Low molecular weight heparins in special populations

Low molecular weight heparins (LMWH) are replacing unfractionated heparin (UH) as safe and effective agents for the prevention and treatment of thromboembolism. Although LMWH offer many advantages over UH, usage is less clearly defined in certain special populations, including renal dysfunction, obesity and pregnancy. This article will briefly review the pharmacology of LMWH and discuss usage in these special populations.     

Assessing protein coding region integrity in cDNA sequencing projects

BACKGROUND: Low molecular weight heparin (LMWH) provides a safe and effective alternative for hemodialysis anticoagulation. While unfractionated (UF) heparin has been implicated in hyperlipidemia, the effect of LMWH on the lipid profile in nondiabetic patients is controversial in chronic hemodialysis. The effect of LMWH in diabetic patients, a high risk group of hyperlipidemia, has not been studied. METHOD: LMWH was tested for its safety and efficacy in 10 nondiabetic Taiwanese patients. To evaluate influence of lipid profile, a crossover study was carried out in 10 type II diabetic patients with poor blood sugar control associated with high triglyceride (430.4 +/- 101.1 mg/dl) and total cholesterol levels (219.2 +/- 12.7 mg/dl) using UF heparin for more than 1 year. These patients were subjected to Fraxiparine, an LMWH, for 6 months and then switched back to UF heparin for another 6 months. Lipid profiles were measured every 2 months without prescribing lipid-lowering agents and the blood sugar was maintained at stationary levels. RESULTS: LMWH is safe and effective in Taiwanese patients as a single bolus injection and maintains a 9.4% higher platelet count immediate postdialysis compared to UF heparin. With high HbA1c levels (9.6 +/- 0.6%), mean triglyceride and VLDL levels started to decrease at the 4th month after LMWH treatment and reached a 34% reduction in triglyceride, a 26.2% reduction in VLDL, and a 19% reduction of total cholesterol/HDL ratio at the 6th month. Increments of triglyceride levels were found at the 6th month after a switch back to UF heparin. The levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, apolipoprotein A-1 and B remained unchanged. CONCLUSION: LMWH may be beneficial to lipid control in hyperlipidemic diabetic patients on hemodialysis.     

Comparative effects of enoxaparin and unfractionated heparin in healthy volunteers on prothrombin consumption in whole blood during coagulation, and release of tissue factor pathway inhibitor

In a randomized crossover study twelve healthy male volunteers (23.5 +/- of 4.8 years, 73.0 +/- 6.4 kg, 180.8 +/- 5.7 cm) received one subcutaneous injection of either enoxaparin (EN) at 40 mg or 1 mg kg-1, or unfractionated heparin (UH) at 5,000 IU at one week intervals. Area under curves (AUC) of Anti-Xa and Anti-IIa activities correlated with EN dose. The relative effectiveness of EN versus UH 5,000 U as assessed by AUC ratio (EN/UH) was 7 and 15 for Anti-Xa activity, 1.3 and 3.1 for Anti-IIa activity after sc injection of EN 40 mg (4,000 Anti-Xa IU and 1,200 Anti-IIa U) and 1 mg kg-1 (7,300 +/- 640 Anti-Xa IU and 2,190 +/- 290 Anti-IIa IU) respectively. In volunteers receiving EN, a dose dependent inhibition of thrombin generation rate in platelet depleted plasma (PDP), measured with a new and simple chromogenic thrombin generation assay, was observed when compared with baseline values. Similarly, intrinsic prothrombin activation in whole blood, evidenced by measuring residual factor II in serum 2 hours after clotting (prothrombin consumption test: PC), was inhibited in a dose dependent manner. In UH treated volunteers, although the inhibition of thrombin generation rate in PDP was similar to that observed with EN 40 mg, prothrombin consumption in whole blood was not significantly modified. Tissue factor pathway inhibitor (TFPI) activity release was increased similarly for UH and EN 40 (1.4 fold increase above baseline values) and 1.9 fold for the higher dose of EN. The discrepancy between prothrombin consumption in whole blood and inhibition of thrombin generation rate in PDP in the UH and not in the EN group strongly suggests that UH and not EN is influenced by the presence of a platelet component. This could be formed during thrombin induced platelet activation. Platelet factor 4 is a possible candidate. Another hypothesis involves the role of TFPI-UH complex anticoagulant activity which might be inhibited more during whole blood coagulation than the TFPI-EN complex.     

Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis after major surgical intervention: update of previous meta-analyses

BACKGROUND: Previous meta-analyses comparing low molecular weight heparin (LMWH) and unfractionated heparin for thrombosis prophylaxis after surgical interventions need updating. METHODS: This is a publication-based meta-analysis of 36 double-blind studies including 16583 patients. Main outcome measures are incidence of deep vein thrombosis (efficacy) and wound haematoma (safety). RESULTS: In general surgery there is no increased efficacy in favour of LMWH (odds ratio (OR) 0.88, 95 per cent confidence interval (c.i.) 0.60-1.30) but there exists a higher incidence of bleeding complications (OR 1.47, 95 per cent c.i. 1.07-2.01). Low-dose LMWH is equally efficacious (OR 1.03, 95 per cent c.i. 0.85-1.26) but safer than unfractionated heparin (OR 0.68, 95 per cent c.i. 0.56-0.82). In orthopaedic surgery there is a trend towards an increased efficacy for LMWH (OR 0.83, 95 per cent c.i. 0.68-1.02) with equivalent safety (OR 0.96, 95 per cent c.i. 0.68-1.36). CONCLUSION: A superiority of LMWH is suggested but heterogeneity might make generalizability to future patients questionable. A meta-analysis on individual patient data should be the next step before randomizing additional patients in future trials.     

Inhibition of repetitive thrombus formation in the stenosed canine coronary artery by enoxaparin, but not by unfractionated heparin

Experiments were designed to compare the antithrombotic efficacy of enoxaparin and unfractionated heparin (UH) in a model of platelet-dependent cyclic flow reductions (CFRs) in the stenosed canine circumflex coronary artery. Low-molecular-weight heparins (LMWHs) are safe and effective in the prevention and treatment of venous thromboembolism. The present experiments were designed to evaluate the potential use of LMWHs in arterial thrombotic indications by comparing the antithrombotic effect of an LMWH with that of UH in an animal model of unstable angina. After establishment of consistent CFRs by experimentally induced vascular stenosis and damage, vehicle (saline), enoxaparin, or UH was administered intravenously as a loading dose plus a continuous infusion for 1 hour. The inhibition of CFRs was taken as an indicator of antithrombotic efficacy. Enoxaparin inhibited repetitive platelet thrombus formation in a dose-dependent manner, with significant inhibition of CFRs achieved at 0.5 mg/kg + 5 microg/kg per minute. This dose of enoxaparin resulted in anti-Xa levels of 0.9 to 1.0 IU/mL, anti-IIa levels of 0.2 to 0.3 IU/mL, activated partial thromboplastin time (APTT) of 1.3-fold over baseline, and a 1.4-fold increase (NS) in template bleeding time. Near-complete abolishment of CFRs was achieved with enoxaparin at 1.0 mg/kg + 10 microg/kg per minute. This dose of enoxaparin produced anti-Xa levels of 2 to 2.2 IU/mL, anti-IIa levels of 0.5 to 0.6 IU/mL, an increase in APTT of 1.4- to 1.5-fold over baseline, and a 1.9-fold increase (P<0.05) in template bleeding time. In contrast, UH had no significant effect on CFRs at a dose (100 U/kg + 10 U/kg per minute) that resulted in anti-Xa levels of 1.2 to 1.6 IU/mL, anti-IIa levels of 1.8 to 2.4 IU/mL, an increase in APTT greater than 10-fold over baseline, and a 2.5-fold increase (P<0.05) in template bleeding time. Compared with the vehicle group, circulating platelet count and hematocrit were not changed significantly by any dose of enoxaparin or UH tested. Enoxaparin, unlike UH, prevented repetitive platelet-dependent thrombus formation in the dog, thereby supporting the potential use of enoxaparin as a replacement for heparin in the treatment of arterial thrombotic disorders such as unstable angina.     

