Epidemiological studies have linked platelet hyperactivity with an increased risk of vascular events. Even more convincing is the evidence from appropriately designed clinical trials showing that antiplatelet agents decrease the risk of vascular events (e.g. myocardial infarction, MI and stroke). These findings are compatible with the known thrombotic action of platelets. A considerable limitation in platelet research is the absence of a reliable, universally accepted marker of platelet activity. Therefore, it is difficult to reliably identify the 'high risk patient' and/or evaluate the efficacy of any administered treatment other than by calculating event rates over a period of time. This review will focus on the preventive aspects of antiplatelet intervention while also briefly considering the assessment of platelet hyperactivity and the mechanisms involved in platelet-induced thrombosis.

mCPP (meta-chlorophenylpiperazine), an agonist at serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 receptors, has been used as a probe of serotonergic function. We assessed its effect on platelet activation by measuring median platelet volume (MPV), the Sonoclot (SCT) pattern and plasma and intraplatelet serotonin. (a) In vitro study: MPV was measured (n = 7) using a high-resolution channelyzer: Saline (median and range (5.23 fl; 5.10-6.18) vs. mCPP (5.36; 5.10-6.44) P = 0.03; ADP (5.42; 5.29-6.44) vs. ADP + mCPP (5.67; 5.42-6.63) P = 0.02; mCPP (5.36; 5.10-6.44) vs. ADP + mCPP (5.67; 5.42-6.63) P = 0.02. Therefore, mCPP increases the MPV and enhances the effect of ADP. (b) In vivo study: The SCT time to inflection (TI) and time to peak (TP) were measured following the oral administration of mCPP (0.5 mg/kg) or aspirin (300 mg) (n = 10). Ingestion of mCPP significantly shortened TI and TP indicating platelet activation. TI: 0 h (mean +/- SD: 10.2 +/- 2.0 min) vs. 6 h (9.3 +/- 1.5) P = 0.03; TP: 0 h (31.9 +/- 7.6) vs. 6 h (23.1 +/- 2.9) P = 0.01. Aspirin had no effect on TI or TP. There were no significant changes in plasma and intraplatelet 5-HT. It is concluded that mCPP activates human platelets via 5-HT receptors.

Peripheral arterial disease (PAD) is associated with platelet hyperactivity. Aspirin and clopidogrel, two platelet inhibitors, act by different mechanisms. Aspirin inhibits thromboxane A2 synthesis and clopidogrel acts on the P2Y12 platelet ADP receptor. We evaluated the effect of clopidogrel (75 mg/day), aspirin (75 mg/day) and then both drugs on several platelet function indices in patients with PAD (n = 20). There was a significant (P = 0.0001) decrease in ADP-induced aggregation, after clopidogrel but not after taking aspirin. Clopidogrel plus aspirin significantly decreased spontaneous platelet aggregation (SPA) (P = 0.01 to P = 0.002) but SPA was not significantly altered by either aspirin or clopidogrel monotherapy. Similarly, monotherapy did not inhibit serotonin (5HT)-induced aggregation but there was a significant inhibition (P = 0.03 to P<0.02) after combination therapy. ADP (0.8 μM)-induced platelet shape change (PSC) was significantly inhibited by clopidogrel (P = 0.004) or aspirin (P = 0.01). This was also true for 5HT-induced PSC (clopidogrel, P = 0.01; aspirin, P = 0.03). Soluble P-selectin decreased significantly (from 32 ± 24 to 25 ± 17 ng/ml, P = 0.04) with combination therapy. Plasma platelet-derived growth factor and intraplatelet 5HT levels were not altered by combination therapy. In PAD, clopidogrel is a more potent inhibitor of ADP-induced platelet activation than aspirin; combination therapy is more effective than clopidogrel or aspirin monotherapy. These potentially clinically relevant findings should be evaluated in appropriately designed trials.

