Adenosine Diphosphate in Red Cells as a Factor in the Adhesiveness of Human Blood Platelets

Gaarder, Anne; Jonsen, Jon; Laland, S.; Hellem, A. J.; Owren, P. A.

doi:10.1038/192531a0

Cited by 772 publications

(251 citation statements)

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“…A recent experimental study investigating the effect of RBC on thrombin generation, showed that the total amount of thrombin activity generated, and the maximum concentration of thrombin achieved, was proportional to the hematocrit. 25 RBC may also take part in thrombus formation by other mechanisms, such as stimulation of platelet aggregation through ADP release, [26][27][28] or possibly through the exposure of phosphatidylserine. 29 The main strengths of our study are its prospective design, the large number of participants recruited from a general population with high attendance rate, the longterm follow-up, and the validation of the venous thromboembolic events.…”

Section: Discussionmentioning

confidence: 99%

Hematocrit and risk of venous thromboembolism in a general population. The Tromso study

Brækkan¹,

Mathiesen²,

Njølstad³

et al. 2009

Haematologica

162

119

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BackgroundHematocrit above the normal range for the population, such as in primary or secondary erythrocytosis, predisposes to both arterial and venous thrombosis. However, little is known about the association between hematocrit and risk of venous thromboembolism in a general population. Design and MethodsHematocrit and related hematologic variables such as hemoglobin, red blood cell count, mean corpuscular volume, and baseline characteristics were measured in 26,108 subjects, who participated in the Tromsø Study in 1994-1995. Incident venous thromboembolic events during follow-up were registered up to September 1 st , 2007. ResultsThere were 447 venous thromboembolic events during a median of 12.5 years of followup. Multivariable hazard ratios per 5% increment of hematocrit for the total population, adjusted for age, body mass index and smoking, were 1.25 (95% CI: 1.08-1.44) for total venous thromboembolism and 1.37 (95% CI: 1.10-1.71) for unprovoked venous thromboembolism. In category-based analyses, men with a hematocrit in the upper 20 th percentile (≥46% in men) had a 1.5-fold increased risk of total venous thromboembolism (95% CI: 1.08-2.21) and a 2.4-fold increased risk of unprovoked venous thromboembolism (95% CI: 1.36-4.15) compared to men whose hematocrit was in the lower 40 th percentile. The risk estimates were higher for men than for women both in continuous and category-based analyses. The findings for hemoglobin and red blood cell count were similar to those for hematocrit, whereas mean corpuscular volume was not associated with venous thromboembolism. ConclusionsOur findings suggest that hematocrit and related hematologic variables such as hemoglobin and red blood cell count are risk factors for venous thromboembolism in a general population.Key words: hematocrit, population range, arterial and venous thrombosis. Study. Haematologica. 2010; 95:270-275. doi:10.3324/haematol.2009 Hematocrit and risk of venous thromboembolism in a general population. The Tromsø study Citation: Braekkan SK, Mathiesen EB, Njølstad I, Wilsgaard T, and Hansen J-B. Hematocrit and risk of venous thromboembolism in a general population. The Tromsø

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Section: Discussionmentioning

confidence: 99%

Hematocrit and risk of venous thromboembolism in a general population. The Tromso study

Brækkan¹,

Mathiesen²,

Njølstad³

et al. 2009

Haematologica

162

119

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“…In the body, ATP is known to be released during platelet thrombus formation (15), catecholamine release from the adrenal medulla (44), shock (42), and strenuous exercise (14). In addition, extracellular ATP plays an important role in many physiological processes.…”

Section: Discussionmentioning

confidence: 99%

Extracellular ATP as a trigger for apoptosis or programmed cell death.

Zheng

Zychlinsky

Liu

et al. 1991

The Journal of Cell Biology

321

179

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Abstract. Extracellular ATP is shown here to induce programmed cell death (or apoptosis) in thymocytes and certain tumor cell lines. EM studies indicate that the ATP-induced death of thymocytes and susceptible tumor cells follows morphological changes usually associated with glucocorticoid-induced apoptosis of thymocytes. These changes include condensation of chromatin, blebbing of the cell surface, and breakdown of the nucleus. Cytotoxicity assays using doublelabeled cells show that ATP-mediated cell lysis is accompanied by fragmentation of the target cell DNA. DNA fragmentation can be set off by ATP but not the nonhydrolysable analogue ATP'yS nor other nucleoside-5'-triphosphates. ATP-induced DNA fragmentation but not ATP-induced 5tCr release can be blocked in cells pretreated with inhibitors of protein or RNA synthesis or the endonuclease inhibitor, zinc; whereas pretreatment with calmidazolium, a potent calmodulin antagonist, blocks both DNA fragmentation and 51Cr release. The biochemical and morphological changes caused by ATP are preceded by a rapid increase in the cytoplasmic calcium of the susceptible cell. Calcium fluxes by themselves, however, are not sufficient to cause apoptosis, as the poreforming protein, perforin, causes cell lysis without DNA fragmentation or the morphological changes associated with apoptosis. Taken together, these results indicate that ATP can cause cell death through two independent mechanisms, one of which, requiring an active participation on the part of the cell, takes place through apoptosis.