Low molecular weight heparin and unfractionated heparin for prevention of thrombo-embolism in general surgery: a meta-analysis of randomised clinical trials

Low molecular weight heparin (LMWH), unfractionated heparin (UFH) and warfarin were compared with respect to efficacy and safety in the prevention of thrombo-embolism in general surgery. Meta-analysis (MA) with a priori definition of the MA protocol was used to combine the results from randomised trials with patients who underwent general surgery and deep-vein thrombosis (DVT) prophylaxis with LMWH, UFH or warfarin. Forty-four studies were identified for assessment and 33 were included, however, none for warfarin. For efficacy (DVT and pulmonary embolism) and major bleeding, no significant difference between the LMWH- and UFH-treated groups was demonstrated. The relative risk of minor bleedings for LMWH versus UFH was 0.75 (0.64-0.88; 95% confidence interval) and is significant (p < 0.05). Within the limitations of the MA, LMWH and UFH did not differ significantly in terms of prevention of thrombo-embolism, but LMWH had a significantly better safety profile. On this basis, LMWH may be preferable to UFH in the prevention of thrombo-embolism in general surgery.     

Losartan blocks aldosterone and renal vascular responses to angiotensin II in humans

In vitro and animal studies have demonstrated that the effect of angiotensin II (Ang II) on aldosterone is mediated through the Ang II type 1 receptor. However, it has been difficult to demonstrate an effect of Ang II type 1 receptor blockade on aldosterone levels in human studies. One possible explanation is that subjects have not been studied under salt-controlled conditions. Therefore, we examined the effects of losartan on the aldosterone and renal plasma flow responses to Ang II infusion in six normotensive subjects under low and high salt conditions. Ang II was infused in graded doses (0.3 to 10 ng/kg per minute) in the presence and absence of losartan (a single 50-mg oral dose). Renal plasma flow was assessed by measurement of para-aminohippurate clearance. Blood pressure, plasma aldosterone levels (low salt conditions only), and para-aminohippurate clearance were measured before and after each Ang II dose. Losartan had no effect on baseline systolic pressure but attenuated the systolic pressure response to exogenous Ang II during both low salt (0.7 +/- 1.9 versus 6.7 +/- 1.4 mm Hg, P = .001) and high salt (2.0 +/- 1.9 versus 12.3 +/- 2.1 mm Hg, P = .006) conditions. Under low salt conditions, losartan reduced the baseline plasma aldosterone level from 1135 +/- 204 to 558 +/- 102 pmol/L (P = .015) and blocked the aldosterone response to Ang II (-49 +/- 110 versus +436 +/- 83 pmol/L, P = .019). During high salt conditions, losartan had no effect on baseline renal plasma flow but attenuated the renal plasma flow response to Ang II (-90.1 +/- 15.1 versus -185.1 +/- 2.6 mL/min per 1.73 m2, P = .013). These data confirm that losartan lowers both basal and exogenous Ang II-stimulated aldosterone levels under low salt conditions. Losartan does not significantly affect baseline renal plasma flow but does attenuate the renal plasma flow response to exogenous Ang II under high salt conditions.     

The clinico-morphological characteristics of myeloid leukemias under the current ecological conditions in Ukraine]

BACKGROUND: The prerequisite of effective haemodialyzation treatment is prevention of blood coagulation in the extracorporeal circulation. The objective of the study was to evaluate the effectiveness, safety and dosage of low-molecular heparin nandroparinum calcium--Fraxiparine (Sanofi) in haemodialyzation treatment of adult patients. METHODS AND RESULTS: In 29 patients (22 men, 7 women, age 54 +/- 12 years) a total of 2125 haemodialyses were made on a capillary dialyzer with a cuprophane membrane extending over 3.6 +/- 0.5 hours, incl. 84 (9 subjects) with acute and 2041 (20 subjects) with chronic irreversible renal failure. In none of the procedures complete coagulation occurred, partial coagulation of the dialyzer or the presence of fibrin deposits in the return line was found only in 148 (7%) haemodialyses, statistically significantly more frequently in acute procedures (48; 57%; p < 0.01), as compared with chronic procedures (100; 5%). The authors did not observe any haemorrhage during or after haemodialysis. The total dose of Fraxiparine needed in acute dialyses was higher (6900 +/- 2400 U.I. aXa) as compared with chronic procedures (5400 +/- 1700 U.I. aXa) the difference is however not statistically significant. In 1910 haemodialyses (89.9%) only a single bolus dose was used 5100 +/- 1400 U.I. aXa Fraxiparine (70 U.I./kg). CONCLUSIONS: Low-molecular heparin Fraxiparine administered as a bolus makes safe and effective anticoagulation during haemodialysis possible and does not call for laboratory follow-up of the anti-Xa level. In acute haemodialyses larger doses are needed.     

