摘要:

Platelets respond to a wide variety of exogenous agonists that bind to distinct receptors on the platelet surface resulting in the intracellular generation of second messengers or the opening of ion channels, setting off a cascade of events leading to both physical and functional changes in the platelet. The cyclic nucleotides, cyclic adenosine 3′5′-monophosphate (CAMP) and cyclic guanosine 3′5′-monophosphate (cGMP) initiate a sequence of intracellular events that modulate many of these reactions in the platelet.

ISSN:0953-7104    

DOI:10.3109/09537109509078445

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

A recent unexpected finding of inhibited platelet aggregation in response to a single (1.64 mmol/l) dose of arachidonic acid (AA), during the relapse of childhood nephrosis, prompted us to assess aggregation in response to multiple doses of AA: 1.64,0.82,0.41,0.20 mmol/l, in two groups of children, in the relapse (n = 34) or remission (n=41) phase of nephrotic syndrome. During relapse: the highest dose of AA (1.64 mmol/l) evoked reversible and inhibited aggregation in 91% of patients. However, at the lower doses there were enhanced responses as measured by both maximum aggregation (%) and slopes of the aggregation curves. In contrast, during remission, irreversible aggregation was obtained at the highest AA dose, while at the lowest two doses (0.41 and 0.20 mmol/l), no aggregation responses were obtained in 4 (9%) and 7 (17%) patients respectively; in those who responded there was a long lag phase. Healthy controls (n = 21) exhibited their highest responses to 1.64 and 0.82 mmol/l AA and at the lowest AA doses (0.41 and 0.20 mmol/l), a total absence of responses was noted in 40% and 71% of samples respectively. We conclude that during relapse platelet sensitivity, as shown by irreversible aggregation in response to multiple AA doses, shifts towards the lower doses, when compared with healthy controls; while during remission responses fall in-between the relapse and control groups, indicating the maintenance of platelet sensitivity during this phase of nephrosis.

ISSN:0953-7104    

DOI:10.3109/09537109509078446

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

Human platelet GP IIb/IIIa and common human viruses showed sequence homologies of up to 220 amino acids. High scoring homologies were found in Herpes Simplex, Varicella Zoster, Epstein-Barr virus, Adenovirus and Cytomegalovirus, all of which cause lifelong latent infections. Further high scoring sequences were found in Measles, Mumps and Rubella, which are sporadically associated with acute autoimmune thrombocytopenic purpura (AITP). Lower scoring homologies were found in Parvovirus, coxsackie B and Human Immunodeficiency Virus. There were frequent homologies to known autoantibody-binding epitopes in the cysteine-rich and intracytoplasmic regions of GP IIb/IIIa, but also with the RGD-binding and calcium-binding regions, and with the nascent GP signal peptide which is not expressed in the functional glycoprotein. Peptides representing the 48 highest scoring viral sequences were synthesised in vitro, and 7 of these viral peptides were shown to inhibit the serum autoantibodies of adults with chronic AITP. The pattern and degree of autoantibody inhibition varied from patient to patient, was concentration dependent and distinct for each peptide. This suggests that polyclonal GP IIb/IIIa autoantibodies are directed to different GP epitopes and are cross reactive in different patients to different viral proteins in different viruses. The results suggest that human viruses have a role in the aetiology of AITP via molecular mimicry of platelet GP IIb/IIIa, and that chronic auto immunity may be related to a persistent antigenic stimulus from lifelong latent viral infections.

ISSN:0953-7104    

DOI:10.3109/09537109509078447

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

Effects of nitric oxide (NO) on thrombin-induced responses in gel-filtered, [32P] Pi-(pre) labeled platelets (GFP) were examined. NO did not alter the levels of32P-labeled polyphosphoinositides in unstimulated platelets and did not inhibit the forskolin-induced elevation of [32P]PIP (phosphatidylinositol 4-phosphate), which indicates that NO does not concomitantly increase the level of cAMP in resting human platelets. In aspirinated platelets NO inhibited thrombin (0.05 U/ml)-induced formation of [32P]phosphatidic acid (PA), secretion of ATP + ADP from the dense granules and secretion of acid glycosidases in a dose-dependent manner. At 0.2 U/ml of thrombin NO still inhibited these responses, although to a lesser degree. In aspirinated platelets in the presence of creatine phosphate/creatine phosphokinase (CP/CPK) to remove secreted ADP, increasing concentrations of NO still produced strong inhibition of [32P] PA-formation and secretory responses.