The objective of this open, longitudinal, controlled study was to assess the effect of trans dermal estradiol alone or combined with cyclical dydrogesterone on the markers of cardiovas cular disease (CVD) risk in postmenopausal women with type 2 diabetes. The control group consisted of postmenopausal diabetic women who declined menopausal hormone replacement therapy (HRT). Twenty-eight postmenopausal women (19 on HRT and 9 controls) with type 2 diabetes were followed up for 12 months. From the active treatment group 14 women with a uterus in situ had 80 μg/24 hr transdermal estradiol (Fematrix 80; Solvay Healthcare Ltd, Southampton, UK) and oral dydrogesterone 10 mg daily for the first 12 days of the calendar month, whereas 5 women with previous hysterectomy had 80 μg/24 hr transdermal estradiol (Fematrix 80) alone. CVD risk markers were measured before and at regular intervals after starting HRT. The main outcome measures were weight, systolic and diastolic blood pressure, fasting plasma glucose, glycated hemoglobin (HbA1c), glucose/insulin ratio, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyc erides, lipoprotein (a), high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and endothelin-1. Transdermal estradiol with or without dydrogesterone in women with type 2 diabetes did not adversely affect any of the measured markers of cardiovascular risk. There was a significant decrease in HbA 1c, total cholesterol, and LDL cholesterol at 6 months in women receiving HRT. Some of the cardiovascular disease risk markers may improve in postmenopausal women with type 2 diabetes with transdermal estradiol. This effect may have important clinical implications and it deserves further investigation in appropriately designed trials.

Clopidogrel acts on the P2Y12 adenosine diphosphate (ADP) purinergic receptors on human platelets. The aim of this study was to establish if a loading dose of clopidogrel inhibits platelet activation in patients with peripheral arterial disease (PAD). Two indices of platelet activation were considered: platelet shape change (PSC) and aggregation. Citrated blood was collected from ten PAD patients who were not on aspirin, at baseline (0 hours) and 2 and 4 hours after these patients ingested a loading dose (300 mg) of clopidogrel. ADP (5 micromo/L)-induced platelet aggregation in whole blood was inhibited after 2 hours (free platelet count, 47% +/- 19% vs. 68% +/- 15%; p < or = 0.001) and 4 hours (47% +/- 19% vs. 66% +/- 16%; p < or = 0.001). There was also a significant inhibition of 5- hydroxytryptamine (SHT, 5.0 micromol/L)-induced platelet aggregation at 2 hours. This trend was also observed for 10-micomol/L ADP-induced aggregation. ADP (0.3-0.4 micromol/L)-induced PSC was significantly inhibited at 4 hours (increase in median platelet volume, 6.3%, 1.8-10.7 vs. 1.2%, 0-5.3; p = 0.01). 5HT (0.5 micromol/L)-induced PSC at 4 hours was also significantly inhibited (8.1, 5.3-10.6 vs. 3.0, 0-8.2; p = 0.03). A loading dose of clopidogrel (300 mg) inhibits platelet activation in PAD patients, as early as 2 hours. To the authors' knowledge, no other study considered the effect of a loading dose of clopidogrel in PAD.

Two types of ADP receptors, P2Y(1) and P2Y(12) are involved in platelet aggregation. The P2X(1) receptor is also present but its role, in terms of platelet function, is not yet defined. The aim of this study was to establish if the ADP receptors, P2Y(1,) P2Y(12) and P2X(1) play a role in controlling platelet shape change (PSC) in human platelets. PSC is an early phase of platelet activation that precedes aggregation. Using a high-resolution channelyzer, PSC was assessed by measuring the median platelet volume (MPV). The P2Y(1) receptor antagonist MRS 2179 (1.06 - 10.25 micro mol/l) blocked ADP-induced PSC (by 100%). The median IC(50) was 3.16 micro mol/l. MRS 2179 also significantly (P = 0.01) inhibited PSC induced by the combination of ADP + serotonin (5HT). The P2Y(12) receptor antagonist AR-C69931MX significantly inhibited (at 10s, P = 0.009; 15 s, P = 0.001 and 30 s, P = 0.015) ADP-induced PSC. The P2X(1) receptor antagonist TNP-ATP had no significant effect on ADP- or ADP + 5HT-induced PSC. We conclude that the IC(50) of a P2Y(1)-blocker can be derived because of the high-resolution and reproducibility of the channelyzer technique. In addition to the P2Y(1) purinoceptor, the P2Y(12)receptor appears to be involved in ADP-induced PSC since this process was significantly inhibited by AR-C69931MX. The channelyzer technique may be more reliable than optical aggregometry to assess PSC.

