Low adjusted-dose acenocoumarol therapy in sickle cell disease: a pilot study.

Vasoocclusion is a continuous process in sickle cell disease (SCD) and accumulates to significant end organ damage, mostly irrespective of the occurrence of manifest acute vasoocclusive events. As there are indications that reversing the hypercoagulable state may be of clinical benefit in sickle cell patients, we performed a randomized, double blind, placebo-controlled, cross-over pilot study to assess the efficacy and safety of low-adjusted dose acenocoumarol therapy (International Normalized Ratio: 1.6-2.0) in SCD. Treatment consisted of either acenocoumarol or placebo for 14 weeks, after which treatment was discontinued for a period of five weeks. Then, patients initially on acenocoumarol received placebo (and vice versa) for 14 weeks. Therapy efficacy was assessed by comparing the frequency of vasoocclusive complications, the occurrence of bleeding, and clotting activation between acenocoumarol and placebo treatment of each individual patient. Twenty-two patients (14 homozygous [HbSS] and 8 double heterozygous sickle-C [HbSC]; aged 20-59 years) completed the entire study. Acenocoumarol treatment did not result in a significant reduction of acute vasoocclusive events (three painful crises during acenocoumarol, five painful crises during placebo). There was a marked reduction of the hypercoagulable state (depicted by a decrease in plasma levels of prothrombin F1.2 fragments [P = 0.002], thrombin-antithrombin complexes [P = 0.003], and D-dimer fragments [P = 0.001]) without the occurrence of major bleeding. Even though no clinical benefit (pertaining to the frequency of painful crises) was detected in this pilot study, the value of low adjusted-dose acenocoumarol for preventing specific events (such as strokes) and as a long-term treatment of sickle cell patients should be subject of further study.     

Perfusion with sickle erythrocytes up-regulates ICAM-1 and VCAM-1 gene expression in cultured human endothelial cells

Sickle cell anemia is characterized by periodic vasoocclusive crises. Increased adhesion of sickle erythrocytes to vascular endothelium is a possible contributing factor to vasoocclusion. This study determined the effect of sickle erythrocyte perfusion at a venous shear stress level (1 dyne/cm(2)) on endothelial cell (EC) monolayers. Sickle erythrocytes up-regulated intercellular adhesion molecule-1 (ICAM-1) gene expression in cultured human endothelial cells. This was accompanied by increased cell surface expression of ICAM-1 and also elevated release of soluble ICAM-1 molecules. Expression of vascular cell adhesion molecule-1 (VCAM-1) messenger RNA (mRNA) was also strikingly elevated in cultured ECs after exposure to sickle cell perfusion, although increases in membrane-bound and soluble VCAM-1 levels were small. The presence of cytokine interleukin-1beta in the perfusion system enhanced the production of ICAM-1 and VCAM-1 mRNA, cell surface expression, and the concentrations of circulating forms. This is the first demonstration that sickle erythrocytes have direct effects on gene regulation in cultured human ECs under well-defined flow environments. The results suggest that perfusion with sickle erythrocytes increases the expression of cell adhesion molecules on ECs and stimulates the release of soluble cell adhesion molecules, which may serve as indicators of injury and/or activation of endothelial cells. The interactions between sickle red blood flow, inflammatory cytokines, and vascular adhesion events may render sickle cell disease patients vulnerable to vasoocclusive crises.     

Endothelial markers and adhesion molecules in acute ischemic stroke--sequential change and differences in stroke subtype

