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• Platelet Activation and catheter intracoronary brachytherapy
  Fuad Lechin
  Published on: 23 November 2015
• Authors' reply: Platelet activation after VBT
  Markus Jaster
  Published on: 23 November 2015
• Platelet activation associated with intracoronary brachytherapy
  Florian Krotz
  Published on: 23 November 2015

• Published on: 23 November 2015

  Platelet Activation and catheter intracoronary brachytherapy

  • Fuad Lechin, MD, PhD
  • Other Contributors:
    • Bertha van der Dijs

  Dear Editor

  We read with great interest the article by Jaster et al. [1] dealing with the failure by aspirin and clopidogrel to inhibit platelet activation during vascular brachytherapy after percutaneous coronary intervention, which is responsible for a higher risk of stent thrombosis. With respect to the above, we would like to inform about some findings dealing with this issue.

  Platelet aggre...

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  Dear Editor

  We read with great interest the article by Jaster et al. [1] dealing with the failure by aspirin and clopidogrel to inhibit platelet activation during vascular brachytherapy after percutaneous coronary intervention, which is responsible for a higher risk of stent thrombosis. With respect to the above, we would like to inform about some findings dealing with this issue.

  Platelet aggregation occurs after platelet activation. Several mechanisms and factors converge to this end including membrane integrin glycoprotein IIb/IIIa and the membrane receptors for fibrinogen as well as the calcium-dependent linkage formation between activated receptors and bivalent fibrinogen resulting in platelet aggregation. The role played by the pro-aggregation mediators such as ADP, ATP, platelet factor 4 (PF4), betathromboglobulin (beta-TG), thromboxane A2 (TXA2), fibrinogen and thrombospondin, which are followed by the translocation of the alpha granule membrane protein P-selectin (CD62) should be taken into account. In addition, the role played by phosphatidylserine, which is the starting point for the coagulation cascade should be taken into account. Despite all the above, we think that the most important factor should be referred to the serotonin content into the platelets (p-5HT). Many research studies have demonstrated the primary role played by p-5HT in the haemostatic process.[2-5] We demonstrated that platelet serotonin content rather than platelet count should be considered as the appropriate index for measuring thrombostasis, since the former parameter and not the latter correlates with bleeding stoppage. [2] Similar findings have been reported by other authors measuring these parameters in an experimental model of ITP in mice. [6] Serotonin is stored in the delta granules of platelets and its release increase during activation. [7] Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cells surface. [8] Furthermore, the presence of serotonin is covalently linked to fibrinogen bound on the surface of the activated platelet where it increases the retention of procoagulant factors on the cell surface. [8] Serotonin, therefore, plays a central role in the haemostatic process and its release is considered the most reliable assay for platelet activation. [7]

  Considering that aspirin reduces platelet aggregation by means of a prostaglandins-mediated mechanism that interferes with platelet serotonin uptake and reduces p-5HT values, [2-5] all factors interfering with platelet serotonin depletion should enhance platelet aggregability. With respect to the above, we found that long-time consumers of prostaglandins inhibitors presented with low levels of p-5HT. [9] This finding is consistent with the fact that tianeptine, a drug which increase platelet serotonin content is able to stop bleeding in patients affected by idiopathic thrombocytopenic purpura, whereas drugs which deplete platelet serotonin content (serotonin uptake inhibitors) and serotonin releasing agents were able to trigger bleeding within the first 3-4 weeks of administration, in ITP patients. [9] These findings fit well with the report by Gurbel et al. [10] demonstrating the failure of clopidogrel plus aspirin therapy addressed to reduce platelet reactivity.

  Summarizing all the above, we believe that the failure by aspirin and clopidogrel to inhibit platelet aggregation in long-term treated patients should be associated to the progressive reduction of p-5HT levels.

  References

  1.Jaster M, Fuster V, Rosenthal P, Pauschinger M, Tran QV, Janssen D, Hinkelbein W, Schimmbeck P, Schultheiss HP, Rauch U. Catheter based intracoronary brachytherapy leads to increased platelet activation. Heart 2004, 90:160-164

  2.Lechin F, van der Dijs B, Orozco B, Jahn E, Rodriguez S, Baez S. Neuropharmacological treatment of refractory idiopathic thrombocytopenic purpura: roles of circulating catecholamines and serotonin. Thromb Haemost 2004; 911254-1256.

  3.Lechin F, van der Dijs B, Orozco B, Rodriguez S, Baez S. Elective stenting, platelet serotonin and thrombotic events (Letter). Platelets 2004; (In press).

