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Essential Thrombocythaemia thrombosis (see also section below).69 Increased expression of

P-selectin, thrombospondin and the activated fibrinogen receptor GPIIb/IIIa, have also been demonstrated in ET and show variable correlation with thrombosis.

Currently, the exact pathogenesis of platelet activation in ET, and the other MPDs, is unknown. A large proportion of patients have a deficiency of lipoxygenase, which could increase the availability of endoperoxides to produce TXA2.70

not increased.73

This could be explained by most ET patients receiving antithrombotic drugs at the time of blood sampling, which may affect platelet activation. For example, aspirin inhibits the expression of CD62P and CD63 on platelets.

However, patients with ET can show an increase in CD62E-positive microparticles.74

However, the same patients have a

tendency for haemorrhagic rather than thrombotic diathesis. Alternative explanations for increased platelet activation include an effect of the janus kinase 2 (JAK2)-activating mutation (found in approximately half of patients with ET), interaction of abnormal haematocrit, activated white cells, turbulent flow or an increase in the known priming effect of thrombopoietin due to elevated thrombopoietin levels.71

There is also a suggestion that JAK2 affects

cMPL cell surface localisation and stability, which may have implications for the pathogenesis of platelet activation.72

Platelet Microparticles in Essential Thrombocythaemia Like patients with other thromboembolic diseases, ET patients show higher levels of platelet-derived microparticles than healthy subjects. However, this is not necessarily a consequence of increased platelet number in ET because microparticle numbers do not correlate with platelet numbers in either ET patients or controls. This suggests that microparticle formation may be a regulated rather than a constitutive process. Despite the large proportion of platelet- derived microparticles in ET patients, the actual number of these microparticles with markers of platelet activation (CD62P and CD63) is

1. McNicol A, Israels SJ, Platelets and anti-platelet therapy, J Pharmacol Sci, 2003;93:381–96.

2. Leslie M, Cell biology. Beyond clotting: the powers of platelets, Science, 2010;328:562–4.

3. Hartwig J, Italiano J Jr, The birth of the platelet, J Thromb Haemost, 2003;1:1580–6.

4. Hoffmeister KM, Felbinger TW, Falet H, et al., The clearance mechanism of chilled blood platelets, Cell, 2003;112:87–97.

5. Andrews RK, Berndt MC, López JA, Platelets, In: Alan MD, Michelson D, Coller BS (eds), Platelets (Second Edition), Burlington: Academic Press, 2006;145–63.

6. Interlandi G, Thomas W, The catch bond mechanism between von Willebrand factor and platelet surface receptors investigated by molecular dynamics simulations, Proteins, 2010;78:2506–22.

7. Kim J, Zhang CZ, Zhang X, et al., A mechanically stabilized receptor-ligand flex-bond important in the vasculature, Nature, 2010;466:992–5.

8. Shen Y, Cranmer SL, Aprico A, et al., Leucine-rich repeats 2-4 (Leu60-Glu128) of platelet glycoprotein Ibalpha regulate shear-dependent cell adhesion to von Willebrand factor, J Biol Chem, 2006;281:26419–23.

9. Yago T, Lou J, Wu T, et al., Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF, J Clin Invest, 2008;118:3195–207.

10. Lopez JA, Andrews RK, Afshar-Kharghan V, et al., Bernard– Soulier syndrome, Blood, 1998;91:4397–418.

11. Nieswandt B, Watson SP, Platelet–collagen interaction: is GPVI the central receptor? Blood, 2003;102:449–61.

12. Schmaier AA, Zou Z, Kazlauskas A, et al., Molecular priming of Lyn by GPVI enables an immune receptor to adopt a hemostatic role, Proc Natl Acad Sci U S A, 2009;106:21167–72.

13. Inoue O, Suzuki-Inoue K, McCarty OJ, et al., Laminin stimulates spreading of platelets through integrin alpha6beta1-dependent activation of GPVI, Blood, 2006;107:1405–12.

14. Arthur JF, Gardiner EE, Matzaris M, et al., Glycoprotein VI is associated with GPIb-IX-V on the membrane of resting and activated platelets, Thromb Haemost, 2005;93:716–23.

15. Arthur JF, Dunkley S, Andrews RK, Platelet glycoprotein VI-related clinical defects, Br J Haematol, 2007;139:363–72.

16. Inwald DP, McDowall A, Peters MJ, et al., CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation, Circ Res, 2003;92:1041–8.

17. Lindmark E, Tenno T, Siegbahn A, Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression, Arterioscler Thromb Vasc Biol, 2000;20:2322–8.

18. Prasad KS, Andre P, He M, et al., Soluble CD40 ligand induces

The presence of CD62E-positive microparticles suggests endothelial activation, a finding substantiated by the higher concentrations of mature vWF in ET. Since the increased mature vWF concentration is not accompanied by a rise in propeptide levels, it is believed that this is a chronic, rather than acute, endothelial activation. An explanation for this could be an interaction between platelets (or platelet fragments) and endothelial cells resulting in cellular activation and generation of microparticles of bilineage origin. Increased numbers of CD41/CD62E-positive microparticles may be of pathophysiological significance since they appear to be related to risk factors for thrombosis in ET.