The progress of a stroke concerns the activation of endothelial cells and platelets. We measured the plasma activities of von Willebrand factor (vWf) and the serum levels of soluble thrombomodulin (sTM) as endothelial markers, and the plasma concentrations of soluble P-selectin (sP-selectin) and soluble E-selectin (sE-selectin) as adhesion molecules during the acute (within 48 h from onset) and subacute (after 1 month from the onset) phases of 52 consecutive patients with acute ischemic stroke and 86 age-matched control subjects. The plasma vWf activities and levels of sP-and sE-selectins in stroke patients were significantly elevated compared with those in controls during both the acute and subacute phases. The serum levels of sTM in stroke patients were significantly higher than those in controls only during the subacute phase. In atherothrombotic infarction, the vWf activities and the levels of sP-selectin, markers for endothelial and platelet activation, remained higher until the subacute phase compared with controls, and the concentrations of sTM, a marker for endothelial injury, were increased during the subacute phase compared with during the acute phase. In lacunar infarction, the levels of sTM and sE-selectin of patients were higher only during the acute phase than controls. These findings suggest that the endothelial cell damage might be maintained until the subacute phase in atherothrombotic infarction, whereas it is remarkable only during the acute phase in lacunar infarction. The evaluation of endothelial markers and adhesion molecules would represent the pathophysiological states of stroke and may provide useful information for the treatment of the ischemic infarction.     

Plasma levels of pentraxin-3, an acute phase protein, are increased during sickle cell painful crisis

The painful crisis accounts for the majority of sickle cell disease (SCD) related hospital admissions. The prototypic long pentraxin 3 (PTX3), an acute phase protein, is elevated in patients with inflammatory and ischemic states. As the sickle cell painful crisis is associated with both inflammation and tissue ischemia, we questioned whether plasma PTX3 levels are increased during and associated with painful crisis severity. Furthermore, since PTX3 up-regulates endothelial expression of tissue factor we studied PTX levels in relation to markers of endothelial and coagulation activation. Plasma levels of PTX3, ultra-sensitive C-reactive protein (US-CRP), prothrombin fragment 1+2, thrombin-antithrombin (TAT) complexes, von Willebrand Factor antigen and soluble vascular adhesion molecule-1 were determined in 105 asymptomatic sickle cell patients, 33 patients during painful crisis and 30 race matched healthy controls. Plasma PTX3 levels were comparable between patients in asymptomatic state and healthy controls, but significantly higher during painful crisis (P<0.01). US-CRP levels were higher in asymptomatic patients compared to controls (P<0.0001) and increased further during painful crisis (P<0.0001). PTX3 levels at presentation with painful crisis correlated significantly with the duration of subsequent hospital admission (r(s) = 0.43; P = 0.013), whereas US-CRP levels did not. PTX3 levels did not correlate with markers of hypercoagulability. The increase of PTX3 levels during painful crisis and their relation to the duration of subsequent hospital stay suggest that PTX3 might serve both as a diagnostic and severity marker of the painful sickle cell crisis.     

Serum levels of angiogenic factors indicate a pro-angiogenic state in adults with sickle cell disease

Hypoxia-induced angiogenesis may play an important role in the pathophysiology of sickle cell disease (SCD). Serum levels of angiopoietin (Ang)-1, Ang-2, vascular endothelial growth factor, placenta growth factor (PlGF), soluble tunica intima endothelial kinase 2 (sTIE2), erythropoietin (EPO) and endothelial activation markers (soluble vascular adhesion molecule-1, soluble intercellular adhesion molecule-1) were determined in controls, HbSS (n = 35) and HbSC (n = 23) patients. In the asymptomatic phase, serum Ang-2 (P < 0.001), EPO (P < 0.001) and sTIE2 (P = 0.03) were elevated in patients. During painful crises, increased Ang-2 (P < 0.001) and PlGF (P = 0.04) occurred in HbSS and Ang-2 (P = 0.05) in HbSC patients. These results indicate a pro-angiogenic state in SCD, mainly because of elevated Ang-2 levels.     