Eur J Vasc Endovasc Surg 25, 281–282 (2003)

Activated platelets play a role in the pathogenesis of coronary heart disease (CHD). Following activation, platelets change shape, aggregate, and release several bioactive substances. The aim of this review is to identify if there is a simple and cost-effective method that indicates platelet activation and predicts the risk of CHD and vascular events. The rationale for identifying high-risk patients is to reduce their risk of vascular events by administering appropriate and effective antiplatelet treatment, like aspirin, clopidogrel, or combination regimens. Many laboratory tests estimating platelet activity have been described. Some are relatively simple, such as spontaneous or agonist-induced platelet aggregation. Other tests include measuring the mean platelet volume (MPV) or plasma soluble P-selectin levels. Some more complex tests include flow cytometry to determine platelet GP Ilb/Illa receptors, platelet surface P-selectin, plateletmonocyte aggregates, and microparticles. Only few prospective studies assessed the predictive value of platelet activation in healthy individuals. Although the MPV seems an 'easy method, there are insufficient data supporting its ability to predict the risk of a vascular event in healthy adults. Platelet aggregation, in whole blood or in platelet-rich plasma was not consistently predictive of vascular risk. Soluble P-selectin measurement is a promising method but it needs further evaluation. Flow cytometry methods are costly, time-consuming, and need specialized equipment. Thus, they are unlikely to be useful in estimating the risk in large numbers of patients. There is as yet no ideal test for the detection of platelet activation. Each currently available test has merits and disadvantages. Simple methods such as the MPV and the determination of platelet release products need further evaluation.

(2003). Mean platelet volume as an indicator of platelet activation: methodological issues. Platelets: Vol. 14, No. 5, pp. 335-336.

The elegant work by Endler et al (2002) showed that an increased mean platelet volume (MPV) was associated with a greater risk of myocardial infarction (MI) in patients with coronary artery disease. This effect was independent of several well-established risk factors (e.g. hypertension, smoking and dyslipidaemia). We have shown that platelet activation (in vivo and in vitro) results in an increase in MPV (Mikhailidis et al, 1990; Barradas et al, 1992). In vitro, this increase tends to be reversible; it is essentially aspirin resistant and it occurs during the platelet shape change (PSC; an early phase of platelet activation that precedes aggregation). We reproducibly assessed PSC with a high-resolution (0·07 fl) channelyser (Jagroop et al, 1996). We also matched the changes in MPV with platelet morphology using electron microscopy (Jagroop et al, 2000). Nevertheless, an EDTA method (like that of Endler et al, 2002) is ideal for clinical use in contrast to our slower (research) technique that requires the preparation of platelet-rich plasma. It remains to be established if platelet activation contributed to the increased MPV observed by Endler et al (2002) in the patients with a greater risk of MI. The effect of drugs on MPV was poorly documented. Our preliminary findings suggest that the administration of clopidogrel to patients with peripheral arterial disease significantly inhibits the ADP-induced increase in MPV, in vitro. This inhibition was enhanced when aspirin was administered together with clopidogrel. There is an urgent need for a practical test to identify which patients would benefit from a change in antiplatelet drug or the addition of a second one. Such a test would also allow the routine assessment of the antiplatelet effect of other drugs, like antihypertensives (e.g. in the studies cited by Endler et al, 2002) and lipid-lowering drugs (Milionis et al, 1999). Dr D. P. Mikhailidis has participated in advisory panels, received research grants and was sponsored for educational meetings by Sanofi-Synthelabo, the manufacturers of clopidogrel.