  4.Lechin F, van der Dijs B. Platelet serotonin and thrombostasis. J Clin Invest Online (Letters) April 21, 2004.

  5.Lechin F, van der Dijs B. Platelet aggregation, platelet serotonin and pancreatitis (Letter). J Pancreas (Online) 2004; 5:8001-3.

  6.Dominguez V, Govezensky T, Gevorkian G, Larralde C. Low platelet counts do not cause bleeding in an experimental model of immune thrombocytopenic purpura in mice. Haematologica 2003; 88:679-87.

  7.Gobbi G, Mirandola P, Tazzari P, Ricci F, Caimi L, Cacchioli A, et al. Flow cytometry detection of serotonin content and release in resting and activated platelets. Br J Haematol 2003; 121: 892-6.

  8.Dale GL, Friese P, Batar P, Hamilton SF, Reed GL, Jackson KW, et al. Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface. Science 2002; 415:175–9.

  9.Lechin F, van der Dijs B, Lechin ME. Neuropharmacological therapy of diseases associated with uncoping stress profile (Th-2 autoimmune diseases). In: Lechin F, van der Dijs B, Lechin ME, eds. Neurocircuitry and Neuroautonomic Disorders. Reviews and Therapeutic Strategies. Basel: Karger, 2002;75-82.

  10.Gurbel PA, Samara WM, Bliden KP. Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stenting: implications for thrombotic events and restenosis. Platelets 2004; 15:95-9.

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Authors' reply: Platelet activation after VBT

  • Markus Jaster, MD
  • Other Contributors:
    • Peter L. Schwimmbeck, and Ursula Rauch

  Dear Editor

  We agree with the opinion of Krötz et al. that endothelial mediated or train source associated effects but not the irradiation itself lead to an increased platelet activation after VBT as pointed out by our publication.[1]

  In contrast to the paper of Krötz et al,[2] in which only relative changes in platelet activation are shown, our data were given as the percentages of act...

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  Dear Editor

  We agree with the opinion of Krötz et al. that endothelial mediated or train source associated effects but not the irradiation itself lead to an increased platelet activation after VBT as pointed out by our publication.[1]

  In contrast to the paper of Krötz et al,[2] in which only relative changes in platelet activation are shown, our data were given as the percentages of activated platelets over time. These parameters have been reported to be a reliable measure for platelet activation.[3] Tschöpe et al. documented that the level of platelet activation at baseline affects the degree of platelet activation and the risk of acute thrombotic events after PCI.[4] In our study, VBT and control patients were comparable not only in clinical baseline data but also in the level of platelet activation before intervention. Therefore, we were able to perform statistical tests between the two study groups. We showed that the platelet activation increased immediately after VBT but not after conventional PCI. This points to a device related effect on platelet activation, since irradiation did not directly increase platelet activation as shown by us and others.[1,5]

  To explain the phenomenon of late thrombosis, a dysfunctional endothelium and a thrombogenic vasculature at the site of irradiation have to be considered as well. We have recently shown in in vitro experiments that irradiation induces an increased tissue factor expression and procoagulant activity in human endothelial cells and leukocytes after days to weeks.[6,7] The activation of the tissue factor pathway due to a highly thrombogenic vasculature at the site of injury may propagate platelet activation even months after VBT. Further studies including the analysis of thrombogenic proteins expressed in the irradiated coronaries are needed to clarify the impact of the vasculature on the occurrence of late thrombosis after VBT.

  References

  1. Krotz F . Platelet activation associated with intracoronary brachytherapy [electonic response to Jaster et al. Catheter based intracoronary brachytherapy leads to increased platelet activation] heartjnl.com 2004http://heart.bmjjournals.com/cgi/eletters/90/2/160#235

  2. Krötz F, Schiele T, Zahler S, et al. Sustained platelet activation following intracoronary beta irradiation. Am J Cardiol 2002; 90: 1381-4.

  3. Michelson AD. Flow cytometry: A clinical test of platelet function. Blood 1996; 12: 4925-36.

  4. Tschoepe D, Schultheiss HP, Kolarov P, et al. Platelet membrane activation markers are predictive for increased risk of acute ischemic events after PTCA. Circulation 1993; 88: 37-42.

  5. Weinmann M, Hoffmann W, Rodegerdts E, et al. Biological effects of ionizing radiation on human blood compounds ex vivo. J Cancer Res Clin Oncol 2000; 126: 584-8.

  6. Li M, Pham VA, Goldin-Lang P, et al. Irradiation induces tissue factor acitvation and increases the procoagulant activity of human endothelial cells. Circulation 2003; 108 (Suppl. IV): IV-112.

