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The coagulation/fibrinolysis balance in systemic sclerosis: evidence for a haematological stress syndrome
Insights
Systemic sclerosis patients exhibit a hypercoagulable state with elevated fibrinogen and von Willebrand factor. They also show impaired fibrinolysis due to defective tissue plasminogen activator release and higher PAI levels, suggesting potential therapeutic targets.
Area of Science:
- Hematology
- Rheumatology
- Vascular Biology
Background:
- Systemic sclerosis (SSc) is a fibrotic disease with vascular origins.
- Understanding the coagulation/fibrinolytic balance is crucial for SSc pathogenesis.
- Microvascular occlusion and fibrosis are key features of SSc.
Purpose of the Study:
- To comprehensively assess haemostatic and fibrinolytic variables in SSc patients.
- To compare coagulation and fibrinolysis markers between SSc patients and controls.
- To investigate differences in these markers between limited and diffuse SSc subtypes.
Main Methods:
- Measured plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complexes (TAT), D-dimer (DD), fibrinogen (FNG), and von Willebrand factor (vWF).
- Assessed tissue plasminogen activator (tPA) release using a venous occlusion test.
- Quantified levels of tPA inhibitor (PAI) and lipoprotein (a) [Lp(a)].
Main Results:
- SSc patients showed higher F1 + 2, DD, FNG, and vWF levels compared to controls.
- Defective tPA release and elevated PAI levels were observed in SSc patients, particularly in diffuse SSc.
- Abnormally high Lp(a) levels were more frequent in SSc patients and associated with fibrinolytic defects.
Conclusions:
- SSc patients are in a hypercoagulable state with impaired fibrinolysis.
- Elevated vWF, DD, and PAI in diffuse SSc suggest more extensive microvascular involvement.
- Targeting thrombin generation and enhancing fibrinolysis may be potential therapeutic strategies for SSc.
Abstract:
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.