OBJECTIVE:To assess risk factors for cardiovascular disease in healthy postmenopausal women who had been uninterruptedly on menopausal hormone replacement therapy (HRT) for at least 5 years or who had not received any HRT.DESIGN:Cross-sectional study.SETTING:The Royal Free Hospital and The Middlesex Hospital.PATIENT(S):A total of 256 healthy postmenopausal women were analyzed: 73 were taking tibolone, 60 were taking transdermal E(2), 58 were taking conjugated equine estrogens (E), and 65 were not taking any menopausal therapy.INTERVENTION(S):Cardiovascular disease risk factors measurement.MAIN OUTCOME MEASURE(S):Total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, lipoprotein(a), insulin, glycated hemoglobin, high sensitivity C-reactive protein, fibrinogen, total antioxidants, and endothelin-1.RESULT(S):The different types of HRT induced disparate changes in the various markers of cardiovascular disease. Significantly higher high sensitivity C-reactive protein concentrations were found in women receiving conjugated equine E and tibolone than in women who were not taking any therapy. Glycated hemoglobin was significantly lower in women receiving transdermal E(2) and tibolone compared to women not on HRT. Women on tibolone had significantly higher systolic blood pressure.CONCLUSION(S):Because high sensitivity C-reactive protein has recently emerged as an important predictor of cardiovascular disease, the higher high sensitivity C-reactive protein levels observed in women on conjugated equine estrogens and on tibolone have potential important clinical implications.

To the Editor: We read the paper by Izaguirre-Avila and associates (1) with interest. These authors documented the platelet inhibitory action of clopidogrel (75 mg/day) in patients with coronary atherosclerosis disease (CAD, n = 41) or with cerebral vascular disease (CVD, n = 49) after 6 and 12 weeks of treatment. Izaguirre-Avila and associates (1) also showed that plasma fibrinogen levels did not change significantly in these patients after treatment with clopidogrel. However, ticlopidine (a drug that also acts on platelet adenosine diphosphate [ADP] receptors such as clopidogrel [2,3]) can decrease the plasma levels of this coagulation factor by about 10%. This effect may be an advantage because plasma fibrinogen is a powerful and independent predictor of vascular risk and an activator of platelets (2-4). The patients studied by Izaguirre-Avila and associates (1) showed a downward trend in fibrinogen concentration. This was especially evident in the CAD group with a decrease in fibrinogen concentration from 2.99 to 2.71 g/L (a decrease of 9.4%, which is similar to that seen with ticlopidine in other studies [2,3]). Do the authors know of a larger study that assessed the effect of clopidogrel on plasma fibrinogen levels? It may be that the numbers they studied were too small to show a significant decrease. Also, would cessation of ticlopidine administration for 1 week bring back the fibrinogen levels to pre-treatment levels in the 18 CVD patients who were taking this antiplatelet drug? We are puzzled by the collagen data (1). In Fig. 2, it is stated that 20 ,ug/mL of collagen was used to induce platelet aggregation. In the text, it is stated 120 mg/mL was used. The difference between these two values is 6,000 fold. Were there two misprints? Even the 20 Atg/mL dose is rather high because you can induce appreciable (e.g., 60%-75% aggregation) with as little 1 ,ug/mL in normal subjects (5,6). We would expect even more aggregation in patients with vascular disease (5). Therefore, it may be difficult to show inhibition when using very high agonist concentrations such as 20,g/mL of collagen. There is evidence that clopidogrel can inhibit platelet aggregation induced by collagen and other non-ADP agonists (e.g., thrombin and U46619, a thromboxane A2 analogue [7,9]). The mechanism responsible probably involves blocking the amplifying effect of ADP released by platelets during aggregation. Another reason why treatment with clopidogrel may inhibit platelet activation by agonists other than ADP may be a decrease in background platelet activity. Thus, other platelet inhibitors (e.g., aspirin and ticlopidine) can prolong the life span of platelets in humans (10,11). This probably means that platelet consumption is decreased, especially because the platelet half-life is shortened in patients with vascular disease (10,11). As far as we know, the effect of clopidogrel on platelet life span in humans has not been assessed. However, we would be very surprised if a prolongation was not reported following treatment with such an effective antiplatelet drug. This mechanism may explain why we found decreased aggregation in response to serotonin (5HT; 5-hydroxytryptamine) 2 hours after administering a loading dose of clopidogrel (300 mg) (unpublished results). Similarly, platelet shape change (PSC) was inhibited after clopidogrel (75 mg/day) on its own, or in combination with aspirin (75 mg/day), for 10 days in patients with peripheral arterial disease (PAD) (12). PAD is associated with platelet hyperactivity (13,14). PSC is an early phase of platelet activation that is aspirin resistant, at least in vitro (15-19). A global inhibition of platelet activity in vivo is supported by the finding of a prolonged bleeding time (p < .01) in the patients studied by Izaguirre-Avila and associates (1). Using a high-resolution channelyzer, we showed that ADP-induced PSC is significantly inhibited after adding ARC69931MX in vitro (19).