Posttreatment with low molecular weight heparin reduces brain edema and infarct volume in rats subjected to thrombotic middle cerebral artery occlusion

Low molecular weight heparin (LMWH) has similar efficacy to unfractionated heparin with less hemorrhagic complications. We studied the neuroprotective effect of LMWH on a rat model of focal-ischemia. Our results revealed that treatment with LMWH at 1 and 3 h following thrombotic MCA occlusion reduced brain edema and infarct size and improved clinical outcome. Treatment with LMWH initiated at 6 h after thrombin injection only partially ameliorated brain damage.     

Substitution of acetic acid for hydrochloric acid in the bicarbonate buffered dialysate

In a multicenter study including 5 dialysis units, blood acetate changes during 4 h dialysis sessions in 141 patients treated with a 4 mM acetate-containing bicarbonate dialysate (ABD) were evaluated and compared to the values of 114 patients using an acetate-free bicarbonate dialysate (AFD). Acetate-free bicarbonate dialysate was delivered by a dialysis machine from the mixing with water for dialysis of a 1/26.2 bicarbonate concentrate, and a 1/35 acid-concentrate in which acetic acid was substituted for hydrochloric acid (Soludia, Fourquevaux, France). This new type of dialysate was routinely in use for 3 years on average (range, from 2 to 5 years). All patients fasted before and during dialysis. Blood samples were withdrawn at the start and at the end of dialysis sessions. The acetate plasma concentration was determined using the acetyl-CoA synthetase enzymatic method (Boehringer, Manheim, Germany). In patients treated with ABD whose predialysis blood acetate levels were in the physiologic range of < or = 100 microM (n = 113), the acetate plasma concentration increased from a predialysis mean value of 22+/-3 microM to a postdialysis mean value of 222+/-11 microM in 88 patients (78% of patients) whereas the acetate plasma concentration changes remained in the range of physiologic values from 21+/-6 to 58+/-7 microM in the other 25 patients. In contrast, patients treated with AFD whose predialysis blood acetate levels were in the physiologic range (n = 108), acetate plasma concentration increased from a predialysis mean value of 49+/-6 microM to 160+/-19 microM in only 13 patients (12% of patients) whereas acetate plasma concentration changes remained in the range of physiologic values of 23+/-2 to 41+/-3 microM in most of the patients of this group. In this study, a significant number of patients, whether receiving standard or acetate-free bicarbonate dialysates, exhibited an extremely high acetate plasma concentration at the start of the dialysis session. Hyperacetatemia was controlled with AFD in patients whose predialysis acetate plasma concentration of 316+/-82 decreased to 55 +/-23 microM (n = 6) at the end of the dialysis session whereas the acetate plasma concentration remained high when the predialysis concentration was 580+/-76 microM, with a postdialysis concentration of 233+/-39 microM (n = 28). It is concluded that in patients whose predialysis blood acetate levels were in the physiologic range, acetate-containing bicarbonate dialysate induces hyperacetatemia whereas postdialysis blood acetate remains in the normal range in such dialysis patients treated with acetate-free dialysate. Chronic hyperacetatemia, which could be found in dialysis patients, is well controlled by dialysis using an acetate-free dialysate.     

