The British Journal of Rheumatology, Vol 36, 1045-1050, Copyright © 1997 by British Society for Rheumatology
PR Ames, S Lupoli, J Alves, T Atsumi, C Edwards, L Iannaccone, MA Khamashta, GR Hughes and V Brancaccio
Systemic sclerosis (SSc) is a disease characterized by progressive
microvascular occlusion and fibrosis resulting in irreversible organ
damage, the pathogenesis of which is felt to be of vascular origin. To gain
a comprehensive view of the coagulation/fibrinolytic balance in SSc, a
number of haemostatic and fibrinolytic variables were measured in 26 SSc
patients (11 limited, 15 diffuse) and in 22 control subjects. Of the
coagulation activation markers, the mean plasma level of prothrombin
fragment 1 + 2 (F1 + 2), but not of thrombin-antithrombin complexes (TAT),
was higher in SSc patients than in controls (P < 0.001). Plasma levels
of fibrin split product D-dimer (DD), fibrinogen (FNG) and von Willebrand
factor (vWF) were higher amongst patients than controls (P < 0.001). vWF
and FNG levels were positively correlated (P < 0.001). Mean levels of DD
and vWF were more elevated in patients with diffuse than limited disease (P
= 0.001 and P = 0.04, respectively). On the fibrinolytic side, defective
tissue plasminogen activator (tPA) release (venous occlusion test,
stimulated level < basal level) was noted in 46% (12/26) of SSc
patients, but only in 4% (1/22) of controls. Patients had higher mean
levels of tPA inhibitor (PAI) than controls (P < 0.001), levels being
more elevated amongst patients with diffuse than limited disease (P =
0.01). An abnormally high lipoprotein (a) [Lp(a)] level was found in 9%
(2/20) of control subjects, but in 30% (8/26) of SSc patients (P = 0.04)
where it clustered with fibrinolytic defects. Altogether, these data
suggest that patients with SSc are in a hypercoagulable state characterized
by elevated plasma levels of FNG and vWF, by a dual hypofibrinolytic
pattern (defective tPA release and elevated PAI), and by increased thrombin
generation with enhanced fibrin formation. Higher levels of vWF, DD and PAI
in patients with diffuse disease are consistent with more extensive
(micro)vascular involvement, although no causal relationship can be
inferred. The lack of a parallel increase of TAT with F1 + 2, in the
presence of normal levels of antithrombin III (ATIII), indirectly suggests
an impairment of the heparan sulphate-ATIII system which would favour
thrombin generation. Since thrombin may act as a mitogen for fibroblasts,
may upregulate vWF, PAI and endothelin production by endothelial cells, and
may promote fibrin deposition on the vessel wall leading to worsening of
microvascular occlusions, limitation of thrombin generation, besides
fibrinolytic enhancement, could represent a possible coadjuvant
interventional strategy.
ORIGINAL PAPERS
The coagulation/fibrinolysis balance in systemic sclerosis: evidence for a haematological stress syndrome
Department of Haematology, St Thomas' Hospital, London.
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