Objectives: an increased intima media thickness (IMT) is an early indicator of the atherosclerotic process. We investigated the early effect of atorvastatin on the common carotid artery (CCA) and common femoral artery (CFA) IMT.Methods: the IMT was measured in the CCA and the CFA of hyperlipidaemic patients referred with peripheral vascular disease. The measurernents were performed using an automated radio frequency IMT technique pre-treatment and at 4 and 8 weeks post-treatment with 20 mg/day atorvastatin.Results: patients (14 men; 11 women), median age 69 years (range: 48-81) had a CCA-IMT mean (SD) of 0.79 (0.21) mm pre-treatment, 0.75 (0.22) mm after 4 weeks, and 0.64 (0.15) inn after 8 weeks. The ANOVA test was significant (p = 0.024) for the CCA-IMT trend. The corresponding CFA-IMT readings were 0.83 (0.13) min, 0.80 (0.09) mm and 0.69 (0.14) min (p = 0.0003). After 8 weeks of treatment there was a significant reduction in total cholesterol 6.0 (0.3) to 4.3 (0.8) nmol/l, p = 0.0004 and low-density lipoprotein cholesterol 3.7 (0.2) to 2.2 (0.5), p = 0.0001. There was a significant decrease in median serum creatinine levels after 8 weeks treatment: 87 mumol/l (range 67-114) to 84 mumol/l (range: 64-112), p = 0.007.Conclusions: cholesterol-lowering with atorvastatin 20 mg/day leads to a decrease in CCA-IMT and CFA-IMT. This difference achieved significance after 8 weeks of treatment, belt a trend was visible at 4 weeks. These rapid changes in IMT may be attributable to an anti-inflammatory effect. IMT measurement may be a useful tool to rapidly assess the effect of drug treatment on the atherosclerotic process.