Aldosterone precursors and hypertension with hypokalemia and adrenal module non caused by primary hyperaldosteronism

The purpose of the study was to evaluate the interest of aldosterone precursors assays in arterial hypertension with hypokaliemia and adrenal nodules non due to aldosterone. Seven hypertensive patients, 3 men and 4 women, aged 59.5 +/- 10.1 years were included in the study. After drug withdrawal, kaliemia was 3.1 +/- 0.3 mmol/l (2.7-3.6), active renin 2.9 +/- 1.4 ng/l, plasma aldosterone (aldo) 108 +/- 49.4 pg/ml, cortisol 13 +/- 3.1 micrograms/100 ml, and [S] 0.47 +/- 0.5 micrograms/100 ml. Adrenal CT scan showed an adenoma in 3 patients (30.5 +/- 5 mm) and an unilateral nodular hyperplasia in 4 patients. In all patients, the plasma levels (RIA, chomatographic step) of the following steroids in the mineralocorticoid (MC) pathway were determined: DOC, 18 OH-DOC, B, 18 OH-B and aldosterone. Two from 7 (28%) exerted aldosterone precursors excess, 1 with DOC-producing adenoma (DOC-PA) (table), and 1 with a partial 11 beta hydroxylase deficiency (DOC: 211 pg/ml; S: 1 mu/100 ml). Aldosterone/DOC + 18 OH-DOC ratio proposed as a malignancy index was decreased in the patient with DOC-PA (8.1). No dysfunction in the MC pathway was identified in the 5 other patients. [table: see text] The study suggests the relevance of aldosterone precursors assays in low renin hypertension non due to aldosterone and in incidentally discovered adrenal masses.     

Impaired cortisol binding to glucocorticoid receptors in hypertensive patients

We compared glucocorticoid receptor binding characteristics and glucocorticoid responsiveness of human mononuclear leukocytes (HML) from hypertensive patients and matched normotensive volunteers. We also considered associations of these variables with plasma renin activity, aldosterone, cortisol, corticotropin, and electrolyte concentrations. We calculated binding affinity (Kd; nmol/L) and capacity (Bmax; sites/cell) for dexamethasone and cortisol from homologous and heterologous competition curves for specific [3H]dexamethasone binding sites on HML isolated from the blood of normotensive volunteers and subjects with essential hypertension. Glucocorticoid responsiveness of HML was evaluated as IC50 values (nmol/L) for dexamethasone and cortisol for the inhibition of lysozyme release. We measured plasma hormones by radioimmunoassay. Kd values (mean+/-SE) for cortisol in HML of hypertensive patients were higher than in control subjects (24.6+/-2.4 versus 17.5+/-1.7 nmol/L, P<.04). Binding capacity (4978+/-391 versus 4131+/-321 sites/cell), Kd values for dexamethasone (6.7+/-0.5 versus 5.7+/-0.3 nmol/L), and IC50 values for dexamethasone (3.4+/-0.3 versus 3.1+/-0.2 nmol/L) and cortisol (12.2+/-1.6 versus 9.5+/-0.3 nmol/L) were not significantly different. Patients with renin values less than 0.13 ng angiotensin I/L per second were markedly less sensitive to cortisol than those with higher values. Both Kd (30.3+/-2.5 versus 19.2+/-2.4 nmol/L) and IC50 values (15.5+/-1.8 versus 8.9+/-1.2 nmol/L) for cortisol were significantly higher in patients with lower renin values (P<.03). Other variables, including plasma hormone and electrolyte values and binding characteristics for dexamethasone, were not different. These data suggest that cortisol binding to glucocorticoid receptor is slightly impaired in patients with essential hypertension. In vivo, this could lead to inappropriate binding of cortisol to mineralocorticoid receptors. Hence, decreased sensitivity to cortisol is associated with renin suppression. This hypothesis is supported by evidence of hypertension and low renin activity, which others have described in patients with primary glucocorticoid resistance due to mutations of the glucocorticoid receptor.     

Induction of the acute-phase reaction increases heparin-binding proteins in plasma

