Mathur, Anthony; (2001) The humoral control of platelet production and its relevance to acute coronary syndromes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Platelets play a fundamental role in the intracoronary thrombo-occlusive events that cause the spectrum of acute coronary syndromes (ACS). The absence of DNA within these cells suggests that heterogeneity in platelet size and reactivity in patients with ACS are predetermined. The recent discovery of several humoral factors that influence platelet production has made it possible to examine the mechanisms that control platelet physiology in ACS. In this thesis I examined differences in platelet volume (MPV), platelet count, platelet activation status and platelet function between two of the most important conditions that comprise ACS, unstable angina (UA) and myocardial infarction (MI). Furthermore, I evaluated if these conditions can be distinguished based on these parameters. In addition I measured circulating levels and genetic polymorphisms of the thrombopoietic factors Thrombopoietin (TPO), Interleukin-6 (IL-6) and Interleukin-11 (IL-11) to ascertain if there is an association between these factors and differences in platelet parameters. I found that platelets from patients with UA differed from those with MI and controls with respect to their size, function and activation status. Both TPO and IL-6 levels were elevated in patients with ACS and related to circulating platelet counts suggesting that they may play a role in the mechanism controlling platelet physiology in these conditions. No relationship was found between polymorphisms in the TPO gene (-602C>T, 1796C>T, 4830C>A and 5713G>A) or receptor (-277G>A) and circulating TPO levels, platelet function or clinical diagnosis. The -174G>A polymorphism in the IL-6 gene was related to IL-6 levels in the ACS patients. Finally, in order to understand how TPO, IL-6 and IL-11 may affect platelet size, number and activation status, I developed an in vitro system of platelet production. This model demonstrated that whilst TPO increased the number of platelets produced it had no effect on their size. IL-6 was found to inhibit the number of platelets produced by these cultures whilst IL-11 increased the size of these cells when administered at a late stage of megakaryocyte (MK) maturation. None of these factors were found to alter platelet activation status. Taken together these findings suggest that whilst platelet size, function and activation status are markedly different in UA compared to MI, these differences cannot be explained by variations in the levels of TPO, IL-6 or IL-11 in isolation.

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