Sobel et al elegantly and convincingly show that unfractionated heparin (UH) binds to the platelet integrin αIIbβ3 (Gp IIb/IIIa).1Sobel M Fish WR Toma N Luo S Bird K Mori K et al.Heparin modulates integrin function in human platelets.J Vasc Surg. 2001; 3: 587-594Abstract Full Text Full Text PDF Scopus (70) Google Scholar This binding then induced aggregation by outside-in signaling. A few additional comments are of relevance. The effect of UH on platelets is not uniform. UH is a more powerful stimulator of in vitro and ex vivo aggregation in situations where platelet hyperactivity is present (eg, peripheral vascular disease,2Mikhailidis DP Barradas MA Jeremy JY Gracey L Wakeling A Dandona P Heparin-induced platelet aggregation in anorexia nervosa and severe peripheral vascular disease.Eur J Clin Invest. 1985; 15: 313-319Crossref PubMed Scopus (67) Google Scholar coronary artery disease,3Greenbaum RA Barradas MA Mikhailidis DP Jeremy JY Evans TR Dandona P Effect of heparin and contrast medium on platelet function during routine cardiac catheterisation.Cardiovasc Res. 1987; 21: 878-885Crossref PubMed Scopus (22) Google Scholar, 4Mikhailidis DP Barradas MA Mier A Boag F Jeremy JY Havard CW et al.Platelet function in patients admitted with a diagnosis of myocardial infarction.Angiology. 1987; 38: 36-45Crossref PubMed Scopus (55) Google Scholar and anorexia nervosa2Mikhailidis DP Barradas MA Jeremy JY Gracey L Wakeling A Dandona P Heparin-induced platelet aggregation in anorexia nervosa and severe peripheral vascular disease.Eur J Clin Invest. 1985; 15: 313-319Crossref PubMed Scopus (67) Google Scholar). The stimulatory effect depends on which anticoagulant preparation is used. Low molecular weight heparin(oid)s (LMWH) are less powerful stimulators than UH.5Barradas MA Mikhailidis DP Epemolu O Jeremy JY Fonseca V Dandona P Comparison of the platelet pro-aggregatory effect of conventional unfractionated heparins and a low molecular weight heparin fraction (CY222).Br J Haem. 1987; 67: 451-457Crossref PubMed Scopus (46) Google Scholar, 6Mikhailidis DP Fonseca V Barradas MA Jeremy JY Dandona P Platelet activation following intravenous injection of a conventional heparin: absence of effect with a low molecular weight heparinoid (Org 10172).Br J Pharmacol. 1987; 24: 415-424Crossref Scopus (29) Google Scholar, 7Mikhailidis DP Barradas MA Mikhailidis AM Magnani H Dandona P Comparison of the effect of a conventional heparin and a low molecular weight heparinoid on platelet function.Br J Clin Pharmacol. 1984; 17: 43-48Crossref PubMed Scopus (52) Google Scholar, 8Jagroop IA Barradas MA Mikhailidis DP A low molecular weight heparin, nadroparin (Fraxiparine), inhibits thrombin-induced platelet shape change and does not enhance spontaneous platelet aggregation.Br J Clin Pharmacol. 1996; 41: 163-165Crossref PubMed Scopus (30) Google Scholar Moreover, porcine mucosa UH (used by Sobel et al) is a less powerful stimulator of aggregation than bovine lung UH.5Barradas MA Mikhailidis DP Epemolu O Jeremy JY Fonseca V Dandona P Comparison of the platelet pro-aggregatory effect of conventional unfractionated heparins and a low molecular weight heparin fraction (CY222).Br J Haem. 1987; 67: 451-457Crossref PubMed Scopus (46) Google Scholar The UH effect on aggregation is enhanced by fibrinogen added in vitro.7Mikhailidis DP Barradas MA Mikhailidis AM Magnani H Dandona P Comparison of the effect of a conventional heparin and a low molecular weight heparinoid on platelet function.Br J Clin Pharmacol. 1984; 17: 43-48Crossref PubMed Scopus (52) Google Scholar This finding may be relevant because UH increases fibrinogen binding to platelets.1Sobel M Fish WR Toma N Luo S Bird K Mori K et al.Heparin modulates integrin function in human platelets.J Vasc Surg. 2001; 3: 587-594Abstract Full Text Full Text PDF Scopus (70) Google Scholar UH also affects an early stage of platelet aggregation—the shape change.8Jagroop IA Barradas MA Mikhailidis DP A low molecular weight heparin, nadroparin (Fraxiparine), inhibits thrombin-induced platelet shape change and does not enhance spontaneous platelet aggregation.Br J Clin Pharmacol. 1996; 41: 163-165Crossref PubMed Scopus (30) Google Scholar, 10Mikhailidis DP Barradas MA O'Donoghue S Dandona P Evidence for in vivo platelet activation following the injection of conventional unfractionated heparin.Platelets. 1990; 1: 189-192Crossref PubMed Scopus (19) Google Scholar These features are relevant to the phenomenon of UH-induced platelet activation because of the following.1.UH is used in patients with vascular disease. As Sobel et al1Sobel M Fish WR Toma N Luo S Bird K Mori K et al.Heparin modulates integrin function in human platelets.J Vasc Surg. 2001; 3: 587-594Abstract Full Text Full Text PDF Scopus (70) Google Scholar point out, platelet activation in these patients is undesirable. The clinical and experimental situations described above provide an opportunity to assess the clinical relevance of direct UH-induced platelet activation.2.The findings described above provide models where the molecular basis of the mechanism described by Sobel et al1Sobel M Fish WR Toma N Luo S Bird K Mori K et al.Heparin modulates integrin function in human platelets.J Vasc Surg. 2001; 3: 587-594Abstract Full Text Full Text PDF Scopus (70) Google Scholar can be assessed. For example, it is expected that LMWH will bind less to Gp IIb/IIIa than UH. Similarly, UH binding and/or outside-in signaling should be enhanced in patients with peripheral vascular disease, especially if they demonstrate platelet hyperactivity. Direct platelet activation by UH may reduce the benefit accrued from the use of this anticoagulant. This concept is likely to be further clarified now that Sobel et al1Sobel M Fish WR Toma N Luo S Bird K Mori K et al.Heparin modulates integrin function in human platelets.J Vasc Surg. 2001; 3: 587-594Abstract Full Text Full Text PDF Scopus (70) Google Scholar have worked out the process of direct UH-induced platelet activation.

BACKGROUND:Erectile dysfunction is associated with cardiovascular risk factors (e.g. hypertension, smoking, dyslipidemia and diabetes) and is more common in patients with cardiovascular disease. We therefore assessed the prevalence of two predictors of vascular events, fibrinogen and lipoprotein-a, in patients with and without erectile dysfunction.METHODS:Men with erectile dysfunction (48 non-smokers, 48 smokers), aged 45-70 years, were compared with controls (21 non-smokers, 21 smokers) with normal erectile function and no known pathology.RESULTS:Serum total cholesterol was significantly higher in non-smokers with erectile dysfunction compared to both control non-smokers and erectile dysfunction smokers. Men with erectile dysfunction who smoked had a significantly higher plasma fibrinogen level than control smokers. Similarly, men with erectile dysfunction, who did not smoke had higher levels of plasma fibrinogen compared to both smokers and non-smokers without erectile dysfunction. No significant difference in serum lipoprotein-a values was found.CONCLUSIONS:These findings support the concept that cardiovascular risk factors are predictors of erectile dysfunction and that this may be another manifestation of vascular disease.

(2001). Mean platelet volume is a useful parameter: a reproducible routine method using a modified Coulter Thrombocytometer. Platelets: Vol. 12, No. 3, pp. 171-171.

Patients with peripheral vascular disease or diabetes mellitus tend to have elevated circulating levels of naturally occurring platelet agonists like serotonin (5 hydroxytryptamine; 5-HT). This bioamine can induce platelet shape change (PSC) an early phase of platelet activation, which is essentially aspirin resistant. In addition, 5-HT exerts other harmful effects (eg stimulating vascular smooth muscle proliferation and inducing vasoconstriction in atheromatous coronary vessels). The aim of this study was to determine whether doxazosin inhibits 5-HT-induced PSC. Doxazosin is a long acting α1-adrenoceptor antagonist, used in the treatment of essential hypertension and/or benign prostatic hyperplasia (BPH). Platelet rich plasma (PRP) was prepared from healthy volunteers (n = 8; five males and three females with a median age of 32 years, range: 26–57). Agonists (5-HT, 0.06–0.5; ADP, 0.1–0.2 μmol/l or U46619, a TXA2analogue, 0.025–0.05 μmol/l) were added to PRP and aliquots were removed at specific time points for median platelet volume (MPV) measurement (using a high-resolution channelyser). The MPV was used as an indicator of PSC. PRP was also incubated with doxazosin (final concentration: 0.33 μM, a concentration similar to therapeutic plasma levels) prior to the addition of each of the above-mentioned agonists. Doxazosin significantly inhibited (P = 0.007 and P = 0.008, at 30 sec and 60 sec, respectively) the 5-HT-induced increase in MPV. Doxazosin did not significantly inhibit ADP- or U46619-induced PSC. The inhibitory effect of doxazosin seems to be specific to platelet 5-HT2 receptors, since there was no effect on ADP- or U46619-induced PSC. This inhibition of platelet activation may be an additional, clinically relevant, advantage. Future in vivo studies should consider assessing the effect of doxazosin on 5-HT-induced platelet activation.

Platelet shape change (PSC) is an early phase of platelet activation that precedes platelet aggregation. This phase of platelet activation is essentially aspirin resistant. PSC was monitored, by measuring the median platelet volume (MPV) using a high resolution channelyser. Angiotensin (Ang) II, added in vitro, caused a significant (P = 0.004) increase in MPV in platelet rich plasma prepared from healthy subjects (n = 14). This increase in MPV was marked (>0.40 fl) in 57% (n = 8) of these subjects and was significantly inhibited (P < 0.008) by losartan (a selective ang ii antagonist) at concentrations similar to those achieved in the circulation during treatment. ang ii also significantly enhanced sub-maximal psc induced by adp and serotonin in all subjects tested. losartan significantly (n = 9; P < 0.001) inhibited u46619 (a thromboxane a2 analogue)-induced PSC. These findings suggest that losartan, in addition to its blood pressure lowering action, has antiplatelet activity. This property may be clinically relevant because of the increased risk of vascular events in hypertensive patients.