We have previously demonstrated that the nonspecific binding of unfractionated heparin (UFH) to plasma proteins has a marked modulating effect on its anticoagulant activity. Since some heparin-binding proteins are also acute-phase-reactant proteins, we explored the possibility that the induction of the acute-phase response can increase the plasma concentrations of heparin-binding proteins. The recovery of a fixed amount of UFH or low-molecular-weight heparin (LMWH) added in vitro to rat plasma samples obtained at various time intervals after the administration of intravenous endotoxin or subcutaneous turpentine was compared with that of saline-treated control animals. The anti-factor Xa activity was measured in the plasma samples before and after the addition of a chemically modified low-affinity heparin (LAH) to displace the proportion of the added heparin that is reversibly bound to plasma proteins. Our results show that at 6 hours post-endotoxin and at 24 hours post-turpentine treatment, virtually no anti-factor Xa activity could be measured in the plasma samples, while the expected levels were obtained for control plasma. After the addition of LAH to displace protein-bound UFH, essentially the same anti-factor Xa levels were measured in the plasma from all three treatment groups. These results indicate that induction of the acute-phase reaction can dramatically increase the levels of heparin-binding proteins in rat plasma. In addition, we compared the anti-factor Xa recovery of UFH with that of an LMWH from the plasma of endotoxin- and saline-treated rats and demonstrated that LMWH binds less to plasma proteins than UFH, even in plasma in which the levels of heparin-binding proteins are markedly elevated. The recovery of a fixed amount of UFH added in vitro to human plasma from septic patients was also reduced, but not to the same extent as seen in rat plasma. Removal of candidate heparin-binding and acute-phase proteins by immunodepletion indicated that vitronectin plays an important role in the nonspecific binding of UFH in patient plasma.     

Elevation of serum phosphate affects parathyroid hormone levels in only 50% of hemodialysis patients, which is unrelated to changes in serum calcium

Hyperphosphatemia is said to cause hyperparathyroidism either by depressing the plasma levels of ionized calcium and/or by affecting serum 1,25(OH)2 vitamin D3 levels. Direct evidence that hyperphosphatemia contributes to hyperparathyroidism in hemodialysis patients is unclear because previous published data are with older parathyroid hormone (PTH) assays. Phosphate was added to the dialysate of 15 patients for 12 wk whose predialysis serum phosphates were between 1.5 and 1.9 mM (4.7 to 5.9 mg/dL) in order to further increase their serum phosphate by 0.75 mM (2.4 mg/dL) without adjustments in other medications. No patient was on vitamin D therapy. In half of the patients, PTH levels remained unchanged (nonresponders; 214 +/- 64 versus 219 +/- 60 ng/L), whereas in the other patients, PTH rose from 204 +/- 53 to 338 +/- 60 ng/L (P < 0.05; responders). The degree of induced hyperphosphatemia was virtually identical in both groups, 1.7 mM increasing to 2.4 mM. Ionized calcium was unchanged in both groups after phosphate. Plasma 1,25(OH)2 vitamin D3 levels were low to start with and remained low throughout. Nonresponders had been on dialysis twice as long as responders and had consumed over seven times more aluminum salts. Nonresponders had higher postdeferoxamine increments in plasma aluminum (3,588 +/- 1,466 versus 603 +/- 390; P < 0.05), although neither these amounts nor plasma levels were in the toxic range.(ABSTRACT TRUNCATED AT 250 WORDS)     

Depletion of intravascular pools of tissue factor pathway inhibitor (TFPI) during repeated or continuous intravenous infusion of heparin in man

Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of the extrinsic coagulation system. TFPI is increased several-fold in postheparin plasma and thereby thought to contribute significantly to the antithrombotic action of heparin. The present study was conducted to investigate how repeated (n = 8) and continuous (n = 6) administration of heparin affect plasma TFPI and the inhibition of tissue factor (TF)-induced coagulation ex vivo in humans. Free TFPI antigen (TFPI Ag) increased from 19.2 +/- 4.0 ng/ml to 204.7 +/- 31.7 ng/ml after intravenous injection of 5000 IU of unfractionated heparin. Five repeated injections of 5000 IU of heparin at 4 h intervals caused a progressive decrease (-45 +/- 8%, p < 0.0001 for time effect) in heparin-releasable TFPI and a progressive shortening of the clotting time as determined in a dilute prothrombin time assay (dPT) (-8.7 +/- 6.1 s, p < 0.0001). The basal concentration of TFPI Ag in plasma collected immediately before each heparin injection was decreased by 29 +/- 15% (p < 0.0001), whereas the dPT was decreased by 6.9 +/- 3.5 s (p < 0.0001). During a 24 h continuous infusion of heparin TFPI Ag decreased from 161.5 +/- 26.0 ng/ml to 35.6 +/- 4.7 ng/ml (-77.3 +/- 5.1%) (p < 0.0001). The contribution of TFPI to the inhibition of TF-induced coagulation during heparin infusion was estimated to decrease from 60 +/- 15% to 20 +/- 10% (p < 0.0001). The present data indicate partial depletion of intravascular pools of TFPI by repeated and continuous heparin administration and thereby attenuation of its contribution to the antithrombotic action of heparin.     