Elevated hypercoagulability markers in hemoglobin SC disease

Hemoglobin SC disease is a very prevalent hemoglobinopathy; however, very little is known about this condition specifically. There appears to be an increased risk of thromboembolic events in hemoglobin SC disease, but studies evaluating the hemostatic alterations are lacking. We describe the findings of a cross-sectional observational study evaluating coagulation activation markers in adult patients with hemoglobin SC, comparing them with those in sickle cell anemia patients and healthy controls. A total of 56 hemoglobin SC and 39 sickle cell anemia patients were included in the study, all in steady state, and 27 healthy controls. None of the patients was taking hydroxyurea. Hemoglobin SC patients had a significantly up-regulated relative expression of tissue factor, as well as elevations in thrombin-antithrombin complex and D-dimer, in comparison to controls (P<0.01). Hemoglobin SC patients had lower tissue factor expression, and thrombin-antithrombin complex and D-dimer levels when compared to sickle cell anemia patients (P<0.05). Markers of endothelial activation (soluble thrombomodulin and soluble vascular cell adhesion molecule-1) and inflammation (tumor necrosis factor-alpha) were both significantly elevated in hemoglobin SC patients when compared to controls, being as high as the levels seen in patients with sickle cell anemia. Overall, in hemoglobin SC patients, higher hemolytic activity and inflammation were associated with a more intense activation of coagulation, and hemostatic activation was associated with two very prevalent chronic complications seen in hemoglobin SC disease: retinopathy and osteonecrosis. In summary, our results demonstrate that hemoglobin SC patients have a hypercoagulable state, although this manifestation was not as intense as that seen in sickle cell anemia.     

Endothelial Function in Patients with Sickle Cell Anemia During and After Sickle Cell Crises

Background:Prior studies have demonstrated increased adherence of sickle cell erythrocytes to vascular endothelial cells. While decreased production of nitric oxide and increased production of adhesion molecules have been implicated in this pathophysiology, the relative contribution of these mechanisms during acute sickle cell crises as compared to steady state conditions have not been elucidated.Methods and results: We studied 10 consecutive young adult patients presenting with a sickle cell crisis. Endothelial function was evaluated by a non-invasive brachial artery shear stress method. Serum levels of adhesion molecules were obtained during the crisis. Both brachial artery responsiveness and serum levels of adhesion molecules were then repeated at steady state. Ten age and gender matched volunteers served as a control group. Impaired endothelial function and impaired endothelium-independent vasodilatation were observed in all sickle cell patients during both steady state and during crisis. Flow mediated dilation (FMD)% was 3.25 ± 2.76% during crisis, 4.57 ± 4.11 at steady state, compared with the control group FMD of 11.64 ± 7.69% (p < 0.001). Flow independent dilation was 10.35 ± 11.3% during crisis, 10.03 ± 6.52% at steady state, compared with control group FID of 24.17 ± 11.87% (p < 0.001). Levels of cell adhesion molecules and markers of inflammation were increased in sickle cell crisis patients compared with the control group: sCD40 ligand levels during the acute crisis were over twice the level of normal matched volunteers (p = 0.02), and similarly significant increases were seen for E-selectin (p = 0.008), ICAM-1 (p = 0.037) and VCAM-1 levels (p = 0.01). The levels of each of these biomarkers was not significantly increased during acute crises as compared to patients’ recovery state.Conclusions: Sickle cell anemia patients have severe systemic endothelial dysfunction as demonstrated by both brachial artery assessment and increased serum levels of adhesion molecules. These abnormalities characterize not only the sickle cell crisis but also the steady state pathophysiology of sickle cell anemia.     

Elevated IL-8 levels during sickle cell crisis

Abstract: The vaso-occlusive process (VOC) in sickle cell disease is of a complex nature. It involves intricate interactions between sickle red blood cells, endothelium and probably also leukocytes. As these interactions are regulated by cytokines, we analyzed the role of the potent neutrophil chemokine IL-8 by measuring serum levels in sickle cell patients during sickle cell crisis. These results were compared to nonsymptomatics and healthy controls. In patients having a vaso-occlusive crisis both HbSS and HbSC patients showed significantly enhanced serum IL-8 levels compared to healthy controls. Several of these patients showed extremely elevated serum IL-8 levels which were independent of the crisis inducing factor. Furthermore, a sickle cell patient with VOC as a complication of rhGM-CSF treatment similarly showed high IL-8 serum levels at crisis onset. Nonsymptomatic sickle cell patients serum IL-8 levels were comparable to healthy controls. These results implicate a role for IL-8 at or during (the initiation of) sickle cell crisis.     

Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion

Sickle cell anemia is characterized by painful vaso-occlusive crises. It is hypothesized that monocytes are activated in sickle cell disease and can enhance vaso-occlusion by activating endothelium. To test this hypothesis, human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (MVEC) with sickle and normal mononuclear leukocytes were incubated, and endothelial activation was measured. Endothelial cells incubated with sickle mononuclear leukocytes were more activated than those incubated with normal mononuclear leukocytes, as judged by the increased endothelial expression of adhesion molecules and tissue factor and the adhesion of polymorphonuclear leukocytes (PMNL). Monocytes, not lymphocytes or platelets, were the mononuclear cells responsible for activating endothelial cells. Sickle monocytes triggered endothelial nuclear factor-kappa B (NF-kappaB) nuclear translocation. Cell-to-cell contact of monocytes and endothelium enhanced, but was not required for, activation. Antibodies to tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1beta) blocked activation of the endothelium by monocytes. Peripheral blood monocytes from patients with sickle cell disease had 34% more IL-1beta (P =.002) and 139% more TNF-alpha (P =.002) per cell than normal monocytes. Sixty percent of sickle monocytes expressed the adhesion molecule ligand CD11b on their surfaces compared with only 20% of normal monocytes (P =.002). Serum C-reactive protein, a marker of systemic inflammation, was increased 12-fold in sickle serum than in normal serum (P =.003). These results demonstrate that sickle monocytes are activated and can, in turn, activate endothelial cells. It is speculated that vascular inflammation, marked by activated monocytes and endothelium, plays a significant role in the pathophysiology of vaso-occlusion in sickle cell anemia.     

Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality

Endothelial cell adhesion molecules orchestrate the recruitment and binding of inflammatory cells to vascular endothelium. With endothelial dysfunction and vascular injury, the levels of endothelial bound and soluble adhesion molecules increase. Such expression is modulated by nitric oxide (NO), and in patients with sickle cell disease (SCD), these levels are inversely associated with measures of NO bioavailability. To further evaluate the role of endothelial dysfunction in a population study of SCD, we have measured the levels of soluble endothelium-derived adhesion molecules in the plasma specimens of 160 adult patients with SCD during steady state. Consistent with a link between endothelial dysfunction and end-organ disease, we found that higher levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were associated with markers indicating renal dysfunction and hepatic impairment. Analysis of soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin and sP-selectin levels indicated partially overlapping associations with sVCAM-1, with an additional association with inflammatory stress and triglyceride levels. Importantly, increased soluble adhesion molecule expression correlated with severity of pulmonary hypertension, a clinical manifestation of endothelial dysfunction. Soluble VCAM-1, ICAM-1, and E-selectin were independently associated with the risk of mortality in this cohort. Our data are consistent with steady state levels of soluble adhesion molecules as markers of pulmonary hypertension and risk of death.     

Clinical relevance of vascular endothelial growth factor levels in sickle cell disease

In recent years, vascular inflammation, marked by activated monocytes and endothelium, has been proven to play a significant role in the pathogenesis of vaso-occlusive events (VOEs) in sickle cell disease (SCD). Vascular endothelial growth factor (VEGF), an endothelial cell mitogen, has been shown to contribute to the increased endothelial cell adhesivity by increasing the expression of cell adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) on the endothelium. We have investigated VEGF alterations in 37 patients with SCD during VOEs and/or steady state. VEGF levels (mean±SEM) were found to be significantly elevated during VOEs (703.1±119.0 pg/ml) when compared with those at steady state (258.0±57.8 pg/ml) and healthy controls (196.6±21.9 pg/ml) (p<0.001). However, we did not find a difference between VEGF concentrations in sickle patients at steady state and the normal subjects (p>0.05). We suggest that considering a possible stimulatory role of tissue hypoxia in VEGF production during VOEs, VEGF levels in sickle patients might be helpful in monitoring disease severity.     

