Effect of Iloprost (ZK 36 374), a Novel Prostacyclin Analogue, on ADP-induced Platelet Aggregation

Wadenvik, Hans; Kutti, Jack

doi:10.1159/000206333

Cited by 7 publications

(3 citation statements)

References 12 publications

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“…23 This treatment completely abolished responses induced by modified amyloid-␤, Hb-AGE, and BSA-AGE as well as the aggregation by TRAP (Figure 2A). Thus the change in light transmission of platelet suspensions stimulated with amyloid proteins depends on undisturbed platelet activating sequences.…”

Section: Effect Of Inhibitors On Amyloid-induced Platelet Aggregationmentioning

confidence: 89%

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Activation of Human Platelets by Misfolded Proteins

Herczenik

Bouma

Korporaal

et al. 2007

ATVB

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Objective-Protein misfolding diseases result from the deposition of insoluble protein aggregates that often contain fibrils called amyloid. Amyloids are found in Alzheimer disease, atherosclerosis, diabetes mellitus, and systemic amyloidosis, which are diseases where platelet activation might be implicated. Methods and Results-We induced amyloid properties in 6 unrelated proteins and found that all induced platelet aggregation in contrast to fresh controls. Amyloid-induced platelet aggregation was independent of thromboxane A 2 formation and ADP secretion but enhanced by feedback stimulation through these pathways. Treatments that raised cAMP (iloprost), sequestered Ca 2ϩ (BAPTA-AM) or prevented amyloid-platelet interaction (sRAGE, tissue-type plasminogen activator [tPA]) induced almost complete inhibition. Modulation of the function of CD36 (CD36 Ϫ/Ϫ mice), p38 MAPK (SB203580), COX-1 (indomethacin), and glycoprotein Ib␣ (Nk-protease, 6D1 antibody) induced Ϸ50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of ␣ IIb ␤ 3 -independent aggregation (agglutination). Conclusions-Protein misfolding resulting in the appearance of amyloid induces platelet aggregation. Amyloid activates platelets through 2 pathways: one is through CD36, p38 MAPK , thromboxane A 2 -mediated induction of aggregation; the other is through glycoprotein Ib␣-mediated aggregation and agglutination. The platelet stimulating properties of amyloid might explain the enhanced platelet activation observed in many diseases accompanied by the appearance of misfolded proteins with amyloid. Key Words: amyloid Ⅲ platelet activation Ⅲ sRAGE Ⅲ tissue plasminogen activator Ⅲ CD36 Ⅲ glycoprotein Ib␣ P roteins typically adopt a well-defined 3-dimensional structure. There is now an increasing amount of evidence that abnormalities in this process have far reaching consequences for human health. Certain mutations and posttranslational modifications such as glycation and oxidation interfere with proper folding, resulting in protein misfolding, aggregation, and ultimately polymerization into insoluble fibrils called amyloid. 1,2 The term amyloidosis defines a group of systemic and localized diseases associated with the deposition of amyloid in different tissues. Alzheimer disease is caused by abnormal folding of amyloid-␤ and formation of amyloid-rich plaques that obstruct neurons and microvessels of the brain. 3 One has argued that these plaques cause the hyperreactivity of platelets observed in these patients as illustrated by P-selectin positive platelets and increased levels of urinary thromboxane A 2 metabolite. 4,5 An environmental risk factor for Alzheimer disease is Herpes Simplex virus. It contains glycoprotein B, a protein fragment that assembles into fibrils that are ultrastructurally indistinguishable from amyloid-␤. 6 Protein misfolding is not restricted to Alzheimer disease but is a common feature in the pathology of atherosclerosis, diabetes mellitus, and systemic amyloidosis. 7-9 Atherosclerotic plaques contain ...

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Section: Effect Of Inhibitors On Amyloid-induced Platelet Aggregationmentioning

confidence: 89%

“…Plasminogen was purified as described. 23 Thrombin receptor (PAR1)-activating peptide (TRAP, SFLLRN) was synthesized with a semi-automatic peptide synthesizer (Labortec AG SP650, Switzerland).…”

Section: Reagentsmentioning

confidence: 99%

Activation of Human Platelets by Misfolded Proteins

Herczenik

Bouma

Korporaal

et al. 2007

ATVB

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“…Finally, the area under each aggregation curve from time zero (i.e. addition of ADP) to 2 rnin was calculated (13). All aggregation studies were made within 1 h from the venipuncture.…”

Section: Platelet Aggregation Studiesmentioning

confidence: 99%

Platelet reactivity, fibrinogen and smoking

Dotevall¹,

Kutti²,

Teger‐Nilsson

et al. 1987

European J of Haematology

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40 young healthy male volunteers (20 habitual smokers and 20 non‐smokers) were investigated with respect to platelet reactivity, plasma fibrinogen and coagulation factor VIII. Smokers had significantly lower systolic blood pressures and higher venous platelet counts. The results for ADP‐induced platelet aggregation, plasma concentrations for the 2 α‐granule proteins, beta‐thromboglobulin and platelet factor 4, did not differ between the 2 study groups involved; nor was there any difference between serum thromboxane B2 formation or plasma factor VIII:C activity. However, as compared to non‐smokers, plasma fibrinogen levels were significantly higher among the smokers.

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