Platelets have multiple and complex physiological functions, most notably their pivotal role in thrombosis and haemostasis. Our increasing knowledge of the biological role of platelets has allowed us to more clearly appreciate the physiological relationships they can have with thrombi and leukocytes. Such information gives us greater insight into the deleterious effects of platelets in diseases such as ET. Further improving our understanding of the function and dysfunction of platelets will allow us to develop appropriate pharmacotherapeutic interventions to maintain platelet activity from both a functional and quantitative perspective. n

beta3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling, Proc Natl Acad Sci U S A, 2003;100:12367–71.

19. Boilard E, Nigrovic PA, Larabee K, et al., Platelets amplify inflammation in arthritis via collagen-dependent microparticle production, Science, 2010;327:580–3.

20. Mackman N, Triggers, targets and treatments for thrombosis, Nature, 2008;451:914–8.

21. Xiang YZ, Kang LY, Gao XM, et al., Strategies for antiplatelet targets and agents, Thromb Res, 2008;123:35–49.

22. Kroll MH, Hellums JD, McIntire LV, et al., Platelets and shear stress. Blood, 1996;88:1525–41.

23. Nesbitt WS, Westein E, Tovar-Lopez FJ, et al., A shear gradient-dependent platelet aggregation mechanism drives thrombus formation, Nat Med, 2009;15:665–73.

24. Maxwell MJ, Westein E, Nesbitt WS, et al., Identification of a 2-stage platelet aggregation process mediating shear- dependent thrombus formation, Blood, 2007;109:566–76.

25. Hagedorn I, Vogtle T, Nieswandt B, Arterial thrombus formation. Novel mechanisms and targets Novel mechanisms and targets, Hamostaseologie, 2010;30:127–35.

26. Hagedorn I, Schmidbauer S, Pleines I, et al., Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding, Circulation, 2010;121:1510–7.

27. Heemskerk JW, Kuijpers MJ, Munnix IC, et al., Platelet collagen receptors and coagulation. A characteristic platelet response as possible target for antithrombotic treatment, Trends Cardiovasc Med, 2005;15:86–92.

28. May AE, Seizer P, Gawaz M, Platelets: inflammatory firebugs of vascular walls, Arterioscler Thromb Vasc Biol, 2008;28:s5–10.

29. Zarbock A, Polanowska-Grabowska RK, Ley K, Platelet– neutrophil interactions: linking hemostasis and inflammation, Blood Rev, 2007;21:99–111.

30. Muller F, Mutch NJ, Schenk WA, et al., Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo, Cell, 2009;139:1143–56.

31. Gailani D, Renne T, Intrinsic pathway of coagulation and arterial thrombosis, Arterioscler Thromb Vasc Biol, 2007;27:2507–13.

32. Peerschke EI, Murphy TK, Ghebrehiwet B, Activation- dependent surface expression of gC1qR/p33 on human blood platelets, Thromb Haemost, 2003;89:331–9.

33. Heemskerk JW, Bevers EM, Lindhout T, Platelet activation and blood coagulation, Thromb Haemost, 2002;88:186–93.

34. Storey RF, Sanderson HM, White AE, et al., The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity,

Br J Haematol, 2000;110:925–34.

35. del Conde I, Nabi F, Tonda R, et al., Effect of P-selectin on phosphatidylserine exposure and surface-dependent thrombin generation on monocytes, Arterioscler Thromb Vasc Biol, 2005;25:1065–70.

36. Khan SY, Kelher MR, Heal JM, et al., Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury, Blood, 2006;108:2455–62.

37. Semple JW, Freedman J, Platelets and innate immunity, Cell Mol Life Sci, 2010;67:499–511.

38. Smyth SS, McEver RP, Weyrich AS, et al., Platelet functions beyond hemostasis, J Thromb Haemost, 2009;7:1759–66.

39. von Hundelshausen P, Weber C, Platelets as immune cells: bridging inflammation and cardiovascular disease, Circ Res, 2007;100:27–40.

40. Kerrigan SW, Cox D, Platelet–bacterial interactions, Cell Mol Life Sci, 2010;67:513–23.

41. Yeaman MR, Platelets in defense against bacterial pathogens, Cell Mol Life Sci, 2010;67:525–44.

42. Rodeghiero F, Stasi R, Gernsheimer T, et al., Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group, Blood, 2009;113: 2386–93.

43. Stasi R, Evangelista ML, Stipa E, et al., Idiopathic thrombocytopenic purpura: current concepts in pathophysiology and management, Thromb Haemost, 2008;99:4–13.

44. Cines DB, Bussel JB, Liebman HA, et al., The ITP syndrome: pathogenic and clinical diversity, Blood, 2009;113:6511–21.

45. Franchini M, Favaloro EJ, Lippi G, Glanzmann thrombasthenia: an update, Clin Chim Acta, 2010;411:1–6.

46. Levine RL, Heaney M, New advances in the pathogenesis and therapy of essential thrombocythemia, Hematology Am Soc Hematol Educ Program, 2008;76–82.

47. Tefferi A, Thiele J, Orazi A, et al., Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel, Blood, 2007;110:1092–7.

48. Michiels JJ, Berneman ZN, Schroyens W, et al., Pathophysiology and treatment of platelet-mediated microvascular disturbances, major thrombosis and bleeding complications in essential thrombocythaemia and polycythaemia vera, Platelets, 2004;15:67–84.

49. Petrides PE, Siegel F, Thrombotic complications in essential



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