found. No significant differences between patients and controls were observed for Lp(a) plasma levels [111 (1–1146) mg/L vs. 103 (11–695) mg/L] and for the presence of FV Leiden (4.5% vs. 4.5%) and FII variant G20210A (3.8% vs. 3.2%). Results and conclusions: Independent risk factors for ISSHL at the multivariate analysis (adjusted for age, sex and the traditional cardiovascular risk factors) were the positivity of aCL: OR 5.6 (95% CI 2.0–15.3); cholesterol levels within the second and third tertiles (with respect to the first tertile): T2 = OR 4.8 (95% CI 1.9–12.6)/T3 = OR 19 (95% CI 7–50.1); PAI-1 and Hcy levels within the third tertile (with respect to the first tertile): OR 20 (95% CI 7.8–78) and OR 4.0 (95% CI 2.0–8.1), respectively. These preliminary data suggest that hypercholesterolemia, hyperhomocysteinemia, elevated PAI-1 levels and anticardiolipin antibodies are associated with ISSHL, so indirectly supporting the hypothesis of a vascular occlusion in the pathogenesis of the disease.

Purpose Elevated lipoprotein(a) [Lp(a)] levels are a recognized risk factor for cardiovascular disease; however, little is known about their effects on venous thromboembolism. Methods We conducted a case-control study of 603 adult patients with a history of venous thromboembolism (at least 6 months after the acute event) and 430 healthy subjects. We measured Lp(a), homocysteine, and antithrombin levels, factor V Leiden and factor II (prothrombin) polymorphisms, and anticardiolipin antibodies. Results Lp(a) levels >300 mg/L were found in 24% (n = 146) of the patients and in 13% (n = 58) of the controls (P = 0.005). In a multivariate analysis adjusted for acquired and hemostasis-related risk factors, there was an independent association between elevated (>300 mg/L) Lp(a) levels and venous thromboembolism (odds ratio=2.1; 95% confidence interval: 1.4 to 3.2; P = 0.002). These results were confirmed in the 341 patients with idiopathic venous thromboembolism, as well as in those with recurrent thromboembolism. Conclusion These results show that Lp(a) is an independent risk factor for venous thromboembolism in adults, suggesting that it may be involved in the pathogenesis of idiopathic and recurrent disease.

Pregnancy is considered as a hypercoagulable state and an increased incidence of thromboembolic phenomena has been reported in pregnant women. Relevant changes in the hemostatic mechanism have been reported during physiological pregnancy: briefly, increased levels of coagulation factors, enhanced thrombin generation and suppression of fibrinolysis are commonly found in women with uncomplicated pregnancy. We recently described progressive increases in fibrinogen and D-dimer plasma levels during normal pregnancy. The increase in D-dimer levels makes difficult their interpretation for the exclusion of thromboembolic phenomena in pregnancy. The behavior of prothrombin fragment 1+2 (F1+2) levels during physiological pregnancy is scarcely known. The aim of this preliminary study was to establish range values of F1+2 plasma levels for different periods of normal pregnancy.

In pregnant women a number of changes in blood clotting and fibrinolysis proteins have been reported so indicating the existence of a state of hypercoagulability. In addition to fibrinogen and antithrombin III (AT), D-dimer is frequently checked during pregnancy, in particular during at risk pregnancy, but the exact pattern of D-dimer modifications during uncomplicated pregnancy is not definitively described. The aim of this study was to establish the range values in three different periods of uncomplicated pregnancy (A: 1-20 wks; B: 21-30 wks; C: 31-40 wks). We measured plasma levels of D-dimer, clottable fibrinogen and AT in 108 consecutive normal pregnant women aged 16 to 42 years. In period A, the range of D-dimer values was 43-211 ng/mL, not different from controls, while fibrinogen levels were significantly higher (p < 0.05) than in matched non pregnant women. Mean D-dimer levels were higher in periods B (p < 0.05) and C (p < 0.05) vs period A. Similarly, mean fibrinogen levels were found more elevated in periods B and C vs period A (p < 0.05). A significant correlation was found between fibrinogen and D-dimer levels (p < 0.001). No differences in AT levels were found among the three periods of pregnancy. The results of this study indicate that levels of D-dimer up to 685 micrograms/L may be reached at the end of physiological pregnancy. This fact should be taken into account in the evaluation of hemostatic studies performed in uncomplicated and complicated pregnant women.

Deep venous thrombosis (DVT) can be a significant complication of the postoperative course in gynaecological surgery, because of traumatism and compression to which the vascular pelvic structures are subjected. A protocol was therefore designed to evaluate the effectiveness and tolerability of defibrotide, a new antithrombotic and profibrinolytic drug, compared with low-dose heparin. The study was conducted on 102 women, undergoing major gynaecological surgery for benign and malignant affections, randomly assigned to the following two treatment groups. A) defibrotide (400 mg i.v./i.m. b.i.d., starting the day before the surgery for 8 days); B) calcium heparin (5000 IU s.c. b.i.d., starting on the day of surgery, for/days). Clinical, haematological and instrumental (Doppler ultrasound) parameters were assessed and no major events were noted in either of the two treatment groups though in the calcium heparin group, 2 patients showed clinical signs of DVT (not confirmed by Doppler ultrasound) and no side effects were noticed, except for a cutaneous rash in one defibrotide patient and an episode of bleeding on the third postoperative day in a patient treated with calcium heparin. Defibrotide proved as effective as calcium heparin in the prevention of DVT in gynaecological surgery.