Diurnal rhythm of cortisol and aldosterone plasma levels in patients with chronic renal insufficiency

In patients with chronic renal failure (CRF) disturbances in cortical adrenal endocrine function were described previously. An increased plasma aldosterone level was documented in several studies [1-4]. The aim of this study was to investigate diurnal rhythms of plasma cortisol and aldosterone in CRF patients. In addition, in 3 patients on maintenance haemodialysis, the effect of dialysis procedure upon the plasma level of these hormones was studied. Ten patients with CRF of different etiologies, mean age 41.2 years, serum creatinine from 166-1336 mumol/L, creatinine clearance 4.2-29.2 ml/min, participated in the study. Blood samples were taken in the recumbent position at 6 am and at 6 h intervals thereafter for 24 h. Another group was made of 3 patients on maintenance haemodialysis for a mean 4.2 years. The effect of dialysis upon plasma cortisol and aldosterone levels was studied in the morning (7-11 h) and afternoon hours (14-18 h), with blood samples taken at one hour intervals. Patients were dialysed on cuprophan and polyacrilonitrile membranes. Plasma cortisol and aldosterone levels were determined using commercial RIA kits from Sorin Biomedica, Italy. The results obtained show that in 8 out of 10 patients with CRF in the predialysis period diurnal rhythm of cortisol was preserved. Investigation of the plasma aldosterone, with a 6 h sampling, however, shows in most of the patients studied no changes indicating a preserved diurnal rhythm. Investigation of the effect of haemodialysis treatment performed for 4 h on cuprophane as well as on PAN membrane, upon the plasma cortisol level has shown in morning hours the unchanged plasma cortisol level, compared to the same patients during the control study. Haemodialysis in the afternoon hours has produced, a small decrease of plasma cortisol during the first two hours, followed by an increase to the predialysis values. Plasma aldosterone levels during the morning and afternoon haemodialysis have shown variations similar to that observed in the same patients during the control study. CONCLUSIONS: This study has shown a preserved circadian rhythm of cortisol in kidney patients with CRF. A clear diurnal rhythm of aldosterone in these patients cannot be established. Investigation of the effect of haemodialysis procedure, performed on cuprophan and PAN, a more permeable membrane, upon the plasma levels of cortisol and aldosterone, has shown variations similar to that observed during the control study.     

Low-molecular-weight heparins

Low-molecular-weight heparins (LMWH) are a new group of parenteral anticoagulants. They represent a major clinical advance in anticoagulation since the identification of unfractionated heparin (UFH) in 1922 and the introduction of the synthetic coumarin derivative, warfarin, in 1948. Their predictable pharmacokinetics, increased bioavailability, and longer plasma half-life allow for once- or twice-daily dosing and eliminate the need for routine laboratory monitoring. This simplified administration stands to alter the clinical practice of anticoagulation. This review high-lights recent clinical trials and focuses on studies comparing LMWH with the other two major anticoagulants: UFH and coumadin.     

Rapid activation of Na+/H+ exchange by aldosterone in renal epithelial cells requires Ca2+ and stimulation of a plasma membrane proton conductance

There is increasing evidence for an additional acute, nongenomic action of the mineralocorticoid hormone aldosterone on renal epithelial cells, leading to a two-step model of mineralocorticoid action on electrolyte excretion. We investigated the acute effect of aldosterone on intracellular free Ca2+ and on intracellular pH in an aldosterone-sensitive Madin-Darby canine kidney cell clone. Within seconds of application of aldosterone, but not of the glucocorticoid hydrocortisone, there was a 3-fold sustained increase of intracellular Ca2+ at a half-maximal concentration of 10(-10) mol/liter. Omission of extracellular Ca2+ prevented this hormone response. In the presence of extracellular Ca2+ aldosterone led to intracellular alkalinization. The Na+/H+ exchange inhibitor ethyl-isopropanol-amiloride (EIPA) prevented the aldosterone-induced alkalinization but not the aldosterone-induced increase of intracellular Ca2+. Omission of extracellular Ca2+ also prevented aldosterone-induced alkalinization. Instead, aldosterone led to a Zn(2+)-dependent intracellular acidification in the presence of EIPA, indicative of an increase of plasma membrane proton conductance. Under control conditions, Zn2+ prevented the aldosterone-induced alkalinization completely. We conclude that aldosterone stimulated net-entry of Ca2+ from the extracellular compartment and a plasma membrane H+ conductance as prerequisites for the stimulation of plasma membrane Na+/H+ exchange which in turn modulates K+ channel acitivity. It is probable that the aldosterone-sensitive H+ conductance maintains Na+/H+ exchange activity by providing an acidic environment in the vicinity of the exchanger. Thus, genomic action of aldosterone determines cellular transport equipment, whereas the nongenomic action regulates transporter activity that requires responses within seconds or minutes, which explains the rapid effects on electrolyte excretion.     