ISSN:0953-7104    

DOI:10.3109/09537109509078448

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

The effects on platelet activation of two different tetrapeptides, KRDS present on human lactotransferrin and RGDS present on adhesive proteins such as human fibrinogenα-chain, were compared by a combination of morphological and functional techniques. Ultrastructural observations ofα-thrombin stimulated platelets (0.05 U/ml), show strong platelet aggregation and fullα-granule release. In the presence of RGDS (0.1-1 mM) aggregation was impaired but secretion was not blocked and platelets had released theirα-granule contents. Platelets appeared uniformly degranulated with a dense central meshwork of microfilaments. In the presence of KRDS (0.5-1 mM), the platelets were activated with shape change and pseudopod formation. Aggregation was also impaired, but to a lesser extent since RGDS is active at a concentration as low as 0.1 mM, and, in contrast to RGDS, secretion was severely reduced. Electron microscopy showed that numerousα-granules were still scattered in the cytoplasmic matrix or often gathered in the centre of the platelet, but the majority of the open canalicular system cisternae remained clear. An immunoelectron microscopic study using immunogold and monospecific antibodies directed against fibrinogen and the a-granule membrane protein P-selectin (GMP 140) was performed. In the presence of RGDS, fibrinogen was released and P-selectin was translocated to the platelet surface; in contrast, in the presence of KRDS, fibrinogen remained localized in theα-granule, and the P-selectin associated with the a-granule. These observations were accompanied by some functional results: thrombin-induced platelet aggregation was inhibited by both peptides, and in contrast to RGDS, secretion was severely reduced in the presence of KRDS: serotonin release from dense granule was reduced by 73% compared to the control. These results show that these two tetrapeptides, in spite of some structural similarities, act differently in impairing platelet function. KRDS interfering with both the dense andα-granule release reaction may be a useful tool for a better understanding of the platelet secretion mechanism.

ISSN:0953-7104    

DOI:10.3109/09537109509078449

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

The DP receptor-dependence of inhibition of platelet aggregation (PA), degranulation, and TXA2synthesis, by PGD2, in human whole blood, has not been established since selective antagonists have only recently been developed. Accordingly, the effects of PGD2(30 nM), were determined using the DP receptor antagonists AH6809 (50µM) and 868C84 (0.5µM), and results were compared with those obtained using the stable and DP receptor-specific agonist 572C85 (30 nM).With collagen at 0.3µg/ml, PGD2markedly inhibited PA (6 vs 91% PA, p>0.03, n = 12) and both AH6809 and 868C84 alone also inhibited PA but less markedly (62 and 63% PA, respectively) and both antagonists largely prevented the antiaggregatory action of PGD2(57 and 52% PA, respectively). PGD2also markedly inhibited TXB2, formation (reflecting inhibition of TXA2synthesis) (19 vs 48 nM TXB2, p>0.03). AH6809 and 868C84 alone had little effect (both 45 nM) but both antagonists significantly reduced the inhibitory effect of PGD2on TXB2formation (35 and 33 nM, respectively, p>0.03 vs PGD2alone). PGD2also inhibitedβ-thromboglobulin release, but only to a similar extent as with AH6809 and 868C84 alone.With collagen at 3.0μg/ml, PGD2again inhibited PA (60 vs 96% PA, p>0.03), AH6809 and 868C84 alone had no effect on PA (98 and 96% respectively) but effectively abolished the antiaggregatory effect of PGD2. PGD2also inhibited TXB2formation (194 vs 339 nM, p>0.03) and this effect of PGD2was effectively abolished both by AH6809 and 868C84 (313 and 308 nM, respectively). Results obtained with 572C85 largely confirmed those obtained with PGD2, and with collagen at 0.3µg/ml, 868C84 effectively abolished inhibition of both PA and TXB2formation by 572C85.Thus, DP receptor-dependent inhibition of both aggregation and TXA2synthesis both by PGD2and the more selective DP receptor agonist 572C85, was established using the DP receptor antagonists AH6809 and 868C84. Results obtained forβ-thromboglobulin release were inconclusive since both AH6809 and 868C84 inhibited release to a similar extent as did PGD2, indicating that a limited effect either on aggregation or TXB2formation does not preclude a greater effect on degranulation.

ISSN:0953-7104    

DOI:10.3109/09537109509078450

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

ISSN:0953-7104    

DOI:10.3109/09537109509078451

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor