P. T. Larsson

Effects of selective LDL-apheresis and pravastatin therapy on platelet function in familial hypercholesterolaemia.

Abstract. Platelet function was studied in 10 patients with familial hypercholesterolaemia, following lipid‐lowering treatment with selective LDL‐apheresis and with the HMG‐CoA reductase inhibitor pravastatin. Platelet function was assessed before, and 2, 5 and 14 days after LDL‐apheresis, and before and after 4 weeks of pravastatin therapy. Both treatments significantly reduced total‐ and LDL‐cholesterol, whereas LDL‐apheresis also reduced VLDL‐cholesterol. Lp(a)‐levels were reduced by LDL‐apheresis and elevated by pravastatin treatment. Pravastatin therapy significantly enhanced platelet aggregability in vivo, as measured by ex vivo filtragometry. Plasma serotonin levels also increased. Other markers of in vivo activation of platelets, i.e. β‐thromboglobulin in plasma and urine, and 11‐dehydro‐thromboxane B2 in urine were unaltered. Adenosine diphosphate‐induced platelet aggregation in vitro remained unchanged during pravastatin therapy, and the platelet volume distribution was not affected. LDL‐apheresis reduced the mean platelet volume, as well as the percentage of large platelets, whereas the percentage of small platelets increased. Other measures of platelet function in vivo or in vitro were, however, unaltered following LDL‐apheresis.

Platelet aggregability in humans: contrasting in vivo and in vitro findings during sympatho‐adrenal activation and relationship to serum lipids

Abstract. Platelet aggregability was studied in 18 healthy volunteers during mental stress (a colour word test; CWT) and low‐ and high‐dose adrenaline infusions using an ex vivo technique (filtragometry) and conventional in vitro aggregometry. CWT and high‐dose adrenaline (3–4 nmol 1‐1 in plasma) shortened filtragometry readings, suggesting increased platelet aggregability in vivo. Low‐dose adrenaline had no effect despite higher adrenaline levels in plasma (0.9 nmol I‐1) than during CWT (0.4 nmol I‐1). Platelet sensitivity to ADP in vitro was reduced following CWT and further reduced following adrenaline infusions. In vitro, adrenaline (50 nmol I‐1) had little effect on platelet aggregation per se, but enhanced aggregability evoked by ADP (at ED50). Adrenaline potentiation of ADP‐induced aggregation was enhanced after CWT, but was not related to filtragometry responsiveness to stress in vivo. Serum LDL‐cholesterol levels were inversely correlated to filtragometry readings at rest, suggesting an adverse influence on platelet aggregability in vivo. HDL‐cholesterol levels were inversely correlated to platelet sensitivity to ADP in vitro, suggesting a positive influence. Thus, sympathp‐adre‐nal activation enhances platelet aggregability in vivo (as assessed by ex vivo filtragometry), but adrenaline alone cannot explain the pro‐aggregatory effect of mental stress. Serum lipoprotein alterations associated with increased risk for atherosclerosis seem to enhance platelet aggregability. The conventional in vitro technique may poorly reflect platelet aggregability in vivo.,

Metoprolol does not reduce platelet aggregability during sympatho-adrenal stimulation

SummaryThe possibility that β-adrenoceptor blockers, especially β1-selective agents might inhibit platelet function is of considerable interest, as this might be of pathophysiological importance in cardiovascular diseases. Platelet function, however, is difficult to assess and in vivo related data are scarce.The effect of one week of treatment with metoprolol 200 mg/day on platelet aggregability during mental stress (colour word conflict test; CWT) and low and high dose adrenaline infusions has been evaluated in a double-blind, placebo-controlled, cross-over study in 10 healthy male volunteers. Platelet function in vivo was assessed using ex vivo filtragometry, and the urinary excretions of β-thromboglobulin (HMW β-TG) and 11-dehydro-TxB2 (a thromboxane metabolite). Conventional in vitro aggregometry and the urinary levels of 2,3-dinor-6-keto-PGF1α (a prostacyclin metabolite) were also studied.During the interventions there was increased platelet aggregability in vivo, as filtragometry readings were shortened by 41±11% during high dose adrenaline infusion, urinary HMW β-TG levels increased and urinary 11-dehydro-TxB2 tended to increase. In contrast, platelet sensitivity to ADP in vitro was reduced. The urinary 2,3-dinor-6-keto-PGF1α levels were increased during the interventions.Despite the cardiovascular and biochemical signs of β-adrenoceptor blockade at rest and during the interventions, metoprolol failed to influence platelet function in vivo, as measured by ex vivo filtragometry, or urinary HMW β-TG or 11-dehydro-TxB2 levels. It tended rather to enhance the stress response measured by ex vivo filtragometry. Platelet aggregability in vitro and urinary 2,3-dinor-6-keto-PGF1α levels were not altered by metoprolol.Thus, metoprolol was not found to reduce platelet aggregability in healthy male volunteers either at rest or during sympatho-adrenal activation. The effect of treatment may still differ in patients; studies in patients with ischaemic heart disease are under way.

Autologous Low Density Lipoprotein Enhances Platelet Aggregation in Whole Blood, as Measured by In Vitro Filtragometry

The influence of low density lipoprotein (LDL) on platelet aggregability was studied using filtragometry and conventional Born aggregometry in vitro. Three different concentrations of autologous LDL, obtained from 9 healthy male volunteers, were incubated for 20 min, at 37°C, with whole blood anticoagulated with low molecular weight heparin (filtragometry) or citrated platelet-rich plasma (PRP; Born aggregometry). The LDL-cholesterol concentration was increased from 1.7 ± 0.2 mmol/1 to 2.4 ± 0.2, 3.5 ± 0.3 and 5.3 ± 0.5 mmol/l, respectively. Adenosine diphospate (ADP)-induced platelet aggregation in whole blood was enhanced in a dose dependent manner by LDL, as assessed by filtragometry (ADP cone, range 0.1-0.3 μM). Platelet aggregability in PRP (Born) was not affected by LDL at the ED(50) for ADP-induced platelet aggregation (i.e. 1-4 μM ADP). The marked platelet activation caused by the high ADP concentrations used with conventional Born aggregometry may have masked a modest LDL-induced platelet activation as a slight increase in spontaneous platelet aggregation was observed in PRP at the intermediate LDL-concentration. The present findings indicate that low concentrations of LDL stimulate platelet aggregability in the physiological whole blood milieu. This adverse effect of LDL-cholesterol may be of clinical importance in patients with hypercholesterolaemia.