Establishing an institution-specific therapeutic range for heparin

The relationship between heparin concentration and activated partial thromboplastin time (aPTT) in pooled plasma was compared with that in patient samples to assess the feasibility of using heparin-spiked pooled plasma in determining a therapeutic range for aPTT. Blood samples were taken from 32 patients who had been receiving intravenous unfractionated heparin sodium for more than 24 hours. The samples were stored at -70 degrees C until anti-Xa assay within three months of collection. Pooled normal plasma was spiked with unfractionated heparin sodium to produce nominal anti-Xa concentrations of 0, 0.05, 0.1, 0.2, and 0.5 unit/mL. Heparin concentrations and a aPTT values were measured, and the relationship between the two was determined by linear regression. For the ex vivo samples, the range of aPTT values corresponding to therapeutic heparin concentrations of 0.3-0.7 anti-Xa unit/mL was 64-106 seconds, which corresponds to an aPTT range of 2.3-3.9 times the mean of the normal range (compared with the traditionally defined therapeutic range of 1.5-2.5 times the control value). For the in vitro samples, the aPTT range corresponding to heparin concentrations of 0.3-0.7 unit/mL was 121-256 seconds, which corresponds to an aPTT range of 4.4-9.4 times the mean of the normal range. Each institution should establish a therapeutic aPTT range by calibrating aPTT values against heparin concentrations from blood samples of patients receiving intravenous heparin.     

Plasma renin and aldosterone in thyroid diseases

The effect of thyroid hormones on the renin-angiotensin-aldosterone system has not been fully resolved. Highly specific immunoassays for measurement of renin, aldosterone, free T4 (fT4), free T3 (fT3) and ultrasensitive TSH enables a direct and more accurate measurement of these hormones. We investigated the relationship between plasma renin, aldosterone and thyroid hormones in the basal state and after intravenous frusemide. This is a cross-sectional study involving 37 patients with thyrotoxicosis, 42 rendered euthyroid with normal fT4, fT3 and TSH levels, 17 with euthyroid levels of fT4 and fT3 but suppressed TSH, and 11 with hypothyroidism. Basal plasma renin was significantly higher in thyrotoxicosis (63.4 +/- 9.8 microU/ml, mean +/- SEM) compared to euthyroid (32.7 +/- 4.4 microU/ml) and hypothyroid (26.7 +/- 9.8 microU/ml). Basal plasma renin for euthyroid with suppressed TSH (41.0 +/- 7.4 microU/ml) was significantly higher than hypothyroid (p = 0.02). Basal plasma aldosterones were not significantly different except for suppressed TSH (157.7 +/- 13 pg/ml), which was higher than normal (109.9 +/- 10.4 pg/ml; p = 0.04). Following frusemide, plasma renin and aldosterone were significantly increased in all groups. Plasma renin was highly correlated to fT3 (r = 0.405, p < 0.001), total T3 (r = 0.359, p < 0.001), fT4 (r = 0.331, p < 0.001) and TSH (r = 0.300, p < 0.001) in the basal state, but less to total T4 (r = 0.248, p < 0.01). Plasma renin correlated poorly to serum aldosterone (r = 0.212, p < 0.03). This study clearly showed that regulation of renin was mainly influenced by fT3, and that aldosterone response to frusemide was blunted in thyrotoxicosis despite normal electrolytes.