Effects of a brief course of azithromycin on soluble cell adhesion molecules and markers of inflammation in survivors of an acute coronary syndrome: A double-blind, randomized, placebo-controlled study

Background

The anti-chlamydial antibiotic, azithromycin, may improve outcome in patients who survive an acute coronary syndrome. The mechanisms are, however, poorly understood. The aims of this study were to define any relationship between Chlamydia pneumoniae seropositivity and levels of specific markers of endothelial activation (soluble cell adhesion molecules) and more general markers of inflammation (C-reactive protein [CRP] and interleukin-6 [IL-6]) and to assess whether azithromycin had any effect on such markers.

Methods

Patients who survived an acute coronary syndrome were randomized to receive treatment with azithromycin (n = 72) or placebo (n = 69) for 5 days. Before therapy, C pneumoniae IgA and IgG titers were checked, with serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, soluble E-selectin (sE-selectin), soluble P-selectin, high-sensitivity CRP, and IL-6. They were rechecked 3 months later.

Results

There were no significant correlations between C pneumoniae titers and levels of CRP, IL-6, or soluble cell adhesion molecules. However, azithromycin treatment significantly reduced mean sICAM-1 levels (P = .006). This effect was more marked in patients with elevated titers of C pneumoniae IgA and IgG. Soluble E-selectin levels were also reduced in patients who were seropositive, but no effects were seen on other endothelial or inflammatory markers.

Conclusions

After an acute coronary syndrome, a 5-day course of azithromycin reduces levels of sICAM-1, a marker of endothelial cell activation. Although these data suggest a potentially beneficial role for azithromycin, they should be interpreted with caution.     

Endothelial activation and inflammation biomarkers in children and adolescents with sickle cell disease

Sickle cell disease pathogenesis is a complex interplay of multiple factors associated with vascular endothelial activation, intense oxidative stress, and increased sickle cell adhesion. The aim of this study was to determine and compare three panels of plasma circulating biomarkers at ‘steady state’ and during veno-occlusive crises (VOC) in a cohort of children and adolescents with SCD and healthy controls. The following biomarkers were assessed: acute phase reactants, endothelial factors, and adhesion molecules. Forty-one SCD pediatric patients and 28 healthy children were enrolled. Patients at ‘steady state’ presented significantly elevated plasma levels of endothelin-1 (ET-1), soluble-VCAM-1 (sVCAM-1), soluble P-selectin (sP-selectin), and d-dimers compared to the control group. ET-1, sP-selectin, platelet-derived growth factor (PDGF), von Willebrand factor (vWf), d-dimers, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) seems to represent additional, but not independent, prognostic markers of VOC crisis. Elevated plasma levels of sP-selectin, ET-1, and sVCAM-1 were associated with VOC frequency. The present study provides preliminary evidence of a possible association between these biomarkers and the endothelial activation at steady state and VOC in childhood SCD. Further prospective studies are required to confirm the potential independent prognostic value of these markers in different stages of pediatric SCD.     

Endothelial inflammation and thrombolysis resistance in acute myocardial infarction

BACKGROUND: Despite recent refinements to thrombolysis for acute myocardial infarction, a significant minority of patients still fail to reperfuse. There is no reliable predictor of this state of "thrombolysis resistance", but platelet and endothelial factors are believed to be important. Cell adhesion molecules are expressed by the endothelium when activated and their shed or soluble portion can be quantified in the peripheral serum, where they may be taken as a measure of endothelial activation. We sought to find a link between markers of endothelial inflammation at time of infarction and failure to reperfuse as measured by vessel occlusion at angiography. METHODS: Patients presenting with their first acute myocardial infarction had levels of soluble adhesion molecules, C-reactive protein and monocyte chemotactic protein-1 measured prior to thrombolysis. An angiogram on day five after admission was performed to establish patency of the index vessel. RESULTS: Levels of soluble vascular adhesion molecule-1 (sVCAM-1) taken prethrombolysis were significantly elevated compared to those with a patent vessel (620+/-90 vs. 418+/-28 ng/ml, P<0.03. The positive predictive value of sVCAM-1 for vessel patency was 88%. CONCLUSIONS: We found elevated serum levels of the adhesion molecule soluble vascular adhesion molecule-1 (sVCAM-1) at presentation in patients with acute myocardial infarction who did not respond to thrombolysis. Endothelial activation may be important in thrombolysis resistance.     