  7. Rauch U, Tran-Quan V, Golding-Lang P, et al. Irradiation of human monocytic cells is associated with an increase in tissue factor expression and procoagulant activity. Eur Heart J 2003; 24 (Suppl.): 475.

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Platelet activation associated with intracoronary brachytherapy

  • Florian Krotz, Physician
  • Other Contributors:
    • Hae-Young Sohn, Volker Klauss, Thomas M Schiele

  Dear Editor

  In the manuscript "Catheter based intracoronary brachytherapy leads to increased platelet activation" the authors observe an increased platelet activation as assessed by the activation markers CD63 (content of platelet lysosomes) and thrombospondin (content of platelet a-granules) immediately following intracoronary intervention. This occurred only when patients had received catheter-based irradiation...

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  Dear Editor

  In the manuscript "Catheter based intracoronary brachytherapy leads to increased platelet activation" the authors observe an increased platelet activation as assessed by the activation markers CD63 (content of platelet lysosomes) and thrombospondin (content of platelet a-granules) immediately following intracoronary intervention. This occurred only when patients had received catheter-based irradiation, but not when conventional PCI was performed.[1]

  We have previously performed a more detailed analysis of the time- course of platelet activation patterns following intracoronary irradiation using a similar experimental design, which was substantiated by assessment of samples obtained from intracoronary and peripheral locations [2]. In accordance with the findings by Jaster and colleagues, we found sings for degranulation of platelets, which occurred 6 hours following the intervention and remained sustained for up to 6 months. We also observed activation parameters to be elevated at 6 hours in patients treated with conventional PCI only. These patients, however, returned to baseline platelet activation levels at 6 months following the intervention, which is a clear sign that indirect effects on platelets, such as disturbed reendothelialisation, which may prevail in irradiated vessels [3], should be responsible for the increase in platelet activation. In accordance with this, clinical data show that thrombotic occlusions of irradiated vessels preferentially occur at later time points following intracoronary irradiation.[4]

  In addition to the findings presented here, we observed not only an increase in markers that appear solely upon activation of platelets (such as CD63 and thrombospondin), but also markers that are constitutively expressed on platelets, such as the fibrinogen receptor subunit CD41, which was upregulated 6 hours following the intervention. Moreover, we could observe long-term upregulation of platelet CD40 ligand, a molecule associated with atherothrombotic disease [5] and decreased endothelial cell migration,[6] which thus could be involved in delayed reendothelialisation.[7]

  Partly diverging from the conclusions that are drawn by Jaster and colleagues, we think that both studies give a strong evidence of indirect effects being responsible for sustained platelet activation following intracoronary irradiation rather than a thrombogenic surface of the source trains or a direct effect on platelets that may take place in vivo only. This is corroborated by the findings of Jasper and colleagues, who cannot induce platelet activation by direct irradiation of isolated platelets [1]. Mechanically damaged endothelium that shows altered and possibly impaired healing in irradiated vessels seems to be a more likely pathophysiological cause for late thrombotic occlusion to us.

  References

  1. Jaster M, Fuster V, Rosenthal P, Pauschinger M, Tran QV, Janssen D et al. Catheter based intracoronary brachytherapy leads to increased platelet activation. Heart 2004;90:160-4.

  2. Krotz F, Schiele TM, Zahler S, Konig A, Rieber J, Kantlehner R et al. Sustained platelet activation following intracoronary beta irradiation. Am.J.Cardiol. 2002;90:1381-4.

  3. Salame MY, Verheye S, Mulkey SP, Chronos NA, King SB, III, Crocker IR et al. The effect of endovascular irradiation on platelet recruitment at sites of balloon angioplasty in pig coronary arteries. Circulation 2000;101:1087-90.

  4. Waksman R, Bhargava B, Mintz GS, Mehran R, Lansky AJ, Satler LF et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J.Am.Coll.Cardiol. 2000;36:65-8.

  5. Andre P, Prasad KS, Denis CV, He M, Papalia JM, Hynes RO et al. CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism. Nat.Med. 2002;8:247-52.

  6. Urbich C, Dernbach E, Aicher A, Zeiher AM, Dimmeler S. CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species. Circulation 2002;106:981-6.

  7. Andre P, Nannizzi-Alaimo L, Prasad SK, Phillips DR. Platelet- derived CD40L: the switch-hitting player of cardiovascular disease. Circulation 2002;106:896-9.

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  Conflict of Interest:
  None declared.

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