The role of intravascular factors in systemic sclerosis and the effect of various therapeutic agents

Rademaker, Marius (1991) The role of intravascular factors in systemic sclerosis and the effect of various therapeutic agents. University of Southampton, Doctoral Thesis.

Abstract

Systemic sclerosis is a disease characterised by reduced blood flow to the skin, the digits and to various organs in the body. The exact initiating factors remain unknown but it is now clear that damage to the vascular endothelium is of primary importance. This results in both morphological changes in blood vessels and functional changes in blood flow which then go on to produce the sclerosis which is the hallmark of the disease. Treatment with the vasodilator nifedipine significantly reduces the number and severity of Raynaud's episodes as well as helping to heal digital ulcers in these patients, although the drug has no demonstrable effect on digital blood flow. This suggests that the mode of action is mediated via a mechanism other than simple vasodilatation. A variety of intravascular factors, including red cell rheology, white cell activation, platelet activity and thrombolysis, have been implicated in this disease. This thesis examines the role of these factors in the pathogenesis of systemic sclerosis and whether they are amenable to treatment with calcium channel antagonists. The ability of red cells to deform is a critical determinant of the flow through the microvasculature. Using a filtration technique, it is clear that the deformability of red cells from patients with systemic sclerosis is diminished and that this can be significantly enhanced in vitro by calcium channel antagonists. It is likely that the reduced filterability is secondary to an increase in intracellular Ca²⁺, as red cells from patients with systemic sclerosis have increased influx of Ca²⁺ across their membranes which can be blocked ex vivo by nifedipine. This alteration in calcium flux is probably mediated via intracellular cAMP as forskolin, prostacyclin, and a phosphodiesterase inhibitor, all known modulators of cAMP activity, result in improved red cell filterability. Nifedipine does not however, affect red cell charge which is reduced in systemic sclerosis. In addition, nifedipine does not influence the production of hydrogen peroxide by polymorphonuclear leucocytes which is significantly increased in systemic sclerosis, as measured by whole blood and isolated polymorphonuclear leucocyte chemiluminescence. Calcium channel antagonists do, however, correct the abnormal activation of platelets and the disturbed thrombolysis demonstrated in patients with systemic sclerosis using the novel instrument, the haemostatometer. There is no doubt that the intravascular changes described above influence disease progression in patients with systemic sclerosis. Unfortunately it has not been possible to correlate these changes with disease activity but this reflects the lack of suitable criteria for quantifying `disease activity'.

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