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“…Autoradiograms of the gels obtained by sodium dodecyl sulfatepolyacrylamide gel electrophoresis of solubilized platelets modified by either [␤- Although ADP (Fig. 1A) is one of the earliest known agonists for platelet activation (1,2), the identity of the receptor is still uncertain. ADP receptors on platelets and magakaryocytes are unique (3); they constitute a subtype P 2T of a class of P 2 purinergic receptors where ADP is the strongest agonist and ATP is an antagonist (4).…”

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confidence: 99%

Inhibition of ADP-induced Platelet Responses by Covalent Modification of Aggregin, a Putative ADP Receptor, by 8-(4-Bromo-2,3-dioxobutylthio)ADP

Puri

Kumar

Chen

et al. 1995

Journal of Biological Chemistry

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ADP is an important platelet agonist which initiates platelet shape change, aggregation, exposure of fibrinogen receptors, and calcium mobilization. Because of the limitations of previously used affinity analogs and photolabeling studies as well as controversies surrounding the identity of an ADP receptor on platelets, we have used an affinity label capable of alkylating a putative exofacial receptor on platelets. We now report that 8-(4-bromo-2,3-dioxobutylthio)adenosine-5-diphosphate (8-BDB-TADP), which is an analog of the natural ligand ADP, blocked ADP-induced platelet shape change, aggregation, exposure of fibrinogen-binding sites, secretion, and calcium mobilization. Following modification by 8-BDB-TADP, the rates of aggregation of platelets induced by thrombin, a calcium ionophore (A23187) or a stimulator of protein kinase C (phorbol myristate acetate) were minimally affected. However, the 8-BDB-TADP-modified platelets exhibited decreased rates of aggregation in response to ADP, as well as collagen and a thromboxane mimetic (U46619), both of which partially require ADP. Autoradiograms of the gels obtained by sodium dodecyl sulfatepolyacrylamide gel electrophoresis of solubilized platelets modified by either [␤- Although ADP (Fig. 1A) is one of the earliest known agonists for platelet activation (1, 2), the identity of the receptor is still uncertain. ADP receptors on platelets and magakaryocytes are unique (3); they constitute a subtype P 2T of a class of P 2 purinergic receptors where ADP is the strongest agonist and ATP is an antagonist (4). The presence of a P 2T receptor on human erythroleukemia cells has recently been demonstrated (5). Previous work from our laboratory demonstrated that 5Ј-p-fluorosulfonylbenzoyladenosine (FSBA) 1 (Fig. 1B), an ADP affinity label, blocked ADP-induced platelet shape change (6), aggregation, and exposure of fibrinogen-binding sites (7) with concomitant covalent modification of a single surface protein, aggregin (100 kDa), an ADP receptor on platelet surface (8, 9). Covalent modification of platelets by FSBA was shown to block platelet aggregation induced by U46619 (a thromboxane mimetic) (10) and collagen (11), suggesting that aggregation induced by these agonists, in part, depends on interaction of ADP with aggregin.Other investigators have proposed different candidates for a putative ADP rceceptor on platelet surface. Greco et al. (12) suggested that there is an ADP-binding site on platelet glycoprotein IIb (GPIIb) based on results obtained by photolabeling of platelets by [ 35

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Adenosine Diphosphate in Red Cells as a Factor in the Adhesiveness of Human Blood Platelets

Cited by 772 publications

References 3 publications

Hematocrit and risk of venous thromboembolism in a general population. The Tromso study

Hematocrit and risk of venous thromboembolism in a general population. The Tromso study

Extracellular ATP as a trigger for apoptosis or programmed cell death.

Inhibition of ADP-induced Platelet Responses by Covalent Modification of Aggregin, a Putative ADP Receptor, by 8-(4-Bromo-2,3-dioxobutylthio)ADP

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