Markers of endothelial and haemostatic function in the treatment of relapsed myeloma with the immunomodulatory agent Actimid (CC-4047) and their relationship with venous thrombosis

We evaluated the serum/plasma levels of cytokines [interleukin (IL)-6, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta2] and markers of coagulation, fibrinolysis, endothelial and platelet activation during the first 4 wk of treatment with the thalidomide analogue Actimid (CC-4047) in 15 patients with relapsed/refractory myeloma. There was evidence of activation of endothelium (soluble vascular cell adhesion molecule, sVCAM), coagulation (prothrombin fragment 1 + 2, PF1 + 2) and fibrinolysis (D-dimers) but no evidence of platelet activation or endothelial cell damage in myeloma patients. These parameters were not affected by the use of CC-4047. Three of four patients with baseline D-dimers levels >500 microg/L subsequently developed deep vein thrombosis (DVT). The hypothesis that D-dimer level >500 microg/L may predict for those patients most at risk of thromboembolism with multiple myeloma undergoing treatment is worthy of further study.     

Sickle cell acute chest syndrome: pathogenesis and rationale for treatment.

Acute chest syndrome (ACS) is a leading cause of death in sickle cell disease (SCD). Our previous work showed that hypoxia enhances the ability of sickle erythrocytes to adhere to human microvessel endothelium via interaction between very late activation antigen-4 (VLA4) expressed on sickle erythrocytes and the endothelial adhesion molecule vascular cell adhesion molecule-1 (VCAM-1). Additionally, hypoxia has been shown to decrease the production of nitric oxide (NO) which inhibits VCAM-1 upregulation. Based on these observations, we hypothesize that during ACS, the rapidly progressive clinical course that can occur is caused by initial hypoxia-induced pulmonary endothelial VCAM-1 upregulation that is not counterbalanced by production of cytoprotective mediators, including NO, resulting in intrapulmonary adhesion. We assessed plasma NO metabolites and soluble VCAM-1 in 36 patients with SCD and 23 age-matched controls. Patients with SCD were evaluated at baseline (n = 36), in vaso-occlusive crisis (VOC; n = 12), and during ACS (n = 7). We observed marked upregulation of VCAM-1 during ACS (1,290 +/- 451 ng per mL; mean +/- 1 SD) with values significantly higher than controls (P <.0001) or patients either in steady state or VOC (P <. 01). NO metabolites were concomitantly decreased during ACS (9.2 +/- 1.5 nmol/mL) with values lower than controls (22.2 +/- 5.5), patients during steady state (21.4 +/- 5.5), or VOC (14.2 +/- 1.2) (P <.0001). Additionally, the ratio of soluble VCAM-1 to NO metabolites during ACS (132.9 +/- 46.5) was significantly higher when compared with controls (P <.0001) or patients either in steady state or VOC (P <.0001). Although hypoxia enhanced in vitro sickle erythrocyte-pulmonary microvessel adhesion, NO donors inhibited this process with concomitant inhibition of VCAM-1. We suggest that in ACS there is pathologic over expression of endothelial VCAM-1. Our investigations also provide a rationale for the therapeutic use in ACS of cytoprotective modulators including NO and dexamethasone, which potentially exert their efficacy by an inhibitory effect on VCAM-1 and concomitant inhibition of sickle erythrocyte-endothelial adhesion.     

Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon

To investigate whether the different pharmacokinetics of acenocoumarol (t(1/2) = 11 h) and phenprocoumon (t(1/2) = 140 h) result in a different quality of anticoagulation, we studied patients from the Leiden anticoagulation clinic treated between 1998 and 1999 for more than 16 weeks. Two hundred and twenty-eight pairs were closely matched for indication for oral anticoagulant therapy (OAT), age, sex and date of start of treatment. Four hundred and fifty six patients with 7245 International Normalized Ratio (INR) checks yielded 230 patient-years. Quality of OAT calculated over the whole treatment period was higher with phenprocoumon as expressed by the number of INR checks in the therapeutic range (phenprocoumon: 42.7%, acenocoumarol: 36.5%, difference: 6.1%, CI(95) of the difference: 3.0-9.3%) and by time in range (phenprocoumon: 46.6%, acenocoumarol: 41.6%, difference: 5.0%, CI(95) of the difference: 1.3-8.6%). After the initial 6 weeks of OAT, the differences became more pronounced (difference: 6.1%, CI(95): 1.8-10.4%). The incidence of severe bleeding complications was similar (phenprocoumon: 0.04/patient/year vs acenocoumarol: 0.03/patient/year) with a slight excess of minor bleeds with phenprocoumon (0.19/patient/year vs 0.06/patient/year). We conclude that phenprocoumon leads to a better quality of OAT than acenocoumarol. As there is no difference in major bleeding complications and only a small difference in minor bleeding complications, phenprocoumon is preferable to acenocoumarol for prolonged OAT.     

Patients who take uneven doses of acenocoumarol exhibit significant fluctuating levels of anticoagulation.

Acenocoumarol is the most widely used oral anticoagulant in Spain. In clinical practice it is usual to cut 4 mg tablets into halves and quarters, so that the total weekly dose may be uniformly distributed. Nevertheless, many patients are told to take uneven doses (e.g. 1/2 tablet one day and 1/4 tablet the next day). The impact of these variations in dosage over the stability of anticoagulation is unknown. We carried out a prospective study comparing a group of 40 patients taking uneven doses of acenocoumarol and another group of 10 patients with uniform doses. All patients were within the therapeutic range at inclusion in the study. The International Normalized Ratio (INR) was determined over two consecutive days in every patient to assess possible fluctuations of anticoagulation. Patients receiving an uneven dosage showed a greater variability of the INR value over two consecutive days, as opposed to patients receiving uniform doses. Variation of the INR resulted in a dose change in 27.5% of cases with uneven dosage and in none of the uniform dose cases. Consistent association was found between every INR value and the dose administered to the patient 2 days before (P < 0.01). Patients who take uneven doses of acenocoumarol exhibit significant fluctuating levels of anticoagulation. This fact has to be considered before making any change in the acenocoumarol dose. The INR value obtained depends greatly on the dose administered 2 days before determination of the INR.     

Benidipine improves oxidized LDL-dependent monocyte and endothelial dysfunction in hypertensive patients with type 2 diabetes mellitus

We investigated the effects of long-term benidipine treatment on levels of monocyte and endothelial cell activation markers in hypertensive patients with (n = 28) and without (n = 10) type 2 diabetes mellitus. Benidipine, 4 mg/day, was administered for 6 months; there were no other changes in any of the patients pharmacologic regimens during benidipine treatment. Clinical and biochemical data obtained before and after benidipine administration were compared; all markers were measured by ELISA. The levels of platelet activation markers (CD62P, CD63, and PAC-1), microparticles (monocyte-derived microparticles: MDMPs, and endothelial cell-derived microparticles: EDMPs), chemokines (monocyte chemotactic peptide 1: MCP-1, regulated on activation normally T-cell expressed and secreted: RANTES) and soluble adhesion markers (soluble E-selectin and soluble ICAM-1) differed in the control and hypertension groups. In addition, levels of platelet, monocyte, and endothelial cell activation markers, microparticles, chemokines, and soluble adhesion molecules were higher in hypertensive patients than in those without type 2 diabetes. Furthermore, benidipine administration decreased the concentrations of all these markers. The effect of this drug was significant in diabetes patients with high levels of antioxidized low-density lipoprotein (LDL) antibody. These results suggest that benidipine is effective for the treatment of oxLDL-dependent vascular disorders in hypertensive patients with type 2 diabetes.